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Translational Research in Surgical Disease

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Translational Research in Surgical Disease REVIEW ARTICLE Translational Research in Surgical Disease Alexander Stojadinovic, MD; Nita Ahuja, MD; Susanna M. Nazarian, MD, PhD; Dorry L. Segev, MD; Lisa Jacobs, MD; Yongchun Wang, MD; John Eberhardt, MD; Martha A. Zeiger, MD Objective: To review cutting-edge, novel, imple- geon familiar with cutting-edge and novel research in their mented and potential translational research and to pro- field of expertise and interest. vide a glimpse into rich, innovative, and brilliant ap- proaches to everyday surgical problems. Data Synthesis: Articles that met criteria were sum- marized in the manuscript. Data Sources: Scientific literature and unpublished re- sults. Conclusions: Multiple avenues have been used for the dis- coveryofimprovedmeansofdiagnosis,treatment,andoverall Study Selection: Articles reviewed were chosen managementofpatientswithsurgicaldiseases.Theseavenues based on innovation and application to surgical dis- have incorporated the use of genomics, electrical impedence, eases. statistical and mathematical modeling, and immunology. Data Extraction: Each section was written by a sur- Arch Surg. 2010;145(2):187-196 HE FOLLOWING REVIEW OF risk of malignancy ranges from 5% to 10% cutting-edge, novel, imple- for follicular lesions (atypia) of undeter- mented and potential trans- mined significance, 20% to 30% for fol- lational research is meant to licular neoplasms, and 50% to 75% for provide a glimpse into rich, nodules with cytological features suspi- Tinnovative, and brilliant approaches to ev- cious of malignancy.1 Because cytology re- eryday surgical problems. It is written pri- sults are indeterminate in up to one- marily by young, innovative surgical sci- third of FNABs, the frequency of diagnostic entists in their field of interest and often or nontherapeutic thyroid resection is sig- in their field of research. The contents in- nificant. Hence, given a 30% rate of inde- clude research on thyroid nodule diagno- terminate cytology with an overall malig- sis, treatment for gastrointestinal stromal nancy prevalence of 20% to 30% in these tumors (GIST) and colon cancer, aortic an- lesions, most patients with indetermi- eurysm treatment, mathematic models for nate cytology who have thyroid resection kidney donor–recipient matching, and have benign histopathology.2 Accurate di- breast cancer treatment. It encompasses agnostic adjuncts to FNAB and clinically mathematical, statistical, and molecular in- relevant treatment-directing decision- novations. support tools that are capable of differen- Author Affiliations: Division of Surgical Oncology, Department tiating benign from malignant nodules of Surgery, Walter Reed Army THYROID NODULE DIAGNOSIS therefore represent an unrealized need in Medical Center, Washington, thyroid surgery. DC (Dr Stojadinovic); Division Although it is the current standard of prac- of Endocrine and Surgical tice for the diagnosis of thyroid nodules, High-Throughput Analysis Oncology (Drs Ahuja, Jacobs, fine-needle aspiration biopsy’s (FNAB) pri- of Thyroid Tumors Wang, and Zeiger), Division of mary shortcoming rests with the differen- Vascular Surgery (Dr Nazarian), tial diagnosis of indeterminate lesions. The We know from review of the Johns Hop- and Division of Transplantation National Cancer Institute Thyroid Fine kins experience that there are 8 histopatho- (Dr Segev), Department of Needle Aspiration State of the Science Con- logical subtypes of thyroid tumors that pose Surgery, The Johns Hopkins University School of Medicine, ference recently supported a 6-tier classi- a diagnostic dilemma for the clinician: pap- Baltimore, Maryland; and fication system for FNAB that includes (1) illary thyroid cancer, follicular variant of Healthcare DecisionQ lesion (atypia) of undetermined signifi- papillary thyroid cancer, follicular cancer, Corporation, Washington, DC cance, (2) follicular neoplasm, and (3) Hürthle cell cancer, adenomatoid nodule, (Dr Eberhardt). nodules suspicious for malignancy.1 The follicular adenoma, Hürthle cell adenoma, (REPRINTED) ARCH SURG/ VOL 145 (NO. 2), FEB 2010 WWW.ARCHSURG.COM 187 ©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 A B C D E F Figure 1. Patterns of RNA splice variants. Variants shown are pre–messenger RNA (exons are color coded) (A); wild-type mRNA with all exons used (B); exon skipping with second exon excluded (C); alternative 5Ј splice site with only the first part of the second exon included (D); alternative 3Ј splice site with only the last part of the second exon included (E); and intron retention with retention of the noncoding intron (F). and lymphocytic thyroiditis nodule.3 All 8 of these tumor shortening of the involved exons; and (5) an interven- types therefore require identification of distinguishing di- ing intron can also be retained (Figure 1).11,12 agnostic markers. By microarray analysis, using data from the genome project, several authors have examined thy- Human Telomerase Reverse Transcriptase roid neoplasms for genetic markers that might be useful Alternative Splice Variant Patterns in the distinction of benign from malignant tumors.4-9 How- in Thyroid Tumors ever, no group has identified a panel of molecular mark- ers that are useful in the distinction of the 8 thyroid tumor types that can be associated with indeterminate FNAB re- Relevant to alternative splicing, Wang et al13 have tested sults, applied the markers to FNA diagnosis in the preop- 133 thyroid tumors including 60 malignant and 73 be- erative setting, and then proven their utility in distinguish- nign tumors for human telomerase reverse transcrip- ing benign from malignant tumors. tase (hTERT) alternative splice variant patterns by re- verse transcriptase polymerase chain reaction. The hTERT Alternative Splicing of Genes alternative splice transcripts tested for and identified in- cluded 4 isoforms: full length, which is the active form, With completion of the genome sequence and the esti- and ␣-deletion, ␤-deletion, and ␣-␤–deletion, which are mated 20 000 to 25 000 genes comprising its entirety, it the inactive or dominant-negative forms. Significant dif- has become clear to investigators that the complexity of ferences in the proportions of all splice variants be- humans cannot be fully explained by so few genes. Al- tween benign and malignant thyroid tumors were iden- ternative splicing of messenger RNA (mRNA) provides tified in this study (PϽ.001). The malignant tumors an intricate means by which individual genes can be ex- exhibited a significantly greater proportion of the func- pressed in various isoforms and it is through this pro- tional full-length variant than the dominant-negative ␣- cess that each mRNA can be translated into several dif- deletion or inactive ␤-deletion and ␣-␤–deletion vari- ferent proteins. This mechanism thereby results in ants. The opposite was true for the benign tumors. These tremendous protein diversity and, in turn, the possibil- differences in splice patterns have also been seen in FNA ity of developing a robust diagnostic tool. Pre-mRNA splic- samples (Yongchun Wang, MD, PhD, and Martha Zeiger, ing is a precisely regulated process in posttranscrip- MD, unpublished data, 2008) and give credence to the tional modification and results in several types of events.10 concept that a more comprehensive splice array analy- The 5 most common splice events are (1) exons are either sis will ultimately be successful in identifying a set of splice skipped or (2) included in the final mRNA; (3) alterna- variant markers that are useful in the distinction be- tive 5Ј (donor) and (4) 3Ј (acceptor) splice sites cause tween benign and malignant thyroid tumors. (REPRINTED) ARCH SURG/ VOL 145 (NO. 2), FEB 2010 WWW.ARCHSURG.COM 188 ©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Preoperative diagnosis classed Worst FNA Maximum nodule US size Thyroid status Nuclear medicine overall Age Overall pathology diagnosis Worst EIS US natural overall Cervical lymph nodes Ethnicity Figure 2. Bayesian Belief Network model. Four variables emerged as predominant predictors of the primary outcome variable, thyroid malignancy, on final histopathology: fine-needle aspiration cytology, maximum nodule size (determined by ultrasound), electrical impedance, and ultrasound characteristics of the nodule. EIS indicates electrical impedance scanning; FNA, fine-needle aspiration; and US, ultrasound. Electrical Impedance Scanning hierarchy of conditional dependence, given prior evi- dence, that defines how independent covariates that in- Stojadinovic et al14 are also studying a promising tech- fluence the outcome of interest also influence one an- nological adjunct to FNAB, electrical impedance scan- other. The network is transparent, providing a graphical ning. A pilot study supported the diagnostic utility of this explanation to the answers provided in the model struc- minimal-risk, rapid, real-time technology in patients with ture. The networks developed by Stojadinovic are ma- thyroid nodules. A prospective clinical trial to define the chine learned, meaning that a heuristic search algo- diagnostic accuracy of electrical impedance scanning for rithm is used to discover the hierarchy of information thyroid nodules revealed that a noninvasive impedance given available training data. scan correctly diagnosed 87% of patients with malig- Data were analyzed from a prospective cohort trial in- nant and 71% of patients with benign dominant thyroid volving
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