EUROPEAN SOCIETY OF ENDOCRINE SURGEONS

ESES Review of Recently Published Literature

Collection: T. Clerici, F. Triponez, M. Demarchi, 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

May-Aug 2019 Data retrival from Pubmed: 12. Dec 2019 Contents

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

Publication count: SR/MA RCT CG Other Page Thyroid ...... 9 ...... 0 ...... 0 ...... 81 ...... 4 Parathyroids ...... 0 ...... 2 ...... 0 ...... 23 ...... 36 Adrenals ...... 2 ...... 1 ...... 0 ...... 26 ...... 46 NET ...... 1 ...... 0 ...... 0 ...... 19 ...... 58 General ...... 1 ...... 0 ...... 0 ...... 15 ...... 66

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 Marco Demarchi, MD Department of Thoracic and Endocrine Surgery, University Hospitals 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, Ph.D Department of Surgery, Cantonal Hospital St. Gallen, St. Gallen, Switzerland [email protected]

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Journals covered

Journal IF2016 Journal IF2016 Acta Cytol 1.562† J Bone Miner Res 6.284 Am J Kidney Dis 7.623 J Clin Endocrinol Metab 5.455 Am J Nephrol 2.542 J Clin Oncol 24.008 Am J Surg 2.612 J Endocrinol 4.706 Am Surgeon 0.700 J Endocrinol Invest -- Ann Surg 8.980 J Nephrol 2.153 Ann Surg Oncol 4.041 J Nucl Med 6.646 ANZ J Surg 1.513 J Surg Oncol 2.993 Br J Surg 5.899 Lancet 47.831 Cancer 5.997 Langenbecks Arch Surg 2.203 Chirurg 0.646 Laryngoscope 2.471 Clin Endocrinol Oxf 3.327 N Engl J Med 72.406 Nat Rev Endocrinol Clin Nucl Med 3.640 18.318 (prev: Nat Clin Pract Endocrinol Metab) Nat Rev Clin Oncol Curr Opin Oncol 3.414 20.693 (prev: Nat Clin Pract Oncol) Endocr Relat Cancer 5.267 Nephrol Dial Transplant 4.470 Endocr Rev 15.745 Nephron Clin Pract 2.138 Eur Arch Otorhinolaryngol 1.660 Neuroendocrinology 3.608 Eur J Endocrinol 4.101 Oncologist 4.962 Eur J Surg Oncol 3.522 Otolaryngol Head Neck Surg 2.276 Gland Surg --- Surg Clin North Am 2.206 Head Neck 3.376 Surg Endosc 3.747 Horm Metab Res 2.268 Surg Laparosc Endosc Percutan Tech 0.938 JAMA Otolaryngol Head Neck Surg 2.951 Surg Oncol 3.304 (prev: Arch Oto …..) JAMA Surg (prev: Arch Surg) 7.956 Surg Oncol Clin N Am 2.281 Int J Cancer 6.513 Surgery 3.904 J Am Coll Surg 4.307 Thyroid 5.515 J Am Soc Nephrol 8.966 Updates In Surgery --- J Bone Miner Metab 2.423 World J Surg 2.673

Journal names are links to the journal’s homepage!, IF2017: Impact factor 2014, †IF 2015, no IF for 2017

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Thyroid

Meta-Analyses Active Surveillance for Small Papillary Thyroid Cancer: A Systematic Review and Meta-Analysis. Thyroid, 29(10):1399-408. S. J. Cho, C. H. Suh, J. H. Baek, S. R. Chung, Y. J. Choi, K. W. Chung, Y. K. Shong and J. H. Lee. 2019. Background: The rapid increase in the incidence of small papillary thyroid carcinoma (PTC) appears to be caused by the detection of small thyroid cancers. Active surveillance (AS) was therefore suggested to overcome this problem. As the results were favorable with low rates of size enlargement and lymph metastasis, the 2015 American Thyroid Association Management Guidelines endorsed AS as an alternative to immediate surgery. As the clinical value of AS is a subject of ongoing active discussions and surveys, we considered a systematic review and meta-analysis to be timely and necessary. Methods: Ovid-MEDLINE and EMBASE databases were searched up to January 5, 2019, for studies reporting patients who were followed up with AS for PTC. Data extraction and methodological quality assessment were performed independently by two radiologists. The primary outcomes were to identify the annual pooled proportions of size enlargement of 3 mm or more and the detection of lymph node metastases at a 5-year follow-up period. These were calculated using an inverse- variance weighting model. An additional outcome was evaluation of the reasons for surgery during AS. Results: The pooled proportion of size enlargement occurring at 5 years was 5.3% [95% confidence interval (CI), 4.4- 6.4%], and the pooled proportion of 5-year lymph node metastasis was 1.6% [CI, 1.1-2.4%]. In many subjects undergoing delayed operations, the reasons for operation were often other than those of size enlargement or lymph node metastasis. Conclusions: AS is effective for the management of small PTC, with a low proportion of size enlargement or lymph node metastasis occurring at 5 years. However, a substantial proportion of the causes of delayed surgery were other than size enlargement or lymph node metastasis, and these situations need to be optimally managed. PubMed-ID: 31368412 http://dx.doi.org/10.1089/thy.2019.0159

Calcitonin negative Medullary Thyroid Carcinoma: a challenging diagnosis or a medical dilemma? BMC Endocr Disord, 19(Suppl 1):45. C. Gambardella, C. Offi, R. Patrone, G. Clarizia, C. Mauriello, E. Tartaglia, F. Di Capua, S. Di Martino, R. M. Romano, L. Fiore, A. Conzo, G. Conzo and G. Docimo. 2019. BACKGROUND: Medullary thyroid carcinoma is a neuroendocrine tumor belonging form a malignant growth of the thyroid parafollicular C-cells, representing from 1 to 10% of all thyroid cancer. The biochemical activity of medullary thyroid carcinoma includes the production of calcitonin and carcinoembryogenic antigen, which are sensitive tumor markers, facilitating the diagnosis, follow-up and prognostication. The diagnosis is reached through the identification of high basal calcitonin serum level or after pentagastrin stimulation test. Medullary thyroid carcinoma is able to produce other relevant biomarkers as procalcitonin, carcinoembryionic antigen and chromogranin A. In Literature are described few cases of medullary thyroid carcinoma without elevation of serum calcitonin, an extremely rare event. The aim of this study was to analyse the presentation, the main features and therapeutic management of medullary thyroid carcinoma associated with negative serum calcitonin levels. METHODS: Using the PubMed database, a systematic review of the current Literature was carried out, up to February 2018. Finally, nineteen articles met our inclusion criteria and were selected according to the modified Newcastle-Ottawa scale. RESULTS: Fourty-nine patients with definitive pathology confirming medullary thyroid carcinoma and with calcitonin serum level in the normal range were identified (24 female, 24 male and not reported gender in 1 case). Mean age was 51.7 years. Serum calcitonin levels were reported for 20 patients with a mean value of 8.66 pg/mL and a range of 0.8-38 pg/mL. Despite the low or undetectable calcitonin serum level, at immunochemistry in almost the half of the cases reported by the Authors, the tumors presented diffuse or focal positivity for calcitonin and carcinoembryionic antigen, while was reported a chromogranin A positivity in 41 of the 43 tested patients. CONCLUSIONS: Calcitonin negative medullary thyroid carcinoma is an extremely rare pathology. The diagnosis and the surveillance is often challenging and delayed, due to the lack of elevation of serum markers as calcitonin and carcinoembryionic antigen. Further studies are needed, to better define options for management of non secretory medullary thyroid carcinoma and to identify new and reliable biomarkers associated to diagnosis and relapse of this medical dilemma. PubMed-ID: 31142313 http://dx.doi.org/10.1186/s12902-019-0367-2

ESES Review of Recently Published Literature 2019-2 Page 4 of 71

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review. Clin Endocrinol (Oxf), 91(6):697-707. J. M. Fussey, B. Vaidya, D. Kim, J. Clark, S. Ellard and J. A. Smith. 2019. BACKGROUND: The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC. METHODS: MEDLINE and Embase databases were searched using the MeSH terms "medullary carcinoma", "epigenetics", "molecular genetics", "microRNAs"; and free text terms "medullary carcinoma", "sporadic medullary thyroid cancer", "sMTC", "RET", "RAS" and "miR". Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale. RESULTS: Twenty-three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR-183 and miR-375 expression and higher rates of lymph node and distant metastasis, and worse survival. CONCLUSIONS: There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual's tumour mutation profile. PubMed-ID: 31301229 http://dx.doi.org/10.1111/cen.14060

Importance of incorporating intraoperative neuromonitoring of the external branch of the superior laryngeal nerve in thyroidectomy: A review and meta-analysis study. Head Neck, 41(6):2034-41. M. Naytah, I. Ibrahim and S. da Silva. 2019. BACKGROUND: Voice changes are frequently reported after thyroidectomy due to injury to the external branch of the superior laryngeal nerve (EBSLN) and paralysis of the cricothyroid muscle, The objective is to evaluate the advantage of intraoperative neuromonitoring (IONM) in identifying EBSLN during thyroid surgery. METHODS: Data sources were MEDLINE, PubMed, Web of Science, and Cochrane Library from January 1, 1995, through July 1, 2018. Published studies of adult patients who had thyroid surgery and an attempt to identify EBSLN done by conventional methods and/or IONM were selected. RESULTS: Seven studies met all inclusion criteria. Patients who had IONM during thyroid surgery had a significantly increased number of identified EBSLN at risk, compared to the control group. CONCLUSION: The use of IONM during open thyroid surgery increases EBSLN identification/visualization, and hence it may decrease the incidence of post-thyroidectomy voice disorders. PubMed-ID: 30706616 http://dx.doi.org/10.1002/hed.25669

Impact of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) on risk of malignancy in patients undergoing lobectomy/thyroidectomy for suspicious for malignancy or malignant fine-needle aspiration cytology findings: a systematic review and meta-analysis. Eur J Endocrinol, M. Bongiovanni, W. Faquin, L. Giovanella, C. Durante, P. Kopp and P. Trimboli. 2019. OBJECTIVE: The second version of the Bethesda System for Reporting Thyroid Cytopathology endorsed the introduction of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as a distinct entity with low malignant potential into clinical practice. Consequently, the risk of malignancy (ROM) of cytological diagnoses has changed, but the magnitude of the change remains uncertain. The present systematic review was undertaken to obtain more robust information about the true impact of NIFTP on the ROM among patients undergoing surgery following a fine-needle aspiration cytology (FNAC) diagnosis of suspicious for malignancy (Bethesda V) or malignant (Bethesda VI). As they are managed surgically, these two diagnostic categories are the primary entities that are clinically impacted by the advent of NIFTP. DESIGN: Systematic review and meta-analysis. METHODS: A comprehensive literature search of online databases was performed in November 2018. The search was conducted looking for data of histologically proven NIFTP with preoperative FNAC. RESULTS: One-hundred-fifty-seven articles were identified and nine were included in the study. Overall, there were 13,752 thyroidectomies with a cancer prevalence of 45.7%. When NIFTP was considered non- malignant, the pooled risk difference for ROM was 5.5%. Applying meta-analysis, the pooled prevalence of NIFTP among nodules with FNAC of Bethesda V or Bethesda VI was 14% and 3%, respectively. CONCLUSION:

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This meta-analysis shows that the inclusion of NIFTP leads to a reduction in the ROM for the Bethesda V and Bethesda VI FNAC diagnostic categories by 14% and 3%, respectively. Clinicians should be aware of these data to avoid overtreatment. PubMed-ID: 31340203 http://dx.doi.org/10.1530/EJE-19-0223

Thyroid nodules as a risk factor for thyroid cancer in patients with Graves' disease: A systematic review and meta-analysis of observational studies in surgically treated patients. Clin Endocrinol (Oxf), 91(4):571-7. A. Papanastasiou, K. Sapalidis, D. G. Goulis, N. Michalopoulos, E. Mareti, S. Mantalovas and I. Kesisoglou. 2019. OBJECTIVE: Graves' disease (GD) is an autoimmune thyroid disorder characterized by hyperthyroidism. The incidence of thyroid cancer in patients with GD varies from 0.15% to 15%. There is conflicting evidence on the role of thyroid nodules as a risk factor for thyroid cancer in patients with GD. DESIGN: Three electronic databases (PubMed, Cochrane Library, Scopus) as well as grey literature sources were searched, from inception until 25 February 2019, for observational studies about the prevalence of thyroid cancer in patients with GD. PATIENTS: Clinical and ultrasonographic examination was necessary preoperatively for all patients to be classified depending on the presence/absence of thyroid nodules. MEASUREMENTS: Primary outcome was the incidence of thyroid cancer. The latter was determined after total or near-total thyroidectomy by the histopathologic report. Statistical analysis was performed with revman 5.3 software. RESULTS: The systematic review and meta-analysis included 7 studies with 2582 patients overall. The prevalence of any thyroid cancer was 11.5%. The presence of at least one thyroid nodule in patients with GD was associated with higher risk for thyroid cancer (odds ratio [OR] 5.3, 95% confidence interval [CI] 2.4-11.6, I(2) 83%). A subgroup analysis showed no difference in thyroid cancer risk in patients with GD according to the number of nodules (solitary versus multiple) (OR 1.4, 95% CI 0.9-2.3, I(2) 0%). CONCLUSIONS: The presence of thyroid nodules is positively associated with the prevalence of thyroid cancer in surgically treated patients with GD. However, further prospective research is needed as the heterogeneity among the studies is high. PubMed-ID: 31369161 http://dx.doi.org/10.1111/cen.14069

Effects of Preoperative Iodine Administration on Thyroidectomy for Hyperthyroidism: A Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg, 160(6):993-1002. C. H. Tsai, P. S. Yang, J. J. Lee, T. P. Liu, C. Y. Kuo and S. P. Cheng. 2019. OBJECTIVE: The current guidelines recommend that potassium iodide be given in the immediate preoperative period for patients with Graves' disease who are undergoing thyroidectomy. Nonetheless, the evidence behind this recommendation is tenuous. The purpose of this study is to clarify the benefits of preoperative iodine administration from published comparative studies. DATA SOURCES: We searched PubMed, Embase, Cochrane, and CINAHL from 1980 to June 2018. REVIEW METHODS: Studies were included that compared preoperative iodine administration and no premedication before thyroidectomy. For the meta-analysis, studies were pooled with the random-effects model. RESULTS: A total of 510 patients were divided into the iodine (n = 223) and control (n = 287) groups from 9 selected studies. Preoperative iodine administration was significantly associated with decreased thyroid vascularity and intraoperative blood loss. Significant heterogeneity was present among studies. We found no significant difference in thyroid volume or operative time. Furthermore, the meta-analysis showed no difference in the risk of postoperative complications, including vocal cord palsy, hypoparathyroidism/hypocalcemia, and hemorrhage or hematoma after thyroidectomy. CONCLUSION: Preoperative iodine administration decreases thyroid vascularity and intraoperative blood loss. Nonetheless, it does not translate to more clinically meaningful differences in terms of operative time and postoperative complications. PubMed-ID: 30721111 http://dx.doi.org/10.1177/0194599819829052

Use of Delphian lymph node metastasis to predict central and lateral involvement in papillary thyroid carcinoma: A systematic review and meta-analysis. Clin Endocrinol (Oxf), 91(1):170-8. J. Huang, W. Sun, H. Zhang, P. Zhang, Z. Wang, W. Dong, L. He and T. Zhang. 2019. OBJECTIVE: Whether Delphian lymph node (DLN) metastasis is a reliable predictor of widespread lymph node metastasis in papillary thyroid carcinoma (PTC) remains controversial. This meta-analysis investigated the value of DLN metastasis for predicting central and lateral involvement in PTC. DESIGN AND METHODS: A literature

ESES Review of Recently Published Literature 2019-2 Page 6 of 71 search using the PubMed, SCIE and the Chinese National Knowledge Infrastructure (CNKI) databases was conducted. Two reviewers independently extracted data and evaluated the studies for inclusion. Fixed-effects and random-effects models were used to analyse the data based on their heterogeneity. A sensitivity analysis was performed, and publication bias was assessed using Begg's funnel plot and Egger's linear regression test. RESULTS: Data from 10 studies were analysed. The risk of central lymph node (CLN) metastasis was significantly higher in the DLN-positive group than in the DLN-negative group (OR = 9.05, 95% CI: 5.13-15.99) with moderate heterogeneity (P = 0.022, I(2) = 53.5%). The risk of lateral lymph node (LLN) metastasis was significantly higher in the DLN-positive group than in the negative group (OR = 10.88, 95% CI: 7.60-15.58), with low heterogeneity (P = 0.603, I(2) = 0.0%). Sensitivity analysis indicated that the results were stable and credible, and no publication bias was found. CONCLUSIONS: Delphian lymph node metastasis is valuable for predicting central and lateral compartment involvement in patients with PTC. The DLN of PTC patients should be dissected intraoperatively and sent for frozen section consultation. If the result is positive, the CLNs should be thoroughly dissected and the LLNs should be further evaluated. PubMed-ID: 30851206 http://dx.doi.org/10.1111/cen.13965

Efficacy and toxicity of sorafenib in the treatment of advanced medullary thyroid carcinoma: A systematic review and meta-analysis. Head Neck, 41(8):2823-9. H. G. Vuong, A. T. N. Ho, T. T. K. Tran, J. Capdevila, M. Benekli, T. Nakazawa, R. Katoh and T. Kondo. 2019. INTRODUCTION: The aim of this study is to investigate and summarize the treatment efficacy and adverse effects (AEs) of sorafenib in the treatment of metastatic medullary thyroid carcinomas (MTCs). METHODS: We included studies reporting the treatment efficacy or drug toxicity of sorafenib as a single therapeutic agent in MTCs. Pooled incidence and its 95% confidence interval (CI) for complete response, partial response (PR), stable disease (SD), and sorafenib-related AEs were calculated using random-effect model. RESULTS: Eight trials with 101 metastatic MTCs were included for meta-analyses. The overall PR and SD were 21% (95% CI = 9-33) and 58% (95% CI = 41-75), respectively. Hand-foot syndrome, diarrhea, alopecia, mucositis, skin rash, fatigue, and hypertension were the most commonly observed AEs. CONCLUSION: Our results show that sorafenib treatment has a modest effect and might be a candidate treatment in patients with metastatic MTCs who have failed other therapeutic regimens. PubMed-ID: 31162772 http://dx.doi.org/10.1002/hed.25832

Randomized controlled trials - None -

Consensus Statements/Guidelines - None -

Other Articles Objectively Measuring Observer Attention in Severe Thyroid-Associated Orbitopathy: A 3D Study. Laryngoscope, 129(5):1250-4. D. Liao, M. Ishii, H. M. Darrach, K. L. Bater, J. Smith, A. W. Joseph, R. S. Douglas, S. S. Joseph and L. E. Ishii. 2019. OBJECTIVE: Measure the attentional distraction of facial deformity related to severe thyroid-associated orbitopathy using three-dimensional (3D) images and eye-tracking technology. METHODS: Observers recruited at an academic tertiary referral center viewed 3D facial images of patients with severe thyroid-associated orbitopathy (TAO) and controls without TAO. An infrared eye-tracking monitor recorded their eye movements and fixations in real time. Multivariate Hotelling's analysis, followed by planned posthypothesis testing, was used to compare fixation durations for predefined regions of interest, including the eyes, nose, mouth, central triangle,

ESES Review of Recently Published Literature 2019-2 Page 7 of 71 and remaining face without the central triangle between severe TAO patients and controls. RESULTS: One hundred sixteen observers (mean age 26.4 years, 51% female) successfully completed the eye-tracking experiment. The majority of their attention was directed toward the central triangle (eyes, nose, mouth). On multivariate analysis, there were significant differences in the distribution of attention between control and severe TAO faces (T(2) = 49.37; F(5,922) = 9.8314, P < 0.0001). On planned posthypothesis testing, observers attended significantly more to the eyes (0.77 seconds, P < 0.0001, 95% confidence interval [CI], 0.51, 1.03 seconds) and less to the nose (-0.42 seconds, P < 0.0001, 95% CI, -0.23, -0.62 seconds) in severe TAO patients. There was no significant difference in time spent on the mouth, the total time spent on the central triangle, or time spent in the remaining face between the two groups. CONCLUSION: Severe TAO distracted observer attention toward the eyes compared to control patients. These data lend insight into how TAO may alter observers' perceptions of these patients. Future studies should investigate how these changes in observer gaze patterns may reflect the social perception of TAO patients. LEVEL OF EVIDENCE: NA Laryngoscope, 129:1250-1254, 2019. PubMed-ID: 30151919 http://dx.doi.org/10.1002/lary.27447

Detection at Public Facilities of (131)I in Patients Treated for Differentiated Thyroid Cancer: Frequency, Sites, Management by Security Agents, and Physician Documentation Recommended for Patients. J Nucl Med, 60(5):638-43. A. Bikas, D. Wu, E. Bethancourt, M. Orquiza, G. Bloom, K. D. Burman, L. Wartofsky and D. Van Nostrand. 2019. Patients treated with (131)I may be identified at security checkpoints at various public facilities. The objective of this survey was to determine the frequency of detection, the spectrum of public facilities, the various methods of management of the situation by security agents, and the spectrum of physician documentation for patients regarding their (131)I therapy. Methods: Data were tabulated from a Thyroid Cancer Survivors' Association, Inc., survey emailed to approximately 15,000 associates and available online from December 2013 to December 2014. Responses were tabulated from respondents who reported that they were 18 y old or older, had received at least 1 (131)I treatment for differentiated thyroid cancer, and were responding regarding their last (131)I treatment. Results: Of 621 respondents, 595 reported an attempt to pass through a public facility security checkpoint. Of these 595 patients, approximately 10% (57) were identified as being radioactive. The facility reported by 43 respondents was an airport for 35% (15), border crossing for 33% (14), government building for 19% (8), shopping mall for 7% (3), train station for 5% (2), and steel recycling plant for 2% (1). The security agent's management of the situation reported by 47 respondents included questioning for 81% (38), allowing them to proceed without a change in travel plans for 57% (27), requesting documentation of the therapy for 55% (26), rescanning for 55% (26), calling a member of the treating team for validation for 17% (8), "strip" searching for 4% (2), detaining such that a change in travel plans was required for 6% (3), and prohibiting continued travel for 4% (2). The period of detainment reported by these 47 respondents was less than 30 min for 57% (27), 30 to less than 60 min for 21% (10), 1 to less than 1.5 h for 15% (7), 1.5 to less than 2 h for 2% (1), 2-4 h for 0% (0), and greater than 4 h for 4% (2). Data regarding physician documentation are presented. Conclusion: The detection of radioactivity at a variety of security checkpoints at public facilities after(131)I therapy occurred in approximately 10% of respondents. Travel inconvenience is not infrequent and may require alteration of travel plans. Physicians should take steps to ensure that patients not only have appropriate documentation of their (131)I therapy with them but also have instructions regarding how security agents may verify their (131)I therapy. PubMed-ID: 30361377 http://dx.doi.org/10.2967/jnumed.118.213256

Still Perfecting Radioiodine in Thyroid Cancer, After All These Years. J Clin Endocrinol Metab, 104(5):1655-7. L. J. Wirth. 2019. PubMed-ID: 30462299 http://dx.doi.org/10.1210/jc.2018-02437

Detection of RET rearrangements in papillary thyroid carcinoma using RT-PCR and FISH techniques - A molecular and clinical analysis. Eur J Surg Oncol, 45(6):1018-24. T. J. Musholt, J. I. Staubitz, R. J. Antonio Camara, P. B. Musholt, D. Humberg, E. Springer and A. Schad. 2019. INTRODUCTION: Oncogenic BRAF and RAS mutations as well as multiple known (and yet unknown) RET fusion oncogenes comprise the majority of causative molecular alterations in papillary thyroid carcinoma (PTC). Apparently "mutation-negative" PTCs encompass a heterogenous group impeding analysis of prognostic significance of underlying genetics. MATERIAL AND METHODS: BRAF wild type PTC tissue of 56 patients was

ESES Review of Recently Published Literature 2019-2 Page 8 of 71 analyzed using two established methods: hybrid-specific RT-PCR for the predominant rearrangement RET/PTC1 and fluorescent in situ hybridization (FISH). Clinical features of the cases with and without RET rearrangement were compared (patient age, gender, tumor size, focality, lymph node affection, and iodine avidity). RESULTS: RT-PCR revealed RET/PTC1 rearrangements in five of 56 tumors (9%). FISH confirmed these, and identified four additional RET rearrangements (9/56; 16%). Loss of the iodine avidity only occurred in cases of RET/PTC hybrids (7/9 tumors), but not in RET/PTC-negative PTCs (0/41 tumors with available uptake information; p=0.029). The risk to develop lymph node metastases was eight times higher in presence of RET rearrangements (p=0.010). CONCLUSIONS: FISH analysis, in contrast to hybrid-specific RT-PCR, revealed infrequent and unknown RET fusion genes. The presence of RET rearrangements was associated with a significantly elevated risk to develop iodine refractory disease and lymph node metastases. Of note, significant clinical discrimination was only achievable when taking the FISH results into account; differences would have been missed when using the RT-PCR method only. Increasing evidence of the clinical impact of RET/PTC- positivity may influence the decision on the extent of surgical resection, especially on lymph node dissection, in PTCs. PubMed-ID: 30472213 http://dx.doi.org/10.1016/j.ejso.2018.11.009

Poorly differentiated thyroid cancer in the context of the revised 2015 American Thyroid Association Guidelines and the Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System (eighth edition). Clin Endocrinol (Oxf), 91(2):331-9. A. Walczyk, J. Kopczynski, D. Gasior-Perczak, I. Palyga, A. Kowalik, M. Chrapek, M. Hejnold, S. Gozdz and A. Kowalska. 2019. OBJECTIVE: Poorly differentiated thyroid cancer (PDTC) is a rare, but aggressive thyroid cancer (TC) and a main cause of death from non-anaplastic follicular cell-derived TC. Assessing the risk of PDTC-related death and the risk of recurrence is important for clinicians. The recent American Thyroid Association (ATA) 2015 guidelines and the updated 8th edition of the American Joint Committee on Cancer/Tumor-Node-Metastasis (AJCC/TNM) staging system should support clinicians in the management approach to PDTC patients. PATIENTS: Forty-six consecutive PDTC patients treated in a single oncologic centre, 2000-2017. MEASUREMENTS: Retrospective analysis of TNM stage, initial risk, response-to-therapy categories, follow-up and final disease status incorporating the ATA 2015 criteria and the 8th AJCC/TNM staging system. Disease-specific survival (DSS) using the Kaplan-Meier method. RESULTS: Of the 46 PDTC 21 (45.6%) were ATA high risk (HR), 22 (47.8%), 17 (37%) and seven (15.2%) were TNM stages I, II, and III-IV, respectively. During a median follow-up of 55.5 months, two (4.3%) patients were recurrent, 18 (39.1%) died of PDTC. The 5-/10-year DSS were 65/57%, respectively. According to the AJCC/TNM, the 5-/10-year DSS of I, II, and III-IV stage were 83/83%; 77/55%, and 0/0%, respectively. According to the 2015 ATA initial risk, the 5-/10-year DSS were 91/72% for ATA intermediate risk and 38/38% for ATA HR patients. CONCLUSIONS: In PDTC patients, the updated AJCC/TNM staging system accurately predicts a high risk of death in stage III-IV, whereas it seems to be inadequate for predicting a very low or low risk of death expected for differentiated TC in stage I-II. The ATA initial HR may be also used to predict a high risk of PDTC-related death. PubMed-ID: 30525210 http://dx.doi.org/10.1111/cen.13910

Diagnostic value of computed tomography combined with ultrasonography in detecting cervical recurrence in patients with thyroid cancer. Head Neck, 41(5):1206-12. E. K. Hong, J. H. Kim, J. Lee, R. E. Yoo, S. C. Kim, M. J. Kim, Y. J. Park, E. J. Chung, Y. J. Ryu, E. Lee, K. M. Kang, T. J. Yun, S. H. Choi and C. H. Sohn. 2019. BACKGROUND: To determine the diagnostic role of CT added to ultrasound for the diagnosis of recurrent differentiated thyroid cancer (DTC) and to evaluate potential benefits for patients. METHODS: A total of 193 patients with recurrent DTC were retrospectively included. The diagnostic performances of ultrasound and combination of ultrasound and CT (ultrasound/CT) in detecting recurrence were compared. Benefits of CT were assessed based on the presence of any recurrence detected only with additional CT. RESULTS: In detecting cervical recurrence, ultrasound/CT showed higher sensitivity (P = .001) and lower specificity (P < .001) than ultrasound alone, overall resulting in higher area under the curve (P < .001). Seventy-nine patients (40.9%) benefited from additional CT in detecting recurrence. CONCLUSION: For reoperation of cervical recurrence in patients with DTC, addition of CT to ultrasound offers better surgical planning by enhancing detection of recurrent cancers that were overlooked with ultrasound alone.

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PubMed-ID: 30552732 http://dx.doi.org/10.1002/hed.25538

Recurrent laryngeal nerve paralysis after thyroid cancer surgery and intraoperative nerve monitoring. Laryngoscope, 129(8):1954-60. K. Mizuno, M. Takeuchi, Y. Kanazawa, M. Kitamura, K. Ide, K. Omori and K. Kawakami. 2019. OBJECTIVES/HYPOTHESIS: This study aimed to investigate the risk of postoperative recurrent laryngeal nerve paralysis (RLNP) with and without the use of intraoperative nerve monitoring (IONM) during thyroid cancer surgery. STUDY DESIGN: Retrospective cohort study. METHODS: This study utilized a nationwide claims database in Japan. Patients who underwent thyroid cancer surgery with and without IONM were included, and postoperative RLNP incidence was compared. RESULTS: The study included 5,804 patients. Multivariable logistic regression analysis revealed that use of IONM was not associated with increased RLNP risk (odds ratio: 1.15; 95% confidence interval: 0.67-1.96). There was no significant effect on RLNP prevention when stratified by tumor or nodal classification. Rather, the patients who had T4 or N1b classifications who received IONM had higher incidences of RLNP. CONCLUSIONS: Use of IONM did not significantly reduce the risk of RLNP. The results for the T4 and N1b populations may be explained by indication bias or unmeasured confounders. LEVEL OF EVIDENCE: NA Laryngoscope, 129:1954-1960, 2019. PubMed-ID: 30582628 http://dx.doi.org/10.1002/lary.27698

Fifty Years After the First Description, MEN 2B Syndrome Diagnosis Is Still Late: Descriptions of Two Recent Cases. J Clin Endocrinol Metab, 104(7):2520-6. R. Elisei, A. Matrone, L. Valerio, E. Molinaro, L. Agate, V. Bottici, D. Viola, C. Giani, V. Cappagli, F. Latrofa, G. Materazzi, L. Torregrossa, C. Ugolini, F. Basolo and C. Romei. 2019. BACKGROUND: Multiple endocrine neoplasia type 2B (MEN 2B) is a very rare syndrome characterized by a very peculiar phenotype with mucosal neuromas, marfanoid habitus, and bumpy lips associated with medullary thyroid cancer (MTC) and pheochromocytoma (PHEO). Although the syndrome was first described 50 years ago, it is still diagnosed too late, when the MTC is metastatic and frequently when the PHEO has already developed. CASE PRESENTATIONS: We report on two cases of MEN 2B that were diagnosed too late, preventing a cure. The cases involve two females who were 25 and 12 years old. Both were previously treated for congenital skeletal abnormalities; however, despite their bumpy lips and mucosal neuromas, MEN 2B syndrome was not recognized. When they arrived at our center for both the presence of thyroid nodules and elevated serum calcitonin values, the MTC was already metastatic, and the older patient had already developed a bilateral PHEO. After 3 years and 1 year of follow-up, the two patients are still alive but with persistent structural and biochemical disease. DISCUSSION: These two cases show that knowledge of this syndrome is still insufficient and that the lack of knowledge impairs the ability to obtain an early diagnosis and cure. Because most patients with MEN 2B have no familial history, the only way to ensure a timely diagnosis is to recognize the MEN 2B phenotype on a clinical basis. PubMed-ID: 30597074 http://dx.doi.org/10.1210/jc.2018-02102

Incidental thyroid papillary microcarcinoma: survival and follow-up. Laryngoscope, 129(7):1722-6. S. Gorostis, T. Raguin, O. Schneegans, C. Takeda, C. Debry and A. Dupret-Bories. 2019. OBJECTIVES/HYPOTHESIS: The aim was to study the survival of incidental thyroid papillary microcarcinoma patients treated with surgery for benign thyroid disease to validate absence of oncological follow-up and reduce unnecessary health expenses. STUDY DESIGN: Retrospective cohort study. METHODS: We analyzed patient's files and interviewed 252 patients by telephone whose cases were submitted to the multidisciplinary meeting of thyroid pathology in Strasbourg, France, for incidental thyroid papillary microcarcinoma without clinical lymph node involvement, between January 1996 and December 2012. RESULTS: Thirteen patients (5.8%) died while the data were being collected; however, none of the deaths were due to the thyroid pathology, and no patients showed signs of relapse of the thyroidectomy or cervical lymph node level. CONCLUSIONS: Our retrospective study shows that patients with incidental localized thyroid papillary microcarcinoma who underwent surgery without radioactive iodine treatment have an identical survival compared to the general population at the same age to validate absence of oncological follow-up and reduce unnecessary health expenses. LEVEL OF EVIDENCE: 3 Laryngoscope, 129:1722-1726, 2019. PubMed-ID: 30618067 http://dx.doi.org/10.1002/lary.27664

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Perioperative magnesium levels in total thyroidectomy and relationship to hypocalcemia. Head Neck, 41(6):1713-8. C. Brophy, R. Woods, M. S. Murphy and P. Sheahan. 2019. BACKGROUND: We have previously shown an association between hypomagnesemia and hypocalcemia after thyroidectomy. However, little is known regarding the trend in magnesium levels in the days after thyroidectomy. Our objective was to study this trend in magnesium levels after thyroidectomy. METHODS: Retrospective review of 173 thyroidectomies with analysis of calcium and magnesium levels on postoperative day 1 (POD1) and POD2. RESULTS: Across the whole group, there was a highly significant decline in magnesium levels between preoperative (0.87 +/- 0.06 mmol/L), POD1 (0.80 +/- 0.07 mmol/L), and POD2 (0.78 +/- 0.08 mmol/L) (P < .0001). The magnitudes of the magnesium level declines were significantly higher, and the absolute magnesium levels on POD1 and POD2 significantly lower, in patients developing hypocalcemia (n = 69). CONCLUSION: Magnesium levels after total thyroidectomy demonstrate a downward trajectory which persists through POD2 and is highly correlated with hypocalcemia. Further study is required to determine if magnesium replacement can alter the course of hypocalcemia in hypocalcemic patients after total thyroidectomy. PubMed-ID: 30628752 http://dx.doi.org/10.1002/hed.25644

Significant racial differences in the incidence and behavior of the follicular variant of papillary thyroid carcinoma. Head Neck, 41(5):1403-11. V. Mehta, T. J. Ow, S. Kim, T. Tharakan, B. Schiff, R. V. Smith and H. In. 2019. BACKGROUND: Increased detection of papillary thyroid cancer (PTC) has led to overtreatment of the largely indolent follicular variant (fvPTC). To guide management of non-aggressive lesions, we investigated whether race predicts PTC variant and tumor behavior. METHODS: Analysis of 258 973 patients from the National Cancer Database diagnosed with PTC in 2004-2014. Clinical and tumor information was compared by race. Multivariate logistic regression was used to predict fvPTC, extrathyroidal extension (ETE), and lymph node metastasis (LNM) of fvPTC. RESULTS: Blacks had the highest fvPTC rate (40% vs white 30%, Hispanic 26%, Asian 25%, P < .001). Blacks had higher odds of fvPTC (aOR = 1.33, 95% CI: 1.28-1.37) and lower odds of ETE than whites (aOR = 0.90, 95% CI: 0.82-0.99) (P < .001). Hispanics and Asians had lower odds of fvPTC (aOR = 0.89, 95% CI: 0.86-0.92 and aOR = 0.81, 95% CI: 0.79-0.84) and higher odds of LNM and ETE than whites (P < .001). CONCLUSIONS: Racial disparities in fvPTC incidence and behavior should be considered to optimize diagnosis and treatment planning. PubMed-ID: 30652370 http://dx.doi.org/10.1002/hed.25596

Neck and Shoulder Motor Function following Neck Dissection: A Comparison with Healthy Control Subjects. Otolaryngol Head Neck Surg, 160(6):1009-18. E. M. Gane, S. M. McPhail, A. L. Hatton, B. J. Panizza and S. P. O'Leary. 2019. OBJECTIVE: To compare the neck and shoulder motor function of patients following neck dissection, including comparison with a group of healthy volunteers. STUDY DESIGN: Cross-sectional study. SETTING: Two tertiary hospitals in Brisbane, Australia. SUBJECTS AND METHODS: Participants included patients 0.5 to 5 years after unilateral nerve-sparing neck dissection and healthy control subjects. Demographic and clinical information was collected with cervical and shoulder motor function measures (scapular resting position, active range of motion, and isometric muscle strength). Differences between groups were examined via regression analyses that included statistical adjustment for the potential effect of age, sex, body mass index, and other disease-related variables. RESULTS: The 57 patients (68%, men; median age, 62 years) were typically older than the 34 healthy controls (47%, men; median age, 46 years). There were no differences between types of nerve-preserving neck dissection for any of the motor function measures. When adjusted for age, sex, and body mass index, healthy volunteers (vs patients) had significantly greater cervical range (eg, extension coefficient [95% CI]: 11.04 degrees [4.41 degrees -17.67 degrees ]), greater affected shoulder range (eg, abduction: 16.64 degrees [1.19 degrees -31.36 degrees ]), and greater isometric strength of the cervical flexors (eg, men: 4.24 kgf [1.56-6.93]) and shoulder flexors (eg, men: 8.00 kgf [1.62-14.38]). CONCLUSIONS: Strength and flexibility of the neck and shoulder are impaired following neck dissection in comparison with healthy controls. Clinicians and researchers are encouraged to consider the neck-and the neck dissection as a whole-as a source of motor impairment for these patients and not just the status of the accessory nerve. PubMed-ID: 30665326 http://dx.doi.org/10.1177/0194599818821885

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A Population-Based Study on NIFTP Incidence and Survival: Is NIFTP Really a "Benign" Disease? Ann Surg Oncol, 26(5):1376-84. A. Eskander, S. F. Hall, M. Manduch, R. Griffiths and J. C. Irish. 2019. BACKGROUND: This study aimed to determine the incidence of noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP) in Ontario, Canada and the predictors of disease-free survival (DFS) by comparing patients with follicular variant papillary thyroid cancer (FVPTC) and patients with NIFTP. METHODS: This population-based retrospective cohort study included all patients who had definitive surgery for well- differentiated thyroid cancer (WDTC) in Ontario, Canada between 1990 and 2001 and were followed until 2014. A conservative decision rule was applied to subtype-select FVPTCs into NIFTPs after pathology report review. The primary outcome was DFS, for which Cox proportional hazard regression analysis was performed to assess the impact of FVPTC versus NIFTP. RESULTS: At pathology re-review of the 725 FVPTC cases, 318 were reclassified as potential NIFTP. The median follow-up time was 15.3 years for the entire cohort and 15.9 years for those alive at the last follow-up visit. Disease failure occurred for 109 patients, 79 (19.4%) in the FVPTC group and 30 (9.4%) in the NIFTP group (p < 0.01). This effect was sustained in the multivariable analysis, with FVPTC showing significantly worse DFS than NIFTP (hazard ratio, 1.84; 95% confidence interval, 1.17-2.89). After recategorization of certain FVPTCs into NIFTPs, the findings showed that NIFTP accounted for 16.8% (1.461/8.699 per 100,000) of all WDTCs. CONCLUSION: The disease failure rate for NIFTP was 9.4%. The NIFTP diagnosis is challenging for the pathologist and may make tumor behavior difficult to predict for this entity. Caution should be used in the management of patients with an NIFTP. PubMed-ID: 30690683 http://dx.doi.org/10.1245/s10434-019-07187-0

Follow-up of large thyroid nodules without surgery: Patient selection and long-term outcomes. Head Neck, 41(6):1696-702. O. Cohen, T. Zornitzki, T. R. Yarkoni, Y. Lahav, D. Schindel, D. Halperin and M. Yehuda. 2019. BACKGROUND: The management of large thyroid nodules remains controversial. Mandatory resection is recommended by some authors. METHODS: All patients with thyroid nodules >/=3 cm between January 2009 and January 2013 were followed until August 2017. Follow-up data were collected using an integrated hospital- community system. RESULTS: A total of 141 nodules were included. Of these, 37/141 (26%) nodules were initially referred to surgery, resulting in a 32% malignancy rate (12/37). The remaining 104/141 (74%) were referred to follow-up. During the follow-up period, 24 additional operations were done, resulting in a 4% malignancy rate (1/24). An indication of nonbenign cytology was significantly associated with malignancy compared with other indications. Median follow-up was 53.5 months. No patient developed regional or distal diseases. The mean change in nodule size during the follow-up period was a 7% reduction, with no significant trend of change over time. CONCLUSION: Careful patient selection based on clinical, sonographic, and cytologic features can reduce diagnostic surgery allowing for safe follow-up of large thyroid nodules without surgery. PubMed-ID: 30694007 http://dx.doi.org/10.1002/hed.25641

Dedicated neck (18) F-FDG PET/CT: An additional tool for risk assessment in thyroid nodules at ultrasound intermediate risk. Clin Endocrinol (Oxf), 90(5):737-43. P. Trimboli, A. Piccardo, M. Alevizaki, C. Virili, M. Naseri, S. Sola, G. Paone, G. Russ and L. Giovanella. 2019. BACKGROUND: Several ultrasound (US) risk stratification systems have been proposed for the assessment of thyroid nodules, and their performance was shown as good. However, the rate of nodules assessed at intermediate risk is not negligible and whether they should be submitted or not to further examination is still under debate. The present study aimed to evaluate the reliability of (18) F-FDG PET/CT in stratifying the risk of malignancy in these lesions. METHODS: Two institutions participated to this retrospective study in which a dedicated (18) F-FDG PET/CT was proposed to patients having a thyroid nodule with US assessment of EU- TIRADS 4 or 5. (18) F-FDG PET/CT did not influence the diagnostic and therapeutic decision. Histology was the gold standard for all patients. RESULTS: Ninety-three patients were included for the study with 48 EU-TIRADS 4 and 45 EU-TIRADS 5 nodules. Of these, 26 underwent thyroidectomy following FNAC suspicious for or consistent with malignancy, 38 for inconclusive cytology, 27 because of large goitre and 2 for high-risk lesion at US. At histology, 35 carcinomas and 58 benign lesions were found. Cancer prevalence was 16.7% in EU- TIRADS 4 and 60% in EU-TIRADS 5. Overall, (18) F-FDG PET/CT was positive in 33/35 cancers (94.5% sensitivity) and negative in 31/58 benign lesions (53.4% specificity). When considering only EU-TIRADS 4, (18) F-FDG PET/CT was positive in 7/8 cancers and negative in 20/40 benign lesions; among these, there were 36

ESES Review of Recently Published Literature 2019-2 Page 12 of 71 cases with FNAC indication according to dimensional cut-off (ie >1.5 cm), and (18) F-FDG PET/CT showed 85.7% sensitivity and 41.4% specificity. CONCLUSIONS: (18) F-FDG PET/CT may have a role in stratifying the cancer risk of thyroid nodules with an intermediate ultrasound assessment. More specifically, thyroid lesions classified as EU-TIRADS 4 and with no (18) F-FDG uptake could be ruled out from further examination, similar to other anamnestic and clinical suspicious factors of patients. Further prospective and cost-effectiveness studies are needed. PubMed-ID: 30740757 http://dx.doi.org/10.1111/cen.13949

High Titers of Thyrotropin Receptor Antibodies Are Associated With Orbitopathy in Patients With Graves Disease. J Clin Endocrinol Metab, 104(7):2561-8. G. J. Kahaly, C. Wuster, P. D. Olivo and T. Diana. 2019. CONTEXT: Serum TSH receptor autoantibody (TSH-R-Ab) is a biomarker of Graves disease (GD). Studies have shown that the levels of this TSH-R-Ab have clinical significance. OBJECTIVE: To differentiate between thyroidal GD only and Graves orbitopathy (GD + GO). DESIGN: Controlled, follow-up study. SETTING: Academic tertiary referral center for GD + GO. SUBJECTS: Sixty patients with GD, GD + GO, and controls. INTERVENTION: Serial serum dilution analyses with six automated, ELISA, and cell-based assays for TSH-R-Ab. MAIN OUTCOME MEASURE: Differentiation among GD phenotypes. RESULTS: All undiluted samples of hyperthyroid-untreated GD patients were positive with the six assays but became negative at dilution 1:9 in four of six assays. In contrast, all undiluted samples of hyperthyroid-untreated GD + GO patients remained positive up to dilution 1:81, P < 0.001. At high dilutions 1:243, 1:729, 1:2187, and 1:6561, the rate of stimulating TSH-R- Ab positivity in the bioassay for GD + GO patients was 75%, 35%, 5%, and 0%, respectively (all P < 0.001). The five ELISA and/or automated assays confirmed this marked difference of anti-TSH-R-Ab detection between GD- only and GD + GO. In comparison, the baseline-undiluted samples of GD vs GD + GO showed an overlap in the ranges of TSH-R-Ab levels. Subsequent to 12-month methimazole treatment, samples from euthyroid GD + GO patients were still TSH-R-Ab positive at the high dilution of 1:243. In contrast, all GD samples were negative already at dilution 1:3. A GD patient with TSH-R-Ab positivity at dilution 1:729 developed de novo GO. CONCLUSIONS: TSH-R-Ab titers, as determined by dilution analysis, significantly differentiate between GD and GD + GO. PubMed-ID: 30753531 http://dx.doi.org/10.1210/jc.2018-02705

Robotic transoral thyroidectomy: Total thyroidectomy and ipsilateral central neck dissection with da Vinci Xi Surgical System. Head Neck, 41(5):1536-40. H. K. Kim, D. Park and H. Y. Kim. 2019. BACKGROUND: Transoral approach for thyroidectomy draws attention recently among the thyroid surgeons, with the merits of cosmetic outcomes and minimal flap dissection. The aim of this study is to demonstrate the details and the steps of transoral robotic thyroidectomy. METHODS: We made three incisions in the gingival- buccal sulcus for three 8-mm intraoral ports: one inverted U-shaped 1-cm midline incision approximately 2 cm above the frenulum, and two 0.5-cm lateral incisions near the commissure of lips. An additional 8-mm axilla port was inserted for countertraction and later drain insertion. RESULTS: Right thyroid lobectomy, ipsilateral central neck dissection, and left thyroid lobectomy were performed with preserving recurrent laryngeal nerves and parathyroid glands. There was no development of transient or permanent hypoparathyroidism, vocal cord palsy, postoperative bleeding, or surgical site infection. CONCLUSION: Transoral robotic total thyroidectomy and ipsilateral central neck dissection using the da Vinci Xi Surgical System are feasible and safe. PubMed-ID: 30758104 http://dx.doi.org/10.1002/hed.25661

Unique mutation patterns in anaplastic thyroid cancer identified by comprehensive genomic profiling. Head Neck, 41(6):1928-34. S. A. Khan, B. Ci, Y. Xie, D. E. Gerber, M. S. Beg, S. I. Sherman, M. E. Cabanillas, N. L. Busaidy, B. A. Burtness, A. M. Heilmann, M. Bailey, J. S. Ross, D. J. Sher and S. M. Ali. 2019. INTRODUCTION: Anaplastic thyroid cancer (ATC) is a highly aggressive thyroid cancer. Those ATC with genomic alterations (GAs) in TSC2, ALK, and BRAF may respond to targeted therapies. METHODS: Comprehensive genomic profiling on 90 ATC specimens identified base substitutions, short insertions and deletions, amplifications, copy number alterations, and genomic rearrangements in up to 315 cancer-related genes and 28 genes commonly rearranged in cancer. RESULTS: Median patient age was 65 (range, 33-86)

ESES Review of Recently Published Literature 2019-2 Page 13 of 71 years, 50 patients were male. There was a mean of 4.2 GA per case, range 1-11. The most common GA were TP53 (66%), BRAF (34%), TERT (32%), CDKN2A (32%), and NRAS (26%). BRAF V600E and NRAS/HRAS/KRAS alteration were mutually exclusive. BRAF, CDKN2A, PIK3CA, and JAK2 were more frequent in patients >70 years of age; while myc, PTEN, and NRAS were more common in those

Recurrent Laryngeal Nerve Reinnervation in Rats Posttransection: Neurotrophic Factor Expression over Time. Otolaryngol Head Neck Surg, 161(1):111-7. M. B. Montalbano, I. Hernandez-Morato, L. Tian, V. X. Yu, S. Dodhia, J. Martinez and M. J. Pitman. 2019. OBJECTIVE: Recurrent laryngeal nerve (RLN) injury causes vocal fold paralysis from which functional recovery is typically absent due to nonselective reinnervation. This study investigates expression of axon guidance cues and their modulators relative to the chronology of reinnervation by examining the expression of glial-derived neurotrophic factor (GDNF), netrin 1, and laminin 111 (LAMA1) in nonpooled laryngeal muscles. This study is the first to describe the post-RLN injury expression pattern of LAMA1, a target of particular interest as it has been shown to switch netrin 1-mediated growth cone attraction to repulsion. STUDY DESIGN: Animal experiment (rat model). SETTING: Basic science laboratory. METHODS: The right RLNs of 64 female Sprague- Dawley rats were transected, with sacrifice at 1, 3, 7, 21, 28, and 56 days postinjury (DPI). Single-animal messenger RNA was isolated from the ipsilateral posterior cricoarytenoid (PCA), lateral thyroarytenoid (LTA), and medial thyroarytenoid (MTA) for quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Immunostaining for LAMA1 expression was performed in the same muscles. RESULTS: LAMA1 was elevated in the PCA at 3 to 56 DPI, LTA at 7 DPI, and MTA at 14 and 28 DPI. This correlates with the chronology of laryngeal reinnervation. Using a new protocol, single-animal muscle qRT-PCR possible and expression results for GDNF and netrin 1 were similar to previous pooled investigations. CONCLUSION: Reliable qRT-PCR is possible with single rat laryngeal muscles. The expression of netrin 1 and LAMA1 is chronologically coordinated with muscle innervation in the LTA and MTA. This suggests that LAMA1 may influence netrin 1 to repel axons and delay LTA and MTA reinnervation. PubMed-ID: 30776993 http://dx.doi.org/10.1177/0194599819831289

[30% downstaging by a new TNM stage classification for differentiated thyroid cancer]. Chirurg, 90(5):415. H. Dralle. 2019. PubMed-ID: 30778606 http://dx.doi.org/10.1007/s00104-019-0819-2

Cost for treatment and follow-up of thyroid cancer increases according to the severity of disease. Head Neck, 41(7):2376-9. S. Y. Kim, S. M. Kim, H. Chang, B. W. Kim, Y. S. Lee, S. S. Kwon, H. Shin, H. S. Chang and C. S. Park. 2019. BACKGROUND: The aim of this study was to provide an analysis of thyroid cancer-related health care costs over a 5-year period, according to the extent of thyroid surgery. METHODS: The study included 33 patients from our institutional database who underwent thyroid cancer surgery in 2010. Patients were divided into four groups based on surgical extent: (1) hemithyroidectomy, (2) total thyroidectomy, (3) total thyroidectomy with ipsilateral radical neck dissection, and (4) total thyroidectomy with bilateral radical neck dissection and mediastinal dissection. Costs for admission and outpatient follow-up for 5 years were analyzed. RESULTS: Costs for outpatient follow-up and admission, and overall cost increased with increasing stage of disease and increasing extent of thyroid surgery. Patients who underwent only hemithyroidectomy had the lowest costs for outpatient follow-up and admission, as well as the lowest overall cost. CONCLUSION: Over the 5-year follow-up period, surgery performed at an early disease stage was the most cost-effective. PubMed-ID: 30784141 http://dx.doi.org/10.1002/hed.25706

Stimulated Thyroglobulin and Thyroglobulin Reduction Index Predict Excellent Response in Differentiated Thyroid Cancers. J Clin Endocrinol Metab, 104(8):3462-72. B. Barres, A. Kelly, F. Kwiatkowski, M. Batisse-Lignier, G. Fouilhoux, B. Aubert, F. Dutheil, I. Tauveron, F.

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Cachin and S. Maqdasy. 2019. CONTEXT: Despite its good prognosis, differentiated thyroid cancer (DTC) is characterized by high rates of disease persistence and recurrence. Estimation of long-term remission (excellent response) thanks to specific parameters could help to individualize the active surveillance schedule. OBJECTIVE: Evaluation of the ability of stimulated thyroglobulin (Tg) and Tg reduction index (TRI) to predict long-term remission in patients with DTC managed by thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND INTERVENTIONS: Observational retrospective study of 1093 patients treated for DTC between 1995 and 2010. Preablation stimulated thyroglobulin (presTg) was measured under thyroid hormone withdrawal just before RAI. Recombinant human TSH-stimulated thyroglobulin (sTg) was measured at first evaluation of the initial management 6 to 12 months after RAI. TRI was calculated based on pre-Tg and sTg. RESULTS: After univariate and multivariate analyses, lymph node invasion (N1, OR = 2.08; 95% CI, 1.19 to 3.64), presTg (OR = 4.04; 95% CI, 2.56 to 6.38), sTg (OR = 2.62; 95% CI, 2.05 to 3.34), and TRI (OR = 0.43; 95% CI, 0.21 to 0.88) were identified as independent prognostic factors influencing the rate of disease persistence or recurrence after the initial management. Receiver operating characteristic analysis identified presTg cutoff (<10 microg/L) to predict excellent response, with a negative predictive value of 94%, and validated for higher stages (T3/T4, N1). Furthermore, sTg <1 microg/L predicts excellent response. TRI >60% for the entire cohort and 62.5% for locally advanced disease (T3/T4, N1) was sensitive predictor for excellent response. CONCLUSION: This study identifies presTg, sTg, and TRI as highly sensitive predictors of excellent response in patients with DTC and subsequently disease-free status. The cutoff of such parameters is also adapted for patients with higher tumor stages (T3/T4, N1). PubMed-ID: 30785995 http://dx.doi.org/10.1210/jc.2018-02680

Thyroidectomy in octogenarians is not associated with poorer postoperative outcomes. Head Neck, 41(8):2500-6. E. H. Wong, M. Smith, B. Fish, P. Jani, C. E. Palme, M. C. Smith and F. Riffat. 2019. BACKGROUND: The elderly represents one of the most rapidly growing subsets of the population. This population experiences a higher incidence of thyroid pathology. However, there are concerns that the elderly also experiences increased perioperative complications and are poor candidates for thyroidectomy. METHODS: Patients who underwent thyroidectomy over the age of 80 years at three tertiary head and neck units were included. Data regarding age, sex, presenting symptoms, comorbidities, preoperative investigations, type of surgery, postoperative complications, and final thyroid pathology were retrieved from hospital records. RESULTS: Of a total of 39 patients (69% women, mean age 83.1), the majority (40.1%) presented with a combination of symptoms: shortness of breath, feeling of pressure in the neck, dysphagia, or tiredness. Two (5.1%) were asymptomatic. Low rates of postoperative complications were encountered and were minor (n = 5). No intensive care unit admissions or mortality was experienced. CONCLUSION: Thyroid surgery in octogenarians carries an acceptable complication profile. PubMed-ID: 30828928 http://dx.doi.org/10.1002/hed.25712

Microscopic positive margins strongly predict reduced disease-free survival in pT4a papillary thyroid cancer. Head Neck, 41(8):2549-54. E. Abraham, D. Roshan, B. Tran, S. Graham, C. Lehane, J. Wykes, P. Campbell and A. Ebrahimi. 2019. BACKGROUND: Although microscopic positive margins appear to have no independent prognostic impact in papillary thyroid cancer (PTC), this may not be the case in pT4a tumors. METHODS: Retrospective analysis of 610 patients with PTC, 39 with pT4a tumors, to determine if microscopic positive margins impact disease-free survival (DFS) in pT4a PTC. RESULTS: On univariate analysis, microscopic positive margins were not associated with reduced DFS in patients with no extrathyroidal extension (ETE) (hazard ratio [HR], 1.7; P = 0.32), microscopic ETE (HR, 1.6; P = 0.36), or macroscopic ETE limited to strap muscles (HR, 1.2; P = 0.87). In contrast, microscopic positive margins were associated with reduced DFS in T4a disease (HR, 4.1; P = 0.04). Disease recurrence was nodal, distant, or biochemical, and did not occur directly at the site of positive margins. CONCLUSION: Although microscopic positive margins do not influence DFS in the majority of patients with PTC, they are associated with a fourfold increased risk of recurrence in pT4a disease. PubMed-ID: 30860642 http://dx.doi.org/10.1002/hed.25730

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Early low-dose rituximab for active thyroid eye disease: An effective and well-tolerated treatment. Clin Endocrinol (Oxf), 91(1):179-86. E. A. Insull, Z. Sipkova, J. David, H. E. Turner and J. H. Norris. 2019. BACKGROUND: Thyroid eye disease (TED) is an autoimmune inflammatory disease that can be disfiguring and potentially sight threatening. Suppression of inflammation in active disease can reduce the risk of visual loss and limit long-term sequelae. Current management involves inflammation suppression using glucocorticoids. The aim of this study was to evaluate the efficacy of early disease intervention with targeted immunomodulatory therapy to alter disease course. This paper reports the efficacy of low-dose rituximab in reducing clinical activity in TED in a small population. METHODS: A retrospective audit of consecutive patients with active TED managed primarily with a 100 mg rituximab infusion. Further glucocorticoid or steroid-sparing agents were prescribed if clinically indicated. Clinical activity score, VISA overall severity score and Oxford Quality of Life score were recorded at each visit as well as TSH receptor antibody levels (TRAb), B cell subsets and adverse reactions. RESULTS: Twelve patients had mean follow-up of 6.3 months. Clinical activity scores significantly decreased (mean score 5.08 to 1.58; P < 0.001), VISA overall severity scores reduced by 50% from 12 to 6, P < 0.001 and the mean cumulative dose of IV methylprednisolone was 2.3 g. 100 mg rituximab induced significant CD19(+) B cell depletion (n = 8, P < 0.001). There was no significant reduction in serum TRAb (n = 8, P = 0.06). A transient infusion-related rash was the only adverse effect, n = 4. QoL scores did not differ markedly before and after treatment. CONCLUSION: Low-dose rituximab is an efficacious, well-tolerated and safe treatment for active TED; reducing disease activity and allowing reduced administration of systemic steroid. PubMed-ID: 30864162 http://dx.doi.org/10.1111/cen.13970

Tumor immune microenvironment characteristics of papillary thyroid carcinoma are associated with histopathological aggressiveness and BRAF mutation status. Head Neck, 41(8):2636-46. C. Means, D. R. Clayburgh, L. Maloney, D. Sauer, M. H. Taylor, M. L. Shindo, L. M. Coussens and T. Tsujikawa. 2019. BACKGROUND: Papillary thyroid carcinoma (PTC) follows an indolent course; however, up to 30% of patients develop recurrent disease requiring further treatment. Profiling PTC immune complexity may provide new biomarkers for improved risk prediction. METHODS: Immune complexity profiles were quantitatively evaluated by multiplex immunohistochemistry (mIHC) in archived tissue sections from 39 patients with PTC, and were assessed for correlations with aggressive histopathological features based on the presence of lymphovascular invasion and/or extrathyroidal extension, and BRAF V600E mutational status. RESULTS: mIHC revealed two distinct immune clusters stratifying patients: a lymphoid-inflamed group (higher CD8(+) T cells, reduced dendritic and mast cells) and a myeloid/hypo-inflamed group that correlated with aggressive pathological features. BRAF mutation was not associated with aggressive pathological features but did correlate with increased mast cell density. CONCLUSIONS: Distinct immune microenvironments exist in PTC correlating with pathological aggressiveness. Immune-based biomarkers associated with possible tumor-immune interactions may be used for risk stratification. PubMed-ID: 30896061 http://dx.doi.org/10.1002/hed.25740

Clinical factors associated with worse quality-of-life scores in United States thyroid cancer survivors. Surgery, 166(1):69-74. S. Goswami, B. J. Peipert, M. N. Mongelli, S. K. Kurumety, I. B. Helenowski, S. E. Yount and C. Sturgeon. 2019. INTRODUCTION: Thyroid cancer survivors are a rapidly growing population in the United States. The factors that drive health-related quality of life (HRQOL) in this population have not been well characterized. We hypothesized that more aggressive treatments and greater treatment-related adverse effects would be associated with worse HRQOL scores in thyroid cancer survivors. METHODS: Thyroid cancer survivors (18-89 years of age) completed an online survey regarding their clinical history in addition to the Patient-Reported Outcomes Measurement Information System (PROMIS) 29 instrument. Univariable and multivariable modeling were performed to evaluate factors associated with worse HRQOL scores. We generated beta-values and 95% confidence intervals to quantify the effect of each independent variable in the model. RESULTS: Thyroid cancer survivors (n = 1,743) reported a high incidence of complications related to surgery and radioactive iodine ablation. Postoperative dysphonia (ss 1.83-3.07) and dysphagia (ss 2.05-3.65) predicted worse HRQOL scores across multiple PROMIS domains. Younger patient age (age <45 years) and short- or long-term complications of radioactive iodine, including gastrointestinal symptoms (51.9%), appetite changes (71.2%), sialadenitis (58.1%), xerostomia (73.3%), and xerophthalmia (45.1%) were associated with worse HRQOL scores (P < .01). CONCLUSION: The factors associated with significantly worse HRQOL scores across multiple PROMIS

ESES Review of Recently Published Literature 2019-2 Page 16 of 71 domains for thyroid cancer survivors included patient age <45 years, postoperative hypocalcemia, dysphonia, dysphagia, scar appearance, and complications from radioactive iodine. Methods of evaluation, management, and prevention of these factors might positively impact HRQOL. PubMed-ID: 30898373 http://dx.doi.org/10.1016/j.surg.2019.01.034

Magnetic detection of sentinel lymph node in papillary thyroid carcinoma: The MAGIC-PAT study results. Eur J Surg Oncol, 45(7):1175-81. J. A. Baena Fustegueras, F. H. Gonzalez, S. G. Caldero, M. C. de la Fuente Juarez, S. R. Lopez, F. R. Riu, N. M. Petit, P. M. Alvarez, A. L. Torello, X. Matias-Guiu and J. J. Olsina Kissler. 2019. INTRODUCTION: Despite the controversy concerning sentinel lymph node biopsy (SLNB) in papillary thyroid carcinoma (PTC), successful detection rates can be achieved by radioguidance and vital dyeing. However, the drawbacks in both techniques are notable. Magnetic-guided SLNB (mSLNB) using superparamagnetic iron oxide (SPIO) nanoparticles is appealing as an alternative procedure. MATERIALS AND METHODS: mSLNB using the Sentimag-Sienna System((R)), total thyroidectomy and central compartment dissection (CCD) were performed on all PTC patients. Lymph node involvement was assessed by postoperative pathological examination. RESULTS: From 2014 to 2016, 33 consecutive patients with PTC were enrolled in the study. A total of 20 patients met the eligibility. mSLNB succeeded in 16 patients, with a detection rate of 80%. A median of two SLN per patient were detected. A median of 10.5 non-sentinel lymph nodes (NSLN) from CCD were examined. Among the patients, 56.25% (9/16) had no metastatic nodes, while 12.5% (2/16) had exclusively SLN involvement. No false negative cases were found. The agreement between SLN and NSLN status was 87.5%. The prediction of NSLN involvement by SLN status showed 100% sensitivity, 81.8% specificity, 71.4% PPV and 100% NPV. Subsequently, mSLNB and the final pathological analysis would discriminate 43.75% (7/16) of patients who would certainly benefit from CCD whilst 56.25% of the total would confirm an unnecessary lymphadenectomy and avoid morbidity. CONCLUSION: mSLNB showed satisfactory performance in PTC with clinical-negative nodes. We have shown mSLNB to be a good predictor of central compartment status that can improve the staging and management of PTC patients. PubMed-ID: 30905393 http://dx.doi.org/10.1016/j.ejso.2019.03.017

The impact of completion thyroidectomy. Eur J Surg Oncol, 45(7):1171-4. R. Sawant, K. Hulse, S. Sohrabi, J. C. L. Yeo, K. Pal, F. W. Gibb, R. Adamson and I. J. Nixon. 2019. INTRODUCTION: The oncological benefit of completion thyroidectomy (CT) following thyroid lobectomy (TL) is presumed to be similar to that of upfront total thyroidectomy(TT), from a patient's perspective the risk and inconvenience of further surgery adds significantly to the impact of the overall treatment. The aim of this study is to assess the impact of CT in terms of the duration of admission and associated complications. METHODS: A study of consecutive patients with DTC identified from prospective MDT records of South-East Scotland from 2009 to 2015. Surgical data was extracted from electronic medical record. RESULTS: Of 361 patients diagnosed with DTC, 161 (45%) had CT. The median postoperative stay was 1 day (range 1-5days). In total 22 patients (14%)suffered complications. Four patients (3%) developed postoperative haematoma. Two (1%) had an identified permanent nerve palsy on the completion side. 13 patients (8%) remained on calcium supplementation for more than 6 months postoperatively and three patients (2%) developed wound complications. CONCLUSIONS: Our study confirms that CT is regularly performed (45%). Recent changes in international guidelines recognize increasing number of patients as eligible for a conservative approach but recommend CT based on whether upfront TT would have been recommended if the TL pathology were known from the outset. Such an approach fails to consider the additional risk and inconvenience of CT on the overall patient experience. Due to a relatively high rate of complications, only those patients who are most likely to benefit from further surgery to facilitate adjuvant radioactive iodine should be offered additional surgery. PubMed-ID: 30910458 http://dx.doi.org/10.1016/j.ejso.2019.03.018

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): a review for clinicians. Endocr Relat Cancer, 26(5):R259-R66. P. W. Rosario and G. F. Mourao. 2019. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an encapsulated or clearly delimited, noninvasive neoplasm with a follicular growth pattern and nuclear features of papillary thyroid carcinoma (PTC). It is considered a 'pre-malignant' lesion of the RAS-like group. Ultrasonography (US), cytology

ESES Review of Recently Published Literature 2019-2 Page 17 of 71 and molecular tests are useful to suspect thyroid nodules that correspond to NIFTP but there is wide overlap of the results with the encapsulated follicular variant of PTC (E-FVPTC). In these nodules that possibly or likely correspond to NIFTP, if surgery is indicated, lobectomy is favored over total thyroidectomy. The diagnosis of NIFTP is made after complete resection of the lesion by observing well-defined criteria. In the case of patients who received the diagnosis of FVPTC and whose pathology report does not show findings of malignancy (lymph node metastasis, extrathyroidal invasion, vascular/capsular invasion), if the tumor was encapsulated or well delimited, the slides can be revised by an experienced pathologist to determine whether the diagnostic criteria of NIFTP are met, but special attention must be paid to the adequate representativeness of the capsule and tumor. Since NIFTP is not 'malignant', tumor staging is not necessary and patients are not submitted to thyroid cancer protocols or guidelines. We believe that patients with NIFTP without associated malignancy and without nodules detected by US of the remnant lobe (if submitted to lobectomy) can be managed like those with follicular adenoma. PubMed-ID: 30913533 http://dx.doi.org/10.1530/ERC-19-0048

Completion thyroidectomy-indications and complications. Eur J Surg Oncol, 45(7):1129-31. A. R. Shaha and R. Michael Tuttle. 2019. PubMed-ID: 30935727 http://dx.doi.org/10.1016/j.ejso.2019.03.028

Thyroid Antibody Status is Associated with Central Lymph Node Metastases in Papillary Thyroid Carcinoma Patients with Hashimoto's Thyroiditis. Ann Surg Oncol, 26(6):1751-8. X. Wen, B. Wang, Q. Jin, W. Zhang and M. Qiu. 2019. OBJECTIVE: The aim of this study was to explore the impact of thyroid antibody status on central lymph node metastases (CLNM) in papillary thyroid carcinoma (PTC) patients with Hashimoto's thyroiditis (HT). METHODS: A retrospective analysis was performed on 346 PTC patients with HT who underwent thyroidectomy and ipsilateral central lymph node dissection (CLND). Histopathological characteristics of the tumor and serum levels of thyroid hormone, as well as antibodies, were collected and analyzed. RESULTS: The multivariate logistic regression analysis showed that being male [odds ratio (OR) 3.269, 95% confidence interval (CI) 1.240-8.619], tumor size > 1 cm [1 cm < diameter (D)

Thyroidectomy Complications in Patients with Diabetes Mellitus. Otolaryngol Head Neck Surg, 161(1):46-51. S. Y. Chung, A. Govindan, A. Babu and A. Tassler. 2019. OBJECTIVE: To (1) analyze postoperative thyroidectomy outcomes in patients with diabetes mellitus (DM), who are prone to deleterious effects of glucose dysmetabolism, and (2) apply findings to optimize perioperative management of diabetics requiring thyroid surgery. STUDY DESIGN: Retrospective database analysis. SETTING: University hospital. SUBJECTS AND METHODS: The National Inpatient Sample was queried using International Classification of Diseases, Ninth Revision, Clinical Modification and Procedure Coding System (PCS) codes for patients with benign or malignant thyroid disease who underwent thyroid surgery between 2002 and 2013. An analysis of demographics, comorbidities, and postoperative outcomes was conducted between a DM vs non-DM cohort using bivariate and multivariate techniques. RESULTS: In total, 103,842 cases met inclusion criteria; 14.2% were diabetics. Diabetics had significantly higher rates of baseline comorbid chronic pulmonary disease, hypertension, obesity, and anemia. Following thyroidectomy, patients with DM were more likely to have vocal cord paresis or paralysis compared to non-DM patients (2.0% vs 1.3%; P < .001). However, when adjusting for demographics and comorbidities, there was no significant difference in this complication

ESES Review of Recently Published Literature 2019-2 Page 18 of 71 between the 2 groups. Diabetics had independently higher rates of cardiac, pulmonary, and urinary complications, as well as transfusion, reintubation, and in-hospital mortality. Diabetics had longer hospital stays (2.76 vs 1.97; P < .001) with higher incurred hospital charges (32,921 vs 25,198; P < .001). CONCLUSION: Although DM often confers metabolic and ischemic derangements secondary to hyperglycemia such as neuropathy, this comorbidity was not independently associated with higher rates of vocal cord paresis or paralysis following thyroid surgery. However, DM predicted other adverse outcomes, including greater cardiac, pulmonary, and urinary complications, as well as transfusion, reintubation, and in-hospital mortality. PubMed-ID: 30961438 http://dx.doi.org/10.1177/0194599819835793

The Importance of Diagnosing Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) Based on the Defined Criteria. Ann Surg Oncol, 26(7):2306-7. P. W. Rosario. 2019. PubMed-ID: 30989494 http://dx.doi.org/10.1245/s10434-019-07354-3

Reply to Letter to the Editor Regarding "The Importance of Diagnosing Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) Based on the Defined Criteria". Ann Surg Oncol, 26(7):2308-10. A. Eskander, S. F. Hall, M. Manduch, R. Griffiths and J. C. Irish. 2019. PubMed-ID: 30993411 http://dx.doi.org/10.1245/s10434-019-07358-z

Risk of incident circulatory disease in patients treated for differentiated thyroid carcinoma with no history of cardiovascular disease. Clin Endocrinol (Oxf), 91(2):323-30. K. A. Toulis, D. Viola, G. Gkoutos, D. Keerthy, K. Boelaert and K. Nirantharakumar. 2019. CONTEXT: The incidence of differentiated thyroid cancer (DTC) is increasing, yet the prognosis is favourable and long-term survival is expected. Exogenous TSH suppression has been used for many years to prevent DTC recurrence and may be associated with increased risks of circulatory diseases. DESIGN: Risks of circulatory disease in patients treated for DTC were compared to randomly matched patients without DTC (controls) up to a 1:5 ratio using age, sex, body mass index (BMI) and smoking as the matching parameters in a population- based, open cohort study using The Health Improvement Network. PATIENTS: A total of 3009 patients treated for DTC with no pre-existing cardiovascular disease were identified and matched to 11 303 controls, followed up to median of 5 years. RESULTS: A total of 1259 incident circulatory events were recorded during the observation period. No difference in the risk of ischaemic heart disease (IHD) (adjusted hazards ratio [aHR]: 1.04, 95% CI: 0.80-1.36) or heart failure (HF) (aHR: 1.27, 95% CI: 0.89-1.81) was detected. The risk of atrial fibrillation (AF) and stroke was significantly higher in patients with DTC (aHR: 1.71, 95% CI: 1.36-2.15 and aHR: 1.34, 95% CI: 1.05-1.72, respectively). In a sensitivity analysis limited to newly diagnosed patients with DTC, only the risk of AF was consistently elevated (aHR: 1.86, 95% CI: 1.33-2.60). CONCLUSIONS: The increased risk of AF in patients who have undergone treatment for DTC but without pre-existing CVD may warrant periodic screening for this arrhythmia. Whereas no evidence of increased risk of IHD or HF was observed, the increased risk of stroke/TIA warrants further investigation. PubMed-ID: 30993728 http://dx.doi.org/10.1111/cen.13990

A multicentre validation study for the EU-TIRADS using histological diagnosis as a gold standard. Clin Endocrinol (Oxf), 91(2):340-7. P. Trimboli, R. Ngu, B. Royer, L. Giovanella, C. Bigorgne, R. Simo, P. Carroll and G. Russ. 2019. OBJECTIVE: Many systems for risk stratification of thyroid nodule with ultrasound (US) have been proposed and the EU-TIRADS issued by the ETA in 2017 was the last to have been published. The present study was undertaken to evaluate whether the malignancy risk of each category corresponded to the given range of the guidelines and assess the diagnostic value of EU-TIRADS in a multi-institutional trial with histology as gold standard. DESIGN: Three institutions in Switzerland, France and United Kingdom shared this retrospective study. Enrolment period was 2013-2017. Included were patients who had undergone surgery with a detailed preoperative thyroid US. METHODS: Cancer risk was calculated for each EU-TIRADS score. Predictivity tests were estimated. Nonparametric statistical analysis was used. RESULTS: The final series included 1058 nodules of which 257 (24.3%) carcinomas. Nodules were classified as EU-TIRADS 2, 3, 4 and 5 in 6.7, 46.4, 26.2 and

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20.7%, respectively. Cancer prevalence was 1.4, 3.5, 17 and 87.7% in classes 2-5, respectively (P < 0.0001). EU-TIRADS 5 had a significantly higher cancer rate than the other summed categories (7.7%; P < 0.0001) with OR 84.7. When EU-TIRADS 4 and 5 were combined, 93% sensitivity and 97% NPV were found and findings of the three institutions were quite similar. Using the recommended criteria for FNA negative predictive value was 90.9%. CONCLUSIONS: The cancer rate was within or close to the given range described in the EU-TIRADS guidelines. The diagnostic value was satisfactory. The results were similar in the three institutions participating in the study. PubMed-ID: 31002419 http://dx.doi.org/10.1111/cen.13997

Association of Surgical Volume and Quality Management in Thyroid Surgery: A Two-Nation Multicenter Study. World J Surg, 43(9):2218-27. D. A. Jakob, P. Riss, C. Scheuba, M. Hermann, C. Kim-Fuchs, C. A. Seiler, M. A. Walter and R. M. Kaderli. 2019. BACKGROUND: High-volume caseload in thyroid surgery is associated with lower postoperative complication rates resulting to better outcomes. The aim of the present study was to investigate the correlation of the departments' annual number of thyroid surgeries on the adherence to consensus guidelines and on the implementation of measures for quality assurance. METHODS: In 2016, we sent an anonymous electronic survey with questions related to the perioperative management in thyroid surgery to all directors of departments in operative medicine in Switzerland and Austria. We compared the pre- and postoperative management with the summarized recommendations of the four most frequently used consensus guidelines. Analogously, we analyzed the implementation of six measures for quality assurance related to thyroid surgery for each participating department. Using logistic regression analysis, we evaluated the correlation of number of guidelines respected and number of measures for quality assurance with the departments' annual number of surgeries performed. Furthermore, we evaluated the number of departments providing thyroid cancer surgery and their experience in neck dissection. RESULTS: The management corresponded in 64.0% to the summarized recommendations. Adherence to the summarized recommendations and implementation of measures for quality assurance were significantly more likely with increasing numbers of surgeries performed (p = 0.049 and p < 0.001). Ninety-two departments provided thyroid cancer surgery, whereas 12/92 (13.0%) were not able to perform central and/or lateral neck dissection. CONCLUSION: Consensus guidelines are insufficiently implemented within thyroid surgery, and quality management is associated with surgical volume. PubMed-ID: 31011819 http://dx.doi.org/10.1007/s00268-019-05012-z

Predicting recurrence of papillary thyroid cancer using the eighth edition of the AJCC/UICC staging system. Br J Surg, 106(7):889-97. N. Chereau, T. O. Oyekunle, A. Zambeli-Ljepovic, H. S. Kazaure, S. A. Roman, F. Menegaux and J. A. Sosa. 2019. BACKGROUND: The AJCC/UICC classification is widely used for predicting survival in papillary thyroid cancer (PTC), but has not been evaluated as a predictor of recurrence. The hypothesis of this study was that the eighth edition of the AJCC system can be used in this novel way. METHODS: All patients in the study underwent surgery for PTC at a high-volume endocrine surgery centre in France between 1985 and 2015. The seventh and eighth editions of the AJCC/UICC staging system for PTC were employed to predict recurrence and disease- specific survival using the Kaplan-Meier and log rank tests. RESULTS: Among 4124 patients (79.7 per cent female), median age was 50 (i.q.r. 38-60) years; 3906 patients (94.7 per cent) underwent total thyroidectomy, with lymph node dissection in 2495 (60.5 per cent). The eighth edition of the AJCC/UICC staging system placed 91.8, 7.1, 0.4 and 0.7 per cent of patients in stages I-IV respectively. After reclassifying patients from the seventh to the eighth AJCC/UICC edition, the disease was downstaged in 23.8 per cent. Over a median follow- up of 7 years, 260 patients (6.4 per cent) developed recurrent disease, including 5.2 per cent of patients with stage I, 19.6 per cent with stage II, 59 per cent with stage III and 50 per cent with stage IV disease, according to the eighth edition. The eighth edition was a better predictor of recurrence than the seventh edition. CONCLUSION: The eighth edition of the AJCC/UICC staging system appears to be a novel tool for predicting PTC recurrence, which is a meaningful outcome for this indolent disease. The eighth edition can be used to risk- stratify patients, keeping in mind that other molecular and pathological predictive factors must be integrated into the assessment of recurrence risk. PubMed-ID: 31012500 http://dx.doi.org/10.1002/bjs.11145

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Lobectomy in patients with differentiated thyroid cancer: indications and follow-up. Endocr Relat Cancer, J. H. Park and J. H. Yoon. 2019. The extent of thyroid surgery for patients with low- and intermediate-risk differentiated thyroid carcinoma (DTC), with a primary tumour <4 cm and no extrathyroidal extension (ETE) or lymph node (LN) metastases, has shifted in a more conservative direction. However, clinicopathological risk factors, including microscopic ETE, aggressive histology, vascular invasion in papillary thyroid carcinoma (PTC), and intermediate volume of LN metastases, can only be identified after completing thyroid lobectomy. It is controversial whether patients with these risk factors should immediately undergo complete thyroidectomy and/or radioactive iodine remnant ablation, or should be monitored without further treatments. Data are conflicting about the prognostic impact of these risk factors on clinical DTC outcomes. Notably, the recurrence rate in patients who underwent thyroid lobectomy is low and the few recurrences that develop during long-term follow-up can readily be detected by neck ultrasonography and treated by salvage surgery with no impact on survival. These findings suggest that a more conservative approach may be a preferred management strategy over immediate completion surgery, despite a slightly higher risk of structural recurrence. Regarding follow-up of post-lobectomy DTC patients, it is reasonable that an initial risk stratification system based on clinicohistological findings be used to guide the short-term follow-up prior to evaluating the response to initial therapy, and that the dynamic risk stratification system based on the response to initial therapy be used to guide long-term follow-up. PubMed-ID: 31018176 http://dx.doi.org/10.1530/ERC-19-0085

Impact of Extranodal Extension on Risk Stratification in Papillary Thyroid Carcinoma. Thyroid, 29(7):963-70. H. I. Kim, J. Hyeon, S. Y. Park, H. S. Ahn, K. Kim, J. M. Han, J. C. Bae, J. H. Shin, J. S. Kim, S. W. Kim, J. H. Chung, T. H. Kim and Y. L. Oh. 2019. Background: The current American Thyroid Association risk-stratification system for papillary thyroid carcinoma (PTC) incorporates the number and size of positive lymph nodes (LNs) but places less weight on extranodal extension (ENE). This study investigated how to incorporate ENE into the current system to predict recurrence better in PTC N1 patients. Methods: A total of 369 N1 PTC patients without distant metastasis were enrolled. The combination of number of positive LNs and LNs with ENE that had the highest C-index were identified with multivariable Cox proportional hazards models. ENE number was incorporated into the current system considering the recurrence rate and unadjusted and adjusted hazard ratios (HRs) of the subgroups. Kaplan- Meier curves for recurrence based on current and alternative systems were compared by log-rank test. Results: The recurrence rate for the subgroup with five or fewer positive LNs and one to three ENEs (7/61; 11.5%) was higher than that of the subgroup with five or fewer positive LNs without ENE (5/129; 3.9%; adjusted HR = 3.42 [confidence interval (CI) 0.99-11.75]; p = 0.050). In contrast, adjusted HRs of the subgroup with more than five positive LNs and one to three ENEs (2.33 [CI 0.52-10.35]) or with four or more ENEs (3.86 [CI 1.05-14.17]) were not higher than those of the subgroup with more than five LNs without ENE (4.47 [1.16-17.19]). Incorporating ENE into the current system as an intermediate-risk group yielded a lower log-rank p-value (0.05 vs. 0.01) than the current system. Conclusions: The presence of ENE in low volume LN metastasis confers an intermediate risk of recurrence. Incorporating ENE into the current system allows more accurate decisions regarding further management of PTC N1 patients. PubMed-ID: 31025609 http://dx.doi.org/10.1089/thy.2018.0541

Thyrotoxicosis with concomitant thyroid cancer. Endocr Relat Cancer, H. Fu, L. Cheng, Y. Jin and L. Chen. 2019. Thyrotoxicosis with concomitant thyroid cancer is rare and poorly recognized, which may result in delayed diagnosis, inappropriate treatment, and even poor prognosis. To provide a comprehensive guidance for clinicians, the etiology, pathogenesis, diagnosis, and treatment of this challenging setting were systematically reviewed. According to literatures available, the etiologies of thyrotoxicosis with concomitant thyroid cancer were categorized into Graves' disease with concurrent differentiated thyroid cancer (DTC) or medullary thyroid cancer, Marine-Lenhart Syndrome with coexisting DTC, Plummer's disease with concomitant DTC, amiodarone-induced thyrotoxicosis with concomitant DTC, central hyperthyroidism with coexisting DTC, hyperfunctioning metastases of DTC and others. The underlying causal mechanisms linking thyrotoxicosis and thyroid cancer were elucidated. Medical history, biochemical assessments, radioiodine uptake, anatomic and metabolic imaging, and ultrasonography guided fine-needle aspiration combined with pathological examinations were found to be critical

ESES Review of Recently Published Literature 2019-2 Page 21 of 71 for precise diagnosis. Surgery remains a mainstay in both tumor elimination and control of thyrotoxicosis, while anti-thyroid drugs, beta-blockers, 131I, glucocorticoids, plasmapheresis, somatostatin analogs, dopamine agonists, radiation therapy, chemotherapy, and tyrosine kinase inhibitors should also be appropriately utilized as needed. PubMed-ID: 31026810 http://dx.doi.org/10.1530/ERC-19-0129

Prognostic significance of TERT promoter and BRAF mutations in TIR-4 and TIR-5 thyroid cytology. Eur J Endocrinol, 181(1):1-11. S. Censi, S. Barollo, E. Grespan, S. Watutantrige-Fernando, J. Manso, M. Iacobone, E. Casal Ide, F. Galuppini, A. Fassina, L. Bertazza, F. Vianello, G. Pennelli and C. Mian. 2019. Objective: Follicular-derived thyroid cancers generally have a good prognosis, but in a minority of cases, they have an aggressive behavior and develop distant metastases, with an increase in the associated mortality. None of the prognostic markers currently available prior to surgery can identify such cases. Methods: TERT promoter and BRAF gene mutations were examined in a series of 436 consecutive TIR-4 and TIR-5 nodes referred for surgery. Follow-up (median: 59 months, range: 7-293 months) was available for 384/423 patients with malignant nodes. Results: TERT promoter and BRAF mutations were detected in 20/436 (4.6%) and 257/434 thyroid nodules (59.2%), respectively. At the end of the follow-up, 318/384 patients (82.8%) had an excellent outcome, 48/384 (12.5%) had indeterminate response or biochemical persistence, 18/384 (4.7%) had a structural persistence or died from thyroid cancer. TERT promoter mutations correlated with older age (P < 0.0001), larger tumor size (P = 0.0002), oxyntic and aggressive PTC variants (P = 0.01), higher tumor stages (P < 0.0001), distant metastases (<0.0001) and disease outcome (P < 0.0001). At multivariate analysis, TERT promoter mutation was not an independent predictor of disease outcome. TERT promoter mutation- (OR: 40.58; 95% CI: 3.06-539.04), and N1b lymph node metastases (OR: 40.16, 95% CI: 3.48-463.04) were independent predictors of distant metastases. BRAF mutation did not predict the outcome, and it correlated with a lower incidence of distant metastases (P = 0.0201). Conclusions: TERT promoter mutation proved an independent predictor of distant metastases, giving clinicians the chance to identify many of the patients who warranted more aggressive initial treatment and closer follow-up. PubMed-ID: 31042674 http://dx.doi.org/10.1530/EJE-19-0073

The 2015 American Thyroid Association guidelines are associated with an increasing rate of hemithyroidectomy for thyroid cancer. Surgery, 166(3):349-55. T. M. Ullmann, K. D. Gray, D. Stefanova, J. Limberg, J. L. Buicko, B. Finnerty, R. Zarnegar, T. J. Fahey, 3rd and T. Beninato. 2019. BACKGROUND: In an attempt to prevent overly aggressive treatment of low-risk thyroid cancers, the American Thyroid Association changed guideline recommendations in late 2015 to state that either hemithyroidectomy or total thyroidectomy are acceptable operations for these patients. We hypothesized that surgeons would increasingly perform hemithyroidectomy after the release of these guidelines. METHODS: The database of the National Surgery Quality Improvement Program was queried to identify all patients with thyroid cancer who were undergoing thyroidectomy between 2009 and 2017. Patients treated before the release of the 2015 American Thyroid Association guidelines were compared with those treated afterward. Temporal trends in operative rates were assessed quarterly using interrupted time series analyses. RESULTS: A total of 35,291 patients were included in the study. Of those, 26,882 (76.2%) were female and 25,193 (71.3%) were white. After the release of the American Thyroid Association guidelines, there was an increase in hemithyroidectomy rate for patients with cancer from 17.3% to 22.0% (P < .001). Interrupted time series analysis controlling for patient factors demonstrated that quarterly growth in the hemithyroidectomy rate accelerated almost 10-fold (P < .001) after publication of the revised guidelines. Of note, there was no corresponding increase in the completion thyroidectomy rate (8.3% versus 7.9%, respectively, P = .213). Patients treated with hemithyroidectomy were more likely to be managed as outpatients (70.8% versus 57.1%, P < .001), had fewer surgical site infections (0.3% versus 0.5%, P = .050), and had fewer unplanned reintubations (0.2% versus 0.4%, P = .005). CONCLUSION: In hospitals participating in the National Surgery Quality Improvement Program, the hemithyroidectomy rate increased significantly after the release of the 2015 American Thyroid Association guidelines. Surgeons at hospitals that participate in the National Surgery Quality Improvement Program may be changing practice patterns in response to these guidelines. PubMed-ID: 31056200 http://dx.doi.org/10.1016/j.surg.2019.03.002

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Incidence, Risk Factors, and Natural Outcome of Vocal Fold Paresis in 920 Thyroid Operations with Routine Pre- and Postoperative Laryngoscopic Evaluation. World J Surg, 43(9):2228-34. M. Heikkinen, K. Makinen, E. Penttila, M. Qvarnstrom, T. Kemppainen, H. Lopponen and J. M. Karkkainen. 2019. BACKGROUND: The aim of this study was to determine the incidence, risk factors, and spontaneous recovery rate of vocal fold paresis (VFP) with routine laryngoscopy before and after thyroid surgery. METHODS: All consecutive patients undergoing primary or redo thyroid surgery between years 2011-2016 were prospectively registered in an electronic database, and scheduled for pre- and postoperative laryngoscopic vocal fold inspection by otolaryngologists independently of the surgical team. RESULTS: A total of 920 thyroid operations with 1296 nerves at risk were performed in 866 patients. Pre- and postoperative laryngoscopy was done in 95% and 98%, respectively. Preoperative VFP was detected in 24 (2.8%) patients. New postoperative VFP was found in 53 of 920 operations (5.8%) and in 55 of 1296 nerves at risk (4.2%). After 12 months, 14 had recovered full vocal fold function and eight had near-complete recovery. VFP was permanent after 29 operations (3.2%); two patients were lost to follow-up with uncertain outcome. Of the 1296 nerves at risk, injury was permanent in 30 (2.3%). In multivariate analysis, patients operated for recurrent goiter had nearly nine times higher risk of new VFP (23% rate), whereas patients with malignant histology had three times higher risk of postoperative VFP (up to 22% rate). CONCLUSION: VFP continues to be a serious complication of thyroid surgery, especially in operations for redo goiter and thyroid malignancy. The incidence of VFP may be underestimated unless laryngoscopic examinations are performed routinely. PubMed-ID: 31065775 http://dx.doi.org/10.1007/s00268-019-05021-y

Distinct Clinical Manifestations of Thyroid Cancer After Hematopoietic Stem Cell Transplantation. Ann Surg Oncol, 26(11):3586-92. T. Y. Lee, S. Lee, J. S. Bae, W. C. Park, S. S. Park, S. E. Lee, J. W. Lee, S. K. Kim, B. Cho and C. K. Jung. 2019. BACKGROUND: The incidence of a secondary solid malignancy after hematopoietic cell transplantation (HCT) is increasing in long-term survivors. OBJECTIVE: The aim of this study was to compare the clinicopathological characteristics of HCT recipients with secondary thyroid cancer (STC), with those of non-HCT thyroid cancer patients. METHODS: We retrospectively investigated 5184 patients who received HCT between 1983 and 2016. Of these, 18 patients developed STC and underwent thyroidectomy due to differentiated thyroid cancer. We compared the clinicopathological characteristics of post-HCT thyroid cancer patients (post-HCT group) with those of a primary differentiated thyroid carcinoma cohort (cohort group) from Seoul St. Mary's Hospital. RESULTS: The mean ages at HCT and thyroidectomy after HCT were 22.0 and 31.8 years, respectively, and the median time interval between HCT and thyroidectomy was 5 years (range 1-16). Compared with the cohort group, the post-HCT group was younger at cancer onset and frequently had a palpable mass at initial diagnosis. The post-HCT group had more aggressive features, including larger tumor size, frequent extrathyroidal extension, lymphatic invasion, perineural invasion, and frequent lateral neck node metastasis and distant metastasis, relative to the cohort group; however, most patients (83.2%) in the post-HCT group were stage I or II. Additionally, BRAF V600E mutation was less frequent in the post-HCT group. CONCLUSIONS: We found that STC after HCT showed younger presentation and more aggressive clinical presentation. Therefore, a policy of regular screening, including neck ultrasound examination, may promote early detection and treatment in HCT recipients. PubMed-ID: 31102091 http://dx.doi.org/10.1245/s10434-019-07442-4

Impact of delayed radioiodine therapy in intermediate-/high-risk papillary thyroid carcinoma. Clin Endocrinol (Oxf), 91(3):449-55. M. Kim, M. Han, M. J. Jeon, W. G. Kim, I. J. Kim, J. S. Ryu, W. B. Kim, Y. K. Shong, T. Y. Kim and B. H. Kim. 2019. OBJECTIVE: It remains unclear whether the time interval between total thyroidectomy and radioactive iodine therapy (RAIT) affects clinical outcomes in papillary thyroid carcinoma (PTC). Therefore, we evaluated the impact of timing of the first post-thyroidectomy RAIT in intermediate-to-high-risk PTC. DESIGN AND PATIENTS: This retrospective propensity score-matched cohort study included 720 PTC patients who received RAIT for <90 or 90-180 days (early and delayed groups, n = 360 each) after thyroidectomy. Responses to therapy, disease- free survival (DFS) and overall survival (OS) were compared between the two groups. RESULTS: After matching, the baseline characteristics of the 360 patients in each group were similarly adjusted. Within the first 2 years after initial therapy, the number of patients classified into excellent, indeterminate, biochemical incomplete

ESES Review of Recently Published Literature 2019-2 Page 23 of 71 and structural incomplete response categories were 221 (61%), 74 (21%), 39 (11%) and 26 (7%) in the early group, and 204 (57%), 73 (20%), 59 (16%) and 24 (7%) in the delayed group, respectively. There was no significant difference in response to therapy between the two groups (P = 0.183). During the median follow-up of 8.6 years, there was no significant difference in DFS (P = 0.060) and OS (P = 0.400) curves between the two groups. Delayed RAIT was not significantly associated with worse DFS (HR = 1.3, 95% CI 0.9-1.8, P = 0.061) or OS (HR = 1.5, 95% CI 0.6-3.4, P = 0.388). CONCLUSIONS: Delaying the first RAIT until 180 days after total thyroidectomy had no impact on restaging, recurrence and mortality in intermediate-to-high-risk PTC. PubMed-ID: 31102417 http://dx.doi.org/10.1111/cen.14039

Papillary Thyroid Cancers with Focal Tall Cell Change are as Aggressive as Tall Cell Variants and Should Not be Considered as Low-Risk Disease. Ann Surg Oncol, 26(8):2533-9. P. J. Bongers, W. P. Kluijfhout, R. Verzijl, M. Lustgarten, M. Vermeer, D. P. Goldstein, K. Devon, L. E. Rotstein, S. L. Asa, J. D. Brierley, R. W. Tsang, S. Ezzat, M. R. Vriens, O. Mete and J. D. Pasternak. 2019. BACKGROUND: The tall cell variant of papillary thyroid carcinoma (PTC) is as an aggressive histological variant. The proportion of tall cells needed to influence prognosis is debated. METHODS: Patients with PTC and tall cells, defined as having a height-to-width ratio of >/= 3:1, seen at a high-volume center between 2001 and 2015, were reviewed. Specimens were classified as (1) focal tall cell change, containing < 30% of tall cells; (2) tall cell variant, >/= 30% of tall cells; and (3) control cases selected from infiltrative classical PTCs without adverse cytologic features. Univariate, sensitivity, and multivariate analyses were performed with persistent/recurrent disease as the primary outcome. RESULTS: We identified 96 PTCs with focal tall cell change, 35 with the tall cell variant and 104 control cases. Factors associated with poor clinical prognosis were significantly greater in those with focal tall cell change and tall cell variants. Regarding primary outcome, hazard ratios were 2.3 (95% confidence interval [CI] 1.0-5.7) for focal tall cell change, and 3.4 (95% CI 1.2-8.7) for tall cell variants compared with controls. Five-year disease-free survival was higher for the control group (92.7%, CI 87.4-98.0) compared with focal tall cell change (76.3%, CI 66.1-86.5) and the tall cell variant (62.2%, CI 43.2- 81.2). When stratified in groups consisting of tall cell proportions (< 10%, 10-19%, 20-29% and >/= 30%), identification of >/= 10% tall cell change was associated with worse outcome (p = 0.002). CONCLUSIONS: PTCs with >/= 10% tall cell change have worse prognosis than those without tall cells. Our data indicate that thyroid cancer management guidelines should consider PTCs with focal tall cell change outside of the low-risk classification. PubMed-ID: 31115855 http://dx.doi.org/10.1245/s10434-019-07444-2

Stage II Differentiated Thyroid Cancer Is a High-Risk Disease in Patients <45/55 Years Old. J Clin Endocrinol Metab, 104(11):4941-8. Z. Liu, X. Shen, R. Liu, G. Zhu, T. Huang and M. Xing. 2019. PURPOSE: The mortality risk of stage II differentiated thyroid cancer (DTC) based on the American Joint Committee on Cancer (AJCC) staging system requires further investigation. METHODS: Retrospective study of DTC in the US Surveillance, Epidemiology, and End Results program for disease-specific mortality risk in various AJCC stages, with patient age stratification of stage II disease. RESULTS: Using AJCC staging system 6.0, hazard ratios (HRs) of mortality for stage II DTC in patients <45 yo and patients >/=45 yo and stages III, IVA, IVB, and IVC compared with stage I were 46.95, 4.95, 9.82, 57.37, 222.10, and 468.68, respectively, showing a robustly higher mortality risk in stage II disease in patients <45 yo than in older patients (P < 0.001), comparable with stage IVA (P = 0.482). Similar results were obtained with AJCC 7.0. With AJCC 8.0, HRs of mortality for stage II in patients <55 yo and patients >/=55 yo and stages III, IVA, and IVB compared with stage I were 75.16, 11.23, 69.45, 134.94, and 235.70, respectively, showing a robustly higher risk in stage II disease in patients <55 yo than in older patients (P < 0.001), comparable with stage III (P = 0.57). Kaplan-Meier survival curves displayed a sharp decline with stage II disease in patients <45/55 yo compared with older patients. CONCLUSIONS: The mortality risk of stage II DTC was sharply differentiated at patient age 45/55 years, being robustly high in younger patients and comparable with stage III/IVA. This emphasizes the importance of considering age when managing stage II DTC and not treating it as a uniformly low-risk disease. PubMed-ID: 31116377 http://dx.doi.org/10.1210/jc.2018-02809

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Association between Hashimoto's thyroiditis and papillary thyroid carcinoma: a retrospective analysis of 305 patients. BMC Endocr Disord, 19(Suppl 1):26. G. Graceffa, R. Patrone, S. Vieni, S. Campanella, S. Calamia, I. Laise, G. Conzo, M. Latteri and C. Cipolla. 2019. BACKGROUND: The association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) is a controversial question that is still under debate, its pathological significance and the eventual clinical implications of this association remaining unclear. METHODS: The data regarding 305 patients were retrospectively analyzed. The patients were divided in two different groups. A first group made up of 142 patients undergoing surgery for differentiated thyroid carcinoma was compared to a control group of 142 analogous subjects operated for normofunctioning goiter. A second group was made up of 163 patients who had undergone total thyroidectomy (TT) with pre-operative diagnosis of HT. RESULTS: In the first group of patients an association with HT was found in 28,6% of the patients with final histopathological diagnosis of PTC versus 7,7% of the patients with histopathological diagnosis of multinodular goiter, which was a significant difference (p < 0.001). In the second group, the association with PTC was found in 43 (40,2%) cases of HT nodular variant and in 3 cases (8,1%) of HT diffuse variant (p < 0.001). CONCLUSIONS: The relationship between HT and PTC is still far from clear and represents an unresolved issue. Our own study has underlined the frequent coexistence of these two pathologies, an aspect not to be neglected in clinical practice. Patients receiving HT diagnosis should undergo careful follow-up and, especially those with the nodular variant, should undergo a frequent both clinical and cytological evaluation of the nodular lesions, taking always into great consideration the surgical approach of total thyroidectomy. PubMed-ID: 31142293 http://dx.doi.org/10.1186/s12902-019-0351-x

Robotic Thyroidectomy Decreases Postoperative Pain Compared With Conventional Thyroidectomy. Surg Laparosc Endosc Percutan Tech, 29(4):255-60. M. K. Kim, H. Kang, G. J. Choi and K. H. Kang. 2019. BACKGROUND: This retrospective study compared postoperative pain between patients undergoing open thyroidectomy (OT) and bilateral axillo-breast approach (BABA) robotic thyroidectomy (RT). MATERIALS AND METHODS: We analyzed the electronic medical records of 1269 patients who underwent OT or RT at Chung- Ang University Hospital between January 1, 2010 and April 30, 2016. On the basis of the surgical procedure performed, patients were categorized into an OT (n=1128) and a BABA RT (BRT) group (n=141). On the basis of covariates, patients in these groups were matched using propensity score matching (n=86 in each group). RESULTS: After propensity score matching, no intergroup differences were observed in the covariates. The visual analogue scale scores for pain on postoperative day 0 were lower in the BRT than in the OT group (2.57+/-0.95 vs. 2.28+/-0.95, P=0.040). However, no statistically significant differences were observed in the use of rescue analgesics, the numerical rating scale score for nausea, and the use of rescue antiemetics. CONCLUSIONS: Pain on postoperative day 0 was lesser in the BRT than in the OT group. Similarly, the severity of nausea was lesser in the BRT group, despite longer operation time and broad dissection performed for docking the robotic arms. PubMed-ID: 31162298 http://dx.doi.org/10.1097/SLE.0000000000000689

Comparing the 7th and 8th Editions of the American Joint Committee on Cancer Staging Systems for Differentiated Thyroid Cancer: Improvements Observed and Future Horizons. Ann Surg Oncol, 26(9):2653-4. H. J. Underwood and K. N. Patel. 2019. PubMed-ID: 31183638 http://dx.doi.org/10.1245/s10434-019-07490-w

The Impact of Post-thyroidectomy Paresis on Quality of Life in Patients with Nodular Thyroid Disease. Otolaryngol Head Neck Surg, 161(4):589-97. J. R. Sorensen, T. Printz, J. Iwarsson, A. M. Grontved, H. Dossing, L. Hegedus, S. J. Bonnema, C. Godballe and C. S. Mehlum. 2019. OBJECTIVE: To investigate the impact of postoperative paresis on disease-specific quality of life (DSQoL) after thyroidectomy in patients with benign nodular thyroid disease. STUDY DESIGN: Observational study. SETTING: University hospital. SUBJECTS AND METHODS: Patients were evaluated before and 3 weeks and 6 months after surgery in an individual prospective cohort study using videolaryngostroboscopy (VLS), voice range profile, voice handicap index (VHI), multidimensional voice program, maximum phonation time (MPT), and auditory

ESES Review of Recently Published Literature 2019-2 Page 25 of 71 perceptual evaluation. Changes in DSQoL were assessed by the Thyroid-specific Patient-Reported Outcome measure. Cohen's effect size was used to evaluate changes. RESULTS: Sixty-two patients were included, 55 of whom completed all examinations. Three weeks after surgery, a blinded VLS examination showed signs of paresis of either the recurrent laryngeal nerve or the external branch of the superior laryngeal nerve (RLN/EBSLN) in 13 patients (24%). A paresis corresponded to a 12 +/- 28 point increase in VHI (P = .002) and was associated with a significant 4.3 +/- 7.5 semitone decrease in the maximum fundamental frequency (P < .001) and a 5.3 +/- 8.2 dB reduction in maximum intensity. Further, it was associated with a 4.5 +/- 11.2 second reduction in MPT (P = .001) and an increase of 0.40 +/- 1.19 in grade, 0.42 +/- 1.41 in roughness, and 0.36 +/- 1.11 in breathiness. Signs of postoperative RLN/EBSLN paresis correlated with an 11.0-point (P = .02) poorer improvement in goiter symptoms at both 3 weeks and 6 months after surgery. CONCLUSION: Signs of RLN/EBSLN paresis after thyroidectomy were associated with less pronounced improvement in goiter symptoms in patients with thyroid nodular disease. However, thyroidectomy was associated with an overall improved DSQoL by 6 months after surgery. PubMed-ID: 31184263 http://dx.doi.org/10.1177/0194599819855379

Thyroid Cancer Patients With No Evidence of Disease: The Need for Repeat Neck Ultrasound. J Clin Endocrinol Metab, 104(11):4981-9. G. Grani, V. Ramundo, R. Falcone, L. Lamartina, T. Montesano, M. Biffoni, L. Giacomelli, M. Sponziello, A. Verrienti, M. Schlumberger, S. Filetti and C. Durante. 2019. CONTEXT: Ultrasonography (US) is considered the most sensitive tool for imaging persistent or recurrent papillary thyroid cancer (PTC) in the neck. OBJECTIVE: To clarify the usefulness of routine neck US in low- and intermediate-risk patients with PTC with no evidence of disease 1 year after thyroidectomy. DESIGN: Retrospective analysis of prospectively recorded data. SETTING: Academic center. PATIENTS: Two hundred twenty-six patients with PTC with sonographically normal neck lymph nodes and unstimulated serum thyroglobulin (Tg) levels that were either undetectable (<0.20 ng/mL) or low (0.21 to 0.99 ng/mL) at the 1-year evaluation. INTERVENTIONS: Yearly assessment: unstimulated serum Tg level, anti-Tg-antibody (TgAb) titer, TSH levels, and ultrasound examination of neck lymph nodes. MAIN OUTCOME MEASURES: Rates of ultrasonographic lymph node abnormalities at the 3-year and last follow-up visits. RESULTS: In patients with an undetectable Tg level at the 1-year evaluation, sonographically suspicious neck lymph nodes were found in 1.2% of patients at 3 years and in 1.8% at the last visit [negative predictive values (NPVs) of 1-year Tg < 0.2 ng/mL: 98.8% (95% CI 95.8% to 99.9%) and 98.2% (95% to 99.6%), respectively]. Similar NPVs emerged for low detectable 1-year Tg levels [98.2% (90.3% to 99.9%) and 94.5% (84.9% to 98.9%) at the 3-year and last visits, respectively]. Seventy-five percent of the nodal lesions were likely false positive; none required treatment. CONCLUSIONS: Low- and intermediate-risk patients with PTC with negative ultrasound findings and unstimulated Tg levels <1 ng/mL at the 1-year evaluation can be safely followed with clinical assessments and unstimulated serum Tg determinations. Neck US might be repeated if TgAb titers rise, or unstimulated Tg levels exceed 1 ng/mL. PubMed-ID: 31206157 http://dx.doi.org/10.1210/jc.2019-00962

Long-Term Treatment with Calcitriol in Postsurgical Hypoparathyroidism Leads to Renal Function Decline. Horm Metab Res, 51(6):362-6. E. Coudenys, T. Van Meerhaeghe, D. Unuane, R. Buyl and B. Bravenboer. 2019. Hypoparathyroidism is a rare endocrine disease with insufficient parathyroid hormone levels. Replacing the missing hormone is not yet a standard therapy. The objective of this retrospective cohort study was to evaluate if the usual therapy regimens of postsurgical hypoparathyroidism with calcitriol have a negative effect on renal function. We performed a chart analysis of patients who were seen in a tertiary care hospital in Brussels, Belgium. A total of 101 subjects were identified as patients with permanent post-surgical hypoparathyroidism, based on the hospital records of patients who underwent a total thyroidectomy between 1996 and 2016, while still being treated with calcitriol. Patients with pre-existing renal insufficiency and/or active malignancy were excluded. The cohort was predominantly female of Caucasian origin. Renal function was evaluated before and after surgery (with a maximum follow-up of 12 years), using the CKD-EPI equation. A multivariate linear regression model was used to correlate renal function decline with the duration of calcitriol therapy, while correcting for the mean calcium phosphate product and age. We found a statistically significant (p=0.027) relationship between the duration of calcitriol treatment and renal function decline at a rate of 1.06 ml/min/1.73 m(2) per year of calcitriol therapy. Our study, although being retrospective, is the first one to demonstrate a relationship between the cumulative use of calcitriol therapy and renal function decline.

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PubMed-ID: 31207657 http://dx.doi.org/10.1055/a-0902-8476

ASO Author Reflections: Cautious Management of NIFTP. Ann Surg Oncol, 26(Suppl 3):645-6. A. Eskander. 2019. PubMed-ID: 31222686 http://dx.doi.org/10.1245/s10434-019-07519-0

Genomic and Transcriptomic Characterization of Papillary Microcarcinomas With Lateral Neck Lymph Node Metastases. J Clin Endocrinol Metab, 104(10):4889-99. D. Perera, R. Ghossein, N. Camacho, Y. Senbabaoglu, V. Seshan, J. Li, N. Bouvier, L. Boucai, A. Viale, N. D. Socci, B. R. Untch, M. Gonen, J. Knauf, J. A. Fagin, M. Berger and R. M. Tuttle. 2019. CONTEXT: Most papillary microcarcinomas (PMCs) are indolent and subclinical. However, as many as 10% can present with clinically significant nodal metastases. OBJECTIVE AND DESIGN: Characterization of the genomic and transcriptomic landscape of PMCs presenting with or without clinically important lymph node metastases. SUBJECTS AND SAMPLES: Formalin-fixed paraffin-embedded PMC samples from 40 patients with lateral neck nodal metastases (pN1b) and 71 patients with PMC with documented absence of nodal disease (pN0). OUTCOME MEASURES: To interrogate DNA alterations in 410 genes commonly mutated in cancer and test for differential gene expression using a custom NanoString panel of 248 genes selected primarily based on their association with tumor size and nodal disease in the papillary thyroid cancer TCGA project. RESULTS: The genomic landscapes of PMC with or without pN1b were similar. Mutations in TERT promoter (3%) and TP53 (1%) were exclusive to N1b cases. Transcriptomic analysis revealed differential expression of 43 genes in PMCs with pN1b compared with pN0. A random forest machine learning-based molecular classifier developed to predict regional lymph node metastasis demonstrated a negative predictive value of 0.98 and a positive predictive value of 0.72 at a prevalence of 10% pN1b disease. CONCLUSIONS: The genomic landscape of tumors with pN1b and pN0 disease was similar, whereas 43 genes selected primarily by mining the TCGA RNAseq data were differentially expressed. This bioinformatics-driven approach to the development of a custom transcriptomic assay provides a basis for a molecular classifier for pN1b risk stratification in PMC. PubMed-ID: 31237614 http://dx.doi.org/10.1210/jc.2019-00431

Disparity in the use of adjuvant radioactive iodine ablation among high-risk papillary thyroid cancer patients. Eur J Surg Oncol, 45(11):2090-5. A. S. Moten, H. Zhao, C. M. Intenzo and A. I. Willis. 2019. BACKGROUND: We sought to identify treatment disparities existing prior to publication of the 2015 American Thyroid Association Management Guidelines in order to identify patients with papillary thyroid cancer (PTC) at risk for receiving inadequate treatment. METHODS: Patients diagnosed with PTC from 2011 to 2013 were identified using Surveillance, Epidemiology and End Results database. High-risk disease was defined as T4, N1, or M1. Chi-square tests compared characteristics of patients with and without high-risk disease and characteristics of high-risk patients who did and did not receive radioactive iodine ablation (RAI). Likelihoods of having high-risk disease, of receiving RAI, and of cause-specific death were calculated using regression analyses. RESULTS: Sample included 32,229 individuals; 7894 (24.5%) had high-risk disease. Mean age was 50.0 years, 24,815 (77.0%) were female, and 21,318 (66.2%) were white. Odds of high-risk disease were greater among males (OR:2.04; 95% CI:1.92-2.16), Hispanics (OR:1.67; 95% CI:1.56-1.79) and Asians (OR:1.49; 95% CI:1.37-1.62), and uninsured (OR:1.24; 95% CI:1.07-1.43), and lower among patients ages 45- 64 (OR:0.57; 95% CI:0.53-0.60), and >/=65 years (OR:0.54; 95% CI:0.50-0.59), and Blacks (OR:0.46; 95% CI:0.40-0.53). Most (69.3%) high-risk patients received RAI. Odds of receiving RAI were lower among patients age >/=65 years (OR:0.67; 95% CI:0.58-0.77), uninsured (OR:0.52; 95% CI:0.41-0.67), or with Medicaid (OR:0.58; 95% CI:0.50-0.69). RAI use reduced the risk of cause-specific mortality (HR:0.29; 95% CI:0.18-0.47). CONCLUSION: Knowledge of these treatment disparities will allow recognition of groups at risk for high-risk disease and receiving inadequate treatment. PubMed-ID: 31253543 http://dx.doi.org/10.1016/j.ejso.2019.06.025

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Effect of surgeons' annual operative volume on the risk of permanent Hypoparathyroidism, recurrent laryngeal nerve palsy and Haematoma following thyroidectomy: analysis of United Kingdom registry of endocrine and thyroid surgery (UKRETS). Langenbecks Arch Surg, 404(4):421-30. S. Aspinall, D. Oweis and D. Chadwick. 2019. PURPOSE: Categorize data to investigate the surgeon volume outcome relationship in thyroidectomies. Determine the evidence base for recommending a minimum number of thyroidectomies performed per year to maintain surgical competency. METHODS: Data on thyroid operations in the United Kingdom Registry of Endocrine and Thyroid Surgery (UKRETS) from 01/09/2010 to 31/08/2016 was analysed. The primary outcome measure was permanent hypoparathyroidism (PH). Recurrent laryngeal nerve palsy (RLN) and post-operative haematoma were also examined. Exclusion criteria included patient age > 85 or < 18 years, and surgeons contributing <10 operations. Data analysis was performed using general additive models and mixed effect logistic regression for PH and binary logistic regression for others. RESULTS: For PH 10313 bilateral thyroid operations were analysed. The Annual rate (AR, p = 0.012) and nodal dissection (P < 10(-7)) were significant factors. 25,038 thyroidectomies were analysed to investigate the effect of surgeon Volume on RLN palsy and haematoma. Age, retrosternal goitre, routine laryngoscopy, re-operation, nodal Dissection, bilateral thyroidectomy, RLN monitoring and surgeon volume were significantly associated with RLN palsy. Post- operative haematoma showed no significant correlation to surgeon volume. Categorisation of AR showed that PH and RLN palsy rates declined in surgeons performing >50 cases/year to a minimum of 3% and 2.6% respectively in highest volume AR group (>100 cases/year). CONCLUSION: Surgeon annual operative volume is a factor in determining outcome from thyroid surgery. Results are limited by a high proportion of missing data, which could potentially bias the outcome, but tentatively suggests the minimum recommended number of thyroid operations / year should be 50 cases. PubMed-ID: 31254103 http://dx.doi.org/10.1007/s00423-019-01798-7

Decision Making in Indeterminate Thyroid Nodules and the Role of Molecular Testing. Surg Clin North Am, 99(4):587-98. J. Mitchell and L. Yip. 2019. Cytologically indeterminate thyroid nodules are associated with a broad range (5%-75%) of malignant risk and accurately informing definitive management poses a challenge. Advancements in molecular testing of fine- needle aspiration biopsies have improved preoperative diagnostic accuracy and prognostication. For indeterminate nodules, such testing ideally will reduce the need for surgery for benign nodules and potentially guide appropriate extent of initial surgery for malignancy. PubMed-ID: 31255193 http://dx.doi.org/10.1016/j.suc.2019.04.002

Long-Term Prognosis of Unilateral and Multifocal Papillary Thyroid Microcarcinoma After Unilateral Lobectomy Versus Total Thyroidectomy. Ann Surg Oncol, 26(9):2952-8. Y. W. Jeon, H. G. Gwak, S. T. Lim, J. Schneider and Y. J. Suh. 2019. BACKGROUND: Multifocal papillary thyroid microcarcinoma (PTMC) has been associated with poor outcomes; however, we often encounter pathologically confirmed unilateral multifocal PTMC after surgery. To date, no consensus on the proper surgical extent for patients with this form of PTMC has been reported. OBJECTIVE: The aim of this study was to analyze the effect of the type of surgical treatment on disease recurrence in patients with unilateral multifocal PTMC. METHODS: We retrospectively analyzed data from 255 patients with unilateral, multifocal, node-negative PTMC between March 1999 and December 2012. We evaluated two groups of patients: those who underwent unilateral lobectomy (Group I, n = 127) and those who underwent total thyroidectomy (Group II, n = 128). During the follow-up period, which lasted a median of 94.8 months, we assessed locoregional recurrence (LRR). RESULTS: There was no statistically significant difference between the two groups with regard to LRR at follow-up (3.15% for Group I vs. 0.78% for Group II; p = 0.244). The association between the type of surgical treatment and LRR remained nonsignificant after adjusting for potential confounders such as age, tumor size, microscopic extrathyroidal extension, and lymphovascular invasion (p = 0.115). During follow-up, the incidence of transient hypocalcemia (0% vs. 8.6%; p = 0.001) and vocal fold paralysis (1.6% vs. 9.4%; p = 0.011) was higher in Group II than in Group I. CONCLUSIONS: Even though randomized controlled trials are the only option to obtain a definitive answer to this question, unilateral lobectomy may be a safe operative option for selected patients with unilateral, multifocal, node-negative PTMC. PubMed-ID: 31264119 http://dx.doi.org/10.1245/s10434-019-07482-w

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Superior Located Papillary Thyroid Microcarcinoma is a Risk Factor for Lateral Lymph Node Metastasis. Ann Surg Oncol, 26(12):3992-4001. K. Back, J. S. Kim, J. H. Kim and J. H. Choe. 2019. BACKGROUND: It is important to identify prognostic factors for lateral lymph node metastasis (LLNM) in papillary thyroid microcarcinoma (PTMC) because they determine the extent of surgery. Several similarly designed studies have investigated predictors of LLNM, but with no more than 1000 cases. In addition, there are no recommendations or guidelines covering the differences in risk by tumor location. This study is the largest, using a papillary thyroid microcarcinoma population with 2967 patients. The purpose of this study is to address predictive factors of LLNM, focusing on lesion location. PATIENTS AND METHODS: We retrospectively reviewed the data of 2967 PTMC patients who underwent total thyroidectomy and central neck dissection and/or lateral neck dissection (unilateral or bilateral) between January 1997 and June 2015. RESULTS: On multivariate analysis, superior lesion [adjusted odds ratio (OR) 3.32, p < 0.000], male gender (adjusted OR 1.39, p = 0.0047), age under 45 years (adjusted OR 1.42, p = 0.015), and central lymph node metastasis (adjusted OR 3.40, p < 0.000) were significant predictors of high-risk LLNM. Superior lesion [hazard ratio (HR) 2.32, p = 0.005] and central lymph node metastasis (CLNM, HR 7.12, p < 0.000) were significant risk factors for locoregional recurrence (LRR). To reduce the effect of selection bias, we performed propensity score matching analysis with regard to tumor location. With a total of 1138 patients with matched data and 569 patients for each location, superior lesion (adjusted OR 3.17, p < 0.000), age under 45 years (adjusted OR 1.73, p = 0.005), and CLNM (adjusted OR 2.77, p < 0.000) were independent predictive factors of LLNM. Superior lesion (HR 2.28, p = 0.04) and CLNM (HR 5.32, p = 0.001) were significant risk factors for LRR. CONCLUSIONS: In addition to young age, male gender, and CLNM identified in previous studies, meticulous assessment for LLNM is required in PTMC patients when lesions are located in the superior pole of the thyroid during preoperative evaluation or postoperative follow-up, because superior located papillary microcarcinoma is a risk factor for LLNM and LRR. PubMed-ID: 31264121 http://dx.doi.org/10.1245/s10434-019-07587-2

Utility of Early Postoperative Unstimulated Thyroglobulin in Influencing Decision Making in Patients with Papillary Thyroid Carcinoma. Ann Surg Oncol, 26(12):4002-7. A. D. McDow, C. M. Shumway, S. C. Pitt, D. F. Schneider, R. S. Sippel and K. L. Long. 2019. BACKGROUND: Serum thyroglobulin is used to screen for disease persistence or recurrence of papillary thyroid carcinoma (PTC). We sought to assess the utility of early postoperative unstimulated thyroglobulin levels (uTg) as a decision-making tool to guide the use of radioactive iodine (RAI) in PTC patients. METHODS: We performed a retrospective analysis of a prospectively maintained database of patients surgically treated for PTC from 2015 to 2017. We analyzed uTg approximately 6 weeks postoperatively. Patients undergoing total thyroidectomy or completion thyroidectomy were included in the study, and patients were analyzed according to postoperative uTg and receipt of RAI. RESULTS: A total of 255 patients were analyzed, with 134 patients meeting the inclusion criteria. The median postoperative uTg was 0.3 ng/mL. Overall, 49.3% (66/134) of patients achieved the target uTg of 0.2-2.0 ng/mL showed benefit from RAI, while patients with uTg > 2.0 ng/mL did not achieve the targeted uTg level regardless of receipt of RAI. CONCLUSIONS: Postoperative uTg may be used to guide the use of RAI. Achieving near-undetectable uTg within 6 weeks postoperatively could aid providers in assessing disease burden and minimize RAI use for patients with a low-risk of disease recurrence. Continued follow-up is necessary to accurately determine long- term outcomes. PubMed-ID: 31267301 http://dx.doi.org/10.1245/s10434-019-07581-8

Identifying risk factors of recurrence for clinically node negative papillary thyroid carcinoma with pathologic N1a. BMC Surg, 19(1):78. Y. J. Ryu, J. S. Cho, M. H. Park and J. H. Yoon. 2019. BACKGROUND: Whether or not to perform prophylactic central lymph node dissection (CLND) in the case of clinically node-negative papillary thyroid cancer (PTC) is controversial. The purpose of this study was to investigate the risk factors for recurrence in clinically node-negative PTC patients who underwent total

ESES Review of Recently Published Literature 2019-2 Page 29 of 71 thyroidectomy plus bilateral central neck dissection and was verified pathologic N1a. METHODS: We retrospectively reviewed the medical records of 1082 PTC patients who underwent total thyroidectomy and prophylactic bilateral CLND between January 2004 and December 2012. We used Cox-proportional hazard regression analyses in order to explore potential predictive factors for recurrence. RESULTS: During a median follow-up (range) of 78 (12-158) months, recurrence occurred in 62 (5.7%) patients. Main tumor size more than 1 cm, gross extrathyroidal extension (ETE), positive lymph node (LN) more than 3, and LN ratio > 0.5 were all significantly associated with recurrence according to univariate analysis. In model I multivariate analysis (tumor size, gross ETE, LN ratio), LN ratio > 5 (hazards ratio [HR], 4.794; 95% confidence interval [CI], 2.674-8.595; p < 0.001) was found to be predictive of recurrence. Gross ETE (HR, 1.794; 95% CI, 1.024-3.143; p = 0.041) and positive LN more than 3 (HR, 2.505; 95% CI, 1.513-4.146; p < 0.001) were predictors for recurrence in model II multivariate analysis (tumor size, gross ETE, the number of positive LN). CONCLUSIONS: We recommend that surgeons try to focus completely on performing prophylactic CLND for patients with suspicious gross ETE during preoperative evaluation. Close monitoring and thorough management are needed for clinically node-negative PTC patients with LN ratio of more than 0.5 and more than 3 positive LN in the central compartment. PubMed-ID: 31277631 http://dx.doi.org/10.1186/s12893-019-0541-5

TERT mRNA Expression as a Novel Prognostic Marker in Papillary Thyroid Carcinomas. Thyroid, 29(8):1105-14. A. Tanaka, M. Matsuse, V. Saenko, T. Nakao, K. Yamanouchi, C. Sakimura, H. Yano, E. Nishihara, M. Hirokawa, K. Suzuki, A. Miyauchi, S. Eguchi, K. I. Yoshiura, S. Yamashita, T. Nagayasu and N. Mitsutake. 2019. Background: Telomerase reverse transcriptase (TERT) promoter mutations have been found in a subset of papillary thyroid carcinomas (PTCs) and are associated with tumor aggressiveness and worse prognosis. However, little is known about the status of TERT mRNA expression and its relationship between TERT promoter mutations and clinicopathological features. Methods: We analyzed 159 PTC samples for TERT promoter mutations using direct DNA sequencing. TERT expression was measured using quantitative reverse transcription polymerase chain reaction. To examine low allelic frequency of TERT promoter mutations with high sensitivity, we used droplet digital polymerase chain reaction (ddPCR). The relationship between the status of the TERT promoter mutation/expression and clinicopathological features including recurrence risk was statistically analyzed. Results: TERT promoter mutations were found in 20 cases (12.6%). However, TERT expression was observed not only in the mutation-positive tumors but also in 56 of 139 (40.3%) mutation- negative tumors. Among them, we detected low allelic frequency of TERT promoter mutations in three samples (5.4%) using ddPCR. We confirmed a significant association between TERT promoter mutations and aggressive clinicopathological features in this series. The risk of recurrence of TERT mutation-negative/expression-positive tumors was significantly higher than that of the mutation-negative/expression-negative tumors, suggesting that TERT expression even in absence of a mutation confers a negative influence on PTCs. Moreover, when we reclassified the mutation-negative cases into two groups based on the TERT expression levels: expression- negative/expression levels <80th percentile and expression levels >80th percentile because minimal expression may have a negligible clinical impact, a higher hazard ratio for recurrence was observed. Interestingly, TERT expression levels in the mutation-negative PTCs were inversely correlated with patient age and the presence of BRAF mutations. Conclusions: We confirm a strong correlation between the presence of TERT promoter mutations and aggressive clinicopathological features in this PTC series. In addition, there were PTCs showing high TERT mRNA expression even in the absence of TERT promoter mutations. These cases also showed a significantly higher recurrence rate. Since the TERT promoter mutations are observed only in elderly patients, TERT mRNA expression can be a useful prognostic marker especially in younger PTC patients. PubMed-ID: 31286848 http://dx.doi.org/10.1089/thy.2018.0695

IL13RA2 Is Differentially Regulated in Papillary Thyroid Carcinoma vs Follicular Thyroid Carcinoma. J Clin Endocrinol Metab, 104(11):5573-84. S. T. Chong, K. M. Tan, C. Y. L. Kok, S. P. Guan, S. H. Lai, C. Lim, J. Hu, C. Sturgis, C. Eng, P. Y. P. Lam and J. Ngeow. 2019. CONTEXT: The interleukin-13 receptor alpha2 (IL13RA2), which is known to be overexpressed in glioblastoma multiforme, plays a role in various cellular processes such as cell migration that may contribute to tumor progression. Studies have attributed IL13RA2 to invasion and metastasis in cancers of the ovary, breast, and pancreas, but the pathological role of IL13RA2 in thyroid cancer is still unclear. OBJECTIVE: This study aims to evaluate IL13RA2 expression in thyroid carcinomas and to examine the role of IL13RA2 in the progression of papillary thyroid carcinoma (PTC). METHODS: IL13RA2 immunochemical staining was performed on tissue microarrays of 137 thyroid carcinomas from patients, and the differential profile of IL13RA2 was validated in

ESES Review of Recently Published Literature 2019-2 Page 30 of 71 thyroid cancer cell lines. In PTC cell lines, we functionally assessed the effects of IL13RA2 underexpression and overexpression on cell proliferation, cell migration, and epithelial-mesenchymal transition (EMT) by using CCK-8, transwell migration assay, quantitative RT-PCR, and Western blot analysis. RESULTS: IL13RA2 expression was significantly correlated with advanced tumor T stage (pT3 or pT4; P = 0.001) and regional lymph node metastasis (pN1; P < 0.001). The staining scores of IL13RA2 were significantly higher in PTC compared with follicular subtypes (P < 0.001) and correlated with advanced tumor stage among PTC samples (pT3 or pT4; P = 0.028). Knockdown of IL13RA2 in B-CPAP cells significantly reduced cell viability, cell migration, and EMT markers including N-cadherin, Vimentin, and Snail. Exogenous overexpression of IL13RA2 in K1 cells increased cell migration and EMT, although cell proliferation was not affected. CONCLUSION: IL13RA2 is differentially regulated in PTC and is involved in cell migration by enhancing EMT. PubMed-ID: 31290966 http://dx.doi.org/10.1210/jc.2019-00040

Total thyroidectomy vs completion thyroidectomy for thyroid nodules with indeterminate cytology/follicular proliferation: a single-centre experience. BMC Surg, 19(1):87. G. Sena, G. Gallo, N. Innaro, N. Laquatra, M. Tolone, R. Sacco and G. Sammarco. 2019. BACKGROUND: Despite total thyroidectomy (TT) is the most practiced procedure for a preoperatively diagnosed neoplastic lesion, according to the ATA guidelines, many surgeons perform completion thyroidectomy (CT) after hemithyroidectomy for patients with preoperative follicular proliferation/indeterminate cytology who are diagnosed with malignancy. CT has a higher complication rate than the primary procedure. The primary endpoint of our study is to compare the morbidity rate after CT with that after primary TT in patients with follicular proliferation/indeterminate cytology. METHODS: We retrospectively reviewed 237 patients who underwent thyroid surgery from 2009 to 2018 at our institution. We recruited only patients with follicular proliferation/indeterminate cytology and excluded those undergoing lymphadenectomies and thyroidectomies for benign pathology and staged thyroidectomies after intraoperative documentation of a RLN lesion. One hundred eighty-six of these patients underwent TT, and fifty-one underwent CT for the detection of differentiated thyroid cancer at the histological exam. RESULTS: No differences were found in the total complication rates between the two groups (OR 0,76, 95% CI 0.35-1.65, P = 0.49). We did not find any significant differences in the subgroup analysis. In particular, no significant differences were identified for transient hypocalcaemia (OR 1.17, 95% CI 0.44-3.11; P = 0,74), permanent hypocalcaemia (OR 1.04, 95% CI 0.21-5.18; P = 0,95), transient unilateral recurrent laryngeal nerve palsy (OR 0.78, 95% CI 0.21-2.81; P = 0,16), permanent unilateral recurrent laryngeal nerve palsy (OR 1.48, 95% CI 0.28-7.85; P = 0,61), and haematoma (OR 1,84, 95% CI 0,16-20,71; P = 0,61). CONCLUSIONS: CT following hemithyroidectomy can be performed with acceptable morbidity in patients with thyroid nodules with preoperative indeterminate cytology/follicular proliferation. PubMed-ID: 31291921 http://dx.doi.org/10.1186/s12893-019-0552-2

[Surgical confirmation of incomplete treatment for primary papillary thyroid carcinoma]. Chirurg, 90(11):936. H. Dralle. 2019. PubMed-ID: 31309247 http://dx.doi.org/10.1007/s00104-019-1004-3

A Cohort Analysis of Clinical and Ultrasound Variables Predicting Cancer Risk in 20,001 Consecutive Thyroid Nodules. J Clin Endocrinol Metab, 104(11):5665-72. T. E. Angell, R. Maurer, Z. Wang, M. I. Kim, C. A. Alexander, J. A. Barletta, C. B. Benson, E. S. Cibas, N. L. Cho, G. M. Doherty, P. M. Doubilet, M. C. Frates, A. A. Gawande, J. F. Krane, E. Marqusee, F. D. Moore, M. A. Nehs, P. R. Larsen and E. K. Alexander. 2019. CONTEXT: Assessing thyroid nodules for malignancy is complex. The impact of patient and nodule factors on cancer evaluation is uncertain. OBJECTIVES: To determine precise estimates of cancer risk associated with clinical and sonographic variables obtained during thyroid nodule assessment. DESIGN: Analysis of consecutive adult patients evaluated with ultrasound-guided fine-needle aspiration for a thyroid nodule >/=1 cm between 1995 and 2017. Demographics, nodule sonographic appearance, and pathologic findings were collected. MAIN OUTCOME MEASURES: Estimated risk for thyroid nodule malignancy for patient and sonographic variables using mixed-effect logistic regression. RESULTS: In 9967 patients [84% women, median age 53 years (range 18 to 95)], thyroid cancer was confirmed in 1974 of 20,001 thyroid nodules (9.9%). Significant ORs for malignancy were demonstrated for patient age <52 years [OR: 1.82, 95% CI (1.63 to 2.05), P < 0.0001], male sex [OR: 1.68

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(1.45 to 1.93), P < 0.0001], nodule size [OR: 1.30 (1.14 to 1.49) for 20 to 19 mm, OR: 1.59 (1.34 to 1.88) for 30 to 39 mm, and OR: 1.71 (1.43 to 2.04) for >/=40 mm compared with 10 to 19 mm, P < 0.0001 for all], cystic content [OR: 0.43 (0.37 to 0.50) for 25% to 75% cystic and OR: 0.21 (0.15 to 0.28) for >75% compared with predominantly solid, P < 0.0001 for both], and the presence of additional nodules >/=1 cm [OR: 0.69 (0.60 to 0.79) for two nodules, OR: 0.41 (0.34 to 0.49) for three nodules, and OR: 0.19 (0.16 to 0.22) for greater than or equal to four nodules compared with one nodule, P < 0.0001 for all]. A free online calculator was constructed to provide malignancy-risk estimates based on these variables. CONCLUSIONS: Patient and nodule characteristics enable more precise thyroid nodule risk assessment. These variables are obtained during routine initial thyroid nodule evaluation and provide new insights into individualized thyroid nodule care. PubMed-ID: 31310316 http://dx.doi.org/10.1210/jc.2019-00664

Follow-Up Strategies for Thyroid Nodules with Benign Cytology on Ultrasound-Guided Fine Needle Aspiration: Malignancy Rates of Management Guidelines Using Ultrasound Before and After the Era of the Bethesda System. Thyroid, 29(9):1227-36. J. H. Yoon, H. S. Lee, E. K. Kim, H. J. Moon, V. Y. Park and J. Y. Kwak. 2019. Background: To evaluate differences in malignancy rates and consequent follow-up strategies for cytologically benign thyroid nodules before and after the introduction of the Bethesda system according to the risk stratification categories of four thyroid management guidelines. Methods: This retrospective study was approved by our institutional review board. In this study, 1716 thyroid nodules with initially benign cytologic diagnosis at ultrasound-guided fine needle aspiration (US-FNA) in 1695 patients were included: 1187 nodules from the pre- Bethesda period and 529 nodules from the post-Bethesda period. Based on US features, the thyroid nodules were categorized into the final assessment categories of the 2015 American Thyroid Association (ATA), the 2016 American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi, the American College of Radiology Thyroid Imaging Reporting and Data System (ACR- TIRADS), and the European Thyroid Association guidelines for Ultrasound Malignancy Risk Stratification systems. Estimated malignancy rates before and after propensity score matching according to follow-up intervals were obtained. Results: Of the 1716 thyroid nodules benign on initial US-FNA, the malignancy rate was 3.2% (38 of 1187) in the pre-Bethesda period and 2.6% (14 of 529) in the post-Bethesda period (p = 0.641). The 2015 ATA high suspicion pattern and the ACR-TIRADS category 5 had high estimated malignancy rates of >5% in the post-Bethesda period (6.52 and 8.57, respectively). Positive findings that indicated US-FNA in the ACR-TIRADS had estimated malignancy rates of 5.26 and 5.67, respectively, while the remaining guidelines had estimated malignancy rates of <5% in both periods. Conclusions: Immediate diagnostic intervention after benign cytologic diagnosis may not be necessary regardless of the cytologic criteria applied, but it can be considered for the highly suspicious categories in the 2015 ATA or the ACR-TIRADS for benign cytologic diagnosis of the Bethesda system. PubMed-ID: 31359839 http://dx.doi.org/10.1089/thy.2018.0769

The Effects of Amiodarone on Thyroid Function in Pediatric and Young Adult Patients. J Clin Endocrinol Metab, 104(11):5540-6. B. Barrett, C. P. Hawkes, A. Isaza and A. J. Bauer. 2019. CONTEXT: Amiodarone is used in patients with arrhythmias, but thyroid dysfunction [amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH)] is a common adverse effect. As the onset of AIT and AIH has not been studied in children, the timing of dysfunction and long-term monitoring are not known in this population. OBJECTIVE: To describe the incidence and timing of amiodarone-induced thyroid dysfunction in children and adolescents, with a secondary aim to identify risk factors for amiodarone-induced thyroid dysfunction, and to identify variance in thyroid hormone surveillance and treatment. DESIGN: Retrospective review of thyroid dysfunction in children and young adults treated with amiodarone between 2007 and 2018. SETTING: Children's Hospital of Philadelphia. PATIENTS: Children and young adults treated with amiodarone. MAIN OUTCOME MEASURES: Prevalence of amiodarone-induced thyroid dysfunction. RESULTS: Of 484 patients, 190 had thyroid-function testing; 17.3% were found to have subclinical hypothyroidism, and 13.7% testing developed hypothyroidism. Hyperthyroidism occurred in 2.1%. In patients with subclinical hypothyroidism, 63% returned to normal thyroid function without thyroid hormone replacement. Only 26% of patients with hypothyroidism had spontaneous normalization of thyroid function. Twenty-five percent of AIT patients had spontaneous normalization of thyroid function. CONCLUSIONS: This study looks at a pediatric and young-adult population in an effort to describe the natural history of amiodarone-induced thyroid dysfunction. Based on our data, we recommend that a complete thyroid-function panel be obtained within the first week and then at weekly

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ASO Author Reflections: The Ability of the AJCC 8th Edition to Predict Risk of Recurrence in Differentiated Thyroid Cancer. Ann Surg Oncol, 26(Suppl 3):672-3. T. Gan and R. W. Randle. 2019. PubMed-ID: 31376039 http://dx.doi.org/10.1245/s10434-019-07683-3

Thyroid primary and metastatic malignant tumours of poor prognosis may mimic subacute thyroiditis - time to change the diagnostic criteria: case reports and a review of the literature. BMC Endocr Disord, 19(1):86. M. Stasiak, R. Michalak and A. Lewinski. 2019. BACKGROUND: The diagnosis of subacute thyroiditis (SAT) is based mainly on the presence of painful thyroid goitre and a significant increase in erythrocyte sedimentation rate (ESR). Proceeding according to these diagnostic criteria may lead to an incorrect diagnosis and treatment. Extremely dangerous is the situation when the diagnosis of SAT is erroneously made based on criteria other than ultrasound (US) image and fine needle aspiration biopsy (FNAB), which leads to delayed diagnosis of malignant tumour with poor prognosis. CASE PRESENTATION: Five patients with typical SAT symptoms are presented. In all of them, anaplastic thyroid cancer or metastatic thyroid tumours were finally diagnosed as the cause of the initial symptoms resembling SAT. Most of the patients were initially misdiagnosed and the proper diagnosis of malignancy was delayed. CONCLUSIONS: The authors have proposed the new diagnostic criteria for SAT, and strongly suggest that thyroid gland US should be included in the main criteria of SAT diagnosis, together with FNAB result excluding the presence of malignant tumour. PubMed-ID: 31387553 http://dx.doi.org/10.1186/s12902-019-0415-y

Lymph node metastasis in suprasternal space in pathological node-positive papillary thyroid carcinoma. Eur J Surg Oncol, 45(11):2086-9. S. T. Yu, J. N. Ge, B. H. Sun, Z. G. Wei and S. T. Lei. 2019. BACKGROUND: The objective of the current study was to investigate the clinical significance of the suprasternal space lymph node (SSLN) in pathological node-positive (pN+) papillary thyroid carcinoma (PTC) patients. METHOD: One hundred and forty patients with pN + PTC who underwent neck dissection were enrolled into this study. SSLN was resected and used as a specimen to investigate the relationship of SSLN with several clinicopathological parameters. RESULTS: The metastasis rate of SSLN was 20.7%. On univariate analysis, we found that SSLN metastasis was significantly associated with primary cancer site (inferior portion), strap muscle invasion, level III metastasis, Level IV metastasis and lymph node metastasis between sternocleidomastoid and sternohyoid muscles. On multivariate analysis, primary cancer site (inferior portion), strap muscle invasion, Level IV metastasis and lymph node metastasis between sternocleidomastoid and sternohyoid muscles were independent risk factors for SSLN metastasis of PTC. CONCLUSION: For pN + PTC patients, special attention should be paid to the issue of SSLN metastasis. PubMed-ID: 31395292 http://dx.doi.org/10.1016/j.ejso.2019.07.034

Factors affecting the approaches and complications of surgery in childhood papillary thyroid carcinomas. Eur J Surg Oncol, 45(11):2078-85. M. Fridman, O. Krasko, D. I. Branovan, S. Dabryian, A. Pisarenko, C. Y. Lo and A. K. Lam. 2019. BACKGROUND: The aim of the study is to analyse the factors related to permanent surgical complications in children and adolescents with papillary thyroid carcinoma treated by total thyroidectomy with central and bilateral neck dissections. METHODS: Children and adolescents aged 4 metastatic lymph nodes in the central neck compartment, presence of distant metastases and

ESES Review of Recently Published Literature 2019-2 Page 33 of 71 younger age of patients at surgery. Patients who received extensive surgery had better relapse-free survival rates (p<0.001). CONCLUSION: Total thyroidectomy and bilateral central as well as lateral neck dissections for children and adolescents with papillary thyroid carcinoma was associated with substantial postoperative complications. Nevertheless, it is associated with better prognosis for young patients with thyroid cancer. Prophylactic compartment-oriented lymph node dissections to these patients could be the management protocol in experienced hands. PubMed-ID: 31395293 http://dx.doi.org/10.1016/j.ejso.2019.07.032

Postoperative Unstimulated Thyroglobulin for the Decision to Use Radioactive Iodine in Patients with Low- or Intermediate-Risk Papillary Thyroid Carcinoma. Ann Surg Oncol, 26(Suppl 3):867-8. P. W. Rosario. 2019. PubMed-ID: 31407180 http://dx.doi.org/10.1245/s10434-019-07722-z

Maternal Thyroid Function, Use of Antithyroid Drugs in Early Pregnancy, and Birth Defects. J Clin Endocrinol Metab, 104(12):6040-8. S. L. Andersen, L. Knosgaard, J. Olsen, P. Vestergaard and S. Andersen. 2019. CONTEXT: Antithyroid drug (ATD) therapy in early pregnancy is associated with birth defects, but more data are needed to substantiate the risk associated with different types of ATD. Furthermore, the role of abnormal maternal thyroid function per se remains unclarified. OBJECTIVE: To evaluate the risk of birth defects associated with the use of ATD in an extended nationwide cohort and the role of abnormal maternal thyroid function in birth cohorts including stored maternal blood samples from early pregnancy. PARTICIPANTS: Danish pregnant women and their live-born children, including 1,243,353 children from a Nationwide Register-Based Cohort (NRBC), 1997 to 2016; 8830 children from the Danish National Birth Cohort (DNBC), 1997 to 2003; and 14,483 children from the North Denmark Region Pregnancy Cohort (NDRPC), 2011 to 2015. MAIN OUTCOME MEASURES: Birth defects diagnosed before 2 years of age. RESULTS: In the NRBC, altogether 2718 (0.2%) children had been exposed to ATD in early pregnancy. The overall frequency of birth defects was 6.7% (95% CI, 6.7% to 6.8%) in nonexposed children and higher after exposure to methimazole/carbimazole (9.6%; 95% CI, 8.2% to 11.2%) and propylthiouracil (8.3%; 95% CI, 6.7% to 10.3%). On the other hand, the frequency of maternal thyroid dysfunction in early pregnancy was similar in the random cohort and in cases of birth defect in the DNBC (12.4 vs 12.6%, P = 0.8) and the NDRPC (15.1 vs 15.4%, P = 0.8). CONCLUSIONS: Results corroborate an increased risk of birth defects associated with the use of ATD in early pregnancy and suggest that abnormal maternal thyroid function is not a major risk factor for birth defects. PubMed-ID: 31408173 http://dx.doi.org/10.1210/jc.2019-01343

Factors Associated With Diagnosis and Treatment of Thyroid Microcarcinomas. J Clin Endocrinol Metab, 104(12):6060-8. N. H. Esfandiari, D. T. Hughes, D. Reyes-Gastelum, K. C. Ward, A. S. Hamilton and M. R. Haymart. 2019. CONTEXT: Nearly one-third of all thyroid cancers are 1 cm. The reported method of nodule discovery differed significantly between patients with cancers 1 cm (P < 0.001). Cancer

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BRAF mutation analysis by ARMS-PCR refines thyroid nodule management. Clin Endocrinol (Oxf), 91(6):834-41. X. Li, E. Li, J. Du, J. Wang and B. Zheng. 2019. BACKGROUND: Fine-needle aspiration (FNA) of thyroid nodules leads to nearly 25% indeterminate nodules, while BRAF(V600E) mutation helps to predicting papillary thyroid carcinoma (PTC). However, the clinical validity and utility of the BRAF(V600E) mutation detected using preoperative FNA samples in a large cohort were rarely reported. AIM: To explore the clinical significance of the BRAF(V600E) mutation on preoperative diagnosis and decision-making in a large FNA cohort in China. DESIGN: This was a prospective study of BRAF(V600E) mutation analysis using an amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in FNA samples. PATIENTS: The study involved 2640 samples from 2307 patients undergoing FNA procedures in a Chinese medical centre. RESULTS: A high mutation rate of 86.7% was found in the PTC population. For indeterminate thyroid nodules, the malignant rate of BRAF(V600E+) and BRAF(V600E-) was 87.8% and 39.5% in the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) III, and 88.2% and 31.8% in the BSRTC IV, respectively. A cost-effective diagnostic model combining both BSRTC grading and BRAF(V600E) mutation status showed the highest sensitivity of 82.9% and specificity of 85.4%. Central lymph node metastasis (CLNM) was independent of the BRAF mutation status and accounted for 34.2% of the patients with PTC. CT values of BRAF(V600E) of patients with PTMC were significantly lower in young patients and patients with CLNM. CONCLUSIONS: The combined analysis of cytological results and BRAF(V600E) mutation is highly recommended in BRAF(V600E) high-prevalence regions, including China. Prophylactic central neck dissection should be performed in selected patients without regard to the BRAF mutation status. PubMed-ID: 31441082 http://dx.doi.org/10.1111/cen.14079

Reply to: Postoperative Unstimulated Thyroglobulin for the Decision to Use Radioactive Iodine in Patients with Low- or Intermediate-Risk Papillary Thyroid Carcinoma. Ann Surg Oncol, 26(Suppl 3):869-70. A. D. McDow. 2019. PubMed-ID: 31463692 http://dx.doi.org/10.1245/s10434-019-07724-x

Clinical Significance of Gross Invasion of Strap Muscles in Patients With 1- to 4-cm-Sized Papillary Thyroid Carcinoma Undergoing Lobectomy. Ann Surg Oncol, 26(13):4466-71. E. Song, W. W. Kim, M. J. Jeon, T. Y. Sung, D. E. Song, T. Y. Kim, K. W. Chung, W. B. Kim, Y. K. Shong, S. J. Hong, Y. M. Lee and W. G. Kim. 2019. BACKGROUND: Given the emerging evidence supporting the lack of prognostic significance of gross extrathyroidal extension invading only strap muscles (strap-gETE), this study investigated whether lobectomy is feasible for patients with strap-gETE. METHODS: A retrospective cohort study was conducted with 636 patients who had 1- to 4-cm-sized papillary thyroid carcinoma (PTC) treated with thyroid lobectomy. Patients with gross invasion of perithyroidal organs other than strap muscles or synchronous distant metastasis were excluded from the study. Disease-free survival (DFS) was compared according to the presence of strap-gETE. RESULTS: Strap-gETE was present in 50 patients (7.9%), with the remaining 586 patients (92.1%) showing no evidence of gETE. During the median follow-up period of 7.4 years, 6% of the patients with strap-gETE and 5.1% of the patients without gETE experienced structural persistent/recurrent disease (p = 0.99). No differences in DFS were observed between the two groups (hazard ratio [HR], 1.24; 95% confidence interval [CI], 0.38-4.08; p = 0.720). After adjustment for five major risk factors (age, gender, tumor size, multifocality, and cervical lymph node metastasis status) in the multivariate analysis, the presence of strap-gETE did not exhibit an independent role in the development of structural persistent/recurrent disease (HR 1.05; 95% CI 0.24-4.53, p = 0.950). CONCLUSIONS: Strap-gETE did not increase the risk of structural persistent/recurrent disease for the patients who underwent lobectomy for 1- to 4-cm-sized PTC. The study data support the limited role of strap-gETE in clinical outcomes and may broaden the indications for lobectomy for patients with PTCs. PubMed-ID: 31471840 http://dx.doi.org/10.1245/s10434-019-07778-x

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Parathyroids

Meta-Analyses - None -

Randomized controlled trials Randomized Controlled Trial Comparing White Light with Near-Infrared Autofluorescence for Parathyroid Gland Identification During Total Thyroidectomy. J Am Coll Surg, 228(5):744-51. F. Dip, J. Falco, S. Verna, M. Prunello, M. Loccisano, P. Quadri, K. White and R. Rosenthal. 2019. BACKGROUND: Parathyroid glands are difficult to identify during total thyroidectomies, and accidental resection can lead to problematic postoperative hypocalcemia. Our main goals were to evaluate the effectiveness of using near-infrared light (NIRL) autofluorescence intraoperatively for parathyroid gland identification and to measure its impact on postoperative hypocalcemia incidence. STUDY DESIGN: Total thyroidectomies were performed on 170 patients with different thyroid pathologies, block-randomized (1:1) into 2 equal groups. Among controls, traditional overhead white light (WL) was used throughout. In the experimental group, NIRL was used to enhance parathyroid gland recognition before thyroid dissection. The number of parathyroid glands identified was compared after thyroid dissection in controls using WL vs pre-dissection in the experimental using NIRL and with WL vs NIRL before thyroid dissection in the experimental group. Postoperative serum calcium levels and hypocalcemia rates were compared. RESULTS: The mean number of parathyroid glands identified pre- dissection with NIRL was the same identified post-dissection with WL (3.5 vs 3.6). In the experimental group, converting from WL to NIRL increased the number of glands detected from 2.6 to 3.5 (p < 0.001), and revealed at least 1 previously missed gland in 67.1% of patients. Calcium levels

Effect of Parathyroidectomy on Cardiovascular Risk Factors in Primary Hyperparathyroidism: A Randomized Clinical Trial. J Clin Endocrinol Metab, 104(8):3223-32. H. Ejlsmark-Svensson, L. Rolighed and L. Rejnmark. 2019. CONTEXT: It remains unclear whether risk of cardiovascular diseases is increased in patients with mild (<1.45 mmol/L) to moderate (>/=1.45 to 1.60 mmol/L) primary hyperparathyroidism (PHPT). OBJECTIVE: We aimed to determine the short-term effect of parathyroidectomy (PTX) on arterial stiffness, cholesterol levels, and blood pressure (BP). DESIGN: This study was a clinical trial randomly allocating patients to either PTX or a control group (no surgery). Follow-up was performed 3 months after surgery in the PTX group and 3 months after baseline in the control group. SETTING: University hospital. PARTICIPANTS: We recruited 79 patients with PHPT; 69 participants completed the study. MAIN OUTCOMES: Office and ambulatory 24-hour BP, pulse wave velocity (PWV), augmentation index, and fasting plasma cholesterol levels. RESULTS: At baseline, participants had a median level of ionized calcium of 1.41 mmol/L (range, 1.33 to 1.60 mmol/L) and PTH of 10.4 pmol/L (4.5 to 30.4 pmol/L). Median age was 64 years (range, 18 to 81) and 72% were females. Following PTX, plasma total cholesterol levels decreased significantly compared with the controls (P = 0.04). Changes in PWV, augmentation index, and ambulatory 24-hour BP did not differ between groups, except for an increase in ambulatory diastolic BP following PTX. However, in patients with baseline levels of ionized calcium >/=1.45 mmol/L, PWV decreased significantly in response to PTX compared with the control group (P = 0.03). CONCLUSION: PTX may decrease risk of cardiovascular diseases in PHPT by lowering total cholesterol levels, although ambulatory diastolic BP increases in response to surgery. Patients with moderate to severe hypercalcemia may benefit from PTX by a decrease in PWV.

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PubMed-ID: 30860588 http://dx.doi.org/10.1210/jc.2018-02456

Consensus Statements/Guidelines - None -

Other Articles Analysis of Activating GCM2 Sequence Variants in Sporadic Parathyroid Adenomas. J Clin Endocrinol Metab, 104(6):1948-52. A. Riccardi, T. Aspir, L. Shen, C. L. Kuo, T. C. Brown, R. Korah, T. D. Murtha, J. Bellizzi, K. Parham, T. Carling, J. Costa-Guda and A. Arnold. 2019. CONTEXT: Sporadic, solitary parathyroid adenoma is the most common cause of primary hyperparathyroidism (PHPT). Apart from germline variants in certain cyclin-dependent kinase inhibitor genes and occasionally in MEN1, CASR, or CDC73, little is known about possible genetic variants in the population that may confer increased risk for development of typical sporadic adenoma. Transcriptionally activating germline variants, especially within in the C-terminal conserved inhibitory domain (CCID) of glial cells missing 2 (GCM2), encoding a transcription factor required for parathyroid gland development, have recently been reported in association with familial and sporadic PHPT. OBJECTIVE: To evaluate the potential role of specific GCM2 activating variants in sporadic parathyroid adenoma. DESIGN AND PATIENTS: Regions encoding hyperparathyroidism-associated, activating GCM2 variants were PCR amplified and sequenced in genomic DNA from 396, otherwise unselected, cases of sporadic parathyroid adenoma. RESULTS: Activating GCM2 CCID variants (p.V382M and p.Y394S) were identified in six of 396 adenomas (1.52%), and a hyperparathyroidism-associated GCM2 non-CCID activating variant (p.Y282D) was found in 20 adenomas (5.05%). The overall frequency of tested activating GCM2 variants in this study was 6.57%, approximately threefold greater than their frequency in the general population. CONCLUSIONS: The examined, rare CCID variants in GCM2 were enriched in our cohort of patients and appear to confer a moderately increased risk of developing sporadic solitary parathyroid adenoma compared with the general population. However, penetrance of these variants is low, suggesting that the large majority of individuals with such variants will not develop a sporadic parathyroid adenoma. PubMed-ID: 30624640 http://dx.doi.org/10.1210/jc.2018-02517

Enhancing Parathyroid Gland Visualization Using a Near Infrared Fluorescence-Based Overlay Imaging System. J Am Coll Surg, 228(5):730-43. M. A. McWade, G. Thomas, J. Q. Nguyen, M. E. Sanders, C. C. Solorzano and A. Mahadevan-Jansen. 2019. BACKGROUND: Misidentifying parathyroid glands (PGs) during thyroidectomies or parathyroidectomies could significantly increase postoperative morbidity. Imaging systems based on near infrared autofluorescence (NIRAF) detection can localize PGs with high accuracy. These devices, however, depict NIRAF images on remote display monitors, where images lack spatial context and comparability with actual surgical field of view. In this study, we designed an overlay tissue imaging system (OTIS) that detects tissue NIRAF and back-projects the collected signal as a visible image directly onto the surgical field of view instead of a display monitor, and tested its ability for enhancing parathyroid visualization. STUDY DESIGN: The OTIS was first calibrated with a fluorescent ink grid and initially tested with parathyroid, thyroid, and lymph node tissues ex vivo. For in vivo measurements, the surgeon's opinion on tissue of interest was first ascertained. After the surgeon looked away, the OTIS back-projected visible green light directly onto the tissue of interest, only if the device detected relatively high NIRAF as observed in PGs. System accuracy was determined by correlating NIRAF projection with surgeon's visual confirmation for in situ PGs or histopathology report for excised PGs. RESULTS: The OTIS yielded 100% accuracy when tested ex vivo with parathyroid, thyroid, and lymph node specimens. Subsequently, the device was evaluated in 30 patients who underwent thyroidectomy and/or parathyroidectomy. Ninety-seven percent of exposed tissue of interest was visualized correctly as PGs by the OTIS, without requiring display monitors or contrast agents. CONCLUSIONS: Although OTIS holds novel potential for enhancing label-free parathyroid visualization directly within the surgical field of view, additional device optimization is required for eventual clinical use.

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PubMed-ID: 30769112 http://dx.doi.org/10.1016/j.jamcollsurg.2019.01.017

Limited clinical utility of intraoperative frozen section during parathyroidectomy for treatment of primary hyperparathyroidism. Am J Surg, 217(5):893-8. J. Li, E. Vasilyeva, J. Hiebert, H. Britton, B. Walker and S. M. Wiseman. 2019. BACKGROUND: This study's objective was to evaluate the utility of intraoperative frozen section (IFS) performed during parathyroidectomy for treatment of primary hyperparathyroidism (PHP), and to identify patients for whom it is most helpful. METHODS: A retrospective chart review was carried out for all patients who underwent parathyroidectomy for treatment of PHP between January 2013 and June 2018. RESULTS: 262 patients made up the final study population. Overall, IFS provided information that influenced the operative plan in 46 patients (17.6%). IFS altered the operative plan in 10.2% of cases that were correctly preoperatively localized, and in 41.5% of cases that were either incorrectly or not preoperatively localized. CONCLUSIONS: IFS did not provide information that influenced the operative plan during parathyroidectomy for treatment of PHP for the majority of patients. Patients that present with normal PTH and hypercalcemia, or those who do not localize preoperatively, are most likely to benefit from IFS. PubMed-ID: 30771863 http://dx.doi.org/10.1016/j.amjsurg.2019.01.032

Subtotal Parathyroidectomy vs Total Parathyroidectomy with Autotransplantation for Secondary Hyperparathyroidism in Dialysis Patients: Short- and Long-Term Outcomes. J Am Coll Surg, 228(6):831-8. P. V. Zmijewski, J. A. Staloff, M. J. Wozniak and P. J. Mazzaglia. 2019. BACKGROUND: Two operations are performed for management of secondary hyperparathyroidism, subtotal parathyroidectomy (SPTX) and total parathyroidectomy with autotransplantation (TPTX-AT). There is no consensus among endocrine surgeons about which operation is the preferred treatment. This study compares the short- and long-term outcomes of SPTX and TPTX-AT for dialysis patients with secondary hyperparathyroidism. STUDY DESIGN: This is a retrospective review of 46 dialysis patients undergoing PTX from 2006 to 2017 at a 719-bed tertiary care hospital. RESULTS: Calcium on postoperative day 1 was 7.7 +/- 0.8 mg/dL for SPTX and 7.9 +/- 1.3 mg/dL for TPTX-AT (p = 0.49). Parathyroid hormone values on postoperative day 1 were 32.6 +/- 26.0 pg/mL for SPTX and 9.5 +/- 4.2 pg/mL for TPTX-AT (p 200 pg/mL at long-term follow-up occurred in 38.9% of SPTX patients vs 6.7% of the TPTX-AT patients (p

The role of F18-fluorocholine positron emission tomography/magnetic resonance imaging in localizing parathyroid adenomas. Eur Arch Otorhinolaryngol, 276(5):1509-16. A. Khafif, M. Masalha, R. Landsberg, L. Domachevsky, H. Bernstine, D. Groshar, O. Azoulay and Y. Lockman. 2019. PURPOSE: Preoperative localization of a parathyroid adenoma is usually obtained by the combination of ultrasound and scintigraphy with technetium-99m methoxyisobutylisonitrile. We evaluated the role of F18- fluorocholine in neck positron emission tomography/magnetic resonance imaging as a novel tool for localizing parathyroid adenomas. METHODS: Patients with primary hyperparathyroidism were recruited from February 2016 to August 2017 and F18-fluorocholine positron emission tomography/magnetic resonance imaging was performed to localize the parathyroid adenoma prior to surgery. We compared sensitivity and accuracy of this modality with ultrasound and technetium-99m methoxyisobutylisonitrile scintigraphy using the verified location of the diseased parathyroid as found in surgery. RESULTS: Nineteen patients were included in our study (15 women and 4 men, mean age 60.5 +/- 9.8 years). Positron emission tomography/magnetic resonance imaging precisely localized the pathologic parathyroid gland in 16/19 cases (84.2%) and predicted the diseased side in

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19/19 cases (100%). Ultrasound and technetium 99 m methoxyisobutylisonitrile sestamibi scintigraphy predicted the location of the parathyroid adenoma in 16/19 (84.2%) and 14/19 (74%), respectively. In 3/19 patients, positron emission tomography/magnetic resonance imaging localized the parathyroid adenoma where as other modalities failed. Positron emission tomography/magnetic resonance imaging was more accurate when compared to each modality separately (p < 0.001, p = 0.017), however, when comparing the three modalities all together no differences were found (p = 0.506). CONCLUSIONS: Localizing parathyroid adenomas with F18- fluorocholine positron emission tomography/magnetic resonance imaging may be a promising secondary imaging modality. PubMed-ID: 30877424 http://dx.doi.org/10.1007/s00405-019-05301-2

Mild sporadic primary hyperparathyroidism: high rate of multiglandular disease is associated with lower surgical cure rate. Langenbecks Arch Surg, 404(4):431-8. E. Trebouet, S. Bannani, M. Wargny, C. Leux, C. Caillard, F. Kraeber-Bodere, K. Renaudin, L. Chaillous, E. Mirallie and C. Ansquer. 2019. BACKGROUND: Mild primary hyperparathyroidism (serum calcium

Intraoperative parathyroid hormone levels /=50% decrease from the baseline level, the rate of persistent primary hyperparathyroidism was greater when intraoperative parathyroid hormone did not decrease to >/=50% from the baseline level (17 of 180 patients [9.4%] vs 49 of 2,474 [2.0%], [OR 5.9, 95% CI 3.2-10.5, P < .001]). Regardless of whether intraoperative parathyroid hormone decreased >/=50%, patients with a lowest intraoperative parathyroid hormone above the normal range (10-65 pg/mL) had greater persistence rates compared with patients with an intraoperative parathyroid hormone <65 pg/mL (30 of 350 [8.6%] vs 36 of 2,304 [1.6%], [OR 6.6, 95% CI 3.4-12.7, P < .001]). Furthermore, patients with a lowest intraoperative parathyroid hormone 40 to 65 pg/mL had increased rates of adjusted persistence compared with patients with lowest intraoperative parathyroid hormone

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8.7, P < .001]). Patients with lowest intraoperative parathyroid hormone <5 to 20 pg/mL did not have decreased rates of persistence compared with patients with lowest intraoperative parathyroid hormone 20 to 40 pg/mL (9 of 996 [0.9%] vs 14 of 923 [1.5%], [OR 0.5, 95% CI 0.2-1.2, P = .14]). CONCLUSION: Patients with a lowest intraoperative parathyroid hormone /=50% decrease from baseline and a final parathyroid hormone in the normal range (<65 pg/mL) had the lowest rates of persistent primary hyperparathyroidism after parathyroidectomy for primary hyperparathyroidism. The single criteria of a lowest intraoperative parathyroid hormone level

American Head and Neck Society Endocrine Surgery Section update on parathyroid imaging for surgical candidates with primary hyperparathyroidism. Head Neck, 41(7):2398-409. M. Zafereo, J. Yu, P. Angelos, K. Brumund, H. H. Chuang, D. Goldenberg, M. Lango, N. Perrier, G. Randolph, M. L. Shindo, M. Singer, R. Smith, B. C. Stack, Jr., D. Steward, D. J. Terris, T. Vu, M. Yao and R. P. Tufano. 2019. Health care consumer organizations and insurance companies increasingly are scrutinizing value when considering reimbursement policies for medical interventions. Recently, members of several American Academy of Otolaryngology-Head & Neck Surgery (AAO-HNS) committees worked closely with one insurance company to refine reimbursement policies for preoperative localization imaging in patients undergoing surgery for primary hyperparathyroidism. This endeavor led to an AAO-HNS parathyroid imaging consensus statement (https://www.entnet.org/content/parathyroid-imaging). The American Head and Neck Society Endocrine Surgery Section gathered an expert panel of authors to delineate imaging options for preoperative evaluation of surgical candidates with primary hyperparathyroidism. We review herein the current literature for preoperative parathyroid localization imaging, with discussion of efficacy, cost, and overall value. We recommend that planar sestamibi imaging, single photon emission computed tomography (SPECT), SPECT/CT, CT neck/mediastinum with contrast, MRI, and four dimensional CT (4D-CT) may be used in conjunction with high-resolution neck ultrasound to preoperatively localize pathologic parathyroid glands. PubMed literature on parathyroid imaging was reviewed through February 1, 2019. PubMed-ID: 31002214 http://dx.doi.org/10.1002/hed.25781

Intraoperative parathyroid hormone (PTH) testing in patients with primary hyperparathyroidism and PTH levels in the normal range. BMC Surg, 18(Suppl 1):124. F. Medas, E. Erdas, G. Loi, F. Podda, L. Barca, G. Pisano and P. G. Calo. 2019. BACKGROUND: Primary hyperparathyroidism is a common endocrine disorder. Hypercalcemia with normal PTH levels is very unusual and can lead to diagnostic difficulties. There are very few very few studies in the literature and all with limited numerical samples. The goal of the present study was to determine the real incidence and characteristics of primary hyperparathyroidism with normal PTH and to evaluate if intraoperative PTH testing is useful in these patients. METHODS: We performed a retrospective review of 314 patients who had undergone parathyroidectomy to treat primary hyperparathyroidism between January 2002 and December 2016. Patients were divided in two groups according to biochemical preoperative findings: in Group A were included patients with normal serum PTH, in Group B those with increased serum PTH. RESULTS: Nine patients (3.7%) were included in group A and 235 in group B. Patients in group A were younger (51.5 +/- 12.9 years vs 59.6 +/- 12.5); preoperative serum calcium and the incidence of coexisting thyroid disease were similar between the two groups. Symptomatic patients were more frequent in Group A (77.8% vs 39.1%; p = 0.048). There were no significant differences regarding preoperative localization studies and surgical procedure. Intraoperative PTH determination demonstrated sensitivity of 86% in group A and 97% in group B, specificity and positive predictive value of 100% in both the groups, negative predictive value of 67% in group A and 79% in group B. Histopathological examination demonstrated a single gland disease in 8 (88.9%) patients in group A and a multi gland disease in 1 (11.1%), in group B single gland disease was found in 218 (92.8%) patients and multi gland disease in 17 (7.2%). Unsuccessful surgery with persistent or recurrent hyperparathyroidism occurred in 1 (11.1%) patient in group A and 4 (1.7%) in group B. CONCLUSIONS: Primary hyperparathyroidism with normal PTH is rare but physicians should be aware of this possibility in patients with hypercalcaemia. Patients with normal PTH levels are younger and more frequently symptomatic. Intraoperative PTH testing plays an important role in the operative management even in such patients.

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PubMed-ID: 31074404 http://dx.doi.org/10.1186/s12893-018-0459-3

Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors. Endocr Relat Cancer, F. Cetani, C. Marcocci, L. Torregrossa and E. Pardi. 2019. Atypical parathyroid adenomas represent a group of intermediate form of parathyroid neoplasms of uncertain malignant potential which show some atypical histological features that represent a challenge for the differential diagnosis with parathyroid carcinomas. They may occur as a sporadic or as a part of hereditary syndromes. The molecular signature of these neoplasms is still unknown and the germline CDC73 mutations appears to be the most common anomaly in this setting suggesting that these cases might represents variants of the hyperparathyroidism-jaw tumor syndrome. The identification of markers predicting the outcome is of great importance to guide an adequate postoperative monitoring and, the same time, relieve of the anxiety of relatively strict monitoring patients not at risk. This review will summarize the current knowledge of the clinical, biochemical, molecular and histological profile of atypical parathyroid adenomas. PubMed-ID: 31085770 http://dx.doi.org/10.1530/ERC-19-0135

Cardiovascular and Cerebrovascular Events After Parathyroidectomy in Patients on Renal Replacement Therapy. World J Surg, 43(8):1981-8. K. M. Ivarsson, S. Akaberi, E. Isaksson, E. Reihner, T. Czuba, K. G. Prutz, N. Clyne and M. Almquist. 2019. BACKGROUND: A majority of patients with end-stage renal disease suffer from secondary hyperparathyroidism, which is associated with osteoporosis and cardiovascular disease. Parathyroidectomy (PTX) is often necessary despite medical treatment. However, the effect of PTX on cardio- and cerebrovascular events (CVE) remains unclear. Data on the effect of PTX from population-based studies are scarce. Some studies have shown decreased incidence of CVE after PTX. The aim of this study was to evaluate the effect of PTX on risk of CVE in patients on renal replacement therapy. METHODS: We performed a nested case-control study within the Swedish Renal Registry (SRR) by matching PTX patients on dialysis or with functioning renal allograft with up to five non-PTX controls for age, sex and underlying renal disease. To calculate time to CVE, i.e., myocardial infarct, stroke and transient ischemic attack, control patients were assigned the calendar date (d) of the PTX of the case patient. Crude and adjusted proportional hazards regressions with random effect (frailty) were used to calculate hazard ratios for CVE. RESULTS: The study cohort included 20,056 patients in the SRR between 1991 and 2009. Among these, 579 patients had undergone PTX, 423 during dialysis and 156 during time with functioning renal allograft. These patients were matched with 1234 dialysis and 736 transplanted non-PTX patients. The adjusted hazard ratio (HR) with 95% confidence interval (CI) of CVE after PTX was 1.24 (1.03- 1.49) for dialysis patients compared with non-PTX patients. Corresponding results for patients with renal allograft at d were HR (95% CI) 0.53 (0.34-0.84). CONCLUSIONS: PTX patients on dialysis at d had a higher risk of CVE than patients without PTX. Patients with renal allograft at d on the other had a lower risk after PTX than patients without PTX. PubMed-ID: 31087130 http://dx.doi.org/10.1007/s00268-019-05020-z

Risk of Distant Metastasis in Parathyroid Carcinoma and Its Effect on Survival: A Retrospective Review from a High-Volume Center. Ann Surg Oncol, 26(11):3593-9. E. A. Asare, A. Silva-Figueroa, K. R. Hess, N. Busaidy, P. H. Graham, E. G. Grubbs, J. E. Lee, M. D. Williams and N. D. Perrier. 2019. BACKGROUND: Development of distant metastases (DM) is associated with markedly decreased survival in parathyroid carcinoma (PC). We sought to identify factors associated with development of DM and to quantify the effect that development of DM had on overall survival (OS). METHODS: Patients with surgically resected local/regional PC treated or surveilled at a tertiary-referral cancer hospital from 1980 to 2017 were included. We assessed the association between biochemical and clinicopathologic factors (preoperative parathyroid hormone (PTH) levels, sex, race, age, preoperative serum calcium levels, serum calcium levels at 6 months postop, tumor size, and extent of resection) with the development of DM. We also assessed the effect of development of DM on OS. RESULTS: Seventy-five patients with PC were assessed; 17 (22.7%) developed DM at a median follow- up of 77 months. The cumulative incidence of DM in the cohort was 20, 30, and 38% at 5, 10, and 20 years respectively. Tumor size > 3.2 cm based on recursive partitioning analysis was the only significant predictor for development of DM (hazard ratio (HR) = 3.51; 95% confidence interval [CI] 1.04-11.91; p = 0.04). Median OS for

ESES Review of Recently Published Literature 2019-2 Page 41 of 71 the entire cohort was 17 years compared with 40 months for the cohort who developed DM. The HR for death after distant metastasis was 9.6 (95% CI 4.2-22.3; p < 0.0001). CONCLUSIONS: Development of distant metastasis during surveillance is associated with decreased OS, including late recurrences. Primary tumor size should be considered in future interval surveillance and development of treatment algorithms. PubMed-ID: 31111352 http://dx.doi.org/10.1245/s10434-019-07451-3

Clinical characteristics and depression score response after parathyroidectomy in primary hyperparathyroidism. Clin Endocrinol (Oxf), 91(3):464-70. A. E. Kearns, R. P. Espiritu, K. Vickers Douglass, P. Thapa and R. A. Wermers. 2019. OBJECTIVE: Several studies indicate that patients with primary hyperparathyroidism (PHPT) undergoing parathyroid surgery have improvement in mood and neuropsychological functioning. The current analysis aims to examine the relationship between biochemical and clinical variables and the improvement in depression scores and in specific symptoms, after parathyroidectomy. DESIGN: A prospective observational case-control study at a referral centre. PATIENTS: Patients with PHPT undergoing parathyroidectomy (n = 88) or thyroid surgery (n = 85). MEASUREMENTS: The Patient Health Questionnaire-9 (PHQ-9) was utilized to obtain depression scores at enrolment and 12 months after surgery. The changes in PHQ-9 were analysed and correlated with baseline clinical and biochemical parameters. RESULTS: At enrolment, there was no difference between the groups in the number with a depression diagnosis (PHPT 34.1%, thyroid surgery, 35.5%, P = 0.86). However, baseline PHQ-9 scores were significantly higher in PHPT (median 7.5, range 0-27) than thyroid surgery patients (median 3.0, range 0-18, P < 0.0001). Following surgery, all PHQ-9 scores, total and symptom group (cognitive, somatic) improved and were no longer different between PHPT (total PHQ-9 median 2, range 0-16) and thyroid (median 1, range 0-14, P = 0.31) groups. Baseline parathyroid hormone level, but not calcium, had a weak relationship with change in PHQ-9 score after parathyroid surgery (P = 0.003). Baseline PHQ-9 score was correlated with change in PHQ-9 score at 12 months after parathyroid surgery (P < 0.001). CONCLUSIONS: Depression scores improve in both somatic and cognitive domains after parathyroidectomy for PHPT and baseline severity of depression predicts the response. PubMed-ID: 31168854 http://dx.doi.org/10.1111/cen.14045

Persistently Elevated PTH After Parathyroidectomy at One Year: Experience in a Tertiary Referral Center. J Clin Endocrinol Metab, 104(10):4473-80. M. Caldwell, J. Laux, M. Clark, L. Kim and J. Rubin. 2019. CONTEXT/OBJECTIVE: Increased PTH after successful parathyroid surgery represents a clinical conundrum. We aimed to determine the prevalence of persistently elevated PTH (PePTH) postsurgery, along with predisposing factors. DESIGN: and Setting: Patients >/= age 18 with parathyroidectomy performed at University of North Carolina Hospitals for primary hyperparathyroidism (PHPT) over a 12-year period were identified from the Carolina Data Warehouse. Clinical and demographic characteristics were collected, transformed, and analyzed. RESULTS: Five hundred seventy patients met initial criteria for PHPT, and of those 407 had postoperative values. One hundred forty-four had laboratory results within 3 to 18 months post operatively. There was no clinical difference between those with and without long-term laboratory follow-up. Presurgery, patients had average calcium of 11 mg/dL and PTH 125.4 pg/mL. Ninety-seven percent of patients had normalized calcium after surgery, but 30% had PePTH, which can be predicted at 3 months. Patients with PePTH (persistent elevation of PTH) after surgery did not differ from those with normalized PTH in terms of sex, age, body mass index, or excised gland weight; presurgery 25-vitamin D was slightly lower, but not abnormal (26 +/- 15 vs 36 +/- 11). The presurgical PTH was significantly higher (P < 0.001) in those with PePTH (156.5 pg/mL compared with presurgical level of 102.5 in those whose PTH normalized). CONCLUSIONS: Nearly one-third of PHPT patients have elevated PTH levels postsurgery in a tertiary hospital setting. At presentation, patients with PePTH tend to have higher PTH relative to calcium levels. Whether PePTH after surgical treatment of PHPT has pathological consequences is unknown. PubMed-ID: 31188435 http://dx.doi.org/10.1210/jc.2019-00705

Is There an Optimal Time for Parathyroidectomy in Patients with Secondary Hyperparathyroidism? World J Surg, 43(8):1989-90. T. S. Wang. 2019. PubMed-ID: 31201495 http://dx.doi.org/10.1007/s00268-019-05063-2

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Intraoperative Decision Making in Parathyroid Surgery. Surg Clin North Am, 99(4):681-91. D. S. Jason and C. J. Balentine. 2019. This article reviews intraoperative decision making related to several important aspects of parathyroid surgery. These include how to systematically identify a missing gland, when to perform a unilateral versus bilateral exploration for cure, approaches to secondary hyperparathyroidism, management of familial hyperparathyroidism, and the treatment of parathyroid cancer. The management of intraoperative complications, such as recurrent laryngeal nerve injury and devascularization of parathyroid glands, also is discussed. PubMed-ID: 31255199 http://dx.doi.org/10.1016/j.suc.2019.04.008

Investigating subtle kidney injury in primary hyperparathyroidism by means of sensitive and specific biomarkers. Clin Endocrinol (Oxf), 91(5):660-8. C. Cipriani, J. Pepe, L. Colangelo, V. Fassino, M. Occhiuto, P. Biondi, L. Nieddu and S. Minisola. 2019. OBJECTIVE: Kidney involvement is a common complication in primary hyperparathyroidism (PHPT). No study so far has assessed the prevalence of kidney injury developing before the reduction in glomerular filtration rate (GFR) in PHPT. The study was aimed at establishing the potential role of biomarkers of kidney injury in detecting subtle renal damage in patients with PHPT. DESIGN: Cross-sectional study. PATIENTS: A total of 69 postmenopausal patients with PHPT and 41 healthy age- and sex-matched subjects were studied. Exclusion criteria were as follows: GFR < 30 mL/min, chronic inflammatory disease, nephrotic syndrome, infection, malignancy, heart failure, recent exposure to iodinated contrast media or nonsteroidal anti-inflammatory drugs. MEASUREMENTS: We measured a panel of sensitive biomarkers of kidney injury in PHPT vs controls. RESULTS: Mean FGF23 and Klotho were higher in PHPT (72 +/- 48 and 811 +/- 366 pg/mL, respectively) than controls (53 +/- 23.5 and 668.6 +/- 17; P < .02 and P < .05). Urine KIM-1/uCr was significantly higher in PHPT (1.4(-6) +/- 1.3(-6) ) than controls (9.2(-7) +/- 7(-7) ; P < .05); this was particularly evident in the CrCl 60-89 mL/min category (1.3(6) +/- 9(7) vs 8.2(-7) +/- 3.6(-7) ; P < .02). Mean values of urine NGAL/uCr were higher in PHPT with (n = 28) compared to those without kidney stones (n = 35; 1.8(-5) +/- 1.4(-5) and 1(-5) +/- 8(-6) ; P < .0001). We found significant positive associations between urine NGAL/uCr and Ca (R = .292, P < .02) and urine KIM1/uCr and PTH (R = .329, P < .01). CONCLUSIONS: We propose the utilization of these molecules, particularly urine KIM-1/uCr and urine NGAL/uCr ratios for the assessment of subtle kidney injury in patients with PHPT. These molecules are elevated in tubular necrosis and have potential role in the development of kidney damage in PHPT, according to the severity of the disease. PubMed-ID: 31309599 http://dx.doi.org/10.1111/cen.14064

Serum Parathyroid Hormone and Risk of Coronary Artery Disease: Exploring Causality Using Mendelian Randomization. J Clin Endocrinol Metab, 104(11):5595-600. H. Melhus, K. Michaelsson and S. C. Larsson. 2019. CONTEXT: Elevated circulating parathyroid hormone concentrations have been associated with increased risk of cardiovascular disease in observational studies, but whether the association is causal is unknown. OBJECTIVE: We used the Mendelian randomization design to test whether genetically increased serum parathyroid hormone (S-PTH) concentrations are associated with coronary artery disease (CAD). DESIGN, SETTING, AND PARTICIPANTS: Five single-nucleotide polymorphisms robustly associated with S-PTH concentrations were used as instrumental variables to estimate the association of genetically higher S-PTH concentrations with CAD. Summary statistics data for CAD were obtained from a genetic consortium with data from 184,305 individuals (60,801 CAD cases and 123,504 noncases). MAIN OUTCOME MEASURE: OR of CAD per genetically predicted one SD increase of S-PTH concentrations. RESULTS: Genetically higher S-PTH concentration was not associated with CAD as a whole or myocardial infarction specifically ( approximately 70% of total cases). The ORs per genetically predicted one SD increase in S-PTH concentration were 1.01 (95% CI: 0.93 to 1.09; P = 0.88) for CAD and 1.02 (95% CI: 0.94 to 1.10; P = 0.64) for myocardial infarction. The lack of association remained in various sensitivity analyses. CONCLUSION: Genetic predisposition to higher S-PTH concentrations does not appear to be an independent risk factor for CAD. PubMed-ID: 31310319 http://dx.doi.org/10.1210/jc.2019-01063

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ASO Author Reflections: Distant Metastatic Parathyroid Carcinoma-Has the "Train Left the Station?". Ann Surg Oncol, 26(11):3600-1. E. A. Asare and N. D. Perrier. 2019. PubMed-ID: 31313033 http://dx.doi.org/10.1245/s10434-019-07622-2

[Surgical treatment of parathyroid carcinoma : Does the initial en bloc resection improve the prognosis?]. Chirurg, 90(11):905-12. S. Wachter, K. Holzer, J. Manoharan, C. Brehm, I. Mintziras, D. K. Bartsch and E. Maurer. 2019. BACKGROUND: Radical en bloc resection of the tumor with ipsilateral hemithyroidectomy and central lymphadenectomy (PTX+HTX) is currently the generally recommended treatment strategy for parathyroid carcinoma (PC) in Germany; however, it remains unclear whether the en bloc resection leads to a prognostic benefit compared to parathyroidectomy (PTX) alone, especially considering disease-free and overall survival. OBJECTIVE: This study analyzed the survival of patients with PC after PTX+HTX compared to patients with PTX. METHODS: Patients with PC were identified from a prospective database and retrospectively analyzed regarding clinicopathological features, surgical treatment, disease-free interval and overall survival. RESULTS: Out of 1705 patients who were operated on because of primary hyperparathyroidism (pHPT), 18 (1.1%) had histologically confirmed PC. In nine patients PTX+HTX was initially performed and the other nine patients received only PTX. After PTX, all of the nine patients developed a recurrence after a median of 18 months (range 7-84 months), while only one patient had a recurrence after PTX+HTX. After PTX a median three (range 2-18) reoperations were indicated for relapse but after PTX+HTX only one patient had to undergo two relapse surgeries (p< 0.001). The recurrence-free survival after PTX+HTX was significantly longer than after PTX (143 vs. 18 months, p= 0.01), while the overall survival of both groups after a median follow-up of 107.5 months did not significantly differ. DISCUSSION: If there is any clinical suspicion of PC, an en bloc resection should be performed to prolong recurrence-free survival and avoid reoperations. PubMed-ID: 31359113 http://dx.doi.org/10.1007/s00104-019-1007-0

Pattern of Intraoperative Parathyroid Hormone and Calcium in the Treatment of Tertiary Hyperparathyroidism. Otolaryngol Head Neck Surg, 161(6):954-9. A. L. M. Casarim, F. Arcadipane, A. S. Martins, A. Del Negro, A. A. N. Rodrigues, A. J. Tincani and E. Marchi. 2019. OBJECTIVE: Tertiary hyperparathyroidism, an autonomous hyperproduction of parathyroid hormone (PTH), has a challenge in its treatment. This study asked whether the intraoperative PTH and calcium drop can confirm the resection of all parathyroid tissues. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary referral medical center. SUBJECTS AND METHODS: The study assessed patients with tertiary hyperparathyroidism who were treated at the Hospital of the State University of Campinas from 2007 to 2015. All patients underwent total parathyroidectomy with autotransplantation of parathyroid fragments. PTH and calcium were collected during the preoperative period; at 10, 20, and 240 minutes after resection of the glands; and at 1 year after the procedure. Data were analyzed by analysis of variance and logistic regression analysis with statistical values of P < .05. RESULTS: Thirty-five patients were assessed: 17 women (48.57%) and 18 men (51.43%). The percentage of PTH drop was statistically significant at all times, unlike the calcium analysis, but only PTH collected at 20 minutes was able to confirm the removal of all parathyroid tissues (P = .029). Based on the receiver operating characteristic curve, the 71.2% drop obtained high sensitivity and specificity (P = .028). CONCLUSIONS: Treatment success can be predicted by analyzing the decrease of intraoperative PTH and not by calcium. The 71.2% PTH drop at 20 minutes after parathyroidectomy had high sensitivity and specificity to predict surgical cure. PubMed-ID: 31359817 http://dx.doi.org/10.1177/0194599819866819

PTH Immunoassay Interference Due to Human Anti-Mouse Antibodies in a Subject With Obesity With Normal Parathyroid Function. J Clin Endocrinol Metab, 104(12):5840-2. M. Laudes, J. Frohnert, K. Ivanova and K. P. Wandinger. 2019. CONTEXT: Immunoassay interference has been most often found with prolactin measurement. However, only few data exist on immunoassay interference for other hormones. CASE DESCRIPTION: A 36-year-old woman with obesity (body mass index, 31 kg/m2) had regularly attended our endocrine unit for type 2 diabetes therapy.

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When she was included as a control subject in a study for obesity management, detailed laboratory testing was performed, including PTH. In the absence of clinical symptoms, she presented with normal calcium, phosphate, and vitamin D levels. However, the PTH levels were >5000 ng/L. These results were obtained using the Roche Elecsys electrochemiluminescence assay. Repeated measurements with this assay (mouse antibody) led to the same findings. However, using an Euroimmun assay (goat antibody), the exact PTH values were measured at 18.0 ng/L. After pretreatment with a heterophilic antibody blocking reagent, the results of the Roche assay had decreased to a normal level. This phenomenon was explained by the detection of human anti-mouse antibodies in the proband's serum. CONCLUSIONS: In cases of prolactin immunoassay interference, endogenous antibodies will bind to the hormone in vivo, resulting in complexes of a high molecular weight that are less efficiently cleared by the kidneys and, thus, accumulate in the blood. In contrast, the PTH values >5000 ng/L detected in our subject most likely had resulted from the specific interference of the human anti-mouse antibodies present in the proband's serum with the assay antibody, resulting in artificial stimulation of the Roche assay detection system ex vivo. PubMed-ID: 31411693 http://dx.doi.org/10.1210/jc.2019-01321

Discordant findings on preoperative imaging for primary hyperparathyroidism and thyroid disease: Choosing the path to follow. Surgery, 166(4):678-85. A. C. Beck, A. K. Kashyap, G. Lal, J. R. Howe, R. J. Weigel, M. M. Graham and S. L. Sugg. 2019. BACKGROUND: Preoperative localization of abnormal parathyroid glands in primary hyperparathyroidism is often obtained by sestamibi, and ultrasonography. We aimed to identify which modality is most accurate when laterality of abnormal glands on preoperative imaging is discordant. METHODS: A single institution retrospective review identified 112 consecutive patients with primary hyperparathyroidism who underwent successful parathyroidectomy and sestamibi with pertechnetate. RESULTS: Sestamibi with pertechnetate had a sensitivity of 72% and positive predictive value of 90%; ultrasonography had sensitivity of 50% and positive predictive value 80%. Patients with thyroiditis had lesser sensitivity and positive predictive value on sestamibi with pertechnetate (53% and 77%, respectively), in contrast to ultrasonography (54%, 88%, respectively). The sensitivity and positive predictive value of sestamibi with pertechnetate and ultrasonography did not differ in patients with thyroid nodules. Seventeen patients (15%) had discordant laterality on preoperative imaging. In discordant cases, sestamibi with pertechnetate was correct in 53% overall but in only 17% of those with thyroiditis (P = .01), whereas ultrasonography was correct in 26% overall but in 50% of those with thyroiditis (P = .01). CONCLUSION: Thyroiditis decreased the sensitivity and positive predictive value of sestamibi with pertechnetate in primary hyperparathyroidism. In patients with discordant laterality on preoperative imaging, sestamibi with pertechnetate is the more accurate choice to guide operative planning, although ultrasonography may be a better guide in those with thyroiditis. PubMed-ID: 31466855 http://dx.doi.org/10.1016/j.surg.2019.05.057

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Adrenals

Meta-Analyses Genotype-phenotype correlations in pheochromocytoma and paraganglioma. Endocr Relat Cancer, J. Crona, A. Lamarca, S. Ghosal, S. Welin, B. Skogseid and K. Pacak. 2019. Pheochromocytoma and paraganglioma (PPGL) can be divided into at least four molecular subgroups. Whether such categorizations are independent factors for prognosis or metastatic disease is unknown. We performed a systematic review and individual patient meta-analysis aiming to estimate if driver mutation status can predict metastatic disease and survival. Driver mutations were used to categorize patients accordingly to three different molecular systems: two subgroups (SDHB mutated or wild type), three subgroups (pseudohypoxia, kinase signaling or Wnt/unknown) and four subgroups (tricarboxylic acid cycle, VHL/EPAS1, kinase signaling or Wnt/unknown). Twenty-one studies and 703 patients were analyzed. Multivariate models for association with metastasis showed correlation with SDHB mutation (OR 5.68 [95% CI 1.79-18.06]) as well as norepinephrine (OR 3.01 [95% CI 1.02-8.79]) and dopamine (OR 6.39 [95% CI 1.62-25.24]) but not to PPGL location. Other molecular systems were not associated with metastasis. In multivariate models for association with survival, age (HR 1.04 [95% CI 1.02-1.06]) and metastases (HR 6.13 [95% CI 2.86-13.13]) but neither paraganglioma or SDHB mutation remained significant. Other molecular subgroups did not correlate with survival. We conclude that molecular categorization accordingly to SDHB provided independent information on the risk of metastasis. Driver mutations status did not correlate independently with survival. These data may ultimately be used to guide current and future risk stratification of PPGL. PubMed-ID: 30893643 http://dx.doi.org/10.1530/ERC-19-0024

Improvement but No Normalization of Quality of Life and Cognitive Functioning After Treatment of Cushing Syndrome. J Clin Endocrinol Metab, 104(11):5325-37. L. H. A. Broersen, C. D. Andela, O. M. Dekkers, A. M. Pereira and N. R. Biermasz. 2019. BACKGROUND: Cushing syndrome is characterized by glucocorticoid excess, which induces physical and mental symptoms, impairments in functional status and perceived health, resulting in impaired quality of life. Biochemical remission is urgently required; however, quality of life and cognitive function may remain impaired. OBJECTIVE: To perform a systematic review and meta-analysis evaluating changes in health-related quality of life and cognitive functioning in patients with Cushing syndrome after treatment. METHODS: Eight electronic databases were searched in March 2017, and PubMed again in May 2018, to identify potentially relevant articles. Eligible studies were (randomized controlled) trials, cohort studies, and cross-sectional studies assessing quality of life or cognitive functioning in patients treated for Cushing syndrome. Differences were expressed as standardized mean difference and reported with 95% confidence intervals. We compared patients before and after treatment (improvement) and patients after treatment and healthy controls (normalization). RESULTS: We included 47 articles with 2643 patients. Most patients had Cushing disease and were in remission after treatment. Quality of life and cognitive functioning improved after treatment in all studied domains. Compared with a healthy control population, quality of life did not normalize. Cognitive functioning normalized in part, but not all, of the studied domains. CONCLUSIONS: Treatment of Cushing syndrome improves quality of life and cognitive functioning. Because normalization was not achieved in quality of life and in some aspects of cognitive functioning, special and continuous attention should be given to these aspects for patients after treatment. Effective interventions for further improvement and possibly normalization are urgently needed. PubMed-ID: 31276166 http://dx.doi.org/10.1210/jc.2019-01054

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Randomized controlled trials Lateral Transperitoneal Adrenalectomy Versus Posterior Retroperitoneoscopic Adrenalectomy for Benign Adrenal Gland Disease: Randomized Controlled Trial at a Single Tertiary Medical Center. Ann Surg, 269(5):842-8. Y. J. Chai, H. W. Yu, R. Y. Song, S. J. Kim, J. Y. Choi and K. E. Lee. 2019. OBJECTIVE: The aim of this study was to compare the surgical outcomes of lateral transperitoneal adrenalectomy (LTA) and posterior retroperitoneoscopic adrenalectomy (PRA) for benign adrenal tumor. BACKGROUND: Although LTA is the standard treatment for benign adrenal gland tumor, PRA has recently gained popularity. Studies comparing the surgical outcomes of the 2 approaches have reported conflicting findings and thus it remains unclear which approach is superior. METHODS: This trial was conducted between September 2012 and February 2016. Patients were randomized to either LTA or PRA groups in a 1:1 ratio using web-based randomization. The primary outcome was operative time, and the secondary outcomes were blood loss, intraoperative hemodynamic stability, postoperative pain, recovery of bowel movement, and complication rates. This trial was registered with ClincalTrials.gov, number NCT01676025. RESULTS: A total of 83 patients were randomly assigned to the LTA group (n = 42) or the PRA group (n = 41). Median follow-up was 31.3 months. The mean operative times of LTA and PRA were comparable (59.7 +/- 18.6 vs 67.6 +/- 28.7 minutes, P = 0.139). Logistic regression analysis showed that male sex [odds ratio (OR) = 4.20] and pheochromocytoma (OR = 5.06) were associated with an operative time >/=60 minutes. There were no differences in the secondary outcomes between the groups. One patient in the PRA group required open conversion. CONCLUSION: Both LTA and PRA were performed safely with similar operative outcomes, and thus are comparable options for the treatment of benign adrenal gland tumor. PubMed-ID: 29189215 http://dx.doi.org/10.1097/SLA.0000000000002603

Consensus Statements/Guidelines - None -

Other Articles Pheochromocytoma Characteristics and Behavior Differ Depending on Method of Discovery. J Clin Endocrinol Metab, 104(5):1386-93. L. M. Gruber, R. P. Hartman, G. B. Thompson, T. J. McKenzie, M. L. Lyden, B. M. Dy, W. F. Young and I. Bancos. 2019. CONTEXT: Modern pheochromocytomas (PHEOs) are often discovered by incidental finding on cross-sectional imaging or mutation-based genetic case detection testing. Little is known about how these PHEOs behave. OBJECTIVE: To describe the characteristics and behavior of PHEOs discovered incidentally on imaging or through mutation-based genetic case detection testing. DESIGN: Retrospective study. SETTING: Referral center. PATIENTS: Consecutive patients with pathology-confirmed PHEOs, treated from 2005 to 2016. MAIN OUTCOME MEASURE(S): Tumor size, plasma/urine fractionated metanephrines and catecholamines, and preoperative management. RESULTS: Two hundred seventy-one patients (52% women, median age 52.0 years) presented with 296 PHEOs. Discovery method was most often incidental finding on cross-section imaging (61%) rather than PHEO-related symptoms (27%) or mutation-based case detection testing (12%). Patients with incidentally discovered PHEOs were older than symptomatic and mutation-based case detection testing patients (median age 56.6 vs 43 vs 35 years, P < 0.0001). Mutation-based case detection PHEOs were smaller than those discovered due to symptoms (median size 29.0 vs 50.5 mm, P = 0.0027). Patients with PHEOs discovered due to symptoms had the highest median concentration of 24-hour urinary metanephrines and total plasma metanephrines (P < 0.0001). These patients required a higher cumulative phenoxybenzamine dose than patients with incidental or case detection PHEO (median 450 vs 375 vs 270 mg, P = 0.029). CONCLUSIONS: PHEOs are primarily discovered due to incidental finding on cross-sectional imaging rather than PHEO-related symptoms. PHEOs discovered through mutation-based genetic case detection testing were smaller and required less alpha-adrenergic blockade preoperatively compared with PHEOs found due to symptoms, which supports routine case detection testing for patients genetically predisposed for PHEOs.

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PubMed-ID: 30462226 http://dx.doi.org/10.1210/jc.2018-01707

Discordance Between Imaging and Adrenal Vein Sampling in Primary Aldosteronism Irrespective of Interpretation Criteria. J Clin Endocrinol Metab, 104(6):1900-6. D. Sam, G. A. Kline, B. So and A. A. Leung. 2019. BACKGROUND: Subtyping of primary aldosteronism (PA) using imaging and adrenal vein sampling (AVS) may yield discordant results, causing confusion in management. Interpretation criteria for AVS lateralization may affect discordance rates. METHODS: We identified consecutive patients with PA who underwent AVS at a quaternary care center between January 2006 and May 2018. Patient demographics, laboratory results, diagnostic imaging, and AVS results were retrieved. Adrenal cross-sectional imaging was compared with AVS findings. The presence of lateralization was defined using varying thresholds for the lateralization index (LI) from >2:1 to >5:1. Discordance was defined by a unilateral lesion on imaging with contralateral or nonlateralization on AVS. RESULTS: A total of 342 patients were included; 68.7% had hypokalemia. With cross-sectional imaging, 191 (55.6%) patients had unilateral lesions, 47 (13.7%) had bilateral lesions, and 104 (30.4%) had normal imaging. Overall discordance rates were high, ranging from 22% to 28% for LI thresholds of >2:1 and >5:1, respectively. Discordance between imaging and AVS was positively correlated with LI threshold stringency (P < 0.001). Patients with normal or bilateral lesions on imaging frequently lateralized on AVS. Lateralization, when present, was approximately equal between left and right sides, irrespective of the LI threshold. CONCLUSIONS: Discrepancies between imaging and AVS were common, even among patients with nonspecific imaging. Discordance was greatest with the strictest AVS interpretation criteria. Even under the most lenient thresholds, apparent discordance between imaging and AVS exceeded 20% and may limit the ability to make surgical decisions. Reliance on imaging alone for detecting lateralization may be misleading. PubMed-ID: 30590677 http://dx.doi.org/10.1210/jc.2018-02089

Laparoscopic adrenalectomy for metastatic disease: Retrospective cohort with long-term, comprehensive follow-up. Surgery, 165(5):958-64. F. T. Drake, T. Beninato, M. X. Xiong, N. V. Shah, W. P. Kluijfhout, T. Feeney, I. Suh, J. E. Gosnell, W. T. Shen and Q. Y. Duh. 2019. BACKGROUND: Several malignancies metastasize to the adrenal gland, especially non-small cell lung cancer, renal cell carcinoma, and melanoma. Adrenalectomy is associated with prolonged survival, but laparoscopic adrenalectomy for this indication is controversial. Our objective was to characterize and quantify outcomes after laparoscopic adrenalectomy for metastases to the adrenal gland. METHODS: A prospectively maintained surgical database and institutional cancer registry were queried for patients who underwent adrenalectomy for metastases. From 1995 to 2016, a total of 62 patients underwent adrenalectomy for metastases, with 59 (95.%) having been performed laparoscopically. Primary end points were cumulative probability of 5-year survival and median survival. Patients in the institutional series were compared with Surveillance, Epidemiology, and End Results patients with metastatic non-small cell lung cancer, renal cell carcinoma, and melanoma. RESULTS: There were no deaths within a 30-day period, 6 complications, and 2 conversions to open adrenalectomy. Non- small cell lung cancer (N=20), renal cell carcinoma (N=14), and melanoma (N=8) were the 3 most common adrenal metastases. Overall, cumulative probability of 5-year survival was 37% and median survival was 34 months (95% CI 26-53 months). Median survival for non-small cell lung cancer was 26 months, for renal cell carcinoma was 67 months, and for melanoma was 30 months (P=NS). There was no demonstrable survival benefit for metachronous versus synchronous presentations, no association with size or disease-free interval, nor the presence/history of other metastases. CONCLUSION: Laparoscopic adrenalectomy for metastases is safe when performed by experienced surgeons. Outcomes are similar or improved compared with series with predominantly open adrenalectomies. Patients selected for laparoscopic adrenalectomy to treat metastatic disease also have prolonged survival compared with Surveillance, Epidemiology, and End Results patients with metastatic non-small cell lung cancer, renal cell carcinoma, or melanoma who do not undergo resection of metastatic disease. PubMed-ID: 30591377 http://dx.doi.org/10.1016/j.surg.2018.11.008

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Retrospective analysis of variant venous anatomy in 303 laparoscopic adrenalectomies and its clinical implications. J Surg Oncol, 119(6):801-6. F. Sun, R. Zhuo, W. Ma, H. He, L. Ye, D. Xu, W. Wang and G. Ning. 2019. BACKGROUND AND OBJECTIVES: To clarify the correlation of variant venous anatomy with adrenal tumor phenotype and surgical outcomes. PATIENTS AND METHODS: This retrospective study included 303 consecutive minimally invasive adrenalectomies from 301 patients. All adrenal veins were identified. We compared the preoperative, intraoperative, and postoperative data between patients with and without variant adrenal venous anatomy. We also explored the factors associated with venous variants. RESULTS: We found variant venous anatomy in 62 of 303 adrenalectomies (20.5%). Compared with patients with normal anatomy, those with variant anatomy were associated with larger tumor size, larger adrenal veins, more adrenal medullary tumors, longer operation time, more estimated intraoperative blood loss, longer length of hospitalization, and more transfusion. Computed tomography (CT) images may improve the identification of venous anatomy. Tumor size and diagnosis of pheochromocytoma were independently related to variant venous anatomy, whereas sex, tumor size, and venous variant influenced hemorrhage. For pheochromocytoma with variant venous anatomy operated on by a single surgeon, robot-assisted laparoscopic adrenalectomy was associated with shorter postoperative hospitalization. CONCLUSIONS: Adrenal vein variants are associated with worse outcomes in adrenal tumors and an optimized surgery strategy should be applied to this group of patients. PubMed-ID: 30697735 http://dx.doi.org/10.1002/jso.25364

Prognosis of Malignant Pheochromocytoma and Paraganglioma (MAPP-Prono Study): A European Network for the Study of Adrenal Tumors Retrospective Study. J Clin Endocrinol Metab, 104(6):2367-74. S. Hescot, M. Curras-Freixes, T. Deutschbein, A. van Berkel, D. Vezzosi, L. Amar, C. de la Fouchardiere, N. Valdes, F. Riccardi, C. Do Cao, J. Bertherat, B. Goichot, F. Beuschlein, D. Drui, L. Canu, P. Niccoli, S. Laboureau, A. Tabarin, S. Leboulleux, B. Calsina, R. Libe, A. Faggiano, M. Schlumberger, F. Borson-Chazot, M. Mannelli, A. P. Gimenez-Roqueplo, P. Caron, H. Timmers, M. Fassnacht, M. Robledo, I. Borget and E. Baudin. 2019. BACKGROUND: Malignant pheochromocytoma and paraganglioma (MPP) are characterized by prognostic heterogeneity. Our objective was to look for prognostic parameters of overall survival (OS) in MPP patients. PATIENTS AND METHODS: Retrospective multicenter study of MPP characterized by a neck-thoraco- abdomino-pelvic CT or MRI at the time of malignancy diagnosis in European centers between 1998 and 2010. RESULTS: One hundred sixty-nine patients from 18 European centers were included. Main characteristics of patients with MPP were: primary pheochromocytoma in 53% of patients; tumor- or hormone-related symptoms in 57% or 58% of cases; positive plasma or urine hormones in 81% of patients; identification of a mutation in SDHB in 42% of cases. Metastatic sites included bone (64%), lymph node (40%), lung (29%), and liver (26%); mean time between initial and malignancy diagnosis was 43 months (range, 0 to 614). Median follow-up was 68 months and median survival 6.7 years. Using univariate analysis, better survival was associated with head and neck paraganglioma, age <40 years, metanephrines less than fivefold the upper limits of the normal range, and low proliferative index. In multivariate analysis, hypersecretion [hazard ratio 3.02 (1.65 to 5.55); P = 0.0004] was identified as an independent significant prognostic factor of worst OS. CONCLUSIONS: Our results do not confirm SDHB mutations as a major prognostic parameter in MPP and suggest additional key molecular events involved in MPP tumor progression. Aside from SDHB mutation, the biology of aggressive MPP remains to be understood. PubMed-ID: 30715419 http://dx.doi.org/10.1210/jc.2018-01968

(11) C-Metomidate PET/CT is a useful adjunct for lateralization of primary aldosteronism in routine clinical practice. Clin Endocrinol (Oxf), 90(5):670-9. P. M. O'Shea, D. O'Donoghue, W. Bashari, R. Senanayake, M. B. Joyce, A. S. Powlson, D. Browne, G. J. O'Sullivan, H. Cheow, I. Mendichovszky, D. Quill, A. Lowery, D. Lappin, M. Gurnell and M. C. Dennedy. 2019. OBJECTIVE: To describe clinical practice experience of (11) C-Metomidate PET/CT as an adjunct to adrenal vein sampling (AVS) in the lateralization of aldosterone-producing adenomas (APA) in primary aldosteronism (PA). CONTEXT: Accurate lateralization of APA in the setting of PA offers the potential for surgical cure and improved long-term cardiovascular outcomes. Challenges associated with AVS, the current gold standard lateralization modality, mean that only a small proportion of potentially eligible patients currently make it through to surgery. This has prompted consideration of alternative strategies for lateralization, including the application of

ESES Review of Recently Published Literature 2019-2 Page 49 of 71 novel molecular PET tracers such as (11) C-Metomidate. DESIGN: Clinical Service Evaluation/Retrospective audit. PATIENTS: Fifteen individuals with a confirmed diagnosis of PA, undergoing lateralization with (11) C- Metomidate PET/CT prior to final clinical decision on surgical vs medical management. MEASUREMENTS: All patients underwent screening aldosterone renin ratio (ARR), followed by confirmatory testing with the seated saline infusion test, according to Endocrine Society Clinical Practice Guidelines. Adrenal glands were imaged using dedicated adrenal CT. (11) C-Metomidate PET/CT was undertaken due to equivocal or failed AVS. Management outcomes were assessed by longitudinal measurement of blood pressure, ARR, number of hypertensive medications following adrenalectomy or institution of medical therapy. RESULTS: We describe the individual lateralization and clinical outcomes for 15 patients with PA. CONCLUSION: (11) C-Metomidate PET/CT in conjunction with adrenal CT and AVS provided useful information which aided clinical decision- making for PA within a multidisciplinary hypertension clinic. PubMed-ID: 30721535 http://dx.doi.org/10.1111/cen.13942

Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia After Unilateral Adrenalectomy. J Clin Endocrinol Metab, 104(7):2985-93. A. Osswald, M. Quinkler, G. Di Dalmazi, T. Deutschbein, G. Rubinstein, K. Ritzel, S. Zopp, J. Bertherat, F. Beuschlein and M. Reincke. 2019. CONTEXT: Unilateral adrenalectomy has been proposed in selected patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH), but its long-term outcome is unclear. OBJECTIVE: The aim of this study was to analyze long-term clinical and biochemical outcomes of unilateral adrenalectomy vs bilateral adrenalectomy in patients with PBMAH in comparison with the outcome of cortisol-producing adenoma (CPA) treated with unilateral adrenalectomy. DESIGN: Retrospective observational study in three German and one Italian academic tertiary care center. PATIENTS AND METHODS: Twenty-five patients with PBMAH after unilateral adrenalectomy (unilat-ADX-PBMAH), nine patients with PBMAH and bilateral adrenalectomy (bilat- ADX-PBMAH), and 39 patients with CPA and unilateral adrenalectomy (unilat-ADX-CPA) were included. RESULTS: Baseline clinical and biochemical parameters were comparable in patients with unilat-ADX-PBMAH, bilat-ADX-PBMAH, and unilat-ADX-CPA. Directly after surgery, 84% of the patients with unilat-ADX-PBMAH experienced initial remission of Cushing syndrome (CS). In contrast, at last follow-up (median, 50 months), 32% of the patients with unilat-ADX-PBMAH were biochemically controlled compared with nearly all patients in the other two groups (P = 0.000). Adrenalectomy of the contralateral side had to be performed in 12% of the initial patients with unilat-ADX-PBMAH. Three of 20 patients with unilat-ADX-PBMAH (15%) died during follow-up, presumably of CS-related causes; no deaths occurred in the other two groups (P = 0.008). Deaths occurred exclusively in patients who were not biochemically controlled after unilateral ADX. CONCLUSIONS: Our data suggest that unilateral adrenalectomy of patients with PBMAH leads to clinical remission and a lower incidence of adrenal crisis but in less sufficient biochemical control of hypercortisolism, potentially leading to higher mortality. PubMed-ID: 30844071 http://dx.doi.org/10.1210/jc.2018-02204

Impaired Glucose Metabolism in Primary Aldosteronism Is Associated With Cortisol Cosecretion. J Clin Endocrinol Metab, 104(8):3192-202. J. Gerards, D. A. Heinrich, C. Adolf, C. Meisinger, W. Rathmann, L. Sturm, N. Nirschl, M. Bidlingmaier, F. Beuschlein, B. Thorand, A. Peters, M. Reincke, M. Roden and M. Quinkler. 2019. CONTEXT: Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and metabolic risks. Recent studies report glucocorticoid cosecretion as a relevant phenotype of PA, which could contribute to associated risks, including type 2 diabetes mellitus (T2DM). The relationship between autonomous cortisol secretion (ACS) and glucose metabolism in PA has not been investigated. OBJECTIVE: To evaluate the prevalence of impaired glucose homeostasis in patients with PA according to cortisol cosecretion. DESIGN: We performed oral glucose tolerance tests (OGTTs) and complete testing for hypercortisolism [1-mg dexamethasone suppression test (DST), late-night salivary cortisol, 24-hour urinary free cortisol] in 161 newly diagnosed patients with PA of the German Conn Registry. Seventy-six of 161 patients were reevaluated at follow-up. We compared our results to a population-based sample from the Cooperative Health Research in the Region of Augsburg (KORA)-F4 study matched to the participants with PA (3:1) by sex, age, and body mass index. RESULTS: At the time of diagnosis, 125 patients (77.6%) had a pathological response in at least one of the Cushing screening tests; T2DM was diagnosed in 6.4% of these 125 cases. Patients with a pathological DST exhibited significantly higher 2-hour plasma glucose in OGTTs and were significantly more often diagnosed with T2DM than were patients with a normal DST (20% vs 0.8%, P < 0.0001) and matched controls from the KORA

ESES Review of Recently Published Literature 2019-2 Page 50 of 71 study (20.6% vs 5.9%, P = 0.022). Patients with PA without ACS tended to have higher homeostatic model assessment of insulin resistance levels than did KORA control subjects (P = 0.05). CONCLUSION: ACS appears frequently in patients with PA and is associated with impaired glucose metabolism, which could increase the risk of T2DM. PA itself seems to enhance insulin resistance. PubMed-ID: 30865224 http://dx.doi.org/10.1210/jc.2019-00299

Pheochromocytoma: 20years of improving surgical care. Am J Surg, 217(5):967-9. T. C. Worrest, E. W. Gilbert and B. C. Sheppard. 2019. BACKGROUND: Laparoscopic adrenalectomy is now the standard for pheochromocytoma. We report two decades of institutional experience with pheochromocytoma adrenalectomy. METHODS: A retrospective review was undertaken of pheochromocytoma adrenalectomy patients between 1997 and 2017. Clinical variables and postoperative complications were recorded. Patients were divided into quartiles for analysis: group 1 from 1997 to 2001, group 2 from 2002 to 2006, group 3 from 2007 to 2011, and group 4 from 2012 to 2017. RESULTS: Eighty-two pheochromocytoma adrenalectomies were identified. The percentage of laparoscopic adrenalectomies increased over time: 60% in group 1-87.5% in group 4 (p=0.03). The average tumor size decreased: 6.4cm (2.8-14.3cm) in group 1-4.6cm (1.2-7.8cm) in group 4 (p=0.03). ICU utilization decreased from 80% to 40.6% (p=0.03) and length of stay decreased from 7.2 days to 2.7 days (p=0.005). Clavien-Dindo grade>3 complications did not differ between the quartiles (p=0.08). CONCLUSION: Pheochromocytoma care has evolved from more open procedures with standard postoperative ICU stay to a laparoscopic resection with targeted ICU care and decreased length of stay. As experience with laparoscopic adrenalectomy increases, patient outcomes improve. PubMed-ID: 30922520 http://dx.doi.org/10.1016/j.amjsurg.2019.03.016

Influence of Adrenal Venous Sampling on Management in Patients with Primary Aldosteronism Independent of Lateralization on Cross-Sectional Imaging. J Am Coll Surg, 229(1):116-24. R. A. Campbell, D. S. Young, C. N. Shaver, S. K. Snyder, S. A. Milan, T. C. Lairmore and D. K. McDonald. 2019. BACKGROUND: Patients with primary aldosteronism undergo imaging of the adrenal glands after confirmation of the disease. Adrenal venous sampling (AVS) is a useful adjunct to imaging, and advocates believe that AVS should be performed before surgical management. Others argue that patients with unilateral lesions on imaging do not require AVS. Although AVS accuracy has been established, few studies have evaluated how AVS alters management. Our study aimed to determine how AVS affected management of these patients. STUDY DESIGN: Patient data were collected retrospectively from the electronic medical records at a single institution. Patients aged 18 years or older who underwent AVS with successful adrenal vein cannulation from 2007 to 2016 were included. The laterality of AVS was compared with laterality of preprocedural imaging for each patient. The management plan before AVS was determined by laterality on preprocedural imaging. The primary outcomes were management of primary aldosteronism, change in management compared with the plan before AVS, and antihypertensive medication use after therapy. RESULTS: Seventy-four patients had successful adrenal venous cannulation. Thirty-three (44.6%) patients had AVS lateralization that was concordant with preprocedural imaging. Forty-one (55.4%) patients had AVS lateralization that was non-concordant with preprocedural imaging. There was a change in management in 29 (39.2%) patients. CONCLUSIONS: Adrenal venous sampling can delineate the source of aldosterone hypersecretion, and often this is not concordant with cross-sectional imaging. We found that many patients avoided a potentially non-curative operation due to AVS. Adrenal venous sampling frequently alters the management of aldosteronomas and should be highly considered in patients before surgical intervention. PubMed-ID: 30930101 http://dx.doi.org/10.1016/j.jamcollsurg.2019.03.012

The use of medical identification jewellery in adults with adrenal insufficiency in Australia. Clin Endocrinol (Oxf), 91(1):41-7. R. L. Rushworth, G. L. Chrisp and D. J. Torpy. 2019. OBJECTIVE: Hydrocortisone stress dosing during illness can prevent adrenal crises (AC) in patients with adrenal insufficiency (AI). When patients cannot communicate, medical identification jewellery may facilitate parenteral hydrocortisone provision but patient adoption rates are not known. DESIGN: A cross-sectional analysis of Australian medical identification jewellery subscription data. PATIENTS: Patients with AI aged 20 years and over with an active subscription to a large medical jewellery provider. MEASUREMENTS: Subscription

ESES Review of Recently Published Literature 2019-2 Page 51 of 71 rates by AI subtype, geographic area, age and gender. RESULTS: There were 1955 patients with AI and an active subscription in the database, corresponding to a subscription rate of 105.79/million or approximately one- third of the AI population. The subscription rate was substantially higher in primary AI (60.72/million) than secondary AI (23.16/million), corresponding to approximately 60.7% and 11.6% of the estimated population prevalence of each disorder, respectively. There was substantial variation in use by state/territory, with the highest subscribing state having a rate of over four times that of the lowest (P < 0.001). Women comprised 64.8% (n = 1266) of the group. Subscription also varied by age, being highest in the 60-69 year age group (165.15/million) and lowest in those aged 30-39 years (47.23/million) (P < 0.001). Few patients (4.8%, n = 94) mentioned, either in their record or on their jewellery, the need for urgent parenteral hydrocortisone in the event of severe illness. CONCLUSIONS: Medical jewellery is a component of AC risk reduction. However, subscription appears to be underutilised in the Australian AI population, especially among patients with secondary AI. Urgent treatment recommendations should be inscribed on the jewellery. PubMed-ID: 30963602 http://dx.doi.org/10.1111/cen.13985

[Long-term results after adrenalectomy for Conn's syndrome with tomographic imaging and lateralization by selective catheterization]. Chirurg, 90(7):588. H. Dralle. 2019. PubMed-ID: 30993364 http://dx.doi.org/10.1007/s00104-019-0959-4

Improving glucocorticoid replacement profiles in adrenal insufficiency. Clin Endocrinol (Oxf), 91(3):367-71. S. Choudhury, S. Lightman and K. Meeran. 2019. There is an increased mortality associated with adrenal insufficiency despite glucocorticoid replacement therapy with a standardized mortality ratio greater than two. The cause of the increased mortality is yet to be definitively elucidated, but may be due to excess steroid exposure, or replacement regimens that are uncoupled from the normal physiological cortisol profile. Cortisol secretion follows an ultradian pattern which is not possible to reproduce using oral replacement. With the advent of new pumps, it is now possible to mimic the pulsatility of the adrenal glands. While the cognitive and emotional benefits of reproducing the ultradian rhythm are known, the presence of long-term benefits is not yet clear. There is a dearth of evidence and high-quality studies to underline our current understanding of the pathophysiology of adrenal insufficiency and replacement therapy. There is a particular lack of research comparing objective outcomes between patients receiving hydrocortisone replacement (either standard therapy or new sustained release preparations), prednisolone replacement and ultradian pumps. Direct comparative studies are now warranted to understand the optimal approach. PubMed-ID: 31017681 http://dx.doi.org/10.1111/cen.13999

Clinical outcomes after surgery for primary aldosteronism: Evaluation of the PASO-investigators' consensus criteria within a worldwide cohort of patients. Surgery, 166(1):61-8. W. Vorselaars, D. J. van Beek, E. L. Postma, W. Spiering, I. H. M. Borel Rinkes, G. D. Valk and M. R. Vriens. 2019. BACKGROUND: In a first step toward standardization, the Primary Aldosteronism Surgical Outcomes investigators introduced consensus criteria defining the clinical outcomes after adrenalectomy for primary aldosteronism. Within this retrospective cohort study, we evaluated the use of these consensus criteria in daily clinical practice in 16 centers in Europe, Canada, Australia, and the United States. METHODS: Patients who underwent unilateral adrenalectomy for primary aldosteronism between 2010 and 2016 were included. Patients with missing data regarding preoperative or postoperative blood pressure or their defined daily dose were excluded. According to the Primary Aldosteronism Surgical Outcomes criteria, patients were classified as complete, partial, or absent clinical success. RESULTS: A total of 380 patients were eligible for analysis. Complete, partial, and absent clinical success was achieved in 30%, 48%, and 22%, respectively. Evaluation of the Primary Aldosteronism Surgical Outcomes criteria showed that in 11% and 47% of patients with partial and absent clinical success, this classification was incorrect or debatable (16% of the total cohort). This concept of a "debatable classification of success" was due mainly to the cutoff of >/=20 mmHg used to indicate a clinically relevant change in systolic blood pressure and the use of percentages instead of absolute values to indicate a change in defined daily dose. CONCLUSION: Although introduction of the Primary Aldosteronism Surgical Outcomes consensus criteria induced substantial advancement in the standardization of postoperative

ESES Review of Recently Published Literature 2019-2 Page 52 of 71 outcomes, our study suggests that there is room for improvement in the concept for success given the observed limitations when the criteria were tested within our international cohort. In line, determining clinical success remains challenging, especially in patients with opposing change in blood pressure and defined daily dose. PubMed-ID: 31053245 http://dx.doi.org/10.1016/j.surg.2019.01.031

Effect of unilateral adrenalectomy on the quality of life of patients with lateralized primary aldosteronism. BMC Surg, 18(Suppl 1):105. M. Citton, G. Viel, F. Torresan, G. P. Rossi and M. Iacobone. 2019. BACKGROUND: Primary aldosteronism (PA) is associated with an increased prevalence of anxiety and depression. Subnormal quality of life (QoL) scores in PA patients may be improved after surgical treatment. The aim of the study was to assess the impact of surgery on health-related QoL and depression status of patients suffering from PA, comparing the results with a control group of patients undergoing surgery for non-secreting adrenal tumors. METHODS: Data on QoL and depression status were prospectively collected, from January 2014 to January 2017, before, early after surgery (at 1 month) and at late follow up (at least 6 months) in patients with unilateral PA and in a control group with non-secreting adrenal tumors submitted to unilateral laparoscopic adrenalectomy. QoL was assessed using the Short Form 36 (SF-36) Health Survey for Physical (PCS) and Mental Component (MCS); the depression status by a 20-item depression scale (DS) questionnaire. RESULTS: Twenty-six PA patients and 15 controls were recruited. Biochemical cure of the disease was achieved following surgery in all PA patients; hypertension was cured in 31% of cases and improved in the remaining 69% of cases. No morbidity occurred in both groups. There were no significant differences between PA patients and controls concerning demographics, preoperative PCS, MCS and DS values. In patients with PA, MCS values improved at early (42.72 +/- 13.68 vs 51.56 +/- 9.03, p = 0.0005) and late follow up (42.72 +/- 13.68 vs 51.81 +/- 7.04, p < 0.0001); also DS values improved at early (15.92 +/- 11.98 vs 8.3 +/- 8.8, p = 0.0002) and late follow up (15.92 +/- 11.98 vs 4.57 +/- 6.11, p < 0.0001). In PA patients PCS values significantly improved at late follow up (51.02 +/- 8.04 vs 55.85 +/- 5.1, p = 0.013). Also in controls an improvement of MCS and DS scores was found at early and late follow up compared to preoperative values, while no significant differences in PCS were found. CONCLUSIONS: Both PA and non-secreting adrenal tumors affect health-related QoL, worsening MCS and DS scores. Adrenalectomy is effective in curing PA, and improving MCS and DS scores at early and late follow-up, in patients with PA and non-secreting adrenal tumors. In PA patient surgery also significantly improves PCS at late follow up. PubMed-ID: 31074381 http://dx.doi.org/10.1186/s12893-018-0432-1

Treatment of Primary Aldosteronism With mTORC1 Inhibitors. J Clin Endocrinol Metab, 104(10):4703-14. B. Trinh, M. Hepprich, M. J. Betz, T. Burkard, C. Cavelti-Weder, E. Seelig, F. Meienberg, D. V. Kratschmar, F. Beuschlein, M. Reincke, A. Odermatt, M. N. Hall, M. Y. Donath and M. M. Swierczynska. 2019. CONTEXT: Mammalian target of rapamycin complex 1 (mTORC1) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA. OBJECTIVE: To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with PA. DESIGN: (i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout. MAIN OUTCOME MEASURES: (i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters. RESULTS: Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients. CONCLUSION: In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with PA, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients. PubMed-ID: 31087053 http://dx.doi.org/10.1210/jc.2019-00563

ESES Review of Recently Published Literature 2019-2 Page 53 of 71

The incidence of endogenous Cushing's syndrome in the modern era. Clin Endocrinol (Oxf), 91(2):263-70. S. Wengander, P. Trimpou, E. Papakokkinou and O. Ragnarsson. 2019. INTRODUCTION: Epidemiological studies on the incidence of Cushing's syndrome (CS) are few and most often includes only patients with the most common form, that is Cushing's disease (CD). OBJECTIVE: To analyse the incidence of endogenous CS in an unselected cohort of patients from western Sweden between 2002 and 2017. METHODS: Medical records from patients who had received a diagnostic code for CS and adrenocortical carcinoma in the Vastra Gotaland County between 2002 and 2017 were reviewed. Eighty-two patients had been diagnosed with endogenous CS in the region during the study period and were included in this analysis. RESULTS: Thirty-nine patients (48%) had CD, 21 (26%) had ectopic ACTH-producing tumour, 17 (21%) had a benign adrenal CS, and 5 (6%) had cortisol-producing adrenocortical carcinoma. Nine of 21 (43%) patients with ectopic CS had an ACTH-producing lung tumour, 4 had a neuroendocrine pancreas tumour, and 5 had an occult tumour. The annual incidence of endogenous CS was 3.2 cases per million/y; 1.5 for CD, 0.8 for ectopic CS, 0.7 for benign adrenal CS and 0.2 for adrenocortical carcinoma. CONCLUSIONS: Approximately three new cases of endogenous CS, per one million inhabitants, were diagnosed annually between 2002 and 2017. Compared with previous reports, proportionally more patients had ectopic CS. The reason for this is unclear although increased awareness of hypercortisolism in patients with malignant tumours in the modern era is a possible explanation. PubMed-ID: 31094003 http://dx.doi.org/10.1111/cen.14014

Biochemically Silent Sympathetic Paraganglioma, Pheochromocytoma, or Metastatic Disease in SDHD Mutation Carriers. J Clin Endocrinol Metab, 104(11):5421-6. K. M. A. Dreijerink, J. A. Rijken, C. J. Compaijen, H. Timmers, A. N. A. van der Horst-Schrivers, R. S. van Leeuwaarde, P. S. van Dam, C. R. Leemans, E. van Dam, C. Dickhoff, C. J. Dommering, P. de Graaf, G. J. C. Zwezerijnen, P. van der Valk, C. W. Menke-Van der Houven van Oordt, E. F. Hensen, E. P. M. Corssmit and E. M. W. Eekhoff. 2019. CONTEXT: Current guidelines do not consistently recommend imaging beyond the head and neck region in succinate dehydrogenase subunit D (SDHD) mutation carriers as long as catecholamine metabolite levels are within the reference range. PARTICIPANTS: We report a series of 10 patients carrying pathogenic variants in the SDHD gene from five tertiary referral centers for paraganglioma (PGL) in the Netherlands, who presented with a sympathetic PGL (sPGL), pheochromocytoma (PHEO), or metastases outside the head and neck region in the absence of excessive catecholamine production. Two of six patients with a biochemically silent sPGL/PHEO developed metastatic disease. Additionally, four patients were found to have metastases outside the head and neck region from head and neck PGL. The average interval between the initial diagnosis and discovery of the silent lesions was 10 (range, 0 to 32) years. CONCLUSIONS: The absence of excessive catecholamine production does not exclude the presence of manifestations of SDHD outside the head and neck region. These findings suggest that a more extensive imaging strategy in SDHD mutation carriers may be warranted for detection of biochemically silent lesions. PubMed-ID: 31194241 http://dx.doi.org/10.1210/jc.2019-00202

Adrenal Insufficiency After Unilateral Adrenalectomy in Primary Aldosteronism: Long-Term Outcome and Clinical Impact. J Clin Endocrinol Metab, 104(11):5658-64. D. A. Heinrich, C. Adolf, F. Holler, B. Lechner, H. Schneider, A. Riester, N. Nirschl, L. Sturm, X. Wang, R. Ladurner, M. Seidensticker, M. Bidlingmaier, F. Beuschlein and M. Reincke. 2019. CONTEXT: Primary aldosteronism (PA) represents a secondary form of arterial hypertension that can be cured by surgery. Evidence of adrenal insufficiency (AI) was recently found in patients with PA who had undergone unilateral adrenalectomy (uADX). OBJECTIVE: To study the incidence and long-term outcome of postoperative AI after uADX for PA. DESIGN: Prospective registry study (August 2014 until the end of 2018). SETTING: Tertiary referral center. PATIENTS: One hundred consecutive patients undergoing uADX for PA were included. All patients underwent postoperative ACTH stimulation testing. INTERVENTION: Postoperative ACTH stimulation testing to identify patients with AI. MAIN OUTCOME MEASURES: Incidence of patients with postoperative AI and definition of long-term outcome. RESULTS: Twenty-seven percent of patients developed postoperative AI. Of these, 48% had postoperative ACTH stimulation serum cortisol levels

ESES Review of Recently Published Literature 2019-2 Page 54 of 71 days; 95% CI: 11 to 137 days; P = 0.016). One patient with severe AI was hospitalized for an acute adrenal crisis. With a cumulative follow-up of 14.5 years, this produced an incidence rate of 6.9 adrenal crises per 100 patient-years. CONCLUSION: We suggest performing postoperative ACTH stimulation tests in all patients who undergo uADX for PA. PubMed-ID: 31225874 http://dx.doi.org/10.1210/jc.2019-00996

Features of synchronous versus metachronous metastasectomy in adrenal cortical carcinoma: Analysis from the US adrenocortical carcinoma database. Surgery, K. M. Prendergast, P. M. Smith, T. B. Tran, L. M. Postlewait, S. K. Maithel, J. D. Prescott, T. M. Pawlik, T. S. Wang, J. Glenn, I. Hatzaras, R. Shenoy, J. E. Phay, L. A. Shirley, R. C. Fields, L. X. Jin, S. M. Weber, A. Salem, J. K. Sicklick, S. Gad, A. C. Yopp, J. C. Mansour, Q. Y. Duh, N. Seiser, K. I. Votanopoulos, E. A. Levine, G. A. Poultsides, C. C. Solorzano and C. M. Kiernan. 2019. BACKGROUND: Adrenocortical carcinoma is a rare, aggressive cancer. We compared features of patients who underwent synchronous versus metachronous metastasectomy. METHODS: Adult patients who underwent resection for metastatic adrenocortical carcinoma from 1993 to 2014 at 13 institutions of the US adrenocortical carcinoma group were analyzed retrospectively. Patients were categorized as synchronous if they underwent metastasectomy at the index adrenalectomy or metachronous if they underwent resection after recurrence of the disease. Factors associated with overall survival were assessed by univariate analysis. RESULTS: In the study, 84 patients with adrenocortical carcinoma underwent metastasectomy; 26 (31%) were synchronous and 58 (69%) were metachronous. Demographics were similar between groups. The synchronous group had more T4 tumors at the index resection (42 vs 3%, P < .001). The metachronous group had prolonged median survival after the index resection (86.3 vs 17.3 months, P < .001) and metastasectomy (36.9 vs 17.3 months, P = .007). Synchronous patients with R0 resections had improved survival compared to patients with R1/2 resections (P = .008). Margin status at metachronous metastasectomy was not associated with survival (P = .452). CONCLUSION: Select patients with metastatic adrenocortical carcinoma may benefit from metastasectomy. Patients with metachronous metastasectomy have a more durable survival benefit than those undergoing synchronous metastasectomy. This study highlights need for future studies examining differences in tumor biology that could explain outcome disparities in these distinct patient populations. PubMed-ID: 31272813 http://dx.doi.org/10.1016/j.surg.2019.05.024

Somatic PRKACA Mutations: Association With Transition From Pituitary-Dependent to Adrenal- Dependent Cushing Syndrome. J Clin Endocrinol Metab, 104(11):5651-7. G. Di Dalmazi, H. Timmers, G. Arnaldi, B. Kusters, M. Scarpelli, K. Bathon, D. Calebiro, F. Beuschlein, A. Hermus and M. Reincke. 2019. CONTEXT: Prolonged adrenal stimulation by corticotropin, as in long-standing Cushing disease (CD), leads to diffuse to nodular hyperplasia. Adrenal functional autonomy has been described in a subset of patients with CD, leading to the hypothesis of transition from ACTH-dependent to ACTH-independent hypercortisolism. OBJECTIVE: With the consideration that the catalytic alpha subunit of protein kinase A (PKA; PRKACA) somatic mutations are the most common finding in adrenal adenomas associated with ACTH-independent Cushing syndrome, our aim was to analyze PRKACA mutations in adrenals of patients with persistent/long-standing CD. DESIGN: Cross-sectional. SETTING: University hospital. PATIENTS: Two patients with long-standing CD and suspicion of coexistence of autonomous adrenal hyperfunction, according to pre and postoperative evaluations, were selected for this study, following an intensive literature search and patient-chart reviewing. INTERVENTION: Clinical data were analyzed. DNA was extracted from adrenal tissue for PRKACA sequencing. PKA activity was assayed. MAIN OUTCOME MEASURE: PRKACA somatic mutations. RESULTS: Both patients showed mutations of PRKACA in the macronodule in the context of micronodular adrenal hyperplasia. One patient harbored the previously described p.Leu206Arg substitution, whereas a p.Ser213Arg missense variation was detected in the adrenal nodule of the second patient. No mutations were detected in the adjacent adrenal cortex of the second patient. In silico analysis predicts that p.Ser213Arg can interfere with the interaction between the regulatory and catalytic subunits of PKA. CONCLUSIONS: Our study shows that PRKACA somatic mutations can be found in adrenal nodules of patients with CD. These genetic alterations could represent a possible mechanism underlying adrenal nodule formation and autonomous cortisol hyperproduction in a subgroup of patients with long-standing CD. PubMed-ID: 31276155 http://dx.doi.org/10.1210/jc.2018-02209

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Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial. J Clin Endocrinol Metab, 104(12):6193-200. B. A. Carneiro, B. Konda, R. B. Costa, R. L. B. Costa, V. Sagar, D. B. Gursel, L. S. Kirschner, Y. K. Chae, S. A. Abdulkadir, A. Rademaker, D. Mahalingam, M. H. Shah and F. J. Giles. 2019. CONTEXT: Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti-PD-1 nivolumab. OBJECTIVE: The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety. DESIGN: Single-arm, multicenter, phase 2 clinical trial with two-stage design. SETTING: Comprehensive cancer center. PATIENTS: Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy. INTERVENTION: Nivolumab (240 mg) IV every 2 weeks. RESULTS: Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment]. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia. CONCLUSION: Nivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population. PubMed-ID: 31276163 http://dx.doi.org/10.1210/jc.2019-00600

Adrenalectomy Completely Cured Hypertension in Patients With Familial Hyperaldosteronism Type I Who Had Somatic KCNJ5 Mutation. J Clin Endocrinol Metab, 104(11):5462-6. Y. F. Lin, K. Y. Peng, C. H. Chang, Y. H. Hu, V. C. Wu, J. S. Chueh and K. D. Wu. 2019. CONTEXT: Familial hyperaldosteronism type I (FH-I) or glucocorticoid-remediable aldosteronism (GRA) is caused by unequal crossing over of the steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. Somatic KCNJ5 mutations have not been reported in patients with GRA; therefore, the appropriate treatment and prognosis of such concurrent cases remain unknown. CASE DESCRIPTION: Two siblings of a Taiwanese family with GRA were found to have adrenal adenomas and somatic KCNJ5 mutations. Complete clinical cure was achieved after unilateral adrenalectomy. Furthermore, the conversion site of the chimeric gene was identified by direct sequencing. CONCLUSIONS: We report the coexistence of a somatic KCNJ5 mutation and GRA. Patients with GRA whose blood pressure management develops resistance to glucocorticoid treatment could therefore benefit from a lateralization test. The promising outcomes after unilateral adrenalectomy presented in this report offer new perspectives for further research into various PA subtypes. PubMed-ID: 31287546 http://dx.doi.org/10.1210/jc.2019-00689

National Treatment Practice for Adrenocortical Carcinoma: Have They Changed and Have We Made Any Progress? J Clin Endocrinol Metab, 104(12):5948-56. J. F. Tierney, S. V. Chivukula, J. Poirier, S. G. Pappas, E. Schadde, M. Hertl, E. Kebebew and X. Keutgen. 2019. BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials published in 2007 and 2012 showed efficacy for adjuvant mitotane in resectable ACC and etoposide/doxorubicin/cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials. METHODS: The National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). chi2 tests were performed, and Cox proportional hazards models were created. RESULTS: From 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 43% (median, 41 months) in the contemporary cohort and 39% (median, 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy

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(P = 0.005), and 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size >/=10 cm, distant metastases, and positive margins were associated with lower survival after resection (hazard ratio range: 1.39 to 3.09; P < 0.03). CONCLUSIONS: Since 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed. PubMed-ID: 31361313 http://dx.doi.org/10.1210/jc.2019-00915

The Steroid Profile of Adrenal Incidentalomas: Subtyping Subjects With High Cardiovascular Risk. J Clin Endocrinol Metab, 104(11):5519-28. G. Di Dalmazi, F. Fanelli, G. Zavatta, S. Ricci Bitti, M. Mezzullo, A. Repaci, C. Pelusi, A. Gambineri, P. Altieri, C. Mosconi, C. Balacchi, R. Golfieri, E. R. Cosentino, C. Borghi, V. Vicennati, R. Pasquali and U. Pagotto. 2019. CONTEXT: Steroid profiling by mass spectrometry has shown implications for diagnosis and subtyping of adrenal tumors. OBJECTIVES: To investigate steroid profiles and their cardiovascular correlates in a large cohort of patients with nonsecreting (NS) adrenal incidentalomas and autonomous cortisol secretion (ACS). DESIGN: Cohort study. SETTING: University hospital. PATIENTS: Patients (n = 302) with incidentally discovered adrenal masses, divided into unilateral adenoma and hyperplasia with ACS (n = 46 and n = 52, respectively) and NS (n = 120 and n = 84, respectively). Post-dexamethasone suppression test (DST) cortisol <50 or >50 nmol/L defined NS and ACS, respectively. INTERVENTION: Analysis of 10-steroid panel by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and clinical data (mean follow-up 39 months). MAIN OUTCOME MEASURES: Difference in baseline and post-DST steroid profiles between groups. Correlation with cardiovascular profile. RESULTS: Patients with unilateral adenomas and ACS showed higher cortisol, 11- deoxycortisol, and corticosterone and lower dehydroepiandrosterone than those with NS adenomas. Patients with ACS hyperplasia showed higher cortisol and lower androgens in women than those with NS. Patients with ACS had reduced suppression of post-DST cortisol, 11-deoxycortisol, and corticosterone, irrespective of adrenal morphology. Post-DST cortisol and corticosterone were associated with higher prevalence of severe/resistant hypertension. Patients with ACS unilateral adenomas showed higher incidence of worsening of hypertensive disease and novel cardiovascular events than those with NS, with post-DST cortisol [hazard ratio (HR) 1.02; 95% CI, 1.01 to 1.03; P < 0.001] and baseline corticosterone (HR 1.06; 95% CI, 1.01 to 1.12; P = 0.031) among the main predictors. CONCLUSIONS: Patients with adrenal incidentalomas showed different steroid profiles, depending on functional status and adrenal morphology, with implications for their cardiovascular status. PubMed-ID: 31381072 http://dx.doi.org/10.1210/jc.2019-00365

Fluorescence techniques in adrenal surgery. Gland Surg, 8(Suppl 1):S22-S7. E. C. Moore and E. Berber. 2019. This chapter describes the use of fluorescence via indocyanine green (ICG) in minimally invasive adrenal surgery (laparoscopic and robotic). ICG is a non-toxic dye that can aid identification of vascular structures and parenchymal tissue planes in real time. The primary utility of ICG fluorescence in adrenal surgery is to help delineate the margins of resection, to guide a more precise operation. In particular, for patients with bilateral adrenal disease or a heredity associated with high risk of recurrence (e.g., VHL, MEN2a) this may facilitate subtotal adrenal resection (e.g., cortical sparing adrenalectomy), obviating the incidence of iatrogenic adrenal insufficiency and its numerous sequelae including lifelong hormone supplementation, osteoporosis and risk of Addisonian crisis. PubMed-ID: 31404180 http://dx.doi.org/10.21037/gs.2019.03.01

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NET

Meta-Analyses An Assessment of Circulating Chromogranin A as a Biomarker of Bronchopulmonary Neuroendocrine Neoplasia: A Systematic Review and Meta-analysis. Neuroendocrinology, A. Malczewska, M. Kidd, S. Matar, B. Kos-Kudla, L. Bodei, K. Oberg and I. M. Modlin. 2019. PubMed-ID: 31266019 http://dx.doi.org/10.1159/000500525

Randomized controlled trials - None -

Consensus Statements/Guidelines - None -

Other Articles Ki-67 and presence of liver metastases identify different progression-risk classes in pancreatic neuroendocrine neoplasms (pNEN) undergoing resection. Eur J Surg Oncol, 45(5):755-60. M. Milione, P. Maisonneuve, A. Pellegrinelli, P. Spaggiari, G. Centonze, J. Coppa, G. Delconte, M. Droz Dit Busset, O. Lanhazo, G. Pruneri and V. Mazzaferro. 2019. In pancreatic neuroendocrine neoplasms (pNEN), size 20%. Tumor size (2cm) was not a predictive factor at any analysis. Intra-class correlation of Ki-67 values on pre-surgical biopsies vs. surgical specimens was 0.99 and Ki-67 classes were correctly identified in 97% of biopsies. Ki-67 and presence of liver metastases are the major prognostic factors in pNEN and identify different progression risks regardless of tumor size. Pre-surgical pNEN biopsy for Ki-67 assessment should be included in the evaluation of patients with 1-2cm tumors to help in the decision on whether to perform surgical resection. PubMed-ID: 30366875 http://dx.doi.org/10.1016/j.ejso.2018.10.052

Somatostatin Receptor Expression Is Associated With Metastasis and Patient Outcome in Pulmonary Carcinoid Tumors. J Clin Endocrinol Metab, 104(6):2083-93. T. Vesterinen, H. Leijon, H. Mustonen, S. Remes, A. Knuuttila, K. Salmenkivi, P. Vainio, J. Arola and C. Haglund. 2019. CONTEXT: Pulmonary carcinoids (PCs) belong to neuroendocrine tumors that often overexpress somatostatin receptors (SSTRs). This overexpression provides a molecular basis for tumor imaging and treatment with somatostatin analogs. OBJECTIVE: To evaluate SSTR1 to SSTR5 distribution in a large set of PC tumors and to investigate whether the expression is associated with clinicopathological and outcome data. DESIGN, SETTING, AND PATIENTS: This retrospective study was conducted at Helsinki University Hospital and University of

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Helsinki. It included 178 PC tumors coupled with patients' clinical data retrieved through Finnish biobanks. After histological reclassification, tissue specimens were processed into next-generation tissue microarray format and stained immunohistochemically with monoclonal SSTR1 to SSTR5 antibodies. MAIN OUTCOME MEASURE: SSTR1 to SSTR5 expression in PC tumors. RESULTS: Expression of SSTR1 to SSTR5 was detected in 52%, 75%, 56%, 16%, and 32% of the tumors, respectively. Membrane-bound staining was observed for all receptors. SSTR2 negativity and SSTR4 positivity was associated with lymph node involvement at the time of surgery (P = 0.014 and P = 0.017, respectively) and with distant metastasis (P = 0.027 and P = 0.015, respectively). SSTR3 and SSTR4 expression was associated with increased risk of shorter survival [P = 0.046, hazard ratio (HR) 4.703, 95% CI 1.027 to 21.533; and P = 0.013, HR 6.64, 95% CI 1.48 to 29.64, respectively], whereas expression of SSTR1 and SSTR2 was associated with improved outcome (P = 0.021, HR 0.167, 95% CI 0.037 to 0.765; and P = 0.022, HR 0.08, 95% CI 0.01 to 0.70, respectively). CONCLUSION: SSTR1 to SSTR5 expression is observed in PCs. As SSTR expression is associated with the tumor's metastatic potential and patient outcome, these receptors may offer the possibility for individualized prognosis estimation. PubMed-ID: 30657933 http://dx.doi.org/10.1210/jc.2018-01931

Survivals of patients with surgically treated and High-grade pancreatic neuroendocrine carcinomas: A comparative study between two American Joint Committee on Cancer 8th tumor-node-metastasis staging systems. Eur J Surg Oncol, 45(6):1054-60. M. Yang, Y. Zhang, L. Zeng, N. W. Ke, C. L. Tan, B. L. Tian, B. Xiang and X. B. Liu. 2019. BACKGROUND AND OBJECTIVE: We aimed to compare the two new defined tumor-node-metastasis (TNM) systems in the American Joint Committee on Cancer (AJCC) 8th staging manual for overall survival (OS) analysis of G3 pancreatic neuroendocrine carcinomas (p-NECs) that are currently proposed for pancreatic exocrine adenocarcinomas (p-EACs) and G1/G2 pancreatic neuroendocrine tumors (p-NETs), respectively. METHODS: The data of patients who were surgically treated and histopathologically diagnosed with G3 p-NECs at West China Hospital of Sichuan University from January 2002 to June 2017 were retrospectively analyzed and compared using the two new AJCC staging systems. RESULTS: Applying the p-EAC AJCC 8th TNM staging system to G3 p-NECs, the estimated 3-year OSs for each stage were 86.7%, 76.0%, 44.5% and 20.7%, respectively (P<0.001). According to the G1/G2 p-NETs staging system, the estimated OSs at 3 years for each new AJCC stage were 100.0%, 83.6%, 47.1% and 20.7%, respectively (P<0.001). The system for p-EACs significantly discriminated the survival difference of G3 p-NECs between Stage I and Stage II (P=0.019), while the other one for G1/G2 p-NETs could not (P=0.108). The consistent results of Akaike information criteria with Harrell's concordance index indicated that the AJCC 8th staging system for p-EACs was superior when applied to G3 p-NECs for its better prognostic stratification and more accurate prediction ability for OS. CONCLUSIONS: Our analysis demonstrated that both TNM systems in the AJCC 8th staging manual were prognostic for patients with G3 p-NECs; however, the classification originally applied to p-EACs was superior and supported its use in clinical practice. PubMed-ID: 30661921 http://dx.doi.org/10.1016/j.ejso.2019.01.010

Medical Management of Gastroenteropancreatic Neuroendocrine Tumors: Current Strategies and Future Advances. J Nucl Med, 60(6):721-7. A. Mohamed and J. R. Strosberg. 2019. Gastroenteropancreatic neuroendocrine tumors are relatively rare neoplasms, characterized by a propensity to secrete hormones that cause distinct clinical syndromes. During the past decade, the systemic treatment landscape has improved significantly: new options include everolimus, an inhibitor of the mammalian target of rapamycin; sunitinib, an angiogenesis inhibitor; and cytotoxic regimens such as capecitabine and temozolomide. Moreover, the recent approval of the radiolabeled somatostatin analog (177)Lu-DOTATATE has had a significant impact on management of neuroendocrine malignancies. In this review, we discuss advances in the medical management of gastroenteropancreatic neuroendocrine tumors within the context of the larger multidisciplinary approach to these diseases. PubMed-ID: 30737297 http://dx.doi.org/10.2967/jnumed.118.214882

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Surgery for Pancreatic Neuroendocrine Tumor G3 and Carcinoma G3 Should be Considered Separately. Ann Surg Oncol, 26(5):1385-93. T. Yoshida, S. Hijioka, W. Hosoda, M. Ueno, M. Furukawa, N. Kobayashi, M. Ikeda, T. Ito, Y. Kodama, C. Morizane, K. Notohara, H. Taguchi, M. Kitano, K. Yane, Y. Tsuchiya, I. Komoto, H. Tanaka, A. Tsuji, S. Hashigo, T. Mine, A. Kanno, G. Murohisa, K. Miyabe, T. Takagi, N. Matayoshi, M. Sakaguchi, H. Ishii, Y. Kojima, K. Matsuo, H. Yoshitomi, S. Nakamori, H. Yanagimoto, Y. Yatabe, J. Furuse and N. Mizuno. 2019. BACKGROUND: The role of surgery in pancreatic neuroendocrine neoplasm grade 3 (pNEN-G3) treatment remains unclear. We aimed to clarify the role of surgery for pNEN-G3, which has recently been reclassified as pancreatic neuroendocrine tumor-G3 (pNET-G3) and pancreatic neuroendocrine carcinoma-G3 (pNEC-G3), with and without metastases, respectively. METHODS: We analyzed a subgroup of patients from the Japanese pancreatic NEC study, a Japanese multicenter case-series study of pNEN-G3. Pathologists subclassified 67 patients as having pNET-G3 or pNEC-G3 based on morphological features. We compared the overall survival (OS) rates among patients who were grouped according to whether they had undergone tumor-targeted surgery for tumors without (SwoM) or with (SwM) metastases, or non-surgical procedures (NS). RESULTS: Data from 21 patients with pNET-G3 (SwoM, n = 6; SwM, n = 5; NS, n = 10) and 46 patients with pNEC-G3 (SwoM, n = 8; SwM, n = 5; NS, n = 33) were analyzed. OS of patients with pNET-G3 was significantly longer after SwoM and SwM than with NS (p = 0.018 and p = 0.022). In contrast, OS did not significantly differ between either SwoM or SwM and NS (p = 0.093 and p = 0.489) among patients with pNEC-G3. CONCLUSION: The role of surgery should be considered separately for pNET-G3 and pNEC-G3. Although SwoM and SwM can be considered for pNET-G3, caution is advised before considering SwM and SwoM for pNEC-G3. PubMed-ID: 30863939 http://dx.doi.org/10.1245/s10434-019-07252-8

Colon Neuroendocrine Tumors: A New Lymph Node Staging Classification. Ann Surg Oncol, 26(7):2028-36. A. C. Fields, J. C. McCarty, P. Lu, B. M. Vierra, L. M. Pak, J. Irani, J. E. Goldberg, R. Bleday, J. Chan and N. Melnitchouk. 2019. BACKGROUND: The American Joint Commission on Cancer, the European Neuroendocrine Tumor Society, and the North American Neuroendocrine Tumor Society all classify colon neuroendocrine tumor (NET) nodal metastasis as N0 or N1. This binary classification does not allow for further prognostication by the total number of positive lymph nodes. This study aimed to evaluate whether the total number of positive lymph nodes affects the overall survival for patients with colon NET. METHODS: The National Cancer Database was used to identify patients with colon NET. Nearest-neighborhood grouping was performed to classify patients by survival to create a new nodal staging system. The Surveillance, Epidemiology, and End Results database was used to validate the new nodal staging classification. RESULTS: Colon NETs were identified in 2472 patients. Distinct 5-year survival rates were estimated for the patients with N0 (no positive lymph nodes; 69.8%; 95% confidence interval [CI], 66.7-72.7%), N1a (1 positive lymph node; 63.9%; 95% CI, 59.6-68.0%), N1b (2-9 positive lymph nodes; 38.9%; 95% CI, 35.4-42.3%), and N2 (>/= 10 positive lymph nodes; 15.7%; 95% CI, 11.9-20.0%; p < 0.001) nodal classifications. The validation population showed distinct 5-year survival rates with the new nodal staging. In multivariable Cox regression, the new nodal stage was a significant independent predictor of overall survival. CONCLUSIONS: The number of positive locoregional lymph nodes in colon NETs is an independent prognostic factor. For patients with colon NETs, N0, N1a, N1b, and N2 classifications for nodal metastasis more accurately predict survival than current staging systems. PubMed-ID: 30927196 http://dx.doi.org/10.1245/s10434-019-07327-6

Defining the Role of Lymphadenectomy for Pancreatic Neuroendocrine Tumors: An Eight-Institution Study of 695 Patients from the US Neuroendocrine Tumor Study Group. Ann Surg Oncol, 26(8):2517-24. A. G. Lopez-Aguiar, M. Y. Zaidi, E. W. Beal, M. Dillhoff, J. G. D. Cannon, G. A. Poultsides, Z. S. Kanji, F. G. Rocha, P. Marincola Smith, K. Idrees, M. Beems, C. S. Cho, A. V. Fisher, S. M. Weber, B. A. Krasnick, R. C. Fields, K. Cardona and S. K. Maithel. 2019. BACKGROUND: Preoperative factors that reliably predict lymph node (LN) metastases in pancreatic neuroendocrine tumors (PanNETs) are unclear. The number of LNs needed to accurately stage PanNETs has not been defined. METHODS: Patients who underwent curative-intent resection of non-functional PanNETs at eight institutions from 2000 to 2016 were analyzed. Preoperative factors associated with LN metastases were identified. A procedure-specific target for LN retrieval to accurately stage patients was determined. RESULTS: Of 695 patients who underwent resection, 33% of tumors were proximal (head/uncinate) and 67% were distal (neck/body/tail). Twenty-six percent of patients (n = 158) had LN-positive disease, which was associated with a

ESES Review of Recently Published Literature 2019-2 Page 60 of 71 worse 5-year recurrence-free survival (RFS; 60% vs. 86%; p < 0.001). The increasing number of positive LNs was not associated with worse RFS. Preoperative factors associated with positive LNs included tumor size >/= 2 cm (odds ratio [OR] 6.6; p < 0.001), proximal location (OR 2.5; p < 0.001), moderate versus well-differentiation (OR 2.1; p = 0.006), and Ki-67 >/= 3% (OR 3.1; p < 0.001). LN metastases were also present in tumors without these risk factors: < 2 cm (9%), distal location (19%), well-differentiated (23%), and Ki-67 < 3% (16%). Median LN retrieval was 13 for pancreatoduodenectomy (PD), but only 9 for distal pancreatectomy (DP). Given that PD routinely includes a complete regional lymphadenectomy, a minimum number of LNs to accurately stage patients was not identified. However, for DP, removal of less than seven LNs failed to discriminate 5-year RFS between LN-positive and LN-negative patients (less than seven LNs: 72% vs. 83%, p = 0.198; seven or more LNs: 67% vs. 86%; p = 0.002). CONCLUSIONS: Tumor size >/= 2 cm, proximal location, moderate differentiation, and Ki- 67 >/= 3% are preoperative factors that predict LN positivity in resected non-functional PanNETs. Given the 9- 23% incidence of LN metastases in patients without such risk factors, routine regional lymphadenectomy should be considered. PD inherently includes sufficient LN retrieval, while DP should aim to remove seven or more LNs for accurate staging. PubMed-ID: 31004295 http://dx.doi.org/10.1245/s10434-019-07367-y

Short-term and long-term outcomes after robot-assisted versus laparoscopic distal pancreatectomy for pancreatic neuroendocrine tumors (pNETs): a multicenter comparative study. Langenbecks Arch Surg, 404(4):459-68. S. Alfieri, G. Butturini, U. Boggi, A. Pietrabissa, L. Morelli, F. Vistoli, I. Damoli, A. Peri, C. Fiorillo, L. Pugliese, M. Ramera, N. De Lio, G. Di Franco, A. Esposito, L. Landoni, F. Rosa, R. Menghi, G. B. Doglietto and G. Quero. 2019. PURPOSE: Minimally invasive surgery has increasingly gained popularity as a treatment of choice for pancreatectomy with encouraging initial results in robotic distal pancreatectomy (RDP). However, few data are available on the comparison between RDP and laparoscopic distal pancreatectomy (LDP) for pancreatic neuroendocrine tumors (pNETs). Our aim, thus, is to compare perioperative and long-term outcomes as well as total costs of RDP and LDP for pNETs. METHODS: All RDPs and LDPs for pNETs performed in four referral centers from 2008 to 2016 were included. Perioperative outcomes, histopathological results, overall (OS) and disease-free survival (DFS), and total costs were evaluated. RESULTS: Ninety-six RDPs and 85 LDPs were included. Demographic and clinical characteristics were comparable between the two cohorts. Operative time was 36.5 min longer in the RDP group (p = 0.009) but comparable to LDP after removing the docking time (247.9 vs 233.7 min; p = 0.6). LDP related to a lower spleen preservation rate (44.7% vs 65.3%; p < 0.0001) and higher blood loss (239.7 +/- 112 vs 162.5 +/- 98 cc; p < 0.0001). Advantages in operative time for RDP were documented in case of the spleen preservation procedures (265 +/- 41.52 vs 291 +/- 23 min; p = 0.04). Conversion rate, postoperative morbidity, and pancreatic fistula rate were similar between the two groups, as well as histopathological data, OS, and DFS. Significant advantages were evidenced for LDP regarding mean total costs (9235 (+/- 1935) euro vs 11,226 (+/- 2365) euro; p < 0.0001). CONCLUSIONS: Both RDP and LDP are safe and efficacious for pNETs treatment. However, RDP offers advantages with a higher spleen preservation rate and lower blood loss. Costs still remain the main limitation of the robotic approach. PubMed-ID: 31055639 http://dx.doi.org/10.1007/s00423-019-01786-x

Primary Gallbladder Neuroendocrine Tumors: Insights into a Rare Histology Using a Large National Database. Ann Surg Oncol, 26(11):3577-85. R. I. Ayabe, M. Wach, S. Ruff, S. Martin, L. Diggs, T. Wiemken, L. Hinyard, J. L. Davis, C. Luu and J. M. Hernandez. 2019. BACKGROUND: Primary gallbladder neuroendocrine tumors (NETs) are rare, poorly understood cancers infrequently encountered at even the largest of tertiary referral centers. We therefore sought to identify a large cohort of patients with gallbladder NETs using a national database, with the aim of defining treatment modalities employed and survival associated with these uncommon malignancies. METHODS: Patients with primary gallbladder NETs were identified in the National Cancer Database, and clinicopathologic characteristics were recorded. A univariate log-rank survival analysis was completed for patients who underwent resection. Parameters found to be significant were entered into a multivariate accelerated failure time analysis. For context, survival comparisons were included for patients who underwent resections for NETs at any gastrointestinal site and for gallbladder adenocarcinoma. RESULTS: Overall, 754 patients with gallbladder NETs were identified. Patients were predominantly female (n = 518, 69%), White (n = 503, 67%), presented with stage IV disease (n = 295, 39%) and had high-grade lesions (n = 312, 41%). The majority underwent resection (n = 480, 64%),

ESES Review of Recently Published Literature 2019-2 Page 61 of 71 primarily simple cholecystectomy (n = 431, 90%), whereas a minority received multimodal therapy (n = 145, 21%). Among patients who underwent resection, older age (p = 0.001), large cell histology (p = 0.012), and positive margins (p = 0.030) were independently associated with worse overall survival. Patients with gallbladder NETs had improved survival relative to those with gallbladder adenocarcinoma (p = 0.001), but significantly worse survival than patients with NETs from other gastrointestinal sites (p < 0.001). CONCLUSIONS: Primary gallbladder NETs are aggressive lesions that carry a worse prognosis than NETs of other gastrointestinal sites. Older age, positive margins, and large cell histology are associated with abbreviated survival after resection. PubMed-ID: 31102094 http://dx.doi.org/10.1245/s10434-019-07440-6

Management of small asymptomatic nonfunctioning pancreatic neuroendocrine tumors: Limitations to apply guidelines into real life. Surgery, 166(2):157-63. S. Partelli, M. Mazza, V. Andreasi, F. Muffatti, S. Crippa, D. Tamburrino and M. Falconi. 2019. BACKGROUND: International guidelines suggest a watchful strategy for small nonfunctioning pancreatic neuroendocrine tumors. The aim of this study was to evaluate the management and indications for surgery in patients with asymptomatic nonfunctioning pancreatic neuroendocrine tumors fluorodeoxyglucose positron emission tomography (18% vs 50%, P = .003), and a higher incidence of cytologically determined G2 tumor (0% vs 14%, P = .008). Conservatively managed patients had a significantly smaller tumor size (12 vs 16 mm, P = .0001). The main reasons determining surgical choice were as follows: patient's preference (32%), positive (18)F-fluorodeoxyglucose positron emission tomography (21.5%), main pancreatic duct dilation (17.5%), cytologically determined G2 tumor (14.5%), and young age (14.5%). At a median follow-up of 40 months, all of the 73 patients conservatively managed were alive, with no evidence of distant metastases and none underwent surgery. Only 5 patients had a tumor growth >20%. CONCLUSION: One-third of patients with asymptomatic small nonfunctioning pancreatic neuroendocrine tumors

The role of perioperative systemic therapy in localized pancreatic neuroendocrine neoplasms. Neuroendocrinology, H. Xie, J. Liu, S. Yadav, X. Keutgen, T. Hobday, J. R. Strosberg and T. Halfdanarson. 2019. Background The role of perioperative systemic therapy (PST) in the management of localized pancreatic neuroendocrine neoplasms (PanNEN) is unclear. Objectives We aimed to evaluate the benefit of PST compared to surgical alone (SA) in patients with localized PanNEN. Method We selected patients with stage I-III PanNEN who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who had both PST and surgical resection were matched with patients who received SA by propensity score at 1-to-1 ratio with nearest neighbor method. Results 4,892 patients were included in this study with median age of 60 years. Factors associated with significant more use of PST compared to SA included age<65 years, community medical facilities, grade 3 tumor, tumor in the pancreatic head, T3-4 tumor and N1 tumor. 301 PST patients were matched with 301 SA patients. In the matched cohort, the PST group had significantly shorter overall survival compared to the SA group (median overall both not reached, p = 0.037). This finding was confirmed by multivariable Cox proportional hazards regression in the original cohort (HR 1.45, 95% CI 1.11-1.89, p = 0.006). Subgroup analyses showed that adjuvant therapy was not associated with improved overall survival in grade 1-2 PanNEN (HR 2.03, 95% CI 1.31-3.16, p = 0.002). Conclusions PST stratified by grade and neoadjuvant or adjuvant therapy compared to surgery alone was not associated with improved overall survival in patients with localized PanNEN. PST for localized PanNEN should be used with caution until prospective data are available. PubMed-ID: 31121586 http://dx.doi.org/10.1159/000501126

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Symptom Burden at the End of Life for Neuroendocrine Tumors: An Analysis of 2579 Prospectively Collected Patient-Reported Outcomes. Ann Surg Oncol, 26(9):2711-21. J. Hallet, L. E. Davis, A. L. Mahar, E. Isenberg-Grzeda, L. D. Bubis, S. Myrehaug, H. Zhao, K. Beyfuss, L. Moody, C. H. L. Law and N. G. Coburn. 2019. BACKGROUND: Given a slow course of disease, end-of-life issues are understudied in neuroendocrine tumors (NETs). To date, there are no data regarding symptoms at the end of life. This study examined symptom trajectories and factors associated with high symptom burden in NETs at the end of life. METHODS: We conducted a retrospective cohort study of NET patients diagnosed from 2004 to 2015 and who died between 2007 and 2016, in Ontario, Canada. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to administrative healthcare datasets. Moderate-to-severe symptom scores (>/= 4 out of 10) in the 6 months before death were analyzed, with multivariable modified Poisson regression identifying factors associated with moderate-to-severe symptoms scores. RESULTS: Among 677 NET decedents, 2579 symptom assessments were recorded. Overall, moderate-to-severe scores were most common for tiredness (86%), wellbeing (81%), lack of appetite (75%), and drowsiness (68%), with these proportions increasing as death approached. For symptoms of lack of appetite, drowsiness, and shortness of breath, the increase was steepest in the 8 weeks before death. On multivariable analyses, the risk of moderate-to-severe symptoms was significantly higher in the last 2 months before death and for patients with shorter survival (< 6 months). Women had higher risks of anxiety, nausea, and pain. CONCLUSION: A high prevalence of moderate-to-severe symptoms was observed for NETs at the end of life, not previously described. The proportion of moderate-to- severe symptoms increases steeply as death nears, highlighting an opportunity for improved management. Combined with identified factors associated with moderate-to-severe symptoms, this information is important to improve patient-centred and personalized supportive care for NETs at the end of life. PubMed-ID: 31147993 http://dx.doi.org/10.1245/s10434-019-07441-5

[Laparoscopic enucleation of insulinomas]. Chirurg, 90(10):858. H. Dralle. 2019. PubMed-ID: 31190080 http://dx.doi.org/10.1007/s00104-019-0986-1

Recurrence and metastatic potential in Type 1 gastric neuroendocrine neoplasms. Clin Endocrinol (Oxf), 91(4):534-43. K. Daskalakis, M. Tsoli, A. Karapanagioti, M. Chrysochoou, D. Thomas, S. Sougioultzis, I. Karoumpalis, G. A. Kaltsas and K. I. Alexandraki. 2019. BACKGROUND: The aim of our study was to assess clinico-pathological and biochemical parameters of Type 1 Gastric Neuroendocrine Neoplasms (GNEN1) with respect to tumours propensity for recurrence and metastasis. METHODS: Hospital charts of GNEN1 patients were reviewed at a single tertiary referral centre. RESULTS: We included 114 consecutive patients (74 women; age at baseline 54.5 +/- 12.7 years [mean +/- SD]) with GNEN1. All tumours (n = 114) were well differentiated; Grade 1 (G1) accounted for 56 patients (49%), whereas 46 (40%) were Grade 2 (G2) and 12 (11%) of unknown Grade. Overall follow-up encompassed 45.3 +/- 46 (mean +/- SD) months in 84 patients who were subjected to annual surveillance; 44 (52%) developed recurrence in the stomach during follow-up with 22 experiencing multiple recurrences; three (2.6%) presented with metastases in locoregional lymph nodes (n = 3) and/or the liver (n = 2); No metastasis or death was reported during follow-up. Median recurrence-free survival (RFS) was 31 months (95% CI: 7.6-54.4). Among clinico-pathological and biochemical parameters investigated, endoscopic intervention compared with surgery (P-value = .009) and higher serum-gastrin levels (s-gastrin) at baseline and first-year follow-up were associated with recurrence (P- value = .022 and .003 respectively) and also shorter RFS (log-rank P = .009 for type of intervention and .014 for s-gastrin, respectively). Receiver Operator Curve analysis of s-gastrin levels at first-year follow-up for recurrence demonstrated an area under the curve of 0.702. CONCLUSION: Despite the relatively high prevalence of G2 tumours, endoscopically and/or surgically treated GNEN1 remains an indolent disease with a low metastatic propensity and no disease-specific mortality reported in our series. Many patients though will experience local recurrence, warranting long-term endoscopic surveillance with s-gastrin biomarker being a complementary tool in recurrence prediction. PubMed-ID: 31254407 http://dx.doi.org/10.1111/cen.14055

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Evaluation and Management of Neuroendocrine Tumors of the Pancreas. Surg Clin North Am, 99(4):793-814. A. T. Scott and J. R. Howe. 2019. Pancreatic neuroendocrine tumors are a diverse group of neoplasms with a generally favorable prognosis. Although they exhibit indolent growth, metastases are seen in roughly 60% of patients. Pancreatic neuroendocrine tumors may produce a wide variety of hormones, which are associated with dramatic symptoms, but the majority are nonfunctional. The diagnosis and treatment of these tumors is a multidisciplinary effort, and management guidelines continue to evolve. This review provides a concise summary of the presentation, diagnosis, surgical management, and systemic treatment of pancreatic neuroendocrine tumors. PubMed-ID: 31255207 http://dx.doi.org/10.1016/j.suc.2019.04.014

Magnetic Resonance Imaging or Endoscopic Ultrasonography for Detection and Surveillance of Pancreatic Neuroendocrine Neoplasms in Patients with Multiple Endocrine Neoplasia Type 1? Horm Metab Res, 51(9):580-5. K. Daskalakis, M. Tsoli, K. I. Alexandraki, A. Angelousi, E. Chatzellis, A. V. Tsolakis, I. Karoumpalis, D. Kolomodi, E. Kassi and G. Kaltsas. 2019. Our aim was to compare the clinical utility of Magnetic Resonance Imaging (MRI) and Endoscopic Ultrasonography (EUS) in identifying Pancreatic Neurondocrine Neoplasms (PanNENs) and monitoring size alterations in Multiple Endocrine Neoplasia type 1 (MEN1) patients. Thirty-one MEN1 patients with PanNENs and concurrent screening by EUS and abdominal MRI were included and 129 pancreatic lesions were detected in total. MRI detected fewer lesions than EUS (n=73 vs. 110, p=0.006). MRI sensitivity and specificity compared to EUS at 20 and 10 mm cut-offs of maximal lesion diameter were 96 and 88% (20 mm cut-off) and 90 and 82%(10 mm cut-off), respectively (concordance rates of 97 and 87% and Cohen's kappa=0.912 and 0.718, respectively). Lesions<1 cm were more often detected with EUS (p=0.025). Data from sequential concurrent imaging on lesion growth rate [n=7 (mean+/-SD: 2 mm/year+/-3.4 mm vs. 1.9 mm/year+/-3.6 mm)] over a period of at least two years as well as pathology data in connection to preoperative concurrent imaging were available in a small number of patients (n=7, p=0.933 for mean differences in maximal lesion diameter). MRI of the pancreas was more readily available and less expensive than EUS in an outpatient setting. In conclusion, MRI performs well compared to EUS for the detection and subsequent surveillance of MEN1-related panNENs larger than 10 mm and seems to be cost-effective. Both modalities could be used at initial assessment and MRI alone could be utilized thereafter in patient surveillance. EUS retains its value in surgical planning and the detection of small mostly functional PanNENs. PubMed-ID: 31295747 http://dx.doi.org/10.1055/a-0931-7005

68Ga-Exendin-4 PET/CT Detects Insulinomas in Patients With Endogenous Hyperinsulinemic Hypoglycemia in MEN-1. J Clin Endocrinol Metab, 104(12):5843-52. K. Antwi, G. Nicolas, M. Fani, T. Heye, F. Pattou, A. Grossman, P. Chanson, J. C. Reubi, A. Perren, B. Gloor, D. R. Vogt, D. Wild and E. Christ. 2019. CONTEXT: Surgical intervention is advised in patients with multiple endocrine neoplasia type-1 (MEN-1) and nonfunctioning pancreatic neuroendocrine tumors (PanNETs) with a size >/=20 mm. Functioning PanNETs, such as in patients with endogenous hyperinsulinemic hypoglycemia (EHH) due to (one or multiple) insulinomas, should be treated surgically independent of size. Preoperative localization of insulinomas is critical for surgery. OBJECTIVE: To evaluate the feasibility and sensitivity of 68Ga-DOTA-exendin-4 positron emission tomography (PET)/CT in the detection of clinically relevant lesions in patients with MEN-1 and EHH in combination with MRI. DESIGN: Post hoc subgroup analysis of a larger prospective imaging study with 52 patients with EHH. PATIENTS: Six of 52 consecutive patients with EHH and genetically proven MEN-1 mutation were included. INTERVENTIONS: All patients received one 68Ga-DOTA-exendin-4 PET/CT and one MRI scan within 3 to 4 days. Thereafter, surgery was performed based on all imaging results. MAIN OUTCOME MEASURES: Lesion- based sensitivity of PET/CT and MRI for detection of clinically relevant lesions was calculated. Readers were unaware of other results. The reference standard was surgery with histology and treatment outcome. True positive (i.e., clinically relevant lesions) was defined as PanNETs >/=20 mm or insulinoma. RESULTS: In six patients, 37 PanNETs were confirmed by histopathology. Sensitivity (95% CI) in the detection of clinically relevant lesions for combined PET/CT plus MRI, MRI, and PET/CT was 92.3% (64% to 99.8%), 38.5% (13.9% to 68.4%), and 84.6% (54.6% to 98.1%), respectively (P = 0.014 for the comparison of PET/CT plus MRI vs MRI). Postsurgery, EHH resolved in all patients. CONCLUSION: 68Ga-DOTA-exendin-4 PET/CT is feasible in patients with MEN-1 and EHH. The combination with MRI is superior to MRI alone in the detection of insulinomas and

ESES Review of Recently Published Literature 2019-2 Page 64 of 71 may guide the surgical strategy. PubMed-ID: 31298706 http://dx.doi.org/10.1210/jc.2018-02754

Anatomic site as prognostic marker of pancreatic neuroendocrine tumors: a cohort study. Eur J Endocrinol, M. Badarna, R. Percik, G. Aharon-Hananel, I. Uri and A. Tirosh. 2019. OBJECTIVE: Patients with pancreatic neuroendocrine tumors (PNET) have variable prognosis, even with comparable tumor grade and stage. In the current study we aimed to evaluate the prognostic utility of the intrapancreatic PNET anatomical site. DESIGN: Cohort study based on the Surveillance Epidemiology and End- Results database. METHODS: Patients diagnosed with nonfunctioning PNET between 2004-2015 were compared by anatomic site for disease-specific mortality and all-cause mortality, using log-rank test and by multivariable cox regression analysis. RESULTS: 4171 patients (1,839 women [44.1%], median age strata 60-64 years, range 10-14 to >/=85 years) were included in our analysis. Patients with PNETs located at the head vs. body/tail of the pancreas had comparable tumor diameter, as well as ethnicity, gender and age distributions, but had higher rates of grade III and IV NET (13.2% vs. 6.6%, and 4.4% vs. 1.9%, respectively, p<0.001). NETs located at the head vs. body/tail of pancreas were more likely to be locally advanced (32.2% vs 19.9%) with no difference in distant metastases (36.4% vs. 33.5%, respectively, p<0.001). Patients with NETs of the head vs. body/tail of the pancreas had higher disease-specific mortality risk in univariate (log-rank test, p<0.001) and multivariable analysis (Hazard ratio 1.34, 95% confidence interval 1.10-1.65, p=0.004). Multivariable analysis for all-cause mortality also showed increased risk for patients with pancreatic head vs. body/tail PNET (HR 1.23, p=0.013). CONCLUSIONS: PNET anatomical location is associated with the mortality risk, and should be considered as a prognostic factor, and as an additional consideration in directing patients management. PubMed-ID: 31299638 http://dx.doi.org/10.1530/EJE-19-0332

Surgical Management, Preoperative Tumor Localization, and Histopathology of 80 Patients Operated on for Insulinoma. J Clin Endocrinol Metab, 104(12):6129-38. M. Andreassen, E. Ilett, D. Wiese, E. P. Slater, M. Klose, C. P. Hansen, N. Gercke, S. W. Langer, A. Kjaer, E. Maurer, B. Federspiel, P. H. Kann, D. K. Bartsch and U. Knigge. 2019. INTRODUCTION: Diagnosis and pathological classification of insulinomas are challenging. AIM: To characterize localization of tumors, surgery outcomes, and histopathology in patients with insulinoma. METHODS: Patients with surgically resected sporadic insulinoma were included. RESULTS: Eighty patients were included. Seven had a malignant tumor. A total of 312 diagnostic examinations were performed: endoscopic ultrasonography (EUS; n = 59; sensitivity, 70%), MRI (n = 33; sensitivity, 58%), CT (n = 55; sensitivity, 47%), transabdominal ultrasonography (US; n = 45; sensitivity, 40%), somatostatin receptor imaging (n = 17; sensitivity, 29%), 18F- fluorodeoxyglucose positron emission tomography/CT (n = 1; negative), percutaneous transhepatic venous sampling (n = 10; sensitivity, 90%), arterial stimulation venous sampling (n = 20; sensitivity, 65%), and intraoperative US (n = 72; sensitivity, 89%). Fourteen tumors could not be visualized. Invasive methods were used in 7 of these 14 patients and localized the tumor in all cases. Median tumor size was 15 mm (range, 7 to 80 mm). Tumors with malignant vs benign behavior showed less staining for insulin (3 of 7 vs 66 of 73; P = 0.015) and for proinsulin (3 of 6 vs 58 of 59; P < 0.001). Staining for glucagon was seen in 2 of 6 malignant tumors and in no benign tumors (P < 0.001). Forty-three insulinomas stained negative for somatostatin receptor subtype 2a. CONCLUSION: Localization of insulinomas requires many different diagnostic procedures. Most tumors can be localized by conventional imaging, including EUS. For nonvisible tumors, invasive methods may be a useful diagnostic tool. Malignant tumors showed reduced staining for insulin and proinsulin and increased staining for glucagon. PubMed-ID: 31369096 http://dx.doi.org/10.1210/jc.2019-01204

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General

Meta-Analyses Identifying the Prevalence of Dysphagia among Patients Diagnosed with Unilateral Vocal Fold Immobility. Otolaryngol Head Neck Surg, 160(6):955-64. D. Zhou, M. Jafri and I. Husain. 2019. OBJECTIVE: To identify dysphagia prevalence and characteristics among patients with unilateral vocal fold immobility (UVFI) through a systematic review of current literature. DATA SOURCES: Embase, PubMed, ScienceDirect, Wiley Online Library. REVIEW METHODS: Four electronic databases were reviewed according to the PRISMA criteria. Original English-language studies examining dysphagia among adult patients with UVFI met eligibility. Two researchers independently analyzed qualified articles. RESULTS: Of 227 studies discovered through the literature search, 17 satisfied eligibility criteria. The prevalence of symptomatic dysphagia ranged from 55.6% to 69.0%, and the aspiration rate was 20.0% to 50.0%. Self-reporting and clinical evaluation were used to identify symptomatic dysphagia, while videofluoroscopic swallowing study and functional endoscopic evaluation of swallowing evaluated aspiration. Left-sided UVFI predominated. The most common causes of UVFI were iatrogenic and idiopathic. Central lesions and acute-onset UVFI were each associated with more severe dysphagia. Patients were more likely to aspirate on liquids versus purees and pastes. Benefits of medialization thyroplasty and vocal cord injection were equivocal. CONCLUSION: A significant portion of patients with UVFI present with dysphagia due to anatomic and physiologic disruptions during the swallow. Study population heterogeneity and small sample sizes in the reviewed studies may have compromised reliability, calling for large- scale studies with rigorous methodology. Future studies should not only strive to identify the mechanics of the disordered swallow but also explore patients' quality of life and the effectiveness of current treatments for dysphagia with underlying UVFI. PubMed-ID: 30526299 http://dx.doi.org/10.1177/0194599818815885

Randomized controlled trials - None -

Consensus Statements/Guidelines - None -

Other Articles Tumor multifocality with vagus nerve involvement as a phenotypic marker of SDHD mutation in patients with head and neck paragangliomas: A (18) F-FDOPA PET/CT study. Head Neck, 41(6):1565-71. V. Amodru, P. Romanet, U. Scemama, M. Montava, N. Fakhry, F. Sebag, F. Castinetti, J. P. Lavieille, A. Loundou, A. Varoquaux, A. Barlier, K. Pacak and D. Taieb. 2019. BACKGROUND: (18) F-FDOPA PET/CT was proved to be a highly sensitive imaging method for detecting head and neck paraganglioma (HNPGL). The primary aim of the study was to evaluate the relationship between tumor characteristics and the SDHx-mutational status in a large series of patients with HNPGL evaluated by (18) F- FDOPA PET/CT. METHODS: A total of 104 patients with HNPGL (65 sporadic/39 SDHx-mutated) were included. RESULTS: In comparison to SDHB/SDC/SDHx-negative cases, patients with SDHD were younger at diagnosis and had a higher rate of multifocal, vagal, and carotid paraganglioma. In patients with SDHD, vagal paraganglia represented the primary site of tumor origin. Multicentric involvement of the vagus nerve alone or in association with other locations was found to be a typical feature of SDHD cases compared to other cases (odds

ESES Review of Recently Published Literature 2019-2 Page 66 of 71 ratio = 59.4). CONCLUSION: The present study shows that tumor multifocality within the vagus nerve is a phenotypic marker of SDHD mutation. This information is essential in the choice of the therapeutic strategy. PubMed-ID: 30584686 http://dx.doi.org/10.1002/hed.25604

Gastric carcinoids: Does type of surgery or tumor affect survival? Am J Surg, 217(5):937-42. A. Crown, H. Kennecke, R. Kozarek, A. G. Lopez-Aguiar, M. Dillhoff, E. W. Beal, G. A. Poultsides, E. Makris, K. Idrees, P. M. Smith, H. Nathan, M. Beems, D. Abbott, A. V. Fisher, R. C. Fields, J. Davidson, S. K. Maithel and F. G. Rocha. 2019. BACKGROUND: Gastric carcinoids are rare neuroendocrine tumors of the gastrointestinal tract. They are typically managed according to their etiology. However, there is little known about the impact of surgical strategy on the long-term outcomes of these patients. METHODS: All patients who underwent resection of gastric carcinoids at 8 institutions from 2000 to 2016 were analyzed retrospectively. Tumors were stratified according to subtype (I, II, III, IV) and resection type (local resection, LR or formal gastrectomy, FG). Clinicopathological parameters, recurrence-free (RFS) and overall survival (OS) were compared between groups. RESULTS: Of 79 patients identified with gastric carcinoids, 34 had type I lesions associated with atrophic gastritis, 4 had type II lesions associated with a gastrinoma, 37 had type III sporadic lesions, and 4 had type IV poorly-differentiated lesions. The mean age of presentation was 56 years in predominantly Caucasian (77%) and female (63%) patients. Mean tumor size was 2.4cm and multifocal tumors were found in 24 (30%) of patients with the majority occurring in those with type I tumors. Lymph node positive tumors were seen in 15 (19%) patients and 7 (8%) had M1 disease; both most often in type IV followed by type III tumors. R0 resection was achieved in 56 (71%) patients while 15 (19%) had R1 resections and 6 (8%) R2 resections. Patients with type I and III tumors were equally likely to have a LR (50% and 43% respectively) compared to FG while those with type II and IV all had FG with one exception. Type IV tumors had the poorest RFS and OS while Type II tumors had the most favorable RFS and OS (p<0.04 and p<0.0004, respectively). While there was no difference in RFS in those patients undergoing FG versus LR, OS was worse in the FG group (p<0.017). This trend persisted when type II and type IV groups were excluded (p<0.045). CONCLUSION: Gastric carcinoid treatment should be tailored to tumor type, as biologic behavior rather than resection technique is the more important factor contributing to long- term outcomes. PubMed-ID: 30686481 http://dx.doi.org/10.1016/j.amjsurg.2018.12.057

Update in the classification and the role of intra-arterial stenting in the management of carotid body paragangliomas. Head Neck, 41(5):1379-86. S. C. Prasad, M. Laus, S. Al-Ghamdi, A. Vashishth, P. Piazza and M. Sanna. 2019. BACKGROUND: To review the Shamblin classification of carotid body paragangliomas (CBPs) and the role of intra-arterial stenting in their surgical management. METHODS: Retrospective case series of 20 patients with 28 CBPs that were surgically resected at our center. Intra-arterial stenting was performed in Shamblin II and II classes. RESULTS: The mean follow-up was 47.8 months. Five (17.9%) tumors were Shamblin class I, 15 (53.6%) were class II, and 8 (28.6%) were class III. Thirteen (68.4%) CBPs were associated with other paragangliomas. The internal carotid artery (ICA) was stented preoperatively in eight (28.6%) cases and occluded in four (14.3%) cases. The tumor extended to the jugular foramen in six cases (21.4%). Intraoperatively, there was an ICA injury in one case of Shamblin II CBP in the present era. CONCLUSIONS: The proposed classification enables the clinician to plan the management of the ICA and the right approach. Stenting of the ICA gives a chance for complete tumor removal with arterial preservation. PubMed-ID: 30771228 http://dx.doi.org/10.1002/hed.25567

Quality of Life in Hypoparathyroidism Improves With rhPTH(1-84) Throughout 8 Years of Therapy. J Clin Endocrinol Metab, 104(7):2748-56. G. Tabacco, Y. D. Tay, N. E. Cusano, J. Williams, B. Omeragic, R. Majeed, M. G. Almonte, M. R. Rubin and J. P. Bilezikian. 2019. CONTEXT: Calcium and vitamin D treatment does not improve reduced quality of life (QOL) in hypoparathyroidism. Recombinant human (rh) PTH(1-84) therapy improves QOL metrics for up to 5 years. Data on QOL beyond this time point are not available. OBJECTIVES: To evaluate the effects of 8 years of rhPTH(1- 84) therapy on QOL and factors associated with long-term benefit. DESIGN: Prospective, open-label trial. SETTING: Referral center. PATIENTS: Twenty patients with hypoparathyoidism. MAIN OUTCOME MEASURES:

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RAND 36-Item Short Form Health Survey (SF-36). RESULTS: rhPTH therapy led to substantial improvement in five of the eight SF-36 domains [vitality, social functioning (SF), mental health (MH), bodily pain (BP) and general health] and three of these domains (SF, MH, BP) were no longer lower than the reference population. The improvement in the mental component summary (MCS) score was sustained through 8 years, while the physical component summary (PCS) score improved through 6 years. A lower baseline QOL score was associated with greater improvement. A threshold value <238 (MCS) and <245 (PCS) predicted long-term improvement in 90% and 100% of the cohort, respectively. In patients whose calcium supplementation was reduced, MCS and PCS scores improved more than those whose supplementation did not decline to the same extent. Improvement in PCS was greater in patients whose calcitriol dosage was reduced and duration of disease was shorter. CONCLUSIONS: rhPTH(1-84) improves long-term well-being in hypoparathyroidism. The improvements are most prominent in those with impaired SF-36 at baseline and those whose requirements for conventional therapy decreased substantially. PubMed-ID: 30776291 http://dx.doi.org/10.1210/jc.2018-02430

Radiotherapy for benign head and neck paragangliomas. Head Neck, 41(7):2107-10. W. M. Mendenhall, C. G. Morris, R. J. Amdur, K. E. Hitchcock, N. L. Silver and P. T. Dziegielewski. 2019. PURPOSE: To update our experience treating benign head-and-neck paragangliomas (PGs) with radiotherapy (RT). METHODS: A total of 149 patients with 176 PGs received curative-intent RT; 126 received RT to 1 PG and 23 to 2 or more PGs. The most common dose fractionation schedule was 45 Gy/25 once-daily fractions/5 weeks which was used to treat 147 PGs (83.5%) in 123 patients (82.6%). Patients were followed with physical examination and CT/MRI. The median follow-up for all patients was 10.6 years (range, 0.2-50.4 years); the median follow-up for surviving patients was 11.1 years (range, 0.2-50.4). RESULTS: The 5-year, 10-year, and 15-year outcomes were: local control, 99%, 96%, and 95%; distant metastasis-free survival, 99%, 99%, and 99%; cause-specific survival, 98%, 98%, and 98%; and overall survival, 90%, 75%, and 64%, respectively. No patient developed a moderate or severe complication, or a radiation-induced second tumor or malignant transformation of the benign PG. CONCLUSION: RT is an effective treatment for head-and-neck PGs with a low risk of complications. PubMed-ID: 30779406 http://dx.doi.org/10.1002/hed.25664

Hypoparathyroidism. N Engl J Med, 380(18):1738-47. R. I. Gafni and M. T. Collins. 2019. PubMed-ID: 31042826 http://dx.doi.org/10.1056/NEJMcp1800213

A Full Phenotype of Paraganglioma Linked to a Germline SDHB Mosaic Mutation. J Clin Endocrinol Metab, 104(8):3362-6. C. Cardot-Bauters, B. Carnaille, S. Aubert, M. Crepin, S. Boury, N. Burnichon and P. Pigny. 2019. CONTEXT: Heterozygous germline pathogenic variants found in succinate dehydrogenase (SDH) complex genes predispose to hereditary paraganglioma (PGL) syndromes. No mosaicism has yet been reported in this setting. DESIGN AND PARTICIPANT: We describe the clinical history of a case of SDH complex, subunit B (SDHB) mosaicism. A 24-year-old woman who developed a cardiogenic shock during dental surgery was diagnosed with a functional para-aortic PGL, which produced predominantly norepinephrine and its metabolites. The tumor was removed and showed a loss of SDHB expression by immunohistochemistry. Four years after initial laparotomy, the patient had a rapid cardiac decompensation during her second pregnancy, despite negative imaging 10 months before. Two recurrent functional PGLs were found and surgically removed. Initial genetic analysis performed by Sanger sequencing did not reveal any germline pathogenic variant in SDHB, VHL, SDHD, SDHC, SDHAF2, RET, MAX, and TMEM127. Next-generation sequencing performed on tumor- and blood-extracted DNAs highlighted the presence of a mosaic rare variant in SDHB (c.557G>A, p.Cys186Tyr) with an allelic ratio of 15% in the blood DNA. CONCLUSIONS: We report the full clinical description of a proband with SDHB mosaicism associated with a functional, recurrent PGL. This case strengthens the necessity to complete the genetic analysis with methodologies able to identify germline mosaicism, especially in the case of early disease onset. PubMed-ID: 31046099 http://dx.doi.org/10.1210/jc.2019-00175

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The Clinical Impact of [(68) Ga]-DOTATATE PET/CT for the Diagnosis and Management of Ectopic Adrenocorticotropic Hormone - Secreting Tumours. Clin Endocrinol (Oxf), 91(2):288-94. T. Wannachalee, A. F. Turcu, I. Bancos, M. A. Habra, A. M. Avram, H. H. Chuang, S. G. Waguespack and R. J. Auchus. 2019. OBJECTIVES: Localization of ectopic ACTH-secreting tumours causing Cushing syndrome (ECS) is essential for clinical management, yet often difficult. [(68) Ga]-DOTATATE PET/CT ([(68) Ga]-DOTA-(Tyr(3) )-octreotate)] is an FDA-approved high-resolution diagnostic tool for imaging neuroendocrine tumours. Data on the clinical utility of [(68) Ga]-DOTATATE in patients with ECS, however, are scarce. The objectives of this study were to determine the efficacy for ECS localization and the clinical benefit of [(68) Ga]-DOTATATE imaging. METHOD: We conducted a retrospective review of all cases with ECS evaluated with [(68) Ga]-DOTATATE from November 2016 through October 2018 at three referral centres. The clinical benefit of [(68) Ga]-DOTATATE was based on detection of new tumours and resultant changes in management. RESULTS: Over the study period, 28 patients with ECS underwent [(68) Ga]-DOTATATE: 17 for identification of the primary tumour and 11 during follow-up. [(68) Ga]-DOTATATE identified the suspected primary ECS in 11/17 patients (65%). Of these, nine patients underwent surgery: eight with confirmed ECS (5 bronchial, 1 thymic, 1 pancreatic and 1 metastatic neuroendocrine tumour of unknown primary origin) and one patient with a false-positive scan (adrenal gland). Of the 11 patients with ECS who underwent [(68) Ga]-DOTATATE evaluation during follow-up, the study led to changes in clinical management in 7/11 (64%) patients. CONCLUSIONS: [(68) Ga]-DOTATATE is sensitive in detecting primary and metastatic ECS, often identifies occult tumours after conventional imaging, and impacts clinical care in the majority of patients. PubMed-ID: 31066920 http://dx.doi.org/10.1111/cen.14008

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges. Clin Endocrinol (Oxf), 91(5):587-607. P. J. Newey. 2019. Recent advances in DNA sequencing technology have led to an unprecedented period of disease-gene discovery offering many new opportunities for genetic testing in the clinical setting. Endocrinology has seen a rapid expansion in the taxonomy of monogenic disorders, which can be detected by an expanding portfolio of genetic tests in both diagnostic and predictive settings. Successful testing relies on many factors including the ability to identify those at increased risk of genetic disease in the busy clinic as well as a working knowledge of the various testing platforms and their limitations. The clinical utility of a given test is dependent upon many factors, which include the reliability of the genetic testing platform, the accuracy of the test result interpretation and knowledge of disease penetrance and expression. The increasing adoption of "high-content" genetic testing based on next-generation sequencing (NGS) to diagnose hereditary endocrine disorders brings a number of challenges including the potential for uncertain test results and/or genetic findings unrelated to the indication for testing. Therefore, it is increasingly important that the clinician is aware of the current evolution in genetic testing, and understands the different settings in which it may be employed. This review provides an overview of the genetic testing workflow, focusing on each of the major components required for successful testing in adult and paediatric endocrine settings. In addition, the challenges of variant interpretation are highlighted, as are issues related to informed consent, prenatal diagnosis and predictive testing. Finally, the future directions of genetic testing relevant to endocrinology are discussed. PubMed-ID: 31254405 http://dx.doi.org/10.1111/cen.14053

Complete and incomplete recurrent laryngeal nerve injury after thyroid and parathyroid surgery: Characterizing paralysis and paresis. Surgery, 166(3):369-74. M. Schneider, V. Dahm, C. Passler, E. Sterrer, G. Mancusi, R. Repasi, E. Gschwandtner, E. Fertl, L. Handgriff and M. Hermann. 2019. BACKGROUND: Injury of the recurrent laryngeal nerve and consequent disorder of vocal fold movement is a typical complication in thyroid and parathyroid surgery. During postoperative laryngoscopy we observed not only a complete standstill (vocal fold paralysis), but also a hypomobility (paresis). In this prospective study, we investigated the difference in incidence and prognosis as well as risk-factors, intraoperative neuromonitoring, and symptoms between vocal fold paralysis and vocal fold paresis. METHODS: Data were prospectively collected and analyzed in a single high-volume thyroid center between 2012 and 2016. Vocal fold paresis was defined as hypomobility in abduction or adduction, a reduction in range and speed of vocal fold movement. Vocal fold paralysis was defined as asymmetry and missing purposeful vocal fold movement. RESULTS: The

ESES Review of Recently Published Literature 2019-2 Page 69 of 71 study included 4,707 surgeries and 7,992 at-risk nerves at risk. Vocal fold paralysis was diagnosed in 374 patients (4.68% of 7,992 nerves at risk) and vocal fold paresis in 114 patients (1.43%). Exclusively in the paralysis group, 36 patients (0.45%) developed permanent loss of vocal fold function (P < .001). In follow-up, vocal fold paresis patients regain normal vocal fold function significantly earlier than vocal fold paralysis (mean duration: 6.96 +/- 6.506 vs 10.77 +/- 7,827 weeks) and presented with significantly less symptoms like hoarseness, diplophonia, dysphagia, and dyspnea (68.8% vs 95.9 %). In intraoperative neuromonitoring, vocal fold paresis showed a significantly higher postresectional N. vagus amplitude than vocal fold paralysis patients (0.349 mV vs 0.114 mV, P < .001). CONCLUSION: After thyroidectomy, vocal fold paresis must be distinguished from vocal fold paralysis and should be implemented as a separate outcome parameter in the postoperative quality assessment. PubMed-ID: 31262569 http://dx.doi.org/10.1016/j.surg.2019.05.019

Therapy of Hypoparathyroidism With rhPTH(1-84): A Prospective, 8-Year Investigation of Efficacy and Safety. J Clin Endocrinol Metab, 104(11):5601-10. Y. D. Tay, G. Tabacco, N. E. Cusano, J. Williams, B. Omeragic, R. Majeed, M. Gomez Almonte, J. P. Bilezikian and M. R. Rubin. 2019. CONTEXT: Conventional treatment of hypoparathyroidism is associated with decreased renal function and increased bone mineral density (BMD). OBJECTIVE: To evaluate the effects of 8 years of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] therapy on key biochemical and densitometric indices. DESIGN: Prospective open-label trial. SETTING: Tertiary medical center. PARTICIPANTS: Twenty-four subjects with hypoparathyroidism. INTERVENTION: Treatment with rhPTH(1-84) for 8 years. MAIN OUTCOME MEASURES: Supplemental calcium and vitamin D requirements, serum calcium and phosphorus levels, calcium-phosphate product, urinary calcium excretion, estimated glomerular filtration rate (eGFR) and BMD. RESULTS: PTH therapy was associated with progressive reduction in supplemental calcium (57%; P < 0.01) and active vitamin D (76%; P < 0.001) requirements over 8 years. Serum calcium concentration was stable; urinary calcium excretion declined 38% (P < 0.01). eGFR remained stable and was related to baseline eGFR and serum calcium levels. Calcium-phosphate product was below the recommended limit; serum phosphorus remained within normal range. Lumbar spine and total hip BMD increased, peaking at 4 (mean +/- SE, 4.6% +/- 1.5%; P = 0.01) and 8 years (2.6% +/- 1.1%; P = 0.02), whereas femoral neck BMD did not change and one-third radius BMD decreased (mean +/- SE, -3.5% +/- 1.1%; P = 0.001). BMD at all sites was higher throughout the 8 years than in the age- and sex-matched reference population. Hypercalcemia and hypocalcemia were uncommon. CONCLUSION: rhPTH(1-84) is a safe and effective treatment for hypoparathyroidism for 8 years. Long-term reductions in supplemental requirements and biochemical improvements with stable renal function are maintained. PubMed-ID: 31310310 http://dx.doi.org/10.1210/jc.2019-00893

Routine Preoperative Laryngoscopy for Thyroid Surgery Is Not Necessary Without Risk Factors. Thyroid, 29(11):1646-52. D. I. Maher, S. Goare, E. Forrest, S. Grodski, J. W. Serpell and J. C. Lee. 2019. Background: Routine preoperative vocal cord (VC) assessment with laryngoscopy in patients undergoing thyroidectomy allows clear documentation of baseline VC function, aids in surgical planning in patients with palsies, and facilitates interpretation of intraoperative neuromonitoring (IONM) findings. We aimed to determine the incidence of preoperative vocal cord palsy (VCP); to evaluate the associated risk factors for preoperative VCP; and to calculate the cost-savings potential of implementing a selective approach. Methods: Patients with a pre-thyroidectomy VC assessment by fiberoptic laryngoscopy were retrospectively recruited from the Monash University Endocrine Surgery Unit database from 2000 to 2018. Cases with preoperative VCP were reviewed for potential contributing factors and compared with a non-palsy cohort. Results: Of the 5987 patients who had preoperative laryngoscopy, VCP was documented in 41 (0.68%) patients. Four clinical parameters were found to be potential indicators of VCP, including: age (p < 0.001), nodule >/=3.5 cm recorded on ultrasound imaging (p = 0.01), presence of voice symptoms (p < 0.001), and previous neck surgery (p < 0.001). Malignant cytology (p = 0.5) and exposure to head and neck irradiation were not different between the groups. Utilizing these risk factors, 2354 (39%) patients had at least one feature that may raise suspicion for preoperative VCP. By performing preoperative laryngoscopy only on this subset of patients, the potential cost savings exceeds 400 Australian Dollars per patient. Conclusions: Using this large dataset, we have established that a VCP is rare in the absence of a large nodule, hoarseness, or previous neck surgery. Therefore, in the era of IONM, we support a selective approach to preoperative laryngoscopy by using the aforementioned criteria.

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PubMed-ID: 31333068 http://dx.doi.org/10.1089/thy.2019.0145

Safety and Efficacy of 5 Years of Treatment With Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism. J Clin Endocrinol Metab, 104(11):5136-47. M. Mannstadt, B. L. Clarke, J. P. Bilezikian, H. Bone, D. Denham, M. A. Levine, M. Peacock, J. Rothman, D. M. Shoback, M. L. Warren, N. B. Watts, H. M. Lee, N. Sherry and T. J. Vokes. 2019. CONTEXT: Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency. OBJECTIVE: To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]. DESIGN: Open-label extension study; 5-year interim analysis. SETTING: 12 US centers. PATIENTS: Adults (N = 49) with chronic hypoparathyroidism. INTERVENTION(S): rhPTH(1-84) 25 or 50 microg/d initially, with 25-microg adjustments permitted to a 100 microg/d maximum. MAIN OUTCOME MEASURE(S): Safety parameters; composite efficacy outcome was the proportion of patients with >/=50% reduction in oral calcium (or

Response to Confounding Factors on the Prediction of Opioid Usage after Thyroidectomy and Parathyroidectomy Surgery. Otolaryngol Head Neck Surg, 161(2):371-2. T. Tharakan, S. Jiang, J. Fastenberg, T. J. Ow, B. Schiff, R. V. Smith and V. Mehta. 2019. PubMed-ID: 31369346 http://dx.doi.org/10.1177/0194599819841607

Confounding Factors on the Prediction of Opioid Usage after Thyroidectomy and Parathyroidectomy Surgery. Otolaryngol Head Neck Surg, 161(2):371. F. G. Kang. 2019. PubMed-ID: 31369347 http://dx.doi.org/10.1177/0194599819841606

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