EUROPEAN SOCIETY OF ENDOCRINE SURGEONS

ESES Review of Recently Published Literature

Collection: T. Clerici, F. Triponez, K. Lorenz, M. Elwerr, J. Hein, L. Osmak, G. Franch-Arcas & C. Martinez-Santos Compilation and design: U. Beutner, [email protected] Affiliations see next page

Jan- Apr 2014 Data retrival from Pubmed: June 5th, 2014

Contents

CTRL-click on category or count number jumps to the according page

Publication count: SR/MA RCT CG Other Page Thyroid ...... 12 ...... 2 ...... 5 ...... 183 ...... 4 Parathyroid...... 0 ...... 2 ...... 1 ...... 36 ...... 77 Adrenals ...... 1 ...... 0 ...... 0 ...... 40 ...... 92 NET ...... 0 ...... 0 ...... 0 ...... 27 ...... 106 GI and General ...... 0 ...... 0 ...... 0 ...... 15 ...... 116

SR: systematic review, MA: meta-analysis, RCT: randomized controlled trial, CG: consensus statement/guidelines Pubmed-ID: PubMed-Identifier (unique number for each Pubmed entry) blue underline: Hyperlink to PubMed entry or web site of publisher. Clicking on hyperlink opens the corresponding web site in browser (in Vista: CTRL-click). Collectors

Thomas Clerici, MD Department of Surgery, Cantonal Hospital St. Gallen, St. Gallen, Switzerland

Frédéric Triponez, MD Department of Thoracic and Endocrine Surgery, University Hospital of Geneva, Geneva, Switzerland

Kerstin Lorenz, MD Malik Elwerr Janine Hein, MD Department of General-, Visceral-, and Vascular Surgery, Martin-Luther University of Halle- Wittenberg, Germany

Liliana Osmak, MD Department of Endocrine Surgery, University Hospital Dijon, Dijon, France

Guzmán Franch-Arcas, MD Endocrine Surgery, Department of General and Digestive Tract Surgery, University Hospital Salamanca, Salamanca, Spain

Cristina Martinez-Santos, MD Endocrine Surgery, Hospital Costa del Sol Marbella, Málaga, Spain

Compilation and Coordination

Ulrich Beutner, PhD Department of Surgery, Cantonal Hospital St. Gallen, St. Gallen, Switzerland [email protected]

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Journals covered

Journal IF2012 Journal IF2012 Acta Cytol 0.69 J Clin Endocrinol Metab 6.430 Am J Kidney Dis 5.294 J Clin Oncol 18.038 Am J Nephrol 2.623 J Endocrinol 4.058 Am J Surg 2.516 J Endocrinol Invest 1.654 Am Surgeon 0.92 J Nephrol 2.015 Ann Surg 6.329 J Nucl Med 5.774 Ann Surg Oncol 4.12 J Surg Oncol 2.644 Anz J Surg 1.098 Lancet 39·06 JAMA Otolaryngol Head Neck Surg 1.779 Langenbecks Arch Surg 1.891 (prev: Arch Oto …..) JAMA Surg (prev: Arch Surg) 4.42 Laryngoscope 1.979 Br J Surg 4.839 N Engl J Med 51.658 Nat Rev Endocrinol Cancer 5.201 11.025 (prev: Nat Clin Pract Endocrinol Metab) Nat Rev Clin Oncol Chirurg 0.517 15.031 (prev: Nat Clin Pract Oncol) Clin Endocrinol Oxf 3.396 Nephrol Dial Transplant 3.371 Clin Nucl Med 2.955 Nephron Clin Pract 1.652 Curr Opin Oncol 4.027 Neuroendocrinology 3.537 Endocr Relat Cancer 5.261 Oncologist 4.10 Endocr Rev 14.873 Otolaryngol Head Neck Surg 1.625 Eur Arch Otorhinolaryngol 1.458 Surg Clin North Am 2.019 Eur J Endorcrinol 3.136 Surg Endosc 3.427 Eur J Surg Oncol 2.614 Surg Laparosc Endosc Percutan Tech 0.876 Head Neck 2.833 Surg Oncol 2.136 Horm Metab Res 2.145 Surg Oncol Clin N Am 1.22 Int J Cancer 6.198 Surgery 3.373 J Am Coll Surg 4.5 Thyroid 3.544 J Am Soc Nephrol 8.98 Updates In Surgery --- J Bone Miner Metab 2.219 World J Surg 2.228 J Bone Miner Res 6.128

Journal names are links to the journal’s homepage!, IF2012: Impact factor 2012

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Thyroid

Meta-Analyses Classification of Aerodigestive Tract Invasion From Thyroid Cancer. Langenbecks Arch Surg, 399(2):209-16. Brauckhoff M. 2014. BACKGROUND: Widely invasive extrathyroidal thyroid cancer invading the aerodigestive tract (ADT) including larynx, trachea, hypopharynx, and/or esophagus occurs in 1-8 % of patients with thyroid cancer and is classified as T4a (current UICC/AJCC system). The T4a stage is associated with impaired tumor-free survival and increased disease-specific mortality. Concerning prognosis and outcome, further subdivisions of the T4a stage, however, have not been made so far. METHODS: This study is based on a systematic review of the relevant literature in the PubMed database. RESULTS: Retrospective studies suggest a better outcome in patients with invasion of the trachea or the esophagus when compared to laryngeal invasion. Regarding surgical strategies, ADT invasion can be classified based on a three-dimensional assessment determining surgical resection options. Regardless of the invaded structure, tumor infiltration of the ADT can be subdivided into superficial, deep extraluminal, and intraluminal invasion. In contrast to superficial ADT invasion, allowing tangential incomplete wall resection (shaving/extramucosal esophagus resection), deeper wall and intraluminal invasions require complete wall resection (either window or sleeve). Based on the Dralle classification (types 1-6), particularly airway invasion, can be further classified according to the vertical and horizontal extents of tumor invasion. CONCLUSIONS: The Dralle classification can be considered as a reliable subdivision system evaluated regarding surgical options as well as oncological outcome. However, further studies determining the prognostic impact of this technically oriented classification system are required. PubMed-ID: 24271275 http://dx.doi.org/10.1007/s00423-013-1142-x

The Accuracy of Thyroid Nodule Ultrasound to Predict Thyroid Cancer: Systematic Review and Meta- Analysis. J Clin Endocrinol Metab, 99(4):1253-63. Brito JP, Gionfriddo MR, Al NA, Boehmer KR, Leppin AL, Reading C, Callstrom M, Elraiyah TA, Prokop LJ, Stan MN, Murad MH, Morris JC, Montori VM. 2014. CONTEXT: Significant uncertainty remains surrounding the diagnostic accuracy of sonographic features used to predict the malignant potential of thyroid nodules. OBJECTIVE: The objective of the study was to summarize the available literature related to the accuracy of thyroid nodule ultrasound (US) in the prediction of thyroid cancer. METHODS: We searched multiple databases and reference lists for cohort studies that enrolled adults with thyroid nodules with reported diagnostic measures of sonography. A total of 14 relevant US features were analyzed. RESULTS: We included 31 studies between 1985 and 2012 (number of nodules studied 18,288; average size 15 mm). The frequency of thyroid cancer was 20%. The most common type of cancer was papillary thyroid cancer (84%). The US nodule features with the highest diagnostic odds ratio for malignancy was being taller than wider [11.14 (95% confidence interval 6.6-18.9)]. Conversely, the US nodule features with the highest diagnostic odds ratio for benign nodules was spongiform appearance [12 (95% confidence interval 0.61-234.3)]. Heterogeneity across studies was substantial. Estimates of accuracy depended on the experience of the physician interpreting the US, the type of cancer and nodule (indeterminate), and type of reference standard. In a threshold model, spongiform appearance and cystic nodules were the only two features that, if present, could have avoided the use of fine-needle aspiration biopsy. CONCLUSIONS: Low- to moderate-quality evidence suggests that individual ultrasound features are not accurate predictors of thyroid cancer. Two features, cystic content and spongiform appearance, however, might predict benign nodules, but this has limited applicability to clinical practice due to their infrequent occurrence. PubMed-ID: 24276450 http://dx.doi.org/10.1210/jc.2013-2928

Quantification of Cancer Risk of Each Clinical and Ultrasonographic Suspicious Feature of Thyroid Nodules: a Systematic Review and Meta-Analysis. Eur J Endocrinol, 170(5):R203-R211. Campanella P, Ianni F, Rota CA, Corsello SM, Pontecorvi A. 2014. OBJECTIVE: In order to quantify the risk of malignancy of clinical and ultrasonographic features of thyroid nodules (TNs), we did a systematic review and meta-analysis of published studies. METHODS: We did a

ESES Review of Recently Published Literature 2014-1 Page 4 of 121 literature search in MEDLINE for studies published from 1st January 1989 until 31st December 2012. Studies were considered eligible if they investigated the association between at least one clinical/ultrasonographic feature and the risk of malignancy, did not have exclusion criteria for the detected nodules, had histologically confirmed the diagnoses of malignancy, and had a univariable analysis available. Two reviewers independently extracted data on study characteristics and outcomes. RESULTS: The meta-analysis included 41 studies, for a total of 29678 TN. A higher risk of malignancy expressed in odds ratio (OR) was found for the following: nodule height greater than width (OR: 10.15), absent halo sign (OR: 7.14), microcalcifications (OR: 6.76), irregular margins (OR: 6.12), hypoechogenicity (OR: 5.07), solid nodule structure (OR: 4.69), intranodular vascularization (OR: 3.76), family history of thyroid carcinoma (OR: 2.29), nodule size >/=4 cm (OR: 1.63), single nodule (OR: 1.43), history of head/neck irradiation (OR: 1.29), and male gender (OR: 1.22). Interestingly, meta-regression analysis showed a higher risk of malignancy for hypoechoic nodules in iodine-sufficient than in iodine-deficient geographical areas. CONCLUSIONS: The current meta-analysis verified and weighed out each suspicious clinical and ultrasonographic TN feature. The highest risk was found for nodule height greater than width, absent halo sign, and microcalcifications for ultrasonographic features and family history of thyroid carcinoma for clinical features. A meta-analysis-derived grading system of TN malignancy risk, validated on a large prospective cohort, could be a useful tool in TN diagnostic work-up. PubMed-ID: 24536085 http://dx.doi.org/10.1530/EJE-13-0995

Systematic Review and Meta-Analysis of Predictors of Post-Thyroidectomy Hypocalcaemia. Br J Surg, 101(4):307-20. Edafe O, Antakia R, Laskar N, Uttley L, Balasubramanian SP. 2014. BACKGROUND: Hypocalcaemia is common after thyroidectomy. Accurate prediction and appropriate management may help reduce morbidity and hospital stay. The aim of this study was to perform a systematic literature review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. METHODS: A systematic search of PubMed, EMBASE and the Cochrane Library databases was undertaken, and the quality of manuscripts assessed using a modified Newcastle-Ottawa Scale. RESULTS: Some 115 observational studies were included. The median (i.q.r.) incidence of transient and permanent hypocalcaemia was 27 (19-38) and 1 (0- 3) per cent respectively. Independent predictors of transient hypocalcaemia included levels of preoperative calcium, perioperative parathyroid hormone (PTH), preoperative 25-hydroxyvitamin D and postoperative magnesium. Clinical predictors included surgery for recurrent goitre and reoperation for bleeding. A calcium level lower than 1.88 mmol/l at 24 h after surgery, identification of fewer than two parathyroid glands (PTGs) at surgery, reoperation for bleeding, Graves' disease and heavier thyroid specimens were identified as independent predictors of permanent hypocalcaemia in multivariable analysis. Factors associated with transient hypocalcaemia in meta-analyses were inadvertent PTG excision (odds ratio (OR) 1.90, 95 per cent confidence interval 1.31 to 2.74), PTG autotransplantation (OR 2.03, 1.44 to 2.86), Graves' disease (OR 1.75, 1.34 to 2.28) and female sex (OR 2.28, 1.53 to 3.40). CONCLUSION: Perioperative PTH, preoperative vitamin D and postoperative changes in calcium are biochemical predictors of post-thyroidectomy hypocalcaemia. Clinical predictors include female sex, Graves' disease, need for parathyroid autotransplantation and inadvertent excision of PTGs. PubMed-ID: 24402815 http://dx.doi.org/10.1002/bjs.9384

A Systematic Review and Meta-Analysis of Total Thyroidectomy Versus Bilateral Subtotal Thyroidectomy for Graves' Disease. Surgery, 155(3):529-40. Feroci F, Rettori M, Borrelli A, Coppola A, Castagnoli A, Perigli G, Cianchi F, Scatizzi M. 2014. BACKGROUND: Our aim was to perform a meta-analysis of high-quality published trials, randomized and observational, comparing total thyroidectomy (TT) and bilateral subtotal thyroidectomy (ST) for Graves' disease. METHODS: All studies published from 1970 to August 2012 were identified. All randomized controlled trials (RCTs) were included. Selection of high-quality, nonrandomized comparative studies (NRCTs) was based on a validated tool (Methodological Index for Nonrandomized Studies). Recurrent hyperthyroidism during follow-up, progression of ophthalmopathy, postoperative temporary and permanent hypoparathyroidism, and permanent recurrent laryngeal nerve (RLN) palsy were compared using odds ratios (ORs). RESULTS: Twenty-three studies were included (4 RCTs and 19 NRCTs) compromising 3,242 patients (1,665 TT, 1,577 ST). TT was associated with a decrease in recurrent hyperthyroidism (P < .00001; OR, 0.10; 95% confidence interval [CI], 0.06-0.18), but with an increase in both temporary (P < .00001; OR, 2.70; 95% CI, 2.04-3.56) and permanent hypoparathyroidism (P = .005; OR, 2.91; 95% CI, 1.59-5.32). Progression of ophthalmopathy (P = .76; OR, 0.90; 95% CI, 0.48-1.71) and permanent RLN palsy (P = .82; OR, 0.91; 95% CI, 0.41-2.02) were similar.

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CONCLUSION: TT offers a better chance of cure of hyperthyroidism than bilateral ST and can be accomplished safely with only a small increase in temporary and permanent hypoparathyroidism. PubMed-ID: 24230962 http://dx.doi.org/10.1016/j.surg.2013.10.017

Radiofrequency Ablation for Treatment of Benign Thyroid Nodules: Systematic Review. Laryngoscope, 124(1):346-53. Fuller CW, Nguyen SA, Lohia S, Gillespie MB. 2014. OBJECTIVE: To summarize the literature published to date on the use of radiofrequency ablation (RFA) in the treatment of benign thyroid nodules, to evaluate the effectiveness of this treatment, and to attempt an evaluation of factors that may influence treatment outcome. STUDY DESIGN: Systematic review with meta-analysis. METHODS: Systematic literature search was performed by two separate authors in four commonly used literature databases. Trials included in meta-analysis included only those presenting prospective data. Meta- analysis compared pretreatment values to post-treatment outcomes. RESULTS: Of 46 full-text articles identified, nine articles satisfied inclusion criteria. Two of these articles were randomized controlled trials comparing RFA to placebo or to some other treatment. One article was a randomized controlled trial comparing one RFA treatment to two treatments. The remaining six articles were noncontrolled, prospective observational studies. All analyzed outcomes showed statistically significant improvements from baseline to final follow-up, including reduction in nodule size, improvement of symptom and cosmetic scores, and withdrawal from methimazole. Improvement in nodule size remained significant in both "hot" and "cold" nodule subgroups. Twelve adverse events were identified across all studies out of 306 total treatments. Two of these events qualified as significant adverse events. None of these events resulted in hospitalization or death. CONCLUSIONS: Radiofrequency ablation is a safe and effective treatment for symptomatic thyroid nodules that are confirmed benign. However, the paucity of level 1 evidence comparing RFA to surgical or to other nonsurgical treatment modalities is concerning. PubMed-ID: 24122763 http://dx.doi.org/10.1002/lary.24406

Unstimulated Highly Sensitive Thyroglobulin in Follow-Up of Differentiated Thyroid Cancer Patients: a Meta-Analysis. J Clin Endocrinol Metab, 99(2):440-7. Giovanella L, Treglia G, Sadeghi R, Trimboli P, Ceriani L, Verburg FA. 2014. CONTEXT: Serum thyroglobulin (Tg) is an indicator of differentiated thyroid cancer (DTC) relapse. OBJECTIVE: Our objective was to conduct a meta-analysis of published data about the diagnostic performance of highly sensitive serum Tg (hsTg) during levothyroxine therapy in DTC follow-up. DATA SOURCES: We performed a comprehensive literature search of PubMed/MEDLINE and Scopus for studies published until July 2013. STUDY SELECTION: Studies investigating the diagnostic performance of basal hsTg in monitoring DTC were eligible. Exclusion criteria were 1) articles not within the field of interest; 2) reviews, letters, or conference proceedings; 3) articles evaluating serum Tg measurement with a functional sensitivity >0.1 ng/mL; 4) overlap in patient data; and 5) insufficient data to reassess diagnostic performance of basal serum hsTg. Data Extraction: Information was collected concerning basic study data, patient characteristics, and technical aspects. For each study, the number of true-positive, false-positive, true-negative, and false-negative findings for basal hsTg, considering stimulated Tg measurement as a reference standard, were recorded. DATA SYNTHESIS: Pooled data demonstrated that the negative predictive value of hsTg was 97% and 99% considering a stimulated Tg measurement >1 ng/mL and >2 ng/mL as cutoffs for positivity, respectively. Despite the high pooled sensitivity of basal hsTg, the pooled specificity, accuracy, and positive predictive value were insufficient to completely substitute for a stimulated Tg measurement. CONCLUSIONS: Basal hsTg measurement has a very high negative predictive value but an insufficient positive predictive value for monitoring DTC patients. Therefore, a Tg stimulation test can be avoided in patients with an undetectable basal hsTg, whereas a stimulated Tg measurement should be considered when hsTg levels are detectable. PubMed-ID: 24285679 http://dx.doi.org/10.1210/jc.2013-3156

Safety of Robotic Thyroidectomy Approaches: Meta-Analysis and Systematic Review. Head Neck, 36(1):137-43. Jackson NR, Yao L, Tufano RP, Kandil EH. 2014. BACKGROUND: This study compared the efficacy of robotic thyroidectomy via a gasless, axillary approach with conventional cervical and endoscopic techniques by meta-analysis. METHODS: Articles were identified from the following keyword searches: robotic/robot-assisted thyroidectomy/thyroid surgery. Outcomes included operative time, hospital stay, complications, and cosmetic satisfaction after surgery. Between-group outcome differences

ESES Review of Recently Published Literature 2014-1 Page 6 of 121 were calculated using random-effects models. RESULTS: In all, 87 publications were identified and 9 studies met inclusion criteria, totaling 2881 patients, 1122 of whom underwent robotic thyroidectomy. Those who underwent robotic surgery reported greater cosmetic satisfaction, with a pooled net mean difference of -1.35 (95% confidence interval [CI]: -1.69, -1.09). Robotic approach operative time was longer than that of the conventional approach (95% CI: 29.23, 54.87), with a trend to be shorter than the endoscopic approaches. Robotic surgery had similar risks to open and endoscopic approaches. CONCLUSIONS: Our meta-analysis suggests that robotic thyroidectomy is as safe, feasible, and efficacious as conventional cervical and endoscopic thyroidectomy, showing superior cosmetic satisfaction than that of conventional thyroidectomy. PubMed-ID: 23471784 http://dx.doi.org/10.1002/hed.23223

A Systematic Review and Meta-Analysis Comparing Surgically-Related Complications Between Robotic- Assisted Thyroidectomy and Conventional Open Thyroidectomy. Ann Surg Oncol, 21(3):850-61. Lang BH, Wong CK, Tsang JS, Wong KP, Wan KY. 2014. BACKGROUND: Despite gaining popularity, robotic-assisted thyroidectomy (RT) remains controversial. This systematic review and meta-analysis is aimed at comparing surgically-related complications between RT and conventional open thyroidectomy (OT). METHODS: A systematic review of the literature was performed to identify studies comparing surgically-related outcomes between RT and OT. Studies that compared >/= 1 surgically-related outcomes between RT and OT were included. Outcomes included operating time, blood loss, complications, and hospital stay. Meta-analysis was performed using a fixed-effects model. RESULTS: Eleven studies were eligible but none were randomized controlled trials. Of the 2,375 patients, 839 (35.3 %) underwent RT, while 1,536 (64.7 %) underwent OT. RT was significantly associated with longer operating time (p < 0.001), hospital stay (p = 0.023) and higher temporary recurrent laryngeal nerve (RLN) injury (p = 0.016). Although there was no correlation between the number of RTs reported in the study and the rate of temporary RLN injury (p = - 0.486, p = 0.328, respectively), routine perioperative laryngoscopy was performed in only 2 of 11 studies. Blood loss (p = 0.485), temporary (p = 0.333) and permanent (p = 0.599) hypocalcemia, hematoma (p = 0.602), and overall morbidity (p = 0.880) appeared comparable. Two (0.2 %) brachial plexus injuries in RT were reported in one study. CONCLUSIONS: Relative to OT, RT was associated with significantly longer operating time, longer hospital stay, and higher temporary RLN injury rate but comparable permanent complications and overall morbidity. Given some of the limitations with the literature and the potential added surgical risks and morbidity in RT, application of the robot in thyroid surgery should be carefully and thoroughly discussed before one decides on the procedure. PubMed-ID: 24271160 http://dx.doi.org/10.1245/s10434-013-3406-7

'Suspicious for Papillary Thyroid Carcinoma' Before and After The Bethesda System for Reporting Thyroid Cytopathology: Impact of Standardized Terminology. Acta Cytol, 58(1):15-22. Olson MT, Boonyaarunnate T, Altinboga AA, Ali SZ. 2014. BACKGROUND: The high-risk 'suspicious for papillary thyroid carcinoma' (SPTC) is a clinically relevant diagnosis in the cytological interpretation of thyroid aspirates. While The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has provided invaluable terminology standardization, a performance comparison for this diagnostic category has not been performed. Therefore, this study evaluates the SPTC diagnosis before and after the introduction of TBSRTC in a large meta-analysis and at a single institution. MATERIALS AND METHODS: The meta-analysis analyzed publications of SPTC or similar diagnoses before and after the introduction of TBSRTC. Similarly our own institutional experience was analyzed for the 8 years surrounding the introduction of TBSRTC. A correlation of the cytopathology and surgical pathology diagnoses was performed. RESULTS: The introduction of TBSRTC coincided with a significant decrease in the fraction of cases called SPTC in the meta-analysis (4.5-3.1%, p < 0.00001) and in the institutional review (1.7-0.9%, p = 0.005). Meanwhile, the malignancy risk for those cases increased significantly in the meta-analysis from 62.5 to 80.5% (p < 0.00001) and trended upwards in the institutional review from 69 to 79% (p = 0.4). The follow-up rate was similar in both time periods in the meta-analysis and the institutional review. CONCLUSIONS: The introduction of TBSRTC coincided with a decrease in the fraction of cases called SPTC and an increase in the malignancy risk associated with that diagnosis. PubMed-ID: 24192286 http://dx.doi.org/10.1159/000355696

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Sorafenib in the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer: a Meta-Analysis. Endocr Relat Cancer, 21(2):253-61. Shen CT, Qiu ZL, Luo QY. 2014. The advent of biologically targeted agents and increased understanding of thyroid carcinogenesis have generated much interest in the development of biologically targeted therapeutic agents for thyroid cancer. Among them, sorafenib is the most commonly studied drug. The current meta-analysis was carried out to estimate the efficacy and safety of sorafenib administered in radioiodine-refractory differentiated thyroid cancer patients. An electronic search was conducted using PubMed/MEDLINE and EMBASE. Statistical analyses were carried out using either random-effects or fixed-effects models according to heterogeneity. All the statistical analyses were carried out using the Stata version 12.0 software. Seven eligible studies were identified. The final results indicated that 22% of the patients (95% CI: 15-28) achieved a partial response. Hand-foot syndrome, diarrhea, fatigue, rash, weight loss, and hypertension were the most frequently observed adverse effects (AEs) associated with sorafenib use and the incidence of these AEs (all grades) was 80% (95% CI: 68-91), 68% (95% CI: 59-77), 67% (95% CI: 57-78), 66% (95% CI: 50-82), 52%(95% CI: 33-72), and 31% (95% CI: 21-42) respectively. Sixty-two percent (95% CI: 36-89) patients required dose reductions due to toxicity of sorafenib. As far as PR and AEs are concerned, the results of this meta-analysis indicate that sorafenib has a modest effect in patients with radioiodine-refractory differentiated thyroid cancer and the high incidence of AEs associated with this agent may affect the quality of patients' lives. Though the use of sorafenib in the treatment of radioiodine- refractory differentiated thyroid cancer is considered promising by most physicians working in this field, more effective agents with less toxicity and cost are still needed. PubMed-ID: 24302666 http://dx.doi.org/10.1530/ERC-13-0438

Systematic Review and Meta-Analysis of Wound Drains After Thyroid Surgery. Br J Surg, 101(5):446-56. Woods RS, Woods JF, Duignan ES, Timon C. 2014. BACKGROUND: Drainage after routine thyroid and parathyroid surgery remains controversial. However, there is increasing evidence from a number of randomized clinical trials (RCTs) suggesting no benefit from the use of drains. METHODS: A systematic review and meta-analysis was performed according to PRISMA guidelines. A literature search was carried out, and RCTs comparing the use of drains versus no drains in patients who underwent thyroid or parathyroid surgery were included. Trials including patients who underwent lateral neck dissection were excluded. Methodological quality was graded and data were extracted by independent reviewers. Risk ratio (RR) or mean difference (MD) with 95 per cent confidence interval (c.i.) was calculated and heterogeneity was assessed. RESULTS: Twenty-five RCTs were included in the meta-analysis comprising 2939 patients. There was no significant difference between the two groups in rate of reoperation for neck haematoma (RR 1.90, 95 per cent c.i. 0.87 to 4.14), ultrasound-assessed fluid volume on day 1 after surgery (MD 2.30 (95 per cent c.i. -0.73 to 5.34) ml), wound collection requiring intervention (RR 0.64, 0.38 to 1.09) or not (RR 0.93, 0.66 to 1.30), transient voice change (RR 2.33, 0.91 to 5.96) and persistent recurrent laryngeal nerve palsy (RR 1.67, 0.22 to 12.51). Length of hospital stay was significantly greater in the drain group (MD 1.25 (0.83 to 1.68) days), as were wound infection rates (RR 2.53, 1.23 to 5.21) and pain score measure using a visual analogue scale from 1 to 10 on day 1 after surgery (MD 1.46 (0.67 to 2.26) units). CONCLUSION: The results indicate that drain use after routine thyroid surgery does not confer a benefit to patients. PubMed-ID: 24633830 http://dx.doi.org/10.1002/bjs.9448

Randomized controlled trials Prospective Randomized Controlled Trial on the Use of Flexible Reinforced Laryngeal Mask Airway (LMA) During Total Thyroidectomy: Effects on Postoperative Laryngopharyngeal Symptoms. World J Surg, 38(2):378-84. Ryu JH, Yom CK, Park DJ, Kim KH, Do SH, Yoo SH, Oh AY. 2014. BACKGROUND: Sore throat, hoarseness, dysphagia, and cough are common laryngopharyngeal discomforts after thyroidectomy. The incidence and severity of laryngopharyngeal symptoms after the use of a flexible reinforced laryngeal mask airway (LMA) were compared with those that occur after the use of a plain endotracheal tube in patients after thyroidectomy. METHODS: Seventy-six patients scheduled for total thyroidectomy were randomized into a plain endotracheal tube group (group E) or a flexible reinforced LMA group (group L). Total intravenous anesthesia (propofol and remifentanil) was used for maintenance of

ESES Review of Recently Published Literature 2014-1 Page 8 of 121 anesthesia. Hemodynamic variables were recorded during induction of anesthesia. The incidence and severity (100-point numerical rating scales) of laryngopharyngeal symptoms, including sore throat, hoarseness, dysphagia, and cough, were assessed at 1, 24, and 48 h after surgery. RESULTS: All patients were placed successfully with an endotracheal tube or a flexible reinforced LMA. The postoperative incidence and severity of sore throat (25 vs. 33 at 24 h, p = 0.035, 17 vs. 28 at 48 h, p = 0.017; 50 [0-100] vs. 80 [20-100] at 1 h, p = 0.002; 30 [0-80] vs. 50 [0-100] at 24 h, p < 0.001; 0 [0-40] vs. 30 [0-90] at 48 h, p < 0.001) and hoarseness were lower in group L than in group E. At 48 h postoperatively, dysphagia (p = 0.005) and cough (p = 0.028) occurred less frequently in group L than in group E patients. CONCLUSION: A flexible reinforced LMA placed during surgery decreases the incidence and severity of laryngopharyngeal symptoms and is a feasible anesthetic tool compared with a conventional endotracheal tube for thyroidectomy. PubMed-ID: 24146195 http://dx.doi.org/10.1007/s00268-013-2269-1

Thyroidectomy: a Novel Endoscopic Oral Vestibular Approach. Surgery, 155(1):33-8. Wang C, Zhai H, Liu W, Li J, Yang J, Hu Y, Huang J, Yang W, Pan Y, Ding H. 2014. BACKGROUND: To date, no report has discussed endoscopic thyroidectomy using the oral vestibular approach (ETOVA). The objective of this study was to evaluate the feasibility, safety, efficacy, and cosmetic results of endoscopic thyroidectomy involving this surgical approach. METHODS: Twenty-four patients with benign thyroid nodules were randomized into the ETOVA (n = 12) and the endoscopic thyroidectomy by areola approach (ETAA) groups (n = 12). Therapeutic effects were assessed at follow-up by physical examination. All patients were followed to evaluate thyroid function and scar formation from endoscopic treatment. RESULTS: Complete resection of all the lesions was performed endoscopically, and no conversion to open surgery was needed. There was no difference between the 2 groups with respect to surgical time (60.4 vs 59.6 min), blood loss (10.8 vs 13.8 mL), postoperative hospital stay (4.9 vs 4.6 d), or cost of surgery (17.6 vs 17.4 thousand yuan). Patients who underwent the areola approach had 3 scars, 10 x 2 mm, 5 x 1 mm, and 5 x 1 mm in size, all of which were visible at the 6-month follow-up. Patients in the ETOVA group did not have any scars. Follow-up showed a significant difference (P = .019) in the satisfaction score between the ETOVA (2.33 +/- 0.65) and the ETAA group (1.58 +/- 0.79). Imaging showed that all patients had complete resection and no residual disease. Severe complications such as subcutaneous accumulation of blood and fluid, superior or recurrent laryngeal nerve injury, and parathyroid dysfunction were not observed. CONCLUSION: ETOVA was found to be safe and feasible and did not leave any scars; however, large-scale, randomized clinical trials are necessary for confirmation. PubMed-ID: 23890962 http://dx.doi.org/10.1016/j.surg.2013.06.010

Consensus Statements/Guidelines Minimally Invasive Follicular Thyroid Cancer (MIFTC)--a Consensus Report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg, 399(2):165-84. Dionigi G, Kraimps JL, Schmid KW, Hermann M, Sheu-Grabellus SY, De WP, Beaulieu A, Tanda ML, Sessa F. 2014. BACKGROUND: This paper aims to review controversies in the management of minimally invasive follicular thyroid carcinoma (MIFTC) and to reach an evidence-based consensus. METHOD: MEDLINE search of the literature was conducted using keywords related to MIFTC. The search term was identified in the title, abstract, or medical subject heading. Available literature meeting the inclusion criteria were assigned the appropriate levels of evidence and recommendations in accordance with accepted international standards. Results were discussed at the 2013 Workshop of the European Society of Endocrine Surgeons devoted to MIFTC. RESULTS: Published papers on MIFTC present inadequate power with a III-IV level of evidence and C grade of recommendation. Several issues demanded a comparison of published studies from different medical reports regarding MIFTC definition, specimen processing, characteristics, diagnosis, prognoses, and therapy. As a consequence, it is difficult to make valuable statements on MIFTC with a sufficient recommendation rating. MIFTC diagnosis requires clearer, unequivocal, and reproducible criteria for pathologist, surgeons, and endocrinologists to use in the management of these patients. If the distinction between MIFTC and WIFTC cannot be made, an expert in thyroid pathologist should be consulted. CONCLUSION: According to published papers, the following conclusions can be drawn. (a) Candidates for hemithyroidectomy are MIFTC with exclusive

ESES Review of Recently Published Literature 2014-1 Page 9 of 121 capsular invasion, patients <45 years old at presentation, tumor size <40 mm, without vascular invasion, and without any node or distant metastases. (b) Candidates for total thyroidectomy are MIFTC in patients >/=45 years at presentation, tumor size >/=40 mm, vascular invasion present, positive nodes, and positive distant metastases. (c) In the absence of clinical evidence for lymph node metastasis, patients with MIFTC do not require prophylactic lymph node dissection. (d) Radio iodine ablation is indicated in elderly patients (>45 years), large tumor size (>40 mm), extensive vascular invasion, presence of distant synchronous or metachronous metastasis, positive nodes, and if recurrence is noted at follow-up. PubMed-ID: 24233345 http://dx.doi.org/10.1007/s00423-013-1140-z

Thyroglobulin Measurement Using Highly Sensitive Assays in Patients With Differentiated Thyroid Cancer: a Clinical Position Paper. Eur J Endocrinol, Giovanella L, Clark P, Chiovato L, Duntas LH, Elisei R, Feldt-Rasmussen U, Leenhardt L, Luster M, Schalin- Jantti C, Schott M, Seregni E, Rimmele H, Smit JW, Verburg FA. 2014. Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous thyrotropin (TSH) is recommended by current clinical guidelines to detect occult disease with maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC. PubMed-ID: 24743400 http://dx.doi.org/10.1530/EJE-14-0148

Multifocal Papillary Thyroid Carcinoma--a Consensus Report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg, 399(2):141-54. Iacobone M, Jansson S, Barczynski M, Goretzki P. 2014. BACKGROUND: Multifocal papillary thyroid carcinoma (MPTC) has been reported in literature in 18-87 % of cases. This paper aims to review controversies in the molecular pathogenesis, prognosis, and management of MPTC. METHODS: A review of English-language literature focusing on MPTC was carried out, and analyzed in an evidence-based perspective. Results were discussed at the 2013 Workshop of the European Society of Endocrine Surgeons devoted to surgery of thyroid carcinoma. RESULTS: Literature reports no prospective randomized studies; thus, a relatively low level of evidence may be achieved. CONCLUSIONS: MPTC could be the result of either true multicentricity or intrathyroidal metastasis from a single malignant focus. Radiation and familial nonmedullary thyroid carcinoma are conditions at risk of MPTC development. The prognostic importance of multifocal tumor growth in PTC remains controversial. Prognosis might be impaired in clinical MPTC but less or none in MPTC <1 cm. MPTC can be diagnosed preoperatively by FNAB and US, with low sensitivity for MPTC <1 cm. Total or near-total thyroidectomy is indicated to reduce the risk of local recurrence. Prophylactic central node dissection should be considered in patients with total tumor diameter >1 cm, or in cases with high number of cancer foci. Completion thyroidectomy might be necessary when MPTC is diagnosed after less than near-total thyroidectomy. Radioactive iodine ablation should be considered in selected patients with MPTC at increased risk of recurrence or metastatic spread. PubMed-ID: 24263684 http://dx.doi.org/10.1007/s00423-013-1145-7

Timing and Extent of Thyroid Surgery for Gene Carriers of Hereditary C Cell Disease--a Consensus Statement of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg, 399(2):185-97. Niederle B, Sebag F, Brauckhoff M. 2014. PURPOSE: This "consensus statement" aims to summarise the current evidence-based knowledge as to

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"timing" and planning the "extent" of thyroid surgery in terms of an optimal balance between the prevention of thyroid malignancy (involving metastasis) and the risks associated with more extended surgery (permanent hypoparathyroidism, permanent paralysis of the recurrent laryngeal nerve). Surgery "in time" is influenced by genetic findings and age. Basal (and stimulated) calcitonin levels may individualise the timing and extent of surgery. MATERIALS AND METHODS: The review of English-language studies addressing the management of REarranged during Transfection proto-oncogene mutation carriers including the time, extent of thyroid surgery and results. Evidence is mostly obtained from well-designed, non-experimental descriptive investigations, such as comparative, correlation and case-control studies (level III) with a grading of recommendation B, or from expert committee reports or opinions and/or the clinical experience of respected authorities (level IV) with a grading of recommendation C, respectively. RESULTS: "Risk level D" includes multiple endocrine neoplasia 2B cases. Thyroidectomy is recommended within the first year of life, preferably as soon as possible, due to the very early transformation of C cell hyperplasia to more aggressive tumours. Calcitonin levels may be less helpful. In patients with codon 634 mutations (risk level C), thyroidectomy between ages 2 and 4 years has been proposed based upon evidence of age-dependent and codon-specific progression of early medullary thyroid cancer. In "risk level B" (codons 609, 611, 618, 620, 630 and 804), tandem mutation (804-778) patients should undergo thyroidectomy before the age of 6 years. "Risk level A" includes patients with mutations in codons 321, 515, 533, 600, 603, 606, 635, 649, 666, 768, 776, 790, 791, 804 (single mutation), 833, 844, 861, 891 or 912. Surgery may be postponed until the age of 10 years. However, postponing surgery and avoiding central (level VI) neck dissection in patients with risk levels A to C are only justified in families with a less aggressive MTC history and in combination with the results of basal (and calcium- or pentagastrin-stimulated) serum calcitonin levels. The moment of transition from C cell hyperplasia to MTC seems to occur when calcitonin levels rise. In patients with normal basal and stimulated calcitonin levels, the chance of micro-MTC increases significantly. CONCLUSIONS: Hereditary C cell disease acts as a model to apply the results of bedside genetic testing, age and calcitonin levels (genotype-age-calcitonin-concept) for the individual timing of thyroid surgery and its extent. PubMed-ID: 24297502 http://dx.doi.org/10.1007/s00423-013-1139-5

Prophylactic Central Neck Disection in Papillary Thyroid Cancer: a Consensus Report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg, 399(2):155-63. Sancho JJ, Lennard TW, Paunovic I, Triponez F, Sitges-Serra A. 2014. BACKGROUND: There remains still no clear answer as to whether or not prophylactic central compartment neck dissection (pCCND) is indicated for the treatment of patients with papillary thyroid cancer. METHODS: The published studies, including single cohort, comparative studies and meta-analysis, were critically appraised. Aspects beyond postoperative complications and loco-regional recurrence rates in the analysis, as the impact of pre- and post-ablation thyroglobuline levels, multifocality, bilaterality and additional risk factors for recurrence, were also considered. RESULTS: Thirty studies and five meta-analyses were assessed. The lack of randomized clinical trials on the subject and the heterogeneity of study populations are the main limiting factors to draw clear conclusions, and a comprehensive list of bias sources has been identified. Recent comparative studies and systematic reviews all associate the pCCND with higher proportions of temporary postoperative hypocalcemia but not with significantly higher permanent hypoparathyroidism, recurrent laryngeal nerve injury or permanent vocal cord paralysis. The risk of recurrence appears to be reduced after pCCND, and the number of patients needed to treat to avoid a recurrence is between 20 and 31. CONCLUSIONS: It is suggested that routine level 6 prophylactic dissections should be risk-stratified. Larger tumours (T3, T4), patients aged 45 years and older or 15 years and younger, male patients, patients with bilateral or multifocal tumours, and patients with known involved lateral lymph nodes could all be candidates for routine unilateral level 6 dissection. The operation should be limited to surgeons who have the available expertise and experience. PubMed-ID: 24352594 http://dx.doi.org/10.1007/s00423-013-1152-8

Other Articles A NSQIP Risk Assessment for Thyroid Surgery Based on Comorbidities. J Am Coll Surg, 218(6):1231-7. Abraham CR, Ata A, Carsello CB, Chan TL, Stain SC, Beyer TD. 2014. BACKGROUND: Thyroid surgery is associated with low mortality and morbidity and often is performed in an ambulatory setting. The majority of patients undergoing thyroidectomy have an uncomplicated outcome, but

ESES Review of Recently Published Literature 2014-1 Page 11 of 121 common comorbidities may increase mortality and morbidity. Due to low complication rates, studies using single surgeon or single institutional data to identify risk factors for adverse outcomes may be limited by inadequate patient volume. STUDY DESIGN: This retrospective cohort study used data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). The study group included all thyroidectomy patients over a 6-year period (2005 to 2010). Common patient comorbidities were identified and analyzed using logistic regression. Risk of adverse outcomes was calculated for single and multiple comorbidities. Statistical significance was set at p < 0.05. RESULTS: The study group included 38,577 consecutive patients. Thirty-day mortality and postoperative morbidity were 0.06% and 1.49%, respectively. The risk factors independently associated with morbidity included hypertension, diabetes, advanced age greater than 70 years, COPD, dialysis, malignant thyroid disease, and surgical approach (total thyroidectomy). Substernal thyroidectomy, hypertension, diabetes, age greater than 70 years, COPD, and dialysis were significant predictors (unadjusted) of mortality. Multiple comorbidities resulted in significant cumulative risk. The presence of 3 or more comorbidities was associated with a postoperative morbidity of 5.1% (p < 0.001) and mortality as high as 12.5%. CONCLUSIONS: Thyroid surgery is generally safe. Common comorbidities significantly increase the risk of adverse outcomes and death. Clinically applicable risk calculation based on overall health may improve patient selection, surgical management, and informed consent. PubMed-ID: 24745620 http://dx.doi.org/10.1016/j.jamcollsurg.2014.01.055

Clinical Impact of Microscopic Extrathyroidal Extension in Patients With Papillary Thyroid Microcarcinoma Treated With Hemithyroidectomy. J Endocrinol Invest, 37(2):167-73. Ahn D, Sohn JH, Jeon JH, Jeong JY. 2014. BACKGROUND: Pathologically confirmed microscopic extrathyroidal extension (ETE) is often identified after hemithyroidectomy in patients with papillary thyroid microcarcinoma (PTMC). Without the presence of microscopic ETE, these patients would be optimal candidates for hemithyroidectomy. AIM: The present study aimed at evaluating the clinical impact of microscopic ETE on the recurrence of PTMC treated with hemithyroidectomy. SUBJECTS AND METHODS: We compared the clinicopathological characteristics and 5- year outcomes for 262 PTMC patients without ETE and 86 with microscopic ETE who were treated with hemithyroidectomy between January 2004 and December 2010. RESULTS: The mean tumour size was larger (0.67 vs. 0.54 cm, p < 0.001) and the proportion of tumours measuring >/=0.5 cm was higher (84.9 vs. 66.8 %, p = 0.001) in patients with microscopic ETE as compared with patients without ETE. Occult multifocal disease was more frequent in patients with microscopic ETE than in those without ETE (14.0 vs. 6.5 %, p = 0.030). However, the recurrence rate was not different between the two groups during the mean 55.8-month follow-up period. In addition, univariate and multivariate analyses revealed no meaningful association between recurrence and microscopic ETE in patients with PTMC treated with hemithyroidectomy. CONCLUSIONS: Although microscopic ETE was associated with large tumour size and multifocal disease, its clinical impact on disease recurrence was not significant in PTMC patients treated with hemithyroidectomy. Therefore, microscopic ETE identified after hemithyroidectomy would not be an absolute indication for completion thyroidectomy in patients with PTMC. PubMed-ID: 24497215 http://dx.doi.org/10.1007/s40618-013-0025-x

Detection of Thyroid Cancer Stem Cells in Papillary Thyroid Carcinoma. J Clin Endocrinol Metab, 99(2):536-44. Ahn SH, Henderson YC, Williams MD, Lai SY, Clayman GL. 2014. CONTEXT: Special populations of cells that can efficiently initiate tumor growth have been characterized, and this feature supports the cancer stem cell theory. These cancer stem cell populations have been identified with CD44 and POU5F1. Most cancer stem cells express high levels of CD44 and low levels of CD24. In thyroid lesions, cancer stem cells have been detected in anaplastic carcinoma. However, little is known about the presence of cancer stem cells in papillary thyroid carcinoma (PTC), especially in recurrent PTC. OBJECTIVE AND DESIGN: PTC cells were labeled and sorted by flow cytometry to obtain two populations. Total RNA was prepared from cells with high CD44 and CD24 expressions (CD44+CD24+) and from cells with high CD44 and low CD24 expressions (CD44+CD24-). The expressions of the stem cell marker POU5F1 and several differentiated thyroid markers were measured via real-time PCR. RESULTS: CD44+. PubMed-ID: 24302752 http://dx.doi.org/10.1210/jc.2013-2558

Intraoperative Neuromonitoring for Surgical Training in Thyroid Surgery: Its Routine Use Allows a Safe Operation Instead of Lack of Experienced Mentoring.

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World J Surg, 38(3):592-8. Alesina PF, Hinrichs J, Meier B, Cho EY, Bolli M, Walz MK. 2014. BACKGROUND: The aim of the present study was to evaluate the influence of intraoperative neuromonitoring (NM) on surgical training. The results of thyroidectomy performed by inexperienced surgeons under the supervision of a consultant surgeon without intraoperative neuromonitoring (ioNM) were compared to those of the operations performed without experienced assistance but under neuromonitoring control. MATERIALS AND METHODS: The study included the thyroid operations performed in our Department between 2005 and 2012. Among them, residents or fellows performed 1,116 procedures. Seven hundred sixty-five operations were conducted without neuromonitoring (NV group) and 351 with NM group. In the NV group 375 unilateral and 390 bilateral operations were performed. In the NM group 149 unilateral and 202 bilateral operations were performed. Primary end point of the study was the incidence of postoperative recurrent laryngeal nerve palsy. A secondary end point was the impact of ioNM on operating time and operative strategy. RESULTS: The incidence of recurrent laryngeal nerve (RLN) palsy was 2.6 % in the NV group and 2.7 % in the NM group [p = ns]. One case of bilateral RLN palsy was observed in the NV group. The operative time was longer in the NM group for both lobectomy and total thyroidectomy (50 vs. 56 min and 76 vs. 81 min, respectively; p < 0.05). CONCLUSIONS: The routine use of intermittent intraoperative neuromonitoring during thyroid operations does not reduce the incidence of RLN palsy. Nevertheless, it allows inexperienced surgeons to perform a safe operation with a complication rate comparable to that obtained under supervision of an experienced surgeon. Moreover, ioNM could avoid the unfortunate occurrence of a bilateral RLN palsy. PubMed-ID: 24305928 http://dx.doi.org/10.1007/s00268-013-2372-3

Comment on Garas Et Al., "Which Hemostatic Device in Thyroid Surgery? A Network Meta-Analysis of Surgical Technologies". Thyroid, 24(4):778-9. Amaral JF, Hinoul P, Schwiers ML, Clymer JW. 2014. PubMed-ID: 24251916 http://dx.doi.org/10.1089/thy.2013.0443

Differentiated Thyroid Carcinoma: an Analysis of 249 Patients Undergoing Therapy and Aftercare at a Single Institution. Clin Nucl Med, 39(2):142-6. Amin A, Badwey A, El-Fatah S. 2014. PURPOSE: Well-differentiated thyroid cancer (WDTC) is rising in incidence across the world over the past 3 decades. We aimed to evaluate the natural history and clinical outcome of differentiated thyroid carcinoma by a retrospective analysis of 249 patients treated at a single institution. METHODS: A cohort of 249 patients who underwent thyroidectomy for WDTC in the last 10 years in Maadi Military Hospital was studied. Main outcome measures were clinical management at the diagnosis, survival, morbidity, and prognostic risk factors. RESULTS: Mean age at diagnosis was 44.7 (SD, 14.6) years, where 52.2% were 45 years or older. Females represent 70.7% (P = 0.01), with female-to-male ratio of 4.1:1. Near-total thyroidectomy was done in 70.7% of the cases where papillary cancer was found in 80.8% and node metastasis in 10.5%. Radioactive I (RA I) was given an all cases (dose range, 80-150 mCi) with ablation success rate of 79.2%. Locoregional recurrence and metastasis (lungs and bones) were found in 2% and 6.8%, respectively. Multivariate Cox regression analysis showed that the mean ablation dose of RA I (odds ratio, 1.045; 95% confidence interval, 0.936-1.1189; P = 0.01) and presence of remote deposits (odds ratio, 1.049; 95% confidence interval, 0.836-1.1189; P = 0.01) are the significant influential factor in ablation success rate and survival, respectively. CONCLUSIONS: Our data suggest that proper ablation dose of RA I and absence of remote metastasis are the powerful predictors for excellent outcome in WDTC patients. PubMed-ID: 24368533 http://dx.doi.org/10.1097/RLU.0000000000000324

In Search of an Unstimulated Thyroglobulin Baseline Value in Low-Risk Papillary Thyroid Carcinoma Patients Not Receiving Radioactive Iodine Ablation. Thyroid, Angell TE, Spencer CA, Rubino BD, Nicoloff JT, LoPresti JS. 2014. Background: The clinical use of serum thyroglobulin (Tg) as a tumor marker in papillary thyroid cancer (PTC) patients following total thyroidectomy continues to evolve, due in part to the introduction of more sensitive (second generation) Tg immunometric assays (Tg2GIMA, functional sensitivity

ESES Review of Recently Published Literature 2014-1 Page 13 of 121 of recurrence. As a result, there is a need to establish the optimal timing and interpretation of serum Tg values while on levothyroxine-induced suppression of thyrotropin (TSH) in thyroidectomized PTC patients with a thyroid remnant. This study examines the pattern of decline and eventual baseline value of unstimulated Tg (uTg) concentrations following total thyroidectomy in patients with low-risk PTC who did not receive RAIA. Methods: The medical records of consecutive patients with thyroid cancer seen at the Los Angeles County+USC Medical Center were retrospectively reviewed. Serial uTg and TSH values from Tg-antibody negative low-risk PTC patients treated with total thyroidectomy and no RAIA were analyzed. Patients were stratified by degree of TSH suppression to assess the effect on uTg. Serial postoperative uTg values were evaluated for the temporal pattern of decline and ultimate baseline. Patients with medullary thyroid cancer (MTC) were studied as a surgical reference group. Results: Records from 577 consecutive thyroid cancer patients were reviewed, of which 36 met all criteria for inclusion. By 6 months, uTg fell to <0.5 ng/mL in 61% of patients and all patients demonstrated uTg <0.5 ng/mL 2 years after surgery. During a median follow up of 5.7 years, uTg values remained below this level. The median uTg values in patients with papillary microcarcinoma, PTC, and MTC were similar at 0.11, 0.12, and 0.09 ng/mL, respectively. Further decline in uTg was not observed once the TSH was <0.5 mIU/L. Conclusions: The uTg values during TSH suppression in Tg antibody-negative, low-risk PTC patients who did not receive RAIA were below 0.5 ng/mL by 6 months postoperatively in most cases and remained stable over the duration of patient follow-up. PubMed-ID: 24697314 http://dx.doi.org/10.1089/thy.2013.0691

Left-Shifted Relation Between Calcium and Parathyroid Hormone in Graves' Disease. J Clin Endocrinol Metab, 99(2):545-51. Annerbo M, Hultin H, Stalberg P, Hellman P. 2014. BACKGROUND: Patients with Graves' disease (GD) have disturbances in calcium regulation with manifestations such as postoperative hypocalcemia. We have investigated the thyroid as well as the parathyroid function in detail. MATERIALS AND METHOD: A series of patients undergoing total thyroidectomy for GD (n = 56) or multinodular goiter (MNG; n = 50) were scrutinized for postoperative hypocalcemia and a need for calcium and/or vitamin D substitution. A citrate-calcium (CiCa) clamp was used in 14 patients and 21 controls to quantify the secretion of PTH in relation to the ionized plasma calcium level. The set point, equal to the plasma-ionized calcium concentration at which 50% of the maximal secretion of PTH is inhibited, as well as other CiCa-related parameters were calculated. RESULTS: Hypocalcemia was present in 48% of GD and 41.2% of patients with MNG postoperatively. Patients with GD had lower calcium levels, 18% had serum Ca less than 2.00 mmol/L compared with 4.0% in the MNG group (P = .02). A higher degree of GD patients were given parenteral calcium substitution during the hospital stay (3.6% vs 0 %) and oral calcium substitution at discharge (48% vs 10%), although they had normal vitamin D3 levels. The GD group showed a significantly left-shifted set point compared with the normal group on the CiCa clamp, 1.16 mmol/L vs 1.20 mmol/L (P < .001) as well as an increased PTH release to hypocalcemic stimulus. GD patients also show an association between degree of subclinical toxicosis at time of surgery and risk for developing postoperative hypocalcemia. CONCLUSION: Patients with GD demonstrate dysregulation of the calcium homeostasis by several parameters. GD patients have lower postoperative serum calcium compared with patients with MNG, lower calcium/PTH set point, and a significantly increased release of PTH to hypocalcemic stimulus compared with controls. The CiCa clamp response in GD patients with normal 25-hydroxyvitamin D3 levels mimics that of obese patients in which vitamin D insufficiency has been proposed as an underlying cause. PubMed-ID: 24248181 http://dx.doi.org/10.1210/jc.2013-2500

The Impact of Molecular Testing on the Surgical Management of Patients With Thyroid Nodules. Ann Surg Oncol, 21(6):1862-9. Aragon HP, Olson MT, Fazeli R, Prescott JD, Pai SI, Schneider EB, Tufano RP, Zeiger MA. 2014. BACKGROUND: The use of molecular tests as an adjunct to FNA diagnosis of thyroid nodules has been increasing. However, the true impact of these tests on surgical practice has not been demonstrated. This study examines the usefulness of molecular testing on surgical management decisions in patients referred for thyroid surgery at a tertiary care center. METHODS: Clinical information was collected from patients who presented to Johns Hopkins Hospital for surgical consultation regarding a thyroid nodule and who underwent molecular testing between August 2009 and March 2013. Tests included an RNA-based gene expression classifier, a DNA-based somatic mutation panel, BRAF, NRAS, and/or RET/PTC translocation. A surgical management algorithm was created by consensus of four thyroid surgeons. Postsurgical pathology analysis in each case was then used to judge the appropriateness of the surgical decision-making and the usefulness of preoperative molecular testing, in guiding surgical planning. RESULTS: Of 114 patients assessed by preoperative molecular

ESES Review of Recently Published Literature 2014-1 Page 14 of 121 testing, 87 (72 %) underwent surgery. Surgical management was altered in nine (10 %) patients on the basis of molecular testing. Of these, surgical management change was appropriate, relative to the postoperative pathology analysis, for three patients and inappropriate for six patients. CONCLUSIONS: In this study, molecular testing of thyroid nodule did not alter the surgical management of the majority of patients with thyroid nodules. These results indicate that molecular testing may be overused in patients for whom the results would not change surgical management. Furthermore, our data question the usefulness of the molecular tests examined in guiding preoperative surgical decision-making. PubMed-ID: 24522987 http://dx.doi.org/10.1245/s10434-014-3508-x

Sentinel Node Biopsy in Papillary Thyroid Cancer--What Is the Potential? Langenbecks Arch Surg, 399(2):245-51. Balasubramanian SP, Brignall J, Lin HY, Stephenson TJ, Wadsley J, Harrison BJ, Craig WL, Smart L, Krukowski Z. 2014. PURPOSE: Sentinel node biopsy (SNB) may identify lymph node metastases in patients with papillary thyroid cancer (PTC), enabling selective application of central node dissection (CND). The aim of this study was to assess the feasibility of implementing SNB in patients undergoing thyroidectomy for a cytologically indeterminate/suspicious/malignant thyroid nodule and to determine the potential improvement in clinical outcomes and the costs associated with the SNB technique. METHODS: The treatment strategies and clinical and pathological outcomes of two retrospective cohorts of patients who underwent preoperative thyroid FNA over a 5-year period in two different centres were studied. The potential for implementing the SNB technique and the benefits and costs associated with implementation were estimated. RESULTS: In centre 1, in 819 adult patients who had thyroid fine-needle aspiration cytology, the final cytology was indeterminate, suspicious and diagnostic of malignancy in 113, 29 and 28 patients, respectively. One hundred eight patients were 'suitable' for SNB. Twenty-three of these patients had PTC, six of whom underwent CND. Of these six patients, node metastasis was absent in five--the cohort in whom prophylactic CND may have been avoided consequent to a negative 'sentinel node' biopsy. Morbidity attributable to CND may have been avoided in up to four patients over a 5-year period. Costs associated with implementation of SNB outweighed any potential savings. Analysis of 491 patients in centre 2 confirmed that the benefit of SNB in PTC was similarly limited; morbidity attributable to CND may have been avoided in up to seven patients over a 5-year period. CONCLUSIONS: Even under ideal conditions (assuming 100 % node identification rate and 0 % false negative rate), the potential short- to medium- term benefit of sentinel node biopsy in patients with thyroid cancer in centres implementing a policy of selective or routine prophylactic CND is low. PubMed-ID: 24446015 http://dx.doi.org/10.1007/s00423-014-1168-8

Nodal Recurrence in the Lateral Neck After Total Thyroidectomy With Prophylactic Central Neck Dissection for Papillary Thyroid Cancer. Langenbecks Arch Surg, 399(2):237-44. Barczynski M, Konturek A, Stopa M, Nowak W. 2014. PURPOSE: The aim of this study was to examine risk factors for nodal recurrence in the lateral neck (NRLN) in patients with papillary thyroid cancer (PTC) who underwent total thyroidectomy with prophylactic central neck dissection (TT + pCND). METHODS: This was a retrospective cohort study of patients with PTC who underwent TT + pCND. Data of all patients treated over a 10-year period (between 1998 and 2007) were analysed. The primary outcome was prevalence of NRLN within the 5-year follow-up after initial surgery. Predictors of NRLN were determined in the univariable and multivariable analysis. RESULTS: Of 760 patients with PTC included in this study, 44 (6.0 %) developed NRLN. In the univariable analysis, the following factors were identified to be associated with an increased risk of NRLN: positive/negative lymph node ratio >/=0.3 (odds ratio (OR) 14.50, 95 % confidence interval (CI) 7.21 to 29.13; p < 0.001), central lymph node metastases (OR 7.47, 95 % CI 3.63 to 15.38; p < 0.001), number of level VI lymph nodes <6 in the specimen (OR 2.88, 95 % CI 1.21 to 6.83; p = 0.016), extension through the thyroid capsule (OR 2.55, 95 % CI 1.21 to 5.37; p = 0.013), localization of the tumour within the upper third of the thyroid lobe (OR 2.35, 95 % CI 1.27 to 4.34; p = 0.006) and multifocal lesions (OR 1.85, 95 % CI 1.01 to 3.41; p = 0.048). CONCLUSIONS: Central lymph node metastases together with positive to negative lymph node ratio >/=0.3 represent the strongest independent prognostic factors for the PTC recurrence in the lateral neck. PubMed-ID: 24213969 http://dx.doi.org/10.1007/s00423-013-1135-9

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Intraoperative Nerve Monitoring Can Reduce Prevalence of Recurrent Laryngeal Nerve Injury in Thyroid Reoperations: Results of a Retrospective Cohort Study. World J Surg, 38(3):599-606. Barczynski M, Konturek A, Pragacz K, Papier A, Stopa M, Nowak W. 2014. BACKGROUND: The prevalence of recurrent laryngeal nerve (RLN) injury is higher in repeat than in primary thyroid operations. The use of intraoperative nerve monitoring (IONM) as an aid in dissection of the scar tissue is believed to minimize the risk of nerve injury. The aim of this study was to examine whether the use of IONM in thyroid reoperations can reduce the prevalence of RLN injury. METHODS: This was a retrospective cohort study of patients who underwent thyroid reoperations with IONM versus with RLN visualization, but without IONM. The database of thyroid surgery was searched for eligible patients (treated in the years 1993-2012). The primary outcomes were transient and permanent RLN injury. Laryngoscopy was used to evaluate and follow RLN injury. RESULTS: The study group comprised 854 patients (139 men, 715 women) operated for recurrent goiter (n = 576), recurrent hyperthyroidism (n = 36), completion thyroidectomy for cancer (n = 194) or recurrent thyroid cancer (n = 48), including 472 bilateral and 382 unilateral reoperations; 1,326 nerves at risk (NAR). A group of 306 patients (500 NAR) underwent reoperations with IONM and 548 patients (826 NAR) had reoperations with RLN visualization, but without IONM. Transient and permanent RLN injuries were found respectively in 13 (2.6 %) and seven (1.4 %) nerves with IONM versus 52 (6.3 %) and 20 (2.4 %) nerves without IONM (p = 0.003 and p = 0.202, respectively). CONCLUSIONS: IONM decreased the incidence of transient RLN paresis in repeat thyroid operations compared with nerve visualization alone. The prevalence of permanent RLN injury tended to be lower in thyroid reoperations with IONM, but statistical validation of the observed differences requires a sample size of 920 NAR per arm. PubMed-ID: 24081538 http://dx.doi.org/10.1007/s00268-013-2260-x

High-Risk Patients With Differentiated Thyroid Cancer T4 Primary Tumors Achieve Remnant Ablation Equally Well Using RhTSH or Thyroid Hormone Withdrawal. Thyroid, 24(3):480-7. Bartenstein P, Calabuig EC, Maini CL, Mazzarotto R, Muros de Fuentes MA, Petrich T, Rodrigues FJ, Vallejo Casas JA, Vianello F, Basso M, Balaguer MG, Haug A, Monari F, Vano RS, Sciuto R, Magner J. 2014. BACKGROUND: Few data exist on using thyrotropin alfa (recombinant human thyroid-stimulating hormone [rhTSH]) with radioiodine for thyroid remnant ablation of patients who have T4 primary tumors (invasion beyond the thyroid capsule). METHODS: A retrospective chart review protocol at nine centers in Europe was set up with special waiver of need for informed consent, along with a careful procedure to avoid selection bias when enrolling patients into the database. Data on 144 eligible patients with T4 tumors were collected (T4, N0-1, M0-1; mean age 49.7 years; 65% female; 88% papillary cancer). All had received (131)I remnant ablation following TSH stimulation with rhTSH or thyroid hormone withdrawal (THW) since January 2000 (rhTSH n=74, THW n=70). The primary endpoint was based on evaluation of diagnostic radioiodine scan thyroid bed uptake more than six months after the ablation procedure, while stimulated serum Tg was a secondary endpoint. Safety was evaluated within 30 days after rhTSH or (131)I. RESULTS: Successful ablation judged by scan was achieved in 65/70 (92.9%) of rhTSH and in 61/67 (91.0%) of THW patients; the success rates were comparable, since noninferiority criteria were met. Although some patients in the initial cohort had tumor in cervical nodes and metastases, considering all evaluable patients regardless of various serum anti-Tg antibody assessments, the stimulated Tg was <2 ng/mL in 48/70 (68.6%) and 39/67 (58.2%) in rhTSH and THW groups respectively; if patients with anti-Tg antibody levels >30 IU/mL were excluded, the stimulated Tg was <2 ng/mL in 42/62 (67.7%) and 37/64 (57.8%) respectively. No serious adverse events occurred within the 30-day window after ablation. CONCLUSIONS: Use of rhTSH as preparation for thyroid remnant ablation in patients with T4 primary tumors achieved a rate of ablation success that was high and noninferior to the rate seen after THW, and rhTSH was well tolerated. PubMed-ID: 24040896 http://dx.doi.org/10.1089/thy.2013.0157

Ultrasonographic Features Associated With Malignancy in Cytologically Indeterminate Thyroid Nodules. Eur J Surg Oncol, 40(2):182-6. Batawil N, Alkordy T. 2014. CONTEXT: Thyroid nodules with indeterminate cytology usually are treated with surgery, but most are benign. Neck ultrasonography has varied results in predicting malignancy. OBJECTIVE: To evaluate the predictive value of ultrasonography and the frequency of malignancy in patients who had indeterminate thyroid nodules. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: There were 78 patients who had thyroid nodules that were diagnosed on cytology (fine needle aspiration) as a follicular lesion (atypia of

ESES Review of Recently Published Literature 2014-1 Page 16 of 121 undetermined significant) or follicular neoplasm. Ultrasonography was available in 69 patients (88%). INTERVENTION AND MAIN OUTCOME MEASURES: Diagnostic fine needle aspiration (cytology), ultrasonography, and surgical pathology of thyroid nodules. RESULTS: Fine needle aspiration was indeterminate in all patients, with follicular lesions in 60 patients (77%) and follicular neoplasm in 18 patients (23%). Ultrasonography showed micro calcification in 6 patients (9%), irregular border in 15 patients (22%), size >/= 3 cm in 31 patients (45%), and hypoechogenicity in 43 patients (62%). Surgical pathology showed that the nodules were benign in 50 patients (64%) and malignant in 28 patients (36%). Malignancy was significantly associated with male sex (relative risk, 2.3), solid nodule structure (relative risk, 2.6), and irregular border (relative risk, 3.6). Compared with other ultrasonographic characteristics, irregular borders had the highest specificity (93%), positive predictive value (80%), and accuracy (78%) for malignancy. CONCLUSIONS: The frequency of malignancy is high in indeterminate thyroid nodules. Based on the limited accuracy or predictive value of ultrasonographic risk factors, surgery is the treatment of choice for indeterminate thyroid nodules. PubMed-ID: 24373298 http://dx.doi.org/10.1016/j.ejso.2013.11.015

Fine-Needle Aspiration of the Thyroid: Correlating Suspicious Cytology Results With Histological Outcomes. Ann Surg Oncol, 21(5):1653-8. Baynes AL, Del RA, McLean C, Grodski S, Yeung MJ, Johnson WR, Serpell JW. 2014. PURPOSE: Fine-needle aspiration cytology (FNAC) assists the diagnosis of thyroid malignancy. A 'suspicious for malignancy' on FNAC creates a management dilemma. The aims of this study were to investigate the malignancy rate for patients with suspicious cytology, and to describe a management approach for those with a suspicious result. METHODOLOGY: A retrospective review of prospectively collected data in an endocrine surgery database was undertaken. Patients undergoing thyroidectomy with preoperative FNAC from 1992 to 2012 were analysed. RESULTS: Preoperative FNAC was undertaken in 2,692 patients, and the FNAC result was 'suspicious for malignancy' in 94 (3.5 %) patients. Of these, 53 (56.4 %) were malignant, with the majority 44 (83.0 %) being papillary thyroid cancer. 48 patients went straight to total thyroidectomy, 40 patients had an initial diagnostic hemithyroidectomy, and 1 patient had a diagnostic isthmusectomy. 5 patients required reoperative total thyroidectomy as an initial procedure. Of the 94 suspicious cases, 55 were reported by an unknown, presumably non-expert, thyroid cytopathologist. 38 of these cases were available for review and re- reporting by an experienced cytopathologist. On review, 28 (73.7 %) were reclassified as cytologically malignant, and all of these were confirmed as malignant on subsequent histopathology. CONCLUSIONS: Suspicious cytology has a high risk of malignancy. Expert thyroid cytopathology can improve diagnostic accuracy and a preoperative malignant diagnosis should be pursued to enable one-stage surgery where possible. PubMed-ID: 24390657 http://dx.doi.org/10.1245/s10434-013-3448-x

Management of Neonates Born to Women With Graves' Disease: a Cohort Study. Eur J Endocrinol, 170(6):855-62. Besancon A, Beltrand J, Le G, I, Luton D, Polak M. 2014. OBJECTIVE: Hyperthyroidism in neonates born to mothers with Graves' disease (GD) can be associated with significant morbidity and mortality, but is still overlooked by clinicians. Management of neonatal hyperthyroidism would be improved by a better understanding of the predictive factors involved. The aim of this study was to evaluate the course of thyroid function and clinical outcomes during the first postnatal month in babies born to mothers with GD. DESIGN: Prospective observational study. METHODS: Sixty-eight neonates born to mothers with GD were managed from birth and divided into three groups based on thyrotropin receptor antibody (TRAb) and anti-thyroid drug (ATD) status in the mother: TRAb(-ve)/ATD(-ve), n=27; TRAb(-ve)/ATD(+) (ve), n=8; and TRAb(+ve)/ATD(+ve), n=33. The main outcome measures were clinical examination, thyroid function tests (TSH, free thyroxine (FT4), free triiodothyronine, and TRAb), echocardiography, thyroid ultrasonography, and bone maturation assessment. RESULTS: None of the infants born to TRAb(-ve) mothers with GD developed neonatal hyperthyroidism. Of the 33 TRAb(+ve)/ATD(+ve) neonates, 24 (72.7%) had positive TRAb on cord blood assays, and seven of these developed neonatal hyperthyroidism. FT4 elevation between days 3 and 7 but not at birth was predictive of the development of hyperthyroidism. CONCLUSIONS: TRAb status should be checked in the third trimester in mothers with GD and on cord blood in their neonates; if positive, it indicates a high risk of neonatal hyperthyroidism. FT4 measurement at birth should be repeated between days 3 and 5 (and by day 7 at the latest); rapid FT4 elevation during the first postnatal week is predictive of hyperthyroidism and warrants ATD therapy. PubMed-ID: 24670885 http://dx.doi.org/10.1530/EJE-13-0994

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Surgical Curability of Medullary Thyroid Cancer in Multiple Endocrine Neoplasia 2B: a Changing Perspective. Ann Surg, 259(4):800-6. Brauckhoff M, Machens A, Lorenz K, Bjoro T, Varhaug JE, Dralle H. 2014. OBJECTIVE: This investigation aimed at exploring the suitability of nonendocrine manifestations preceding medullary thyroid cancer (MTC) for early diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). BACKGROUND: MEN 2B patients, running a high risk of metastatic MTC, must be diagnosed early for biochemical cure. METHODS: Forty-four MEN 2B patients carrying inherited (3 patients) and de novo (41 patients) M918T RET mutations were examined for signs and symptoms prompting MEN 2B. RESULTS: All 3 patients with inherited mutations were diagnosed before the age of 1 year and cured of their C-cell disease. Among 41 patients with de novo mutations, MEN 2B was diagnosed in 12 patients after recognition of nonendocrine manifestations [intestinal ganglioneuromatosis (6 patients), oral symptoms (5 patients), ocular ("tearless crying") (4 patients), and skeletal stigmata (1 patient) alone or concomitantly]. In the remaining 29 patients with de novo mutations, the diagnosis of MEN 2B was triggered by symptomatic MTC (28 patients) or pheochromocytoma (1 patient). The former patients, being significantly (P < 0.001) younger (means of 5.3 vs 17.6 years) and having lower calcitonin levels (means of 115 vs 25,519 pg/mL), smaller tumors (67% vs 0% were

Overdiagnosis of Thyroid Cancer and Graves' Disease. Thyroid, 24(2):402-3. Brito JP, Gionfriddo M, Morris JC, Montori VM. 2014. PubMed-ID: 23931639 http://dx.doi.org/10.1089/thy.2013.0425

Utilization and Impact of Repeat Biopsy for Follicular Lesion/Atypia of Undetermined Significance. World J Surg, 38(3):628-33. Broome JT, Cate F, Solorzano CC. 2014. BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) created a new diagnostic category,follicular lesion/atypia of undetermined significance(FLUS/AUS). The recommended management of FLUS/AUS lesions is repeat biopsy to re-classify the lesion and guide therapy. Prior surgical studies suggest a higher than expected malignancy rate for FLUS/AUS. The present study evaluates a large institutional experience with all FLUS/AUS lesions analyzing use and impact of repeat biopsy. METHODS: A total of 322 patients with FLUS/AUS cytology have been retrospectively identified since adoption of the BSRTC (2/2009- 6/2012). Patient demographics, the results of clinical follow-up, repeat biopsy, or surgical pathology results were evaluated. RESULTS: Among the 322 patients, 16 had concurrent cytology of higher acuity and were excluded. For the remaining 306 patients, 101 (33 %) underwent repeat biopsy, yielding 49 (48.5 %) with FLUS/AUS, 43 (42.5 %)with benign cytology, and 9 (9 %) with higher acuity cytology. Among the 205 patients without repeat biopsy,117 (57 %) chose thyroidectomy, and 88 (43 %) are being observed. Overall, 170/306 (55.6 %) patients underwent surgery to remove the index lesion, yielding a malignancy rate of 16.5 %. In contrast, the malignancy rate for the entire cohort was 28/306 (9 %). CONCLUSIONS: Repeat biopsy was underutilized in FLUS/AUS cases. Repeat biopsy allows a significant proportion of FLUS/AUS patients without other indications for surgery to move to surveillance. In patients who have indications for thyroidectomy regardless of FLUS/AUS results,repeat biopsy does not appear necessary. Malignancy and thyroidectomy rates were similar among patients who did or did not have a repeat biopsy. Further data must be obtained to determine the long-term outcomes for surveillance of FLUS/AUS lesions in patients who do not undergo surgical removal. PubMed-ID: 24233659 http://dx.doi.org/10.1007/s00268-013-2330-0

Medullary Thyroid Carcinoma Preferentially Secreting Procalcitonin. Thyroid, Bugalho MJ, Madureira D, Domingues R, Pereira T, Cortez L. 2014. PubMed-ID: 24684321 http://dx.doi.org/10.1089/thy.2013.0664

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A Prospective Study on Surgical-Site Infections in Thyroid Operation. Surgery, 155(4):675-81. Bures C, Klatte T, Gilhofer M, Behnke M, Breier AC, Neuhold N, Hermann M. 2014. BACKGROUND: To evaluate the incidence and the microbe spectrum of surgical-site infections (SSIs) in patients undergoing elective thyroid operation and to develop a risk factor-based predictive model. METHODS: This prospective study included 6,778 consecutive patients who underwent thyroid operation at a single institution between 2007 and 2012. SSI was defined according to the Centers for Disease Control and Prevention. Regression models were fitted to evaluate risk factors for SSI. A predictive nomogram was constructed from relevant variables in the multivariable analysis. Discrimination and calibration of the nomogram were assessed. RESULTS: The cumulative incidence of SSI after 30 days was 0.49%. The median time from operation to SSI was 7 days (interquartile range, 4-10.5 days). SSI was classified as superficial incisional in 30 cases (93.8%), deep incisional in 1 case (3.1%), and organ/space in 1 case (3.1%). Staphylococcus aureus was the most common isolate. In multivariable analysis, duration of operation (P = .004) and American Society of Anesthesiologists' score (P = .031) were identified as independent risk factors for SSI. These variables formed the basis of a nomogram, which was validated internally by bootstrapping and reached a predictive accuracy of 70.1%. The calibration curve showed a good agreement between predicted probability and actual observation. CONCLUSION: The cumulative incidence of SSI in thyroid operation is <0.5%. American Society of Anesthesiologists' score and the duration of operation are independent risk factors for SSI. Antibiotic prophylaxis may be considered for selected patients based on the individual risk profile. PubMed-ID: 24502803 http://dx.doi.org/10.1016/j.surg.2013.12.002

Is Poorly Differentiated Thyroid Cancer Poorly Characterized? J Clin Endocrinol Metab, 99(4):1167-9. Burman KD. 2014. PubMed-ID: 24702015 http://dx.doi.org/10.1210/jc.2014-1549

Elastosonographic Strain Index in Thyroid Nodules With Atypia of Undetermined Significance. J Endocrinol Invest, 37(2):127-33. Cakir B, Ersoy R, Cuhaci FN, Aydin C, Polat B, Kilic M, Yazgan A. 2014. AIM: In this study, we aimed to evaluate the diagnostic accuracy of elastosonography (ESG) scoring and strain ratio in patients who had atypia of undetermined significance (AUS) cytology and underwent surgery for thyroid nodules. MATERIALS AND METHODS: 250 patients were included in this study. They had at least one nodule in thyroid USG, underwent USG-guided FNAC according to the current guidelines and had AUS cytology according to the Bethesda system. Both elastosonographic color scoring and strain index were evaluated. RESULTS: A total of 270 nodules in 250 patients were evaluated. Histopathologically, 81 (30 %) nodules were malignant and 189 (70 %) were benign. According to the ESG, 10 (3.7 %) nodules were assigned a score of 1, while 13 (4.8 %) nodules were assigned a score of 5. All of the nodules with an ESG score of 1 were histopathologically benign and 92.3 % of the patients with ESG score 5 were in the malignant group. Median SI in the benign histopathologic group was significantly lower compared to malignant group [(2.58 (IQR = 2.35) vs. 14.54 (IQR = 10.71)]. The optimal SI cut-off value to distinguish between the benign and malignant nodules was 6.66, with a sensitivity of 98.77 % and specificity of 96.30 %. CONCLUSION: Our study is one of the first studies evaluating the role of SI for discriminating malignant and benign nodules with AUS cytology. Malignant nodules had a significantly higher stiffness compared to benign ones and SI had high sensitivity, specificity, positive predictive value, negative predictive value and accuracy for these nodules. We think SI may be helpful for the presurgical selection of nodules with AUS cytology. PubMed-ID: 24497211 http://dx.doi.org/10.1007/s40618-013-0005-1

Follicular Nodules (Thy3) of the Thyroid: Is Total Thyroidectomy the Best Option? BMC Surg, 14:12. Calo PG, Medas F, Santa CR, Podda F, Erdas E, Pisano G, Nicolosi A. 2014. BACKGROUND: Identification of the best management strategy for nodules with Thy3 cytology presents particular problems for clinicians. This study investigates the ability of clinical, cytological and sonographic data to predict malignancy in indeterminate nodules with the scope of determining the need for total thyroidectomy in these patients. METHODS: The study population consisted of 249 cases presenting indeterminate nodules (Thy3): 198 females (79.5%) and 51 males (20.5%) with a mean age of 52.43 +/- 13.68 years. All patients underwent total thyroidectomy. RESULTS: Malignancy was diagnosed in 87/249 patients (34.9%); thyroiditis co-

ESES Review of Recently Published Literature 2014-1 Page 19 of 121 existed in 119/249 cases (47.79%) and was associated with cancer in 40 cases (40/87; 45.98%). Of the sonographic characteristics, only echogenicity and the presence of irregular margins were identified as being statistically significant predictors of malignancy. 52/162 benign lesions (32.1%) and 54/87 malignant were hypoechoic (62.07%); irregular margins were present in 13/162 benign lesions (8.02%), and in 60/87 malignant lesions (68.97%). None of the clinical or cytological features, on the other hand, including age, gender, nodule size, the presence of microcalcifications or type 3 vascularization, were significantly associated with malignancy. CONCLUSIONS: The rate of malignancy in cytologically indeterminate lesions was high in the present study sample compared to other reported rates, and in a significant number of cases Hashimoto's thyroiditis was also detected. Thus, considering the fact that clinical and cytological features were found to be inaccurate predictors of malignancy, it is our opinion that surgery should always be recommended. Moreover, total thyroidectomy is advisable, being the most suitable procedure in cases of multiple lesions, hyperplastic nodular goiter, or thyroiditis; the high incidence of malignancy and the unreliability of intraoperative frozen section examination also support this preference for total over hemi-thyroidectomy. PubMed-ID: 24597765 http://dx.doi.org/10.1186/1471-2482-14-12

Oral Liquid Levothyroxine Treatment at Breakfast: a Mistake? Eur J Endocrinol, 170(1):95-9. Cappelli C, Pirola I, Gandossi E, Formenti A, Castellano M. 2014. OBJECTIVE: Taking levothyroxine (L-T(4)) with coffee or with water followed by coffee intake within a few minutes results in poor TSH response in many patients. T(4) is available in tablet form worldwide, but novel formulations in soft gel capsule or liquid form are now available. DESIGN: We fortuitously identified a euthyroid patient who wrongly consumed liquid L-T(4) with coffee at breakfast; after changing the time of consumption to 30 min before breakfast, no change in TSH, free T(4) (fT(4)), and free tri-iodothyronine (fT(3)) concentrations was observed. Once the first patient was identified, additional stable euthyroid patients who consumed liquid L- T(4) with coffee were identified. METHODS: Patients were recruited by searching our 'thyroid patients' database. All the patients on liquid L-T(4) treatment were contacted by phone to ask them whether they took L-T(4) at breakfast. We identified 54 patients who were submitted to TSH, fT(4), and fT(3) evaluation, with the indication that the same dosage of L-T(4) be consumed 30 min before breakfast. We determined their TSH, fT(4), and fT(3) concentrations after 3 and 6 months again. RESULTS: no significant difference in thyroid hormone concentrations was observed in patients when they consumed L-T(4) at breakfast or when they consumed it 30 min before breakfast for 3 and 6 months (TSH: 2.5+/-1.1 vs 2.5+/-1.1 and 2.4+/-1.1 mIU/l respectively, fT(4): 12.4+/-2.4 vs 12.5+/-2.4 and 12.3+/-2.1 pg/ml respectively, and fT(3): 3.4+/-0.6 vs 3.4+/-0.6 and 3.3+/-0.5 pg/ml respectively). CONCLUSION: Oral liquid L-T(4) formulations could diminish the problem of L-T(4) malabsorption caused by coffee when using traditional tablet formulations. PubMed-ID: 24123095 http://dx.doi.org/10.1530/EJE-13-0693

Comparison Between Preconsultation Ultrasonography and Office Surgeon-Performed Ultrasound in Patients With Thyroid Cancer. World J Surg, 38(3):622-7. Carneiro-Pla D, Amin S. 2014. BACKGROUND: Cervical ultrasonography (US) is mandatory before surgery for thyroid cancer and recommended for thyroid nodule evaluation. Therefore, most patients undergo thyroid ultrasound before surgical evaluation. Several US findings are critical for adequate surgical planning but they are often not mentioned on preconsultation US. The goal of this study is to compare the preconsultation US findings with surgeon-performed US (SUS) and describe the changes in management as a consequence of SUS findings in patients with thyroid cancer. METHODS: The charts of 194 consecutive patients with thyroid cancer (2007-2013) from a single institution were reviewed. Preconsultation US and SUS reports were available for 136 patients. Mention of nodes, local invasion, thyroid nodule features/location, and presence of intrathoracic extension was recorded and changes in preoperative and/or operative management based on SUS findings were described. RESULTS: From 136 patients with the diagnosis of thyroid cancer, SUS changed the management of 61 (45 %) patients by identifying preoperatively central and/or lateral node metastasis, indicating preoperative biopsy of suspicious thyroid lesions/nodes, and pointing out thyroid intrathoracic extension. When compared to SUS, the preconsultation US failed to mention node status in 101 (74 %) patients, suspicious nodule features in 60/111 (54 %) patients with suspicious lesions, bilateral thyroid lesions in 19/88 (22 %) patients with bilateral nodules, local invasion in 5/5 (100 %), and intrathoracic extension in 5/5 (100 %) cases. CONCLUSION: Surgeon- performed US changed the operative management of patients with thyroid cancer by demonstrating additional and distinct information compared to preconsultation US in almost half of the patients. Ultrasound is more

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Screening for Thyroid Cancer in Patients With Familial Adenomatous Polyposis. Ann Surg, Cetta F, Ugolini G, Martellucci J, Gotti G. 2014. PubMed-ID: 24394556 http://dx.doi.org/10.1097/SLA.0000000000000442

TSH Measurement Is Not an Appropriate Screening Test for Autonomous Functioning Thyroid Nodules: a Retrospective Study of 368 Patients. Eur J Endocrinol, 170(4):593-9. Chami R, Moreno-Reyes R, Corvilain B. 2014. OBJECTIVE: Based on the assumption that normal TSH concentration rules out the presence of autonomous functioning thyroid nodules (AFTNs), clinical guidelines on the management of thyroid nodules only recommend a thyroid scan if TSH concentration is subnormal. However, the proportion of AFTN presenting with a normal TSH is unknown. Our objective is therefore to determine the proportion of AFTNs with a normal TSH level to ascertain whether a normal TSH really rules out an AFTN. DESIGN: Retrospective study on 368 patients with an AFTN. METHODS: Thyroid scans with a diagnosis of AFTN were reviewed retrospectively by one of us (R Moreno-Reyes), blinded to the clinical data. The diagnosis of solitary AFTN was confirmed in 368 patients. Among them, we selected 217 patients based on the absence of another thyroid nodule >10 mm, the absence of medical conditions able to interfere with thyroid function, and the completeness of the data. RESULTS: The proportion of AFTNs with normal TSH was 49%. This proportion increased to 71% in patients for whom thyroid scan was performed in the workup of a thyroid nodule. CONCLUSIONS: Our data suggest that serum TSH is not an effective screening tool to diagnose AFTNs. Using 'TSH-only' screening, as recommended by the majority of guidelines, the diagnosis of AFTN would have been missed in 71% of our patients in the workup of a thyroid nodule. Thyroid scan remains the gold standard for detecting AFTN and should be considered before performing fine-needle aspiration cytology (FNAC), as the reliability of FNAC in an unsuspected AFTN remains unclear. PubMed-ID: 24451082 http://dx.doi.org/10.1530/EJE-13-1003

American Thyroid Association Statement on Optimal Surgical Management of Goiter. Thyroid, 24(2):181-9. Chen AY, Bernet VJ, Carty SE, Davies TF, Ganly I, Inabnet WB, III, Shaha AR. 2014. BACKGROUND: Goiter, or benign enlargement of the thyroid gland, can be asymptomatic or can cause compression of surrounding structures such as the esophagus and/or trachea. The options for medical treatment of euthyroid goiter are short-lived and are limited to thyroxine hormone suppression and radioactive iodine ablation. The objective of this statement article is to discuss optimal surgical management of goiter. METHODS: A task force was convened by the Surgical Affairs Committee of the American Thyroid Association and was tasked with writing of this article. RESULTS/CONCLUSIONS: Surgical management is recommended for goiters with compressive symptoms. Symptoms of dyspnea, orthopnea, and dysphagia are more commonly associated with thyromegaly, in particular, substernal goiters. Several studies have demonstrated improved breathing and swallowing outcomes after thyroidectomy. With careful preoperative testing and thoughtful consideration of the type of anesthesia, including the type of intubation, preparation for surgery can be optimized. In addition, planning the extent of surgery and postoperative care are necessary to achieve optimal results. Close collaboration of an experienced surgical and anesthesia team is essential for induction and reversal of anesthesia. In addition, this team must be cognizant of complications from massive goiter surgery such as bleeding, airway distress, recurrent laryngeal nerve injury, and transient hypoparathyroidism. With careful preparation and teamwork, successful thyroid surgery can be achieved. PubMed-ID: 24295043 http://dx.doi.org/10.1089/thy.2013.0291

Should Atypia of Undetermined Significance Be Subclassified to Better Estimate Risk of Thyroid Cancer? Am J Surg, 207(3):331-6. Chen JC, Pace SC, Khiyami A, McHenry CR. 2014. BACKGROUND: Atypia or follicular lesion of undetermined significance (AUS) is a cytologic category of thyroid aspirates with a wide range of reported malignancy. We aimed to determine whether specific cytologic features

ESES Review of Recently Published Literature 2014-1 Page 21 of 121 are associated with different rates of thyroid malignancy. METHODS: All thyroid fine needle aspiration biopsies with AUS from 2010 to 2012 were reanalyzed. Cytologic features were correlated with final pathology. Cytopathologists were blinded to the original cytologic interpretation and final diagnosis. RESULTS: Seventy-six patients had AUS; 39 (54%) underwent surgery with a malignancy rate of 18%. Specimens with moderate or large amount of thin colloid and absent or few nuclear inclusions had a >88% rate of benign disease. More than rare nuclear inclusions or grooves were associated with a higher rate of cancer (75% vs 9%, P = .005; 45% vs 7%, P = .003). CONCLUSIONS: Patients with AUS and more than rare nuclear inclusions or grooves are at higher risk for cancer and should forego repeat fine needle aspiration biopsy and undergo thyroidectomy. PubMed-ID: 24581759 http://dx.doi.org/10.1016/j.amjsurg.2013.09.022

Does Extracapsular Extension Impact the Prognosis of Papillary Thyroid Microcarcinoma? Ann Surg Oncol, 21(5):1659-64. Chereau N, Buffet C, Tresallet C, Tissier F, Golmard JL, Leenhardt L, Menegaux F. 2014. BACKGROUND: Extracapsular (EC) extension is a pejorative factor in papillary thyroid carcinoma (PTC). However, the impact of EC extension in microcarcinoma (micro-pT3) remains controversial, and all pT3 patients are currently considered to be at high risk of recurrence. OBJECTIVE: This study sought to determine the risk of recurrence in patients with micro-pT3 and to compare their outcomes with other pT3 (macro-pT3) and low-risk patients. PATIENTS AND METHODS: All consecutive patients who received surgery for PTC in our department from January 1978 to December 2011 were included in this study. We compared three patient groups: micro-pT3 (

Functional Regeneration of Recurrent Laryngeal Nerve Injury During Thyroid Surgery Using an Asymmetrically Porous Nerve Guide Conduit in an Animal Model. Thyroid, 24(1):52-9. Choi JS, Oh SH, An HY, Kim YM, Lee JH, Lim JY. 2014. BACKGROUND: Vocal cord paralysis (VCP) caused by recurrent laryngeal nerve (RLN) damage during thyroidectomy commonly results in serious medico-legal problems. The purpose of this study was to evaluate the usefulness of an asymmetrically porous polycaprolactone (PCL)/Pluronic F127 nerve guide conduit (NGC) for functional regeneration in a RLN injury animal model. METHODS: A biodegradable, asymmetrically porous PCL/F127 NGC with selective permeability was fabricated for use in this study. A 10-mm segment of left RLN was resected in 28 New Zealand white rabbits, and then an asymmetrically porous NGC or a nonporous silicone tube was interposed between both stumps and securely fixed. Vocal cord mobility was endoscopically evaluated at one, four, and eight weeks postoperatively. Nerve growth through NGCs was assessed by toluidine blue staining, and thyroarytenoid (TA) muscle atrophy was evaluated by hematoxylin and eosin staining. Immunohistochemical stainings for acetylcholinesterase (AchE), anti-neurofilament (NF), and anti-S100 protein were also conducted, and transmission electron microscopy (TEM) was used to evaluate functional nerve regeneration. RESULTS: At eight weeks postoperatively, endoscopic evaluations showed significantly better recovery from VCP in the asymmetrically porous PCL/F127 NGC group (6 of 10 rabbits) than in the silicone tube group (1 of 10 rabbits). Continued nerve growth on the damaged nerve endings was observed with time in the asymmetrically porous PCL/F127 NGC-interposed RLNs. TA muscle dimensions and AchE expressions in TA muscle were significantly greater in the asymmetrically porous PCL/F127 NGC group than in the silicone tube group. Furthermore, immunohistochemical staining revealed the expression of NF and S100 protein in the regenerated nerves in the asymmetrically porous PCL/F127 NGC group at eight weeks postoperatively, and at this time, TEM imaging showed myelinated axons in the regenerated RLNs. CONCLUSION: The study shows that asymmetrically porous PCL/F127 NGC provides a favorable environment for RLN regeneration and that it has therapeutic potential for the regeneration of RLN damage.

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PubMed-ID: 24015805 http://dx.doi.org/10.1089/thy.2013.0338

Use of Spiral Computed Tomography Volumetry for Determining the Operative Approach in Patients With Graves' Disease. World J Surg, 38(3):639-44. Choi JY, Lee KE, Koo dH, Kim KH, Kim E, Bae DS, Jung SE, Youn YK. 2014. BACKGROUND: The purposes of the present study were to assess (1) the correlation between the weight of the postoperative thyroid specimen and the spiral computed tomography (CT) volumetry results of the thyroid gland in patients with Graves' disease, and (2) the utility of CT volumetry for determining the operative approach. METHODS: From 2009 to 2010, a total of 56 patients with Graves' disease underwent total or subtotal thyroidectomy. An enhanced spiral CT was taken in all patients prior to the operation. From 2.5 mm-thick slices of the thyroid gland, the surface area was calculated to measure the volume of the thyroid gland. The glandular volume was compared to the weight of the postoperative thyroid specimen. RESULTS: A total of 42 and 14 patients underwent total and subtotal thyroidectomy, respectively. The mean weight of the postoperative thyroid specimen was 43.9 +/- 33.4 g, and the mean volume obtained by CT volumetry was 44.2 +/- 32.8 mL. A good correlation was observed between the weight of the postoperative thyroid specimen and the volume calculated by CT (r = 0.98, p < 0.001). When 100 mL was set as the higher cut-off value of the thyroid volume for minimally invasive thyroid surgery, the estimated blood loss showed a significant difference between the >100 mL and the

(131)I SPECT/CT Demonstrated Ovarian Endometrioma. Clin Nucl Med, 39(2):193-5. Chuang TL, Hsu CS, Wang YF. 2014. A 44-year-old woman had a history of papillary thyroid carcinoma and underwent total thyroidectomy and I ablation therapy. During the follow-up, 2-mCi I cancer workup showed an unusual shape of uptake in the pelvic region. Hybrid SPECT/CT revealed uptake posterior to the uterus, where sonography showed an 85.4-mm right ovarian endometrioma just corresponding to the location. Laparoscopic salpingo-oophorectomy showed right ovarian endometrioma (7 cm) and left ovarian cyst (4 cm). Pathologic findings showed bilateral endometriosis. After that survey, follow-up I cancer workup showed left supraclavicular, pretracheal, and right hilar metastatic lymphadenopathy with pulmonary metastasis, but no pelvic uptake was noted. PubMed-ID: 24300362 http://dx.doi.org/10.1097/RLU.0000000000000306

Extrathyroidal Extension Predicts Extranodal Extension in Patients With Positive Lymph Nodes: An Important Association That May Affect Clinical Management. Thyroid, Clain JB, Scherl S, Dos RL, Turk A, Wenig BM, Mehra S, Karle WE, Urken ML. 2014. Background: While there is consensus that significant extrathyroidal extension (ETE) (T4) should upstage a patient with well-differentiated thyroid cancer, the importance of minimal ETE (T3) remains controversial. Additionally, the importance of nodal metastases on prognosis has come under scrutiny. Recent publications highlight the importance of size, number of positive nodes, and, in particular, the presence of extranodal extension (ENE) as measures of disease aggressiveness. In this study, we examined whether ETE is a predictor of ENE. Methods: A retrospective review was conducted from January 2004 to March 2013. All node-positive patients who underwent total or completion thyroidectomy were included. Histologic features defined by the College of American Pathologists (CAP) protocol for thyroid carcinoma were recorded. Results: A total of 193 patients qualified for review. Patients who were found to have ETE were 12 times more likely to have lymph nodes in the primary setting with ENE than patients with intrathyroidal primary tumors (p<0.000). After exclusion of all T4 cases (n=6), patients with minimal ETE were 13 times more likely to have ENE than those with no ETE (p<0.000). Twenty percent of microcarcinomas with ETE demonstrated ENE. Conclusion: We have found that the biology of the primary tumor is conferred to the lymph node in that the presence of ETE leads to a significantly higher incidence of ENE. Awareness of this relationship should be accounted for in the management of primary and recurrent lymph nodes. This study shows that minimal ETE is a significant predictor of ENE.

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Although long-term survival and recurrence follow-up is not available for the majority of patients in this series, the presence of ENE as a surrogate for more aggressive disease biology and its strong association with minimal ETE supports the upstaging of patients with minimal ETE. PubMed-ID: 24443878 http://dx.doi.org/10.1089/thy.2013.0557

A Survey of Preferences Regarding Surgical Approach to Thyroid Surgery. World J Surg, 38(3):696-703. Coorough NE, Schneider DF, Rosen MW, Sippel RS, Chen H, Schwarze ML, Mazeh H. 2014. BACKGROUND: Transaxillary thyroidectomy (TAT) has gained popularity in East Asian countries; however, to date there have been no attempts to evaluate the preferences regarding TAT in the US population. The aim of this study is to assess the preferences and considerations associated with TAT in an American cohort. METHODS: Self-administered surveys were distributed to 966 adults at various locations in a single state. Questions assessed preferences for the surgical approach, acceptable risks and extra costs, and willingness to pursue TAT despite reduced cancer treatment efficacy. RESULTS: The response rate was 84 %, with a mean age of 40 +/- 17 years. The majority of respondents were female. Of the respondents, 82 % preferred TAT to a cervical thyroidectomy (CerT), all risks being equal; 51 % of the respondents were willing to accept a 4 % complication rate with TAT, and 16 % stated they would agree to pay up to an additional $US5,000 for the TAT approach. When presented with thyroid cancer, 20 % of all respondents still preferred TAT, even if it would not cure their disease. Patients preferring TAT over CerT were younger, female, more willing to accept complications and spend additional money, and, most significantly, preferred the TAT approach, even if it was less likely to cure their cancer. CONCLUSIONS: Although this survey presents a hypothetical question for people who do not have thyroid disease, the majority of respondents preferred TAT over CerT. Furthermore, a substantial number were willing to accept higher complication rates and increased costs for TAT. PubMed-ID: 24366272 http://dx.doi.org/10.1007/s00268-013-2405-y

Immunohistochemistry for BRAF(V600E) Antibody VE1 Performed in Core Needle Biopsy Samples Identifies Mutated Papillary Thyroid Cancers. Horm Metab Res, 46(5):370-4. Crescenzi A, Guidobaldi L, Nasrollah N, Taccogna S, Cicciarella Modica DD, Turrini L, Nigri G, Romanelli F, Valabrega S, Giovanella L, Onetti MA, Trimboli P. 2014. BRAF(V600E) is the most frequent genetic mutation in papillary thyroid cancer (PTC) and has been reported as an independent predictor of poor prognosis of these patients. Current guidelines do not recommend the use of BRAF(V600E) mutational analysis on cytologic specimens from fine needle aspiration due to several reasons. Recently, immunohistochemistry using VE1, a mouse anti-human BRAF(V600E) antibody, has been reported as a highly reliable technique in detecting BRAF-mutated thyroid and nonthyroid cancers. The aim of this study was to test the reliability of VE1 immunohistochemistry on microhistologic samples from core needle biopsy (CNB) in identifying BRAF-mutated PTC. A series of 30 nodules (size ranging from 7 to 22 mm) from 30 patients who underwent surgery following CNB were included in the study. All these lesions had had inconclusive cytology. In all cases, both VE1 and BRAF(V600E) genotypes were evaluated. After surgery, final histology demonstrated 21 cancers and 9 benign lesions. CNB correctly diagnosed 20/20 PTC and 5/5 adenomatous nodules. One follicular thyroid cancer and 4 benign lesions were assessed at CNB as uncertain follicular neoplasm. VE1 immunohistochemistry revealed 8 mutated PTC and 22 negative cases. A 100% agreement was found when positive and negative VE1 results were compared with BRAF mutational status. These data are the first demonstration that VE1 immunohistochemistry performed on thyroid CNB samples perfectly matches with genetic analysis of BRAF status. Thus, VE1 antibody can be used on thyroid microhistologic specimens to detect BRAF(V600E)-mutated PTC before surgery. PubMed-ID: 24570209 http://dx.doi.org/10.1055/s-0034-1368700

Encapsulation Status of Papillary Thyroid Microcarcinomas Is Associated With the Risk of Lymph Node Metastases and Tumor Multifocality. Horm Metab Res, 46(2):138-44. Cupisti K, Lehwald N, Anlauf M, Riemer J, Werner TA, Krieg A, Witte J, Chanab A, Baldus SE, Krausch M, Raffel A, Herdter C, Schott M, Knoefel WT. 2014. The management of papillary microcarcinoma (PMC) of the thyroid is controversial, especially after partial thyroid resection for benign thyroid disease. In order to detect prognostic factors for PMC, we analyzed 116 patients with PMC for encapsulation status and lymph node metastases. Between 10/1992 and 12/2010, 116

ESES Review of Recently Published Literature 2014-1 Page 24 of 121 patients with PMC have been operated in our department (87 females, 29 males, median age 49 years). Eighty per cent of PMCs were diagnosed postoperatively. Seventy-six patients (66%) received a more extended resection with either thyroidectomy, near total thyroidectomy, or Dunhill operation either primarily or after completion operation, whereas 40 patients (34%) had only partial resection. Fifty patients (43%) received radioiodine (RIA) ablation. Lymph node metastases were found in 21 patients (18%). Univariate analysis showed four risk factors to be significantly associated with the risk of lymph node metastasis (p<0.05): male gender, younger age, age group<50 years and nonencapsulation of the tumor. Multivariate analysis demonstrated statistical significance for gender and tumor capsulation status. The tumor capsulation status also correlated with tumor multifocality. Our data show that the risk of lymph node metastases is significantly higher in partially or nonencapsulated PMC than in encapsulated specimens. We therefore suggest that the WHO classification should be extended to a compulsory notification of the encapsulation status in PMC. PubMed-ID: 24356791 http://dx.doi.org/10.1055/s-0033-1361158

Superior Laryngeal Nerve Quantitative Intraoperative Monitoring Is Possible in All Thyroid Surgeries. Laryngoscope, 124(4):1035-41. Darr EA, Tufano RP, Ozdemir S, Kamani D, Hurwitz S, Randolph G. 2014. OBJECTIVES/HYPOTHESIS: To report normative electromyography (EMG) data on the external branch of the superior laryngeal nerve (EBSLN) and to compare this to analogous data of the recurrent laryngeal nerve (RLN) and vagus nerve (VN) during intraoperative neural monitoring (IONM) using both the standard monopolar stimulator probe and a novel bipolar stimulator probe. STUDY DESIGN: Prospective multiple tertiary care center study. METHOD: A prospective study of EBSLN, RLN and VN EMG data in 22 thyroid surgeries was performed. Subjects with preoperative vocal fold paralysis were excluded. Postoperative laryngoscopy was normal in all subjects. Normative EMG data were acquired using both a standard monopolar and a novel bipolar stimulator probe, as well as a novel endotracheal tube. Cricothyroid muscle (CTM) twitch response during EBSLN stimulation was analyzed. RESULTS: In 100% of cases, EBSLN was identified and quantifiable EMG response was observed. EMG amplitude did not change despite extensive nerve dissection and multiple nerve stimulations. EBSLN amplitude was similar for left and right sides for patients under age 50 and aged 50 or older, for both genders, and with monopolar and bipolar stimulators. CONCLUSIONS: Intraoperative neural monitoring may be used to safely assist in EBSLN identification during thyroid surgery in 100% of patients. A novel endotracheal tube allows for quantifiable EBSLN EMG activity in 100% of cases. Monopolar and bipolar stimulator probes produce similar EMG data. LEVEL OF EVIDENCE: 4. PubMed-ID: 24115215 http://dx.doi.org/10.1002/lary.24446

Is Intraoperative Calcitonin Monitoring Useful to Modulate the Extension of Neck Dissection in Patients With Medullary Thyroid Carcinoma? World J Surg, 38(3):568-75. De CC, Raffaelli M, Milano V, Carrozza C, Zuppi C, Bellantone R, Lombardi CP. 2014. BACKGROUND: The extension of the compartment-oriented neck dissection at primary surgery in medullary thyroid carcinoma (MTC) is controversial. Because a <50 % decrease in intraoperative calcitonin levels (IO-CT) after total thyroidectomy plus central neck dissection (TT-CND) has been associated with residual disease, IO- CT monitoring has been proposed to predict the completeness of surgery. The goal of the present prospective study was to verify the accuracy of IO-CT monitoring. METHODS: All patients scheduled for primary surgery for suspected or proven MTC between November 2010 and January 2013 were included. Calcitonin was measured pre-incision (basal level), after tumor manipulation, at the time TT-CND was accomplished (ablation level), 10 and 30 min after ablation. A decrease >50 % with respect to the highest IO-CT level 30 min after ablation was considered predictive of cure. RESULTS: Twenty-six patients were included, and IO-CT monitoring identified 18 of 23 cured patients (true negative results) and 2 of 3 patients with persistent disease (true positive result). In 5 patients with normal basal and stimulated postoperative calcitonin levels, a decrease <50 % was observed (false positive results). In one of three patients with persistent disease a >50 % decrease in IO-CT was observed (false negative results). Specificity, sensitivity, and accuracy of IO-CT were 78.2, 66.6, and 76.9 %, respectively. CONCLUSIONS: Intraoperative calcitonin monitoring is not highly accurate in predicting the completeness of surgical resection. In the present series, relying on IO-CT would result in limited resection in about one third of the patients with residual neck disease and in unnecessary lateral neck dissection in about 20 % of the cured patients. PubMed-ID: 24253105 http://dx.doi.org/10.1007/s00268-013-2328-7

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Schwannoma Mimicking a Neoplastic Thyroid Nodule. Updates Surg, 66(1):85-7. De SB, Del RP, Sianesi M. 2014. Schwannoma is a rare benign tumor of nerve fibers that originates from neuronal sheath cells; it is frequently located extramedullary and about 25-45 % of this type of neoplastic lesion is localized in the head and in the neck. Primary schwannoma of the thyroid gland is very uncommon. We report the case of a 50-year-old female patient affected by schwannoma of the thyroid gland underwent total thyroidectomy for nodule of the left lobe suspicious for neoplasm, without complications. PubMed-ID: 23269639 http://dx.doi.org/10.1007/s13304-012-0189-5

Potential Effects of Molecular Testing of Indeterminate Thyroid Nodule Fine Needle Aspiration Biopsy on Thyroidectomy Volume. World J Surg, 38(3):634-8. Dedhia PH, Rubio GA, Cohen MS, Miller BS, Gauger PG, Hughes DT. 2014. BACKGROUND: Increasing utilization of genetic expression profiling (GEP) for thyroid nodules with indeterminate fine needle aspiration (FNA) results will potentially decrease the number of patients requiring diagnostic thyroidectomy. This study sought to determine the potential effects of GEP for indeterminate thyroid FNA results on thyroidectomy volume. METHODS: A retrospective review of thyroidectomy procedures performed over 1 year at the University of Michigan in the endocrine surgery division evaluated the indications for thyroidectomy, FNA Bethesda classification, and final surgical pathology to determine how application of GEP on indeterminate FNA results would affect decision for surgery and subsequent thyroidectomy volume. RESULTS: During the study period, 358 thyroidectomies were performed. The indication for procedure included: FNA findings, n = 122; symptomatic multinodular goiter, n = 85; nodule >4 cm, n = 30; Graves', n = 26; other, n = 95. FNA was performed in 231 patients. Bethesda classification included: benign, n = 69; malignant, n = 55; follicular lesion of undetermined significance, n = 59; follicular neoplasm, n = 20; suspicious for malignancy, n = 16; nondiagnostic, n = 12. If standard GEP was performed for all indeterminate FNA results, it would have influenced the decision for surgery in 68 (19 %) patients. Assuming 38 % of indeterminate FNA specimens will have benign results on genetic profiling, 27 patients would not have undergone thyroidectomy, translating into a 7.2 % decrease in overall thyroidectomy volume over a year. CONCLUSIONS: In an academic endocrine surgery program, the most common indication for thyroidectomy is an FNA result; however, standard application of GEP for all indeterminate thyroid FNAs would result in a minimal reduction in overall thyroidectomy volume. PubMed-ID: 24435929 http://dx.doi.org/10.1007/s00268-013-2430-x

Follicular Thyroid Carcinoma Metastasis to the Internal Jugular Vein Demonstrated by 131I SPECT/CT. Clin Nucl Med, 39(4):e270-e273. do Nascimento BB, de Sa Camargo Etchebehere EC, Montalli Assumpcao LV, Tincani AJ, de Oliveira SA, Baracat J, Engelbrecht Zantut-Wittmann D, Dario RC. 2014. Cervical uptake detected by 131I whole body scintigraphy (131I-WBS) may be due to thyroid remnants or loco- regional metastases. We describe a patient with follicular carcinoma submitted to total thyroidectomy. 131I-WBS showed left cervical linear uptake and focal areas of uptake in the abdomen and pelvis. SPECT/CT images demonstrated a potential thrombus in the left jugular vein (confirmed by doppler neck ultrasound and MRI) as well as bone metastases. The patient was submitted to thrombectomy and histopathology confirmed metastasis of follicular carcinoma. PubMed-ID: 24566419 http://dx.doi.org/10.1097/RLU.0b013e3182952959

Hämostatische Instrumente Bei Schilddrüsenoperationen. Chirurg, 85(2):151. Dralle H. 2014. Hintergrund und Fragestellung Nicht nur bei der subtotalen, sondern auch bei der in den letzten Jahren zunehmend bevorzugten totalen Lappenresektionen kommt der exakten Blutstillung seit Kochers Zeiten eine zentrale Bedeutung bei der Rekurrens und Nebenschilddrüsen schonenden Schilddrüsenoperation zu. Viele Chirurgen verwenden heute anstelle der althergebrachten Ligatur („Clamp-and-tie"-Technik) energiebasierte („energy-based") hämostatische Instrumente zur Resektion und Blutstillung kleinerer Gefäße, aber auch zur Versorgung der Polgefäße. Die vorliegende Untersuchung hatte zum Ziel, im Rahmen einer Metaanalyse die Vor- bzw. Nachteile von 3 Blutstillungsverfahren hinsichtlich der wichtigsten postoperativen Outcome-Parameter zu untersuchen:

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• konventionelle Ligatur, • Ultraschalldissektion (Harmonic) und • Ligasure. Methoden Insgesamt 35 von 2000 bis 2012 publizierte prospektiv-randomisierte kontrollierte (RCT-)Studien mit Daten zu früh-postoperativen Outcome-Parametern wurden aus 96 in Embase, Medline, Cochrane Library und PubMed gelisteten RCT-Studien ausgewählt. Die untersuchten Outcome-Parameter waren: Operationszeit, Blutverlust, Rekurrensparese, Hypoparathyreoidismus, Serombildung, Drainagemenge, Krankenhausverweildauer und Kosten. Zur Kalkulation des Einflusses des Publikationsjahres und der Qualität der RCT-Studie wurden verschiedene statistische Methoden eingesetzt. Die RCT-Studien kamen aus 16 Ländern, Italien rangierte mit 13 Studien an erster Stelle, gefolgt von Deutschland und Türkei (je 3), Belgien, Griechenland und Frankreich (je 2). Ergebnisse Eine paarweise Analyse der Outcome-Parameter war in folgender Studienanzahl möglich: 35 zur Operationszeit, je 27 zu Hypoparathyreoidismus und Serombildung, 22 zur Rekurrensparese, je 15 zu Drainagemenge und Krankenhausverweildauer, 11 zu Blutverlust und 6 zu Kosten. Aus dem umfangreichen Datenmaterial lassen sich folgende Hauptergebnisse hinsichtlich der drei untersuchten Blutstillungsverfahren extrahieren: • Die Ultraschallkoagulation zeigte das beste Profil hinsichtlich der Outcome-Parameter Operationszeit, Hypoparathyreoidismus, Blutverlust, Drainageverluste und Kosten; nachrangig waren Ligasure und konventionelle Ligatur. • Im Gegensatz dazu wies die Ultraschallkoagulation das höchste Risiko für eine postoperative Rekurrensparese auf, die konventionelle Ligatur das diesbezüglich niedrigste Risiko. • Bezüglich Krankenhausverweildauer und Serombildung war erneut die Ultraschallkoagulation am besten, gefolgt von konventioneller Ligatur und zuletzt Ligasure. Die Autoren schlussfolgern, dass mit Ausnahme des wichtigen Outcome-Parameters Rekurrensparese die Ultraschallkoagulation das beste Blutstillungsprofil aufweist. Diskussion Die vorliegende Metaanalyse ist die erste und bislang einzige ihrer Art, die den Versuch unternimmt, wesentliche postoperative Outcome-Parameter der drei aktuell praktizierten Blutstillungstechniken in der Schilddrüsenchirurgie zu untersuchen. Unklar ist, wie einige der analysierten Outcome-Parameter definiert wurden (z. B. Rekurrensparese: transient oder permanent, pro operierter Seite oder pro operierten Patienten, Studien mit lückenloser postoperativer Laryngoskopie oder Laryngoskopie nur bei Symptomatik; Hypoparathyreoidismus nur nach totaler Thyreoidektomie oder auch nach unilateraler oder bilateral-subtotaler Resektion). Das schränkt den Wert der Metaanalyse nicht unerheblich ein. Fazit Energiebasierte Blutstillungsverfahren sind hilfreich und potenziell operationszeitverkürzend, ob sie die Nachblutungsrate vermindern oder geringere chirurgische Erfahrungen kompensieren können, bleibt unklar. Hinsichtlich der postoperativen Rekurrenspareserate ist die konventionelle Ligatur den neuen Blutstillungsverfahren derzeit noch überlegen. http://link.springer.com/article/10.1007%2Fs00104-013-2691-9 http://dx.doi.org/10.1007/s00104-013-2691-9

[Surgery for Benign Goiter in Germany: Fewer Operations, Changed Resectional Strategy, Fewer Complications] Strumachirurgie in Deutschland: Weniger Operationen, Geanderte Resektionsstrategien, Weniger Komplikationen. Chirurg, 85(3):236-45. Dralle H, Stang A, Sekulla C, Rusner C, Lorenz K, Machens A. 2014. BACKGROUND: The increase of certain operations in the wake of the introduction of the German Diagnosis- Related Groups (G-DRG) system rekindled debate on the risk-benefit profile of what is widely being perceived as a too high number of thyroidectomies for benign goiter in Germany. MATERIAL AND METHODS: The numbers of thyroidectomy for benign goiter from 2005-2011 were obtained from the Federal Bureau of Statistics ("Statistisches Bundesamt"). For the purpose of the study, the following operation and procedure key (OPS) codes were selected: hemithyroidectomy (OPS code 5-061); partial thyroid resection (OPS code 5-062); total thyroidectomy (OPS code 5-063); and thyroid surgeries via sternotomy (OPS code 5-064). The rates of permanent hypoparathyroidism and vocal cord palsy were calculated based on two prospective multicenter evaluation studies conducted in 1998-2001 (PETS 1) and 2010-2013 (PETS 2) in Germany. RESULTS: Between 2005 and 2011, the number of thyroidectomies for benign thyroid goiter decreased by 8 %, and the age-standardized surgery rate decreased by 6 % in men (2005: 599 per 1 million; 2011: 565 per 1 million) and 11 % in women (2005: 1641 per 1 million; 2011: 1463 per 1 million). At the same time, the rates of partial and

ESES Review of Recently Published Literature 2014-1 Page 27 of 121 subtotal thyroidectomy decreased by 59 % in men and 64 % in women, whereas the rates of hemithyroidectomy and total thyroidectomy increased by 65 % (113 %) in men and 42 % (97 %) in women. Despite a greater proportion of thyroidectomies over time, the approximated rates for postoperative hypoparathyroidism were reduced from 2.98 to 0.83 % and for postoperative vocal cord palsy from 1.06 to 0.86 %. Irrespective of that decline, either complication was more frequent after total than after subtotal thyroidectomy. CONCLUSION: The total number of thyroid surgeries due to benign goiter has decreased substantially in Germany from 2005 through 2011. Despite changes in the resectional strategy with an increase in the total number thyroidectomies and a decrease of subtotal resections, the rates for postoperative hypoparathyroidism and vocal cord palsy have decreased. The complication rates for total thyroidectomy, however, are still higher compared to subtotal resection. An individualized risk-oriented surgical approach is warranted. PubMed-ID: 24595482 http://dx.doi.org/10.1007/s00104-013-2705-7

[Size of Postoperative Thyroid Remnant As Oncological Quality Parameter] Grosse Des Postoperativ Nuklearmedizinischen Schilddrusenrestes Als Onkologischer Qualitatsparameter. Chirurg, 85(3):256. Dralle H. 2014. PubMed-ID: 24496752 http://dx.doi.org/10.1007/s00104-014-2706-1

Pathological Characteristics and Clinical Perspectives of Papillary Thyroid Cancer: Study of 714 Patients. Eur Arch Otorhinolaryngol, 271(1):141-8. Dzepina D, Zurak K, Petric V, Cupic H. 2014. Papillary thyroid cancer belongs to most commonly diagnosed well-differentiated malignant tumor of the thyroid gland, with only minority of cases being more aggressive, recurring locoregionally and developing distant metastatic foci. The aim of this study was to determine the clinical relationship between parameters of age, gender, size of primary tumor, intraglandular dissemination and regional metastatic spread and evaluate the importance of each parameter; analyze other major aggressive factors (tumor border, thyroid capsule invasion, perivascular, perilymphatic spread) on prevalence and extent of intraglandular dissemination and relation to metastatic spread in neck. This study is a retrospective analysis of clinical and pathological data from 714 patients with papillary thyroid cancer, presented and operated at the Department of ENT/Head and Neck surgery, Sisters of Charity University Hospital, Zagreb, in the period from 1980 to 2008. All patients were operated upon with total thyroidectomy and some type of neck lymphonode dissection (paratracheal or lateral). In results, we found 46.9% tumors were aggressive; 34.7% tumors were multicentric, with foci in the contralateral lobe nearly twice as often as in the ipsilateral lobe; 27.8% were regionally metastatic, with equal distribution between paratracheal and lateral regions. In conclusion, we revealed contralateral lobe multicentricity and male gender as independent risk factors for regional metastatic dissemination. Nodular goiter has been identified as a protective parameter. PubMed-ID: 23568042 http://dx.doi.org/10.1007/s00405-013-2472-6

Prophylactic Central Neck Dissection Increases the Cost of Thyroid Cancer Care. Ann Surg Oncol, 21(2):354-5. Elfenbein DM, Sippel RS. 2014. PubMed-ID: 24100961 http://dx.doi.org/10.1245/s10434-013-3301-2

Molecular Profiles of Papillary Thyroid Tumors Have Been Changing in the Last Decades: How Could We Explain It? J Clin Endocrinol Metab, 99(2):412-4. Elisei R. 2014. PubMed-ID: 24502514 http://dx.doi.org/10.1210/jc.2014-1130

Genome-Wide Methylation Patterns in Papillary Thyroid Cancer Are Distinct Based on Histological Subtype and Tumor Genotype. J Clin Endocrinol Metab, 99(2):E329-E337.

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Ellis RJ, Wang Y, Stevenson HS, Boufraqech M, Patel D, Nilubol N, Davis S, Edelman DC, Merino MJ, He M, Zhang L, Meltzer PS, Kebebew E. 2014. CONTEXT: Aberrant DNA methylation is known to be a major factor in oncogenesis and cancer progression, but effects of methylation in papillary thyroid cancer (PTC) are not well defined. OBJECTIVE: The objective of the study was to identify altered methylation patterns, which may be associated with PTC disease behavior. Design: This study was a genome-wide methylation analysis of PTC. SETTING: The study was conducted at the National Institutes of Health Clinical Center. PATIENTS: PTC tissue from 51 patients were analyzed and compared with normal thyroid tissue from seven patients. INTERVENTIONS: CpG methylation status was assessed using advanced genome-wide methylation bead chips. OUTCOME MEASURES: Altered methylation patterns in PTC were analyzed by stage, recurrence, histological subtype of tumor, and tumor genotype. RESULTS: PTC is globally hypomethylated compared with normal thyroid with 2837 differentially methylated CpG sites. The follicular variant of PTC demonstrated less differential methylation with only 569 differentially methylated CpG sites. Tumors with mutations in BRAF, RET/PTC, and RAS demonstrated a 3.6-fold increase in the number of differentially methylated sites compared with wild-type tumors. The differentially methylated genes were associated with oncological pathways including cellular movement, growth, and proliferation. CONCLUSION: PTC is epigenetically distinct from the follicular variant of PTC and by gene mutation status (BRAF, RET/PTC, and RAS). PubMed-ID: 24423287 http://dx.doi.org/10.1210/jc.2013-2749

Recurrent Laryngeal Nerve Palsy During Surgery for Benign Thyroid Diseases: Risk Factors and Outcome Analysis. Surgery, 155(3):522-8. Enomoto K, Uchino S, Watanabe S, Enomoto Y, Noguchi S. 2014. BACKGROUND: We investigated the risk factors for postoperative recurrent laryngeal nerve (RLN) palsy and related outcomes in patients with benign thyroid diseases. MATERIAL AND METHODS: From 2008 to 2010, 844 thyroidectomies for benign thyroid diseases (benign nodules in 447; Graves' disease in 377; huge goiter attributable to Hashimoto thyroiditis in 20) were performed at Noguchi Thyroid Clinic and Hospital Foundation. The otolaryngologists screened all patients for the presence or absence of RLN palsy by laryngoscope, both pre- and postoperatively. When RLN palsy was present, the patients were checked periodically by laryngoscopy without additional drug therapy until the recovery of vocal cord palsy or loss of contact. RESULTS: A total of 1,374 nerves were at risk during the thyroid surgery (bilateral risk in 530, unilateral risk in 314). No patient exhibited a bilateral RLN palsy. Unilateral postoperative RLN palsies were found in 45 patients (benign nodules in 25, Graves' disease in 19, and Hashimoto thyroiditis in 1). The RLN was involuntarily amputated in five patients during the operation. The incidence of RLN palsy was 5.3% per patient and 3.3% per nerve. The incidence of RLN palsy was greater in patients who underwent complete unilateral thyroid lobe resection compared with partial resection of the lobe (P = .04). The occurrence of RLN palsy was associated with the need for reoperation caused by postoperative bleeding and the reduced weight of the thyroid remnant in Graves' disease (P = .04 and P = .03, respectively). Among 40 patients with RLN palsy and excluding 5 amputated patients, the RLN palsy resolved in 34 patients (85%) within 12 months after the procedure. The remaining 6 patients (15%) were considered to have permanent RLN palsies. CONCLUSION: Complete resection of the thyroid lobe and reoperation for postoperative bleeding are the risk factors for postoperative RLN palsy in patients with benign thyroid nodules. In Graves' disease, smaller weight of the residual thyroid tissue contributes to the occurrence of RLN palsy. Most RLN palsies that do not require amputation of the nerve resolve spontaneously within 12 months after surgery. In this study, the palsy remained in 1.3% (11/844) of patients. PubMed-ID: 24468039 http://dx.doi.org/10.1016/j.surg.2013.11.005

The Effect of Extent of Surgery and Number of Lymph Node Metastases on Overall Survival in Patients With Medullary Thyroid Cancer. J Clin Endocrinol Metab, 99(2):448-54. Esfandiari NH, Hughes DT, Yin H, Banerjee M, Haymart MR. 2014. CONTEXT: Total thyroidectomy with central lymph node dissection is recommended in patients with medullary thyroid cancer (MTC). However, the relationship between disease severity and extent of resection on overall survival remains unknown. OBJECTIVE: The aim of the study was to identify the effect of surgery on overall survival in MTC patients. METHODS: Using data from 2968 patients with MTC diagnosed between 1998 and 2005 from the National Cancer Database, we determined the relationship between the number of cervical lymph node metastases, tumor size, distant metastases, and extent of surgery on overall survival in patients with MTC. RESULTS: Older patient age (5.69 [95% CI, 3.34-9.72]), larger tumor size (2.89 [95% CI, 2.14-3.90]), presence

ESES Review of Recently Published Literature 2014-1 Page 29 of 121 of distant metastases (5.68 [95% CI, 4.61-6.99]), and number of positive regional lymph nodes (for >/=16 lymph nodes, 3.40 [95% CI, 2.41-4.79]) were independently associated with decreased survival. Overall survival rate for patients with cervical lymph nodes resected and negative, cervical lymph nodes not resected, and 1-5, 6-10, 11-16, and >/=16 cervical lymph node metastases was 90, 76, 74, 61, 69, and 55%, respectively. There was no difference in survival based on surgical intervention in patients with tumor size 2.0 cm and no distant metastases, all surgical treatments resulted in a significant improvement in survival compared to no surgery (P < .001). In patients with distant metastases, only total thyroidectomy with regional lymph node resection resulted in a significant improvement in survival (P < .001). CONCLUSIONS: The number of lymph node metastases should be incorporated into MTC staging. The extent of surgery in patients with MTC should be tailored to tumor size and distant metastases. PubMed-ID: 24276457 http://dx.doi.org/10.1210/jc.2013-2942

Impact of Molecular Screening for Point Mutations and Rearrangements in Routine Air-Dried Fine-Needle Aspiration Samples of Thyroid Nodules. Thyroid, 24(2):305-13. Eszlinger M, Krogdahl A, Munz S, Rehfeld C, Precht Jensen EM, Ferraz C, Bosenberg E, Drieschner N, Scholz M, Hegedus L, Paschke R. 2014. BACKGROUND: The diagnostic limitations of thyroid fine-needle aspiration (FNA), such as the indeterminate category, can be partially overcome by molecular analyses. However, until now, rearrangements have only been detected in fresh FNA material and the number of follicular thyroid carcinomas (FTCs) was rather low in previous studies. We aimed at investigating the impact of point mutations and rearrangement detection in a set of routine air-dried FNA smears with a higher percentage of FTCs. METHODS: RNA and DNA was extracted from 310 FNAs (164 indeterminate, 57 malignant, 89 benign) and corresponding formalin-fixed paraffin-embedded tissue (156 follicular adenomas [FAs], 32 FTCs, 44 papillary thyroid carcinomas [PTCs], 9 follicular variant PTCs, and 69 goiters). PAX8/PPARG and RET/PTC rearrangements were detected by qPCR, BRAF and RAS mutations by high-resolution melting PCR and by pyrosequencing. RESULTS: Forty-seven mutations were detected in the FNAs: 22 BRAF, 13 NRAS, and 3 HRAS mutations, 8 PAX8/PPARG, and one RET/PTC-rearrangement. While the presence of a BRAF and RET/PTC mutation was associated with cancer in 100% of samples each, the presence of a RAS and PAX8/PPARG mutation was associated with cancer in only 12% and 50% of samples, respectively. In the indeterminate group 4 of 25 carcinomas were identified by molecular FNA screening, which increased the sensitivity from 67% (cytology alone) to 75% (cytology plus molecular screening). CONCLUSION: Molecular screening for point mutations and rearrangements is feasible in air-dried FNAs. Although the impact of detecting point mutations and rearrangements in FNAs has most likely been overestimated in previous studies, molecular FNA analyses improve presurgical diagnostics. The detection of BRAF mutations in FNA may improve the choice of surgery and postsurgical treatment. Further data are necessary to elucidate the true impact of detecting RAS and PAX8/PPARG mutations in FNAs. The inclusion of additional rare somatic mutations and miRNA markers might further improve the impact of molecular FNA diagnostics. PubMed-ID: 23837487 http://dx.doi.org/10.1089/thy.2013.0278

Predictive Factors of Contralateral Paratracheal Lymph Node Metastasis in Papillary Thyroid Cancer: Prospective Multicenter Study. Otolaryngol Head Neck Surg, 150(2):210-5. Eun YG, Lee YC, Kwon KH. 2014. OBJECTIVE: To analyze patterns of central lymph node (LN) metastasis to specific compartments in the neck and predictive factors of contralateral paratracheal LN metastasis in patients who underwent prophylactic bilateral central LN dissection for papillary thyroid cancer (PTC). STUDY DESIGN: Prospective study. SETTING: Multitertiary centers. SUBJECTS AND METHODS: One hundred forty consecutive patients underwent total thyroidectomy and prophylactic bilateral central LN dissection for unilateral PTC without evidence of central LN metastatic disease based on preoperative ultrasound imaging. The central LN compartment was divided into prelaryngeal, ipsilateral/contralateral paratracheal, and pretracheal regions. The patterns of central LN metastasis and clinicopathologic variables for predicting contralateral metastasis were analyzed. RESULTS: Fifty-one (36.4%) of 140 patients had nodal involvement in the central compartment. Twelve (23.5%) patients had ipsilateral paratracheal LN metastasis, 17 (33.3%) had ipsilateral paratracheal and pretracheal LN metastasis, 14 (27.5%) had bilateral paratracheal LN metastasis, 9 (17.6%) had pretracheal-only LN metastasis, and 8 (15.7%) had prelaryngeal LN metastasis. Ipsilateral paratracheal LN metastasis was found to independently predict contralateral paratracheal LN metastasis in patients without central LN metastatic disease. CONCLUSIONS: Contralateral paratracheal LN metastasis is associated with ipsilateral paratracheal LN

ESES Review of Recently Published Literature 2014-1 Page 30 of 121 metastasis. This information may help to determine the optimal extent of prophylactic central LN dissection in patients with PTC. PubMed-ID: 24367047 http://dx.doi.org/10.1177/0194599813514726

Central Regulation of Hypothalamic-Pituitary-Thyroid Axis Under Physiological and Pathophysiological Conditions. Endocr Rev, 35(2):159-94. Fekete C, Lechan RM. 2014. TRH is a tripeptide amide that functions as a neurotransmitter but also serves as a neurohormone that has a critical role in the central regulation of the hypothalamic-pituitary-thyroid axis. Hypophysiotropic TRH neurons involved in this neuroendocrine process are located in the hypothalamic paraventricular nucleus and secrete TRH into the pericapillary space of the external zone of the median eminence for conveyance to anterior pituitary thyrotrophs. Under basal conditions, the activity of hypophysiotropic TRH neurons is regulated by the negative feedback effects of thyroid hormone to ensure stable, circulating, thyroid hormone concentrations, a mechanism that involves complex interactions between hypophysiotropic TRH neurons and the vascular system, cerebrospinal fluid, and specialized glial cells called tanycytes. Hypophysiotropic TRH neurons also integrate other humoral and neuronal inputs that can alter the setpoint for negative feedback regulation by thyroid hormone. This mechanism facilitates adaptation of the organism to changing environmental conditions, including the shortage of food and a cold environment. The thyroid axis is also affected by other adverse conditions such as infection, but the central mechanisms mediating suppression of hypophysiotropic TRH may be pathophysiological. In this review, we discuss current knowledge about the mechanisms that contribute to the regulation of hypophysiotropic TRH neurons under physiological and pathophysiological conditions. PubMed-ID: 24423980 http://dx.doi.org/10.1210/er.2013-1087

Conservative Management of Thyroglobulin-Positive, Nonlocalizable Thyroid Carcinoma. Head Neck, 36(2):155-7. Frank RW, Middleton L, Stack BC, Jr., Spencer HJ, Riggs AT, Bodenner DL. 2014. BACKGROUND: The purpose of this study was to demonstrate a role for observation of patients with differentiated thyroid cancer (DTC) with persistent, nonlocalizable disease. METHODS: Our study was conducted on outpatients seen at our institution from 1999 to 2009 having total thyroidectomy, radioactive iodine (RAI) ablation, measurable serum thyroglobulin (Tg), and no evidence of disease on whole body or positron emission tomography (PET) scans. RESULTS: Nineteen patients in our study group aged 20 to 73 with an average follow-up of 5.5 years (range, 2-12 years); all were treated with postoperative RAI (99-210 mCi, average 119). Mean Tg ranged from 0.41 to 4.34. Tg levels remained stable or gradually decreased in all patients. CONCLUSION: After total thyroidectomy and RAI therapy, patients may present with mildly elevated Tg values without localizable disease. These patients may have additional RAI treatments based on the Tg elevation. However, our clinical experience has shown that many of these patients will have Tg levels that either achieve stability or decrease over time without further treatment. PubMed-ID: 23728951 http://dx.doi.org/10.1002/hed.23272

Efficacy of Thyroid Blockade on Thyroid Radioiodine Uptake in 123I-MIBG Imaging. J Nucl Med, 55(2):211-5. Friedman NC, Hassan A, Grady E, Matsuoka DT, Jacobson AF. 2014. Although iodinated radiopharmaceuticals usually contain a small quantity of unbound iodine, it is difficult to establish the degree to which thyroid activity on scintigraphic images reflects uptake of free radioiodine. The objective of the present study was to examine the effectiveness of thyroid blockade in subjects undergoing (123)I-meta-iodobenzylguanidine (mIBG) imaging and to estimate the relative contribution of bound and unbound radioiodine to imaging findings. METHODS: All subjects were participants in prospective trials of (123)I- mIBG cardiac imaging in which pretreatment with thyroid blockade was optional unless locally required. In a pilot project, 15 subjects (6 blocked) had thyroid uptake measured at 4 h using a probe system. Fifteen-minute (early) and 4-h (late) anterior planar chest images that included the thyroid region were visually scored for thyroid uptake (scale of 0-4) in another group of 152 subjects (98 blocked). Quantitative analysis based on thyroid regions of interest was performed on anterior planar images from a further sample of 669 subjects (442 blocked). For all 3 investigations, quantitative comparisons of thyroid uptake were made between the blocked and nonblocked subjects. RESULTS: There was no statistical difference between probe uptake of the 6 blocked and 9 nonblocked subjects. However, in the second series, mean visual score on the late images was significantly

ESES Review of Recently Published Literature 2014-1 Page 31 of 121 lower for blocked than nonblocked subjects (P < 0.001). In the region-of-interest analyses, net thyroid counts were significantly higher on the late images of nonblocked subjects (P < 0.0001), and compared with early images, 87% of subjects who received blockade showed decreased or unchanged counts whereas 75% of nonblocked subjects had increased net thyroid activity. In nonblocked subjects, an estimated 79% of thyroid counts on late images could be attributed to unbound (123)I. CONCLUSION: On the basis of 3 different methods for assessing thyroid uptake of (123)I, use of thyroid blockade pretreatment in (123)I-mIBG imaging prevents increase of thyroid activity over time because of uptake of unbound (123)I. In most subjects, there is a low level of (123)I-mIBG thyroid activity that probably represents specific uptake in sympathetic nerve terminals. PubMed-ID: 24385600 http://dx.doi.org/10.2967/jnumed.113.124826

Prognostic Implications of Papillary Thyroid Carcinoma With Tall-Cell Features. Thyroid, 24(4):662-70. Ganly I, Ibrahimpasic T, Rivera M, Nixon I, Palmer F, Patel SG, Tuttle RM, Shah JP, Ghossein R. 2014. BACKGROUND: The prognostic implications of the diagnosis of a papillary thyroid carcinoma (PTC) with tall-cell features are unknown. METHODS: All PTC patients identified between 1985 and 2005 were analyzed histologically. Classical PTC cases were defined as having <30% tall cells, PTC with tall-cell features (PTC TCF) as 30%-49% tall cells, and tall-cell variant of PTC (TCV) as >/= 50% tall cells. All classical PTC, PTC TCF, and TCV >/= 1 cm in size were included. RESULTS: A total of 453 patients satisfied the inclusion criteria (288 classical PTC, 31 PTC TCF, and 134 TCV). Classical PTC patients were younger than their PTC TCF and TCV counterparts (p<0.0002). There was an increase in tumor size from classical PTC to PTC TCF and TCV (p=0.05). Extensive extrathyroid extension and positive margins were more often present in TCV and PTC TCF than in classical PTC (p=0.0001 and p=0.03 respectively). Overall pathologic tumor (pT) stage was more advanced in TCV and PTC TCF than in classical PTC (p<0.0001). Total thyroidectomy and radioactive iodine therapy were more often performed and administered in TCV patients than in their PTC TCF and classical PTC counterparts (p=0.001 and p=0.0001 respectively). Median follow-up was 9.3 years. Ten-year disease-specific survival (DSS) was lower in TCV (96%) and PTC TCF (91%) than in classical PTC (100%; p<0.001). Ten-year distant recurrence-free survival (RFS) was higher in classical PTC (98%) than in PTC TCF (89%) and TCV (96%; p=0.03). In multivariate analysis, the presence of more than five positive nodes and extranodal extension were the only independent prognostic factors of neck and distant RFS respectively. Four (2.4%) of 165 PTC TCF and PTC TCV developed poorly differentiated or anaplastic carcinoma in their recurrence, while none of the 288 classical PTC transformed into higher grades (p=0.017). CONCLUSIONS: PTC TCF and TCV have similar clinicopathologic features that are more aggressive than classical PTC. PTC TCF and TCV have similar DSS and distant RFS but poorer outcomes than classical PTC. PTC TCF are currently being treated like classical PTC, that is, less aggressively than TCV. PTC TCF and TCV TCV have a higher rates of high-grade transformation than classical PTC. Consideration should be given to using a 30% tall-cell threshold to diagnose TCV. PubMed-ID: 24262069 http://dx.doi.org/10.1089/thy.2013.0503

Laminin-5gamma-2 (LAMC2) Is Highly Expressed in Anaplastic Thyroid Carcinoma and Is Associated With Tumor Progression, Migration, and Invasion by Modulating Signaling of EGFR. J Clin Endocrinol Metab, 99(1):E62-E72. Garg M, Kanojia D, Okamoto R, Jain S, Madan V, Chien W, Sampath A, Ding LW, Xuan M, Said JW, Doan NB, Liu LZ, Yang H, Gery S, Braunstein GD, Koeffler HP. 2014. CONTEXT: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy having no effective treatment. Laminin subunit-gamma-2 (LAMC2) is an epithelial basement membrane protein involved in cell migration and tumor invasion and might represent an ideal target for the development of novel therapeutic approaches for ATC. OBJECTIVE: The objective of the investigation was to study the role of LAMC2 in ATC tumorigenesis. DESIGN: LAMC2 expression was evaluated by RT-PCR, Western blotting, and immunohistochemistry in tumor specimens, adjacent noncancerous tissues, and cell lines. The short hairpin RNA (shRNA) approach was used to investigate the effect of LAMC2 knockdown on the tumorigenesis of ATC. RESULTS: LAMC2 was highly expressed in ATC samples and cell lines compared with normal thyroid tissues. Silencing LAMC2 by shRNA in ATC cells moderately inhibited cell growth in liquid culture and dramatically decreased growth in soft agar and in xenografts growing in immunodeficient mice. Silencing LAMC2 caused cell cycle arrest and significantly suppressed the migration, invasion, and wound healing of ATC cells. Rescue experiments by overexpressing LAMC2 in LAMC2 knockdown cells reversed the inhibitory effects as shown by increased cell proliferation and colony formation. Microarray data demonstrated that LAMC2 shRNA significantly altered the expression of genes associated with migration, invasion, proliferation, and survival. Immunoprecipitation studies showed that

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LAMC2 bound to epidermal growth factor receptor (EGFR) in the ATC cells. Silencing LAMC2 partially blocked epidermal growth factor-mediated activation of EGFR and its downstream pathway. Interestingly, cetuximab (an EGFR blocking antibody) or EGFR small interfering RNA additively enhanced the antiproliferative activity of the LAMC2 knockdown ATC cells compared with the control cells. CONCLUSIONS: To our knowledge, this is the first report investigating the effect of LAMC2 on cell growth, cell cycle, migration, invasion, and EGFR signaling in ATC cells, suggesting that LAMC2 may be a potential therapeutic target for the treatment of ATC. PubMed-ID: 24170107 http://dx.doi.org/10.1210/jc.2013-2994

Autoimmune Thyroiditis in Benign and Malignant Thyroid Nodules: 16-Year Results. Head Neck, 36(4):531-5. Giagourta I, Evangelopoulou C, Papaioannou G, Kassi G, Zapanti E, Prokopiou M, Papapostolou K, Karga H. 2014. BACKGROUND: It is controversial whether autoimmune thyroiditis is associated with higher frequency of papillary thyroid carcinoma (PTC). METHODS: This was a cross-sectional, retrospective study. PTCs were compared to benign nodules regarding the prevalence of autoimmune thyroiditis over 16 years. RESULTS: A similar proportion of autoimmune thyroiditis was observed in both benign and/or malignant nodules. Mean nodule size in cases with autoimmune thyroiditis was smaller than those without autoimmune thyroiditis. Multivariate analysis showed a negative association between the coexistence of autoimmune thyroiditis and lymph node and/or distant metastases. Lymph nodes involvement and distant metastases were lower in the PTC with autoimmune thyroiditis compared to those without autoimmune thyroiditis. Capsular invasion was a strong predictor for distant metastases attenuated by the presence of autoimmune thyroiditis. CONCLUSION: Thyroid nodules with autoimmune thyroiditis are not more likely to be malignant than those without autoimmune thyroiditis. The coexistent autoimmune thyroiditis may be beneficial as a decreased incidence of lymph nodes involvement and distant metastasis was seen in those patients. PubMed-ID: 23729390 http://dx.doi.org/10.1002/hed.23331

Thyroglobulin As Early Prognostic Marker to Predict Remission at 18-24 Months in Differentiated Thyroid Carcinoma. Clin Endocrinol (Oxf), 80(2):301-6. Gonzalez C, Aulinas A, Colom C, Tundidor D, Mendoza L, Corcoy R, Mato E, Alcantara V, Urgell RE, de LA. 2014. INTRODUCTION: Thyroglobulin (Tg), the most common marker to determine remission of differentiated thyroid carcinoma (DTC), can take 18 months or longer to be undetectable. We hypothesized that Tg stimulated after surgery and immediately before radioiodine treatment (baseline-stimulated Tg) could be a good predictor of remission at 18-24 months. The aim of this study was to evaluate the role of baseline-stimulated Tg as early prognostic marker of DTC. PATIENTS AND METHODS: Retrospective study of 133 patients with DTC from 1998 to 2010 (age at diagnosis 47.4 +/- 16.8, follow-up 5.09 +/- 3.2 years). Initial subset analysis was performed after excluding patients with positive TgAb, who were later included in the second. Baseline-stimulated Tg was divided into tertiles. Multivariate logistic regression analysis included baseline Tg and other known prognostic markers and receiver operating characteristic (ROC) curve to identify the best cut-off level of baseline Tg were performed. RESULTS: Baseline-stimulated Tg in the highest tertile was the only predictive variable of persistence of disease at 18-24 months in the initial analysis (OR 45.3, P < 0.01). In the second analysis, the predictive variables were baseline-stimulated Tg (OR 39.6, P < 0.001), presence of TgAb (OR 23.4, P < 0.005) and uptake outside of the thyroid bed post-treatment whole body scan (WBS; OR 5.3, P < 0.05) were predictive of persistence of disease. The ROC curve showed that baseline-stimulated Tg below 8.55 mug/l identified 95% of disease-free patients at 18-24 months after initial treatment. CONCLUSIONS: Baseline-stimulated Tg is a good predictor of remission of disease at 18-24 months after initial treatment and could be a useful marker to stratify risk immediately after surgery. PubMed-ID: 23826916 http://dx.doi.org/10.1111/cen.12282

Thyroid Function: Hyperthyroidism-Psychiatric Issues. Nat Rev Endocrinol, 10(2):65. Greenhill C. 2014. PubMed-ID: 24342884 http://dx.doi.org/10.1038/nrendo.2013.253

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Thyroid Gland: Duration of Intravenous Glucocorticoid Therapy in Patients With Graves Ophthalmopathy. Nat Rev Endocrinol, 10(1):2. Greenhill C. 2014. PubMed-ID: 24189511 http://dx.doi.org/10.1038/nrendo.2013.224

Nodal Metastasis MicroRNA Expression Correlates With the Primary Tumour in MTC. ANZ J Surg, 84(4):235-9. Gundara JS, Zhao JT, Gill AJ, Clifton-Bligh R, Robinson BG, Delbridge L, Sidhu SB. 2014. INTRODUCTION: Lymph node metastases represent a diagnostic and management challenge in patients with disseminated medullary thyroid carcinoma (MTC). Our understanding of microRNA (miRNA) profiles of metastatic disease also remains limited and may unveil novel therapeutic strategies for these patients. METHODS: MTC patients with a history of total thyroidectomy and lymph node dissection were identified from within the prospective Sydney University Endocrine Surgical Unit database. Patients with available formalin-fixed paraffin-embedded tumour tissue were included and clinicopathological data were collated. Total RNA was extracted and quantitave polymerase chain reaction (qPCR) analysis performed on the primary tumour and a corresponding lymph node metastasis for expression of miRNAs of proven significance in MTC (miR-9*, miR- 183 and miR-375). RESULTS: Tissue was available for analysis in seven patients. The median age at diagnosis was 55 years (range: 22-67). Median tumour size was 18 mm (range: 6-55) and over a median follow-up period of 34 months (range: 1-210), five further operations were undertaken for residual disease. One patient died of metastatic disease. Pairwise correlations of qPCR expression levels between primary tumours and corresponding lymph node metastases revealed significant correlations for miR-9* (P < 0.001), miR-183 (P = 0.001) and miR-375 (P = 0.004). CONCLUSION: miRNA expression patterns in nodal metastases significantly reflect those of the primary tumour in MTC. This further validates previously reported miRNA profile analyses and reiterates the potential significance of miR-9*, -183 and -375 in the pathophysiology of MTC. The possibility of lymph node biopsy miRNA analysis driven clinical decision making may now also be a possibility where conventional techniques are unhelpful. PubMed-ID: 23072640 http://dx.doi.org/10.1111/j.1445-2197.2012.06291.x

Racial and Socioeconomic Disparities in Presentation and Outcomes of Well-Differentiated Thyroid Cancer. J Clin Endocrinol Metab, 99(1):133-41. Harari A, Li N, Yeh MW. 2014. CONTEXT: Racial/ethnic minorities suffer disproportionate morbidity and mortality from chronic diseases. OBJECTIVE: Our objective was to assess racial and socioeconomic status (SES) disparities in well- differentiated thyroid cancer (WDTC) patients. DESIGN AND PARTICIPANTS: We conducted a retrospective cohort study on 25 945 patients with WDTC (1999-2008) from the California Cancer Registry (57% white, 4% black, 24% Hispanic, and 15% Asian-Pacific Islander [API]). MAIN OUTCOMES: We evaluated effect of race and SES variables on stage of cancer presentation and overall/disease-specific survival. RESULTS: Significant differences in stage of presentation between all racial groups were found (P<.001), with minority groups presenting with a higher percentage of metastatic disease as compared with white patients (black, odds ratio [OR]=1.36 with confidence interval [CI] 1.01-1.84; Hispanic, OR=1.89 [CI, 1.62-2.21], API, OR=1.82 [CI, 1.54- 2.15]). Hispanic (OR=1.59, [CI, 1.48-1.72]) and API (OR=1.32 [1.22-1.44]) patients also presented with higher odds of regional disease. Patients with the lowest SES presented with metastatic disease more often than those with the highest SES (OR=1.45 [CI, 1.16-1.82]). Those that were poor/uninsured and/or with Medicaid insurance had higher odds of presenting with metastatic disease as compared with those with private insurance (OR=2.41, [CI, 2.10-2.77]). Unadjusted overall survival rates were higher among API and Hispanic patients and lower among black patients (P<.001 vs white patients). Adjusted overall survival also showed a survival disadvantage for black patients (hazard ratio=1.4, [CI, 1.10-1.73]) and survival advantage for API patients (hazard ratio=0.83, [CI, 0.71-0.97]). In disease-specific survival analyses, when only those patients with metastatic disease were analyzed separately, black patients again had the lowest survival rates, and Hispanic/API patients had the highest survival rates (P<.04). CONCLUSION: Black patients and those with low SES have worse outcomes for thyroid cancer. API and Hispanic patients may have a protective effect on survival despite presenting with more advanced disease. PubMed-ID: 24243631 http://dx.doi.org/10.1210/jc.2013-2781

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Reply to Letter: "Optimization of Staging of the Neck With Prophylactic Central and Lateral Neck Dissection for Papillary Thyroid Carcinoma". Ann Surg, Hartl DM. 2014. PubMed-ID: 24441812 http://dx.doi.org/10.1097/SLA.0000000000000511

Prophylactic Level II Neck Dissection Guided by Frozen Section for Clinically Node-Negative Papillary Thyroid Carcinoma: Is It Useful? World J Surg, 38(3):667-72. Hartl DM, Al GA, Borget I, Leboulleux S, Mirghani H, Schlumberger M. 2014. BACKGROUND: Prophylactic lateral neck dissection (PLND) is generally not performed for papillary thyroid carcinoma(PTC). When performed, occult metastases are found in upto 50 % of patients, although the incidence of occult level II nodes seems low. Our aim was to evaluate frozen section analysis-oriented elective level II PLND in patients with clinically node-negative (cN0) PTC. METHODS: This retrospective study included patients with cN0 PTC treated with total thyroidectomy and prophylactic bilateral central and lateral neck dissection of ipsilateral levels III and IV. Frozen section analysis of PLND III and IV was performed. If positive, the PLND was extended to level II. We measured the accuracy of frozen section analysis, the incidence of occult level II metastasis, and oncologic outcomes. RESULTS: A total of 295 patients were included. For frozen section analysis, the sensitivity was 71.0 %, specificity 99.6 %, positive predictive value 97.8 %, negative predictive value 92.4 %, overall accuracy 93.2 %. Definitive analysis found lateral node metastases in 63 of the 295(21 %) patients. Extension to level II was performed in 27 of 46 cases (59 %). Level II contained metastatic nodes in 12 of 27 (44 %) patients. There was no difference in total doses of 131I administered to patients with or without level II disease. Even when extension of PLND to level II was not performed, no cases of recurrent or persistent disease in level II occurred. CONCLUSIONS: Frozen section analysis was highly accurate.The rate of occult metastases in level II was low. Detection of additional metastases in level II did not modify subsequent treatment or the rate of recurrence and is not useful for routine application. PubMed-ID: 24231907 http://dx.doi.org/10.1007/s00268-013-2316-y

Expert Surgeon's Quiet Eye and Slowing Down: Expertise Differences in Performance and Quiet Eye Duration During Identification and Dissection of the Recurrent Laryngeal Nerve. Am J Surg, 207(2):187-93. Harvey A, Vickers JN, Snelgrove R, Scott MF, Morrison S. 2014. BACKGROUND: Long quiet eye (QE) duration is central to expertise in sports, while cognitive "slowing down" has been identified as a perceptual skill possessed by skilled surgeons. Eye-tracking evidence is lacking about the relationship of QE duration to slowing down in surgeons. The aim of this study was to examine QE duration, hand movement time (MT), fixation location, and fixation duration in highly experienced (HE) and less experienced (LE) surgeons. METHODS: A mobile eye tracker and camera recorded coupled gaze and hand movements. Performance was quantified by blinded review. RESULTS: HE surgeons were rated higher than LE surgeons but did not differ in operating time or MT. HE and LE surgeons differed in fixation duration on the ligament of Berry during phases 1 and 2 and QE duration on the recurrent laryngeal nerve in phase 2. CONCLUSIONS: Long-duration fixation on the ligament of Berry and long-duration QE on the recurrent laryngeal nerve combined with no significant differences in MT provide empirical evidence that HE surgeons cognitively slow down more than LE surgeons during critical phases of the operation. PubMed-ID: 24476801 http://dx.doi.org/10.1016/j.amjsurg.2013.07.033

Src Inhibitors in Suppression of Papillary Thyroid Carcinoma Growth. Head Neck, 36(3):375-84. Henderson YC, Toro-Serra R, Chen Y, Ryu J, Frederick MJ, Zhou G, Gallick GE, Lai SY, Clayman GL. 2014. BACKGROUND: Papillary thyroid carcinoma is the most common thyroid malignancy. Most papillary thyroid carcinomas contain BRAF mutations or RET/PTC rearrangements, thus providing targets for biologic therapy. Our previous studies had suggested papillary thyroid carcinomas (PTCs) with a BRAF mutation and the RET/PTC1 rearrangement have different sensitivities to MEK1/2 inhibitors, suggesting different signaling transduction pathways were involved. METHODS: Src signaling transduction pathway in PTC cells was examined using Src inhibitors (PP2, SU6656, or dasatinib) and si-Src RNA in vitro by Western blot analysis and proliferation analysis. An orthotopic xenograft mouse model was used for the in vivo studies using dasatinib. RESULTS: In PTC cells, Src inhibitors suppressed p-Src and p-FAK and inhibited cell growth. In addition,

ESES Review of Recently Published Literature 2014-1 Page 35 of 121 significant suppression and extension of the p-ERK1/2 dephosphorylation were detected in RET/PTC1- rearranged cells in combination with an MEK inhibitor (CI-1040). The Src family kinase/ABL inhibitor, dasatinib, significantly decreased tumor volume in mice inoculated with PTC cells carrying the RET/PTC1 rearrangement. In BRAF-mutated PTC cells, Src inhibitors effectively suppressed p-Src expression and dasatinib significantly decreased tumor volume with twice daily treatment. CONCLUSION: Src inhibitors effectively inhibited the Src signaling transduction pathway in PTC cells in vitro and dasatinib suppressed tumor growth in vivo. These results suggested that Src signaling transduction pathway plays an important role in regulating growth in PTC cells. Combination of Src and MEK1/2 inhibitors extended the dephosphorylation of extracellular signal-regulated kinase (ERK)1/2 in PTCs carrying the RET/PTC1 rearrangement suggesting that combination therapy with complementary inhibitors of other signaling transduction pathways may be needed to effectively suppress growth and induce apoptosis in these cells. PubMed-ID: 23729178 http://dx.doi.org/10.1002/hed.23316

Outcomes of Total Thyroidectomy With Therapeutic Central and Lateral Neck Dissection With a Single Dose of Radioiodine in the Treatment of Regionally Advanced Papillary Thyroid Cancer and Effects on Serum Thyroglobulin. Ann Surg Oncol, 21(5):1647-52. Hughes DT, Miller BS, Cohen MS, Doherty GM, Gauger PG. 2014. BACKGROUND: Achieving an undetectable serum thyroglobulin (Tg) level (<1.0 ng/mL) after surgical and radioiodine treatment for papillary thyroid cancer (PTC) is associated with low recurrence rates and has been termed biochemical remission. This study aimed to determine the effectiveness of total thyroidectomy with therapeutic central and lateral neck dissection for regionally advanced (T1-4bN1bM0) PTC with regard to posttreatment Tg levels. METHODS: This is a single-institution retrospective cohort study of patients with regionally advanced PTC initially treated with total thyroidectomy and therapeutic levels 2-7 neck dissection from 2002 to 2012. Pathologic findings, complications, serum Tg levels, and outcomes were analyzed. RESULTS: Sixty-one patients were initially treated with total thyroidectomy and therapeutic central and lateral neck dissection for PTC involving the lateral cervical nodes (N1b). The median number of lymph nodes excised and positive was 27 (range 5-112) and 9 (range 1-67), respectively. Extranodal extension occurred in 48 %. Radioiodine was administered after surgery with a median total dose of 150 mCi (range 30-244 mCi). Recurrent or persistent cervical disease occurred in 8 (13 %) and 3 (5 %) patients, respectively, and required additional radioiodine treatment in 2 and reoperative neck dissection in 10. Three patients developed new distant metastasis, and 1 died during the median follow-up of 20 months (range 1-109 months). Undetectable unstimulated Tg (<1.0 ng/mL) without clinically detectable recurrence was experienced in 68 % of patients with initial treatment. CONCLUSIONS: Biochemical remission can be experienced in most patients presenting with regionally advanced PTC with total thyroidectomy and compartment based therapeutic neck dissection followed by a single dose of radioiodine. PubMed-ID: 24385210 http://dx.doi.org/10.1245/s10434-013-3467-7

Outcomes in Patients With Poorly Differentiated Thyroid Carcinoma. J Clin Endocrinol Metab, 99(4):1245-52. Ibrahimpasic T, Ghossein R, Carlson DL, Nixon I, Palmer FL, Shaha AR, Patel SG, Tuttle RM, Shah JP, Ganly I. 2014. BACKGROUND: Poorly differentiated thyroid cancer (PDTC) accounts for only 1-15% of all thyroid cancers. Our objective is to report outcomes in a large series of patients with PDTC treated at a single tertiary care cancer center. METHODS: A total of 91 patients with primary PDTC were treated by initial surgery with or without adjuvant therapy at Memorial Sloan-Kettering Cancer Center from 1986 to 2009. Outcomes were calculated by the Kaplan-Meier method. Clinicopathological characteristics were compared for PDTC patients who died of disease to those who did not by the chi(2) test. Factors predictive of disease-specific survival (DSS) were calculated by univariate and multivariate analysis using the log rank and Cox proportional hazards method, respectively. RESULTS: With a median follow-up of 50 months, the 5-year overall survival and DSS were 62 and 66%, respectively. The 5-year locoregional and distant control were 81 and 59%, respectively. Of 27 disease- specific deaths, 23 (85%) were due to distant disease. Age >/= 45 years, pathological tumor size >4 cm, extrathyroidal extension, higher pathological T stage, positive margins, and distant metastases (M1) were predictive of worse DSS on univariate analysis. Multivariate analysis showed that only pT4a stage and M1 were independent predictors of worse DSS. CONCLUSIONS: With appropriate surgery and adjuvant therapy, excellent locoregional control can be achieved in PDTC. Disease-specific deaths occurred due to distant metastases and rarely due to uncontrolled locoregional recurrence in this series.

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PubMed-ID: 24512493 http://dx.doi.org/10.1210/jc.2013-3842

Airtight Tracheocutaneostomy After Window Resection of the Trachea for Invasive Papillary Thyroid Carcinoma: Experience of 109 Cases. World J Surg, 38(3):660-6. Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, Miya A. 2014. BACKGROUND: There are some tracheal surgeries for invasive papillary thyroid carcinoma (PTC) requiring tracheal resection. We create an airtight tracheocutaneostomy (TCS) by suturing the tracheal hole to the skin when window resection of the trachea is required. Here, we present the outcomes of PTC patients who underwent surgery with airtight TCS. METHODS: We enrolled 109 patients (18 males and 91 females) who underwent initial surgery for PTC and TCS after partial window resection of the trachea between 1987 and 2010. The average patient age was 61 and the average follow-up was 99 months. The TCS was closed using a local skin flap 3-6 months after surgery in 78 patients, and it closed spontaneously in 13 patients. The TCS of the remaining 18 patients was not closed for various reasons, such as a poor general condition, permanent bilateral vocal cord paralysis, and loss to follow-up. RESULTS: None of the 109 patients showed any serious complications of TCS. Minor wound infection, partial skin necrosis, granulation, and air leakage were observed in 12 (11 %), 2 (2 %), 7 (6 %), and 4 (4 %) patients, respectively. Infection was more likely to occur in patients whose cricoid cartilage was resected (p = 0.0456). Although macroscopically curative surgery was performed for all patients, 38 patients (35 %) had a suspiciously positive margin in the resected tracheal mucosa. Five margin- positive (13 %) and five margin-negative (7 %) patients showed excision site recurrence, but the margin status did not directly affect the prognosis. External beam radiation therapy (EBRT) (50-60 Gy) was administered to nine patients, none of whom showed excision site recurrence, although eight were microscopically margin- positive. Among various clinicopathological features, tumor size > 4 cm and age >/= 60 years were significant (p = 0.0281) and marginal (p = 0.0771) predictors of excision site recurrence on univariate analysis. On multivariate analysis, age >/= 60 years (p = 0.0484) and tumor size > 4 cm (p = 0.0763) were independent and marginal predictors of excision site recurrence, respectively. To date, 14 and 17 patients have shown lymph node and distant recurrence, respectively, and nine have died of PTC. CONCLUSIONS: Tracheocutaneostomy is a safe surgical technique after partial window resection of the trachea, although we have to be careful of infection when resecting the cricoid cartilage. Large tumor size and old age are risk factors for excision site recurrence. EBRT may be useful to prevent excision site recurrence, especially in patients with a suspected positive margin. PubMed-ID: 23982781 http://dx.doi.org/10.1007/s00268-013-2197-0

BRAF(V600E) Mutation Analysis in Papillary Thyroid Carcinoma: Is It Useful for All Patients? World J Surg, 38(3):679-87. Ito Y, Yoshida H, Kihara M, Kobayashi K, Miya A, Miyauchi A. 2014. BACKGROUND: The BRAF(V600E) mutation has been adopted as a prognostic factor in papillary thyroid carcinoma (PTC). However, it remains unclear whether routine BRAF mutation analysis is useful in establishing a prognosis for PTC patients. In the present study we investigated BRAF mutation analysis in a large number of PTC patients with long-term follow-up. PATIENTS AND METHODS: We enrolled 766 patients from our hospital who underwent initial surgery for PTC without distant metastasis at diagnosis between 1996 and 2001, and whose BRAF mutation of primary lesions could be analyzed. The average age and follow-up period were 51 years and 130 months, respectively. RESULTS: To date, 77 (10 %) and 37 (5 %) patients have developed lymph node and distant recurrence, respectively, and 10 (1 %) have died of PTC. The BRAF mutation was positive in 281 patients (37 %), and it had no prognostic impact on lymph node recurrence-free (LNRFS) (p = 0.700), distant recurrence-free (DRFS) (p = 0.696), and cause-specific (CSS) (p = 0.125) survival in our entire series. However, CSS of BRAF mutation-positive high-risk patients based on AMES (p = 0.030), MACIS (score >6) (p = 0.017), the UICC stage (IVa) (p = 0.021), CIH classification (Sugitani et al. Surgery 135:139-148, 2004) (p = 0.015), and our own classification system (Ito et al. World J Surg 34:2570-2580, 2010) (p = 0.010) were significantly poorer than CSS of mutation-negative high-risk patients. The BFAF mutation did not affect CSS of non-high-risk patients, although the incidence of the BRAF mutation did not significantly differ between high-risk and non-high-risk groups based on these classification systems. The BRAF mutation was not related to LNRFS and DRFS in the subsets of high-risk and non-high-risk patients. CONCLUSIONS: BRAF mutation analysis is useful in estimating the CSS of high-risk PTC patients based on the representative classification systems. It was not related to the prognosis in non-high-risk patients, at least those living in Japan. PubMed-ID: 24052184 http://dx.doi.org/10.1007/s00268-013-2223-2

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Quality of Life Improves After Strabismus Surgery in Patients With Graves' Orbitopathy. Eur J Endocrinol, 170(5):785-9. Jellema HM, Merckel-Timmer E, Kloos R, Saeed P, Mourits MP. 2014. OBJECTIVE: To evaluate the influence of strabismus surgery on quality of life (QoL) in Graves' orbitopathy (GO) patients. DESIGN: Prospective study of case series. METHODS: Consecutive GO-patients who were scheduled for their first strabismus surgery were included in the study. The patients completed the GO-QoL questionnaire within 3 months before the surgery and 2-4 months after the surgery. A complete orthoptic examination, including the field of binocular single vision (BSV), was performed. Clinically relevant response (CRR) in the QoL was also evaluated. RESULTS: In this study, 28 patients were included. The GO-QoL score for visual functioning was 46.3+/-24.2 before surgery and 65.7+/-30.5 after surgery (P=0.009). The GO-QoL score for appearance changed from 60.6+/-25.9 to 69.5+/-24.2 (P=0.005). After surgery, the field of BSV increased from 24.3+/-34.8 to 68.5+/-36.0 points (P=0.000). A weak correlation was found between the field of BSV and the visual functioning score after surgery (r=0.417; P=0.034). CRR was found in 20 (71%) patients. Those with a CRR showed a larger field of BSV (P=0.002) and better GO-QoL scores (P=0.008). CONCLUSIONS: GO-QoL score increases significantly for both visual functioning and appearance after the first strabismus surgery in GO- patients, showing the highest improvement for the visual functioning questions. Both the GO-QoL and field of BSV outcomes correlate well with the CRR. PubMed-ID: 24493116 http://dx.doi.org/10.1530/EJE-13-0973

Focal Thoracic Uptake Mimicking Lung Metastasis on 131I Post-Therapy Whole-Body Scan in Patients With Thyroid Carcinoma. Clin Nucl Med, 39(4):360-2. Jia C, Moadel R, Freeman LM. 2014. Whole-body 131I scan after total thyroidectomy is important in the evaluation of radioiodine avid metastatic foci in patients with differentiated thyroid carcinoma. False-positive uptakes are occasionally seen in the thoracic region which should be evaluated carefully and not mistaken as lung metastases. We report here 2 cases of abnormal focal thoracic uptake, 1 case of a pleuropericardial cyst and 1 case of focal bronchiectasis, that could potentially be confused with lung metastasis. Careful correlation with diagnostic CT and subsequent follow-up studies suggested that these were not metastatic lesions. PubMed-ID: 24598344 http://dx.doi.org/10.1097/RLU.0b013e31829959ce

Primary Amyloid Goiter Mimicking Rapid Growing Thyroid Malignancy. Eur Arch Otorhinolaryngol, 271(2):417-20. Joung KH, Park JY, Kim KS, Koo BS. 2014. Amyloid accumulation in the thyroid gland leading to a clinically detectable mass, known as amyloid goiter, is a rare condition associated with primary amyloidosis. Moreover, a localized primary amyloid goiter involving only the thyroid gland is rarer still. Here, we report a patient with a localized primary amyloid goiter that had grown rapidly, causing dysphagia and dyspnea on exercise, and confused us with malignancy such as anaplastic carcinoma. After surgery, no further symptoms occurred. A diagnosis of amyloid goiter was established on microscopic examination. In patients with a rapidly enlarging thyroid gland presenting with dysphagia, dyspnea, or hoarseness, amyloid goiter and malignancy should both be suspected, even when systemic amyloidosis is not suspected. PubMed-ID: 24150545 http://dx.doi.org/10.1007/s00405-013-2777-5

The Increase in Thyroid Cancer Incidence During the Last Four Decades Is Accompanied by a High Frequency of BRAF Mutations and a Sharp Increase in RAS Mutations. J Clin Endocrinol Metab, 99(2):E276-E285. Jung CK, Little MP, Lubin JH, Brenner AV, Wells SA, Jr., Sigurdson AJ, Nikiforov YE. 2014. CONTEXT: Thyroid cancer incidence rates in the United States and globally have increased steadily over the last 40 years, primarily due to a tripling of the incidence of papillary thyroid carcinoma (PTC). OBJECTIVE: The purpose of this study was to analyze trends in demographic, clinical, pathologic, and molecular characteristics of PTC from 1974 to 2009. DESIGN AND SETTING: We identified and histologically reviewed 469 consecutive cases of PTC from one US institution from 4 preselected periods (1974 to 1985, 1990 to 1992, 2000, and 2009) and assessed BRAF and RAS point mutations and RET/PTC rearrangements among 341 tumors >/=0.3 cm in size. Changes over time were analyzed using polytomous and binary logistic regression; all analyses were adjusted for age and sex. RESULTS: During this period, the median age of patients at diagnosis increased from

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37 to 53 years (P < .001) and the percentage of microcarcinomas (

Candidates for Limited Lateral Neck Dissection Among Patients With Metastatic Papillary Thyroid Carcinoma. World J Surg, 38(4):863-71. Kang BC, Roh JL, Lee JH, Cho KJ, Gong G, Choi SH, Nam SY, Kim SY. 2014. BACKGROUND: Papillary thyroid carcinoma (PTC) is associated with an excellent prognosis but frequently spreads to regional lymph nodes. The extent of neck dissection, particularly routine level II or V lymphadenectomy, is still controversial as it may lead to spinal accessory nerve injury and associated postoperative morbidities. We assessed the diagnostic value of preoperative ultrasonography (US) plus computed tomography (CT) for detecting metastatic lymph nodes and for identifying predictors of level II or V metastasis in patients with PTC. METHODS: The results of US and CT were compared with histopathologic findings at various neck levels in 209 previously untreated PTC patients with lateral cervical nodal metastases who underwent total thyroidectomy with central and lateral neck dissection. Clinicopathologic predictors for level II or V metastases were identified. RESULTS: Pathologic metastases to level II and V were observed in 53.6 and 25.4 % of patients, respectively. Occult metastases were found in 34.5 and 16.8 %, respectively. The sensitivities of US plus CT for levels II and V were 64.6 and 50.9 %, respectively. Image-based, isolated lateral level IV involvement and macroscopic extranodal extension were independently associated with level II metastasis or either level II or V metastasis (p < 0.01). Macroscopic extranodal extension was also independently associated with level V metastasis (p = 0.001). CONCLUSIONS: Patients with image-based, isolated lateral level IV involvement and no macroscopic extranodal extension are potential candidates for limited level III-IV dissection or prophylactic level II lymphadenectomy omission. Level V lymphadenectomy may be omitted in patients without macroscopic extranodal extension. PubMed-ID: 24337241 http://dx.doi.org/10.1007/s00268-013-2361-6

Fine-Needle Aspiration Cytology of Thyroid Nodules With Hurthle Cells: Cytomorphologic Predictors for Neoplasms, Improving Diagnostic Accuracy and Overcoming Pitfalls. Acta Cytol, 58(2):145-52. Kasper KA, Stewart J, III, Das K. 2014. OBJECTIVES: Hurthle cells (HCs) are follicular-derived oncocytic cells seen in a variety of neoplastic and nonneoplastic pathologic entities of the thyroid gland. This study was to report our experience of the surgical outcome on the finding of HCs on fine-needle aspiration biopsies (FNABs) of thyroid nodules, to identify cytologic predictors of HC neoplasms and an attempt to overcome diagnostic pitfalls. STUDY DESIGN: This was a retrospective study of all FNAB of thyroid nodules with findings of HCs with subsequent surgical resection. The FNAB slides of 70 thyroid nodules were blindly reviewed for specific cytomorphologic characteristics. The cytologic findings were correlated with the corresponding final surgical pathology diagnosis. RESULTS: The patients ranged in age from 25 to 78 years with a male:female ratio of 1:2. There were 19 false-negative and 4 false-positive cases. Overall high cellularity, scant colloid and >90% HCs on FNAB are consistently seen in a neoplastic HC process. All cases of Hashimoto's thyroiditis were associated with prominent nucleoli and 92% of cases demonstrating transgressing vessels were neoplastic. CONCLUSION: Diagnostic accuracy can be improved by following the current Bethesda classification system. A constellation of cytomorphologic features in conjunction with clinical findings can be considered a strong predictor of a neoplastic process. PubMed-ID: 24525356 http://dx.doi.org/10.1159/000358264

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Outcome of Vocal Cord Function After Partial Layer Resection of the Recurrent Laryngeal Nerve in Patients With Invasive Papillary Thyroid Cancer. Surgery, 155(1):184-9. Kihara M, Miyauchi A, Yabuta T, Higashiyama T, Fukushima M, Ito Y, Kobayashi K, Miya A. 2014. BACKGROUND: The recurrent laryngeal nerve (RLN) may be involved by thyroid cancer even in patients with functioning vocal cords preoperatively. In such cases, we try to preserve the nerve with sharp dissection. As a result of the dissection, the nerve may become thinner than its original thickness. Here we call this operative procedure "partial layer resection of the RLN," if the thickness of the preserved nerve is less than half of its original size. However, there is no report on postoperative vocal cord function after this procedure. METHODS: We report on 4,585 patients with papillary thyroid cancer who underwent their initial surgery in Kuma Hospital. Among them, 18 patients underwent "partial layer resection of the RLN." We also performed histologic examinations on the RLNs resected because of cancer invasion in 3 other patients. RESULTS: Postoperatively, 2 patients had functioning vocal cords, 13 had transient vocal cord paralysis, and the remaining 3 had permanent paralysis. Thus, 83% (15/18) of the present patients who underwent partial layer resection of the RLN had functioning vocal cords 1 year after surgery. In patients with transient paralysis, the phonation efficiency index (PEI) 1 year after operation recovered to normal range from the low PEI immediately after operation. Histologic examinations of resected RLN revealed that 78-82% of the cross-section of the nerve is composed of perineural connective tissue surrounding the nerve fibers. CONCLUSION: An unexpectedly high proportion (83%) of the patients who underwent partial layer resection of the RLN achieved functioning vocal cords and nearly normal phonation postoperatively. PubMed-ID: 24646959 http://dx.doi.org/10.1016/j.surg.2013.06.052

Central Neck Dissection Using a Bilateral Axillo-Breast Approach for Robotic Thyroidectomy: Comparison With Conventional Open Procedure After Propensity Score Matching. Surg Laparosc Endosc Percutan Tech, 24(1):67-72. Kim BS, Kang KH, Kang H, Park SJ. 2014. BACKGROUND: Despite advancements in surgical robot technology, the da Vinci-assisted central neck dissection (CND) in thyroid cancer remains challenging. The aim of this study is to evaluate the feasibility of robotic thyroidectomy and CND. METHODS: Between March 2011 and July 2012, 515 consecutive patients who had undergone thyroidectomy and CND for papillary thyroid carcinoma were retrospectively reviewed. A thyroid surgeon performed either an open thyroidectomy and CND (n=392) or a robotic thyroidectomy and CND (n=123) using the bilateral axillo-breast approach (BABA). Propensity score matching using 10 clinicopathologic factors was used to generate 2 matched cohorts, each composed of 123 patients. RESULTS: Mean age, body mass index, and tumor size were lower in those who underwent BABA compared with an open procedure before propensity matching. Evaluation of stimulated thyroglobulin levels did not show significant differences between the 2 groups. After cohort matching, significant differences in age, body mass index, and tumor size between the 2 groups were no longer present. The matched cohort showed that the number of retrieved lymph nodes was lower in the BABA (8.74+/-5.13) than in the open thyroidectomy (10.71+/-6.68) (P=0.006). CONCLUSIONS: BABA robotic thyroidectomy revealed that a less-extensive CND was obtained when compared with an open procedure. BABA may be suitable for thyroid cancer without lymphadenopathy in central neck compartment. Conversely, BABA should not be recommended to a patient with thyroid cancer when multiple lymph node metastases in the lower central neck compartment are suspected. PubMed-ID: 24487161 http://dx.doi.org/10.1097/SLE.0b013e3182a4bfec

Feasibility of Super-Selective Neck Dissection for Indeterminate Lateral Neck Nodes in Papillary Thyroid Carcinoma. Head Neck, 36(4):487-91. Kim H, Jin YJ, Cha W, Jeong WJ, Ahn SH. 2014. BACKGROUND: Therapeutic lateral compartment neck dissection is recommended for cases of papillary thyroid carcinoma with biopsy-proven lymph node metastasis. The purpose of this study was to evaluate the efficacy and safety of super-selective neck dissection for patients with clinically suspicious lymph node metastasis not confirmed by biopsy. METHODS: Among 620 patients treated for papillary thyroid carcinoma between 2008 and 2010, 34 had suspicious lymph node enlargement in the lateral neck and underwent total thyroidectomy with super-selective neck dissection. RESULTS: Metastatic disease was confirmed in 38.2% patients (13 of 34) with indeterminate lymph nodes identified by preoperative CT and/or ultrasonography who underwent super-selective neck dissection. Most harvested lymph nodes were located at level IV. There was no recurrence during a mean follow-up period of 31.6 months. CONCLUSION: Patients with clinically suspicious lateral neck nodes that are

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Risk Factors for Recurrence After Therapeutic Lateral Neck Dissection for Primary Papillary Thyroid Cancer. Ann Surg Oncol, 21(6):1884-90. Kim SJ, Park SY, Lee YJ, Lee EK, Kim SK, Kim TH, Jung YS, Ryu J, Myong JP, Chung KW. 2014. BACKGROUND: Lateral lymph node metastasis is an important prognostic factor and is predictive of tumor recurrence and cause-specific survival in patients with papillary thyroid cancer (PTC). However, the factors predicting recurrence and clinical outcomes after therapeutic lateral neck dissection are not well established. The aims of this study were to evaluate the incidence, pattern, and factors predictive of PTC recurrence after therapeutic lateral neck dissection. MATERIALS AND METHODS: The records of 126 consecutive patients who underwent total thyroidectomy with therapeutic lateral neck dissection for primary PTC at the National Cancer Center were retrospectively reviewed. The factors predictive of recurrence were determined using both univariate and multivariate analyses considering several clinicopathologic variables. RESULTS: The median follow-up period was 61.2 months, during which 22 patients (17.5 %) experienced recurrence with 1 death (0.8 %) due to disease. Locoregional recurrence and distant metastasis were found in 20 cases (15.9 %) and 2 cases (1.6 %), respectively. Male gender, aggressive histology, number of lymph node metastases, initial level of T4-off Tg per ng/mL, and ATA risk categories (high risk) were independent risk factors for recurrence. Of note, initial T4-off Tg levels greater than 4.2 ng/mL showed highest sensitivity and specificity in predicting recurrence. CONCLUSIONS: These results provide useful information regarding the clinical outcomes after therapeutic lateral neck dissection for primary PTC and can be used to identify at-risk patients who need aggressive treatment and intensive surveillance for postoperative recurrence. PubMed-ID: 24515566 http://dx.doi.org/10.1245/s10434-014-3507-y

Risk of Lymph Node Metastases in Multifocal Papillary Thyroid Cancer Associated With Hashimoto's Thyroiditis. Langenbecks Arch Surg, 399(2):229-36. Konturek A, Barczynski M, Nowak W, Wierzchowski W. 2014. AIMS: The aim of this study was to evaluate the risk factors of lymph nodes metastases (LNM) in patients with papillary thyroid cancer (PTC) and coexisting Hashimoto's thyroiditis (HT). PATIENTS AND METHODS: This was a retrospective cohort study of patients with PTC and HT who had undergone total thyroidectomy (TT) with central neck dissection (CND) over an 11-year period (between 2002 and 2012). Pathological reports of all eligible patients were reviewed. Multivariable analysis was performed to identify risk factors of LNM. RESULTS: During the study period, PTC was diagnosed in 130 patients with HT who had undergone TT with CND (F/M ratio = 110:20; median age, 52.4 +/- 12.7 years). Multifocal lesions were observed in 28 (21.5 %) patients. LNM were identified in 25 of 28 (89.3 %) patients with multifocal PTC and HT versus 69 of 102 (67.5 %) patients with a solitary focus of PTC and HT (p = 0.023). In multivariable analysis, multifocal disease was identified as an independent risk factor for LNM (odds ratio, 3.99; 95 % confidence interval, 1.12 to 14.15; p = 0.033). CONCLUSIONS: Multifocal PTC in patients with HT is associated with an increased risk of LNM. Nevertheless, the clinical importance of this finding needs to be validated in well-designed prospective studies. PubMed-ID: 24407910 http://dx.doi.org/10.1007/s00423-013-1158-2

Upregulation of HGF and C-MET Is Associated With Subclinical Central Lymph Node Metastasis in Papillary Thyroid Microcarcinoma. Ann Surg Oncol, Koo BS, Kim JM, Seo ST, Yoon YH, Kwon KR, Kim SH, Kwon HW, Bae WJ, Lim YC. 2014. BACKGROUND: Identification of a novel biomarker of subclinical lymph node metastasis (SLNM) in papillary thyroid microcarcinoma (PTMC) could provide important clues regarding SLNM in PTMC. We evaluated the significance of HGF and c-Met expression in surgically removed tumor tissue from PTMC patients as a predictive marker of SLNM. METHODS: We analyzed the immunohistochemical relationship between HGF and c-Met expression and SLNM in 113 surgically treated PTMC patients with clinically negative nodes presurgery. In addition, we explored whether HGF/c-Met pathway activation enhanced the in vitro migration and invasion of PTC cells. RESULTS: Positive immunohistochemical HGF and c-Met staining was found in 107 (95 %) and 103 (91 %) cases, respectively. The HGF staining distribution was as follows: no staining in 6 cases, weak staining in

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43, moderate staining in 55, and strong staining in 9. Of the nine cases with strong HGF staining, eight (89 %) had SLNM. The c-Met staining distribution was as follows: no staining in 10 cases, weak staining in 39, moderate staining in 59, and strong staining in 5. Of the five cases with strong c-Met staining, three (60 %) had SLNM. The presence of SLNM was strongly correlated with HGF and c-Met expression in PTMC in a univariate analysis (P < 0.05). HGF overexpression was also associated with SLNM in a multivariate analysis (P < 0.05). Stimulation with exogenous HGF and constitutive activation of c-Met enhanced the migration and invasion of PTC cells in vitro by enhancing VEGF-A expression. CONCLUSIONS: HGF/c-Met pathway activation is associated with SLNM of the central neck in PTMC. PubMed-ID: 24562934 http://dx.doi.org/10.1245/s10434-014-3553-5

SPECT/CT of Metastatic Struma Ovarii. Clin Nucl Med, 39(2):186-7. Koo PJ, Klingensmith WC, III, Bagrosky BM, Haugen BR. 2014. A 41-year-old woman presented with multiple right lower quadrant masses which were removed and consistent with metastatic follicular thyroid cancer. Thyroidectomy revealed no primary malignancy and evaluation of her ovaries was positive for struma ovarii. The patient was diagnosed with metastatic struma ovarii stage IV. Nine days following the patient's second therapy with I for recurrent disease, planar and SPECT/CT imaging demonstrated multiple I avid peritoneal nodules. At least one of them, located along the medial margin of the spleen, would have been difficult to diagnose without hybrid SPECT/CT imaging. PubMed-ID: 23797234 http://dx.doi.org/10.1097/RLU.0b013e3182995971

Patterns of Structural Recurrence in Papillary Thyroid Cancer. World J Surg, 38(3):653-9. Kruijff S, Petersen JF, Chen P, Aniss AM, Clifton-Bligh RJ, Sidhu SB, Delbridge LW, Gill AJ, Learoyd D, Sywak MS. 2014. BACKGROUND: Papillary thyroid carcinoma (PTC) is uncommonly associated with tumor-related mortality, although local recurrence can be a frequent and difficult problem. This study was conducted to clarify the pattern of structural locoregional recurrence in PTC. MATERIAL AND METHOD: A retrospective cohort study of patients undergoing surgical intervention for PTC was undertaken. Data were collected from a comprehensive thyroid cancer database maintained within a single tertiary referral center. The primary outcome measure was cancer recurrence requiring surgical intervention. Secondary outcome measures were site of recurrence, time to recurrence, and risk factors for recurrence. RESULTS: In the period 1980-2013, 1,183 patients with PTC were included in the study. The overall rate of structural recurrence requiring reoperative surgery was 7.9 %. The median time to reoperation was 31 months. Younger age, male gender, large primary tumor diameter, and number of positive lymph nodes at initial presentation were all significantly associated with disease recurrence. The lateral compartments (levels I, II, III, IV, V) were involved almost twice as frequently as the central compartment (level VI) (67 vs 32 %, P < 0.01). The distribution of recurrences was level I (1 %), level II (12 %), level III (18 %), level IV (18 %), level V (17 %), level VI (32 %), level VII (2 %). CONCLUSIONS: In a center with a liberal approach to central compartment lymph node dissection for PTC, the lateral neck compartment is the most common site of structural recurrence requiring reoperative surgery. PubMed-ID: 24149717 http://dx.doi.org/10.1007/s00268-013-2286-0

Pediatric Endocrine Surgery: a 20-Year Experience at the Mayo Clinic. J Clin Endocrinol Metab, 99(2):399-406. Kundel A, Thompson GB, Richards ML, Qiu LX, Cai Y, Schwenk FW, Lteif AN, Pittock ST, Kumar S, Tebben PJ, Hay ID, Grant CS. 2014. CONTEXT: Surgically managed endocrinopathies are rare in children. Most surgeons have limited experience in this field. Herein we report our operative experience with pediatric patients, performed over two decades by high- volume endocrine surgeons. SETTING: The study was conducted at the Mayo Clinic (a tertiary referral center). PATIENTS: Patients were <19 years old and underwent an endocrine operation (1993-2012). MAIN OUTCOME MEASURES: Demographics, surgical procedure, diagnoses, morbidity, and mortality were retrospectively reviewed. RESULTS: A total of 241 primary cases included 177 thyroid procedures, 13 neck dissections, 24 parathyroidectomies, 14 adrenalectomies, 7 paragangliomas, and 6 pancreatic procedures. Average age of patients was 14.2 years. There were 133 total thyroidectomies and 40 hemithyroidectomies. Fifty-three cases underwent a central or lateral neck dissection. Six-month follow-up was available for 98 total thyroidectomy patients. There were four cases of permanent hypoparathyroidism (4%) and no permanent recurrent laryngeal

ESES Review of Recently Published Literature 2014-1 Page 42 of 121 nerve (RLN) paralyses. Sequelae of neck dissections included temporary RLN neurapraxia and Horner's syndrome. Parathyroidectomy was performed on 24 patients: 20 with primary hyperparathyroidism (HPT), three with tertiary HPT, and one with familial hypocalciuric hypocalcemia. Three patients (16%) had recurrent HPT, all with multiglandular disease. One patient had temporary RLN neurapraxia. We performed seven bilateral and seven unilateral adrenalectomies; eight were laparoscopic. Indications included pheochromocytoma, Cushing's syndrome, adrenocortical carcinoma, congenital adrenal hyperplasia, and ganglioneuroma. One death was due to adrenocortical carcinoma. Five paraganglioma patients had succinate dehydrogenase subunit B mutations, and one recurred. Six patients with insulinoma underwent enucleation (n = 5) or distal pancreatectomy (n = 1). A single postoperative abscess was managed nonoperatively. CONCLUSION: Pediatric endocrine procedures are uncommon but can be safely performed with complication rates comparable to those of the adult population. It is imperative that these operations be performed by high-volume surgeons. PubMed-ID: 24423286 http://dx.doi.org/10.1210/jc.2013-2617

Incidence and Risk Factors for Injuries to the Recurrent Laryngeal Nerve During Neck Surgery in the Moderate-Volume Setting. Langenbecks Arch Surg, 399(4):509-15. Landerholm K, Wasner AM, Jarhult J. 2014. PURPOSE: Total lobectomy is currently recommended also in benign thyroid disease in order to reduce the risk of goitre recurrence, an approach claimed not to increase post-operative morbidity. The aim of the study was to analyse risk factors for recurrent laryngeal nerve (RLN) palsy during neck surgery, with particular interest in complications after total lobectomy and subtotal resection, respectively. METHODS: All consecutive patients operated for thyroid and parathyroid diseases at one institution between 1984 and 2011 were prospectively recorded, and 1,322 patients were included. Patients with permanent post-operative RLN palsy were re- examined in 2011. RESULTS: The risk of permanent RLN palsy after parathyroid surgery was 0.3 %. Patients operated for thyroid cancer had a 5.9 % risk of permanent nerve injury, higher than that of patients with benign thyroid disease (1.4 %; P = 0.029). Independent risk factors for RLN paralysis after benign thyroid surgery were intrathoracic goitre (odds ratio (OR), 3.57; 95 % confidence interval, 1.70-7.48), ipsilateral redo-surgery (OR, 3.64; 1.00-13.28) and total lobectomy (OR, 2.41; 1.05-5.55). At long-time follow-up (median, 10 years), 7 of 12 patients with permanent RLN palsy still suffered moderate or severe symptoms. CONCLUSIONS: RLN paralysis is an infrequent complication after neck surgery, but with major negative impact on patients' well-being when permanent. Hemithyroidectomy/total thyroidectomy is increasingly preferred over subtotal resection in multinodular goitre. This is supported by an increased risk of RLN injury during redo-surgery for recurrency but should be carefully weighed against individual risk factors for nerve palsy, including surgical experience and volume. PubMed-ID: 24402457 http://dx.doi.org/10.1007/s00423-013-1154-6

Is BRAFV600E Mutation a Marker for Central Nodal Metastasis in Small Papillary Thyroid Carcinoma? Endocr Relat Cancer, 21(2):285-95. Lang BH, Chai YJ, Cowling BJ, Min HS, Lee KE, Youn YK. 2014. Utilizing BRAF(V600E) mutation as a marker may reduce unnecessary prophylactic central neck dissection (pCND) in clinically nodal negative (cN0) neck for small (

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PubMed-ID: 24402044 http://dx.doi.org/10.1530/ERC-13-0291

Evaluating the Incidence, Clinical Significance and Predictors for Vocal Cord Palsy and Incidental Laryngopharyngeal Conditions Before Elective Thyroidectomy: Is There a Case for Routine Laryngoscopic Examination? World J Surg, 38(2):385-91. Lang BH, Chu KK, Tsang RK, Wong KP, Wong BY. 2014. BACKGROUND: Routine preoperative laryngeal examination remains controversial. We aimed to assess the utility of preoperative routine flexible laryngoscopy (FL) by looking at the incidence, clinical significance and predictors for preoperative vocal cord paresis (VCP) and incidental laryngopharyngeal conditions (LPC) in our consecutive cohort. METHODS: A total of 302 patients underwent laryngeal examination by an independent otorhinolaryngologist and were specifically asked about voice/swallowing symptoms suggestive of VCP 1 day before surgery. As well as vocal cord (VC) mobility, the naso-pharynx and larynx were examined using FL. Any VCP and/or LPC was recorded. VCP was defined as reduced or absent movement in one or more VC. An LPC was considered clinically significant if the ensuing thyroidectomy was changed or deferred. RESULTS: Seven (2.3 %) patients had preoperative VCP, while an additional seven patients had an incidental LPC. Of the seven VCPs, five were caused by previous thyroidectomy, while two were caused by a benign goitre. The incidence of asymptomatic VCP in a previously non-operated cohort was 1/245 (0.41 %). Voice/swallowing symptoms (p = 0.033) and previous thyroidectomy (p < 0.001) were the two significant predictors for VCP. The seven incidental LPCs were vallecular cyst (n = 1), VC scar and polyp (n = 2), nasopharyngeal cyst and polyp (n = 3) and redundant arytenoid mucosa (n = 1); however, as they were benign, all seven patients proceeded to thyroidectomy as planned. CONCLUSIONS: Given the low incidence (0.41 %) of asymptomatic VCP in a previously non-operated cohort and that none of the seven LPCs were considered clinically significant, routine preoperative laryngoscopic examination should be reserved for those with previous thyroidectomy and/or voice/swallowing symptoms. PubMed-ID: 24065418 http://dx.doi.org/10.1007/s00268-013-2259-3

A Cost-Minimization Analysis Comparing Total Thyroidectomy Alone and Total Thyroidectomy With Prophylactic Central Neck Dissection in Clinically Nodal-Negative Papillary Thyroid Carcinoma. Ann Surg Oncol, 21(2):416-25. Lang BH, Wong CK. 2014. BACKGROUND: Total thyroidectomy (TT) with prophylactic central neck dissection (pCND) remains controversial for clinically nodal-negative (cN0) papillary thyroid carcinoma (PTC), and the issue of cost rarely has been examined. We evaluated whether pCND at the time of TT is more cost-saving than TT alone in the medium- to long-term. METHODS: For a hypothetical group of 50-year-old females with a 1.5-cm cN0 PTC, a decision-tree model using TreeAge Software was developed to simulate outcomes and compare the 20-year accumulative direct cost between TT alone and TT+pCND strategies. Baseline values and ranges were determined from a systematic review of the literature. Sensitivity analyses were conducted to test model strength. Cost estimate of surgical procedures, complications, and radioiodine (RAI) ablation was based on government gazette. RESULTS: The cost accrued per patient for the primary operation under TT alone and TT+pCND strategies were USD 6,702.81 and USD 10,062.35, respectively, whereas the cost for the reoperative procedure were USD 12,981.40 and USD 12,509.09, respectively. The 20-year accumulative cost for TT alone and TT+pCND strategies were USD 19,888.36 and USD 22,760.86, respectively. The incremental cost per patient was USD 2,872.50. In the univariate and bivariate sensitivity analyses, no change in conclusion was seen by varying the rates of complications, annualized locoregional recurrences and RAI, or by extending the model to 50 years. CONCLUSIONS: From a pure economic institution's perspective, TT+pCND is more expensive in the medium- and long-term and seems less justified compared with TT alone for cN0 PTC. PubMed-ID: 23982258 http://dx.doi.org/10.1245/s10434-013-3234-9

Antithyroid Drug Use in Early Pregnancy and Birth Defects. Time Windows of Relative Safety and High Risk? Eur J Endocrinol, Laurberg P, Andersen SL. 2014. ANTITHYROID DRUGS (ATDS) MAY HAVE TERATOGENIC EFFECTS WHEN USED IN EARLY PREGNANCY.OBJECTIVE: To review the association between the time period of ATD exposure in early pregnancy and the development of birth defects. METHODS: We identified publications on birth defects after

ESES Review of Recently Published Literature 2014-1 Page 44 of 121 early pregnancy exposure to the ATDs Methimazole (MMI) (and its prodrug Carbimazole (CMZ)), and Propylthiouracil (PTU). Cases of birth defects after ATD treatment had been initiated or terminated within the first 10 weeks of pregnancy were identified and studied in detail. RESULTS: 92 publications were read in detail. Two recent large controlled studies showed ATD associated birth defects in 2-3 % of exposed children, and MMI/CMZ associated defects were often severe. 17 of the publications included cases of birth defects with early pregnancy stop/start of ATD treatment, and these cases suggested that the high risk was confined to gestational weeks 6-10, which is the major period of organogenesis. Thus, the cases reported suggest that the risk of birth defects could be minimized if pregnant women terminate ATD intake before gestational week six. CONCLUSION: Both MMI and PTU use in early pregnancy may lead to birth defects in 2-3 % of the exposed children. MMI associated defects are often severe. Proposals are given on how to minimize the risk of birth defects in fertile women treated for hyperthyroidism with ATDs. PubMed-ID: 24662319 http://dx.doi.org/10.1530/EJE-14-0135

Lobectomy and Prophylactic Central Neck Dissection for Papillary Thyroid Microcarcinoma: Do Involved Lymph Nodes Mandate Completion Thyroidectomy? World J Surg, 38(4):872-7. Lee CR, Son H, Lee S, Kang SW, Jeong JJ, Nam KH, Chung WY, Park CS. 2014. BACKGROUND: The present study was designed to investigate the necessity of completion thyroidectomy for patients who underwent thyroid lobectomy for low-risk papillary thyroid microcarcinoma (PTMC) that was later pathologically diagnosed as central lymph node (CLN) metastasis. METHODS: Between 1986 and 2001, we assessed 551 patients who underwent thyroidectomy with prophylactic ipsilateral central compartment neck dissection, and 409 patients were followed-up completely. Thyroid lobectomy were performed in 281 and 128 patients, respectively. The patients were divided into two groups according to CLN metastasis. Clinicopathological profiles and follow-up details were investigated by retrospective chart review. RESULTS: The CLN-positive and -negative groups were comprised of 43 (15.2 %) and 238 patients (84.8 %), respectively. The mean ages of the two groups were not significantly different (p > 0.05). The mean tumor size of the CLN-positive group (6.8 mm) was significantly larger than that of the CLN-negative group (5.6 mm; p < 0.05). Microscopic capsular invasion was significantly higher in the CLN-positive group (51.2 vs. 23.9 %; p < 0.05). Overall, 21 patients (7.4 %, 21/281) experienced recurrence. Among these, 2 (4.7 %, 2/43) and 19 (8.0 %, 19/238) were in the CLN-positive and -negative groups, respectively. There was no significant correlation between CLN metastasis and tumor recurrence. CONCLUSIONS: Postoperative recurrence was lower in the CLN-positive group, and there was no significant correlation between CLN metastasis and tumor recurrence. Our results suggest that it is not necessary to perform completion thyroidectomy for PTMC patients who have undergone thyroid lobectomy and who have been pathologically diagnosed with CLN metastasis. PubMed-ID: 24305923 http://dx.doi.org/10.1007/s00268-013-2348-3

Prognostic Significance of the Number of Metastatic Lymph Nodes to Stratify the Risk of Recurrence. World J Surg, 38(4):858-62. Lee J, Song Y, Soh EY. 2014. BACKGROUND: Prophylactic dissection facilitates identification of central lymph node (LN) metastasis in patients with papillary thyroid cancer (PTC). Because most staging systems do not stratify risks by the number of LN metastases, postoperative treatments vary among different institutions. Therefore we investigated the significance of number of LN metastases in risk stratification for recurrence in PTC. MATERIAL AND METHODS: A retrospective review was performed for 3,305 patients who had undergone thyroidectomy at Ajou University Hospital. A total of 2,462 patients (73.5 %) underwent total thyroidectomy, and another 3,152 (94.1 %) underwent central LN dissection. Lateral cervical LN dissection had been performed in 420 patients (12.5 %). RESULTS: There were 115 patients with recurrence (3.4 %). Recurrence-free rates were 94.6 % at 5 years and 89.4 % at 10 years. On univariate analysis, prognostic factors for recurrence were extent of thyroidectomy, tumor size, capsular invasion, T stage, N stage, number of LN metastasis, TNM stage, and radioactive iodine (RAI) therapy. On multivariate analysis, number of LN metastasis and N stage were significant prognostic factors for recurrence. Recurrence-free rate was significantly different between patients with 0-1 LN and those with 2 or more LN. CONCLUSIONS: Number of metastatic LN was a significant prognostic factor, in addition to the N stage. Therefore, number of metastatic LN must be considered for postoperative staging system to tailor treatment and follow-up recommendations. In addition, patients with >/=2 metastatic LN may benefit from total thyroidectomy and RAI therapy with postoperative follow-up with serum thyroglobulin. PubMed-ID: 24305921 http://dx.doi.org/10.1007/s00268-013-2345-6

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Atypia of Undetermined Significance in Thyroid Fine-Needle Aspiration Cytology: Prediction of Malignancy by US and Comparison of Methods for Further Management. Ann Surg Oncol, Lee KH, Shin JH, Oh YL, Hahn SY. 2014. BACKGROUND: Further management for thyroid nodules with cytological atypia of undetermined significance (AUS) has made controversial conclusions. The aim of this study was to evaluate the most reliable ultrasonography (US) findings to predict malignancy in thyroid nodules with AUS, and to compare inconclusive rates of repeat fine-needle aspiration (rFNA) and core needle biopsy (CNB) in nodules with AUS. METHODS: We retrospectively reviewed cases of thyroid nodules with AUS from 8,421 US-guided fine-needle aspirations in our institution between 2010 and 2012. Nodules were confirmed either surgically or followed-up for at least 1 year and were compared based on nodule size, US findings, and US diagnosis to predict malignancy. Inconclusive rates of rFNA and CNB after initial AUS were compared. RESULTS: The incidence of AUS in all thyroid nodules was 3.2 % (273 of 8,421). Malignancies were identified in 42.1 % (64 of 152) nodules with surgery or sufficient follow-up. In univariate analysis, not-oval to round shape, irregular margin, taller-than-wide orientation, hypoechogenicity, marked hypoechogenicity, microcalcifications, and malignant US diagnosis were more frequent in actual malignancies (p < 0.05). In multivariate analysis, hypoechogenicity, marked hypoechogenicity, and malignant US diagnosis were significantly more frequent in malignancies (p < 0.05). With respect to further management of AUS, the inconclusive rate of CNB (17.6 %, 6/34) was significantly lower than that of rFNA (37.3 %; 44 of 118) (p = 0.032). CONCLUSIONS: Nodule echogenicity and US diagnosis can be predictive factors of malignancies for the thyroid nodules with cytological AUS. The CNB is more useful than rFNA for reducing the frequency of inconclusive results after initial AUS. PubMed-ID: 24566858 http://dx.doi.org/10.1245/s10434-014-3568-y

Surgical Completeness of Robotic Thyroidectomy: a Prospective Comparison With Conventional Open Thyroidectomy in Papillary Thyroid Carcinoma Patients. Surg Endosc, 28(4):1068-75. Lee S, Lee CR, Lee SC, Park S, Kim HY, Son H, Kang SW, Jeong JJ, Nam KH, Chung WY, Park CS, Cho A. 2014. BACKGROUND: Using the da Vinci((R)) robotic system, surgeons can complete secure thyroidectomy without noticeable neck scarring. This study compared the surgical completeness of transaxillary robotic thyroidectomy (RT) with conventional open procedures (OT) in treating papillary thyroid carcinoma (PTC) patients. MATERIALS AND METHODS: From April 2009 through February 2011, 94 PTC patients underwent total thyroidectomy with central compartment neck dissection (CCND) at Yonsei University College of Medicine. All patients received 1.1 GBq radioactive iodine (RAI) ablation, post-therapy whole-body scans (TxWBS), and diagnostic WBS (DxWBS) 1 year later. We prospectively compared patient clinicopathologic characteristics and surgical completeness between the two groups. RESULTS: Fifty-one patients underwent OT and 43 underwent RT. Mean age was significantly younger in the RT group. Tumor size, capsular-invasion frequency, multifocality, bilaterality, and central nodal metastasis were not different between the two groups. The number of retrieved nodes during CCND did not significantly differ between the groups. There was no significant difference between the OT and RT groups in stimulated thyroglobulin levels acquired during TxWBS and DxWBS. The RAI uptake ratios at TxWBS were significantly higher in the RT group compared with the OT group; however, follow-up DxWBS showed no difference in RAI uptake ratios. Also, the ablation success rate was similar between the two groups. There were no abnormal findings in follow-up neck ultrasonography in either group. CONCLUSION: Remnant thyroid tissue ablation after transaxillary RT was successfully managed by 1.1 GBq RAI. RT showed similar surgical completeness versus conventional OT, and provides a safe and feasible surgical option for PTC patients. PubMed-ID: 24221277 http://dx.doi.org/10.1007/s00464-013-3303-y

Clinical Outcomes in Patients With Non-Diagnostic Thyroid Fine Needle Aspiration Cytology: Usefulness of the Thyroid Core Needle Biopsy. Ann Surg Oncol, 21(6):1870-7. Lee SH, Kim MH, Bae JS, Lim DJ, Jung SL, Jung CK. 2014. BACKGROUND: Patients with non-diagnostic thyroid fine needle aspiration cytology (FNAC) results undergo repeat FNAC or core needle biopsy (CNB) for definite diagnosis or surgical resection, or are followed up by clinical and ultrasound surveillance. We aimed at evaluating the risk of malignancy in patients with non- diagnostic FNACs and their clinical outcomes according to the follow-up modality. METHODS: We retrospectively reviewed 1,496 (8.8 %) cases with a non-diagnostic result on a first aspiration among 17,045

ESES Review of Recently Published Literature 2014-1 Page 46 of 121 thyroid FNACs performed between October 2008 and August 2012. Of the non-diagnostic FNACs, 389 patients underwent a second FNAC; 125, CNB; and 89, thyroidectomy by clinical indication. The remaining patients were clinically followed up. RESULTS: The rate of a second non-diagnostic result was significantly higher on repeat FNAC than on CNB (33.2 vs. 2.4 %; p < 0.001). There was no significant difference in the malignancy risk among patients initially non-diagnostic, twice non-diagnostic, and thrice or more non-diagnostic, nor did this differ from the rate following CNB. No further malignancy was found in cases with >/=2 non-diagnostic CNBs. The malignancy risk was 51 % in those who underwent thyroidectomy. The sensitivity for detecting malignancy was 65 and 70 % for repeat FNACs and first CNBs, respectively, with no false positives seen in either test. CONCLUSIONS: Approximately one-third of repeat FNACs after an initial non-diagnostic aspirate are non- diagnostic on repeat examination, and the malignancy risk may not reduce following repetitively non-diagnostic FNACs. However, a single CNB may be enough to exclude malignancy risk for patients with a non-diagnostic aspirate. PubMed-ID: 24526545 http://dx.doi.org/10.1245/s10434-013-3365-z

Familial History of Non-Medullary Thyroid Cancer Is an Independent Prognostic Factor for Tumor Recurrence in Younger Patients With Conventional Papillary Thyroid Carcinoma. J Surg Oncol, 109(2):168-73. Lee YM, Yoon JH, Yi O, Sung TY, Chung KW, Kim WB, Hong SJ. 2014. BACKGROUND: It is not clear whether familial non-medullary thyroid cancer (FNMTC) is more aggressive and has a poorer prognosis, than sporadic carcinoma. Therefore, the optimal clinical approach for FNMTC is yet to be established. In this study, we investigated the biological behavior and prognosis of FNMTC compared with its sporadic counterpart. METHODS: Between 1996 and 2004, 1,262 patients underwent a total thyroidectomy for conventional PTC at Asan Medical Center and 113 (9.0%) were diagnosed with FNMTC. We compared the clinico-pathologic characteristics, treatment modalities, and prognosis between familial and sporadic NMTC. RESULTS: FNMTC was significantly more multi-centric than sporadic. We also found that family history itself was an independent risk factor for recurrence. Moreover, disease-free survival in the familial group was significantly shorter than in the sporadic group in the subgroups in which age was <45 years, and in which the tumors were multi-centric, bilateral, and of N1b node status. CONCLUSION: FNMTC may be considered as a separate clinical entity with a higher rate of recurrence and worse DFS than its sporadic counterpart. Furthermore, familial history of NMTC is an independent risk factor for recurrence, especially in younger patients with conventional PTC. PubMed-ID: 24132694 http://dx.doi.org/10.1002/jso.23447

Post-Operative Neck Ultrasound and Risk Stratification in Differentiated Thyroid Cancer Patients With Initial Lymph Node Involvement. Eur J Endocrinol, 170(6):837-46. Lepoutre-Lussey C, Maddah D, Golmard JL, Russ G, Tissier F, Tresallet C, Menegaux F, Aurengo A, Leenhardt L. 2014. OBJECTIVE: Cervical ultrasound (US) scan is a key tool for detecting metastatic lymph nodes (N1) in patients with papillary thyroid cancer (PTC). N1-PTC patients are stratified as intermediate-risk and high-risk (HR) patients, according to the American Thyroid Association (ATA) and European Thyroid Association (ETA) respectively. The aim of this study was to assess the value of post-operative cervical US (POCUS) in local persistent disease (PD) diagnosis and in the reassessment of risk stratification in N1-PTC patients. DESIGN: Retrospective cohort study. METHODS: Between 1997 and 2010, 638 N1-PTC consecutive patients underwent a systematic POCUS. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of POCUS for the detection of PD were evaluated and a risk reassessment using cumulative incidence functions was carried out. RESULTS: After a median follow-up of 41.6 months, local recurrence occurred in 138 patients (21.6%), of which 121 were considered to have PD. Sensitivity, specificity, NPV, and PPV of POCUS for the detection of the 121 PD were 82.6, 87.4 95.6, and 60.6% respectively. Cumulative incidence of recurrence at 5 years was estimated at 26% in ETA HR patients, 17% in ATA intermediate-risk patients, and 35% in ATA HR patients respectively. This risk fell to 9, 8, and 11% in the above three groups when the POCUS result was normal and to <6% when it was combined with thyroglobulin results at ablation. CONCLUSION: POCUS is useful for detecting PD in N1-PTC patients and for stratifying individual recurrence risk. Its high NPV could allow clinicians to tailor follow-up recommendations to individual needs. PubMed-ID: 24659355 http://dx.doi.org/10.1530/EJE-13-0888

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Papillary Thyroid Carcinoma Nodal Surgery Directed by a Preoperative Radiographic Map Utilizing CT Scan and Ultrasound in All Primary and Reoperative Patients. Head Neck, 36(2):191-202. Lesnik D, Cunnane ME, Zurakowski D, Acar GO, Ecevit C, Mace A, Kamani D, Randolph GW. 2014. BACKGROUND: To study the diagnostic accuracy of physical examination (PE), ultrasonography (US), contrastenhanced computed tomography (CT) and in preoperative detection of macroscopic nodal metastasis in primary/recurrent papillary thyroid carcinoma (PTC) patients to determine if the routine addition of CT would be beneficial in accurate preoperative lymph-node surgery planning. METHODS: In a tertiary center prospective study, 162 PTC patients underwent preoperative lymph-node evaluation by PE, US, and CT. Sensitivity, specificity, positive/negative predictive value (PPV/NPV) of each nodal detection technique were calculated in central/lateral cervical compartments. The gold standard for diagnostic-accuracy was surgical pathology. RESULTS: In patients undergoing primary (Group I)/revision (Group II) surgical treatment for PTC, combined US/CT yielded significantly higher sensitivity for macroscopic lymph-node detection in both lateral and central neck, most marked in Group I-central compartment. CONCLUSIONS: Combined preoperative US/CT provides reliable, objective, preoperative macroscopic nodal metastasis map to design rational nodal surgery in primary/revision PTC patients. PubMed-ID: 23554058 http://dx.doi.org/10.1002/hed.23277

Consequences of Excess Iodine. Nat Rev Endocrinol, 10(3):136-42. Leung AM, Braverman LE. 2014. Iodine is a micronutrient that is essential for the production of thyroid hormones. The primary source of iodine is the diet via consumption of foods that have been fortified with iodine, including salt, dairy products and bread, or that are naturally abundant in the micronutrient, such as seafood. Recommended daily iodine intake is 150 microg in adults who are not pregnant or lactating. Ingestion of iodine or exposure above this threshold is generally well-tolerated. However, in certain susceptible individuals, including those with pre-existing thyroid disease, the elderly, fetuses and neonates, or patients with other risk factors, the risk of developing iodine- induced thyroid dysfunction might be increased. Hypothyroidism or hyperthyroidism as a result of supraphysiologic iodine exposure might be either subclinical or overt, and the source of the excess iodine might not be readily apparent. PubMed-ID: 24342882 http://dx.doi.org/10.1038/nrendo.2013.251

Role of Preoperative Basal Calcitonin Levels in the Timing of Prophylactic Thyroidectomy in Patients With Germline RET Mutations. World J Surg, 38(3):576-81. Lifante JC, Blanchard C, Mirallie E, David A, Peix JL. 2014. BACKGROUND: The American Thyroid Association (ATA) published recommendations for the timing of prophylactic surgery for medullary thyroid carcinoma based on the specific mutation, patient age, family history, and serum calcitonin levels. The aim of this study was to assess the role of preoperative basal calcitonin (prebCt) levels in predicting the presence of medullary carcinoma of the thyroid in patients with RET mutations. METHODS: We conducted a retrospective study in two endocrine surgery departments. Between 1986 and 2012, a total of 32 patients with RET mutations underwent prophylactic thyroidectomy. The patients were stratified into four ATA risk levels: A, B, C, and D. RESULTS: All of the patients were biologically cured. Microcarcinoma was observed in the final pathology report for four of the 20 patients with normal prebCt (25 %) and for nine of the 12 patients with elevated prebCt (75 %). In the level A group, four patients with normal prebCt and one patient with elevated prebCt presented with microcarcinoma. In the level C group, one patient with normal prebCt and six of the seven patients with elevated prebCt (86 %) presented with microcarcinoma. CONCLUSIONS: PrebCt can predict the presence of microcarcinoma according to surgical pathological analysis. Patients with microcarcinoma can be biochemically and clinically cured using prophylactic thyroidectomy. PubMed-ID: 24357249 http://dx.doi.org/10.1007/s00268-013-2413-y

Treatments for Complications of Tracheal Sleeve Resection for Papillary Thyroid Carcinoma With Tracheal Invasion. Eur J Surg Oncol, 40(2):176-81. Lin S, Huang H, Liu X, Li Q, Yang A, Zhang Q, Guo Z, Chen Y. 2014.

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OBJECTIVE: To evaluate the treatment, prognosis, and complications of differentiated thyroid carcinoma with tracheal invasion. We report our outcomes from a single center using a tracheal sleeve resection. PATIENTS AND METHODS: Retrospective analysis of clinicopathological data on tracheal sleeve resection in patients with thyroid cancer and accompanying tracheal invasion from January 2009 to July 2012. The postoperative complications were analyzed and the literature was reviewed. RESULTS: Nineteen patients with thyroid carcinoma and accompanying tracheal invasion underwent tracheal sleeve resection followed by end-to-end anastomosis. The median survival time was 22 months. Five patients (5/19) developed postoperative complications. The major complications included bilateral recurrent laryngeal nerve paralysis (2 cases), tracheal anastomotic stenosis (1 case), esophageal fistula (2 cases), and anastomotic dehiscence (2 cases). The treatment for these complications included partial posterior cordectomy by CO(2) laser for bilateral recurrent laryngeal nerve paralysis; CO(2) laser treatment followed by postoperative external beam radiotherapy (EBRT) (20 Gy/10 times) for tracheal anastomotic stenosis, femoral anterior dissociative flap to repair esophageal fistula, and a T-tube positioned in the wound in cases of anastomotic dehiscence. CONCLUSIONS: Tracheal sleeve resection remain a safe option with less morbidity and perioperative complications for the management of patients with differentiated thyroid carcinoma accompanied by intratracheal invasion. PubMed-ID: 24388407 http://dx.doi.org/10.1016/j.ejso.2013.12.008

Risk of Thyroid Cancer in Patients With Thyroiditis: a Population-Based Cohort Study. Ann Surg Oncol, 21(3):843-9. Liu CL, Cheng SP, Lin HW, Lai YL. 2014. BACKGROUND: The causative relationship between autoimmune thyroiditis and thyroid cancer remains a controversial issue. The aim of this population-based study was to investigate the risk of thyroid cancer in patients with thyroiditis. METHODS: From the Longitudinal Health Insurance Database 2005 (LHID2005) of Taiwan, we identified adult patients newly diagnosed with thyroiditis between 2004 and 2009 (n = 1,654). The comparison cohort (n = 8,270) included five randomly selected age- and sex-matched controls for each patient in the study cohort. All patients were followed up from the date of cohort entry until they developed thyroid cancer or to the end of 2010. Multivariate Cox regression was used to assess the risk of developing thyroid cancer. A total of 1,000 bootstrap replicates were created for internal validation. RESULTS: A total of 35 patients developed thyroid cancer during the study period, of whom 24 were from the thyroiditis cohort and 11 were from the comparison cohort (incidence 353 and 22 per 100,000 person-years, respectively). After adjusting for potential confounding factors, the hazard ratio (HR) for thyroid cancer in patients with thyroiditis was 13.24 (95 % CI 6.40-27.39). Excluding cancers occurring within 1 year of follow-up, the HR remained significantly increased (6.64; 95 % CI 2.35-18.75). Hypothyroidism was not an independent factor associated with the occurrence of thyroid cancer. CONCLUSIONS: We found an increased risk for the development of thyroid cancer after a diagnosis of thyroiditis, independent of comorbidities. PubMed-ID: 24201747 http://dx.doi.org/10.1245/s10434-013-3363-1

The European Society of Endocrine Surgeons Perspective of Thyroid Cancer Surgery: an Evidence- Based Approach. Langenbecks Arch Surg, 399(2):135-9. Lorenz K, Niederle B, Steinmuller T, Dralle H. 2014. PubMed-ID: 24504672 http://dx.doi.org/10.1007/s00423-013-1157-3

Results of Intraoperative Neuromonitoring in Thyroid Surgery and Preoperative Vocal Cord Paralysis. World J Surg, 38(3):582-91. Lorenz K, Abuazab M, Sekulla C, Schneider R, Nguyen TP, Dralle H. 2014. BACKGROUND: Systematic studies of intermittent intraoperative neuromonitoring (IONM) have shown that IONM enhances recurrent laryngeal nerve (RLN) identification via functional assessment, but does not significantly reduce rates of vocal cord (VC) paralysis (VCP). The reliability of functional nerve assessment depends on the preoperative integrity of VC mobility. The present study was therefore performed to analyze the validity of IONM in patients with pre-existing VC paralysis. METHODS: Of 8,128 patients, 285 (3.5 %) with preoperative VCP underwent thyroid surgery using standardized IONM of the RLN and vagus nerves (VNs). VC function was assessed by pre- and postoperative direct videolaryngoscopy. Quantitative parameters of IONM in patients with VCP were compared with IONM in patients with intact VC function. Clinical symptoms and surgical outcomes of patients with pre-existing VCP were analyzed. RESULTS: A total of 244 patients revealed negative, and 41 revealed positive IONM on the side of the VCP. VCP with positive IONM revealed significantly lower

ESES Review of Recently Published Literature 2014-1 Page 49 of 121 amplitudes of VN and RLN than intact VN (p = 0.010) and RLN (p = 0.011). Symptoms of patients with VCP included hoarseness (25 %), dyspnea (29 %), stridor (13 %), and dysphagia (13 %); 13 % were asymptomatic. New VCP occurred in five patients, ten needed tracheostomy for various reasons, and one patient died. CONCLUSIONS: Patients with pre-existing VCP revealed significantly reduced amplitude of ipsilateral VN and RLN, indicating retained nerve conductivity despite VC immobility. Preoperative laryngoscopy is therefore indispensable for reliable IONM and risk assessment, even in patients without voice abnormalities. PubMed-ID: 24346632 http://dx.doi.org/10.1007/s00268-013-2402-1

Progression of Medullary Thyroid Cancer in RET Carriers of ATA Class A and C Mutations. J Clin Endocrinol Metab, 99(2):E286-E292. Machens A, Lorenz K, Dralle H. 2014. CONTEXT: There is no histopathological or radiological information on the natural course of tumor growth and lymph node metastasis in medullary thyroid cancer (MTC). OBJECTIVE: This investigation aimed at determining annual rates of tumor growth and lymph node metastasis in hereditary MTC at the surgical pathology level. DESIGN: This was a retrospective analysis. SETTING: The setting was a tertiary referral center. PATIENTS: Included were 172 carriers of American Thyroid Association (ATA) class C (95 patients) and class A rearranged during transfection (RET) mutations (77 patients) with MTC. INTERVENTION: The intervention was compartment-oriented surgery. MAIN OUTCOME MEASURES: Comparisons of means between index and nonindex patients yielded incremental primary tumor diameter and incremental number of lymph node metastases, which were divided by incremental patient age at tissue diagnosis. RESULTS: Annual primary tumor growth was 0.4-0.5 mm in node-negative carriers of ATA class A and C mutations. In node-positive carriers, annual primary tumor growth was 2.6 mm (ATA class C mutations) and 1.2 mm (ATA class A mutations), more than 6-fold (2.6 vs 0.4 mm) and more than 2-fold greater (1.2 vs 0.5 mm) than in their node- negative peers. Node-positive carriers revealed an annual rate of lymph node metastasis of 0.6-0.7 nodes independent of ATA class. CONCLUSIONS: Small MTCs may take longer than 10 years to become big enough to visualize on imaging. These slow growth rates highlight the importance of following up on patients for very long time periods to uncover at least some tumoral sources of persistent calcitonin production. PubMed-ID: 24297798 http://dx.doi.org/10.1210/jc.2013-3343

Tyrosine Kinase Inhibitor Treatments in Patients With Metastatic Thyroid Carcinomas: a Retrospective Study of the TUTHYREF Network. Eur J Endocrinol, 170(4):575-82. Massicotte MH, Brassard M, Claude-Desroches M, Borget I, Bonichon F, Giraudet AL, Do CC, Chougnet CN, Leboulleux S, Baudin E, Schlumberger M, de la Fouchardiere C. 2014. OBJECTIVE: Tyrosine kinase inhibitors (TKIs) are used to treat patients with advanced thyroid cancers. We retrospectively investigated the efficacy of TKIs administered outside of clinical trials in metastatic sites or locally advanced thyroid cancer patients from five French oncology centers. DESIGN AND METHODS: THERE WERE 62 PATIENTS (37 MEN, MEAN AGE: 61 years) treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%) outside of clinical trials; 22 had papillary, five had follicular, five had Hurthle cell, 13 had poorly differentiated, and 17 had medullary thyroid carcinoma (MTC). Thirty-three, 25, and four patients were treated with one, two, and three lines of TKIs respectively. Primary endpoints were objective tumor response rate and progression-free survival (PFS). Sequential treatments and tumor response according to metastatic sites were secondary endpoints. RESULTS: Among the 39 sorafenib and 12 sunitinib treatments in differentiated thyroid carcinoma (DTC) patients, partial response (PR) rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line compared with first-line sorafenib or sunitinib therapy (6.7 vs 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment. CONCLUSIONS: This is the largest retrospective study evaluating TKI therapies outside of clinical trials. DTC patients treated with second- line therapy had stable disease as best response, but had a similar median PFS compared with the first-line treatment. PubMed-ID: 24424318 http://dx.doi.org/10.1530/EJE-13-0825

Thyroid Lobectomy for Papillary Thyroid Cancer: Long-Term Follow-Up Study of 1,088 Cases. World J Surg, 38(1):68-79. Matsuzu K, Sugino K, Masudo K, Nagahama M, Kitagawa W, Shibuya H, Ohkuwa K, Uruno T, Suzuki A, Magoshi S, Akaishi J, Masaki C, Kawano M, Suganuma N, Rino Y, Masuda M, Kameyama K, Takami H, Ito K.

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2014. BACKGROUND: Total thyroidectomy is well accepted as initial surgery for papillary thyroid cancer (PTC), but the extent of the thyroidectomy remains a matter of controversy. This study was designed to investigate the long- term clinical outcome of PTC patients who had undergone thyroid lobectomy and to elucidate the indications of lobectomy as initial surgery. METHODS: The cases of 1,088 PTC patients who underwent thyroid lobectomy with curative intent at Ito Hospital between 1986 and 1995 were analyzed retrospectively in this study. None of the patients had received postoperative radioactive iodine (RAI) ablation therapy. The median follow-up period was 17.6 years. All clinical outcomes, including recurrence and death as a result of PTC or other reasons, were evaluated. To establish the indications for lobectomy as initial surgery for PTC, the potential risk factors, such as age, sex, primary tumor size, extrathyroidal invasion, and clinical lymph node metastasis at the time of the initial surgery, were assessed statistically for associations with recurrence and disease-related death. RESULTS: The remnant-thyroid recurrence-free survival (RT-RFS) rate, the regional- lymph-node recurrence-free survival (L- RFS) rate, and the distant-recurrence-free survival (D-RFS) rate as of 25 years after surgery were 93.5, 90.6, and 93.6%, respectively. The cause-specific survival (CSS) rate at 25 years was 95.2%. Univariate and multivariate analyses showed that none of the factors assessed were significantly associated with the RT-RFS rate. Tumor size, clinical lymph node metastasis, and extrathyroidal invasion were significantly associated with the L-RFS rate. The D-RFS and CSS rates were both significantly lower in the group of patients who were aged 45 years old or older, the group whose tumors were larger than 40 mm, and the group with extrathyroidal invasion. Based on the above findings, we classified the patients into four groups according to age <45 or >/= 45 years, tumor size 40 mm, whether clinical lymph node metastasis was present, and whether extrathyroidal invasion was present. None of the patients without any of these four risk factors died of PTC. On the other hand, 22 patients who died of PTC were positive for one or more of these four factors. CONCLUSIONS: The long-term clinical outcome of the PTC patients who had been treated by lobectomy without RAI ablation was excellent. Based on the above results, we concluded that lobectomy is a valid alternative to total thyroidectomy for the treatment of PTC patients who are younger than aged 45 years, whose tumor diameter is 40 mm or less, and who do not have clinical lymph node metastasis or extrathyroidal invasion. PubMed-ID: 24081532 http://dx.doi.org/10.1007/s00268-013-2224-1

Redefining Classification of Central Neck Dissection in Differentiated Thyroid Cancer. Head Neck, 36(2):286-90. McAlister ED, Goldstein DP, Rotstein LE. 2014. Therapeutic central neck dissection for differentiated thyroid cancer is recommended in the setting of clinically positive disease. The role of lymphadenectomy in patients with clinically negative disease is a matter of controversy and therefore extent of surgery varies. The boundaries of the central neck are variably described, as are the components of a central neck dissection. Patients with aggressive disease are managed with a comprehensive dissection, yet there is no classification system to distinguish this from a less rigorous operation. Therefore, there is variability in reporting and difficulty in the interpretation of results in the published literature. Here we propose a novel classification system for central neck dissection in thyroid cancer that allows accurate reporting of extent of surgery. The objectives are to reduce ambivalence and allow documentation of extent of lymphadenectomy, such that comparisons can be made between the varied strategies in the management of the central compartment. PubMed-ID: 23508631 http://dx.doi.org/10.1002/hed.23237

Breaking Tolerance to Thyroid Antigens: Changing Concepts in Thyroid Autoimmunity. Endocr Rev, 35(1):59-105. McLachlan SM, Rapoport B. 2014. Thyroid autoimmunity involves loss of tolerance to thyroid proteins in genetically susceptible individuals in association with environmental factors. In central tolerance, intrathymic autoantigen presentation deletes immature T cells with high affinity for autoantigen-derived peptides. Regulatory T cells provide an alternative mechanism to silence autoimmune T cells in the periphery. The TSH receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (Tg) have unusual properties ("immunogenicity") that contribute to breaking tolerance, including size, abundance, membrane association, glycosylation, and polymorphisms. Insight into loss of tolerance to thyroid proteins comes from spontaneous and induced animal models: 1) intrathymic expression controls self-tolerance to the TSHR, not TPO or Tg; 2) regulatory T cells are not involved in TSHR self-tolerance and instead control the balance between Graves' disease and thyroiditis; 3) breaking TSHR tolerance involves contributions from major histocompatibility complex molecules (humans and induced mouse models), TSHR polymorphism(s) (humans), and alternative splicing (mice); 4) loss of tolerance to Tg before TPO indicates that

ESES Review of Recently Published Literature 2014-1 Page 51 of 121 greater Tg immunogenicity vs TPO dominates central tolerance expectations; 5) tolerance is induced by thyroid autoantigen administration before autoimmunity is established; 6) interferon-alpha therapy for hepatitis C infection enhances thyroid autoimmunity in patients with intact immunity; Graves' disease developing after T-cell depletion reflects reconstitution autoimmunity; and 7) most environmental factors (including excess iodine) "reveal," but do not induce, thyroid autoimmunity. Micro-organisms likely exert their effects via bystander stimulation. Finally, no single mechanism explains the loss of tolerance to thyroid proteins. The goal of inducing self-tolerance to prevent autoimmune thyroid disease will require accurate prediction of at-risk individuals together with an antigen-specific, not blanket, therapeutic approach. PubMed-ID: 24091783 http://dx.doi.org/10.1210/er.2013-1055

BRAF Mutation Status in Papillary Thyroid Carcinoma: Significance for Surgical Strategy. Langenbecks Arch Surg, 399(2):225-8. Miccoli P, Basolo F. 2014. BACKGROUND: BRAF mutation is probably the only molecular marker acting as a risk factor that is available before surgery: for this reason, soon after it became quite widespread, it seemed an important tool as a guide towards an individualized surgical therapy in papillary thyroid carcinoma. PURPOSE: Capsule invasion, multifocality, and lymph node involvement are the most important parameters influencing the choice of surgical strategy in front of small papillary cancers and, in more detail, of micro papillary carcinomas. The relationship between these parameters and the BRAF mutation are closely examined through the more recent literature. Capsular invasion seems to show the strongest correlation with the mutation and this has important correlations, thus suggesting that a more aggressive local surgery might be advisable, whereas the correlation between the mutation and lymph node involvement would be weaker, at least according to the most recent studies. CONCLUSIONS: The personalization of surgical therapy, today, seems easier to achieve thanks to molecular testing. In particular, an important result could be in the short term reduction in the number of completion thyroidectomies following simple lobectomies. Also, post operative radioactivated iodine therapies should be more carefully evaluated and tailored according to BRAF status. A possible flow chart for the decision of the therapeutic approach is proposed in accordance to the results of the literature. PubMed-ID: 24375266 http://dx.doi.org/10.1007/s00423-013-1153-7

Retroauricular Robotic Thyroidectomy With Concomitant Neck-Lift Surgery. Ann Surg Oncol, Mohamed SE, Saeed A, Moulthrop T, Kandil E. 2014. BACKGROUND: Robotic-assisted thyroid surgery using a retroauricular approach was reported as a novel remote access technique for hemithyroidectomy. We report our experience with this remote access technique using a single incision in the retroauricular crease and occipital hairline incision. For the first time, we show additional neck-lift surgery performed concomitantly to achieve better cosmetic outcomes. METHODS: Robotic retroauricular left hemithyroidectomy with concomitant neck-lift surgery was performed in a 59-year-old female patient who was referred for management of a 1.7 cm thyroid nodule located in the mid-lower right thyroid lobe, with fine-needle aspiration biopsy suggestive for follicular neoplasm. The patient had redundant submental skin in her neck, and was planning for a future neck-lift surgery. A concomitant neck lift was performed by the plastic surgeon using the same retroauricular approach to perform the operation. The patient agreed to participate in Institutional Review Board approved protocol. RESULTS: Total operative time was 115 min-flap creation time was 50 min, robot docking time was 10 min, operative console time was 25 min, and concomitant neck-lift surgery extended for 30 min. Estimated blood loss was approximately 30 ml. The patient was discharged home on the same day of surgery and had no postoperative complications. Final pathology confirmed benign follicular adenoma. CONCLUSIONS: Our experience with robotic retroauricular thyroidectomy showed that it is a feasible and safe remote access approach. We suggest that concomitant neck lift can be done in a select group of patients with excess skin on the neck. This approach can be offered to patients with benign and indeterminate thyroid lesions, and future prospective studies are warranted to evaluate the oncological efficacy of this approach in patients with thyroid cancer. PubMed-ID: 24419757 http://dx.doi.org/10.1245/s10434-013-3470-z

Anaplastic Thyroid Carcinoma: a 25-Year Single-Institution Experience. Ann Surg Oncol, 21(5):1665-70. Mohebati A, Dilorenzo M, Palmer F, Patel SG, Pfister D, Lee N, Tuttle RM, Shaha AR, Shah JP, Ganly I. 2014. BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors accounting for

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1-5 % of primary thyroid malignancies. In this retrospective review, we aim to evaluate the prognostic factors, treatment approaches, and outcomes of patients with ATC treated at a single institution. MATERIALS AND METHODS: We retrospectively identified 95 patients with ATC from an institutional database between 1985 and 2010. A total of 83 patients with sufficient records were included in this study. Patient, tumor, and treatment characteristics were recorded. Disease-specific survival (DSS) was determined by the Kaplan-Meier method, and factors predictive of outcome were determined by univariate and multivariate analysis. RESULTS: Of the 83 patients, 41 were male and 42 were female. The median age at presentation was 60 years (range 28-89 years) with a median survival of 8 months. The 1- and 2-year DSS were 33 and 23 %, respectively. On univariate analysis, age less than 60 years, clinically N0 neck, absence of clinical extrathyroidal extension (cETE), gross total resection, and multimodality treatment were statistically significant predictors of improved survival. On multivariate analysis, absence of cETE, multimodality therapy, and gross total resection were predictors of improved outcome. CONCLUSIONS: In patients with locoregional limited disease, multimodality treatment with gross total surgical resection and postoperative radiotherapy with or without chemotherapy offers the best local control and DSS. PubMed-ID: 24554064 http://dx.doi.org/10.1245/s10434-014-3545-5

Surgical Approach and Radioactive Iodine Therapy for Small Well-Differentiated Thyroid Cancer. J Endocrinol Invest, 37(1):57-64. Momesso DP, Vaisman F, Caminha LS, Pessoa CH, Corbo R, Vaisman M. 2014. BACKGROUND: Management of small well-differentiated thyroid cancer (DTC) has generated much debate regarding the surgical approach and radioactive iodine treatment (RAI). AIM: The aim of the study was to evaluate the impact of surgical extension and RAI on the outcome of DTC

Thyroid Metastasectomy. J Surg Oncol, 109(1):36-41. Montero PH, Ibrahimpasic T, Nixon IJ, Shaha AR. 2014. Metastases to the thyroid gland are uncommon. Renal, lung, breast, and colon cancer and melanoma are the most common primary diseases implicated. Few retrospective series have been reported. Treatment decisions must be individualized, and will depend on the state of systemic disease. Selected patients could benefit from surgical treatment. Although most patients selected for surgery will not be cured, the aim of surgery is to avoid the complications of uncontrolled central neck disease. PubMed-ID: 24122778 http://dx.doi.org/10.1002/jso.23452

Malignancy Risk Stratification in Thyroid Nodules With Benign Results on Cytology: Combination of Thyroid Imaging Reporting and Data System and Bethesda System. Ann Surg Oncol, 21(6):1898-903. Moon HJ, Kim EK, Kwak JY. 2014. BACKGROUND: The indications of repeat fine-needle aspiration (FNA) for thyroid nodules with benign results of the Bethesda system were investigated. METHODS: A total of 1,398 nodules were classified according to the Thyroid Imaging Reporting and Data System (TIRADS). TIRADS category 3 included nodules without solidity, hypoechogenicity or marked hypoechogenicity, microlobulated or irregular margins, microcalcifications, and

ESES Review of Recently Published Literature 2014-1 Page 53 of 121 taller-than-wide shape on ultrasonography (US). Categories 4a, 4b, 4c, and 5 included nodules with one, two, three or four, or five suspicious US features, respectively. The malignancy risks, and odds ratio (OR) with 95 % confidence interval (CI) were calculated. Analyses were performed for all nodules, nodules >10 mm, and nodules 10 mm, the malignancy risks of categories 4c and 5 were 2.7 and 20 %, respectively, and the ORs were 10.7 (95 % CI 1.2-93.7) and 236.1 (95 % CI 12.6-4426.4), respectively. In nodules

Autophagy and Thyroid Carcinogenesis: Genetic and Epigenetic Links. Endocr Relat Cancer, 21(1):R13-R29. Morani F, Titone R, Pagano L, Galetto A, Alabiso O, Aimaretti G, Isidoro C. 2014. Thyroid cancer is the most common cancer of the endocrine system and is responsible for the majority of deaths from endocrine malignancies. Although a large proportion of thyroid cancers belong to well differentiated histologic subtypes, which in general show a good prognosis after surgery and radioiodine ablation, the treatment of radio-resistant papillary-type, of undifferentiated anaplastic, and of medullary-type thyroid cancers remains unsatisfactory. Autophagy is a vesicular process for the lysosomal degradation of protein aggregates and of damaged or redundant organelles. Autophagy plays an important role in cell homeostasis, and there is evidence that this process is dysregulated in cancer cells. Recent in vitro preclinical studies have indicated that autophagy is involved in the cytotoxic response to chemotherapeutics in thyroid cancer cells. Indeed, several oncogenes and oncosuppressor genes implicated in thyroid carcinogenesis also play a role in the regulation of autophagy. In addition, some epigenetic modulators involved in thyroid carcinogenesis also influence autophagy. In this review, we highlight the genetic and epigenetic factors that mechanistically link thyroid carcinogenesis and autophagy, thus substantiating the rationale for an autophagy-targeted therapy of aggressive and radio- chemo-resistant thyroid cancers. PubMed-ID: 24163390 http://dx.doi.org/10.1530/ERC-13-0271

Classification of Locoregional Lymph Nodes in Medullary and Papillary Thyroid Cancer. Langenbecks Arch Surg, 399(2):217-23. Musholt TJ. 2014. BACKGROUND: Among the various thyroid malignancies, medullary and papillary thyroid carcinomas are characterized by predominant locoregional lymph node metastases that may cause morbidity and affect patient survival. Although lymph node metastases are frequently detected, the optimal strategy aiming at the removal of all tumor tissues while minimizing the associated surgical morbidity remains a matter of debate. PURPOSE: A uniform consented terminology and classification is a precondition in order to compare results of the surgical treatment of thyroid carcinomas. While the broad distinction between central and lateral lymph node groups is generally accepted, the exact boundaries of these neck regions vary significantly in the literature. Four different classification systems are currently used. The classification system of the American Head and Neck Society and the corresponding classification system of the Union for International Cancer Control (UICC) are based on observations of squamous cell carcinomas and appointed to needs of head and neck surgeons. The classification of the Japanese Society for Thyroid Diseases and the compartment classification acknowledge the distinctive pattern of metastasis in thyroid carcinomas. CONCLUSIONS: Comparison of four existing classification systems reveals underlying different treatment concepts. The compartment system meets the necessities of thyroid carcinomas and is used worldwide in studies describing the results of lymph node dissection. Therefore, the German Association of Endocrine Surgery has recommended using the latter system in their recently updated guidelines on thyroid carcinoma. PubMed-ID: 24306103 http://dx.doi.org/10.1007/s00423-013-1146-6

Evaluation of Genetic Biomarkers for Distinguishing Benign From Malignant Thyroid Neoplasms. Am J Surg, 207(4):596-601. Nagar S, Ahmed S, Peeples C, Urban N, Boura J, Thibodeau B, Akervall J, Wilson G, Long G, Czako P. 2014.

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BACKGROUND: Fine-needle aspiration (FNA) aids in the diagnosis of thyroid nodules. The expression of previously implicated genes was examined to potentially discriminate between benign and malignant thyroid samples. METHODS: Patients included for study had cytology demonstrating follicular cells of undetermined significance, atypical cells of undetermined significance, follicular neoplasm, or suspicion of malignancy with one of the following postoperative diagnoses: follicular thyroid adenomas, follicular thyroid carcinomas, or follicular variant of papillary thyroid carcinomas (FV-PTCs). FNA and tumor expression of human telomerase reverse transcriptase (hTERT), high-mobility group A2 (HMGA2), and trefoil factor 3/3-galactoside-binding lectin (T/G ratio) were analyzed. RESULTS: T/G ratios were not significantly different in the malignant and benign groups. HMGA2 was overexpressed in carcinoma states; however, only FV-PTCs were significant (P = .006). Tumor hTERT expression was detected in 25% of follicular thyroid carcinomas, whereas 5% of FV-PTCs and 10% of follicular thyroid adenomas had expression. FNA aspirates showed similar results. CONCLUSIONS: Although HMGA2 and hTERT showed differential expression, they did not consistently differentiate benign from malignant. Further study based on global gene expression is needed to identify markers that could serve as a diagnostic tool. PubMed-ID: 24713092 http://dx.doi.org/10.1016/j.amjsurg.2013.06.012

Well Differentiated Thyroid Cancer: Are We Over Treating Our Patients? Eur J Surg Oncol, 40(2):129-32. Nixon IJ, Shah JP. 2014. PubMed-ID: 24373300 http://dx.doi.org/10.1016/j.ejso.2013.12.003

Determination of the Optimal Time Interval for Repeat Evaluation After a Benign Thyroid Nodule Aspiration. J Clin Endocrinol Metab, 99(2):510-6. Nou E, Kwong N, Alexander LK, Cibas ES, Marqusee E, Alexander EK. 2014. INTRODUCTION: The optimal timing for repeat evaluation of a cytologically benign thyroid nodule greater than 1 cm is uncertain. Arguably, the most important determinant is the disease-specific mortality resulting from an undetected thyroid cancer. Presently there exist no data that evaluate this important end point. METHODS: We studied the long-term status of all patients evaluated in our thyroid nodule clinic between 1995 and 2003 with initially benign fine-needle aspiration (FNA) cytology. The follow-up interval was defined from the time of the initial benign FNA to any one of the following factors: thyroidectomy, death, or the most recent clinic visit documented anywhere in our health care system. We sought to determine the optimal timing for repeat assessment based on the identification of falsely benign malignancy and, most important, disease-related mortality due to a missed diagnosis. RESULTS: One thousand three hundred sixty-nine patients with 2010 cytologically benign nodules were followed up for an average of 8.5 years (range 0.25-18 y). Thirty deaths were documented, although zero were attributed to thyroid cancer. Eighteen false-negative thyroid malignancies were identified and removed at a mean 4.5 years (range 0.3-10 y) after the initial benign aspiration. None had distant metastasis, and all are alive presently at an average of 11 years after the initial falsely benign FNA. Separate analysis demonstrates that patients with initially benign nodules who subsequently sought thyroidectomy for compressive symptoms did so an average of 4.5 years later. CONCLUSIONS: An initially benign FNA confers negligable mortality risk during long-term follow-up despite a low risk of identifying several such nodules as thyroid cancer. Because such malignancies appear adequately treated despite detection at a mean 4.5 years after falsely benign cytology, these data support a recommendation for repeat thyroid nodule evaluation 2-4 years after the initial benign FNA. PubMed-ID: 24276452 http://dx.doi.org/10.1210/jc.2013-3160

Disease Outcomes and Nodal Recurrence in Patients With Papillary Thyroid Cancer and Lateral Neck Nodal Metastases. ANZ J Surg, 84(4):240-4. O'Neill CJ, Coorough N, Lee JC, Clements J, Delbridge LW, Sippel R, Sywak MS, Chen H, Sidhu SB. 2014. BACKGROUND: The prognostic influence of lateral neck nodal metastases present at the time of diagnosis of papillary thyroid cancer (PTC) remains controversial. This study aims to document disease outcomes and nodal recurrence rates in such patients. METHODS: Patients with PTC and lateral neck nodal metastases who underwent concurrent total thyroidectomy, central and lateral compartment neck dissection between 2000 and 2010 were identified from the prospectively maintained surgical databases of The University of Sydney and University of Wisconsin Endocrine Surgical Units. Disease outcomes and nodal recurrence rates were compared

ESES Review of Recently Published Literature 2014-1 Page 55 of 121 at 12 months post-operatively and in longer-term follow-up. RESULTS: During this 11-year period, 121 patients were identified. Mean age was 45 years; 58% were female and 98% underwent post-operative radioactive iodine ablation. At a median follow-up of 31 months (range 12-140), there were no disease-specific deaths and disease-free survival (defined by stimulated serum thyroglobulin (Tg) < 2.0 mug/L, negative clinical and radiological examination) was 66%. Of the 50 patients with persistently elevated Tg measured 12 months post- operatively, 15 developed clinical lateral neck nodal recurrence. All have undergone re-operative surgery. Elevated stimulated Tg at 12 months post-operatively and a nodal ratio of >30% were significantly associated with an increased risk of lateral neck nodal recurrence. CONCLUSION: With total thyroidectomy, formal compartmental neck dissection and radioactive iodine treatment, disease-free survival can be achieved in the majority of patients with PTC and synchronous lateral neck nodal metastases. A persistently elevated Tg post- operatively and a high ratio of metastatic nodes identify patients at increased risk of locoregional recurrence. PubMed-ID: 23316684 http://dx.doi.org/10.1111/ans.12045

Radioactive Iodine Remnant Uptake After Completion Thyroidectomy: Not Such a Complete Cancer Operation. Ann Surg Oncol, 21(4):1379-83. Oltmann SC, Schneider DF, Leverson G, Sivashanmugam T, Chen H, Sippel RS. 2014. BACKGROUND: Given limitations in preoperative diagnostics, thyroid lobectomy followed by completion thyroidectomy (CT) for differentiated thyroid cancer (DTC) may be required. It is unclear whether resection quality by CT differs from that by total thyroidectomy (TT). Additional surgeon or patient factors may also influence the "completeness" of resection. This study evaluated how CT and surgeon volume influence the adequacy of resection as measured by radioactive iodine (RAI) remnant uptake. METHODS: A retrospective review of a prospectively collected thyroid database was queried for patients treated for DTC with TT or CT followed by RAI ablation. CT patients were matched 1:2 by age, sex, and tumor size to TT patients. Surgeon volume, time to completion, and continuity of surgeon care were reviewed. RESULTS: Over 18 years, 45 patients with DTC had CT and RAI. Mean age was 48 +/- 2 years, and 76 % were female, with a tumor size of 2.7 +/- 0.3 cm. CT had higher remnant uptake than TT (0.07 vs. 0.04 %; p = 0.04). CT performed by a high- volume surgeon had much lower remnant uptakes (0.06 vs. 0.22 %; p = 0.04). Remnant uptake followed a stepwise decrease with involvement of a high-volume surgeon for part or all of the surgical management (p = 0.11). Multiple regression analysis found CT (p = 0.02) and surgeon volume (p = 0.04) to significantly influence uptake after controlling for other factors. CONCLUSIONS: Single-stage TT provides a better resection based on smaller thyroid remnant uptakes than CT for patients with thyroid cancer. If a staged operation for cancer is necessary, surgeon volume may affect the completeness of resection. PubMed-ID: 24378987 http://dx.doi.org/10.1245/s10434-013-3450-3

Reoperative Experience With Papillary Thyroid Cancer. World J Surg, 38(3):645-52. Onkendi EO, McKenzie TJ, Richards ML, Farley DR, Thompson GB, Kasperbauer JL, Hay ID, Grant CS. 2014. BACKGROUND: Intense postoperative monitoring has resulted in increasing detection of patients with recurrent papillary thyroid cancer (PTC). Our goals included quantifying successful reoperation, and analyzing surgical complications and reasons for relapse. METHODS: From 1999 to 2008, a total of 410 patients underwent reoperation for PTC relapse. We analyzed post-reoperative disease outcomes, reasons for relapse, and complications. RESULTS: Bilateral reoperative thyroidectomy was performed in 13 (3 %) patients; lobectomy, 34 (8 %); central neck (VI) soft tissue local recurrence excision, 47 (11.5 %); bilateral VI node dissection, 107 (26 %); unilateral VI dissection, 112 (27 %); levels II-V dissection, 93 (23 %); levels III-V, 86 (21 %); lateral single- or two-compartment dissection, 51 (12 %); and node picking, 20 (5 %) of level VI and 53 (13 %) lateral neck. Complications occurred in 6 %; including hypoparathyroidism, 3 %; unintentional recurrent laryngeal nerve (RLN) paralysis, 3 %; phrenic nerve injury, 0.5 %; spinal accessory nerve injury, 0.5 %; and chyle leak in 1.6 %. Of 380 (93 %) patients with follow-up (mean 5.2 years); 274 (72 %) patients are alive with no structural evidence of disease, 38 % developed disease relapse (mean 2.1 years), 42 (11 %) died from PTC, and 55 (14 %) are alive with disease. The reason for relapse was a false negative pre-reoperative ultrasound (US) in 18 (5 %), nodal recurrence in the operative field in 37 (10 %), a combination of these two reasons in 10 (3 %), and disease virulence (local or systemic recurrence) in 81 (21 %). CONCLUSIONS: Although 72 % of patients were rendered structurally disease free after reoperation, nearly 40 % suffered additional relapse. Improved surgical technique or preoperative localization might positively affect 15-20 %; at least 20 % reflect the biologic aggressiveness of the disease.

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PubMed-ID: 24305931 http://dx.doi.org/10.1007/s00268-013-2379-9

Polydimethylsiloxane for Injection Laryngoplasty: Two Cases Necessitating Tracheotomy. Eur Arch Otorhinolaryngol, 271(4):839-44. Ovari A, Witt G, Schuldt T, Hingst V, Pau HW, Jackel M, Dommerich S. 2014. The surgical treatment of glottic insufficiency due to lesions of the recurrent laryngeal nerve has become a routine procedure in the last few decades. In particular, injection laryngoplasty with polydimethylsiloxane (PDMS) has proved to be an easy, effective and safe method for vocal fold medialization. It is a biologically inert substance having almost ideal properties as a filler; complications related to its intralaryngeal use such as migration, or granuloma formation are extremely rare and allergic reactions have not been reported as yet. We discuss two cases representing the first description of acute severe complications after injection laryngoplasty with PDMS. PubMed-ID: 24500415 http://dx.doi.org/10.1007/s00405-014-2897-6

Deregulation of MicroRNA Expression in Thyroid Neoplasias. Nat Rev Endocrinol, 10(2):88-101. Pallante P, Battista S, Pierantoni GM, Fusco A. 2014. MicroRNAs (miRNAs) have emerged as a class of powerful gene expression regulators. Acting at the post- transcriptional level, miRNAs modulate the expression of at least one-third of the mRNAs that are encoded by the human genome. The expression of a single gene can be regulated by several miRNAs, and every miRNA has more than one target gene. Thus, the miRNA regulatory circuit, which affects essential cellular functions, is of enormous complexity. Moreover, a fundamental role for miRNAs has been determined in the onset and progression of human cancers. Here, we summarize the main alterations in miRNA expression that have been identified in thyroid neoplasias and examine the mechanisms through which miRNA deregulation might promote thyroid cell transformation. We also discuss how the emerging knowledge on miRNA deregulation could be harnessed for the diagnosis and treatment of thyroid neoplasias. PubMed-ID: 24247220 http://dx.doi.org/10.1038/nrendo.2013.223

Caveolin-1 Expression in Papillary Thyroid Carcinoma: Correlation With Clinicopathological Parameters and BRAF Mutation Status. Otolaryngol Head Neck Surg, 150(2):201-9. Paskas S, Jankovic J, Marecko I, Isic DT, Tatic S, Cvejic D, Savin S. 2014. OBJECTIVE: We aimed to investigate the role of caveolin-1 in papillary thyroid carcinoma pathogenesis. STUDY DESIGN: Case series with chart review. SETTING: Institute for the Application of Nuclear Energy. SUBJECTS AND METHODS: We evaluated the expression of caveolin-1 in papillary thyroid carcinoma (PTC) by Western blot (WB) and compared the findings with immunohistochemical (IHC) expression of both epithelial and stromal caveolin-1 on the corresponding histological specimens. The results were related to clinicopathological features and BRAF mutation status. RESULTS: Caveolin-1 expression was found in malignant thyroid epithelium and more abundantly in tumor stroma but varied in both compartments within and between PTC subtypes. Caveolin- 1 expression in the epithelium was more intense in classical PTC than in the other histological types. On the contrary, stromal caveolin-1 expression was stronger in the follicular, solid, and trabecular PTC variants than in classical PTC. Trends for down-regulation of caveolin-1 expression in epithelium and up-regulation in stroma from the classical via follicular to the solid variant were observed. The relation of WB and IHC results with clinicopathological parameters showed lower caveolin-1 tissue content in BRAF mutated tumors (P < .05), a positive correlation of epithelial caveolin-1 expression with lymph node metastasis (P < .05), and a negative association of stromal caveolin-1 expression with the degree of neoplastic infiltration and BRAF status. CONCLUSION: Altered expression of caveolin-1 in the thyroid epithelial and stromal compartments may be involved in the pathogenesis of PTC. The potential clinical significance of caveolin-1 expression, as well as its relation to BRAF mutation status, deserves further investigation. PubMed-ID: 24255086 http://dx.doi.org/10.1177/0194599813512781

Hesperetin Activates the Notch1 Signaling Cascade, Causes Apoptosis, and Induces Cellular Differentiation in Anaplastic Thyroid Cancer. Ann Surg Oncol, Patel PN, Yu XM, Jaskula-Sztul R, Chen H. 2014.

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BACKGROUND: Anaplastic thyroid cancer (ATC) is characterized by very aggressive growth with undifferentiated features. Recently, it has been reported that the Notch1 signaling pathway, which affects thyrocyte proliferation and differentiation, is inactivated in ATC. However, it remains largely unknown whether using Notch1 activating compounds can be an effective therapeutic strategy in ATC. Therefore, in this study, we aimed to evaluate the drug effects of a potential Notch activator hesperetin on ATC cell. METHODS: A unique ATC cell line HTh7 was used to evaluate the drug effects of hesperetin. The Notch1 activating function and cell proliferation were evaluated. The mechanism of growth regulation was investigated by the detection of apoptotic markers. The expression levels of thyrocyte-specific genes were quantified for ATC redifferentiation. RESULTS: Upregulated expression of Notch1 and its downstream effectors hairy and enhancer of split 1 (Hes1) and Hes1 related with YRPW motif was observed in hesperetin-treated ATC cells. The enhanced luciferase signal also confirmed the functional activity of hesperetin-induced Notch1 signaling. Hesperetin led to a time- and dose- dependent decrease in ATC cell proliferation. The cell-growth inhibition was mainly caused by apoptosis as evidenced by increased levels of cleaved poly ADP ribose polymerase and cleaved caspase-3 as well as decreased survivin. Additionally, hesperetin induced the expression levels of thyrocyte-specific genes including thyroid transcription factor 1 (TTF1), TTF2, paired box gene 8, thyroid stimulating hormone receptor, and sodium/iodide symporter. CONCLUSIONS: Hesperetin activates the Notch1 signaling cascade and suppresses ATC cell proliferation mainly via apoptosis. Hesperetin also induces cell redifferentiation of ATC, which could be useful clinically. PubMed-ID: 24419754 http://dx.doi.org/10.1245/s10434-013-3459-7

Cricothyroid Muscle Dysfunction Impairs Vocal Fold Vibration in Unilateral Vocal Fold Paralysis. Laryngoscope , 124(1):201-6. Pei YC, Fang TJ, Li HY, Wong AM. 2014. OBJECTIVES/HYPOTHESIS: The relevance of the cricothyroid (CT) muscle in patients with unilateral vocal fold paralysis (UVFP) remains controversial. To clarify the functional significance of the CT muscle in patients with UVFP, the confounding effect of the severity of recurrent laryngeal nerve injury should be taken into consideration. In the present study, quantitative laryngeal electromyography (LEMG) was used to measure the severity of paralysis of the thyroarytenoid-lateral cricoarytenoid (TA-LCA) muscle complex to allow the functional contribution of the CT muscle to be determined. STUDY DESIGN: Cross-sectional study performed in an otolaryngology outpatient clinic. METHODS: Thirty-one patients with a main diagnosis of UVFP were recruited. The main outcome measures included LEMG examination, quantitative LEMG analysis of the TA-LCA muscle complex, UVFP-related quality-of-life questionnaire (Voice Outcome Survey [VOS]), voice acoustics analysis, videolaryngostroboscopy, and general quality-of-life questionnaire (Short Form-36 Health Survey [SF-36]) assessments. RESULTS: The vocal cord position did not differ between patients with and without CT muscle impairment. Patients with both TA-LCA and CT paralysis showed poorer vocal fold vibration (P = .048) and higher fundamental frequency (P = .02), and the VOS and SF-36 were both poorer compared with patients with only TA-LCA paralysis. CONCLUSIONS: Although the vocal cord position was not influenced by CT muscle function, coexisting CT muscle paralysis may damage the voice by impairing vocal fold vibration in UVFP patients. PubMed-ID: 23712513 http://dx.doi.org/10.1002/lary.24229

[Minimally Invasive Video-Assisted Thyroidectomy: Establishment in a Thyroid Center] Minimalinvasive, Videoassistierte Schilddrusenresektion: Etablierung in Einem Schilddrusenzentrum. Chirurg, 85(3):246-52. Piniek A, Schuhmann R, Coerper S. 2014. BACKGROUND: This study retrospectively evaluated a series of patients who underwent minimally invasive video-assisted thyroidectomy (MIVAT) during the introduction stage of this surgical technique at the Martha- Maria Hospital in Nuremberg. PATIENTS AND METHODS: The eligibility criteria for MIVAT were a thyroid volume < 25 ml, nodules < 30 mm, no thyroiditis, no preoperative evidence of carcinoma and no previous neck surgery. A retrospective evaluation was performed together with a control group of patients who underwent conventional thyroid surgery during the same time period and included a follow-up for general patient satisfaction and cosmetic results. RESULTS: Between August 2008 and July 2009 a total of 55 patients underwent MIVAT including 8 conversions to open surgery and 45 patients who underwent conventional surgery served as matched controls. No significant differences in terms of perioperative complication rates were found (e.g. recurrent laryngeal nerve palsy, hypocalcemia or secondary hemorrhage). The mean operating time was significantly longer in the MIVAT group (96.8 +/- 3.7 min vs. 69.8 +/- 2.3 min, p = 0.001) whereas a significant decrease in the mean operating time for hemithyroidectomy after 5 months was observed (98.1 +/- 3.77 min vs.

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76.0 +/- 4.98 min, p = 0.013). Patients in the MIVAT group were more satisfied with the cosmetic outcome (8.5 +/- 0.3 vs. 8.2 +/- 0.2, p = 0.05) as well as with the overall surgical procedure (9.0 +/- 0.3 vs. 8.6 +/- 0.2, p = 0.02). CONCLUSION: During introduction of the MIVAT procedure a learning effect can be observed which is hallmarked by a decrease in operating time and conversion rate to open surgery. Moreover, no significant differences in terms of main postoperative complications were found so that MIVAT can be considered a safe and feasible technique under the conditions of correct eligibility criteria. PubMed-ID: 24218083 http://dx.doi.org/10.1007/s00104-013-2624-7

Cell Cycle Deregulation and TP53 and RAS Mutations Are Major Events in Poorly Differentiated and Undifferentiated Thyroid Carcinomas. J Clin Endocrinol Metab, 99(3):E497-E507. Pita JM, Figueiredo IF, Moura MM, Leite V, Cavaco BM. 2014. Background: Anaplastic thyroid carcinomas (ATCs) are among the most lethal malignancies, for which there is no effective treatment. Objective: In the present study, we aimed to elucidate the molecular alterations contributing to ATC development and to identify novel therapeutic targets. Design: We profiled the global gene expression of five ATCs and validated differentially expressed genes by quantitative RT-PCR in an independent set of tumors. In a series of 26 ATCs, we searched for pathogenic alterations in genes involved in the most deregulated cellular processes, including the hot spot regions of RAS, BRAF, TP53, CTNNB1 (beta-catenin), and PIK3CA genes, and, for the first time, a comprehensive analysis of components involved in the cell cycle [cyclin-dependent kinase (CDK) inhibitors (CDKI): CDKN1A (p21(CIP1)); CDKN1B (p27(KIP1)); CDKN2A (p14(ARF), p16(INK4A)); CDKN2B (p15(INK4B)); CDKN2C (p18(INK4C))], cell adhesion (AXIN1), and proliferation (PTEN). Mutational analysis was also performed in 22 poorly differentiated thyroid carcinomas (PDTCs). Results: Expression profiling revealed that ATCs were characterized by the underexpression of epithelial components and the up regulation of mesenchymal markers and genes from TGF-beta pathway, as well as, the overexpression of cell cycle-related genes. In accordance, the up regulation of the SNAI2 gene, a TGF-beta-responsive mesenchymal factor, was validated. CDKN3, which prevents the G1/S transition, was significantly up regulated in ATCs and PDTCs and aberrantly spliced in ATCs. Mutational analysis showed that most mutations were present in TP53 (42% of ATCs; 27% of PDTCs) or RAS (31% of ATCs; 18% of PDTCs). TP53 and RAS alterations showed evidence of mutual exclusivity (P = .0354). PIK3CA, PTEN, and CDKI mutations were present in 14%-20% of PDTCs, and in 10%-14% of ATCs. BRAF, CTNNB1, and AXIN1 mutations were rarely detected. Conclusion: Overall, this study identified crucial roles for TP53, RAS, CDKI, and TGF-beta pathway, which may represent feasible therapeutic targets for ATC and PDTC treatment. PubMed-ID: 24423316 http://dx.doi.org/10.1210/jc.2013-1512

The Na+/I- Symporter (NIS): Mechanism and Medical Impact. Endocr Rev, 35(1):106-49. Portulano C, Paroder-Belenitsky M, Carrasco N. 2014. The Na(+)/I(-) symporter (NIS) is the plasma membrane glycoprotein that mediates active I(-) transport in the thyroid and other tissues, such as salivary glands, stomach, lactating breast, and small intestine. In the thyroid, NIS-mediated I(-) uptake plays a key role as the first step in the biosynthesis of the thyroid hormones, of which iodine is an essential constituent. These hormones are crucial for the development of the central nervous system and the lungs in the fetus and the newborn and for intermediary metabolism at all ages. Since the cloning of NIS in 1996, NIS research has become a major field of inquiry, with considerable impact on many basic and translational areas. In this article, we review the most recent findings on NIS, I(-) homeostasis, and related topics and place them in historical context. Among many other issues, we discuss the current outlook on iodide deficiency disorders, the present stage of understanding of the structure/function properties of NIS, information gleaned from the characterization of I(-) transport deficiency-causing NIS mutations, insights derived from the newly reported crystal structures of prokaryotic transporters and 3-dimensional homology modeling, and the novel discovery that NIS transports different substrates with different stoichiometries. A review of NIS regulatory mechanisms is provided, including a newly discovered one involving a K(+) channel that is required for NIS function in the thyroid. We also cover current and potential clinical applications of NIS, such as its central role in the treatment of thyroid cancer, its promising use as a reporter gene in imaging and diagnostic procedures, and the latest studies on NIS gene transfer aimed at extending radioiodide treatment to extrathyroidal cancers, including those involving specially engineered NIS molecules. PubMed-ID: 24311738 http://dx.doi.org/10.1210/er.2012-1036

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Postoperative PTH Measurement Is Not a Reliable Predictor for Hypocalcemia After Total Thyroidectomy in Vitamin D Deficiency: Prospective Study of 203 Cases. World J Surg, 38(3):564-7. Pradeep PV, Ramalingam K. 2014. BACKGROUND: Several factors have been used to predict post total thyroidectomy (TT) hypocalcemia. Serum intact PTH (PTH) levels <10 pg/mL after TT is considered to be the most accurate predictor. The aim of the present study was to evaluate the accuracy of PTH as a predictor of post-TT hypocalcemia in patients with vitamin D deficiency. MATERIALS AND METHODS: The present prospective study was conducted from 2009 to 2011 and included patients undergoing TT for benign goiter. The PTH levels 8 h after TT in patients who were vitamin D sufficient (group A; S Vit D >20 ng/mL) versus those who were vitamin D deficient (group B) were compared. Comparison was also performed between patients belonging to group A and group B who developed hypocalcemia. Appropriate statistical tests were applied. RESULTS: A total of 203 patients (19 males, 184 females) underwent TT; 58.6 % (n = 119) belonged to group A and 41.4 % (n = 84) to group B. Their mean age was 36.81 +/- 12.9 years, and the mean duration of goiter was 45.35 +/- 54.6 months. Hypocalcemia occurred in 41 patients (20.2 %). Among them 15 belonged to group A and 26 to group B (p = 0.002). The mean PTH in patients who developed hypocalcemia was 12.75 +/- 8.91 versus 22.58 +/- 15.38 in those who did not develop hypocalcemia (p = 0.00). Furthermore it was seen that the mean PTH in vitamin D sufficient hypocalcemic patients (n = 15) was 7.12 +/- 1.79 and that in vitamin D deficient hypocalcemic patients (n = 26) was 16 +/- 9.77 (p = 0.001) CONCLUSIONS: Our findings suggest that the fall in PTH after TT in vitamin D deficient patients is unreliable in predicting hypocalcemia and should not be relied on to plan early postoperative discharge. PubMed-ID: 24305924 http://dx.doi.org/10.1007/s00268-013-2350-9

Thyroid Surgery Without Antibiotic Prophylaxis: Experiences With 1,030 Patients From a Teaching Hospital in China. World J Surg, 38(4):878-81. Qin Q, Li H, Wang LB, Li AH, Chen LJ, Lu Q. 2014. OBJECTIVE: Our objective was to evaluate the outcome of thyroidectomy without the use of prophylactic antibiotics. This study was held from January 2005 to May 2012 in a teaching hospital in Dongguan, China. METHODS: A total of 1,030 thyroidectomy patients were retrospectively reviewed and basic data were recorded, including age, sex, peri-operative antibiotic use, type of thyroid surgery done, and post-operative complications. Either an open approach or an endoscopic approach was performed according to the doctor's or patient's preference following a strict aseptic technique. The drain was routinely placed. Any complications were analyzed. RESULTS: A total of 834 (81 %) females and 196 (19 %) males were included, giving a ratio of 4.2:1. The average age was 38.3 years. The mean operation time was 85.3 min. Pathological type included 818 (79.4 %) nodular goiter, 34 (3.3 %) Graves' disease, 102 (9.9 %) nodular papillary hyperplasia, 12 (1.2 %) Hashimoto's disease, 62 (6 %) papillary carcinoma, and 2 (0.2 %) medullary carcinoma. Four patients had postoperative bleeding, four had temporally recurrent nerve paralysis. Only one had wound infection (0.09 %). CONCLUSION: Antibiotic prophylaxis in elective thyroidectomy is not an essential pre-operation preparation for all patients, if guidelines for antibiotic prophylaxis in clean surgery are adhered to and surgeons have sophisticated skills in the procedure. PubMed-ID: 24452291 http://dx.doi.org/10.1007/s00268-014-2453-y

Intraoperative Neural Monitoring in Thyroid Cancer Surgery. Langenbecks Arch Surg, 399(2):199-207. Randolph GW, Kamani D. 2014. BACKGROUND: Intraoperative neural monitoring (IONM) has increasingly garnered the attention of the surgeons performing thyroid and parathyroid surgery around the world. Current studies suggest a majority of general and head and neck surgeons utilize neural monitoring in their thyroid surgical case load in both the US and Germany. PURPOSE: We aim to present an up-to-date review of the application of IONM specifically focusing on its utility in thyroid cancer surgery. Neural monitoring is discussed particularly as it relates to neural prognosis, the issues of staged thyroid surgery for thyroid cancer, and new horizons in the monitoring of the superior laryngeal nerve (SLN) and prevention of neural injury through continuous vagal neural monitoring. CONCLUSION: IONM, as it relates to thyroid surgery, has obtained a widespread acceptance as an adjunct to the gold standard of visual nerve identification. The value of IONM in prognosticating neural function and in intraoperative decision making regarding proceeding to bilateral surgery is also well-known. Initial data on recent extensions of IONM in the form of SLN monitoring and continuous vagal nerve monitoring are promising. Continuous vagal nerve monitoring expands the utility of IONM by providing real-time electrophysiological

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Thyroid Cancer in 2013: Advances in Our Understanding of Differentiated Thyroid Cancer. Nat Rev Endocrinol, 10(2):69-70. Reiners C. 2014. Studies published in 2013 have addressed the question of whether the rising incidence of differentiated thyroid cancer is actually the result of overdiagnosis. Advances have also been made in the treatment of differentiated thyroid cancer, including improvements in radioiodine therapy. PubMed-ID: 24296516 http://dx.doi.org/10.1038/nrendo.2013.247

Predictive Factors of Thyroid Cancer in Patients With Graves' Disease. World J Surg, 38(1):80-7. Ren M, Wu MC, Shang CZ, Wang XY, Zhang JL, Cheng H, Xu MT, Yan L. 2014. BACKGROUND: The best preoperative examination in Graves' disease with thyroid cancer still remains uncertain. The objectives of the present study were to investigate the prevalence of thyroid cancer in Graves' disease patients, and to identify the predictive factors and ultrasonographic features of thyroid cancer that may aid the preoperative diagnosis in Graves' disease. METHODS: This retrospective study included 423 patients with Graves' disease who underwent surgical treatment from 2002 to 2012 at our institution. The clinical features and ultrasonographic findings of thyroid nodules were recorded. The diagnosis of thyroid cancer was determined according to the pathological results. RESULTS: Thyroid cancer was discovered in 58 of the 423 (13.7 %) surgically treated Graves' disease patients; 46 of those 58 patients had thyroid nodules, and the other 12 patients were diagnosed with incidentally discovered thyroid carcinomas without thyroid nodules. Among the 58 patients with thyroid cancer, papillary microcarcinomas were discovered in 50 patients, and multifocality and lymph node involvement were detected in the other 8 patients. Multivariate regression analysis showed younger age was the only significant factor predictive of metastatic thyroid cancer. Ultrasonographic findings of calcification and intranodular blood flow in thyroid nodules indicate that they are more likely to harbor thyroid cancers. CONCLUSIONS: Because the influencing factor of metastatic thyroid cancers in Graves' disease is young age, every suspicious nodule in Graves' disease patients should be evaluated and treated carefully, especially in younger patients because of the potential for metastasis. PubMed-ID: 24166025 http://dx.doi.org/10.1007/s00268-013-2287-z

The Role of Thyroidectomy in Metastatic Disease to the Thyroid Gland. Ann Surg Oncol, 21(2):434-9. Romero Arenas MA, Ryu H, Lee S, Morris LF, Grubbs EG, Lee JE, Perrier ND. 2014. BACKGROUND: Whether thyroidectomy for metastases to the thyroid is associated with a survival benefit remains debatable; in general, palliation and disease control are accepted goals in this setting. We evaluated the clinical features and overall survival of patients with thyroid metastasis treated by thyroid resection or nonoperatively. METHODS: This retrospective analysis included 90 patients identified with metastasis to the thyroid confirmed pathologically via thyroidectomy (n = 31) or fine-needle aspiration biopsy (n = 59). Overall survival was calculated by the Kaplan-Meier method, and differences between groups were calculated by Pearson's chi (2) coefficient. RESULTS: The most common primary malignancies were renal cell (20%), head and neck (19%), and lung (18%). The median time from primary tumor diagnosis to thyroid metastasis diagnosis was 37.4 months (range 0-210 months). Most metastases (69%) were metachronous, and 12% were isolated. The median follow-up after diagnosis of thyroid metastasis was 11.5 months (range 0-112 months). Median overall survival was longer in thyroidectomy patients compared to the fine-needle aspiration group (34 vs. 11 months, P < 0.0001). Patients with renal cell primary tumors were more likely to undergo thyroidectomy than patients with other primary tumors (78 vs. 24%, P < 0.0001). Nearly all patients with lung primary tumors died within 24 months of thyroid metastasis diagnosis, and thyroidectomy was only offered to three patients. CONCLUSIONS: Thyroidectomy was safe for selected patients with metastatic disease to the thyroid. Patients with metachronous or renal cell metastasis to the thyroid and whose primary tumor is/was treatable may be appropriate candidates for resection. Lung cancer metastasis to the thyroid is generally an ominous sign. PubMed-ID: 24081800 http://dx.doi.org/10.1245/s10434-013-3282-1

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Predictive Factors of Malignancy in Thyroid Nodules With Repeatedly Nondiagnostic Cytology (Bethesda Category I): Value of Ultrasonography. Horm Metab Res, 46(4):294-8. Rosario PW, Penna GC, Calsolari MR. 2014. One possible result of fine-needle aspiration (FNA) of thyroid nodules is "nondiagnostic" cytology. Consensus exists in these cases to repeat FNA guided by ultrasonography (US), but the result obtained may continue to be nondiagnostic. The objective of this study was to evaluate predictive factors of malignancy (including US) in nodules with indication for FNA whose cytology result was classified as "nondiagnostic" on 2 occasions. The sample consisted of 158 patients with thyroid nodules >5 mm with indication for FNA whose material obtained by US-guided FNA was classified as nondiagnostic on 2 occasions according to the criteria of the Bethesda classification. Papillary thyroid carcinoma (PTC) was confirmed by histology in 23/158 cases (14.5%). Sex, age, family history of PTC, palpation, number of nodules, serum TSH, or circulating antithyroperoxidase antibodies were not predictors of malignancy. Only US predicted risk of malignancy. US showed a sensitivity of 65.2% and a specificity of 90.4%. When US indicated the nodule to be "suspicious for malignancy", histology confirmed PTC in 15/28 cases (positive predictive value 53.4%). When the nodule showed no suspicious US features, histology detected malignancy in only 8/130 cases (negative predictive value 94%). The diagnostic accuracy of the US was 89.5%. The present results suggest that, in cases of patients with thyroid nodules and repeatedly nondiagnostic cytology, ultrasonographic findings represent an excellent parameter for the selection of those who could be followed up by periodic US and those who should be referred for thyroidectomy because of the risk of malignancy. PubMed-ID: 24505030 http://dx.doi.org/10.1055/s-0034-1367044

Lymph Node Ratio of the Central Compartment Is a Significant Predictor for Locoregional Recurrence After Prophylactic Central Neck Dissection in Patients With Thyroid Papillary Carcinoma. Ann Surg Oncol, 21(1):277-83. Ryu IS, Song CI, Choi SH, Roh JL, Nam SY, Kim SY. 2014. BACKGROUND: Lymph node ratio (LNR) is an important prognosis factor in many solid cancers, but there have been few reports of LNR in papillary thyroid carcinoma (PTC). This study investigated LNR of the central compartment to determine whether LNR has clinical significance as a prognostic predictor for recurrence after prophylactic central neck dissection (pCND) in patients with PTC. METHODS: The study includes 295 consecutive patients who underwent total thyroidectomy with bilateral pCND, which was pathologically diagnosed as N1a PTC. LNR was calculated as the ratio of positive LN to total LN removed. RESULTS: LNR of 0.65 was significantly meaningful for recurrence when three or more LNs were collected (P < 0.001). The 10- year estimated recurrence-free survival rates were 98.6 % for patients with LNR 0.65 (P < 0.001). Univariate analysis revealed that increasing tumor size and LNR >0.65 were significantly associated with recurrence (P < 0.05 each). No significant association with recurrence was found for age >/=45 years, male gender, microscopic extrathyroidal extension, coexistent chronic lymphocytic thyroiditis, T classification, multicentricity, number of positive LN, and extranodal extension (P > 0.05 each). The only independent variable for recurrence identified by multivariate analysis was LNR >0.65 (P < 0.001). CONCLUSIONS: LNR may be a useful predictor to stratify the likelihood of recurrence after pCND in patients with pathologic N1a PTC. PubMed-ID: 24006096 http://dx.doi.org/10.1245/s10434-013-3258-1

The Prognostic Relevance of Psammoma Bodies and Ultrasonographic Intratumoral Calcifications in Papillary Thyroid Carcinoma. World J Surg, 38(3):748. Sabaretnam M, Timothy J, Kamalaretnam M, Maniketh I. 2014. PubMed-ID: 23982783 http://dx.doi.org/10.1007/s00268-013-2214-3

SMALL MEDULLARY THYROID CARCINOMA (MTC): POSTOPERATIVE CALCITONIN RATHER THAN TUMOUR SIZE PREDICT DISEASE PERSISTENCE AND PROGRESSION. Eur J Endocrinol, Saltiki K, Rentziou G, Stamatelopoulos K, Georgiopoulos G, Stavrianos C, Lanbrinoudaki E, Alevizaki M. 2014. OBJECTIVE: Recently, smallMTCs (

ESES Review of Recently Published Literature 2014-1 Page 62 of 121 up for 0.9-30.9yrs. Patients were classified according to tumour size (cm) group1: 0.1-0.5 (n=33), group2: 0.6- 0.8 (n=33), group3: 0.8-1.0 (n=29), group4: 1.1-1.5 (n=33). RESULTS: Preoperative and postoperative calcitonin levels were positively associated with tumour size (p<0.001). Capsular and lymph node invasion were more frequent in groups 3 and 4 (p<0.03); stage was more advanced and outcome less favourable with increasing tumour size (p<0.001). Group1 and 2 patients were more frequently cured (group1: 87.8% group 2: 72.7%, group 3: 68.9% and group 4: 48.5%, p=0.002). The 10year probability of lack of disease progression according to tumour size did not differ significantly between the 4 groups; it differed marginally between patients with tumour 0.1-1.0 and 1.1-1.5cm (96.6%, 81.3%, x2=4.03, p=0.045, Log Rank). Postoperative calcitonin was the only predictor significantly associated with the 10-year progression of disease. Postoperative calcitonin levels >/=4.65 pg/ml predicted disease persistence (sensitivity 93.8 %, specificity 90%) and >/=14.5 pg/ml disease progression (sensitivity 100%, specificity 82%, ROC analysis). CONCLUSIONS: Tumour size may be of clinical importance only in patients with MTCs>1cm. Postoperative calcitonin is more important predictor than size for disease progression. PubMed-ID: 24760539 http://dx.doi.org/10.1530/EJE-14-0076

Thyroidectomy As Primary Treatment Optimizes Body Mass Index in Patients With Hyperthyroidism. Ann Surg Oncol , Schneider DF, Nookala R, Jaraczewski TJ, Chen H, Solorzano CC, Sippel RS. 2014. OBJECTIVE: The purpose of this study was to determine how the timing of thyroidectomy influenced postoperative weight change. METHODS: We conducted a two-institution study, identifying patients treated with total thyroidectomy for hyperthyroidism. Patients were classified as 'early' if they were referred for surgery as the first treatment option, or 'delayed' if they were previously treated with radioactive iodine (RAI). Groups were compared with the Student's t-test or chi 2 test where appropriate. RESULTS: There were 204 patients undergoing thyroidectomy for hyperthyroidism. Of these, 171 patients were classified as early and 33 were classified as delayed. Overall, patients gained 6.0 % +/-0.8 of their preoperative body weight at last follow-up. Preoperative body mass indexes (BMIs) were similar between groups (p = 0.98), and the median follow-up time was 388 days (range 15-1,584 days). Both groups gained weight until they achieved a normal thyroid-stimulating hormone (TSH) postoperatively. After achieving a normal TSH, the early group stabilized or lost weight (-0.2 lbs/day), while the delayed group continued to gain weight (0.02 lbs/day; p = 0.61). At last follow-up, there were significantly more patients in the delayed group who increased their BMI category compared with the early group (42.4 vs. 21.6 %; p = 0.01). Twice as many patients in the delayed group moved up or into an unhealthy BMI category (overweight or obese) compared with the early group (39.4 vs. 19.3 %; p = 0.01). CONCLUSIONS: Compared with patients initially treated with RAI, patients with hyperthyroidism who underwent surgery as the first treatment were less likely to become overweight or obese postoperatively. PubMed-ID: 24522995 http://dx.doi.org/10.1245/s10434-014-3542-8

A Ten-Year Clinical Update of a Large RET P.Gly533Cys Kindred With Medullary Thyroid Carcinoma Emphasizes the Need for an Individualized Assessment of Affected Relatives. Clin Endocrinol (Oxf), 80(2):235-45. Signorini PS, Franca MI, Camacho CP, Lindsey SC, Valente FO, Kasamatsu TS, Machado AL, Salim CP, Delcelo R, Hoff AO, Cerutti JM, Dias-da-Silva MR, Maciel RM. 2014. OBJECTIVE: Reviewing the clinical outcomes of a large kindred with a RET p.Gly533Cys mutation, 10 years after the first description of this kindred, has provided an important set of clinical data for healthcare decision- making. DESIGN AND PATIENTS: We identified 728 RET533 Brazilian relatives, spread out over 7 generations. We performed clinical examination, biochemical and imaging analyses in the proband and in 103 carriers. MEASUREMENT AND RESULTS: The proband has been followed without evidence of structural disease in the last 10 years but with elevated calcitonin. The clinical and surgical features of 60 thyroidectomized RET533 relatives were also described. Forty-six patients had MTC (21-72 years), and 11 patients had C-cell hyperplasia (CCH) (5-42 years). Twelve MTC patients with lymph node metastases had a tumour size of 0.7-2.8 cm. Calcitonin level and CEA were correlated with disease stage, and none of the patients presented with an altered PTH or metanephrine. A 63-year-old woman developed pheochromocytoma and breast cancer. Two other RET533 relatives developed lung squamous cell carcinoma and melanoma. CONCLUSIONS: A vast clinical variability in RET533 presentation was observed, ranging from only an elevated calcitonin level (3%) to local metastatic disease (25%). Many individuals were cured (42%) and the majority had controlled chronic disease (56%), reinforcing the need for individualized ongoing risk stratification assessment. The importance of this update relies on the fact that it allows us to delineate the natural history of RET 533 MEN2A 10 years after its first description.

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PubMed-ID: 23745650 http://dx.doi.org/10.1111/cen.12264

Defining Anatomical Landmarks for Robotic Facelift Thyroidectomy. World J Surg, 38(1):92-5. Singer MC, Heffernan A, Terris DJ. 2014. BACKGROUND: Robotic facelift thyroidectomy (RFT) is a straightforward remote access thyroidectomy technique. While the anatomy encountered during RFT is well known to surgeons, the vector of approach during this technique may be less familiar. In order to facilitate safe and efficient performance of RFT, the relationships of key anatomical landmarks associated with this technique were determined. METHODS: Eight anatomical dissections were performed in cadavers and included performance of RFT and definition of discrete anatomical relationships. Morphologic assessments of the great auricular nerve (GAN), omohyoid (OH) muscle, inferior constrictor (IC) muscle, and recurrent laryngeal nerve (RLN) were conducted. RESULTS: The mean distance from the incision apex to the anterior and posterior aspects of the GAN were 3.8 +/- 1.2 and 7.7 +/- 0.8 cm. From the apex of the incision to the OH muscle was 11.1 +/- 1.7 cm on average. The OH muscle was located 1.3 +/- 0.5 cm inferior to an axial line drawn through the inferior aspect of the thyroid notch. The anterior branch of the RLN was identified coursing deep to the inferior margin of the IC muscle a mean of 1.2 +/- 0.2 cm lateral to the origin of this muscle on the cricoid cartilage. CONCLUSIONS: Characterization of the key anatomical landmarks of the lateral neck and thyroid compartment associated with RFT, including the GAN, OH muscle, and RLN, allows for rapid recognition of these critical structures during this operation. Surgeons learning this approach should be familiar with these relationships. PubMed-ID: 24101022 http://dx.doi.org/10.1007/s00268-013-2246-8

Reply to Letter: "Surgery for Asymmetrical Multinodular Goiter". Ann Surg, Sitges-Serra A. 2014. PubMed-ID: 24424139 http://dx.doi.org/10.1097/SLA.0000000000000379

RNA Sequencing Identifies Multiple Fusion Transcripts, Differentially Expressed Genes, and Reduced Expression of Immune Function Genes in BRAF (V600E) Mutant Vs BRAF Wild-Type Papillary Thyroid Carcinoma. J Clin Endocrinol Metab, 99(2):E338-E347. Smallridge RC, Chindris AM, Asmann YW, Casler JD, Serie DJ, Reddi HV, Cradic KW, Rivera M, Grebe SK, Necela BM, Eberhardt NL, Carr JM, McIver B, Copland JA, Aubrey TE. 2014. CONTEXT: The BRAF V600E mutation (BRAF-MUT) confers an aggressive phenotype in papillary thyroid carcinoma, but unidentified additional genomic abnormalities may be required for full phenotypic expression. OBJECTIVE: RNA sequencing (RNA-Seq) was performed to identify genes differentially expressed between BRAF-MUT and BRAF wild-type (BRAF-WT) tumors and to correlate changes to patient clinical status. DESIGN: BRAF-MUT and BRAF-WT tumors were identified in patients with T1N0 and T2-3N1 tumors evaluated in a referral medical center. Gene expression levels were determined (RNA-Seq) and fusion transcripts were detected. Multiplexed capture/detection and digital counting of mRNA transcripts (nCounter, NanoString Technologies) validated RNA-Seq data for immune system-related genes. PATIENTS: BRAF-MUT patients included nine women, three men; nine were TNM stage I and three were stage III. Three (25%) had tumor infiltrating lymphocytes. BRAF-WT included five women, three men; all were stage I, and five (62.5%) had tumor infiltrating lymphocytes. RESULTS: RNA-Seq identified 560 of 13 085 genes differentially expressed between BRAF-MUT and BRAF-WT tumors. Approximately 10% of these genes were related to MetaCore immune function pathways; 51 were underexpressed in BRAF-MUT tumors, whereas 4 (HLAG, CXCL14, TIMP1, IL1RAP) were overexpressed. The four most differentially overexpressed immune genes in BRAF-WT tumors (IL1B; CCL19; CCL21; CXCR4) correlated with lymphocyte infiltration. nCounter confirmed the RNA-Seq expression level data. Eleven different high-confidence fusion transcripts were detected (four interchromosomal; seven intrachromosomal) in 13 of 20 tumors. All in-frame fusions were validated by RT-PCR. CONCLUSION: BRAF-MUT papillary thyroid cancers have reduced expression of immune/inflammatory response genes compared with BRAF-WT tumors and correlate with lymphocyte infiltration. In contrast, HLA-G and CXCL14 are overexpressed in BRAF-MUT tumors. Sixty-five percent of tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of these newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-MUT and BRAF-WT tumors.

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PubMed-ID: 24297791 http://dx.doi.org/10.1210/jc.2013-2792

Lack of Association Between High Serum Thyroid-Stimulating Hormone Level and Risk of Papillary Thyroid Microcarcinomas. Head Neck, 36(1):43-6. Sohn SY, Kim HJ, Jang HW, Kim SW, Chung JH. 2014. BACKGROUND: High serum thyroid-stimulating hormone (TSH) is associated with thyroid carcinoma in patients with thyroid nodules. However, previous studies suggests that TSH is not involved in the pathogenesis of small thyroid carcinomas. We performed this study to evaluate serum TSH as a malignancy predictor in the assessment of small thyroid nodules. METHODS: We retrospectively analyzed 3791 patients who underwent thyroidectomy. We classified all patients into 3 to 5 groups by serum TSH or nodule size and analyzed the association of serum TSH and risk of papillary thyroid carcinoma (PTC). RESULTS: The frequency of PTC increased as serum TSH increased. Serum TSH and older age were associated with the risk of PTC in multivariate analysis (p < .0001). In subgroup analysis, the risk of PTC increased as serum TSH increased with thyroid nodules > 1 cm (p < .05). CONCLUSIONS: Serum TSH may not be useful for clinical risk assessment of small thyroid nodules. PubMed-ID: 23728859 http://dx.doi.org/10.1002/hed.23252

Optimization of Staging of the Neck With Prophylactic Central and Lateral Neck Dissection for Papillary Thyroid Carcinoma. Ann Surg, Sterpetti AV. 2014. PubMed-ID: 24441800 http://dx.doi.org/10.1097/SLA.0000000000000510

Biological Differential Diagnosis of Follicular Thyroid Tumor and Hurthle Cell Tumor on the Basis of Telomere Length and HTERT Expression. Ann Surg Oncol, Sugishita Y, Kammori M, Yamada O, Yamazaki K, Ito KI, Fukumori T, Yoshikawa KI, Yamada T. 2014. BACKGROUND: The most difficult thyroid tumors to diagnose by histology are follicular carcinomas (FTCs) and Hurthle cell carcinomas (HCCs). Telomere alteration and human telomerase reverse transcriptase (hTERT) expression have been observed in most human cancers and are known to be a feature of malignancy. The purpose of this study was to clarify whether hTERT protein expression and telomere alteration could be applicable biological markers for distinguishing FTC from HCC. METHODS: We investigated a total of 78 thyroid tumor cases, including 14 FTCs, 47 follicular adenomas (FTAs), 5 HCCs, and 12 Hurthle cell adenomas (HCAs). hTERT protein expression was examined by immunohistochemistry, and telomere length was determined by tissue quantitative fluorescence in situ hybridization. RESULTS: Positivity for hTERT protein expression was observed in 86 % of FTCs and 49 % of FTAs. Telomeres in FTCs were significantly shorter than those in FTAs. All HCCs and HCAs (100 %) expressed hTERT protein. Telomeres in HCCs were significantly shorter than those in HCAs. CONCLUSIONS: Our results suggest that hTERT protein expression and telomere shortening would be applicable as biological markers to distinguish FTC from FTA. Previous studies have suggested that follicular tumor and Hurthle cell tumor should be classified biologically as distinct tumors. All Hurthle cell tumors expressed hTERT protein and HCCs had markedly shortened telomeres, suggesting that follicular tumor and Hurthle cell tumor might be biologically distinct entities. PubMed-ID: 24562933 http://dx.doi.org/10.1245/s10434-014-3552-6

Super-Radical Surgery for Anaplastic Thyroid Carcinoma: a Large Cohort Study Using the Anaplastic Thyroid Carcinoma Research Consortium of Japan Database. Head Neck, 36(3):328-33. Sugitani I, Hasegawa Y, Sugasawa M, Tori M, Higashiyama T, Miyazaki M, Hosoi H, Orita Y, Kitano H. 2014. BACKGROUND: The consequences of super-radical resection in patients with anaplastic thyroid carcinoma (ATC) have not been fully investigated. METHODS: This retrospective study used the multicenter ATC Research Consortium of Japan database. Among 233 stage IVB patients, 23 underwent super-radical resection (group S). Outcomes for group S were compared to those for patients with restricted curative surgery (group R; n = 49), palliative surgery (group P; n = 72) or no surgery (group N; n = 80). RESULTS: One-year cause-specific survival rate for group S was 33%. It was identical to group R (p = .94) and significantly better than groups N and P (p =

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.0065). Permanent tracheostomy was significantly more frequent in group S than in other groups, but only 5 patients died directly from local disease. CONCLUSIONS: Radical resection offers significantly better outcomes than limited surgery. Super-radical procedures may be indicated in select patients to avoid mortality due to locally uncontrolled disease at the expense of tracheostomy. PubMed-ID: 23729360 http://dx.doi.org/10.1002/hed.23295

Association Between Serum Thyrotropin Concentration and Growth of Asymptomatic Papillary Thyroid Microcarcinoma. World J Surg, 38(3):673-8. Sugitani I, Fujimoto Y, Yamada K. 2014. BACKGROUND: Thyrotropin (TSH) is a known thyroid growth factor. Several studies have suggested its potential role in carcinogenesis and the progression of differentiated thyroid carcinoma. We have been conducting a prospective trial of nonsurgical observation for asymptomatic papillary thyroid microcarcinoma (PMC) since 1995. The aim of this study was to investigate whether serum TSH concentrations can be used to predict PMC growth. METHODS: This study examined 415 asymptomatic PMCs.Three hundred twenty-two patients decided to undergo nonsurgical observation by ultrasonography and were followed for >/= 2 years. RESULTS: After a mean of 6.5 years of observation (range 2-22 years), 25 lesions (6 %) had increased in size, 377(91 %) showed no change and 13 (3 %) had decreased in size. Both baseline TSH and mean TSH during follow-up for PMC that increased in size did not differ significantly from those lesions that were unchanged or decreased in size. Increases in size were seen in 0 of 18 (0 %), 15 of 260(6 %), 10 of 126 (8 %), and 0 of 11 (0 %) for PMCs with baseline TSH <0.50, 0.50-1.99, 2.00-3.99, and >/= 4.00 mIU/L, respectively. A logistic regression model analyzing the association between baseline TSH and outcome showed an odds ratio of 1.01 (95 % confidence interval [CI], 0.66-1.29). No significant correlations were apparent between mean TSH during follow-up and change in PMC volume (r = 0.019, p = 0.70). CONCLUSIONS: No significant association between TSH and tumor progression was verified during the nonsurgical observation trial for PMC. TSH is not a good predictor of PMC growth. PubMed-ID: 24233662 http://dx.doi.org/10.1007/s00268-013-2335-8

MEN1 Gene Mutation and Reduced Expression Are Associated With Poor Prognosis in Pulmonary Carcinoids. J Clin Endocrinol Metab, 99(2):E374-E378. Swarts DR, Scarpa A, Corbo V, Van CW, van EM, Gatti G, Henfling ME, Papotti M, Perren A, Ramaekers FC, Speel EJ, Volante M. 2014. CONTEXT: MEN1 gene alterations have been implicated in lung carcinoids, but their effect on gene expression and disease outcome is unknown. OBJECTIVE: Our objective was to analyze MEN1 gene and expression anomalies in lung neuroendocrine neoplasms and their correlations with clinicopathologic data and disease outcome. DESIGN: We examined 74 lung neuroendocrine neoplasms including 58 carcinoids and 16 high-grade neuroendocrine carcinomas (HGNECs) for MEN1 mutations (n = 70) and allelic losses (n = 69), promoter hypermethylation (n = 65), and mRNA (n = 74) expression. Results were correlated with disease outcome. RESULTS: MEN1 mutations were found in 7 of 55 (13%) carcinoids and in 1 HGNEC, mostly associated with loss of the second allele. MEN1 decreased expression levels correlated with the presence of mutations (P = .0060) and was also lower in HGNECs than carcinoids (P = .0024). MEN1 methylation was not associated with mRNA expression levels. Patients with carcinoids harboring MEN1 mutation and loss had shorter overall survival (P = .039 and P = .035, respectively) and low MEN1 mRNA levels correlated with distant metastasis (P = .00010) and shorter survival (P = .0071). In multivariate analysis, stage and MEN1 allelic loss were independent predictors of prognosis. CONCLUSION: Thirteen percent of pulmonary carcinoids harbor MEN1 mutation associated with reduced mRNA expression and poor prognosis. Also in mutation-negative tumors, low MEN1 gene expression correlates with an adverse disease outcome. Hypermethylation was excluded as the underlying mechanism. PubMed-ID: 24276465 http://dx.doi.org/10.1210/jc.2013-2782

Comparison of Surgical Completeness Between Robotic Total Thyroidectomy Versus Open Thyroidectomy. Laryngoscope, 124(4):1042-7. Tae K, Song CM, Ji YB, Kim KR, Kim JY, Choi YY. 2014. OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate the surgical completeness of robotic total

ESES Review of Recently Published Literature 2014-1 Page 66 of 121 thyroidectomy compared with conventional open thyroidectomy. STUDY DESIGN: Retrospective, case-control study. METHODS: We studied 245 patients with papillary thyroid carcinoma who underwent total thyroidectomy and postoperative radioactive iodine (RAI) ablation. Of these, 62 patients underwent robotic thyroidectomy by a gasless unilateral axillo-breast (GUAB) or axillary (GUA) approach, and 183 underwent conventional open thyroidectomy. We analyzed serum TSH-stimulated thyroglobulin (Tg) and RAI uptake at the time of RAI remnant ablation to compare surgical completeness in the two groups. RESULTS: Tumor characteristics and complications did not differ between the two groups except TNM stage. The mean TSH-stimulated Tg at the first RAI ablation was significantly higher in the robotic group (10.20 +/- 9.98 ng/ml) than in the open group (3.85 +/- 6.79 ng/ml) (P <0.001). In subgroup analysis of the robotic group by the period in which operations took place, TSH-stimulated Tg was significantly higher than in the open group in the first (13.28 +/- 11.91 ng/ml) and second (10.45 +/- 9.30 ng/ml) periods, but there was no significant difference in the third period (6.00 +/- 6.26 ng/ml, P = 0.141). The RAI uptake rate at the first RAI ablation did not differ between the two groups, and TSH-stimulated Tg after RAI ablation was similar. CONCLUSION: The surgical completeness of robotic total thyroidectomy by a GUAB/GUB approach is comparable to that of open thyroidectomy, if performed by experienced robotic thyroid surgeons in properly selected patients. LEVEL OF EVIDENCE: 3b. Laryngoscope, 124:1042-1047, 2014. PubMed-ID: 24338236 http://dx.doi.org/10.1002/lary.24511

Thyroid Cancer in Graves' Disease: Is Surgery the Best Treatment for Graves' Disease? ANZ J Surg, 84(4):231-4. Tamatea JA, Tu'akoi K, Conaglen JV, Elston MS, Meyer-Rochow GY. 2014. BACKGROUND: Graves' disease is a common cause of thyrotoxicosis. Treatment options include anti-thyroid medications or definitive therapy: thyroidectomy or radioactive iodine (I(131) ). Traditionally, I(131) has been the preferred definitive treatment for Graves' disease in New Zealand. Reports of concomitant thyroid cancer occurring in up to 17% of Graves' patients suggest surgery, if performed with low morbidity, may be the preferred option. The aim of this study was to determine the rate of thyroid cancer and surgical outcomes in a New Zealand cohort of patients undergoing thyroidectomy for Graves' disease. METHOD: This study is a retrospective review of Waikato region patients undergoing thyroid surgery for Graves' disease during the 10- year period prior to 1 December 2011. RESULTS: A total of 833 patients underwent thyroid surgery. Of these, 117 were for Graves' disease. Total thyroidectomy was performed in 82, near-total in 33 and subtotal in 2 patients. Recurrent thyrotoxicosis developed in one subtotal patient requiring I(131) therapy. There were two cases of permanent hypoparathyroidism and one of permanent recurrent laryngeal nerve palsy. Eight patients (6.8%) had thyroid cancer detected, none of whom had overt nodal disease. Five were papillary microcarcinomas (one of which was multifocal), two were papillary carcinomas (11 mm and 15 mm) and one was a minimally invasive follicular carcinoma. CONCLUSION: Thyroid cancer was identified in approximately 7% of patients undergoing surgery for Graves' disease. A low complication rate (<2%) of permanent hypoparathyroidism and nerve injury (<1%) supports surgery being a safe alternative to I(131) especially for patients with young children, ophthalmopathy or compressive symptoms. PubMed-ID: 22985335 http://dx.doi.org/10.1111/j.1445-2197.2012.06233.x

Hybrid-Type Endoscopic Thyroidectomy (HET: Tori's Method) for Differentiated Thyroid Carcinoma Including Invasion to the Trachea. Surg Endosc, 28(3):902-9. Tori M. 2014. BACKGROUND: Endoscopic thyroidectomy (ET) or robotic thyroidectomy is yet to be applied to thyroid carcinoma invasive to the trachea and to wide lymph node node metastasis. On the other hand, small-incision thyroidectomy lacks sufficient working space and clear vision. The author has newly developed hybrid-type endoscopic thyroidectomy (HET) to overcome these problems. METHODS: From March 2011 to February 2012, HET was performed for 85 patients. Clinicopathologic characteristics were analyzed. To evaluate the superiority of HET for malignancy representatively, conventional lobectomy with central compartment node dissection (CCND) performed 1 year previously was compared with HET. In lobectomy and node dissection, a single skin incision (1.5 cm) is made above the clavicle, with a port incision (5 mm) made 3 cm below the clavicle. Then CCND is performed directly through the incision by lifting up the isthmus. To obtain sufficient working space for the lobectomy, the strap muscles are taped and pulled toward the head, then hung by the cradle. The thyroid lobe is retracted to the midline with a retractor, followed by isolation of the inferior laryngeal nerve and transection of the inferior thyroid vessels with the monitor of the scope. Lateral lymph nodes dissection can be performed at the same time, if necessary. In total thyroidectomy, the same procedure is performed at the opposite side. The scalpel can be used to shave through each incision in case of tracheal invasion. RESULTS:

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Of the 85 cases, 62 were malignant, involving papillary thyroid carcinoma (PTC), and 23 were benign. Total thyroidectomy was performed for 22 of the PTC cases and CCND for 49 of the cases. Shaving for tracheal invasion was performed for eight patients. No mortality, complications, recurrence, or metastasis was found 1-2 years after the operation. Compared with conventional thyroidectomy, HET was superior in blood loss, visual analog scale, and postoperative hospital stay. CONCLUSION: The author's method (Tori's method) might be less invasive, cosmetically excellent, and moreover, safe and feasible for differentiated thyroid carcinoma including invasion to the trachea. PubMed-ID: 24263457 http://dx.doi.org/10.1007/s00464-013-3245-4

Calcitonin Measurement in Aspiration Needle Washout Fluids Has Higher Sensitivity Than Cytology in Detecting Medullary Thyroid Cancer: a Retrospective Multicentre Study. Clin Endocrinol (Oxf), 80(1):135-40. Trimboli P, Cremonini N, Ceriani L, Saggiorato E, Guidobaldi L, Romanelli F, Ventura C, Laurenti O, Messuti I, Solaroli E, Madaio R, Bongiovanni M, Orlandi F, Crescenzi A, Valabrega S, Giovanella L. 2014. OBJECTIVE: Only few studies analysed the capability of cytology in detecting medullary thyroid cancer (MTC), and they reported a low accuracy of this diagnostic technique. Recently, calcitonin (CT) measurement in aspiration needle washout (FNA-CT) of thyroid and neck lesions has been reported as a sensitive tool for MTC. The aim of this study is to compare the sensitivity of FNA-CT and cytology in detecting MTC and to assess a cut- off value of FNA-CT for clinical practice. PATIENTS: Thirty-eight MTC lesions from 36 patients were retrospectively studied, diagnosed and treated in four different centres. Furthermore, 52 nonmedullary lesions from subjects undergone biopsy following increased serum CT were collected as a control group. RESULTS: Cytology detected MTC in 21/37 lesions with 56.8% sensitivity. The median FNA-CT value was 2000 pg/ml (range 58-10 000 pg/ml) in MTC and 2.7 pg/ml (range <2-13 pg/ml) in controls (P < 0.001). Using a cut-off of 39.6 pg/ml, MTC lesions could be identified with 100% sensitivity and specificity. As the most important finding, 14 histologically proved MTC lesions could be detected by FNA-CT, despite they were cytologically diagnosed as benign or nonconclusive. CONCLUSIONS: This study shows, as the first in a multicentre series, that FNA-CT sensitivity is higher than that of cytology in diagnosing MTC. To avoid false-negative MTC by cytology, CT measurement in aspiration needle washout is to be performed in all patients undergoing biopsy following high serum CT. PubMed-ID: 23627255 http://dx.doi.org/10.1111/cen.12234

Impact of Early Vs Late Postoperative Radioiodine Remnant Ablation on Final Outcome in Patients With Low-Risk Well-Differentiated Thyroid Cancer. Clin Endocrinol (Oxf), 80(3):459-63. Tsirona S, Vlassopoulou V, Tzanela M, Rondogianni P, Ioannidis G, Vassilopoulos C, Botoula E, Trivizas P, Datseris I, Tsagarakis S. 2014. OBJECTIVE: Postoperative radioiodine remnant ablation (RRA) represents an adjunctive therapeutic modality in patients with differentiated thyroid cancer (DTC). The impact of late vs early RRA on the outcome of DTC is currently unclear. The aim of the study was to evaluate the outcome of patients with DTC according to RRA timing. DESIGN RETROSPECTIVE STUDY PATIENTS: A total of 107 TNM stage 1 DTC patients were divided into two groups. In group A (n = 50), RRA was administered in less than 4.7 months median 3.0 (range 0.8-4.7), while in group B (n = 57) in more than 4.7 months median 6 (4.8-30.3) after thyroidectomy. Remission was achieved when stimulated serum Tg levels were undetectable, in the absence of local recurrence or cervical lymph node metastases on the neck ultrasound. RESULTS: All patients underwent near-total thyroidectomy. The mean age at diagnosis was 49.3 years (range: 18-79 years). There were no statistically significant differences in the histological subtype, the TNM stage, the dose of radioiodine and the time of follow-up, between the two groups. After the RRA treatment, 44 group A patients (88%) were in remission and 6 (12%) in persistence; while in group B, 52 (91.2%) were in remission, 1 (1.8%) in persistence and 4 (7%) in recurrence. At their latest follow- up median 87.3 (23.3-251.6 months), all patients were in remission, either as a result of further iodine radioiodine therapy (in 11 patients) or watchful monitoring. CONCLUSIONS: The timing of RRA seems to have no effect on the long-term outcome of the disease. Therefore, urgency for radioiodine ablation in patients with low-risk thyroid cancer is not recommended. PubMed-ID: 23895145 http://dx.doi.org/10.1111/cen.12301

The Epidemic of Thyroid Cancer in the United States: the Role of Endocrinologists and Ultrasounds. Thyroid, 24(3):472-9.

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Udelsman R, Zhang Y. 2014. BACKGROUND: The incidence of thyroid cancer has increased at an alarming rate in both men and women in the United States. The etiology of this epidemic is unclear. We tested the hypothesis that a significant component of this epidemic is due to increased detection of occult disease. We examined whether the density of endocrinologists and general surgeons as well as employment of cervical ultrasonography were factors associated with this epidemic. METHODS: Thyroid cancer incidence rates by states were obtained from the United States Cancer Statistics 1999-2009 reported by the National Program of Cancer Registries. The densities of endocrinologists and general surgeons and the employment of cervical ultrasonography were calculated on a statewide basis and correlated with the incidence of thyroid cancer. RESULTS: Age-standardized incidence rates of thyroid cancer have increased in every state in the United States. Significant regional variations were noted, with the highest incidence rates in the northeast and the lowest in the south. The incidence rates were significantly correlated with the density of endocrinologists (r = 0.58, p<0.0001 for males; r = 0.44, p = 0.0031 for females) and the employment of cervical ultrasonography (r = 0.40, p = 0.0091 for males; r = 0.36, p = 0.0197 for females). Both the density of endocrinologists and general surgeons and employment of cervical ultrasonography could explain 57% of the variability in state-level incidence for males and 49% for females. CONCLUSIONS: These data offer evidence to suggest that the epidemic of thyroid cancer is due to increased detection of a reservoir of previously occult disease. The increased detection of thyroid cancer results in therapeutic interventions including surgery and radioactive thyroid treatment that may be of limited benefit. PubMed-ID: 23937391 http://dx.doi.org/10.1089/thy.2013.0257

Oncologic Outcomes After Completion Thyroidectomy for Patients With Well-Differentiated Thyroid Carcinoma. Ann Surg Oncol, 21(4):1374-8. Untch BR, Palmer FL, Ganly I, Patel SG, Michael TR, Shah JP, Shaha AA. 2014. BACKGROUND: At our institution, thyroid lobectomy is employed as a definitive operation for unifocal intrathyroidal low risk cancers and thus completion thyroidectomy is rarely performed. The purpose of this study was to identify the indications for selective completion thyroidectomy and to report oncologic outcomes. METHODS: A retrospective review was performed to identify patients who underwent planned completion thyroidectomy for well-differentiated thyroid carcinoma (WDTC) from 2001 to 2010 based on initial lobectomy pathology. Assessment for risk of recurrence was based on the American Thyroid Association Initial Risk Stratification. RESULTS: During the 10-year study period, 79 patients underwent completion thyroidectomy for WDTC. Forty-four (56 %) patients were low risk and 35 (44 %) were intermediate risk. Completion thyroidectomy was recommended for 64 patients, whereas 15 patients were given an option of surveillance but ultimately decided to have surgery. Patients in the "recommended group" had more T3 tumors and fewer T1a tumors (p = 0.005 and 0.006, respectively). These patients also were more likely to be intermediate risk (p = 0.008) and to present with aggressive histology (p = 0.002). The rate of contralateral tumors (n = 27) was similar between both groups (35 and 33 %, respectively). Contralateral cancers were micropapillary in 24 of 27 (89 %) patients, 10 (40 %) of whom had multifocal disease. There were two pulmonary recurrences and no local-regional recurrences (median follow-up of 42.3 months). CONCLUSIONS: Completion thyroidectomy is infrequent and performed for a select group of intermediate and low risk WDTCs at our institution with low recurrence rates. Incidental multifocal and unifocal contralateral cancers are common after completion thyroidectomy. PubMed-ID: 24366419 http://dx.doi.org/10.1245/s10434-013-3428-1

Optimal Timing of Surgery for Differentiated Thyroid Cancer in Pregnant Women. World J Surg, 38(3):704-8. Uruno T, Shibuya H, Kitagawa W, Nagahama M, Sugino K, Ito K. 2014. BACKGROUND: Differentiated thyroid cancer (DTC) is the second most common cancer diagnosed in pregnant women, but there is no consensus as to whether surgery should be performed during pregnancy or after delivery. METHODS: We retrospectively reviewed the records of 45 patients with DTC operated on during pregnancy or within 1 year after delivery, and we compared the clinicopathological features and outcomes of the patients operated during pregnancy (group A, n = 24) and the patients operated after delivery (group B, n = 21). RESULTS: All 45 patients were histologically diagnosed with well-differentiated papillary thyroid cancer. Nineteen (79 %) of the 24 patients in group A underwent thyroidectomy during the second trimester. No complications associated with surgery or general anesthesia were reported in either group. There were no significant differences between the two groups in terms of age, tumor size, incidence of lymph node metastasis, or incidence of extrathyroidal extension. No distant metastases were detected in any of the patients. Two small for date infants (8.3 %) and 2 heavy for date infants (8.3 %) were delivered in group A, but only 1 small for date

ESES Review of Recently Published Literature 2014-1 Page 69 of 121 infant (4.7 %) was delivered in group B. There were no miscarriages, and none of the infants in either group had birth defects. Because 3 patients in group A and 1 patient in group B experienced a local recurrence, salvage surgeries were performed. CONCLUSIONS: Although thyroid surgery was performed safely in the second trimester, surgery after delivery was also acceptable. Surgery after delivery is recommended for most patients with non-aggressive DTC. PubMed-ID: 24248429 http://dx.doi.org/10.1007/s00268-013-2334-9

Extreme Blood Pressure Oscillations in a Patient With a MEN-2a Syndrome. J Clin Endocrinol Metab, 99(3):701-2. van den Meiracker AH, van den Berg B, de HW, Bakker J. 2014. PubMed-ID: 24433002 http://dx.doi.org/10.1210/jc.2013-3857

Thyroglobulin Antibodies Could Be a Potential Predictive Marker for Papillary Thyroid Carcinoma. Ann Surg Oncol, Vasileiadis I, Boutzios G, Charitoudis G, Koukoulioti E, Karatzas T. 2014. BACKGROUND: Hashimoto thyroiditis (HT) is associated with an increased risk of developing papillary thyroid carcinoma (PTC). The relationship between thyroid autoimmunity and cancer remains controversial. The purpose of this study was to investigate whether the preoperative TgAb could be a potential predictor of PTC in patients with thyroid nodules and to assess whether there is an association of preoperative TgAb with lymph node metastases. METHODS: This retrospective, nonrandomised study included 854 patients who underwent standard total thyroidectomy. Benign thyroid nodules were diagnosed in 447 patients, and 407 presented with malignant nodules. The examined parameters included the clinical characteristics, preoperative TSH and TgAb levels, and the histopathological characteristics of the tumour. RESULTS: Tumour size >10 mm (p = 0.01), the presence of PTC (p < 0.001), elevated TSH levels (2.64 +/- 1.28 muU/ml vs. 2.09 +/- 0.98 muU/ml, p = 0.001), HT (p < 0.001), and lymph node metastasis (p = 0.005) were significantly associated with positive TgAb. Additionally, tumour size >10 mm (p < 0.001), preoperative TgAb positivity (p = 0.003), and elevated TSH levels (TSH > 3.4 muU/ml, p = 0.038) were independent risk factors for PTC based on the multivariate logistic regression analysis. CONCLUSIONS: This study showed that TgAb positivity was an independent risk factor for PTC. A positive correlation between TgAb and PTC in patients with indeterminate nodules was existed. Additionally, a positive correlation existed between TgAb and lymph node metastases in patients with PTC. Prospective studies with a larger number of patients and long-term follow-up are needed clarify the potential role of positive serum TgAb in the prediction of PTC. PubMed-ID: 24595799 http://dx.doi.org/10.1245/s10434-014-3593-x

Clinical and Pathological Characteristics of Incidental and Nonincidental Papillary Thyroid Microcarcinoma in 339 Patients. Head Neck, 36(4):564-70. Vasileiadis I, Karatzas T, Vasileiadis D, Kapetanakis S, Charitoudis G, Karakostas E, Kouraklis G. 2014. BACKGROUND: We analyzed the incidence and the clinicopathological characteristics of papillary thyroid microcarcinoma (PTMC) in a high prevalence region of goiter with the purpose to investigate differences between incidental and nonincidental PTMC. METHODS: A total of 2236 patients who underwent total thyroidectomy from 2001 to 2009 were reviewed retrospectively. Papillary carcinoma was diagnosed in 583 patients. Of these, 339 patients with PTMC were included in the study. Clinicopathological features were evaluated by univariate and multivariate analysis. RESULTS: The prevalence of incidental PTMC was 12% of all patients who underwent surgery for thyroid disease. Univariate analysis showed that bilaterality (p = .001), autoimmune thyroid disease (p = .049), size of tumor >5 mm (p < .001), multifocality (p < .001), lymph node metastasis (p < .001), and capsule invasion (p < .001) were significantly associated with nonincidental PTMC. The incidence of lymph node metastasis in incidental PTMC was 5% versus 33% in nonincidental, suggesting that the biological behavior may be different in the 2 categories. CONCLUSION: Our results indicate that a high rate of PTMC presented 1 or more risk factors including multifocality, bilaterality, capsule invasion, and lymph node metastasis. Therefore, we suggest total thyroidectomy followed by adequate exploration of the central neck compartment for possible nodal involvement and resection as a safe therapeutic approach. PubMed-ID: 23780707 http://dx.doi.org/10.1002/hed.23333

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Differentiated Thyroid Cancer: a New Perspective With Radiolabeled Somatostatin Analogues for Imaging and Treatment of Patients. Thyroid, 24(4):715-26. Versari A, Sollini M, Frasoldati A, Fraternali A, Filice A, Froio A, Asti M, Fioroni F, Cremonini N, Putzer D, Erba PA. 2014. BACKGROUND: The expression of somatostatin receptors (SSTR) in thyroid cells may offer the possibility to identify metastatic lesions and to select patients for peptide receptor radionuclide therapy (PRRT). We investigated (68)Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) to select patients with progressive differentiated thyroid cancer (DTC) for PRRT as well as treatment response and toxicity in treated patients. METHODS: We enrolled 41 patients with progressive radioiodine-negative DTC (24 women and 17 men; mean age=54.3 years, median=59 years, range=19-78 years). In all patients, [(18)F]FDG- PET/CT was performed to determine recurrent disease with enhanced glucose metabolism, and (68)Ga- DOTATOC PET/CT was used to identify SSTR expression. Dosimetric evaluation was performed with (111)In- DOTATOC scintigraphy. Eleven patients were treated with PRRT receiving a fractionated injection of 1.5-3.7 GBq (90)Y-DOTATOC/administration. Serial (68)Ga-DOTATOC PET/CT scans were performed in all treated patients to evaluate treatment response. Parameters provided by (68)Ga-DOTATOC PET/CT were analyzed as potential therapeutic predictors to differentiate responding from nonresponding. In all treated patients, adverse events and toxicity were recorded. RESULTS: (68)Ga-DOTATOC PET/CT were positive in 24/41 of radioiodine- negative DTC patients. Based on the high expression of SSTR detected by (68)Ga-DOTATOC PET/CT, 13 patients were suitable for PRRT. Two out of 13 patients were not treated due to the lack of fulfillment of other study inclusion criteria. PRRT induced disease control in 7/11 patients (two partial response and five stabilization) with a duration of response of 3.5-11.5 months. Objective response was associated with symptoms relief. Functional volume (FV) over time obtained by PET/CT was the only parameter demonstrating a significant difference between lesions responding and nonresponding to PRRT (p=0.001). Main PRRT adverse events were nausea, asthenia, and transient hematologic toxicity. One patient experienced permanent renal toxicity. CONCLUSIONS: In our series, SSTR imaging provided positive results in more than half of the cases with radioiodine-negative DTC, and about one third of patients were eligible for PRRT. (68)Ga-DOTATOC PET/CT seems a reliable tool both for patient selection and evaluation of treatment response. In our experience, FV determination over time seems to represent a reliable parameter to determine tumor response to PRRT, although further investigations are needed to better define its role. PubMed-ID: 24102584 http://dx.doi.org/10.1089/thy.2013.0225

Voice Outcomes After Total Thyroidectomy, Partial Thyroidectomy, or Non-Neck Surgery Using a Prospective Multifactorial Assessment. J Am Coll Surg, Vicente DA, Solomon NP, Avital I, Henry LR, Howard RS, Helou LB, Coppit GL, Shriver CD, Buckenmaier CC, Libutti SK, Shaha AR, Stojadinovic A. 2014. BACKGROUND: Voice alteration remains a significant complication of thyroid surgery. We present a comparison of voice outcomes between total thyroidectomy (TT), partial thyroidectomy (PT), and non-neck (NN) surgery using a multifactorial voice-outcomes classification tool. STUDY DESIGN: Patients with normal voice (n = 112) were enrolled between July 2004 and March 2009. The patients underwent TT (n = 54), PT (n = 35), or NN (n = 23) surgery under general endotracheal anesthesia as part of a prospective observational study involving serial multimodality voice evaluation preoperatively, and at 2 weeks, 3 months, and 6 months postoperatively. Patients with adverse voice outcomes were grouped into the negative voice outcomes (NegVO) category, including patients with objective (abnormality on videolaryngostroboscopy and substantial voice dysfunction) and subjective (normal videolaryngostroboscopy but with notable voice impairment) NegVO. Voice outcomes were compared among study groups. RESULTS: Negative voice outcomes occurred in 46% (95% CI, 34-59%) and 14% (95% CI, 6-30%) of TT and PT groups, respectively. No NegVOs were observed after NN surgery. Early NegVOs were more common in the TT group than in the NN or PT groups (p < 0.001). Most voice disturbances resolved by 6 months (TT 84%; PT 92%) with no difference in NegVO among all groups (p = 0.23). Black race and significant changes in certain voice outcomes measures at the 2-week follow-up visit were identified as predictors of late (3 to 6 months) NegVO. CONCLUSIONS: This comprehensive voice outcomes study revealed that the extent of thyroidectomy impacts voice outcomes in the early postoperative period, and identified risk factors for late NegVO in post-thyroidectomy patients who should be considered for early voice rehabilitation referral. PubMed-ID: 24745621 http://dx.doi.org/10.1016/j.jamcollsurg.2014.03.019

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Thyroid Nodules (>/=4 Cm): Can Ultrasound and Cytology Reliably Exclude Cancer? World J Surg, 38(3):614-21. Wharry LI, McCoy KL, Stang MT, Armstrong MJ, LeBeau SO, Tublin ME, Sholosh B, Silbermann A, Ohori NP, Nikiforov YE, Hodak SP, Carty SE, Yip L. 2014. BACKGROUND: Whether a threshold nodule size should prompt diagnostic thyroidectomy remains controversial. We examined a consecutive series of patients who all had thyroidectomy for a >/=4 cm nodule to determine (1) the incidence of thyroid cancer (TC) and (2) if malignant nodules could accurately be diagnosed preoperatively by ultrasound (US), fine needle aspiration biopsy (FNAB) cytology and molecular testing. METHODS: As a prospective management strategy, 361 patients with 382 nodules >/=4 cm by preoperative US had thyroidectomy from 1/07 to 3/12. RESULTS: The incidence of a clinically significant TC within the >/=4 cm nodule was 22 % (83/382 nodules). The presence of suspicious US features did not discriminate malignant from benign nodules. Moreover, in 86 nodules >/=4 cm with no suspicious US features, the risk of TC within the nodule was 20 %. US-guided FNAB was performed for 290 nodules, and the risk of malignancy increased stepwise from 10.4 % for cytologically benign nodules, 29.6 % for cytologically indeterminate nodules and 100 % for malignant FNAB results. Molecular testing was positive in 9.3 % (10/107) of tested FNAB specimens, and all ten were histologic TC. CONCLUSIONS: In a large consecutive series in which all >/=4 cm nodules had histology and were systematically evaluated by preoperative US and US-guided FNAB, the incidence of TC within the nodule was 22 %. The false negative rate of benign cytology was 10.4 %, and the absence of suspicious US features did not reliably exclude malignancy. At minimum, thyroid lobectomy should be strongly considered for all nodules >/=4 cm. PubMed-ID: 24081539 http://dx.doi.org/10.1007/s00268-013-2261-9

Paradigm Shifts in Thyroid Hormone Replacement Therapies for Hypothyroidism. Nat Rev Endocrinol, 10(3):164-74. Wiersinga WM. 2014. Impaired psychological well-being, depression or anxiety are observed in 5-10% of hypothyroid patients receiving levothyroxine, despite normal TSH levels. Such complaints might hypothetically be related to increased free T(4) and decreased free T(3) serum concentrations, which result in the abnormally low free T(4):free T(3) ratios observed in 30% of patients on levothyroxine. Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone. Levothyroxine plus liothyronine combination therapy is gaining in popularity; although the evidence suggests it is generally not superior to levothyroxine monotherapy, in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. Disappointing results with combination therapy could be related to use of inappropriate levothyroxine and liothyronine doses, resulting in abnormal serum free T(4):free T(3) ratios. Alternatively, its potential benefit might be confined to patients with specific genetic polymorphisms in thyroid hormone transporters and deiodinases that affect the intracellular levels of T(3) available for binding to T(3) receptors. Levothyroxine monotherapy remains the standard treatment for hypothyroidism. However, in selected patients, new guidelines suggest that experimental combination therapy might be considered. PubMed-ID: 24419358 http://dx.doi.org/10.1038/nrendo.2013.258

The Feasibility and Efficacy of Secondary Neck Dissections in Thyroid Cancer Metastases. Eur Arch Otorhinolaryngol, 271(4):795-9. Wierzbicka M, Gurgul E, Wasniewska-Okupniak E, Gryczynska M, Piorunek T, Ruchala M. 2014. The purpose of the study was to assess the feasibility of secondary neck dissections (ND) in different types of thyroid cancer (TC), to evaluate the influence of ND extent on morbidity and to describe biochemical and clinical outcomes. 51 patients previously operated for TC (33-well differentiated TC-WDTC, 15 medullary TC-MTC, 3 poorly differentiated TC-PDTC) presenting detectable nodal disease. Reoperations covered I-VII neck levels. Radical neck dissection was performed in 22 patients, selective neck dissection in 29 patients. 14 central compartment (CC), 10 mediastinal and 41 level IV excisions were performed. Postoperative complications occurred in 13 patients: 4 chyle leaks, 3 massive bleedings, 8 permanent vocal cord pareses, hypoparathyroidism in 22 patients (43.1%), 2 patients expired in perioperative period. In WDTC: in seven patients thyroglobulin level normalized directly after ND, in ten patients in the follow-up; six patients developed distant metastases. None of the patients with MTC achieved calcitonin level <10 pg/ml; nine patients developed distant metastases. None of the patients with PDTC achieved Tg <2 mg/ml; two patients died, the third developed distant metastases. Secondary ND in TC present a challenge by means of surgical approach and possibility of complications. In MTC and PDTC the long-term results were unsatisfactory. In WDTC, the

ESES Review of Recently Published Literature 2014-1 Page 72 of 121 secondary ND should be performed due to strong indications. Metastases localization in levels IV, VI, VII were connected with high complication rate, but these surgeries were crucial for satisfactory oncological outcomes. PubMed-ID: 23771319 http://dx.doi.org/10.1007/s00405-013-2588-8

Nonspecific Iodine Accumulation in Surgical Suture Material Mimicking Follicular Thyroid Cancer Bone Metastasis in (131)I Scintigraphy. Clin Nucl Med, 39(2):209-10. Winkens T, Nietzsche S, Gottschaldt M, Freesmeyer M. 2014. A 23-year-old man with follicular thyroid carcinoma and cervical lymph node metastases showed a clear I focus on the skull after radioiodine therapy; therefore, an osseous metastasis was suspected. I and MRI fusion suggested the I focus to be adjacent to an epicranial suture from an early childhood trepanation for epidural hematoma. Radio-guided surgery found dark brown material to be the source of the radiation and successfully removed the material. Subsequent electron microscopy revealed a thread within the dark brown material, suggesting suture material as the cause of I accumulation. PubMed-ID: 24368531 http://dx.doi.org/10.1097/RLU.0000000000000297

Esophageal Metastasis From Papillary Thyroid Cancer: Diagnosis by 131I SPECT/CT. Clin Nucl Med, 39(1):e73-e74. Wisotzki C, Friese M, Ehresmann J, Derlin T. 2014. We report a case of esophageal metastasis from papillary thyroid cancer diagnosed by I SPECT/CT. A 70-year- old man presented with increasing thyroglobulin levels 13 years after thyroidectomy and ablation with I for thyroid cancer. The whole-body radioiodine scan demonstrated marked tracer uptake in the mediastinum, and SPECT/CT could clearly localize the activity to the esophagus. Subsequent surgical resection with histopathologic evaluation revealed an esophageal metastasis from papillary thyroid cancer. I SPECT/CT is a valuable tool for evaluation and precise anatomical localization of the foci of radionuclide activity in thyroid cancer, enabling adequate treatment. PubMed-ID: 23455522 http://dx.doi.org/10.1097/RLU.0b013e3182816303

A Cost-Utility Analysis for Prophylactic Central Neck Dissection in Clinically Nodal-Negative Papillary Thyroid Carcinoma. Ann Surg Oncol, 21(3):767-77. Wong CK, Lang BH. 2014. BACKGROUND: Although prophylactic central neck dissection (pCND) may reduce future locoregional recurrence after total thyroidectomy (TT) for low-risk papillary thyroid carcinoma (PTC), it is associated with a higher initial morbidity. We aimed to compare the long-term cost-effectiveness between TT with pCND (TT+pCND) and TT alone in the institution's perspective. METHODS: Our case definition was a hypothetical cohort of 100,000 nonpregnant female patients aged 50 years with a 1.5-cm cN0 PTC within one lobe. A Markov decision tree model was constructed to compare the estimated cost-effectiveness between TT+pCND and TT alone after a 20-year period. Outcome probabilities, utilities, and costs were estimated from the literature. The threshold for cost-effectiveness was set at US$50,000 per quality-adjusted life year (QALY). Sensitivity and threshold analyses were used to examine model uncertainty. RESULTS: Each patient who underwent TT+pCND instead of TT alone cost an extra US$34.52 but gained an additional 0.323 QALY. In fact, in the sensitivity analysis, TT+pCND became cost-effective 9 years after the initial operation. In the threshold analysis, none of the scenarios that could change this conclusion appeared clinically possible or likely. However, TT+pCND became cost-saving (i.e., less costly and more cost-effective) at 20 years if associated permanent vocal cord palsy was kept

Is Vocal Cord Asymmetry Seen on Transcutaneous Laryngeal Ultrasonography a Significant Predictor of Voice Quality Changes After Thyroidectomy? World J Surg, 38(3):607-13. Wong KP, Lang BH, Ng SH, Cheung CY, Chan CT, Chan MY. 2014.

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BACKGROUND: Vocal cord asymmetry (VCA) on laryngoscopic examination (LE) may suggest voice impairment after thyroidectomy, but LE may cause patient discomfort. We aimed to correlate the presence of postoperative VCA assessed by noninvasive transcutaneous laryngeal ultrasonography (TLUSG) with voice quality changes after thyroidectomy. METHODS: A total of 169 patients scheduled for thyroidectomy completed two validated voice symptoms questionnaires-the GRBAS (grade, roughness, breathiness, asthenia, strain) scale and the voice impairment score (VIS)-and underwent TLUSG and LE at 1 day before and 7-10 days after thyroidectomy. Postoperative VCA was apparent in 51 patients on TLUSG (group I), whereas there was no VCA in the other 118 patients (group II, controls). The GRBAS scale and VIS results were compared between the groups. RESULTS: Before operation, the two groups had comparable preoperative GRBAS and VIS status. After operation, the "grade" and "roughness" components on the GRBAS scale were significantly worse in group I than in group II: 0.24 versus 0.07 (p = 0.016) and 0.33 versus 0.14 (p = 0.022), respectively. "Grade" and "roughness" in the GRBAS scale significantly worsened after the operation in group I: from 0.04 to 0.24 (p = 0.008) and from 0.02 to 0.33 (p = 0.001), respectively. They did not change in group II. Also, the overall VIS was significantly worse after thyroidectomy in group I: 4.97 versus 12.97 (p < 0.001). CONCLUSIONS: VCA seen on TLUSG significantly correlated with "grade" and "roughness" components on the GRBAS scale and the overall VIS. Thus, VCA might be used as a surrogate of postoperative voice changes. PubMed-ID: 24271694 http://dx.doi.org/10.1007/s00268-013-2337-6

Intraoperative Neuromonitoring for the Early Detection and Prevention of RLN Traction Injury in Thyroid Surgery: a Porcine Model. Surgery, 155(2):329-39. Wu CW, Dionigi G, Sun H, Liu X, Kim HY, Hsiao PJ, Tsai KB, Chen HC, Chen HY, Chang PY, Lu IC, Chiang FY. 2014. BACKGROUND: Operative traction of the thyroid lobe is a necessary component of thyroid surgery. This surgical maneuver can cause traction injury of the recurrent laryngeal nerve (RLN), and this complication has been reported to be the most common mechanism of nerve injury. The goal of this study was to investigate the electromyographic (EMG) signal pattern during an acute RLN traction injury and establish reliable strategies to prevent the injury using intraoperative neuromonitoring (IONM). METHODS: Fifteen piglets (30 RLNs) underwent IONM via automated periodic vagal nerve stimulation and had their EMG tracings recorded and correlated with various models of nerve injury. RESULTS: In the pilot study, a progressive, partial EMG loss was observed under RLN tractions with different tension (n = 8). The changes in amplitudes were more marked and consistent than were the changes in latency. The EMG gradually gained partial recovery after the traction was relieved. Among the nerves injured with electrothermal (n = 4), clamping (n = 1), and transection (n = 1) models, the EMG showed immediate partial or complete loss, and no gradual EMG recovery was observed. Another 16 RLNs were used to investigate the potential of EMG recovery after different extents of RLN traction. We noted the EMG showed nearly full recovery if the traction stress was relieved before the loss of signal (LOS), but the recovery was worse if prolonged or repeated traction was applied. The mean restored amplitudes after the traction was relieved before, during, and after the LOS were 98 +/- 3% (n = 6), 36 +/- 4% (n = 4), and 15 +/- 2% (n = 6), respectively. CONCLUSION: RLN traction injury showed graded, partial EMG changes; early release of the traction before the EMG has degraded to LOS offers a good chance of EMG recovery. IONM can be used as a tool for the early detection of adverse EMG changes that may alert surgeons to correct certain maneuvers immediately to prevent irreversible nerve injury during the thyroid operation. PubMed-ID: 24084598 http://dx.doi.org/10.1016/j.surg.2013.08.015

Thyroid Hormone, Thyromimetics, and Metabolic Efficiency. Endocr Rev, 35(1):35-58. Yehuda-Shnaidman E, Kalderon B, Bar-Tana J. 2014. Thyroid hormone (TH) has long been recognized as a major modulator of metabolic efficiency, energy expenditure, and thermogenesis. TH effects in regulating metabolic efficiency are transduced by controlling the coupling of mitochondrial oxidative phosphorylation and the cycling of extramitochondrial substrate/futile cycles. However, despite our present understanding of the genomic and nongenomic modes of action of TH, its control of mitochondrial coupling still remains elusive. This review summarizes historical and up-to-date findings concerned with TH regulation of metabolic energetics, while integrating its genomic and mitochondrial activities. It underscores the role played by TH-induced gating of the mitochondrial permeability transition pore (PTP) in controlling metabolic efficiency. PTP gating may offer a unified target for some TH pleiotropic activities and may serve as a novel target for synthetic functional thyromimetics designed to modulate metabolic efficiency. PTP gating by long-chain fatty acid analogs may serve as a model for such strategy.

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PubMed-ID: 23970761 http://dx.doi.org/10.1210/er.2013-1006

Molecular Testing of Thyroid Nodules: Distinguishing Misuse From Appropriate Use. Ann Surg Oncol, 21(6):1768-9. Yip L, Carty SE. 2014. PubMed-ID: 24504925 http://dx.doi.org/10.1245/s10434-014-3514-z

A Nomogram for Predicting Malignancy in Thyroid Nodules Diagnosed As Atypia of Undetermined Significance/Follicular Lesions of Undetermined Significance on Fine Needle Aspiration. Surgery, 155(6):1006-13. Yoon JH, Lee HS, Kim EK, Moon HJ, Kwak JY. 2014. BACKGROUND: We hypothesized that a nomogram constructed of clinical and imaging variables could be applied to predicting the risk of malignancy in thyroid nodules diagnosed as atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS) on ultrasonographic fine-needle aspiration (US-FNA). METHODS: This retrospectively designed study included 393 thyroid nodules in 392 patients (mean age, 49 +/- 12 years), which were diagnosed as AUS/FLUS with US-FNA during the study period. Medical records, US images, and cytopathology results were reviewed and analyzed. The 393 thyroid nodules were divided into training and validation sets. Logistic regression analysis was performed to predict the probability of malignancy, and nomograms were constructed using the training set and subsequently applied to the validation set. RESULTS: Three sets of nomograms were constructed separately using clinical factors and (1) individual US features; (2) final assessment of US; and (3) the number of suspicious US features. All 3 sets of nomograms built were proven accurate and discriminative, these nomograms had an area under the receiver operating characteristic curve (AUC) of 0.817 (95% confidence interval [CI], 0.757-0.877) when using clinical factors and individual US features, an AUC of 0.769 (95% CI, 0.705-0.833) wen using final assessment, and an AUC of 0.779 (95% CI, 0.718-0.840) when using the number of suspicious US features. The AUC of each validation set was 0.754 (95% CI, 0.659-0.850), 0.757 (95% CI, 0.661-0.853), and 0.721 (95% CI, 0.621-0.820), respectively. CONCLUSION: Nomograms constructed in our study using US can be utilized in predicting the probability of malignancy in thyroid nodules diagnosed as AUS/FLUS on US-FNA, and may help in selecting patients who are at high risk for malignancy. PubMed-ID: 24630147 http://dx.doi.org/10.1016/j.surg.2013.12.035

Lower Incidence of Postpartum Thyrotoxicosis in Women With Graves Disease Treated by Radioiodine Therapy Than by Subtotal Thyroidectomy or With Antithyroid Drugs. Clin Nucl Med, 39(4):326-9. Yoshihara A, Noh JY, Watanabe N, Iwaku K, Kobayashi S, Suzuki M, Ohye H, Matsumoto M, Kunii Y, Mukasa K, Ito K. 2014. PURPOSE OF THE REPORT: The incidence of postpartum thyrotoxicosis (PT) in Graves disease (GD) patients treated with antithyroid drugs (ATDs) is higher than in the general population, but the incidence of PT among GD patients who had been treated with radioiodine (RI) or by subtotal thyroidectomy before their pregnancy is not well known. SUBJECTS AND METHODS: We reviewed the cases of women with GD who had become pregnant, and we selected the 188 women who had undergone RI therapy before the pregnancy and the 148 women who had undergone subtotal thyroidectomy for GD before the pregnancy as the subjects of this study. The ATD subjects were 107 women with GD who had become pregnant after being treated with ATDs alone before their pregnancy and were in remission before and throughout the pregnancy. RESULTS: The overall incidence of PT was 2.1% (4/188) in the RI group, 23.6% (35/148) in the subtotal thyroidectomy group, and 55.1% (59/107) in the ATD group. There were no cases of permanent thyrotoxicosis in the RI group. CONCLUSIONS: The incidence of PT among women with GD who have undergone RI therapy before their pregnancy was significantly low compared to thyroidectomy group and ATD group. This finding is interesting because the incidence of PT in the RI group was lower than subtotal thyroidectomy group even though thyroid volume had been greatly reduced by thyroidectomy. RI treatment is recommended in the choice of treatment for childbearing-age women as regards the risk of postpartum recurrence. PubMed-ID: 24566408 http://dx.doi.org/10.1097/RLU.0000000000000386

Number of Central Lymph Node Metastasis for Predicting Lateral Lymph Node Metastasis in Papillary Thyroid Microcarcinoma.

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Head Neck, 36(1):101-6. Zeng RC, Zhang W, Gao EL, Cheng P, Huang GL, Zhang XH, Li Q. 2014. BACKGROUND: The purpose of this study was to present our evaluation of the relationship between the number of positive central lymph nodes and lateral lymph node metastasis in patients with papillary thyroid microcarcinoma (PTMC). METHODS: Up to 141 patients with PTMC were divided into 3 groups according to different positive central lymph node classifications as follows: group A, no positive central lymph node; group B, 1 positive central lymph node; and group C, 2 or more positive central lymph nodes. RESULTS: Incidence of lateral lymph node metastasis was 30.5% (43 of 141). It was significantly high in group C compared with groups A and B, although there was no significant difference between groups A and B. Number of positive central lymph node >/=2, underlying Hashimoto thyroiditis, and extrathyroidal extension were the independent predictive factors for lateral lymph node metastasis on multivariate analysis. CONCLUSION: Lateral lymph node metastasis was mainly observed in patients with >/=2 positive central lymph nodes, which is an independent predictive factor for lateral lymph node metastasis. Therefore, >/=2 positive central lymph nodes may be valuable in predicting lateral lymph node metastasis. PubMed-ID: 23900787 http://dx.doi.org/10.1002/hed.23270

Histone Deacetylation of NIS Promoter Underlies BRAF V600E-Promoted NIS Silencing in Thyroid Cancer. Endocr Relat Cancer, 21(2):161-73. Zhang Z, Liu D, Murugan AK, Liu Z, Xing M. 2014. The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the chromatin immunoprecipitation approach, we examined histone acetylation status on the lysine residues H3K9/14, H3K18, total H4, and H4K16 at the NIS promoter under the influence of BRAF V600E. We found that expression of stably or transiently transfected BRAF V600E inhibited NIS expression while the deacetylase inhibitor SAHA stimulated NIS expression in PCCL3 rat thyroid cells. Although BRAF V600E enhanced global histone acetylation, it caused histone deacetylation at the NIS promoter while SAHA caused acetylation in the cells. In human thyroid cancer BCPAP cells harboring homozygous BRAF V600E mutation, BRAF V600E inhibitor, PLX4032, and MEK inhibitor, AZD6244, increased histone acetylation of the NIS promoter, suggesting that BRAF V600E normally maintained histone in a deacetylated state at the NIS promoter. The regions most commonly affected with deacetylation by BRAF V600E were the transcriptionally active areas upstream of the translation start that contained important transcription factor binding sites, including nucleotides -297/-107 in the rat NIS promoter and -692/-370 in the human NIS promoter. Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer. PubMed-ID: 24243688 http://dx.doi.org/10.1530/ERC-13-0399

Is Carbon Nanoparticle Useful in Thyroid Surgery Regardless of Surgery Extent and Experience? Otolaryngol Head Neck Surg, 150(3):503. Zhang Z, Wang Y. 2014. PubMed-ID: 24567341 http://dx.doi.org/10.1177/0194599813517863

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Parathyroid

Meta-Analyses - None -

Randomized controlled trials Vitamin D Supplementation After Parathyroidectomy: Effect on Bone Mineral Density-a Randomized Double-Blind Study. J Bone Miner Res, 29(4):960-7. Norenstedt S, Pernow Y, Zedenius J, Nordenstrom J, Saaf M, Granath F, Nilsson IL. 2014. Patients with primary hyperparathyroidism (PHPT) have higher bone turnover, lower bone mineral density (BMD), and an increased risk of fractures. They also have a high incidence of low vitamin D levels (25-OH- vitamin D <50 nmol/L) that could worsen the negative effect on the bone. In this double-blinded clinical trial, 150 patients with PHPT were randomized, after successful parathyroidectomy (PTX), to 1-year daily treatment with either cholecalciferol 1600 IU and calcium carbonate 1000 mg (D+) or calcium carbonate alone (D-). BMD was measured in the lumbar spine, femoral neck, total hip, distal and 33% radius using dual-energy X-ray absorptiometry (DXA) before surgery and after 1 year of study medication. Median age was 60 (range 30-80) years and there were 119 (79%) women and 31 (21%) men; 76% had 25-OH-D <50 nmol/L before PTX and 50% had persistent elevated parathyroid hormone (PTH) 6 weeks after PTX. A similar increase in BMD in the lumbar spine, femoral neck, and total hip was observed in both groups (D+ : 3.6%, 3.2%, and 2.7%, p<0.001, respectively; and D-: 3.0%, 2.3%, and 2.1%, respectively, p<0.001). Patients with vitamin D supplementation also increased their BMD in distal radius (median 2.0%; interquartile range, -1.7% to 5.4%; p=0.013). The changes in BMD, especially in the hips, were correlated to the baseline concentrations of PTH, ionized calcium, and bone markers (p<0.001). A benefit from vitamin D substitution was observed among patients with a persistent postoperative PTH elevation, who also improved their BMD at 33% radius and radius ultradistal (p<0.05). In conclusion, except for a minor improvement of radius BMD, our data show no beneficial effect on BMD or bone turnover markers of vitamin D supplementation after PTX. Preoperative PTH seems to have the strongest association with improvement in BMD. PubMed-ID: 24115138 http://dx.doi.org/10.1002/jbmr.2102

Vitamin d Treatment in Primary Hyperparathyroidism: a Randomized Placebo Controlled Trial. J Clin Endocrinol Metab, 99(3):1072-80. Rolighed L, Rejnmark L, Sikjaer T, Heickendorff L, Vestergaard P, Mosekilde L, Christiansen P. 2014. Context: Low 25-hydroxyvitamin D levels are common in patients with primary hyperparathyroidism (PHPT) and associated with higher PTH levels and hungry bone syndrome after parathyroidectomy (PTX). However, concerns have been raised about the safety of vitamin D supplementation in PHPT. Objective: We aimed to assess safety and effects on calcium homeostasis and bone metabolism of supplementation with high doses of vitamin D in PHPT patients. Design, Setting: This was an investigator-initiated double-blind, randomized, placebo-controlled, parallel-group trial from a single center. Patients: Forty-six PHPT patients were recruited, with a mean age of 58 (range 29-77) years, and 35 (76%) were women. Interventions: Intervention included daily supplementation with 70 mug (2800 IU) cholecalciferol or identical placebo for 52 weeks. Treatment was administered 26 weeks before PTX and continued for 26 weeks after PTX. Main Outcome Measures: PTH, calcium homeostasis, and bone metabolism were evaluated. Results: Preoperatively, 25-hydroxyvitamin D increased from 50 to 94 nmol/L in the treatment group and decreased from 57 to 52 nmol/L in the placebo group (P < .001). Compared with placebo, vitamin D decreased PTH significantly by 17% before PTX (P = .01), increased lumbar spine bone mineral density by 2.5% (P = .01), and decreased C-terminal beta-CrossLaps by 22% (P < .005). The trabecular bone score did not change in response to treatment, but improved after PTX. Postoperatively, PTH remained lower in the cholecalciferol group compared with the placebo group (P = .04). Plasma creatinine and plasma and urinary calcium did not differ between groups. Conclusions: Daily supplementation with a high vitamin D dose safely improves vitamin D status and decreases PTH in PHPT patients. The vitamin D treatment is accompanied by reduced bone resorption and improved bone mineral density before operation.

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PubMed-ID: 24423366 http://dx.doi.org/10.1210/jc.2013-3978

Consensus Statements/Guidelines Diagnostic, Therapeutic and Healthcare Management Protocols in Parathyroid Surgery: II Consensus Conference of the Italian Association of Endocrine Surgery Units (U.E.C. CLUB). J Endocrinol Invest, 37(2):149-65. Rosato L, Raffaelli M, Bellantone R, Pontecorvi A, Avenia N, Boniardi M, Brandi ML, Cetani F, Chiofalo MG, Conzo G, De PM, Gasparri G, Giordano A, Innaro N, Leopaldi E, Mariani G, Marcocci C, Marini P, Miccoli P, Nasi P, Pacini F, Paragliola R, Pelizzo MR, Testini M, De TG. 2014. AIM: To update the Diagnostic-Therapeutic-Healthcare Protocol (Protocollo Diagnostico-Terapeutico- Assistenziale, PDTA) created by the U.E.C. CLUB (Association of the Italian Endocrine Surgery Units) during the I Consensus Conference in 2008. METHODS: In the preliminary phase, the II Consensus involved a selected group of experts; the elaboration phase was conducted via e-mail among all members; the conclusion phase took place during the X National Congress of the U.E.C. CLUB. The following were examined: diagnostic pathway and clinical evaluation; mode of admission and waiting time; therapeutic pathway (patient preparation for surgery, surgical treatment, postoperative management, management of major complications); hospital discharge and patient information; outpatient care and follow-up. CONCLUSIONS: The PDTA for parathyroid surgery approved by the II Consensus Conference (June 2013) is the official PDTA of the U.E.C. CLUB. PubMed-ID: 24497214 http://dx.doi.org/10.1007/s40618-013-0022-0

Other Articles Pregnancy Outcomes in Women With Primary Hyperparathyroidism. Eur J Endocrinol, Abood A, Vestergaard P. 2014. OBJECTIVE: To study pregnancy and pregnancy outcomes in women with primary hyperparathyroidism and controls. DESIGN: Register based retrospective cohort study of women aged 16-44 years with a diagnosis of primary hyperparathyroidism, and age- and gender matched non-exposed controls in Denmark. METHODS: The patients and controls were identified using the Danish National Hospital Discharge Register for the period 1977- 2010. The outcomes were determined using the Birth Register, the Abortion Register, and the LPR (National Hospital Discharge Register). The primary outcome was the relative risk of abortions in patients compared to controls. RESULTS: A total of 1,057 women with primary hyperparathyroidism, and 3,171 controls were identified. The number of women giving, birth and experiencing abortions did not differ between the two groups (live births: p=0.21, abortions: p=0.12). Also birth weight, length, Apgar score, and gestation length at abortion did not differ. Within the first year after the diagnosis was made, gestation length was lower than in controls. However, this was linked to more deliveries by caesarian sections. CONCLUSIONS: A diagnosis of primary hyperparathyroidism did not seem to increase the rate of abortions in our study. Reducing the abortion-risk may therefore not be an indication for parathyroidectomy during pregnancy in patients with mild primary hyperparathyroidism. The PHPT diagnosis does not seem to affect birth weight, length and Apgar score. The higher number of deliveries by cesarean section after the diagnosis was made may be associated with lower gestation age. The strategy for delivery should be carefully considered in pregnant women with primary hyperparathyroidism. PubMed-ID: 24743398 http://dx.doi.org/10.1530/EJE-13-0966

Primary Hyperparathyroidism: an Analysis of Failure of Parathyroidectomy. World J Surg, 38(3):534-41. Bagul A, Patel HP, Chadwick D, Harrison BJ, Balasubramanian SP. 2014. BACKGROUND: Preoperative imaging in patients undergoing surgery for primary hyperparathyroidism (PHPT) is used primarily to facilitate targeted parathyroidectomy. Failure of preoperative localisation mandates a bilateral exploration. It is thought that the results of imaging may also predict the success of surgery. The aims of this study were to assess whether the findings on preoperative localisation influenced outcomes following parathyroidectomy for PHPT and to explore factors underlying failure to cure at surgery. METHODS: We

ESES Review of Recently Published Literature 2014-1 Page 78 of 121 analysed outcomes of all patients who underwent first-time surgery for PHPT in two centres over a 5-year period to determine an association with demographic characteristics and findings on preoperative imaging. Records of patients not cured by initial surgery were reviewed to explore factors underlying failure to cure. RESULTS: The failure rate (persistent disease) in the entire cohort was 5 % (25/541) (bilateral neck explorations, 5 %; unilateral exploration, 7 %; targeted approach, 4 %), while two patients developed recurrent disease. In patients who had undergone dual imaging with an ultrasound scan and (99m)Tc-sestamibi scintigraphy, failure rates with "lateralised and concordant" imaging, "nonconcordant" imaging, and "dual-negative" imaging were 2, 9, and 11 %, respectively (p = 0.01). Of the 25 patients with persistent disease, multigland disease (MGD) was present in 52 % (13/25) and ectopic adenoma in 24 % (6/12). CONCLUSIONS: Patients with PHPT who do not have lateralised and concordant dual imaging are at higher risk of persistent disease. A significant proportion of failures are due to the inability to recognise the presence and/or extent of MGD. PubMed-ID: 24381047 http://dx.doi.org/10.1007/s00268-013-2434-6

Ultrasound-Guided Methylene Blue Dye Injection for Parathyroid Localization in the Reoperative Neck. World J Surg, 38(1):88-91. Candell L, Campbell MJ, Shen WT, Gosnell JE, Clark OH, Duh QY. 2014. BACKGROUND: The goal of this study was to review a single institution's experience using intraoperative ultrasound-guided (ioUSG) methylene blue dye injection for the localization and removal of enlarged parathyroid glands in patients with primary hyperparathyroidism and a history of previous neck surgery. METHODS: We performed a retrospective review of nine consecutive patients who underwent reoperative parathyroidectomy using ioUSG methylene blue dye injection. RESULTS: All patients had successful resolution of their hyperparathyroidism, with at least a 50 % decrease in intraoperative parathyroid hormone level after resection. One patient had transient recurrent laryngeal nerve paresis. There were no permanent recurrent laryngeal nerve injuries or cases of permanent hypoparathyroidism. CONCLUSIONS: Blue dye injection is a safe and effective method of localizing diseased parathyroid glands in the reoperative neck. PubMed-ID: 24132819 http://dx.doi.org/10.1007/s00268-013-2234-z

The Third/Second Generation PTH Assay Ratio As a Marker for Parathyroid Carcinoma: Evaluation Using an Automated Platform. J Clin Endocrinol Metab, 99(3):E453-E457. Cavalier E, Betea D, Schleck ML, Gadisseur R, Vroonen L, Delanaye P, Daly AF, Beckers A. 2014. Background: Parathyroid carcinoma (PCa) is rare and often difficult to differentiate initially from benign disease. Because PCa oversecretes amino PTH that is detected by third-generation but not by second-generation PTH assays, the normal 3rd/2nd generation PTH ratio (<1) is inverted in PCa (ie, >1). Objective: The objective of the investigation was to study the utility and advantages of automated 3rd/2nd generation PTH ratio measurements using the Liaison XL platform over existing manual techniques. Setting: The study was conducted at a tertiary- referral academic center. Design: This was a retrospective laboratory study. Subjects: Eleven patients with advanced PCa (mean age 56.0 y). The controls were patients with primary-hyperparathyroidism (n = 144; mean age 53.8 y), renal transplantation (n = 41; mean age 50.6 y), hemodialysis (n = 80; mean age 65.2 y), and healthy elderly subjects (n = 40; mean age 72.6 y). Results: The median (interquartile range) 3rd/2nd generation PTH ratio was 1.16 (1.10-1.38) in the PCa group, which was significantly higher than the control groups: hemodialysis: 0.74 (0.71-0.75); renal transplant: 0.77 (0.73-0.79); primary hyperparathyroidism: 0.76 (0.74-0.78); healthy elderly: 0.80 (0.74-0.83). An inverted 3rd/2nd-generation PTH ratio (>1) was seen in 9 of 11 PCa patients (81.8%) and in 7 of 305 controls (2.3%): 3 of 80 hemodialysis (3.8%), and 4 of 144 primary- hyperparathyroidism patients (2.8%). Of four PCa patients who had a normal PTH ratio with the manual method, two had an inverted 3rd/2nd-generation PTH ratio with the automated method. Conclusions: Study of the 3rd/2nd-generation PTH ratio in large patient populations should be feasible using a mainstream automated platform like the Liaison XL. The current study confirms the utility of the inverted 3rd/2nd-generation PTH ratio as a marker of PCa (sensitivity: 81.8%; specificity: 97.3%). PubMed-ID: 24423313 http://dx.doi.org/10.1210/jc.2013-3730

Parathyroidectomy Improves Symptomatology and Quality of Life in Patients With Secondary Hyperparathyroidism. Surgery, 155(2):320-8. Cheng SP, Lee JJ, Liu TP, Yang TL, Chen HH, Wu CJ, Liu CL. 2014. BACKGROUND: The parathyroidectomy assessment of symptoms (PAS) score was designed initially for

ESES Review of Recently Published Literature 2014-1 Page 79 of 121 primary hyperparathyroidism to provide a specific symptom assessment and was validated later in secondary and tertiary hyperparathyroidism. The aim of our study was to evaluate changes in the PAS scores and quality of life before and after parathyroidectomy for secondary hyperparathyroidism. METHODS: This prospective study included 49 consecutive patients who underwent parathyroidectomy for secondary hyperparathyroidism. The PAS and Short Form (SF)-36 questionnaires were completed before parathyroidectomy and at 12 months postoperatively. RESULTS: All 13 symptoms included in the PAS score improved significantly. The mean +/- standard deviation PAS score decreased from 545 +/- 263 to 284 +/- 201 (P < .0001) after parathyroidectomy. Quality of life was enhanced in both physical (40.3 +/- 17.1 to 59.0 +/- 14.9; P < .0001) and mental (47.6 +/- 17.1 to 63.7 +/- 13.0; P < .0001) components. The PAS score was inversely correlated with the SF-36 global score preoperatively and postoperatively (r(2) = 0.48 and 0.25; P < .001). The change in PAS score also correlated with the change in SF-36 global score (r(2) = 0.29; P < .001). Multiple linear regression analysis showed that preoperative PAS score and bone mineral density T-score were predictors of the decrease in PAS score. Preoperative SF-36 global score and intact parathyroid hormone levels were predictors of the increment in SF- 36 score. CONCLUSION: The symptom burden of secondary hyperparathyroidism has a negative impact on a patient's quality of life. Parathyroidectomy is associated with a marked improvement in symptoms and quality of life. PubMed-ID: 24035616 http://dx.doi.org/10.1016/j.surg.2013.08.013

18F-FDG PET Rarely Provides Additional Information to 11C-Methionine PET Imaging in Hyperparathyroidism. Clin Nucl Med, 39(3):237-42. Chicklore S, Schulte KM, Talat N, Hubbard JG, O'Doherty M, Cook GJ. 2014. AIM: The aim of this study was to assess the utility of combined C-methionine and F-FDG PET/CT imaging in hyperparathyroidism. PATIENTS AND METHODS: We reviewed all scans performed for hyperparathyroidism with both C-methionine and F-FDG PET/CT or PET in our institution since 1993. Forty-three patients (47 pairs of scans) were included (13 men and 30 women) with a mean age of 63 years. C-methionine and F-FDG PET/CT scans were classified as positive or negative for localization of abnormal parathyroid tissue, and the site of uptake was noted in the positive scans. Other concurrent imaging (Tc-MIBI scintigraphy, ultrasonography, CT, or MRI) findings were also noted when performed. Clinical follow-up information was available in 27 patients (30 episodes). RESULTS: Of the 47 PET scan episodes, 23 (49%) were positive. Twenty-two C-methionine scans showed abnormal focal localization of which 10 also showed concordant abnormal F-FDG uptake. One patient was positive with F-FDG and negative with C-methionine.Of the 16 patients who underwent subsequent surgery, 6 had concordant C-methionine, F-FDG, and surgical findings; 6 had concordant C-methionine and surgical findings; 1 had concordant F-FDG and surgical findings; and 3 had both PET scans negative but had adenomas excised during surgery.Of the 3 with both PET scans negative and discordant surgical findings, 1 had mediastinal parathyroid lipoadenoma excised and 2 had normally sited parathyroid adenoma excised. CONCLUSIONS: F-FDG PET/CT rarely provides additional information and could be saved for patients in whom C-methionine PET/CT is negative. PubMed-ID: 24445273 http://dx.doi.org/10.1097/RLU.0000000000000340

TSH Prevents Bone Resorption and With Calcitriol Synergistically Stimulates Bone Formation in Rats With Low Levels of Calciotropic Hormones. Horm Metab Res, 46(5):305-12. Dumic-Cule I, Draca N, Luetic AT, Jezek D, Rogic D, Grgurevic L, Vukicevic S. 2014. Thyroid-stimulating hormone exerts both antiresorptive and anabolic effects on bone remodeling in aged ovariectomized rats and thyroid stimulating hormone-receptor null mice, supported by clinical results demonstrating that low thyroid-stimulating hormone level is associated with increased bone loss. To further explore the effect of thyroid-stimulating hormone on bone metabolism we introduced here a rat model with removed thyroid and parathyroid glands to obtain low serum concentrations of thyroid and parathyroid hormone, calcitonin and 1,25(OH)2D3. Surgery resulted in hypocalcemia, low parathyroid and thyroid hormone, 1,25(OH)2D3, C-telopeptide, and osteocalcin serum level. Intermittent administration of thyroid-stimulating hormone resulted in a further decrease of serum calcium and decreased level of serum C-telopeptide due to the suppression of bone resorption, while in the same animals osteocalcin in serum was higher indicating an increased bone formation rate. A combination of thyroid-stimulating hormone and 1,25(OH)2D3 significantly increased the serum Ca2+, C-telopeptide and serum osteocalcin values. MicroCT analyses of the distal femur and proximal tibia showed that rats treated with 1,25(OH)2D3 alone or in a combination with thyroid-stimulating hormone had an increased trabecular bone volume, and enhanced trabecular bone quality. Biomechanical

ESES Review of Recently Published Literature 2014-1 Page 80 of 121 testing of the trabecular bone showed an increased maximal load for 105% and 235%, respectively, in rats treated with 1,25(OH)2D3 alone, or in a combination with thyroid-stimulating hormone. We suggest that thyroid- stimulating hormone independently of calciotropic hormones suppressed bone resorption and stimulated bone formation, while in combination with 1,25(OH)2D3 acted synergistically on bone formation resulting in an increased bone volume. PubMed-ID: 24446158 http://dx.doi.org/10.1055/s-0033-1363989

Parathyroid Gland: Hypoparathyroidism--Replacing PTH. Nat Rev Endocrinol, 10(1):3. Greenhill C. 2014. PubMed-ID: 24165998 http://dx.doi.org/10.1038/nrendo.2013.214

Dual-Isotope 99mTc-MIBI/123I Parathyroid Scintigraphy in Primary Hyperparathyroidism: Comparison of Subtraction SPECT/CT and Pinhole Planar Scan. Clin Nucl Med, 39(1):32-6. Hassler S, Ben-Sellem D, Hubele F, Constantinesco A, Goetz C. 2014. PURPOSE: In patients with primary hyperparathyroidism, the preoperative imaging objective is to locate accurately and reliably uniglandular or multiglandular hyperfunctioning parathyroid, to guide surgery, particularly for minimally invasive method. Subtraction planar scintigraphy with dual-isotope (I/Tc-MIBI) is an efficient examination to specify abnormal parathyroid location, but without accurate anatomic reference. This lack should be avoided by a hybrid SPECT/CT image acquisition. METHODS: We compared planar scans (neck and mediastinum parallel-hole, associated with anterior neck pinhole) to neck and mediastinum SPECT/CT, all with subtraction (I/Tc-MIBI) method, in exact location of abnormal parathyroid in 50 patients with sporadic primary hyperparathyroidism. Surgical and histological findings were used as the standard of comparison. RESULTS: Sensitivity is equivalent for the 2 protocols (86% and 75% for SPECT/CT and planar protocol, respectively, P = 0.15), but SPECT/CT was highly specific (specificity 100% and 90% for SPECT/CT and planar protocol, respectively, P = 0.04). In patients with concomitant thyroid disease, subtraction SPECT/CT appeared to be more sensitive than planar protocol (88% and 62% for SPECT/CT and planar protocol, respectively, P = 0.04). CONCLUSIONS: In preoperative assessment of primary hyperparathyroidism and to guide surgery, we propose to perform first subtraction SPECT/CT and to complete it with neck pinhole, only if tomoscintigraphy is negative. PubMed-ID: 24152647 http://dx.doi.org/10.1097/RLU.0000000000000272

Perioperative Changes in Cortical Excitability, Mood, and Quality of Life in Patients With Primary Hyperparathyroidism: a Pilot Study Using Transcranial Magnetic Stimulation. Eur J Endocrinol, 170(2):201-9. Hermsen A, Eienbroker A, Haag A, Mylius V, Hamer HM, Menzler K, Karakas E, Rosenow F. 2014. OBJECTIVE: Serum calcium (Ca(2)(+)) and parathyroid hormone (PTH), amongst others, modify cortical excitability. Alterations in cortical excitability were shown in patients with epilepsy as well as hyper- or hypoparathyroidism. In patients with primary hyperparathyroidism (pHPT), preoperative elevated serum calcium and parathyroidectomy (PTx) may affect mood and quality of life. We hypothesized that perioperative changes in Ca(2)(+) and PTH in pHPT will affect cortical excitability and improve subjective health. DESIGN AND METHODS: Transcranial magnetic stimulation (TMS) was performed before and after surgery in 15 pHPT patients. We measured resting motor threshold, cortical silent period (CSP), short intracortical inhibition, and intracortical facilitation. Health questionnaires were administered before, 1 day and 6 months after PTx, along with the disease-specific Pasieka's parathyroid assessment of symptoms (PAS), which was, to our knowledge, its first use in German. RESULTS: SURGERY WAS SUCCESSFUL IN ALL PATIENTS. TMS- MEASUREMENTS REMAINED UNCHANGED WHEN ANALYZING ALL PATIENTS IN THIS PILOT STUDY. POSTOPERATIVELY, DEPRESSION DECLINED (P=0.05) AND QUALITY OF LIFE IMPROVED SIGNIFICANTLY (P=0.001) IN THE SF-36-SUBSCALES: vitality, social functioning, mental health and subjective health transition (post-hoc analysis). The PAS proved early relief of disease-specific symptoms (P<0.001). CONCLUSIONS: We found unchanged cortical excitability comparing pre- and post-PTx in this pilot study. Mood and quality of life improved postoperatively. The German PAS is valuable in detecting disease- specific changes early after PTx. PubMed-ID: 24174287 http://dx.doi.org/10.1530/EJE-13-0552

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Open Mini-Incision Parathyroidectomy for Solitary Parathyroid Adenoma: Surgical Limitations. Eur Arch Otorhinolaryngol, 271(3):625. Irkorucu O, Deger KC, Reyan E, Arslan E. 2014. PubMed-ID: 23812552 http://dx.doi.org/10.1007/s00405-013-2599-5

Presence of Small Parathyroid Glands in Renal Transplant Patients Supports Less-Than-Total Parathyroidectomy to Treat Hypercalcemic Hyperparathyroidism. Surgery, 155(1):22-32. Jager MD, Emmanouilidis N, Jackobs S, Kespohl H, Hett J, Musatkin D, Trankenschuh W, Schrem H, Klempnauer J, Scheumann GF. 2014. BACKGROUND: Parathyroid glands (PG) are rarely analyzed in renal transplant (RTX) patients. This study analyzes comparatively PG of RTX and end-stage renal disease (ESRD) patients. The clinical part of the study evaluates if total parathyroidectomy with autotransplantation (TPT+AT) treats appropriately hypercalcemic hyperparathyroidism in RTX patients. METHODS: TPT+AT was performed in 15 of 23 RTX and 21 of 27 ESRD patients. Remaining patients underwent less-than-total PT. Volume and stage of hyperplasia were determined from 86 PG of RTX and 109 PG of ESRD patients. Patients were categorized according to the presence of small PG (volume < 100 mm(3)). Calcium homeostasis and hyperparathyroidism were evaluated 2 years after PT in RTX patients. RESULTS: PG of RTX patients were significantly smaller, but similar hyperplastic in comparison to PG of ESRD patients. Small PG were more frequent in RTX than in ESRD patients (19% vs 6%) and mainly graded normal or diffuse hyperplastic (94%). Forty-seven percent of RTX, but only 14% of ESRD, patients receiving a total PT possessed >/=1 small PG (P < .05). Overall, PT treated successfully hypercalcemic hyperparathyroidism. However, TPT+AT caused permanent hypocalcemia in 50% of RTX patients without small PG and even in 83% of RTX patients with small PG. All RTX patients receiving less-than-total PT were normocalcemic at 2-year follow-up. Logistic regression revealed a 10.7 times greater risk of permanent hypocalcemia in RTX patients with small PG receiving TPT+AT compared with RTX patients without small PG receiving TPT+AT or RTX patients undergoing less-than-total PT. CONCLUSION: Surgeons performing PT should be aware of the high frequency of small and less diseased PG in RTX patients. In this context, TPT+AT might overtreat hypercalcemic hyperparathyroidism in RTX patients, especially when small PG are present. PubMed-ID: 24621404 http://dx.doi.org/10.1016/j.surg.2013.06.011

Open Mini-Incision Parathyroidectomy for Solitary Parathyroid Adenoma. Eur Arch Otorhinolaryngol, 271(3):555-60. Kelly CW, Eng CY, Quraishi MS. 2014. Parathyroid surgery is the acceptable definitive treatment for primary hyperparathyroidism (pHPT) due to parathyroid adenoma. Open mini-incision parathyroidectomy (O-MIP) has an excellent cure rate and minimal morbidity. We aim to demonstrate the safety, efficacy and subjective patient satisfaction of O-MIP and investigate the accuracy of pre-operative radiological localisation in relation to operative findings. A retrospective review of patients who underwent O-MIP for pHPT due to solitary parathyroid adenoma from April 2006 to August 2012 was performed. All patients were initially investigated by an endocrinologist to confirm pHPT with pre-operative localisation imaging using ultrasound scan (USS) and 99mTc-sestamibi (MIBI). One hundred and fifty consecutive patients were included with a median age of 62 years. Pre-operative USS and MIBI scans were concordant in 71 % of cases. In combined modality (USS and MIBI), localisation was 94.8 % accurate. There was 95.5 % identification of parathyroid tissue confirmed by intra-operative frozen section. Ninety-one percent of patients were treated as a day case. The median operative time was 60 min. The mean pre-operative calcium level was 2.98 mmol/l, and the short-to-medium term mean calcium level was 2.49 (Paired t test, p < 0.001). There was no significant complication. O-MIP confers significant advantages over the traditional gold standard treatment of bilateral neck exploration. Accurate localisation is the key to successful O-MIP. In experienced hands, ultrasound and MIBI may be the only pre-operative investigations required for accurate localisation. PubMed-ID: 23653305 http://dx.doi.org/10.1007/s00405-013-2443-y

Negative Parafibromin Staining Predicts Malignant Behavior in Atypical Parathyroid Adenomas. Ann Surg Oncol, 21(2):426-33. Kruijff S, Sidhu SB, Sywak MS, Gill AJ, Delbridge LW. 2014. BACKGROUND: The histopathological criteria for carcinoma proposed by the World Health Organization (WHO) are imperfect predictors of the malignant potential of parathyroid tumors. Negative parafibromin (PF) and positive protein gene product 9.5 (PGP9.5) staining are markers of CDC73 mutation and occur commonly in carcinoma

ESES Review of Recently Published Literature 2014-1 Page 82 of 121 but rarely in adenomas. We investigated whether PF and PGP9.5 staining could be used to predict the behavior of atypical parathyroid adenomas--tumors with atypical features that do not fulfill WHO criteria for malignancy. METHODS: Long-term outcomes were compared across four groups: group A, WHO-positive criteria/PF- negative staining; group B, WHO(+)/PF(+), group C; WHO(-)/PF(-); and group D, WHO(-)/PF(+). RESULTS: Eighty-one patients were included in the period 1999-2012: group A (n = 13), group B (n = 14), group C (n = 21), and group D (n = 33). Mortality and recurrence rates, respectively, for group A were 15 and 38%, for group B 7 and 36%, for group C 0 and 10%, and for group D 0 and 0%. The PGP9.5(+) ratios for groups A to D were 85, 78, 71, and 12%, further informing prognosis. Five-year disease-free survival for groups A to D were 55, 80, 78, and 100%, respectively. Tumor recurrence was significantly associated with PF (p = 0.048) and PGP9.5 (p = 0.003) staining. CONCLUSIONS: Although WHO criteria are essential to differentiate parathyroid carcinoma from benign tumors, the presence of negative PF staining in an atypical adenoma predicts outcome better, whereas PF-positive atypical adenomas do not recur and can be considered benign. PF-negative atypical adenomas have a low but real recurrence risk and should be considered tumors of low malignant potential. PubMed-ID: 24081804 http://dx.doi.org/10.1245/s10434-013-3288-8

Operative Failure in Minimally Invasive Parathyroidectomy Utilizing an Intraoperative Parathyroid Hormone Assay. Ann Surg Oncol, 21(6):1878-83. Lee S, Ryu H, Morris LF, Grubbs EG, Lee JE, Harun N, Feng L, Perrier ND. 2014. BACKGROUND: Minimally invasive parathyroidectomy (MIP) is a targeted operation to cure primary hyperparathyroidism utilizing intraoperative parathyroid hormone monitoring (IOPTH). The purpose of this study was to quantify the operative failure of MIP. METHODS: Utilizing institutional parathyroid surgery database, demographic, operative, and biochemical data were analyzed for successful and failed MIP. Operative failure was defined as <6 months of eucalcemia after operation. RESULTS: Five hundred thirty-eight patients (96.6 %) had successful MIP with mean follow-up of 13 months, and 19 (3.4 %) had operative failure. The major cause of operative failure (11 of 19) was the result of surgeons' inability to identify all abnormal parathyroid glands. The remaining eight operative failures were the result of falsely positive IOPTH results. Eleven of 19 patients whose MIP had failed underwent a second parathyroid surgery. All but one of these patients achieved operative success, and 9 patients had missed multigland disease. Only 46 (8.3 %) of 557 patients had conversion to bilateral cervical exploration (BCE). Eighty percent of patients had more than 70 % IOPTH decrease, and all had successful operations. Patients with a marginal IOPTH decrease (50-59 %) had a treatment failure rate of 20 %. CONCLUSIONS: The most common cause of operative failure in MIP utilizing IOPTH was the result of surgeons' failure to identify all abnormal parathyroid glands. Falsely positive IOPTH is rare, and a targeted MIP utilizing IOPTH can achieve an excellent operative success rate without routine BCE. Selective BCE on patients with marginal IOPTH decrease may improve surgical outcome. PubMed-ID: 24452409 http://dx.doi.org/10.1245/s10434-013-3479-3

Parathyroidectomy Improves Cardiovascular Outcome in Nondiabetic Dialysis Patients With Secondary Hyperparathyroidism. Clin Endocrinol (Oxf), 80(4):508-15. Lin HC, Chen CL, Lin HS, Chou KJ, Fang HC, Liu SI, Hsu CY, Huang WC, Huang CW, Huang CK, Chang TY, Chang YT, Lee PT. 2014. OBJECTIVE: Secondary hyperparathyroidism and its associated abnormalities in mineral metabolism and haemodynamic changes increase the cardiovascular risk in patients with end-stage renal disease (ESRD). Our objective was to determine the association of parathyroidectomy (PTX) with major cardiovascular events in nondiabetic dialysis patients with severe secondary hyperparathyroidism (SHPTH). DESIGN AND PATIENTS: We performed a cohort study with fifty-three nondiabetic ESRD patients who were treated with maintenance haemodialysis and who had intact parathyroid hormone (PTH) levels > 800 pg/ml. Participants received either only medical therapy or medical therapy and total PTX with autotransplantation for SHPTH. MEASUREMENTS: We evaluated the associations between PTX and major cardiovascular events including death, cerebrovascular accident and myocardial infarction. The biochemical and haemodynamic changes associated with PTX were measured. RESULTS: During the mean follow-up of 72 months, twenty-three patients received only medical treatment (medical group) while thirty patients underwent PTX in addition to medical treatment (PTX group). The two groups were comparable in respect of baseline characteristics. PTX group was found to be associated with a reduced incidence of major cardiovascular events (P = 0.021). A multiple Cox regression analysis showed that the variable significantly associated with major cardiovascular events was treatment modality (medical therapy vs medical therapy and parathyroidectomy, hazard ratio = 26.12, 95% CI = 1.30-526.27, P = 0.033). Blood

ESES Review of Recently Published Literature 2014-1 Page 83 of 121 pressure, haemoglobin, alkaline phosphatase, calcium, phosphate and calcium x phosphate product significantly improved after PTX. CONCLUSIONS: PTX was associated with better cardiovascular outcome in nondiabetic dialysis patients with severe SHPTH. PubMed-ID: 24102421 http://dx.doi.org/10.1111/cen.12333

Parathyroid Surgery in the Elderly: Should Minimally Invasive Surgery Be Abandoned? Ann Surg Oncol, 21(4):1369-73. Mekel M, Gilshtein H, Chapchay K, Bishara B, Krausz MM, Freund HR, Kluger Y, Eid A, Mazeh H. 2014. BACKGROUND: Single adenoma is the cause of 80 % of primary hyperparathyroidism (PHPT) resulting in wide acceptance of minimally invasive parathyroidectomy (MIP). The incidence of PHPT increases with age. Little information is available regarding the prevalence of multiglandular disease (MGD) in older patients. METHODS: The records of 537 patients that underwent parathyroid surgery between January 2005 and October 2012 at two endocrine surgery referral centers were retrospectively reviewed. Comparison was performed between patients younger than 65 and older than 65 years of age. Clinical variables included preoperative laboratories and imaging, extent of neck exploration, number of glands excised, and intraoperative parathyroid hormone levels during surgery. RESULTS: There were 374 (70 %) patients in the younger age group (YG) and 163 (30 %) patients in the older age group (OG). The mean age was 50 +/- 0.5 and 71 +/- 0.4 years, respectively. There was no difference between the groups in terms of gender or laboratory results. MGD was significantly more common in the OG (24 % vs. 12 %; p = 0.001) and similarly MIP was less commonly completed in the OG (49 % vs. 68 %; p < 0.001). Cure rates were comparable between the OG and YG (93 % vs. 95 %; p = 0.27). In the OG, patients with MGD had significantly smaller glands as compared to patients with single adenomas in this group (331 +/- 67 vs. 920 +/- 97 mg; p = 0.006, respectively). CONCLUSIONS: MGD in PHPT was found to be more prevalent in older patients. Planning a bilateral neck exploration should be considered in older patients, especially when a relatively small gland is suggested by imaging or encountered during surgery. PubMed-ID: 24306663 http://dx.doi.org/10.1245/s10434-013-3402-y

Osteoprotegerin Serum Levels in Primary Hyperparathyroidism and Changes Following Surgery. Horm Metab Res, 46(5):375. Minisola S, Cipriani C, Piemonte S, Colangelo L, Pepe J, Romagnoli E. 2014. PubMed-ID: 24415533 http://dx.doi.org/10.1055/s-0033-1363278

Improvement of Sleep Disturbance and Insomnia Following Parathyroidectomy for Primary Hyperparathyroidism. World J Surg, 38(3):542-8. Murray SE, Pathak PR, Schaefer SC, Chen H, Sippel RS. 2014. BACKGROUND: The aim of the present study was to investigate the incidence of sleep disturbance and insomnia in patients with primary hyperparathyroidism (PHPT), and to evaluate the effect of parathyroidectomy. METHODS: A questionnaire was prospectively administered to adult patients with PHPT who underwent curative parathyroidectomy over an 11-month period. The questionnaire, administered preoperatively and 6 months postoperatively, included the Insomnia Severity Index (ISI) and eight additional questions regarding sleep pattern. Total ISI scores range from 0 to 28, with >7 signifying sleep difficulties and scores >14 indicating clinical insomnia. RESULTS: Of 197 eligible patients undergoing parathyroidectomy for PHPT, 115 (58.3 %) completed the preoperative and postoperative questionnaires. The mean age was 60.0 +/- 1.2 years and 80.0 % were women. Preoperatively, 72 patients (62.6 %) had sleep difficulties, and 29 patients (25.2 %) met the criteria for clinical insomnia. Clinicopathologic variables were not predictive of clinical insomnia. There was a significant reduction in mean ISI score after parathyroidectomy (10.3 +/- 0.6 vs 6.2 +/- 0.5, p < 0.0001). Postoperatively, 79 patients (68.7 %) had an improved ISI score. Of the 29 patients with preoperative clinical insomnia, 21 (72.4 %) had resolution after parathyroidectomy. Preoperative insomnia patients had an increase in total hours slept after parathyroidectomy (5.4 +/- 0.3 vs 6.1 +/- 0.3 h, p = 0.02), whereas both insomnia patients and non-insomnia patients had a decrease in the number of awakenings (3.7 +/- 0.4 vs 1.9 +/- 0.2 times, p = 0.0001). CONCLUSIONS: Sleep disturbances and insomnia are common in patients with PHPT, and the majority of patients will improve after curative parathyroidectomy. PubMed-ID: 24142330 http://dx.doi.org/10.1007/s00268-013-2285-1

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Subcutaneous Injection Is a Simple and Reproducible Option to Restore Parathyroid Function After Total Parathyroidectomy in Patients With Secondary Hyperparathyroidism. Surgery, 155(4):682-8. Ng JC, Wang W, Chua MJ, Tan MS, Tan NC, Soo KC, Tan HK, Iyer NG. 2014. BACKGROUND: Secondary hyperparathyroidism is a common clinical problem seen in patients with end-stage renal disease (ESRD) undergoing hemodialysis. In patients with severe persistent hyperparathyroidism, parathyroidectomies are often required. OBJECTIVES: We sought to evaluate the feasibility and efficacy of total parathyroidectomy followed by subcutaneous injection of parathyroid autograft compared with surgical implantation. METHODS: We conducted a retrospective study of 132 patients with confirmed diagnoses of ESRD treated with hemodialysis or peritoneal dialysis, with secondary hyperparathyroidism who had undergone total parathyroidectomies. Clinical and biochemical characteristics, including preoperative and postoperative intact parathyroid hormone levels were recorded and compared between patients who had undergone subcutaneous injection or surgical implantation of autograft. RESULTS: From February 2005 to February 2012, 132 patients who had undergone total parathyroidectomies were included in our study. To compare the techniques of subcutaneous injection and surgical implantation, pre- and postoperative biochemistry was recorded and analyzed. Preoperative biochemistry was comparable in both groups. However, autograft recovery was significantly faster in the group with subcutaneous injection compared with surgical implantation (P = .03). Median time to parathyroid recovery was 2 months for injection compared with 9 months for implantation. There was no remarkable difference in the recurrence rates between the 2 groups. CONCLUSION: Subcutaneous injection of parathyroid tissue is a feasible and simple alternative to the more commonly used method of surgical implantation. PubMed-ID: 24612625 http://dx.doi.org/10.1016/j.surg.2013.12.019

Bilateral Neck Exploration in Patients With Primary Hyperparathyroidism and Discordant Imaging Results: a Single-Centre Study. Eur J Endocrinol, 170(5):719-25. Philippon M, Guerin C, Taieb D, Vaillant J, Morange I, Brue T, Conte-Devolx B, Henry JF, Slotema E, Sebag F, Castinetti F. 2014. INTRODUCTION: Focused parathyroidectomy is the treatment of choice for patients with concordant positive imaging. Bilateral cervical exploration is performed for cases with discordant imaging, yet more than 70% of those cases are the result of a single-gland disease. As focused parathyroidectomy is generally costless and harmless, for cases with discordant imaging, we tried to determine whether preoperative characteristics can lead to a diagnosis of single-gland disease. METHODS: This study included 182 patients treated for primary hyperparathyroidism by bilateral exploration from 2009 to 2012 at La Timone Hospital, Marseille, France. We classified patients based on preoperative images and pathological results (single-gland or multiglandular disease). We then compared the demographical, laboratory and imaging results. We also asked a senior nuclear medicine practitioner who was blind to the ultrasound and pathological results to perform a second reading. RESULTS: Of the total number of patients, 15.4% had negative, 54.4% discordant and 30.2% concordant imaging. After reviewing the scintigraphy results, 8% of the cases with discordant imaging would have been classified as concordant with ultrasound. Subtraction scintigraphy obtained better results than dual-phase scintigraphy (concordance with ultrasound in 50 vs 31% with classical scintigraphy). For the cases of discordant imaging, no predictive factors of single-gland disease could be identified. Ultrasound and scintigraphy were similarly effective in determining the correct location of the abnormal gland. CONCLUSION: Discordant results of preoperative imaging modalities do not discriminate between uniglandular and multiglandular diseases in hyperparathyroidism. Diagnostic differentiation between the different causes of hyperparathyroidism requires improvements in imaging techniques and might benefit from subtraction scintigraphy. PubMed-ID: 24569082 http://dx.doi.org/10.1530/EJE-13-0796

Muscle Function Is Impaired in Patients With "Asymptomatic" Primary Hyperparathyroidism. World J Surg, 38(3):549-57. Rolighed L, Amstrup AK, Jakobsen NF, Sikjaer T, Mosekilde L, Christiansen P, Rejnmark L. 2014. BACKGROUND: Patients with "asymptomatic" primary hyperparathyroidism (PHPT) often describe improvement after surgery. METHODS: We evaluated muscle and balance function, quality of life (QoL), and well-being in 58 PHPT patients and 58 population-based matched controls in a cross-sectional study. We tested whether patients considered "asymptomatic" according to international guidelines have functional impairment. RESULTS: Mean age of the patients and controls was 59 years, and 47 (81 %) were women. Patients had higher levels of plasma PTH and ionized calcium. Creatinine and 25-hydroxyvitamin D levels did not differ between groups. Altogether,

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16 (28 %) patients were "asymptomatic." Compared with controls, PHPT was associated with significantly lower QoL in all eight domains of the short form-36 questionnaire, lower well-being (WHO Five Well-Being Index; p < 0.001), and impaired postural stability during normal standing with eyes open (p < 0.05) or closed (p < 0.001). Maximum isometric muscle strength was reduced in both upper (p < 0.01) and lower (p < 0.001) extremities. Physical performance was decreased during 10 repeated chair stands (p < 0.001) and time to walk 3 m forward and back (p < 0.05). Restricting analyses to "asymptomatic" patients showed significantly lower muscle strength at knee extension and flexion and impaired postural stability than in matched controls. CONCLUSIONS: PHPT is associated with deleterious effects on muscles and QoL. Impairments also apply to patients with mild disease, normally considered "asymptomatic." This may explain why "asymptomatic" patients report improvements following surgery. The impaired muscle function may contribute to increased fracture risk independent of bone mineral density. PubMed-ID: 24101026 http://dx.doi.org/10.1007/s00268-013-2273-5

Predictors of Recurrence in Primary Hyperparathyroidism: an Analysis of 1386 Cases. Ann Surg, 259(3):563-8. Schneider DF, Mazeh H, Chen H, Sippel RS. 2014. OBJECTIVE: The purpose of this study was to determine whether the operative approach independently influenced recurrence and to identify perioperative predictors of recurrence. BACKGROUND: Intraoperative parathyroid hormone (IoPTH) monitoring has enabled surgeons to perform minimally invasive parathyroidectomy (MIP). Yet, the long-term durability of this approach has recently been questioned. STUDY DESIGN: A retrospective review was performed, and cases of initial neck surgery for nonfamilial primary hyperparathyroidism were selected for analysis. Cases were classified as either open parathyroidectomy (OP) when both sides of the neck were explored or MIP when only one side was explored. Kaplan-Meier estimates were plotted for disease-free survival, and a Cox proportional hazards model was developed to evaluate factors associated with recurrence for both the entire cohort and the MIP subset. Further comparisons were made between those who recurred and those who did not recur. RESULTS: In the past 10-year period, 1368 parathyroid operations for primary hyperparathyroidism were performed at our institution. A total of 1006 were MIP whereas 380 were OP. There were no differences in recurrence between the MIP and OP groups (2.5% vs 2.1%; P = 0.68), and the operative approach (MIP vs OP) did not independently predict recurrent disease in our multivariate analysis. The percentage decrease in IoPTH was protective against recurrence for both the entire cohort (hazard ratio = 0.96; 95% confidence interval = 0.93-0.99; P = 0.03) and the MIP subset. A higher postoperative PTH also independently predicted disease recurrence. CONCLUSIONS: Operative approach does not independently predict recurrent hyperparathyroidism. The percentage decrease in IoPTH is one of many adjuncts the surgeon can use to determine which patients are best served by bilateral exploration whereas the postoperative PTH can guide follow-up after parathyroidectomy. PubMed-ID: 24263316 http://dx.doi.org/10.1097/SLA.0000000000000207

Oncologic Resection Achieving R0 Margins Improves Disease-Free Survival in Parathyroid Cancer. Ann Surg Oncol , 21(6):1891-7. Schulte KM, Talat N, Galata G, Gilbert J, Miell J, Hofbauer LC, Barthel A, Diaz-Cano S, Bornstein SR. 2014. BACKGROUND: Parathyroid cancer has a poor mid-term prognosis, often because of local recurrence, observed in half of all patients. Modern diagnostic workup increasingly enables a preoperative diagnosis of parathyroid cancer. There is limited evidence that more comprehensive oncologic surgery can reduce the risk of local recurrence. This study aims to identify the best specific surgical approach in parathyroid cancer. METHODS: This observational cohort study comprises 19 consecutive patients who had undergone oncologic or nononcologic resection for parathyroid cancer. Baseline parameters were compared by using univariate analysis; outcomes were assessed by chi (2) testing and Kaplan-Meier statistics. RESULTS: Fifteen of 19 patients were primarily operated on in our tertiary center between 1996 and 2013, and four were referred for follow-up because of their cancer diagnosis. Patient cohorts defined by histologic R-status were comparable for established risk factors: sex, calcium levels, low-risk/high-risk status, and presence of vascular invasion. Oncologic resections were performed in 13 of 15 patients primarily treated in the center and 0 of 4 treated elsewhere (chi (2) = 5.6; p < 0.01). R0 margins were achieved in 11 of 13 (85 %) undergoing oncologic resection and 1 of 6 (17 %) undergoing local excision (chi (2) = 8.1; p < 0.01). R0 margins and primary oncologic resection were associated with higher disease-free survival rates (chi (2) = 7.9; p = 0.005 and chi (2) = 4.7; p = 0.03, respectively). Revision surgery achieved R0 margins in only 2 of 4 (50 %) of patients. CONCLUSIONS: In parathyroid cancer, a more comprehensive surgery (primary oncologic resection) provides significantly better outcomes than local excision as a result of reduction of R1 margins and locoregional recurrence.

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PubMed-ID: 24522991 http://dx.doi.org/10.1245/s10434-014-3530-z

High Cardiac Background Activity Limits 99mTc-MIBI Radioguided Surgery in Aortopulmonary Window Parathyroid Adenomas. BMC Surg, 14:22. Schwarzlmuller T, Brauckhoff K, Lovas K, Biermann M, Brauckhoff M. 2014. BACKGROUND: Radioguided surgery using 99m-Technetium-methoxyisobutylisonitrile (99mTc-MIBI) has been recommended for the surgical treatment of mediastinal parathyroid adenomas. However, high myocardial 99mTc-MIBI uptake may limit the feasibility of radioguided surgery in aortopulmonary window parathyroid adenoma. CASE PRESENTATION: Two female patients aged 72 (#1) and 79 years (#2) with primary hyperparathyroidism caused by parathyroid adenomas in the aortopulmonary window were operated by transsternal radioguided surgery. After intravenous injection of 370 MBq 99mTc-MIBI at start of surgery, the maximum radioactive intensity (as counts per second) was measured over several body regions using a gamma probe before and after removal of the parathyroid adenoma. Relative radioactivity was calculated in relation to the measured ex vivo radioactivity of the adenoma, which was set to 1.0. Both patients were cured by uneventful removal of aortopulmonary window parathyroid adenomas of 4400 (#1) and 985 mg (#2). Biochemical cure was documented by intraoperative measurement of parathyroid hormone as well as follow-up examination. Ex vivo radioactivity over the parathyroid adenomas was 196 (#1) and 855 counts per second (#2). Before parathyroidectomy, relative radioactivity over the aortopulmonary window versus the heart was found at 1.3 versus 2.6 (#1) and 1.8 versus 4.8 (#2). After removal of the adenomas, radioactivity within the aortopulmonary window was only slightly reduced. CONCLUSION: High myocardial uptake of 99mTc-MIBI limits the feasibility of radioguided surgery in aortopulmonary parathyroid adenoma. PubMed-ID: 24758398 http://dx.doi.org/10.1186/1471-2482-14-22

Surgeon-Driven Thyroid Interrogation of Patients Presenting With Primary Hyperparathyroidism. J Am Coll Surg, 218(4):674-83. Sloan DA, Davenport DL, Eldridge RJ, Lee CY. 2014. BACKGROUND: Primary hyperparathyroidism (pHPT) is an increasingly prevalent disease affecting all age groups. The authors sought to determine the impact of a "thyroid interrogation" practice protocol on the surgical treatment of patients with the diagnosis of pHPT referred to a single surgeon. STUDY DESIGN: We performed a retrospective review of prospectively gathered data on parathyroidectomy (PTX) patients undergoing both a prospective clinical thyroid evaluation and thyroid ultrasound between January 2008 and October 2012. RESULTS: Only 5.6% of 468 PTX patients were referred to a single surgeon for both parathyroid and thyroid surgical evaluation; 31% of patients had known pre-existing thyroid disease (hypothyroidism most commonly), and 22% of patients had palpable thyroid abnormalities unrecognized in 67% of cases by the referring physician. Of the 468 patients, 2.6% had a history of classic head and neck radiation exposure, 2.6% a history of radio- iodine treatment, and 3% a family history of thyroid cancer. Thyroid abnormalities were found on ultrasound in 61% of patients, and 26% of patients underwent thyroid biopsies. Parathyroid and thyroid surgery was combined for 18.4% of patients; indications included obstructive symptoms (3.2%), hyperthyroidism (0.9%), intraoperative findings (5.1%), and concern for malignancy (9.2%). Malignancy was diagnosed in 23 patients (4.9%), only 8 of whom had been referred for thyroid evaluation. CONCLUSIONS: The majority of patients referred for PTX had evidence of thyroid pathology. For an important minority of these patients, benign and malignant disease was identified that merited surgical treatment at the time of PTX. We recommend comprehensive thyroid evaluation of patients referred for PTX. PubMed-ID: 24529807 http://dx.doi.org/10.1016/j.jamcollsurg.2013.12.021

The Histone Methyltransferase EZH2, an Oncogene Common to Benign and Malignant Parathyroid Tumors. Endocr Relat Cancer, 21(2):231-9. Svedlund J, Barazeghi E, Stalberg P, Hellman P, Akerstrom G, Bjorklund P, Westin G. 2014. Primary hyperparathyroidism (pHPT) resulting from parathyroid tumors is a common endocrine disorder with incompletely understood etiology. In renal failure, secondary hyperparathyroidism (sHPT) occurs with multiple tumor development as a result of calcium and vitamin D regulatory disturbance. The aim of this study was to investigate a potential role of the histone 3 lysine 27 methyltransferase EZH2 in parathyroid tumorigenesis. Parathyroid tumors from patients with pHPT included adenomas and carcinomas. Hyperplastic parathyroid glands from patients with HPT secondary to uremia and normal parathyroid tissue specimens were included in

ESES Review of Recently Published Literature 2014-1 Page 87 of 121 this study. Quantitative RT-PCR, western blotting, bisulfite pyrosequencing, colony formation assay, and RNA interference were used. EZH2 was overexpressed in a subset of the benign and in all malignant parathyroid tumors as determined by quantitative RT-PCR and western blotting analyses. Overexpression was explained by EZH2 gene amplification in a large fraction of tumors. EZH2 depletion by RNA interference inhibited sHPT-1 parathyroid cell line proliferation as determined by tritium-thymidine incorporation and colony formation assays. EZH2 depletion also interfered with the Wnt/beta-catenin signaling pathway by increased expression of growth- suppressive AXIN2, a negative regulator of beta-catenin stability. Indeed, EZH2 contributed to the total level of aberrantly accumulated transcriptionally active (nonphosphoylated) beta-catenin in the parathyroid tumor cells. To our knowledge EZH2 gene amplification presents the first genetic aberration common to parathyroid adenomas, secondary hyperplastic parathyroid glands, and parathyroid carcinomas. This supports the possibility of a common pathway in parathyroid tumor development. PubMed-ID: 24292603 http://dx.doi.org/10.1530/ERC-13-0497

Impact of Parathyroidectomy on Serum FGF23 and Soluble Klotho in Hemodialysis Patients With Severe Secondary Hyperparathyroidism. J Clin Endocrinol Metab, 99(4):E652-E658. Takahashi H, Komaba H, Takahashi Y, Sawada K, Tatsumi R, Kanai G, Suzuki H, Kakuta T, Fukagawa M. 2014. CONTEXT: Klotho is a transmembrane protein that functions as a coreceptor for fibroblast growth factor 23 (FGF23). Klotho is cleaved and released into the circulation; however, the main site of production, physiological role, and regulation of soluble Klotho in humans are largely unknown. OBJECTIVE: The aim of this study was to determine the impact of parathyroidectomy (PTx) on serum FGF23 and soluble Klotho levels in patients with severe secondary hyperparathyroidism. DESIGN AND SETTING: This was a prospective, single-arm trial conducted at Tokai University School of Medicine. PATIENTS: Thirteen hemodialysis patients with severe secondary hyperparathyroidism who were candidates for PTx participated in the study. INTERVENTIONS: All patients underwent total PTx with forearm autotransplantation. MAIN OUTCOME MEASURES: We evaluated changes in serum FGF23 and soluble Klotho levels for 90 days after PTx. Other biochemical parameters related to mineral and bone metabolism were also assessed. RESULTS: At baseline, serum FGF23 levels were markedly elevated, whereas serum soluble Klotho levels were modestly decreased. PTx resulted in a marked, progressive decline in serum FGF23 levels together with significant reductions in serum calcium, phosphorus, and intact PTH levels. The serum soluble Klotho levels were reduced 13% from baseline on the day after PTx; however, these levels then increased progressively, reaching 34% above the postoperative values. CONCLUSIONS: Our results suggest that the parathyroid gland is not the major site of soluble Klotho production in patients with end-stage renal disease, and the production of Klotho by other organ(s) is affected by alterations in mineral metabolism or medications taken after PTx. PubMed-ID: 24476081 http://dx.doi.org/10.1210/jc.2013-4050

Cinacalcet Induces Apoptosis in Parathyroid Cells in Patients With Secondary Hyperparathyroidism: Histological and Cytological Analyses. Nephron Clin Pract, 124(3-4):224-31. Tatsumi R, Komaba H, Kanai G, Miyakogawa T, Sawada K, Kakuta T, Fukagawa M. 2013. BACKGROUND/AIMS: Previous studies reported a reduction in parathyroid gland volume during treatment with cinacalcet in patients with secondary hyperparathyroidism (SHPT). However, it remains to be determined whether cinacalcet accelerates apoptosis of hyperplastic parathyroid cells in these patients. METHODS: The study subjects were 16 hemodialysis patients who had undergone parathyroidectomy for severe SHPT. We compared the expression of the apoptotic marker TUNEL and the proliferative marker Ki67 by immunohistochemistry and the expression of CYP27B1 by quantitative real-time PCR in hyperplastic parathyroid glands from patients treated with cinacalcet (cinacalcet group; n = 8) and those not treated with cinacalcet (non- cinacalcet group; n = 8). We also examined the effect of cinacalcet on parathyroid cell death in in vitro cell culture with TUNEL staining, using parathyroid cells from SHPT patients. RESULTS: Compared with the non- cinacalcet group, the expression of TUNEL was significantly increased but was accompanied with significantly increased Ki67 expression in the parathyroid glands from the cinacalcet group. In vitro examination showed dose- and time-dependent increases of apoptotic cells by adding cinacalcet into culture medium. We also found that the expression of CYP27B1 showed a three-fold increase in glands from the cinacalcet group compared to that of the non-cinacalcet group. CONCLUSION: Our data suggest that cinacalcet induces apoptosis of human parathyroid cells, but this effect may be overcome by more aggressive proliferation of parathyroid cells in patients with severe, cinacalcet-resistant SHPT.

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PubMed-ID: 24503607 http://dx.doi.org/10.1159/000357951

Effect of Parathyroidectomy Versus Risedronate on Volumetric Bone Mineral Density and Bone Geometry at the Tibia in Postmenopausal Women With Primary Hyperparathyroidism. J Bone Miner Metab , 32(2):151-8. Tournis S, Fakidari E, Dontas I, Liakou C, Antoniou J, Galanos A, Marketou H, Makris K, Katsalira K, Trovas G, Lyritis GP, Papaioannou N. 2014. The objective of the study was to evaluate the effect of parathyroidectomy (PTX) versus 35 mg once-weekly (ow) risedronate administration on volumetric bone mineral density (vBMD) and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism (PHPT). Our open-label prospective observational study included 32 postmenopausal women with PHPT as the study group: 16 underwent PTX and 16 were treated with 35 mg ow risedronate for 2 years. We assessed areal BMD (aBMD) by DXA, and vBMD and bone mineral content (BMC) (cortical and trabecular area) by peripheral quantitative computed tomography (pQCT) at the tibia at baseline and at 2 years. Risedronate did not result in any significant change on vBMD and structural pQCT indices. PTX resulted in significant increase in trabecular (trab) BMC (6.44 %) and vBMD (4.64 %), with percent increase being significantly higher than risedronate (p < 0.05). At cortical sites, there was no significant change following PTX. However, the percent change in cortical (cort) vBMD was higher following PTX versus risedronate (0.39 % vs. -0.26 %, p < 0.05). In conclusion, in postmenopausal women with PHPT, PTX is superior to ow risedronate, in terms of improvement of trabecular mineralization and vBMD at the tibia, whereas the effect at cortical sites is less pronounced. PubMed-ID: 23700284 http://dx.doi.org/10.1007/s00774-013-0473-6

Interpretation of Plasma PTH Concentrations According to 25OHD Status, Gender, Age, Weight Status, and Calcium Intake: Importance of the Reference Values. J Clin Endocrinol Metab, 99(4):1196-203. Touvier M, Deschasaux M, Montourcy M, Sutton A, Charnaux N, Kesse-Guyot E, Fezeu LK, Latino-Martel P, Druesne-Pecollo N, Malvy D, Galan P, Hercberg S, Ezzedine K, Souberbielle JC. 2014. CONTEXT: Reference values for plasma PTH assessment were generally established on small samples of apparently healthy subjects, without considering their 25-hydroxyvitamin D (25OHD) status or other potential modifiers of PTH concentration. OBJECTIVE: Our objective was to assess ranges of plasma PTH concentration in a large sample of adults, stratifying by 25OHD status, age, gender, weight status, and calcium intake. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional survey is based on 1824 middle-aged Caucasian adults from the Supplementation en Vitamines et Mineraux Antioxydants study (1994). MAIN OUTCOME MEASURES: Plasma PTH and 25OHD concentrations were measured by an electrochemoluminescent immunoassay. Extreme percentiles of plasma PTH concentrations were assessed specifically in subjects who had plasmatic values of 25OHD of 20 ng/mL or greater and 30 ng/mL or greater. RESULTS: Among subjects with 25OHD status of 20 ng/mL or greater, the 97.5th percentile of plasma PTH concentration was 45.5 ng/L. By using this value as a reference, 5% of the subjects with plasma 25OHD less than 20 nmol/L had a high plasma PTH level, reflecting secondary hyperparathyroidism. Among vitamin D- replete subjects (25OHD status of 20 ng/mL or greater), the 97.5th percentile of plasma PTH was higher in overweight/obese subjects (51.9 vs 43.5 ng/L among normal weight subjects). CONCLUSIONS: The reference value for plasma PTH defined in this vitamin D-replete population was far below the value currently provided by the manufacturer (65 ng/L) and varied according to overweight status. These results may contribute to improve the diagnosis of primary and secondary hyperparathyroidism and subsequent therapeutic indication. PubMed-ID: 24527713 http://dx.doi.org/10.1210/jc.2013-3349

Cure Predictability During Parathyroidectomy. World J Surg, 38(3):525-33. Udelsman R, Donovan P, Shaw C. 2014. BACKGROUND: A mathematical model for primary hyperparathyroidism (1 degrees HPTH) was developed and embedded in software to yield intraoperative predictability curves. METHODS: A total of 1,754 consecutive 1 degrees HPTH operative cases were screened to select 617 [554 single adenoma (SA), 63 multigland] patients with complete preoperative, intraoperative (pre-exploration, time 0, every 5 min post-resection), and postoperative parathyroid hormone (PTH) and calcium data. Data transformations and models were hypothesized and tested, including inverse functions, differences, half-lives, differences from projected half-lives, second-order kinetics, second-order derivatives, and time-dependent ratios. Sub-models of ratios were

ESES Review of Recently Published Literature 2014-1 Page 89 of 121 developed for time-dependent and initial-value combinations. For each time segment the log odds were modeled using multiple logistic stepwise regression. An idealized model was selected, embedded in software, and installed in a laptop computer to enable intraoperative decision analyses, PTH curve plotting, and storage and transmission of data. A subsequent cohort of 100 consecutive unselected patients [81 SAs, 19 multigland (13 hyperplasia, 2 MEN1, 1 lithium, 3 double adenomas)] inclusive of seven remedial cervical explorations were tested. RESULTS: The model predicted an overall curative resection in 95 % of patients. In SA patients, cure was predicted in 78/81 patients with a mean probability of 99.3 % at 11.8 +/- 10.4 min post-resection. In three cured patients, the software failed to suggest cure, because of a low baseline PTH or delayed clearance. The model also correctly predicted residual hyperfunctioning tissue in all tested multigland patients. All multigland patients underwent additional exploration with resection of residual disease resulting in a mean predicted cure rate of 97.9 % at 10.6 +/- 7.3 min post-resection completion in 17 patients. In two patients, the software predicted a mean cure rate of 22 % due to either a low PTH baseline or delayed clearance. Overall, the software accurately predicted cure in 95 of 100 cured cases. CONCLUSIONS: This intraoperative prediction software expedites termination of surgery with a high level of curative confidence. Alternatively, the model accurately predicts residual disease prompting additional exploration. Because the model is based on a large set of multivariate regression curves, PTH values obtained at any post-resection sampling interval generate prediction data with far greater accuracy than existing algorithms. The software is designed for convenient operative use and can print, store, and electronically transmit probability analyses and PTH curves in real-time. PubMed-ID: 24240672 http://dx.doi.org/10.1007/s00268-013-2327-8

Denosumab for Management of Parathyroid Carcinoma-Mediated Hypercalcemia. J Clin Endocrinol Metab, 99(2):387-90. Vellanki P, Lange K, Elaraj D, Kopp PA, El MM. 2014. CONTEXT: Most of the morbidity and mortality from parathyroid cancer is due to PTH-mediated hypercalcemia. Classically, management mainly consists of surgical resection, chemotherapy, and alleviation of hypercalcemia using bisphosphonates and calcium receptor agonists. The use of denosumab in the treatment of parathyroid cancer-mediated hypercalcemia has not been reported. OBJECTIVE: The aim of this report is to describe the effect of denosumab on parathyroid cancer-induced hypercalcemia. SUBJECT, MEASURES, AND RESULT: The patient is a 39-year-old man with metastatic parathyroid cancer who presented at age 35. His calcium levels initially responded to surgery, bisphosphonates, calcium receptor agonist, and chemotherapy (dacarbazine). However, his disease progressed, and his hypercalcemia became refractory to these measures in the setting of rising PTH levels. The addition of denosumab, a humanized monoclonal antibody inhibiting receptor activator of nuclear factor kappaB ligand resulted in successful management of his hypercalcemia for an additional 16 months. CONCLUSIONS: Denosumab can be effective in the treatment of refractory hypercalcemia in parathyroid cancer. It may also be of potential use in settings of benign hyperparathyroid-related hypercalcemia such as parathyromatosis, where hypercalcemia is not amenable to surgery or medical therapy with bisphosphonates and calcium receptor agonists. PubMed-ID: 24178790 http://dx.doi.org/10.1210/jc.2013-3031

Techniques of Parathyroid Exploration at North American Endocrine Surgery Fellowship Programs: What the Next Generation Is Being Taught. Am J Surg, 207(4):527-32. Wang TS, Pasieka JL, Carty SE. 2014. BACKGROUND: Minimally invasive techniques are now often used to treat primary hyperparathyroidism but with uncertain conformity and some controversy. Endocrine surgery fellowships (ESFPs) have recently proliferated. METHODS: The directors of the 19 ESFPs recognized by the American Association of Endocrine Surgeons were polled to identify the approaches currently taught to trainees. RESULTS: With 100% participation, all ESFPs obtain >/=1 imaging study, and 95% use ultrasound to assess for concurrent thyroid nodules that require care. For an apparent single adenoma, all ESFPs minimize dissection, use intraoperative parathyroid hormone monitoring, and, if multiglandular disease is identified, perform 4-gland exploration. Outpatient surgery (89%) and postoperative oral calcium use (68%) are common. All programs define cure as durable normocalcemia (median, 6 months). CONCLUSIONS: American Association of Endocrine Surgeons fellowship programs teach congruent management strategies that include focused dissection, intraoperative parathyroid hormone use, and intent to cure. These consistencies define a future standard for assessment of parathyroidectomy outcomes. PubMed-ID: 24495320 http://dx.doi.org/10.1016/j.amjsurg.2013.05.012

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The Final Intraoperative Parathyroid Hormone Level: How Low Should It Go? World J Surg, 38(3):558-63. Wharry LI, Yip L, Armstrong MJ, Virji MA, Stang MT, Carty SE, McCoy KL. 2014. BACKGROUND: In minimally invasive surgery for primary hyperparathyroidism (HPT), intraoperative parathyroid hormone (IOPTH) monitoring assists in obtaining demonstrably better outcomes, but optimal criteria are controversial. METHODS: The outcomes of 1,108 initial parathyroid operations for sporadic HPT using IOPTH monitoring from 1997 to 2011 were stratified by final post-resection IOPTH level. All patients had adequate follow-up to verify cure. RESULTS: With mean follow-up of 1.8 years (range 0.5-14.3 years), parathyroidectomy using IOPTH monitoring failed in 1.2 % of cases, with an additional 0.5 % incidence of long-term recurrence at a mean of 3.2 years (range 0.8-6.8 years) postoperatively. Operative success was equally likely with a final IOPTH drop to 41-65 pg/mL vs 50 % but not into the normal range, surgical failure was 19 times more likely (3.8 vs. 0.2 %; p = 0.015). Long-term recurrence was more likely in patients with a final IOPTH level of 41-65 pg/mL than with a level 50 % from baseline is a strong predictor of operative success. Patients with a final IOPTH level between 41-65 pg/mL should be followed beyond 6 months for long-term recurrence. PubMed-ID: 24253106 http://dx.doi.org/10.1007/s00268-013-2329-6

Calciphylaxis. Lancet, 383(9922):1067. Zhou Q, Neubauer J, Kern JS, Grotz W, Walz G, Huber TB. 2014. PubMed-ID: 24582472 http://dx.doi.org/10.1016/S0140-6736(14)60235-X

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Adrenals

Meta-Analyses (131)I-MIBG Therapy for Malignant Paraganglioma and Phaeochromocytoma: Systematic Review and Meta-Analysis. Clin Endocrinol (Oxf), 80(4):487-501. van Hulsteijn LT, Niemeijer ND, Dekkers OM, Corssmit EP. 2014. BACKGROUND: (131)I-MIBG therapy can be used for palliative treatment of malignant paraganglioma and phaeochromocytoma. The main objective of this study was to perform a systematic review and meta-analysis assessing the effect of (131)I-MIBG therapy on tumour volume in patients with malignant paraganglioma/phaeochromocytoma. METHODS: A literature search was performed in December 2012 to identify potentially relevant studies. Main outcomes were the pooled proportions of complete response, partial response and stable disease after radionuclide therapy. A meta-analysis was performed with an exact likelihood approach using a logistic regression with a random effect at the study level. Pooled proportions with 95% confidence intervals (CI) were reported. RESULTS: Seventeen studies concerning a total of 243 patients with malignant paraganglioma/phaeochromocytoma were treated with (131)I-MIBG therapy. The mean follow-up ranged from 24 to 62 months. A meta-analysis of the effect of (131)I-MIBG therapy on tumour volume showed pooled proportions of complete response, partial response and stable disease of, respectively, 0.03 (95% CI: 0.06-0.15), 0.27 (95% CI: 0.19-0.37) and 0.52 (95% CI: 0.41-0.62) and for hormonal response 0.11 (95% CI: 0.05-0.22), 0.40 (95% CI: 0.28-0.53) and 0.21 (95% CI: 0.10-0.40), respectively. Separate analyses resulted in better results in hormonal response for patients with paraganglioma than for patients with phaeochromocytoma. CONCLUSIONS: Data on the effects of (131)I-MIBG therapy on malignant paraganglioma/phaeochromocytoma suggest that stable disease concerning tumour volume and a partial hormonal response can be achieved in over 50% and 40% of patients, respectively, treated with (131)I-MIBG therapy. It cannot be ruled out that stable disease reflects not only the effect of MIBG therapy, but also (partly) the natural course of the disease. PubMed-ID: 24118038 http://dx.doi.org/10.1111/cen.12341

Randomized controlled trials - None –

Consensus Statements/Guidelines - None -

Other Articles Impact of Surgical Resection for Subdiaphragmatic Paragangliomas. World J Surg, 38(3):733-41. Abadin SS, Ayala-Ramirez M, Jimenez C, Dickson PV, Liang Y, Lazar AJ, Hornick JL, Cotton M, Sui D, Rich T, Lee JE, Grubbs E, Perrier ND. 2014. BACKGROUND: Subdiaphragmatic paraganglioma is a rare neuroendocrine tumor for which scarce data exist regarding long-term patient outcome following resection. The aim of this study was to determine the association of surgical resection with survival. METHODS: A retrospective study at a tertiary care center was performed. Demographics, genetics, histology, and operative details were reviewed. Patients were grouped according to margin status (R0, R1, or R2) and survival calculated. RESULTS: A total of 50 patients with subdiaphragmatic paragangliomas underwent primary resection from 1999 to 2012. Median age at operation was 46 years, with a median tumor size of 6.0 cm. Of these patients, 30 (60 %) had a R0 resection, 11 (22 %) had a R1 resection, and 9 (18 %) had a R2 resection. There was no operative mortality, and 17 (34 %) patients had metastatic disease. Six (12 %) patients died, four (8 %) of whom had metastatic disease. Univariate analysis identified that

ESES Review of Recently Published Literature 2014-1 Page 92 of 121 age >50 years (p = 0.02) and undergoing a R2 resection (p = 0.03) were associated with a shorter overall survival (OS). Those with metastases at some point after their initial diagnosis had a shorter disease-free survival (DFS) than those without metastases (p = 0.04). Of 27 patients tested, 12 (44 %) had a germline succinyl dehydrogenase B (SDHB) mutation. SDHB immunohistochemistry identified 18 patients (of 27 who underwent staining) who had loss of SDHB expression in which 7 of 11 patients (63 %) who underwent genetic testing had a genetic mutation. CONCLUSIONS: Surgical resection of subdiaphragmatic paraganglioma is safe. Survival was longest in patients who were younger, with no metastases, or had a R0 or R1 resection. Patients who test negative for a germline mutation should undergo SDHB immunostaining to identify potential hereditary carriers missed by current genetic testing. PubMed-ID: 24390286 http://dx.doi.org/10.1007/s00268-013-2443-5

Predictors of Malignancy in Primary Aldosteronism. Langenbecks Arch Surg, 399(1):93-8. Agha A, Hornung M, Iesalnieks I, Schreyer A, Jung EM, Haneya A, Schlitt HJ. 2014. INTRODUCTION: Primary aldosteronism (PA, also Conn syndrome) is a benign disease in majority of cases. However, malignant transformation has been described. Present study reports on three cases of aldosterone producing adrenocortical carcinoma (APAC) in comparison to patients with benign PA. PATIENTS AND METHODS: Data of patients undergoing adrenalectomy for benign PA were compared to patients with APAC. Retrospective chart analysis was performed. All patients received spironolactone for 6-8 weeks preoperatively. RESULTS: Seventy-four patients underwent adrenalectomy for PA between 1994 and 2011. Three of them revealed an APAC. Patients with APAC presented with a significantly lower serum potassium level (1.7 mmol/l vs. 3.4 mmol/l, p = 0.001) and significant larger tumors (5.2 vs. 1.8 cm, p = 0.002). In addition, aldosterone/renin (A/R) ratio 675 in patients with APAC as compared to 74 in patients with benign PA (p = 0.0001). Sixty-eight of 71 patients with benign PA underwent minimal invasive surgery, whereas all three patients with APAC were operated conventionally. All patients with APAC developed disease recurrence 6-18 months postoperatively. CONCLUSION: Tumor size >4 cm and a very high A/R ratio seems to predictors of malignancy in patients with PA. If these criteria are present, open adrenalectomy should be performed instead of endoscopic procedure. PubMed-ID: 24048685 http://dx.doi.org/10.1007/s00423-013-1121-2

Prospective Study to Compare Peri-Operative Hemodynamic Alterations Following Preparation for Pheochromocytoma Surgery by Phenoxybenzamine or Prazosin. World J Surg, 38(3):716-23. Agrawal R, Mishra SK, Bhatia E, Mishra A, Chand G, Agarwal G, Agarwal A, Verma AK. 2014. BACKGROUND: Prospective studies comparing the efficacy of selective versus nonselective alpha blockers for preoperative preparation of pheochromocytoma (PCC) are lacking. In this prospective nonrandomized study, we compared the outcome of preoperative preparation with phenoxybenzamine (PBZ) and prazosin (PRZ) in terms of perioperative hemodynamic alterations. METHODS: The study was conducted at a tertiary referral center from July 2010 to December 2012. Thirty-two patients with PCC underwent operation after adequate preparation with PBZ (n = 15) or PRZ (n = 17). Five pediatric and adolescent patients were excluded because of different hemodynamics in this population. Perioperative monitoring was done for pulse rate (PR) and blood pressure(BP) alterations, occurrence of arrhythmias, and time taken to achieve hemodynamic stability. Groups were compared with the Mann-Whitney test, Student's t test, and the chi2 test as applicable. RESULTS: Patients in the two groups were similar in age,gender, 24 h urinary metanephrine and normetanephrine levels, and type of procedure. Patients prepared with PRZ had significantly more intraoperative episodes of transient hypertension (systolic BP >/= 160 mmHg) and hypertensive urgency (BP >180/110 mmHg) (p 0.02, 0.03, respectively). More patients receiving PRZ suffered from transient severe hypertension (SBP >/= 220 mmHg) (p 0.03). The PRZ group also had more median maximum SBP (233 mmHg vs PBZ 181.5 mmHg) (p = 0.01) and lesser median minimum SBP (71 mmHg vs PBZ 78 mmHg) (p 0.03). No significant differences were found between the study groups for changes in PR, postoperative BP alterations,occurrence of arrhythmias, and time taken to achieve hemodynamic stability. CONCLUSIONS: PBZ was found superior to PRZ in having fewer intraoperative hemodynamic fluctuations. PubMed-ID: 24233658 http://dx.doi.org/10.1007/s00268-013-2325-x

Long-Term Prognosis of Patients With Pediatric Pheochromocytoma. Endocr Relat Cancer, 21(1):17-25. Bausch B, Wellner U, Bausch D, Schiavi F, Barontini M, Sanso G, Walz MK, Peczkowska M, Weryha G,

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Dall'igna P, Cecchetto G, Bisogno G, Moeller LC, Bockenhauer D, Patocs A, Racz K, Zabolotnyi D, Yaremchuk S, Dzivite-Krisane I, Castinetti F, Taieb D, Malinoc A, von DE, Roessler J, Schmid KW, Opocher G, Eng C, Neumann HP. 2014. A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine. PubMed-ID: 24169644 http://dx.doi.org/10.1530/ERC-13-0415

Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome. N Engl J Med, 370(11):1019-28. Beuschlein F, Fassnacht M, Assie G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B. 2014. BACKGROUND: Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. METHODS: We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol- producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol- secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro. RESULTS: Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A-->C in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased. CONCLUSIONS: Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.). PubMed-ID: 24571724 http://dx.doi.org/10.1056/NEJMoa1310359

Phenotypic Variability and Risk of Malignancy in SDHC-Linked Paragangliomas: Lessons From Three Unrelated Cases With an Identical Germline Mutation (p.Arg133*). J Clin Endocrinol Metab, 99(3):E489-E496. Bickmann JK, Sollfrank S, Schad A, Musholt TJ, Springer E, Miederer M, Bartsch O, Papaspyrou K, Koutsimpelas D, Mann WJ, Weber MM, Lackner KJ, Rossmann H, Fottner C. 2014. Context: Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndrome types 1-4 and are associated with multiple and recurrent pheochromocytomas and PGLs. SDHC mutations most frequently result in benign, nonfunctional head-and neck PGLs (HNPGLs).

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The malignant potential of SDHC mutations remains unclear to date. Objectives: We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue. Design: In three unrelated patients referred for routine genetic testing, SDHB, SDHC, and SDHD genes were sequenced, and gross deletions were excluded by multiplex ligation-dependent probe amplification (MLPA). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry. Results: In a patient with a nonfunctioning thoracic PGL metastatic to the bone, the lungs, and mediastinal lymph nodes, we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics, but both showed benign HNPGLs. Conclusions: We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL, although malignancy is probably rare. PubMed-ID: 24423348 http://dx.doi.org/10.1210/jc.2013-3486

Surgical Management of Adrenal Metastases. J Surg Oncol, 109(1):31-5. Bradley CT, Strong VE. 2014. In the presence of a history of cancer, adrenal masses are commonly, but not exclusively, metastases. Depending upon the status of the patient's ongoing cancer therapy, overall tumor burden, and performance score, adrenalectomy is a viable treatment option. Herein we review the prevalence, diagnostic evaluation, and selection for surgical treatment of adrenal metastases. Additional attention is paid to recent data supporting the safety and oncologic efficacy of laparoscopic adrenalectomy. PubMed-ID: 24338382 http://dx.doi.org/10.1002/jso.23461

Comparison of Outcomes After Laparoscopic Versus Posterior Retroperitoneoscopic Adrenalectomy: a Pilot Study. Surg Laparosc Endosc Percutan Tech, 24(1):62-6. Cabalag MS, Mann GB, Gorelik A, Miller JA. 2014. BACKGROUND: Posterior retroperitoneoscopic adrenalectomy (PRA) was popularized by Walz and colleagues as an alternative approach to minimally invasive adrenalectomy, offering less postoperative pain and faster return to normal activity compared with laparoscopic transperitoneal adrenalectomy (LA). The authors have recently changed from LA to PRA in suitable patients and audited their outcomes. METHODS: Data were prospectively collected for 10 patients who underwent PRA, and a chart review and telephone interviews were conducted with 13 consecutive patients who underwent LA by the same surgeon. Patient demographics, tumor characteristics, analgesia use, operative and anesthetic time, length of stay, and complications were recorded. RESULTS: Data were collected for 13 LAs and 10 PRAs. Patients' baseline characteristics, including age, BMI, and tumor size, were similar between the 2 groups. There were no conversions to open surgery, transfusions, or deaths. Operative time was similar between the 2 groups. PRA patients required less, inpatient postoperative opioid analgesia compared with LA patients (median 1.25 vs. 23 mg of intravenous morphine equivalent, P=0.003), and had a shorter length of stay (median 1 vs. 2 d, P<0.001). The median total days on opioids were lower for PRA patients compared with LA patients (0.5 vs. 9 d, P<0.001). CONCLUSION: Our initial results supports previously published findings that PRA is a safe procedure, with a relatively short learning curve, resulting in reduced postoperative analgesia use, and reduced length of hospital stay when compared with the laparoscopic transperitoneal approach. PubMed-ID: 24487160 http://dx.doi.org/10.1097/SLE.0b013e31828fa71f

STAR Splicing Mutations Cause the Severe Phenotype of Lipoid Congenital Adrenal Hyperplasia: Insights From a Novel Splice Mutation and Review of Reported Cases. Clin Endocrinol (Oxf), 80(2):191-9. Camats N, Pandey AV, Fernandez-Cancio M, Fernandez JM, Ortega AM, Udhane S, Andaluz P, Audi L, Fluck CE. 2014. OBJECTIVE: The steroidogenic acute regulatory protein (StAR) transports cholesterol to the mitochondria for steroidogenesis. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH) which is characterized by impaired synthesis of adrenal and gonadal steroids causing adrenal insufficiency, 46,XY

ESES Review of Recently Published Literature 2014-1 Page 95 of 121 disorder of sex development (DSD) and failure of pubertal development. Partial loss of StAR activity may cause adrenal insufficiency only. PATIENT: A newborn girl was admitted for mild dehydration, hyponatremia, hyperkalemia and hypoglycaemia and had normal external female genitalia without hyperpigmentation. Plasma cortisol, 17OH-progesterone, DHEA-S, androstendione and aldosterone were low, while ACTH and plasma renin activity were elevated, consistent with the diagnosis of primary adrenal insufficiency. Imaging showed normal adrenals, and cytogenetics revealed a 46,XX karyotype. She was treated with fluids, hydrocortisone and fludrocortisone. DESIGN, METHODS AND RESULTS: Genetic studies revealed a novel homozygous STAR mutation in the 3' acceptor splice site of intron 4, c.466-1G>A (IVS4-1G>A). To test whether this mutation would affect splicing, we performed a minigene experiment with a plasmid construct containing wild-type or mutant StAR gDNA of exons-introns 4-6 in COS-1 cells. The splicing was assessed on total RNA using RT-PCR for STAR cDNAs. The mutant STAR minigene skipped exon 5 completely and changed the reading frame. Thus, it is predicted to produce an aberrant and shorter protein (p.V156GfsX19). Computational analysis revealed that this mutant protein lacks wild-type exons 5-7 which are essential for StAR-cholesterol interaction. CONCLUSIONS: STAR c.466-1A skips exon 5 and causes a dramatic change in the C-terminal sequence of the protein, which is essential for StAR-cholesterol interaction. This splicing mutation is a loss-of-function mutation explaining the severe phenotype of our patient. Thus far, all reported splicing mutations of STAR cause a severe impairment of protein function and phenotype. PubMed-ID: 23859637 http://dx.doi.org/10.1111/cen.12293

Laparoscopic Adrenal Metastasectomy: Appropriate, Safe, and Feasible. Surg Endosc, 28(3):816-20. Chen JY, Ardestani A, Tavakkoli A. 2014. BACKGROUND: The role of adrenalectomy in management of isolated metastatic adrenal tumors is increasingly established. Laparoscopy is becoming the preferred approach for these resections. We evaluated surgical and oncological outcomes of patients who underwent laparoscopic versus open adrenal metastasectomy and assessed the effect of such surgery on postoperative adjuvant therapy and survival. METHODS: We reviewed our institutional experience with adult patients who underwent an adrenal metastasectomy from 1997 to 2013. We assessed preoperative tumor size, operating room (OR) time, status of resection margin, and length of stay (LOS), as well as oncological outcomes including the use of adjuvant chemotherapy and radiotherapy within 1 year of surgery and 5-year survival. The chi (2) test, Mann-Whitney U test, and Kaplan-Meier curve were used for statistical analysis. RESULTS: Thirty-eight patients were identified. Lung was the primary site of malignancy (52.6 % of cases). Of the metastasectomies, 55.2 % (n = 21) were performed laparoscopically and 44.7 % (n = 17) were open. In the laparoscopic group, median tumor size was 2.6 cm versus 4.8 cm in the open group (p = 0.09). Median OR time and complication rates were similar between the 2 groups. The laparoscopic group, however, trended toward a shorter LOS (3 days laparoscopic vs. 4 days for open; p = 0.07). At 1 year, 37 % of all patients had not required any adjuvant chemotherapy or adjuvant radiotherapy. CONCLUSIONS: This series confirms that adrenal metastasectomy leads to favorable oncological outcomes in select patient groups, with over one-third of patients not requiring adjuvant therapy for at least 1 year after their resection. Laparoscopic approach leads to excellent oncological resection margins without increasing OR time and with a possible reduction in LOS. PubMed-ID: 24337189 http://dx.doi.org/10.1007/s00464-013-3274-z

Pheochromocytoma Crisis Resulting in Acute Heart Failure and Cardioembolic Stroke in a 37-Year-Old Man. Surgery, 155(4):726-7. Cohen JK, Cisco RM, Scholten A, Mitmaker E, Duh QY. 2014. PubMed-ID: 23305592 http://dx.doi.org/10.1016/j.surg.2012.11.013

Biochemical Diagnosis of Phaeochromocytoma Using Plasma-Free Normetanephrine, Metanephrine and Methoxytyramine: Importance of Supine Sampling Under Fasting Conditions. Clin Endocrinol (Oxf) , 80(4):478-86. Darr R, Pamporaki C, Peitzsch M, Miehle K, Prejbisz A, Peczkowska M, Weismann D, Beuschlein F, Sinnott R, Bornstein SR, Neumann HP, Januszewicz A, Lenders J, Eisenhofer G. 2014. OBJECTIVE: To document the influences of blood sampling under supine fasting versus seated nonfasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine. DESIGN AND METHODS: Biochemical testing for PPGL

ESES Review of Recently Published Literature 2014-1 Page 96 of 121 was performed on 762 patients at six centres, two of which complied with requirements for supine sampling after an overnight fast and four of which did not. Phaeochromocytomas and paragangliomas were found in 129 patients (67 noncompliant, 62 compliant) and not in 633 patients (195 noncompliant, 438 compliant). RESULTS: Plasma concentrations of normetanephrine and methoxytyramine did not differ between compliant and noncompliant sampling conditions in patients with PPGL but were 49-51% higher in patients without PPGL sampled under noncompliant compared with compliant conditions. The 97.5 percentiles of distributions were also higher under noncompliant compared with compliant conditions for normetanephrine (1.29 vs 0.79 nmol/l), metanephrine (0.49 vs 0.41 nmol/l) and methoxytyramine (0.42 vs 0.18 nmol/l). Use of upper cut-offs established from seated nonfasting sampling conditions resulted in substantially decreased diagnostic sensitivity (98% vs 85%). In contrast, use of upper cut-offs established from supine fasting conditions resulted in decreased diagnostic specificity for testing under noncompliant compared with compliant conditions (71% vs 95%). CONCLUSIONS: High diagnostic sensitivity of plasma normetanephrine, metanephrine and methoxytyramine for the detection of PPGL can only be guaranteed using upper cut-offs of reference intervals established with blood sampling under supine fasting conditions. With such cut-offs, sampling under seated nonfasting conditions can lead to a 5.7-fold increase in false-positive results necessitating repeat sampling under supine fasting conditions. PubMed-ID: 24102244 http://dx.doi.org/10.1111/cen.12327

Long-Term Survival After Adrenalectomy for Stage I/II Adrenocortical Carcinoma (ACC): a Retrospective Comparative Cohort Study of Laparoscopic Versus Open Approach. Ann Surg Oncol, 21(1):284-91. Donatini G, Caiazzo R, Do CC, Aubert S, Zerrweck C, El-Kathib Z, Gauthier T, Leteurtre E, Wemeau JL, Vantyghem MC, Carnaille B, Pattou F. 2014. BACKGROUND: Laparoscopic adrenalectomy (LA) is the standard treatment for benign adrenal lesions. The laparoscopic approach has also been increasingly accepted for adrenal metastases but remains controversial for adrenocortical carcinoma (ACC). In a retrospective cohort study we compared the outcome of LA versus open adrenalectomy (OA) in the treatment of stage I and II ACC. METHODS: This was a double cohort study comparing the outcome of patients with stage I/II ACC and a tumor size <10 cm submitted to LA or OA at Lille University Hospital referral center from 1985 to 2011. Main outcomes analyzed were: postoperative morbidity, overall survival, and disease-free survival. RESULTS: Among 111 consecutive patients operated on for ACC, 34 met the inclusion criteria. LA and OA were performed in 13 and 21 patients, respectively. Baseline patient characteristics (gender, age, tumor size, hormonal secretion) were similar between groups. There was no difference in postoperative morbidity, but patients in LA group were discharged earlier (p < 0.02). After a similar follow-up (66 +/- 52 for LA and 51 +/- 43 months for OA), Kaplan-Meier estimates of disease-specific survival and disease-free survival were identical in both groups (p = 0.65, p = 0.96, respectively). CONCLUSIONS: LA was associated with a shorter length of stay and did not compromise the long-term oncological outcome of patients operated on for stage I/II ACC

Complementary Somatic Mutations of KCNJ5, ATP1A1, and ATP2B3 in Sporadic Aldosterone Producing Adrenal Adenomas. Endocr Relat Cancer, 21(1):L1-L4. Dutta RK, Welander J, Brauckhoff M, Walz M, Alesina P, Arnesen T, Soderkvist P, Gimm O. 2014. PubMed-ID: 24179102 http://dx.doi.org/10.1530/ERC-13-0466

Adrenocortical Carcinoma. Endocr Rev, 35(2):282-326. Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ, Hammer GD. 2014. Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis. Here we summarize the knowledge about diagnosis, epidemiology, pathophysiology, and therapy of ACC. Over recent years, multidisciplinary clinics have formed and the first international treatment trials have been conducted. This review focuses on evidence gained from recent basic science and clinical research and provides perspectives from the experience of a large multidisciplinary clinic dedicated to the care of patients with ACC.

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PubMed-ID: 24423978 http://dx.doi.org/10.1210/er.2013-1029

Treatment and Health Outcomes in Adults With Congenital Adrenal Hyperplasia. Nat Rev Endocrinol, 10(2):115-24. Han TS, Walker BR, Arlt W, Ross RJ. 2014. Congenital adrenal hyperplasia (CAH) is a genetic disorder caused by defective steroidogenesis that results in glucocorticoid deficiency; the most common underlying mutation is in the gene that encodes 21-hydroxylase. Life-saving glucocorticoid treatment was introduced in the 1950s, and the number of adult patients is now growing; however, no consensus has been reached on the management of CAH beyond childhood. Adult patients are prescribed a variety of glucocorticoids, including hydrocortisone, prednisone, prednisolone, dexamethasone and combinations of these drugs taken in either a circadian or reverse circadian regimen. Despite these personalized treatments, biochemical control of CAH is only achieved in approximately one-third of patients. Some patients have a poor health status, with an increased incidence of obesity and osteoporosis, and impaired fertility and quality of life. The majority of poor health outcomes seem to relate to inadequate treatment rather than the genotype of the patient. Patients receiving high doses of glucocorticoids and the more potent synthetic long-acting glucocorticoids are at an increased risk of obesity, insulin resistance and a reduced quality of life. Further research is required to optimize the treatment of adult patients with CAH and improve health outcomes. PubMed-ID: 24342885 http://dx.doi.org/10.1038/nrendo.2013.239

Port-Site Metastasis After Laparoscopic Removal of an Isolated Adrenal Metastasis in a Patient With Breast Cancer Detected With FDG PET/CT. Clin Nucl Med, 39(2):203-5. Kajary K, Molnar P, Lengyel Z, Szakall S Jr. 2014. Adrenal metastasis from breast cancer rarely occurs in the course of this disease. Laparoscopic surgery has increased in the therapy for malignant tumors because of its lower morbidity and mortality compared with conventional surgical methods. However, complications such as the appearance of a port-site metastasis may also occur. Clinical examination and conventional cross-sectional imaging usually reveal this only at advanced stage. The authors reported on a case with abdominal wall port-site metastasis detected with F-FDG PET/CT 33 months after the laparoscopic removal of a late-onset, PET/CT-verified adrenal metastasis from lobular breast cancer. PubMed-ID: 24152655 http://dx.doi.org/10.1097/RLU.0000000000000288

Calculating Optimal Surveillance for Detection of Von Hippel-Lindau-Related Manifestations. Endocr Relat Cancer, 21(1):63-71. Kruizinga RC, Sluiter WJ, de Vries EG, Zonnenberg BA, Lips CJ, van der Horst-Schrivers AN, Walenkamp AM, Links TP. 2014. von Hippel-Lindau (VHL) mutation carriers develop benign and malignant tumors, requiring regular surveillance. The aim of this study was to calculate the optimal organ-specific age to initiate surveillance and optimal intervals to detect initial and subsequent VHL-related manifestations. In this study, we compare these results with the current VHL surveillance guidelines. We collected data from 82 VHL mutation carriers in the Dutch VHL surveillance program. The cumulative proportion of carriers diagnosed with a first VHL-related manifestation was estimated by the Kaplan-Meier method. The Poisson distribution model was used to calculate average time to detection of the first VHL-related manifestation and subsequent manifestations. We used this to calculate the optimal organ-specific age to initiate surveillance and the surveillance interval that results in a detection probability of 5%. The calculated organ-specific ages to initiate surveillance were 0 years (birth) for adrenal glands, 7 years for the retina, 14 years for the cerebellum, 15 years for the spinal cord, 16 years for pancreas, and 18 years for the kidneys. The calculated surveillance intervals were 4 years for the adrenal glands, biennially for the retina and pancreas, and annually for the cerebellum, spinal cord, and kidneys. Compared with current VHL guidelines, the calculated starting age of surveillance was 6 years later for the retina and 5 years earlier for adrenal glands. The surveillance intervals were two times longer for the retina and four times longer for the adrenal glands. To attain a 5% detection probability rate per organ, our mathematical model indicates that several modifications of current VHL surveillance guidelines should be considered. PubMed-ID: 24132471 http://dx.doi.org/10.1530/ERC-13-0308

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Role of SDHAF2 and SDHD in Von Hippel-Lindau Associated Pheochromocytomas. World J Surg, 38(3):724-32. Kugelberg J, Welander J, Schiavi F, Fassina A, Backdahl M, Larsson C, Opocher G, Soderkvist P, Dahia PL, Neumann HP, Gimm O. 2014. BACKGROUND: Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel-Lindau (VHL) syndrome. In VHL, only about 30 % of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs. MATERIALS AND METHODS: Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. RESULTS AND CONCLUSIONS: LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p < 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome. PubMed-ID: 24322175 http://dx.doi.org/10.1007/s00268-013-2373-2

Retroperitoneal Pheochromocytoma With Thorax and Bilateral Neck Chemodectoma in Patients With Multiorgan Sarcoidosis. Clin Nucl Med, 39(4):e258-e262. Kunikowska J, Grabowska L, Toutounchi S, Cieszanowski A, Witkowska M. 2014. A 37-year-old man with multiorgan sarcoidosis, hypertension, and abdominal mass on CT was referred to the nuclear medicine department. PET/CT with 68Ga DOTATATE demonstrated an increased uptake in the abdominal mass and in the mediastinum, neck (bilaterally), and right jugular foramen; low uptake was observed in hilar and groin lymph nodes. MRI revealed abnormal focal lesions, showing increased signal on T2-weighted fat-saturated images, marked contrast enhancement on T1-weighted gradient-echo images, and restricted diffusion in the same locations as on PET/CT. Patients underwent surgery of abdominal mass and right neck tumors, with histologic diagnosis consistent with extra-adrenal pheochromocytoma and neck chemodectoma. PubMed-ID: 24458174 http://dx.doi.org/10.1097/RLU.0000000000000325

Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia. N Engl J Med, 370(11):1071-2. Louiset E, Lefebvre H. 2014. PubMed-ID: 24620879 http://dx.doi.org/10.1056/NEJMc1316140

Whole Exome Sequencing Is an Efficient and Sensitive Method for Detection of Germline Mutations in Patients With Phaeochromcytomas and Paragangliomas. Clin Endocrinol (Oxf), 80(1):25-33. McInerney-Leo AM, Marshall MS, Gardiner B, Benn DE, McFarlane J, Robinson BG, Brown MA, Leo PJ, Clifton- Bligh RJ, Duncan EL. 2014. BACKGROUND: Genetic testing is recommended when the probability of a disease-associated germline mutation exceeds 10%. Germline mutations are found in approximately 25% of individuals with phaeochromcytoma (PCC) or paraganglioma (PGL); however, genetic heterogeneity for PCC/PGL means many genes may require sequencing. A phenotype-directed iterative approach may limit costs but may also delay diagnosis, and will not detect mutations in genes not previously associated with PCC/PGL. OBJECTIVE: To assess whether whole exome sequencing (WES) was efficient and sensitive for mutation detection in PCC/PGL. METHODS: Whole exome sequencing was performed on blinded samples from eleven individuals with PCC/PGL and known mutations. Illumina TruSeq (Illumina Inc, San Diego, CA, USA) was used for exome capture of seven samples, and NimbleGen SeqCap EZ v3.0 (Roche NimbleGen Inc, Basel, Switzerland) for five

ESES Review of Recently Published Literature 2014-1 Page 99 of 121 samples (one sample was repeated). Massive parallel sequencing was performed on multiplexed samples. Sequencing data were called using Genome Analysis Toolkit and annotated using annovar. Data were assessed for coding variants in RET, NF1, VHL, SDHD, SDHB, SDHC, SDHA, SDHAF2, KIF1B, TMEM127, EGLN1 and MAX. Target capture of five exome capture platforms was compared. RESULTS: Six of seven mutations were detected using Illumina TruSeq exome capture. All five mutations were detected using NimbleGen SeqCap EZ v3.0 platform, including the mutation missed using Illumina TruSeq capture. Target capture for exons in known PCC/PGL genes differs substantially between platforms. Exome sequencing was inexpensive (<$A800 per sample for reagents) and rapid (results <5 weeks from sample reception). CONCLUSION: Whole exome sequencing is sensitive, rapid and efficient for detection of PCC/PGL germline mutations. However, capture platform selection is critical to maximize sensitivity. PubMed-ID: 24102379 http://dx.doi.org/10.1111/cen.12331

Long-Term Follow-Up in Adrenal Incidentalomas: an Italian Multicenter Study. J Clin Endocrinol Metab, 99(3):827-34. Morelli V, Reimondo G, Giordano R, Della CS, Policola C, Palmieri S, Salcuni AS, Dolci A, Mendola M, Arosio M, Ambrosi B, Scillitani A, Ghigo E, Beck-Peccoz P, Terzolo M, Chiodini I. 2014. Context: The long-term consequences of subclinical hypercortisolism (SH) in patients with adrenal incidentalomas (AIs) are unknown. Setting and Patients: In this retrospective multicentric study, 206 AI patients with a >/=5-year follow-up (median, 72.3 mo; range, 60-186 mo) were enrolled. Intervention and Main Outcome Measures: Adrenocortical function, adenoma size, metabolic changes, and incident cardiovascular events (CVEs) were assessed. We diagnosed SH in 11.6% of patients in the presence of cortisol after a 1 mg- dexamethasone suppression test >5 mug/dL (138 nmol/L) or at least two of the following: low ACTH, increased urinary free cortisol, and 1 mg-dexamethasone suppression test >3 mug/dL (83 nmol/L). Results: At baseline, age and the prevalence of CVEs and type 2 diabetes mellitus were higher in patients with SH than in patients without SH (62.2 +/- 11 y vs 58.5 +/- 10 y; 20.5 vs 6%; and 33.3 vs 16.8%, respectively; P < .05). SH and type 2 diabetes mellitus were associated with prevalent CVEs (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1- 9.0; and OR, 2.0; 95% CI, 1.2-3.3, respectively), regardless of age. At the end of the follow-up, SH was diagnosed in 15 patients who were without SH at baseline. An adenoma size >2.4 cm was associated with the risk of developing SH (sensitivity, 73.3%; specificity, 60.5%; P = .014). Weight, glycemic, lipidic, and blood pressure control worsened in 26, 25, 13, and 34% of patients, respectively. A new CVE occurred in 22 patients. SH was associated with the worsening of at least two metabolic parameters (OR, 3.32; 95% CI, 1.6-6.9) and with incident CVEs (OR, 2.7; 95% CI, 1.0-7.1), regardless of age and follow-up. Conclusion: SH is associated with the risk of incident CVEs. Besides the clinical follow-up, in patients with an AI >2.4 cm, a long-term biochemical follow-up is also required because of the risk of SH development. PubMed-ID: 24423350 http://dx.doi.org/10.1210/jc.2013-3527

Pitfalls in the Diagnosis and Differential Diagnosis of Cushing's Syndrome. Clin Endocrinol (Oxf), 80(3):333-4. Nieman L. 2014. PubMed-ID: 24303816 http://dx.doi.org/10.1111/cen.12362

Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia. N Engl J Med, 370(11):1071. Nishikawa T, Iwata M, Sasano H. 2014. PubMed-ID: 24620880 http://dx.doi.org/10.1056/NEJMc1316140#SA1

Cortisol Secretion From Adrenal Adenomas Discovered As Incidentalomas Is Responsive to ACTH. Clin Endocrinol (Oxf), 80(3):335-41. Olsen H, Olofsson L, Mjoman M. 2014. OBJECTIVE: Adrenal adenomas discovered as incidentalomas may secrete cortisol and cause subclinical hypercortisolism. This cortisol secretion is considered to be autonomous. The aim was to investigate whether cortisol secretion by adenomas is responsive to ACTH. DESIGN: Descriptive retrospective study of consecutive patients. PATIENTS: Eighty patients found to have adrenal incidentalomas during 2008 and 2009 at our hospital were examined, and 50 patients with a unilateral adenoma were included in the study. MEASUREMENTS: Cortisol and ACTH were measured at baseline and using 1-mg overnight dexamethasone suppression test

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(DST). The cortisol response to ACTH was calculated using the expression: (cortisolbasal -cortisolDST )/(ACTHbasal -ACTHDST ). RESULTS: The patients were divided into three groups according to their basal ACTH: >/=3.0 pm (29 patients), 2.0-2.9 pm (9 patients) and <2.0 pm (12 patients). Cortisol at DST was similar in the three groups: 30, 46 and 43 nm (P = 0.10). The cortisol response to ACTH increased stepwise between the groups: 98, 172 and 249 nm/pm (P = 0.000, undetectable ACTH was set to 0 pm). Basal ACTH was negatively correlated with the size of the adenoma and positively correlated with the attenuation of the adenoma at unenhanced CT (P = 0.03 and P = 0.04, respectively). CONCLUSIONS: Patients with adrenal adenomas and low basal ACTH show increased cortisol response to ACTH, and the adenomas seem to be the source of the increased cortisol secretion. The increased response to ACTH could be a pathogenic factor in metabolic complications of subclinical hypercortisolism. The cortisol response to ACTH may therefore be a useful measure of subclinical hypercortisolism. PubMed-ID: 23865937 http://dx.doi.org/10.1111/cen.12295

Evaluation of Right Adrenal Vein Cannulation by Computed Tomography Angiography in 140 Consecutive Patients Undergoing Adrenal Venous Sampling. Eur J Endocrinol, 170(4):601-8. Onozawa S, Murata S, Tajima H, Yamaguchi H, Mine T, Ishizaki A, Sugihara H, Oikawa S, Kumita S. 2014. OBJECTIVE: As it is now known that primary aldosteronism (PA) is more prevalent than was previously recognized, and is a potentially curable cause of hypertension and related cardiovascular diseases, the search for a safe and effective means of its diagnosis has reemerged as a topic of interest. Adrenal venous sampling is the gold standard for diagnosis of PA, but the technique is challenging and the small right adrenal vein can be particularly difficult to cannulate. Our objective was to evaluate the usefulness of computed tomography during angiography (angio-CT) in increasing the success of adrenal venous sampling and to identify factors associated with cannulation failure. DESIGN: Retrospective review. METHODS: A total of 140 consecutive patients with suspected PA except Cushing's syndrome treated at a single hospital from June 2008 to May 2013 were included. Catheter misplacement and correct cannulation rates before angio-CT and success rate of sampling after angio-CT were calculated. Univariate analysis for factors related to incorrect cannulation included gender, age, height, weight, BMI, and adrenal nodules. Successful sampling was biochemically defined according to cortisol concentrations in the venous blood samples. RESULTS: Angio-CT detected misplaced catheters in 13 patients (9.3%). The calculated correct cannulation rate of adrenal vein sampling increased from 86.4% before angio-CT to 95.7% after CT (P<0.001, McNemar's test). Univariate analysis showed a tendency for a higher rate of failure of right adrenal venous sampling in taller patients (P=0.052, Mann-Whitney's U test). CONCLUSION: Angio-CT improved success of adrenal venous sampling. PubMed-ID: 24459237 http://dx.doi.org/10.1530/EJE-13-0741

Seasonal Variation in Plasma Free Normetanephrine Concentrations: Implications for Biochemical Diagnosis of Pheochromocytoma. Eur J Endocrinol, 170(3):349-57. Pamporaki C, Bursztyn M, Reimann M, Ziemssen T, Bornstein SR, Sweep FC, Timmers H, Lenders JW, Eisenhofer G. 2014. BACKGROUND: Higher plasma concentrations of catecholamines in winter than in summer have been established, but whether this impacts the plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. OBJECTIVE: In this study, we examined seasonal variations in the plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming ('arterialization' of venous blood) on blood flow and measured concentrations. METHODS: The measurements of the plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for the measurements of plasma metanephrines and forearm blood flow before and after forearm warming. RESULTS: There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, the plasma concentrations of normetanephrine were higher (P<0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P<0.0001). These differences resulted in a twofold higher (P=0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (P=0.0010). Forearm warming increased blood flow and lowered (P=0.0020) plasma normetanephrine concentrations. CONCLUSIONS: The plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in

ESES Review of Recently Published Literature 2014-1 Page 101 of 121 winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false- positive results. PubMed-ID: 24497497 http://dx.doi.org/10.1530/EJE-13-0673

Seasonal Variations of Plasma Normetaneprine Levels: the Authors Reply. Eur J Endocrinol, 170(5):L3. Pamporaki C, Eisenhofer G. 2014. PubMed-ID: 24723669 http://dx.doi.org/10.1530/EJE-14-0142

Pheochromocytoma Presenting With Remote Bony Recurrence Twenty Years After Initial Surgery: Detection With 68Ga-DOTANOC PET/CT. Clin Nucl Med, 39(4):365-6. Parida GK, Dhull VS, Sharma P, Bal C, Kumar R. 2014. Pheochromocytomas are rare tumors which can be malignant in 10% of cases. We present the case of a 75- year-old woman who presented with headache and palpitation for 1 year. She had a past history of right adrenalectomy for pheochromocytoma 20 years back. In between, the patient was asymptomatic. Twenty-four- hour urinary vanillylmandelic acid was raised. Noncontrast CT and ultrasound of abdomen were unremarkable. The patient underwent 68Ga-DOTANOC PET/CT that showed metastasis to left ilium, which was confirmed on biopsy. PubMed-ID: 23640231 http://dx.doi.org/10.1097/RLU.0b013e31828e98f0

Synchronous Bilateral Adrenalectomy for Cushing's Syndrome: Laparoscopic Versus Posterior Retroperitoneoscopic Versus Robotic Approach. World J Surg, 38(3):709-15. Raffaelli M, Brunaud L, De CC, Hoche G, Oragano L, Bresler L, Bellantone R, Lombardi CP. 2014. BACKGROUND: Synchronous endoscopic bilateral adrenalectomy (BilA) can effectively provide definitive cure of hypercortisolism in ACTH-dependent Cushing's syndrome and in primary adrenal bilateral disease. We compared three different approaches for BilA: transabdominal laparoscopic BilA (TL-BilA), simultaneous posterior retroperitoneoscopic BilA (PR-BilA), and robot-assisted BilA (RA-BilA). METHODS: All patients who underwent BilA between January 1999 and December 2012 at two referral centers (one performing TL-BilA and PR-BilA and one performing RA-BilA) were included. A comparative analysis was performed. RESULTS: Twenty-nine patients were included: 5 underwent TL-BilA, 11 underwent PR-BilA, and 13 underwent RA-BilA. No significant difference was found concerning age, gender, diagnosis, and previous abdominal surgery. No conversion to open approach was registered. Operative time was significantly shorter for the PR-BilA group than for the TL-BilA and RA-BilA groups (157.4 +/- 54.6 vs 256.0 +/- 43.4 vs 221.5 +/- 42.2 min, respectively) (P < 0.001). No significant difference was found concerning intraoperative and postoperative complications rate and time to first flatus. Drains were used routinely after PR-BilA and TL-BilA and electively in four RA-BilA patients (P < 0.001). Hospital stay was longer in the TL-BilA and PR-BilA groups than in the RA-BilA group (12.0 +/- 5.7 vs 10.8 +/- 3.7 vs 4.4 +/- 1.7 days, respectively) (P < 0.001). No recurrence or disease-related death was registered. CONCLUSIONS: Operative time was significantly shorter in the PR-BilA group, because it eliminates the need to reposition the patient. The number of drains and the length of hospital stay were reduced after RA- BilA, but this was likely related to different management protocols in different settings. Because no significant difference was found in terms of postoperative outcome, none of the three operative approaches can be considered the preferable one. PubMed-ID: 24240671 http://dx.doi.org/10.1007/s00268-013-2326-9

Adrenalectomy Outcomes Are Superior With the Participation of Residents and Fellows. J Am Coll Surg, Seib CD, Greenblatt DY, Campbell MJ, Shen WT, Gosnell JE, Clark OH, Duh QY. 2014. BACKGROUND: Adrenalectomy is a complex procedure performed in many settings, with and without residents and fellows. Patients often ask, "Will trainees be participating in my operation?" and seek reassurance that their care will not be adversely affected. The purpose of this study was to determine the association between trainee participation and adrenalectomy perioperative outcomes. STUDY DESIGN: We performed a cohort study of patients who underwent adrenalectomy from the 2005 to 2011 American College of Surgeons NSQIP database.

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Trainee participation was classified as none, resident, or fellow, based on postgraduate year of the assisting surgeon. Associations between trainee participation and outcomes were determined via multivariate linear and logistic regression. RESULTS: Of 3,694 adrenalectomies, 732 (19.8%) were performed by an attending surgeon with no trainee, 2,315 (62.7%) involved a resident, and 647 (17.5%) involved a fellow. The participation of fellows was associated with fewer serious complications (7.9% with no trainee, 6.0% with residents, and 2.8% with fellows; p < 0.001). In a multivariate model, the odds of serious 30-day morbidity were lower when attending surgeons operated with residents (odds ratio = 0.63; 95% CI, 0.45-0.89). Fellow participation was associated with significantly lower odds of overall (odds ratio = 0.51; 95% CI, 0.32-0.82) and serious (odds ratio = 0.31; 95% CI, 0.17-0.57) morbidity. There was no significant association between trainee participation and 30-day mortality. CONCLUSIONS: In this analysis of multi-institutional data, the participation of residents and fellows was associated with decreased odds of perioperative adrenalectomy complications. Attending surgeons performing adrenalectomies with trainee assistance should reassure patients of the equivalent or superior care they are receiving. PubMed-ID: 24702888 http://dx.doi.org/10.1016/j.jamcollsurg.2014.02.020

Adrenal Ganglioneuroma: Features and Outcomes of 27 Cases at a Referral Cancer Centre. Clin Endocrinol (Oxf), 80(3):342-7. Shawa H, Elsayes KM, Javadi S, Morani A, Williams MD, Lee JE, Waguespack SG, Busaidy NL, Vassilopoulou- Sellin R, Jimenez C, Habra MA. 2014. BACKGROUND: Adrenal ganglioneuroma (AGN) is a rare neurogenic tumour that can mimic other adrenal neoplasms. Limited information, mostly derived from small cases series, is available for AGN. METHODS: A retrospective review for AGNs seen at a tertiary referral centre describing important features to distinguish AGN from other adrenal neoplasms. RESULTS: Of 53 ganglioneuromas, 27 were AGNs. Median age was 31 years (range, 1.7-64 years) and median tumour size was 8 cm (range, 1.5-20 cm). Seventeen AGNs (63%) were detected incidentally and nine patients (33%) presented with abdominal/back discomfort. Catecholamine levels, available for 21 patients, were normal. On computed tomography (CT), most AGNs were homogenous and well circumscribed with a median density of 32.5 Hounsfield units (HU) on unenhanced CT; 40 HU on postcontrast venous phase; and 66.5 HU on delayed postcontrast phase. On magnetic resonance imaging (MRI), AGNs had hypo-intense signal on T1-weighted images with heterogeneous hyperintense signal on T2-weighted images. In four patients, there was no tumour growth during median follow-up of 48 months (range, 21-60 months). One patient had malignant peripheral nerve sheath tumour arising from AGN. Thirteen patients with resected AGN had no recurrence during a median follow-up of 50 months (range, 2-135 months). CONCLUSIONS: We herein describe the largest AGN series reported to date. Isolated AGNs do not produce catecholamines and have CT imaging characteristics that can help in distinguishing them from other adrenal and para-adrenal neoplasms. The natural history of AGNs is usually benign, although local extra-adrenal extension or malignant transformation can rarely occur. PubMed-ID: 24033606 http://dx.doi.org/10.1111/cen.12320

Adrenal Cancer in 2013: Time to Individualize Treatment for Adrenocortical Cancer? Nat Rev Endocrinol, 10(2):76-8. Stratakis CA. 2014. 2013 was a good year for adrenocortical cancer, as the new knowledge gained holds great promise for patients. Advances were made in genetics, epigenetics, the advent of related technological and bioinformatic tools, and the feasibility of massive screening of people and samples. PubMed-ID: 24393782 http://dx.doi.org/10.1038/nrendo.2013.263

Next-Generation Sequencing for the Genetic Screening of Phaeochromcytomas and Paragangliomas: Riding the New Wave, but With Caution. Clin Endocrinol (Oxf), 80(1):23-4. Toledo RA, Dahia PL. 2014. PubMed-ID: 24168015 http://dx.doi.org/10.1111/cen.12357

Increased Long-Term Remission After Adequate Medical Cortisol Suppression Therapy As Presurgical Treatment in Cushing's Disease. Clin Endocrinol (Oxf), 80(2):184-90.

ESES Review of Recently Published Literature 2014-1 Page 103 of 121 van den Bosch OF, Stades AM, Zelissen PM. 2014. OBJECTIVE: In the last decade, pre-operative medical cortisol suppression therapy has frequently been used in Cushing's disease to normalize cortisol concentrations pre-operatively. Our aim was to assess the efficacy of presurgical medical cortisol suppression therapy in Cushing's disease. DESIGN AND METHODS: We retrospectively assessed the medical files of all patients with Cushing's disease that received presurgical cortisol suppression therapy with ketoconazole or metyrapone and underwent subsequent transsphenoidal surgery between 1990 and 2010 at our centre. We retrieved the pretreatment regimen, adequacy of pretreatment, early postoperative serum cortisol levels, adverse effects and long-term remission status. RESULTS: Nineteen of 33 patients (58%) obtained long-term remission after pituitary surgery without additional postoperative therapy. Thirteen of 16 patients with adequate presurgical cortisol suppression therapy had postoperative cortisol concentrations <50 nmol/l. The 16 patients with adequate presurgical cortisol suppression had a higher long- term remission rate after primary surgery compared with the 13 patients with borderline or inadequate pretreatment (81% vs 38%; P < 0.05). CONCLUSIONS: Adequate presurgical cortisol suppression treatment with ketoconazole or metyrapone in Cushing's disease seems to be associated with suppressed postoperative cortisol concentrations and an increased long-term remission rate. PubMed-ID: 23841642 http://dx.doi.org/10.1111/cen.12286

Diagnosis of Endocrine Disease: Biochemical Diagnosis of Phaeochromocytoma and Paraganglioma. Eur J Endocrinol, 170(3):R109-R119. van BA, Lenders JW, Timmers HJ. 2014. Adrenal phaechromocytomas and extra-adrenal sympathetic paragangliomas (PPGLs) are rare neuroendocrine tumours, characterised by production of the catecholamines: noradrenaline, adrenaline and dopamine. Tumoural secretion of catecholamines determines their clinical presentation which is highly variable among patients. Up to 10-15% of patients present entirely asymptomatic and in 5% of all adrenal incidentalomas a PPGL is found. Therefore, prompt diagnosis of PPGL remains a challenge for every clinician. Early consideration of the presence of a PPGL is of utmost importance, because missing the diagnosis can be devastating due to potential lethal cardiovascular complications of disease. First step in diagnosis is proper biochemical analysis to confirm or refute the presence of excess production of catecholamines or their metabolites. Biochemical testing is not only indicated in symptomatic patients but also in asymptomatic patients with adrenal incidentalomas or identified genetic predispositions. Measurements of metanephrines in plasma or urine offer the best diagnostic performance and are the tests of first choice. Paying attention to sampling conditions, patient preparation and use of interfering medications is important, as these factors can largely influence test results. When initial test results are inconclusive, additional tests can be performed, such as the clonidine suppression test. Test results can also be used for estimation of tumour size or prediction of tumour location and underlying genotype. Furthermore, tumoural production of 3-methoxytyramine is associated with presence of an underlying SDHB mutation and may be a biomarker of malignancy. PubMed-ID: 24347425 http://dx.doi.org/10.1530/EJE-13-0882

Phaeochromocytoma [Corrected] Crisis. Clin Endocrinol (Oxf), 80(1):13-22. Whitelaw BC, Prague JK, Mustafa OG, Schulte KM, Hopkins PA, Gilbert JA, McGregor AM, Aylwin SJ. 2014. Phaeochromocytoma [corrected] crisis is an endocrine emergency associated with significant mortality. There is little published guidance on the management of phaeochromocytoma [corrected] crisis. This clinical practice update summarizes the relevant published literature, including a detailed review of cases published in the past 5 years, and a proposed classification system. We review the recommended management of phaeochromocytoma [corrected] crisis including the use of alpha-blockade, which is strongly associated with survival of a crisis. Mechanical circulatory supportive therapy (including intra-aortic balloon pump or extra-corporeal membrane oxygenation) is strongly recommended for patients with sustained hypotension. Surgical intervention should be deferred until medical stabilization is achieved. PubMed-ID: 24102156 http://dx.doi.org/10.1111/cen.12324

Adrenal Function: Bilateral Macronodular Adrenal Hyperplasia-New Genetic and Pathophysiological Insights. Nat Rev Endocrinol, 10(2):63. Wilson C. 2014.

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PubMed-ID: 24342883 http://dx.doi.org/10.1038/nrendo.2013.252

Molecular Markers and Targeted Therapies for Adrenocortical Carcinoma. Clin Endocrinol (Oxf), 80(2):159-68. Xu Y, Qi Y, Zhu Y, Ning G, Huang Y. 2014. Adrenocortical carcinoma (ACC) is a lethal disease with poor prognosis and lack of effective therapeutic options. Systemic treatment is often employed to treat patients with advanced ACC, but outcomes are disappointing. During the last decade, some of the causative genetic mutations in sporadic ACCs have been identified. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers. Preclinical investigations and clinical trials of tyrosine kinase inhibitors and anti-angiogenic compounds have been initiated to seek target therapy of ACCs. This review summarizes the current view of molecular alterations involved in the pathophysiology of adrenocortical carcinogenesis. The rationale for testing targeted therapies of ACC is also presented. PubMed-ID: 24304415 http://dx.doi.org/10.1111/cen.12358

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NET

Meta-Analyses - None -

Randomized controlled trials - None -

Consensus Statements/Guidelines - None -

Other Articles Surgical Resection of Carotid Body Paragangliomas: 10 Years of Experience. Am J Surg, 207(2):293-8. Amato B, Bianco T, Compagna R, Siano M, Esposito G, Buffone G, Serra R, de FS. 2014. BACKGROUND: Carotid body tumors (CBTs) are relatively rare neoplasms, and even if they are considered predominantly benign, there is an indication for early surgical removal. The objective of this study was to conduct a review of the surgical management of CBTs. METHODS: A retrospective study identified 34 cases (12 men and 19 women) of tumors in patients who had undergone surgical resection of pathologically confirmed CBTs over a period of 10 years from 2001 to 2011 in 2 academic departments of general surgery in Italy. RESULTS: In our series, 10 CBTs (31%) were Shamblin class I, 13 (41%) were class II, and 9 tumors (27%) were class III. Two patients (6%) had transient cerebral ischemia immediately after operation. One patient (3%) died of postoperative cerebral ischemia after surgery for internal carotid artery thrombosis. CONCLUSIONS: The experience of this casuistry shows that the procedure is relatively low risk for Shamblin I and II classes, whereas there is an increasing risk of neurovascular complications for Shamblin III class. PubMed-ID: 24119888 http://dx.doi.org/10.1016/j.amjsurg.2013.06.002

A Single Institution's Experience With Surgical Cytoreduction of Stage IV, Well-Differentiated, Small Bowel Neuroendocrine Tumors. J Am Coll Surg, 218(4):837-44. Boudreaux JP, Wang YZ, Diebold AE, Frey DJ, Anthony L, Uhlhorn AP, Ryan P, Woltering EA. 2014. BACKGROUND: Well-differentiated neuroendocrine tumors (NETs) of the gastrointestinal tract are rare, slow- growing neoplasms. Clinical outcomes in a group of stage IV, well-differentiated patients with NETs with small bowel primaries undergoing cytoreductive surgery and multidisciplinary management at a single center were evaluated. STUDY DESIGN: The charts of 189 consecutive patients who underwent surgical cytoreduction for their small bowel NETs were reviewed. Information on the extent of disease, complications, and Kaplan-Meier survival were collected from the patient records. RESULTS: A total of 189 patients underwent 229 cytoreductive operations. Ten percent of patients required an intraoperative blood transfusion and 3% (6 of 229) had other intraoperative complications. For all 229 procedures performed, mean (+/- SD) stay in the ICU was 4 +/- 3 days and in the hospital was 9 +/- 10 days. Before discharge, 51% of patients had no postoperative complications and 39% of patients had only minor complications. In a 30-day follow-up period from discharge, 85% of patients had no additional complications and 13% had only minor complications. The 30-day postoperative death rate was 3% (5 of 189). Mean survival from histologic diagnosis of NET was 236 months. The 5-, 10-, and 20-year Kaplan-Meier survival rates from diagnosis were 87%, 77%, and 41%, respectively. CONCLUSIONS: Cytoreductive surgery in patients with well-differentiated midgut NETs has low mortality and complication rates and is associated with prolonged survival. We believe that cytoreductive surgery is a key component in the care of patients with NETs.

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PubMed-ID: 24655881 http://dx.doi.org/10.1016/j.jamcollsurg.2013.12.035

Fine Needle Aspiration of Oncocytic Variants of Pancreatic Neuroendocrine Tumor: a Report of Three Misdiagnosed Cases. Acta Cytol, 58(2):131-7. Chen S, Wang X, Lin J. 2014. OBJECTIVES: An oncocytic variant of pancreatic neuroendocrine tumors (PanNET) is exceedingly rare. Here we report cytomorphological features of the oncocytic variant of PanNET and discuss how to avoid diagnostic pitfalls. STUDY DESIGN: A computerized search of our laboratory information system was performed over an 18-year period to identify all cytology and surgical pathology cases where a diagnosis of PanNET was made or considered in the differential diagnosis. Three cases of the oncocytic variant of PanNET were identified. RESULTS: Endoscopic ultrasound-guided fine needle aspiration (FNA) smears showed cohesive clusters of large atypical cells with abundant eosinophilic granular cytoplasm, anisonucleosis, nuclear enlargement and overlapping, prominent nucleoli, and a relatively smooth nuclear membrane. Nuclei were round to oval with finely granular chromatin. Additional features included rare isolated cells and glandular formation. Some of these morphological features, such as anisonucleosis, nuclear enlargement, and overlapping, prominent nucleoli, are also commonly seen in the pancreatic adenocarcinoma. All these cases were misclassified by FNA as adenocarcinoma (2 cases) or suspicious for carcinoma (1 case) and were histologically confirmed to be oncocytic variants of PanNET. CONCLUSIONS: Useful salient features of the oncocytic variant of PanNET include abundant eosinophilic granular cytoplasm, finely granular chromatin, and relatively smooth nuclear membrane. The awareness of this variant will help to avoid misdiagnosis. PubMed-ID: 24335139 http://dx.doi.org/10.1159/000357035

Reply: Comment on: "Tumor Aggressiveness and Patient Outcome in Cancer of the Pancreas Assessed by Dynamic 18F-FDG PET/CT". J Nucl Med, 55(2):351-2. Dimitrakopoulou-Strauss A, Frenkel A, Epelbaum R. 2014. PubMed-ID: 24323815 http://dx.doi.org/10.2967/jnumed.113.132845

TCEB3C a Putative Tumor Suppressor Gene of Small Intestinal Neuroendocrine Tumors. Endocr Relat Cancer, 21(2):275-84. Edfeldt K, Ahmad T, Akerstrom G, Janson ET, Hellman P, Stalberg P, Bjorklund P, Westin G. 2014. Small intestinal neuroendocrine tumors (SI-NETs), formerly known as midgut carcinoids, are rare and slow- growing neoplasms. Frequent loss of one copy of chromosome 18 in primary tumors and metastases has been observed. The aim of the study was to investigate a possible role of TCEB3C (Elongin A3), currently the only imprinted gene on chromosome 18, as a tumor suppressor gene in SI-NETs, and whether its expression is epigenetically regulated. Primary tumors, metastases, the human SI-NET cell line CNDT2.5, and two other cell lines were included. Immunohistochemistry, gene copy number determination by PCR, colony formation assay, western blotting, real-time quantitative RT-PCR, RNA interference, and quantitative CpG methylation analysis by pyrosequencing were performed. A large majority of tumors (33/43) showed very low to undetectable Elongin A3 expression and as expected 89% (40/45) displayed one gene copy of TCEB3C. The DNA hypomethylating agent 5-aza-2'-deoxycytidine induced TCEB3C expression in CNDT2.5 cells, in primary SI-NET cells prepared directly after surgery, but not in two other cell lines. Also siRNA to DNMT1 and treatment with the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in a cell type-specific way. CpG methylation at the TCEB3C promoter was observed in all analyzed tissues and thus not related to expression. Overexpression of TCEB3C resulted in a 50% decrease in clonogenic survival of CNDT2.5 cells, but not of control cells. The results support a putative role of TCEB3C as a tumor suppressor gene in SI-NETs. Epigenetic repression of TCEB3C seems to be tumor cell type-specific and involves both DNA and histone methylation. PubMed-ID: 24351681 http://dx.doi.org/10.1530/ERC-13-0419

Unusual Case of Cowden-Like Syndrome, Neck Paraganglioma, and Pituitary Adenoma. Head Neck, 36(1):E12-E16. Efstathiadou ZA, Sapranidis M, Anagnostis P, Kita MD. 2014. BACKGROUND: Pituitary tumors, paragangliomas, and Cowden syndrome do not usually occur together.

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METHODS: The synchronous presentation of papillary thyroid carcinoma and neck paraganglioma was revealed in a 43-year-old woman who had been diagnosed with a microprolactinoma one decade before and now presented with a constellation of characteristics that are components of Cowden syndrome, specifically macrocephaly, multiple skin papules, fibrocystic mammary disease, and uterine leiomyofibroma. RESULTS: Germline mutation analysis of phosphatase and tensin homolog (PTEN), succinate dehydrogenase subunit B (SDHB), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit D (SDHD) was performed with revelation of 3 polymorphic sites in introns 1, 4, and 8 of the PTEN gene and 1 polymorphic site in exon 1 of the SDHB gene, but absence of known pathogenic mutations. CONCLUSION: The coexistence of Cowden-like syndrome, neck paraganglioma, and pituitary adenoma is described for the first time, and could represent a novel genetic syndrome with an as yet unidentified common genetic basis. PubMed-ID: 23804288 http://dx.doi.org/10.1002/hed.23420

Quantitative Imaging of Serotonergic Biosynthesis and Degradation in the Endocrine Pancreas. J Nucl Med, 55(3):460-5. Eriksson O, Selvaraju RK, Johansson L, Eriksson JW, Sundin A, Antoni G, Sorensen J, Eriksson B, Korsgren O. 2014. Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the major constituent, has been implicated in insulin release and beta cell proliferation. In this study, we investigated the feasibility of quantitative noninvasive imaging of the serotonergic metabolism in the pancreas using the PET tracer (11)C-5- hydroxy-l-tryptophan ((11)C-5-HTP). METHODS: Uptake of (11)C-5-HTP, and its specificity for key enzymes in the serotonergic metabolic pathway, was assessed in vitro (INS-1 and PANC1 cells and human islet and exocrine preparations) and in vivo (nonhuman primates and healthy and diabetic rats). RESULTS: In vitro tracer uptake in endocrine cells (INS-1 and human islets), but not PANC1 and exocrine cells, was mediated specifically by intracellular conversion into serotonin. Pancreatic uptake of (11)C-5-HTP in nonhuman primates was markedly decreased by inhibition of the enzyme dopa decarboxylase, which converts (11)C-5-HTP to (11)C- serotonin and increased after inhibition of monoamine oxidase-A, the main enzyme responsible for serotonin degradation. Uptake in the rat pancreas was similarly modulated by inhibition of monoamine oxidase-A and was reduced in animals with induced diabetes. CONCLUSION: The PET tracer (11)C-5-HTP can be used for quantitative imaging of the serotonergic system in the endocrine pancreas. PubMed-ID: 24525204 http://dx.doi.org/10.2967/jnumed.113.125187

Predictors of Long-Term Outcome in Patients With Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors After Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate. J Nucl Med, 55(2):183-90. Ezziddin S, Attassi M, Yong-Hing CJ, Ahmadzadehfar H, Willinek W, Grunwald F, Guhlke S, Biersack HJ, Sabet A. 2014. Outcome analyses for patients with gastroenteropancreatic neuroendocrine tumors (GEP NET) after peptide receptor radionuclide therapy (PRRT) are still limited, especially with regard to the impact of the Ki-67 index. Using a single-center analysis, we aimed to establish predictors of survival. METHODS: We retrospectively analyzed a consecutive cohort of 74 patients who had metastatic GEP NET and underwent PRRT with (177)Lu- octreotate (mean activity of 7.9 GBq per cycle, aimed at 4 treatment cycles at standard intervals of 3 mo). Patients (33 with pancreatic NET and 41 with nonpancreatic GEP NET) had unresectable metastatic disease graded as G1 or G2 (G1/G2) and documented morphologic or clinical progression within less than 12 mo or uncontrolled disease under somatostatin analog treatment. Responses were evaluated according to modified Southwest Oncology Group criteria. Potential predictors of survival were analyzed with the Kaplan-Meier curve method (log-rank test) and multivariate analysis (P < 0.05). RESULTS: The response rates were 36.5% partial response, 17.6% minor response, 35.1% stable disease, and 10.8% progressive disease for the entire cohort; 54.5% partial response, 18.2% minor response, 18.2% stable disease, and 9.1% progressive disease for pancreatic NET; and 22.0% partial response, 17.1% minor response, 48.8% stable disease, and 12.2% progressive disease for nonpancreatic GEP NET. The median progression-free survival and overall survival were 26 mo (95% confidence interval, 18.3-33.7) and 55 mo (95% confidence interval, 48.8-61.2), respectively. Besides the Ki-67 index, a Karnofsky performance score of less than or equal to 70%, a hepatic tumor burden of greater than or equal to 25%, and a baseline plasma level of neuron-specific enolase of greater than 15 ng/mL independently predicted shorter overall survival (hazard ratio, 2.1-3.1). Patients with a Ki-67 index of greater than 10% still had median progression-free survival and overall survival of 19 and 34 mo, respectively. CONCLUSION: The results of this study demonstrated the favorable response and long-term outcome of patients with G1/G2 GEP NET after PRRT. Independent predictors of survival were the Ki-67 index, the patient's

ESES Review of Recently Published Literature 2014-1 Page 108 of 121 performance status (Karnofsky performance scale score), the tumor burden, and the baseline neuron-specific enolase level. Even patients with a Ki-67 index of greater than 10% seemed to benefit from PRRT, with a good response and a notable long-term outcome. We present the first evidence, to our knowledge, that even in patients with metastatic disease the distinction between G1 and G2-in particular, between G1 (Ki-67 index of 1%-2%) and low-range G2 (Ki-67 index of 3%-10%)-provides prognostic stratification. PubMed-ID: 24434296 http://dx.doi.org/10.2967/jnumed.113.125336

Significance of DNA Index for Differentiation Between IPMN Adenoma (IPMN A) and IPMN Borderline Type (IPMN B). Langenbecks Arch Surg, 399(3):408. Faber W, Jürgensen C, Schirmeier A, Klein F, Denecke T, Grieser C, Seehofer D, Neuhaus P, Bahra M. 2014. Background: Cystic pancreas lesions like intraductal papillary mucinous neoplasm (IPMN) are diagnosed more often. The indication for resection is usually provided by sectional imaging and specific criteria, for example Sendai criteria. The aim of this study was to analyze the importance of the DNA index / ploidy grade by differentiation between IPMN adenoma (IPMN A) and IPMN borderline type (IPMN B). Methods: 16 patients underwent pancreatic resection due to an IPMN. In addition to the routine histopathologic analysis DNA-index and DNA ploidy grade were determined, using the DNA image cytometry. The histopathologic findings and the preoperative Sendai criteria were compared with the results of DNA analysis. Results: 4 cases of IPMN A and 12 cases of IPMN B were performed. In the total cohort 8 patients had the main duct type IPMN and further 8 the branch type IPMN. All patients with IPMN B showed an aneuploide histogram with DNA indices = 1.3 (1.3 - 1.5), whereas all patients with IPMN A showed an euploide histogram with DNA indices = 1.3 (1.0 - 1.3). In the subcollective with IPMN B 5 patients showed a branch type IPMN. Only one patient with IPMN B performed all three Sendai criteria. Three further patients with IPMN B showed two Sendai criteria. All other patients with IPMN B showed only one or none Sendai criterion. Conclusion: In the diagnosis of IPMN the determination of DNA index is a useful diagnostic extend. In our patient collective the ploidy index correlated exactly with the histopathological picture (aneuploidy = IPMN B) and was significantly superior to the Sendai criteria. Therefore the image DNA cytometry may represent a useful diagnostic extend by the indication and in the monitoring of patients with IPMN. http://rd.springer.com/article/10.1007/s00423-014-1175-9 http://dx.doi.org/10.1007/s00423-014-1175-9

Penetrance of Functioning and Nonfunctioning Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1 in the Second Decade of Life. J Clin Endocrinol Metab, 99(1):E89-E96. Goncalves TD, Toledo RA, Sekiya T, Matuguma SE, Maluf FF, Rocha MS, Siqueira SA, Glezer A, Bronstein MD, Pereira MA, Jureidini R, Bacchella T, Machado MC, Toledo SP, Lourenco DM, Jr. 2014. CONTEXT: Data are scarce on the penetrance of multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-PETs) and insulinomas in young MEN1 patients. A potential positive correlation between tumor size and malignancy (2-3 cm, 18%; >3 cm, 43%) has greatly influenced the management of MEN1 adults with NF-PETs. OBJECTIVE: The aim of the study was to estimate the penetrance of NF-PETs, insulinomas, and gastrinomas in young MEN1 carriers. DESIGN: The data were obtained from a screening program (1996-2012) involving 113 MEN1 patients in a tertiary academic reference center. PATIENTS: Nineteen MEN1 patients (aged 12-20 y; 16 patients aged 15-20 y and 3 patients aged 12-14 y) were screened for NF-PETs, insulinomas, and gastrinomas. METHODS: Magnetic resonance imaging/computed tomography and endoscopic ultrasound (EUS) were performed on 10 MEN1 carriers, magnetic resonance imaging/computed tomography was performed on five patients, and four other patients underwent an EUS. RESULTS: The overall penetrance of PETs during the second decade of life was 42% (8 of 19). All eight PET patients had NF-PETs, and half of those tumors were multicentric. One-fifth of the screened patients (21%; 4 of 19) harbored at least one large tumor (>2.0 cm). Insulinoma was detected in two NF-PET patients (11%) at the initial screening; gastrinoma was not present in any cases. Six of the 11 (54%) screened patients aged 15-20 years who underwent an EUS had NF-PETs. Potential false-positive EUS results were excluded based on EUS-guided biopsy results, the reproducibility of the NF-PET findings, or the observation of increased tumor size during follow-up. Distal pancreatectomy and the nodule enucleation of pancreatic head tumors were conducted on three patients with large tumors (>2.0 cm; T2N0M0) that were classified as grade 1 neuroendocrine tumors (Ki-67<2%). CONCLUSIONS: Our data demonstrated high penetrance of NF-PETs in 15- to 20-year-old MEN1 patients. The high percentage of the patients presenting consensus criteria for surgery for NF-PET alone or NF-PET/insulinoma suggests a potential benefit for the periodic surveillance of these tumors in this age group.

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PubMed-ID: 24178797 http://dx.doi.org/10.1210/jc.2013-1768

Neuroendocrine Cancer: Insulinomas-Recurrent Mutations Identified in YY1. Nat Rev Endocrinol, 10(3):127. Greenhill C. 2014. PubMed-ID: 24366121 http://dx.doi.org/10.1038/nrendo.2013.259

Multiple Small Branch-Duct IPMN in Imaging in Familial Pancreatic Cancer - Indicator for Concomitant High Grade Pancreatic Intraepithelial Neoplasia? Langenbecks Arch Surg, 399(3):403. Heeger K, Bargello M, Matthäi E, Kloeppel G, Esposito I, Heverhagen JT, Gress TM, Slater EP, Langer P, Bartsch DK. 2014. Background: Screening programs for familial pancreatic cancer (FPC) are currently based on endoscopic ultrasonography and / or magnetic resonance imaging. In up to 40% of individuals at risk, cystic lesions are detected, which are suspicious for small intraductal papillary mucinous neoplasms of the branch ducts (BD- IPMN). The pathological importance of these lesions in the setting of FPC is yet unknown. Methods: Individuals at risk from a prospective screening program for familial pancreatic cancer with small "imaging" IPMNs of the branch-duct type (BD-IPMN), who underwent pancreatic resection, were analysed regarding clinico-pathological data and the locations of pancreatic lesions. Results: In the last 10 years (2002-2012) 172 individuals at risk out of 60 FPC families took part in the screening program. Twelve of these individuals at risk had multiple small (2-10mm) unicystic lesions or multicystic lesions in the pancreatic body and tails suspicious for BD-IPMNs upon MRI imaging. After interdisciplinary counselling, 7 individuals decided to undergo pancreatic resection (6x total pancreatectomy, 1x PPPD), although none fulfilled the consensus criteria for IPMN resection.Histological examination revealed BD-IPMNs with low or moderate dysplasia of the gastric type in combination with multifocal PanIN2 and PanIN3 lesions in 6 individuals. One patient had only tiny ductectasias in the pancreatic tail with multifocal PanIN2 lesions in the entire gland and one PanIN3 lesion in the pancreatic head. Surprisingly, the location of the most dysplastic histological lesions did not correspond to the preoperatively detected lesions and were not visible in preoperative imaging. Conclusion: In the setting of FPC, the presence of multiple small BD-IPMN in imaging may indicate the presence of high-grade PanIN lesions elsewhere in the pancreas. http://link.springer.com/article/10.1007%2Fs00423-014-1175-9 http://dx.doi.org/10.1007/s00423-014-1175-9

Increased Rate of Clinically Relevant Pancreatic Fistula After Deep Enucleation of Small Pancreatic Tumors. Langenbecks Arch Surg, 399(3):315-21. Heeger K, Falconi M, Partelli S, Waldmann J, Crippa S, Fendrich V, Bartsch DK. 2014. PURPOSE: Only small, potentially benign pancreatic tumors located >/=3 mm distant from the main pancreatic duct (MPD) are considered good candidates for enucleation. This study evaluates the outcome of enucleations with regard to their distance to the MPD. METHODS: Clinical characteristics, complications, and outcomes of prospectively documented patients with small (3 mm), as determined by intraoperative ultrasonography (IOUS). RESULTS: Sixty patients underwent DE (n = 30) or SE (n = 30) with IOUS. Both groups did not differ regarding age, tumor size, pathology, and operating time. Complications occurred in 24/30 (80 %) patients of the DE group compared to 15/30 (50 %) patients after SE (P = 0.029). Mortality was nil. The most frequent complication was pancreatic fistula (POPF) occurring in 22/30 (73.3 %) patients after DE and 9/30 (30 %) patients undergoing SE (P = 0.002). Especially, the rate of clinically significant POPF types B and C was higher after DE (21 of 30 patients) compared to SE (7 of 30 patients, P = 0.0006). Univariate and multivariate analyses revealed DE as the only significant factor that negatively influenced the occurrence of POPF. Postoperative hospital stay tended to be longer after DE (15 vs. 11.5 days, P = 0.050). All but two patients with metastatic gastrinoma and two patients, who died of unrelated causes, showed no evidence of disease after a median follow-up of 24 (3-235) months. CONCLUSIONS: Deep enucleation of small, potentially benign pancreatic tumors should be considered with caution given the high rate of clinically relevant POPF. PubMed-ID: 24522434 http://dx.doi.org/10.1007/s00423-014-1171-0

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18F-Fluorodihydroxyphenylalanine PET/CT in Patients With Neuroendocrine Tumors of Unknown Origin: Relation to Tumor Origin and Differentiation. J Nucl Med, 55(3):367-72. Imperiale A, Rust E, Gabriel S, Detour J, Goichot B, Duclos B, Kurtz JE, Bachellier P, Namer IJ, Taieb D. 2014. This work was performed to evaluate the performance of (18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) PET/CT in detecting primary neuroendocrine tumors (NETs) occult on morphologic and functional imaging, in relation to tumor origin and differentiation. METHODS: A retrospective study of NET patients who were investigated with (18)F-FDOPA PET/CT imaging in 2 academic endocrine tumor centers was conducted. Only patients with negative conventional and somatostatin receptor scintigraphy (SRS) results were studied. RESULTS: Twenty-seven patients were evaluated with (18)F-FDOPA PET/CT, 23 at their initial staging and 4 during their follow-up. The primary occult NET was localized by (18)F-FDOPA PET/CT in 12 patients (overall sensitivity, 44%; 52% in patients evaluated at initial diagnosis), leading to tumor resection in all cases. The primary tumors were distributed and graded as follows: 1 duodenum G2 lesion, 7 ileum G2 lesions, 2 terminal ileum G1 lesions, 1 pancreas G2 lesion, and 1 gallbladder G3 lesion. Patients with positive (18)F-FDOPA PET/CT results had higher values of serum chromogranin A (100% vs. 20%, P = 0.0003), serotonin, or urinary 5- hydroxyindolacetic acid (83% vs. 20%, P = 0.003). Two false-negative results were related to poorly differentiated duodenal and prostatic NETs (G3). (18)F-FDOPA PET/CT showed more metastatic anatomic regions than SRS in 17 patients. CONCLUSION: (18)F-FDOPA PET appears to be a sensitive functional imaging tool for the detection of primary NETs occult on SRS, especially tumors with a well-differentiated pattern and serotonin secretion. PubMed-ID: 24343986 http://dx.doi.org/10.2967/jnumed.113.126896

Postoperative Surveillance of Small Appendiceal Carcinoid Tumors. Am J Surg, 207(3):342-5. Murray SE, Lloyd RV, Sippel RS, Chen H, Oltmann SC. 2014. BACKGROUND: The necessity and frequency of postoperative surveillance for appendiceal carcinoid tumors /=1 of the following: imaging (n = 9), medical oncology referral (n = 7), colonoscopy (n = 5), and laboratory studies (n = 5). There were no recurrences or disease-specific deaths during a median follow-up period of 5 years (range, 0-15 years). CONCLUSIONS: Appendiceal carcinoids

Indication for Liver Transplantation in Young Patients With Small Intestinal NETs Is Rare? World J Surg, 38(3):742-7. Norlen O, Daskalakis K, Oberg K, Akerstrom G, Stalberg P, Hellman P. 2014. BACKGROUND: A majority of patients with small intestinal neuroendocrine tumors (SI-NETs) present with or develop liver metastases (LM). A number of treatments for LM are used clinically, including liver transplantation (LTx). Indications for LTx are under debate; young age(<65 years), absence of extrahepatic disease, resected primary tumor and limited extent of LM have been suggested as inclusion criteria for LTx with the aim to optimize outcome. MATERIALS AND METHODS: From our series of 672 patients with SI-NET treated at the University Hospital in Uppsala between 1985 and 2012, we identified 78 patients according to the following criteria: <65 years of age, locoregional surgery (LRS) of the primary tumor and mesenteric metastases successfully performed, LM present but no extrahepatic disease. Baseline was chosen as the first date the following points were met: First visit to our center,LRS performed, LM present. The patients underwent treatment according to the standard clinical protocols at our center, and during this time period we did not perform or refer any SI-NET patients for LTx. Kaplan-Meier survival analyses were performed in three different groups based on hypothetical criteria for LTx. RESULTS: Five-year overall survival rates for patients <65 years (n = 78) and <55 years (n = 36) of age were 84 +/- 8 and 92 +/- 9 %, respectively. For patients fulfilling the Milan criteria (n = 33) the 5-year survival was 97 +/- 6 %. CONCLUSIONS: Most young patients (<65 years) with SINET and LM have a favorable survival with standardized multimodality treatment. Indeed, most survival figures reported after LTx of NET do

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Reassessment of the Current American Joint Committee on Cancer Staging System for Pancreatic Neuroendocrine Tumors. J Am Coll Surg, 218(2):188-95. Qadan M, Ma Y, Visser BC, Kunz PL, Fisher GA, Norton JA, Poultsides GA. 2014. BACKGROUND: Adopting a unified staging system for pancreatic neuroendocrine tumors (PNETs) has been challenging. Currently, the American Joint Committee on Cancer (AJCC) recommends use of the pancreatic adenocarcinoma staging system for PNETs. We sought to explore the prognostic usefulness of the pancreatic adenocarcinoma staging system for PNETs. STUDY DESIGN: The Surveillance, Epidemiology, and End Results program data were used to identify patients with PNETs who underwent curative-intent surgical resection from 1983 to 2008. The discriminatory ability of the AJCC system was examined and a new TNM system was devised using extent of disease variables. RESULTS: In 1,202 patients identified, lymph node metastasis was associated with worse 10-year overall survival after resection (51% vs 63%; p < 0.0001), as was the presence of distant metastatic disease (35% vs 62%; p < 0.0001). The current AJCC system (recorded by the Surveillance, Epidemiology, and End Results program in 412 patients since 2004) distinguished 5-year overall survival only between stages I and II (p = 0.01), but not between stages II and III (p = 0.97), or stages III and IV (p = 0.36). By modifying the T stage to be based on size alone (0.1 to 1.0 cm, 1.1 to 2.0 cm, 2.1 to 4.0 cm, and >4.0 cm) and revising the TNM subgroups, we propose a novel TNM system with improved discriminatory ability between disease stages (stages I vs II; p = 0.16; II vs III; p < 0.0001; and III vs IV; p = 0.008). CONCLUSIONS: In this study evaluating the current AJCC staging system for PNETs, there were no significant differences detected between stages II and III or stages III and IV. We propose a novel TNM system that might better discriminate between outcomes after surgical resection of PNETs. PubMed-ID: 24321190 http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.001

Grading the Neuroendocrine Tumors of the Lung: an Evidence-Based Proposal. Endocr Relat Cancer, 21(1):1-16. Rindi G, Klersy C, Inzani F, Fellegara G, Ampollini L, Ardizzoni A, Campanini N, Carbognani P, De Pas TM, Galetta D, Granone PL, Righi L, Rusca M, Spaggiari L, Tiseo M, Viale G, Volante M, Papotti M, Pelosi G. 2014. Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow- up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 >/=25; G1 vs G2, P=0.021; and G2 vs G3, P2-47, G3 >47; G1 vs G2, P10% of sample; G1 vs G2, P

18F-DOPA and Other Radiopharmaceuticals for Imaging Unknown Primary Neuroendocrine Tumors. J Nucl Med, 55(3):357-9. Schillaci O. 2014. PubMed-ID: 24396031 http://dx.doi.org/10.2967/jnumed.113.133116

In Vitro Induction of Humoral Immuneresponse to Pancreatic Cancer Cells. Langenbecks Arch Surg, 399(3):403.

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Seifert M, Seifert G, Langenmair ER, Hopt U, Wittel UA. 2014. Background: Patients with pancreatic carcinoma have a grim prognosis. They are often diagnosed in late stages of the disease and are hard to treat. Immunotherapy of tumors has been an intriguing field of research with mentionable breakthroughs. Here, we test the possibility of inducing an in vitro antibody response against pancreatic carcinoma antigens. We analyze the specificity and overall characteristics of the elicited humoral response and test its binding capacity with regard to 5 pancreatic carcinoma cell (PCC) lines. Methods: Plasma membrane fragments (PMFs) of five cultured PCCs were isolated and added to cultures of isolated peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n=8) for 14 days. To simulate T- cell signaling, we added IL-21, IL-4 and anti-CD40 mAB. Using ELISAs, we tested the quantity and specificity of IgG formed against PMFs and the intact PCCs they originated from. To visualize human antibody binding to tumor cell surface antigens on human PCCs, we used a fluorescent anit-human-IgG-antibody. Results: IgG were formed in all cases. There was an increase of quantity when T-cell signaling was simulated, though this did not reach significance. Interestingly, significantly less IgG was produced by PBMCs presented with tumor antigens except in the cases of PANC-1 and MIAPACA when T-simulation was added (p<0.05). PMFs from PANC-1 cells elicited significant and specific IgG formation against PANC-1-PMFs in comparison to the control (p=0.026). Additionally, simulation of T-cells had a significant impact on binding of these antibodies to tumor cell anigens (p=0.019). However, using a hole cell assay IgG binding to intact PCCs was not observed unanimously (p=0.66), yet it was observed in individual cases. We were able to visualize cell surface binding by immunofluorescent staining. Conclusion: Humoral immune response with tumor antigens and T-cell simulation can be induced in vitro. This response has potential to generate antibodies specific to tumor antigens. http://rd.springer.com/article/10.1007/s00423-014-1175-9 http://dx.doi.org/10.1007/s00423-014-1175-9

[It Is Unnecessary to Discontinue Aspirin Therapy Before Pancreatic Resection] Ein Absetzen Von Aspirin Vor Pankreasresektionen Ist Nicht Notwendig. Chirurg, 85(3):258. Strobel O, Buchler MW. 2014. PubMed-ID: 24496754 http://dx.doi.org/10.1007/s00104-014-2709-y

Combination of Cross-Sectional and Molecular Imaging Studies in the Localization of Gastroenteropancreatic Neuroendocrine Tumors. Neuroendocrinology, Toumpanakis C, Kim MK, Rinke A, Bergestuen DS, Thirlwell C, Khan MS, Salazar R, Oberg K. 2014. Molecular imaging modalities exploit aspects of Neuroendocrine Tumors (NET) pathophysiology for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET determine which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available molecular imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clinical scenarios. Somatostatin Receptor Scintigraphy (SRS) continues to have a central role in the diagnostic work-up of patients with NET, as it also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that 68Gallium (Ga)-DOTA PET techniques may replace SRS in the future, not only because of their technical advantages, but also because they are superior in patients with small-volume disease, skeletal metastases and in those with occult primary tumors as well. Carbon-11 (11C)-5-hydroxy-L-tryptophan (5-HTP) PET and 18F-dihydroxyphenylalanine (18F-DOPA) PET are new molecular imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of 68Ga-DOTA PET. Glucagon-Like-Peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, however it is currently available only in a very few centers. Fluroine-18 (18F)-fluorodeoxyglucose (18F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow growing nature. However, according to subsequent data, 18F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki-67 values >10%. According to limited data, 18F-FDG avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining molecular imaging techniques (e.g. 18F-FDG PET and 68Ga-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above mentioned molecular imaging studies should always be reviewed and interpreted in a Multi-Disciplinary (Tumor Board) Meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for evaluation of treatment response and disease follow-up. (c) 2014 S. Karger AG, Basel.

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PubMed-ID: 24458014 http://dx.doi.org/10.1159/000358727

Neuroendocrine Tumours: the Role of Imaging for Diagnosis and Therapy. Nat Rev Endocrinol, 10(2):102-14. van EM, Sundin A, Krenning EP, Kwekkeboom DJ. 2014. In patients with neuroendocrine tumours (NETs), a combination of morphological imaging and nuclear medicine techniques is mandatory for primary tumour visualization, staging and evaluation of somatostatin receptor status. CT and MRI are well-suited for discerning small lesions that might escape detection by single photon emission tomography (SPECT) or PET, as well as for assessing the local invasiveness of the tumour or the response to therapy. Somatostatin receptor imaging, by (111)In-pentetreotide scintigraphy or PET with (68)Ga-labelled somatostatin analogues, frequently identifies additional lesions that are not visible on CT or MRI scans. Currently, somatostatin receptor scintigraphy with (111)In-pentetreotide is the more frequently available of the two techniques to determine somatostatin receptor expression and is needed to select patients for peptide receptor radionuclide therapy. In the future, because of its higher sensitivity, PET with (68)Ga-labelled somatostatin analogues is expected to replace somatostatin receptor scintigraphy. Whereas (18)F-FDG-PET is only used in high-grade neuroendocrine cancers, PET-CT with (18)F-dihydroxy-L-phenylalanine or (11)C-5- hydroxy-L-tryptophan is a useful problem-solving tool and could be considered for the evaluation of therapy response in the future. This article reviews the role of imaging for the diagnosis and management of intestinal and pancreatic NETs. Response evaluation and controversies in NET imaging will also be discussed. PubMed-ID: 24322649 http://dx.doi.org/10.1038/nrendo.2013.246

Quantitative and Qualitative Intrapatient Comparison of 68Ga-DOTATOC and 68Ga-DOTATATE: Net Uptake Rate for Accurate Quantification. J Nucl Med, 55(2):204-10. Velikyan I, Sundin A, Sorensen J, Lubberink M, Sandstrom M, Garske-Roman U, Lundqvist H, Granberg D, Eriksson B. 2014. Quantitative imaging and dosimetry are crucial for individualized treatment during peptide receptor radionuclide therapy (PRRT). (177)Lu-DOTATATE and (68)Ga-DOTATOC/(68)Ga-DOTATATE are used, respectively, for PRRT and PET examinations targeting somatostatin receptors (SSTRs) in patients affected by neuroendocrine tumors. The aim of the study was to quantitatively and qualitatively compare the performance of (68)Ga- DOTATOC and (68)Ga-DOTATATE in the context of subsequent PRRT with (177)Lu-DOTATATE under standardized conditions in the same patient as well as to investigate the sufficiency of standardized uptake value (SUV) for estimation of SSTR expression. METHODS: Ten patients with metastatic neuroendocrine tumors underwent one 45-min dynamic and 3 whole-body PET/CT examinations at 1, 2, and 3 h after injection with both tracers. The number of detected lesions, SUVs in lesions and normal tissue, total functional tumor volume, and SSTR volume (functional tumor volume multiplied by mean SUV) were investigated for each time point. Net uptake rate (Ki) was calculated according to the Patlak method for 3 tumors per patient. RESULTS: There were no significant differences in lesion count, lesion SUV, Ki, functional tumor volume, or SSTR volume between (68)Ga-DOTATOC and (68)Ga-DOTATATE at any time point. The detection rate was similar, although with differences for single lesions in occasional patients. For healthy organs, marginally higher uptake of (68)Ga- DOTATATE was observed in kidneys, bone marrow, and liver at 1 h. (68)Ga-DOTATOC uptake was higher in mediastinal blood pool at the 1-h time point (P = 0.018). The tumor-to-liver ratio was marginally higher for (68)Ga-DOTATOC at the 3-h time point (P = 0.037). Blood clearance was fast and similar for both tracers. SUV did not correlate with Ki linearly and achieved saturation for a Ki of greater than 0.2 mL/cm(3)/min, corresponding to an SUV of more than 25. CONCLUSION: (68)Ga-DOTATOC and (68)Ga-DOTATATE are suited equally well for staging and patient selection for PRRT with (177)Lu-DOTATATE. However, the slight difference in the healthy organ distribution and excretion may render (68)Ga-DOTATATE preferable. SUV did not correlate linearly with Ki and thus may not reflect the SSTR density accurately at its higher values, whereas Ki might be the outcome measure of choice for quantification of SSTR density and assessment of treatment outcome. PubMed-ID: 24379222 http://dx.doi.org/10.2967/jnumed.113.126177

Global DNA Methylation Patterns Through an Array-Based Approach in Small Intestinal Neuroendocrine Tumors. Endocr Relat Cancer, 21(1):L5-L7. Verdugo AD, Crona J, Starker L, Stalberg P, Akerstrom G, Westin G, Hellman P, Bjorklund P. 2014.

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PubMed-ID: 24192231 http://dx.doi.org/10.1530/ERC-13-0481

Zebrafish As an Innovative Model for Neuroendocrine Tumors. Endocr Relat Cancer, 21(1):R67-R83. Vitale G, Gaudenzi G, Dicitore A, Cotelli F, Ferone D, Persani L. 2014. Tumor models have a relevant role in furthering our understanding of the biology of malignant disease and in preclinical cancer research. Only few models are available for neuroendocrine tumors (NETs), probably due to the rarity and heterogeneity of this group of neoplasms. This review provides insights into the current state-of- the-art of zebrafish as a model in cancer research, focusing on potential applications in NETs. Zebrafish has a complex circulatory system similar to that of mammals. A novel angiogenesis assay based on the injection of human NET cell lines (TT and DMS79 cells) into the subperidermal space of the zebrafish embryos has been developed. Proangiogenic factors locally released by the tumor graft affect the normal developmental pattern of the subintestinal vessels by stimulating the migration and growth of sprouting vessels toward the implant. In addition, a description of the striking homology between zebrafish and humans of molecular targets involved in tumor angiogenesis (somatostatin receptors, dopamine receptors, mammalian target of rapamycin), and currently used as targeted therapy of NETs, is reported. PubMed-ID: 24292602 http://dx.doi.org/10.1530/ERC-13-0388

Assessment of Tumor Growth in Pancreatic Neuroendocrine Tumors in Von Hippel Lindau Syndrome. J Am Coll Surg, 218(2):163-9. Weisbrod AB, Kitano M, Thomas F, Williams D, Gulati N, Gesuwan K, Liu Y, Venzon D, Turkbey I, Choyke P, Yao J, Libutti SK, Nilubol N, Linehan WM, Kebebew E. 2014. BACKGROUND: The incidence of pancreatic neuroendocrine tumors (PNETs) is increasing, but only a subset of these heterogeneous tumors will progress to malignant disease, which is associated with a poor prognosis. Currently, there are limited data on the natural history of these tumors and it is difficult to determine which patients require surgical intervention because the risk of metastatic disease cannot be accurately determined. STUDY DESIGN: We conducted a prospective study of 87 patients with von Hippel Lindau syndrome-associated solid pancreatic lesions to determine the natural history of these tumors with biochemical testing, follow-up anatomic and functional imaging, and advanced imaging analysis, with a median follow-up of 4 years. RESULTS: Approximately 20% of consecutive tumor measurements during follow-up were decreased in size and 20% showed no change. This included 2 of 4 surgically proven malignant tumors, which had a net decrease in tumor size over time. Tumor volume, as derived from greatest diameter and volumetric measurements, showed good correlation to pathology tumor measurement of surgically resected tumors (Spearman rank correlation rho = 0.72, p = 0.0011, and rho = 0.83, p < 0.0001, respectively). Tumor density measurement had an inverse relationship with tumor size (Spearman rank correlation -0.22, p = 0.0047). A tumor density cutoff of 200 was 75% specific for malignant tumors. CONCLUSIONS: Pancreatic neuroendocrine tumors demonstrate a nonlinear growth pattern, which includes periods of no growth and apparent decrease in size by imaging. These growth patterns are variable and are not associated with tumor grade and malignancy. Tumor density, as measured in this cohort, may offer a specific diagnostic tool for malignant disease. PubMed-ID: 24440063 http://dx.doi.org/10.1016/j.jamcollsurg.2013.10.025

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GI and General

Meta-Analyses - None -

Randomized controlled trials - None -

Consensus Statements/Guidelines - None -

Other Articles Management of Endocrine Disease: GH Excess: Diagnosis and Medical Therapy. Eur J Endocrinol, 170(1):R31-R41. Andersen M. 2014. Acromegaly is predominantly caused by a pituitary adenoma, which secretes an excess of GH resulting in increased IGF1 levels. Most of the GH assays used currently measure only the levels of the 22 kDa form of GH. In theory, the diagnostic sensitivity may be lower compared with the previous assays, which have used polyclonal antibodies. Many GH-secreting adenomas are plurihormonal and may co-secrete prolactin, TSH and alpha-subunit. Hyperprolactinaemia is found in 30-40% of patients with acromegaly, and hyperprolactinaemia may occasionally be diagnosed before acromegaly is apparent. Although trans-sphenoidal surgery of a GH- secreting adenoma remains the first treatment at most centres, the role of somatostatin analogues, octreotide long-acting repeatable and lanreotide Autogel as primary therapy is still the subject of some debate. Although the normalisation of GH and IGF1 levels is the main objective in all patients with acromegaly, GH and IGF1 levels may be discordant, especially during somatostatin analogue therapy. This discordance usually takes the form of high GH levels and an IGF1 level towards the upper limit of the normal range. Pasireotide, a new somatostatin analogue, may be more efficacious in some patients, but the drug has not yet been registered for acromegaly. Papers published on pasireotide have reported an increased risk of diabetes mellitus due to a reduction in insulin levels. Pegvisomant, the GH receptor antagonist, is indicated - alone or in combination with a somatostatin analogue - in most patients who fail to enter remission on a somatostatin analogue. Dopamine-D2- agonists may be effective as monotherapy in a few patients, but it may prove necessary to apply combination therapy involving a somatostatin analogue and/or pegvisomant. PubMed-ID: 24144967 http://dx.doi.org/10.1530/EJE-13-0532

Resection of the Primary Pancreatic Neuroendocrine Tumor in Patients With Unresectable Liver Metastases: Possible Indications for a Multimodal Approach. Surgery, 155(4):607-14. Bertani E, Fazio N, Botteri E, Chiappa A, Falconi M, Grana C, Bodei L, Papis D, Spada F, Bazolli B, Andreoni B. 2014. BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) present in more than 50% of cases with liver metastases as the only systemic localization. Liver metastases are unresectable in 80% of cases at diagnosis. In the context of a metastatic disease, the benefit of primary tumor removal in terms of survival is controversial. METHODS: A single-center series of patients with PNETs presenting with synchronous unresectable hepatic metastases and treated within a framework of a multidisciplinary team was analyzed retrospectively to assess the prognostic factors and the potential benefit of primary tumor resection on long-term survival. RESULTS: At the time of diagnosis, 12 of 43 patients (28%) underwent primary tumor resection. After a median follow-up of 5 years (range, 0.6-14 years), 22 disease-related deaths were observed. The corresponding 5-year survival and

ESES Review of Recently Published Literature 2014-1 Page 116 of 121 median disease-specific duration of survival were 58% and 77 months, respectively. In the operated and nonoperated patients the 5-year disease-specific survival was 82% and 50%, respectively (P = .027). At multivariate analysis, patients with primary tumor removed had an improved survival compared with patients who did not (hazard ratio 0.18; 95% CI 0.05-0.66; P = .010). Other important factors associated with improved survival at multivariate analysis were lesser age, lesser Ki-67 index, and 25% less liver tumor burden. CONCLUSION: In the present series of patients with PNETs and unresectable liver metastases, resection of the primary tumor was associated with an improved survival. This observation suggests that resection of the primary tumor should be part of a global therapeutic strategy and its indication and timing should be discussed within a multidisciplinary team. PubMed-ID: 24582492 http://dx.doi.org/10.1016/j.surg.2013.12.024

Sporadic Nonfunctioning Pancreatic Neuroendocrine Tumors: Prognostic Significance of Incidental Diagnosis. Surgery, 155(1):13-21. Birnbaum DJ, Gaujoux S, Cherif R, Dokmak S, Fuks D, Couvelard A, Vullierme MP, Ronot M, Ruszniewski P, Belghiti J, Sauvanet A. 2014. BACKGROUND: Sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed as incidentalomas, and their resection is usually recommended. The prognostic significance of this diagnosis feature is poorly studied, and management of these tumors remains controversial. Clinical, pathologic characteristics and outcome of resected incidentally diagnosed NF-PNET (Inc) were compared with resected symptomatic NF-PNET (Symp) to better assess their biologic behavior and tailor their management. METHODS: From 1994 to 2010, 108 patients underwent resection for sporadic nonmetastatic NF-PNET. Diagnosis was considered as incidental in patients with no abdominal symptoms or symptoms unlikely to be related to tumor mass. Patients with Inc were compared with patients with Symp, regarding demographics, postoperative course, pathology, and disease-free survival (DFS). RESULTS: Of the 108 patients, 65 (61%) had incidentally diagnosed tumors. Pancreas-sparing pancreatectomies (enucleation/central pancreatectomy) were performed more frequently in Inc (62% vs 30%, P = .001). Inc tumors were more frequently <20 mm (65% vs 42%, P = .019), staged T1 (62% vs 33%, P = .0001), node negative (85% vs 60%; P = .005), and grade 1 (66% vs 33%, P = .0001). One postoperative death occurred in the Inc group, and postoperative morbidity was similar between the two groups (60% vs 65%, P = .59). DFS was substantially better in the Inc group (5-year DFS = 92% vs 82%, P = .0016). CONCLUSION: Incidentally diagnosed NF-PNETs are associated with less aggressive features compared with symptomatic lesions but cannot always be considered to be benign. Operative resection remains recommended for most. Incidentally diagnosed NF-PNET may be good candidates for pancreas-sparing pancreatectomies. PubMed-ID: 24238123 http://dx.doi.org/10.1016/j.surg.2013.08.007

Incidental Diagnosis As Prognostic Factor in Different Tumor Stages of Nonfunctioning Pancreatic Endocrine Tumors. Surgery, 155(1):145-53. Crippa S, Partelli S, Zamboni G, Scarpa A, Tamburrino D, Bassi C, Pederzoli P, Falconi M. 2014. BACKGROUND: Incidentally discovered nonfunctioning pancreatic endocrine tumors (NF-pNETs) increasingly are being detected, and their management is debated. Moreover, the prognostic importance of incidental diagnosis for locally advanced or metastatic NF-pNETs is unknown. The aim of this study is to analyze the outcomes of incidentally discovered/symptomatic NF-pNETs stratified by tumor stage. A preliminary experience with nonoperative treatment of incidental NF-pNETs is reported. METHODS: Consecutive patients with symptomatic/incidental NF-PETs observed between 1990 and 2009 were analyzed, with different tumor stages considered. Nonoperative management of incidental NF-pNETs was evaluated. RESULTS: Among 355 patients with NF-pNETs, the diagnosis was incidental in 124 (35%). Incidental NF-pNETs were associated more commonly with lower tumor stages compared with symptomatic tumors (P < .0001), but 30% of incidental NF- pNETs were stage III-IV. Incidental NF-pNETs had greater rates of radical resections and of R0 margins (P < .0001). Five-year progression-free survival (PFS) was 83% and 32% for incidental and symptomatic NF-pNETs, respectively (P < .0001). Five-year PFS was better for incidental NF-pNETs compared with symptomatic tumors for each tumor stage, including stage III (69% vs 27%, P < .0001) and stage IV (60% vs 17%, P = .112). After a median follow-up of 36 months, there was no tumor progression in 12 patients who underwent nonoperative management of incidental NF-pNETs. CONCLUSION: A total of 30% of incidental NF-pNETs present with stage III-IV disease. PFS is much greater for incidental NF-pNETs compared with symptomatic patients, and this difference is evident also for stage III-IV tumors, suggesting that absence of symptoms may indicate a less-

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GEP-NETS Update: Functional Localisation and Scintigraphy in Neuroendocrine Tumours of the Gastrointestinal Tract and Pancreas (GEP-NETs). Eur J Endocrinol, 170(5):R173-R183. de Herder WW. 2014. For patients with neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas (GEP) (GEP-NETs), excellent care should ideally be provided by a multidisciplinary team of skilled health care professionals. In these patients, a combination of nuclear medicine imaging and conventional radiological imaging techniques is usually mandatory for primary tumour visualisation, tumour staging and evaluation of treatment. In specific cases, as in patients with occult insulinomas, sampling procedures can provide a clue as to where to localise the insulin- hypersecreting pancreatic NETs. Recent developments in these fields have led to an increase in the detection rate of primary GEP-NETs and their metastatic deposits. Radiopharmaceuticals targeted at specific tumour cell properties and processes can be used to provide sensitive and specific whole-body imaging. Functional imaging also allows for patient selection for receptor-based therapies and prediction of the efficacy of such therapies. Positron emission tomography/computed tomography (CT) and single-photon emission CT/CT are used to map functional images with anatomical localisations. As a result, tumour imaging and tumour follow-up strategies can be optimised for every individual GEP-NET patient. In some cases, functional imaging might give indications with regard to future tumour behaviour and prognosis. PubMed-ID: 24723670 http://dx.doi.org/10.1530/EJE-14-0077

Neuroendocrine Carcinomas: Optimal Surgery of Peritoneal Metastases (and Associated Intra- Abdominal Metastases). Surgery, 155(1):5-12. Elias D, David A, Sourrouille I, Honore C, Goere D, Dumont F, Stoclin A, Baudin E. 2014. AIM: To report the results of complete cytoreductive surgery (CCRS) of peritoneal metastases from neuroendocrine tumor (NET) and to compare patients treated with or without hyperthermic intraperitoneal chemotherapy (HIPEC). BACKGROUND: Aggressive management of peritoneal metastases from NET (in most of the cases associated with other types of metastases) has not been addressed in the literature, but these metastases affect overall survival. PATIENTS AND METHODS: From 1994 to 2012, 41 patients underwent CCRS, with HIPEC (n = 28) from 1994 to 2007 but without HIPEC (n = 13) from 2008 to 2012. Liver metastases were treated during the same operative procedure in 66% of the patients. RESULTS: Mortality was 2% and morbidity 56%. Overall survival at 5 and 10 years was 69% and 52%, respectively, and disease-free survival at 5 and 10 years was 17% and 6%, respectively. At 5 years, peritoneal metastases and liver metastases recurred in 47% and in 66% of cases, respectively. Overall survival was not different between patients treated with or without HIPEC, but disease-free survival was greater in the HIPEC group (P = .018), mainly because of fewer lung and bone metastases. CONCLUSION: CCRS of peritoneal metastases from a NET is feasible in most of the patients and seems to increase survival rates. We were unable to determine whether adding HIPEC had a positive or a negative impact. PubMed-ID: 24084595 http://dx.doi.org/10.1016/j.surg.2013.05.030

A Single Institution's 26-Year Experience With Nonfunctional Pancreatic Neuroendocrine Tumors: a Validation of Current Staging Systems and a New Prognostic Nomogram. Ann Surg, 259(2):204-12. Ellison TA, Wolfgang CL, Shi C, Cameron JL, Murakami P, Mun LJ, Singhi AD, Cornish TC, Olino K, Meriden Z, Choti M, Diaz LA, Pawlik TM, Schulick RD, Hruban RH, Edil BH. 2014. OBJECTIVE: To validate the 2010 American Joint Committee on Cancer (AJCC) and 2006 European Neuroendocrine Tumor Society (ENETS) tumor staging systems for pancreatic neuroendocrine tumors (PanNETs) using the largest, single-institution series of surgically resected patients in the literature. BACKGROUND: The natural history and prognosis of PanNETs have been poorly defined because of the rarity and heterogeneity of these neoplasms. Currently, there are 2 main staging systems for PanNETs, which can complicate comparisons of reports in the literature and thereby hinder progress against this disease. METHODS: Univariate and multivariate analyses were conducted on the prognostic factors of survival using 326 sporadic, nonfunctional, surgically resected PanNET patients who were cared for at our institution between 1984 and

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2011. Current and proposed models were tested for survival prognostication validity as measured by discrimination (Harrel's c-index, HCI) and calibration. RESULTS: Five-year overall-survival rates for AJCC stages I, II, and IV are 93% (88%-99%), 74% (65%-83%), and 56% (42%-73%), respectively, whereas ENETS stages I, II, III, and IV are 97% (92%-100%), 87% (80%-95%), 73% (63%-84%), and 56% (42%-73%), respectively. Each model has an HCI of 0.68, and they are no different in their ability to predict survival. We developed a simple prognostic tool just using grade, as measured by continuous Ki-67 labeling, sex, and binary age that has an HCI of 0.74. CONCLUSIONS: Both the AJCC and ENETS staging systems are valid and indistinguishable in their survival prognostication. A new, simpler prognostic tool can be used to predict survival and decrease interinstitutional mistakes and uncertainties regarding these neoplasms. PubMed-ID: 23673766 http://dx.doi.org/10.1097/SLA.0b013e31828f3174

Lymphadenectomy for Pancreatic Neuroendocrine Tumors: Is That the Relevant Debate? Ann Surg, 259(2):213-4. Ferrone CR. 2014. PubMed-ID: 24398923 http://dx.doi.org/10.1097/SLA.0000000000000533

Comment on "Predicting Aggressive Behavior in Nonfunctioning Pancreatic Neuroendocrine". Surgery, 155(3):582-4. Gaujoux S, Sauvanet A, Partelli S, Falconi M, Ruszniewski P. 2014. PubMed-ID: 24462075 http://dx.doi.org/10.1016/j.surg.2013.11.004

Regional Lymphadenectomy Is Indicated in the Surgical Treatment of Pancreatic Neuroendocrine Tumors (PNETs). Ann Surg, 259(2):197-203. Hashim YM, Trinkaus KM, Linehan DC, Strasberg SS, Fields RC, Cao D, Hawkins WG. 2014. OBJECTIVE: To explore the prognostic importance and preoperative predictors of lymph node metastasis in an effort to guide surgical decision making in patients with pancreatic neuroendocrine tumors (PNETs). BACKGROUND: PNETs are uncommon, and the natural history of the disease is not well described. As a result, there remains controversy regarding the optimal management of regional lymph nodes during resection of the primary tumor. METHODS: A retrospective review of a prospectively maintained database of patients who underwent surgery for locoregional PNET between 1994 and 2012 was performed. Logistic regression was used to identify predictors of nodal metastasis. Overall survival and disease-free survival were calculated using Kaplan-Meier method. Results were expressed as P values and odds ratio estimates, with 95% confidence intervals. RESULTS: One hundred thirty-six patients were identified, of whom 50 (38%) patients had nodal metastasis. The frequency of lymph node metastasis was higher for larger tumors [> 1.5 cm (odds ratio [OR] = 4.7)], tumors of the head as compared with body-tail of the pancreas (OR = 2.8), tumors with Ki-67 greater than 20% (OR = 6.7), and tumors with lymph vascular invasion (OR = 3.6) (P < 0.05). Median disease-free survival was lower for patients with nodal metastases (4.5 vs 14.6 years, P < 0.0001). CONCLUSIONS: Lymph node metastasis is predictive of poor outcomes in patients with PNETs. Preoperative variables are not able to reliably predict patients where the probability of lymph node involvement was less than 12%. These data support inclusion of regional lymphadenectomy in patients undergoing pancreatic resections for PNET. PubMed-ID: 24253141 http://dx.doi.org/10.1097/SLA.0000000000000348

Prognostic Impact of Diagnosing Colorectal Neuroendocrine Carcinoma Using the World Health Organization 2010 Classification. Surgery, 155(4):650-8. Lee JL, Yu CS, Kim M, Hong SM, Lim SB, Kim JC. 2014. BACKGROUND: Neuroendocrine carcinomas (NECs) arising in the large intestine are rare neoplasms with highly aggressive behavior. The aim of the study was to compare the 2000 and 2010 World Health Organization (WHO) classification of these colorectal NECs. METHODS: We conducted a retrospective study of patients diagnosed with colorectal NECs according to the WHO 2000 classification who underwent surgery at the Asan Medical Center between May 2000 and December 2010. The data were reevaluated to assess their consistency with the WHO 2010 classification. RESULTS: For 20 of the 34 patients (59%), the 2000 and 2010 WHO classifications yielded the same NEC diagnosis (NEC group), whereas for 14 of the 34 patients (41%), the WHO 2010 classification mandated a diagnosis of G1 or G2 neuroendocrine tumors (NETs) rather than NECs (G1/G2

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NET group). The NEC group was older than the G1/G2 NET group (64 vs 55 years; P = .05). Tumor differentiation in the NEC group was poorer than in the G1/G2 NET group (percentage of poorly differentiated tumor, 70% vs 7%; P < .001). In both groups based on the 7th American Joint Committee on Cancer staging, most of the tumors were advanced at the time of diagnosis, reaching stage IIIB (6 NEC vs 10 NET) and stage IV (10 NEC vs 3 NET). The 5-year overall survival in the 2 groups was different (P = .02), but not the 5-year disease-free survival (P = .24). CONCLUSION: These results indicate that the WHO 2010 classification of colorectal NEC is more accurate and has better prognostic value than the WHO 2000 classification. PubMed-ID: 24468036 http://dx.doi.org/10.1016/j.surg.2013.11.012

Non-Pheochromocytoma (PCC)/Paraganglioma (PGL) Tumors in Patients With Succinate Dehydrogenase-Related PCC-PGL Syndromes: a Clinicopathological and Molecular Analysis. Eur J Endocrinol, 170(1):1-12. Papathomas TG, Gaal J, Corssmit EP, Oudijk L, Korpershoek E, Heimdal K, Bayley JP, Morreau H, van DM, Papaspyrou K, Schreiner T, Hansen T, Andresen PA, Restuccia DF, van K, I, van Leenders GJ, Kros JM, Looijenga LH, Hofland LJ, Mann W, van Nederveen FH, Mete O, Asa SL, de Krijger RR, Dinjens WN. 2014. OBJECTIVE: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated. DESIGN AND METHODS: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC. RESULTS: Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression. CONCLUSIONS: These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency. PubMed-ID: 24096523 http://dx.doi.org/10.1530/EJE-13-0623

Cognitive Impairment Associated With Carcinoid Syndrome. Ann Surg, 259(2):355-9. Pasieka JL, Longman RS, Chambers AJ, Rorstad O, Rach-Longman K, Dixon E. 2014. OBJECTIVES: To evaluate the cognitive performance of patients with carcinoid syndrome (CS) compared with population norms and cancer patients with non-neuroendocrine (non-NET) liver metastases. BACKGROUND: The release of serotonin into the systemic circulation from metastatic small bowel neuroendocrine tumors (SB NET) causes CS. Many patients with CS followed in a multidisciplinary NET clinic seemed to exhibit a unique cognitive impairment. Because serotonin is known to influence a range of cognitive function, the question arouse as to whether cognitive impairment is another manifestation of CS. METHODS: Patients were recruited from the multidisciplinary NET and the hepatobilary cancer clinics at the cancer center. The CS group consisted of patients with proven SB NETs metastatic to liver; the cancer comparison group consisted of patients with liver metastases from non-NET cancer. All completed a self-reported cognitive questionnaire and a battery of 6 standardized neurocognitive tests. Both groups were compared to age/sex/educational-matched norms. RESULTS: Thirty-six patients with CS and 20 with non-NET metastases were enrolled. Patients with CS reported greater cognitive dysfunction in all cognitive domains than both norms and the comparison cancer group. On cognitive testing, patients with CS demonstrated weakness in initiation, processing speed, visual memory, cognitive efficiency, and delayed verbal recall compared with norms. Although the patients with non- NET cancer also demonstrated some cognitive dysfunction compared with norms, the patients with CS did significantly worse on delayed recall (P = 0.03) and marginally slower on speeded mental flexibility (P = 0.097) compared with patients with non-NET cancer. CONCLUSION: This study confirmed our clinical observation that patients with CS suffer from cognitive impairment that is different from the non-NET cancer group and population norms.

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PubMed-ID: 23478527 http://dx.doi.org/10.1097/SLA.0b013e318288ff6d

Prospective Evaluation of the Clinical Utility of 18-Fluorodeoxyglucose PET CT Scanning in Patients With Von Hippel-Lindau-Associated Pancreatic Lesions. J Am Coll Surg, 218(5):997-1003. Sadowski SM, Weisbrod AB, Ellis R, Patel D, Alimchandani M, Quezado M, Millo C, Venzon DJ, Nilubol N, Linehan WM, Kebebew E. 2014. BACKGROUND: The natural history of pancreatic neuroendocrine neoplasms (PNENs) in patients with Von Hippel-Lindau (VHL) disease is poorly defined. Management of patients with PNENs is challenging because there are no reliable preoperative criteria to detect malignant lesions, and the majority of resected tumors are found to be benign. The aim of this study was to determine whether 18-fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) uptake predicts growth and detects malignant VHL-associated PNENs. STUDY DESIGN: We performed a prospective study of 197 patients with VHL-associated pancreatic lesions. Clinical and imaging characteristics were analyzed to study the associations between FDG-PET uptake, tumor growth, and the development of metastatic disease. RESULTS: One hundred nine of 197 patients had solid pancreatic lesions and underwent both CT and (18)FDG-PET scanning, which identified 165 and 144 lesions, respectively. Metastatic disease was detected by (18)FDG-PET in 3 patients in whom it was not detected by CT scan and suggested non-neoplastic disease in 3 patients. Maximum standardized uptake values (SUV) on (18)FDG-PET correlated with tumor size on CT (r = 0.47, p < 0.0001), and an increase in SUVmax was associated with tumor growth (r = 0.36, p = 0.0062). No association was seen between (18)FDG-PET uptake and age, VHL genotype, or serum chromogranin A levels. CONCLUSIONS: Scanning with FDG-PET identifies metastatic disease not detected by CT scan and avoids resection of non-PNEN lesions that have no malignant potential in patients with VHL-associated PNENs. It should be considered as a valuable functional imaging modality in the clinical management of patients with VHL-associated PNENs. PubMed-ID: 24661849 http://dx.doi.org/10.1016/j.jamcollsurg.2014.01.004

Long-Term Results of Endoscopic Resection for Type I Gastric Neuroendocrine Tumors. J Surg Oncol, 109(2):71-4. Uygun A, Kadayifci A, Polat Z, Yilmaz K, Gunal A, Demir H, Bagci S. 2014. BACKGROUND: A number of different therapies, including endoscopic resection, have been suggested for the treatment of Type 1 gastric neuroendocrine tumors (NETs). The current study aimed to determine the long-term efficacy of endoscopic resection for Type 1 gastric NETs. METHODS: Twenty-two patients (from 1999 to 2012) with Type 1 gastric NETs were included in the study. All patients were treated with endoscopic resection and received regular followed-up appointments at a tertiary referral center. RESULTS: All patients were initially diagnosed with hypergastrinemia, atrophic gastritis and intestinal metaplasia. Polyps' diameters were >1 cm in 4 patients, and between 0.5 and 1 cm in 18 patients. All detectable lesions were successfully resected. One patient required surgery due to gastric perforation during endoscopic mucosal resection. Recurrence was detected in four patients (18%) and endoscopic resection was performed again. Local or distant metastasis was not observed in any patient during follow-up. Median follow-up time was 7 years, with a maximum of 14 years. Seventeen patients (78%) completed a 5-year follow-up period, and overall disease-free survival rate was 100%. CONCLUSIONS: Long-term follow-ups with 22 patients suggest that endoscopic resection of Type 1 gastric NETs is a safe and effective treatment option with a relatively low recurrence rate. PubMed-ID: 24165913 http://dx.doi.org/10.1002/jso.23477

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