Search

Objective: To assess the attitudes of residents and program directors (PDs) involved in flexible training to gauge satisfaction with this training paradigm and elicit limitations., Design: Anonymous surveys were sent to residents and PDs in participant programs. Respondents were asked to rate responses on a 5-point Likert scale (1 = strongly disagree and 5 = strongly agree)., Setting: A total of 9 residency programs that are collaborating to prospectively study the effect of flexible tracks on resident performance and outcome., Participants: A total of 138 residents who were in clinical years 4 and 5 and 10 PDs., Results: Of the 138 possible residents, 100 responded to the resident survey (72.5% response rate). Among resident respondents, 33% were participating in a flexible track option. The most frequently listed specialties of focus were cardiothoracic surgery (19%), vascular surgery (13%), acute care surgery (11%), colorectal surgery (8%), surgical oncology (7%), and pediatric surgery (7%). Participants in flexible tracks tended to strongly agree that their career would be enhanced by flexible rotations; interestingly, of those not in flexible tracks, most tended to also agree that flexible rotations would enhance their future careers. Flexible track participants report receiving greater autonomy on flexible rotations and believe they would be better prepared for fellowship and career. They express overall very high satisfaction with the flexible experience. Limitations expressed by residents (in flexible tracks or not) include uncertainty for how this paradigm serves those interested in comprehensive general surgery, concern about scheduling difficulties, and some displeasure in missing high-volume general surgery rotations in lieu of specialty-focused rotations. The PD survey was completed by 8 of 9 PDs for a response rate of 89%. All the respondents agreed or strongly agreed that careers of residents are enhanced by flexible rotations and that important operative and clinical experiences are gained. Overall, 87.5% of PD respondents agreed or strongly agreed that those in flexible tracks have greater opportunities for mentorship in their chosen field. PDs also expressed high levels of satisfaction with flexible rotations. Limitations include concerns that the flexibility option presents scheduling difficulties and does not go far enough in reforming postgraduate education., Conclusions: This survey of 9 residency programs participating in flexible tracks indicates satisfaction with this training option. The role of comprehensive general surgery as a training end point and scheduling difficulties remain as major challenges. Outcomes of graduates in these tracks and control peers are being prospectively evaluated., (Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Recent advances in research on thyroid carcinogenesis have yielded applications of diagnostic molecular biomarkers and profiling panels in the management of thyroid nodules. The specific utility of these novel, clinically available molecular tests is becoming widely appreciated, especially in perioperative decision making by the surgeon regarding the need for surgery and the extent of initial resection., Methods: A task force was convened by the Surgical Affairs Committee of the American Thyroid Association and was charged with writing this article., Results/conclusions: This review covers the clinical scenarios by cytologic category for which the thyroid surgeon may find molecular profiling results useful, particularly for cases with indeterminate fine-needle aspiration cytology. Distinct strengths of each ancillary test are highlighted to convey the current status of this evolving field, which has already demonstrated the potential to streamline decision making and reduce unnecessary surgery, with the accompanying benefits. However, the performance of any diagnostic test, that is, its positive predictive value and negative predictive value, are exquisitely influenced by the prevalence of cancer in that cytologic category, which is known to vary widely at different medical centers. Thus, it is crucial for the clinician to know the prevalence of malignancy within each indeterminate cytologic category, at one's own institution. Without this information, the performance of the diagnostic tests discussed below may vary substantially.

Background: There are three subtypes of follicular variant papillary thyroid carcinoma (fvPTC): completely encapsulated, well circumscribed, and infiltrative. While infiltrative tumors are more aggressive than completely encapsulated, controversy exists regarding management of fvPTC subtypes. We compared the clinicopathologic features of fvPTC subtypes to those of classic PTC (cPTC) to help guide fvPTC management, using cPTC as a reference., Methods: A retrospective review was performed on 316 patients with PTC treated at a single institution from 2004 to 2011. There were 197 cPTC and 119 fvPTC tumors, including completely encapsulated (n = 46), well circumscribed (n = 46), and infiltrative (n = 27). Clinicopathologic data were compared between groups., Results: fvPTC patients had larger tumors than cPTC patients (1.6 cm vs. 1.2 cm, p = 0.001), but age, sex, and family history did not differ. Thirty-one percent of cPTC tumors had extrathyroidal extension compared to 0 % of completely encapsulated, 0 % of well-circumscribed, and 52 % of infiltrative fvPTC tumors (p < 0.05). Central lymph node metastasis occurred in 50 % of cPTC compared to 0 % in completely encapsulated, 20 % in well-circumscribed, and 72 % in infiltrative fvPTC tumors (p < 0.05). Notably, lymph node metastasis was significantly lower in completely encapsulated than in well-circumscribed tumors, without a difference in the median number of nodes sampled. There were no differences in lymphovascular invasion or extranodal extension., Conclusions: Like cPTC tumors, infiltrative fvPTC tumors have aggressive clinicopathologic features and thus should be treated similarly. Conversely, completely encapsulated and well-circumscribed tumors have less aggressive features compared to cPTC and are more self-limiting; however, well-circumscribed tumors still have a notable incidence of lymph node metastasis. Clinicians should consider this variability in their management algorithm for fvPTC.

Purpose: The safety of single-incision laparoscopic cholecystectomy (SILC) has been proven in well-selected patients. The objective of this study was to determine whether SILC can be offered to all patients with any indication for cholecystectomy., Methods: A total of 173 consecutive SILCs were performed between January 2010 and November 2012 with no exclusion criteria. Demographic data, operative, and postoperative outcomes were prospectively collected and analyzed., Results: Patients with acute cholecystitis and gallstone pancreatitis had longer operative times and a higher conversion to 4-port cholecystectomy than patients with biliary colic. Similar relationships were seen when comparing patients with obesity to nonobese patients. There were no differences in complication rates between the groups., Conclusions: SILC can be safely offered to patients with a wide spectrum of biliary disease with the understanding that this may result in increased operative times and a higher likelihood of conversion to multiport laparoscopy.

Introduction: Acute biliary pathology is a risk factor for conversion to open surgery and increased surgical morbidity during laparoscopic cholecystectomy (LC). The purpose of our study was to examine the impact of an advanced laparoscopic fellowship-trained surgeon on risks of conversion, surgical morbidity, and postoperative complications in this patient population., Methods: Of 1382 patients who underwent an LC from January 2008 to August 2011, 592 patients were diagnosed with an acute biliary process and were included in the study. Patients were divided into two groups; those operated on by an advanced laparoscopic fellowship-trained surgeon (N=237), and those operated on by a non-laparoscopic fellowship-trained surgeon (N=355). The primary end-points were conversion rates and surgical morbidity. The secondary end-point was operative time., Results: Fellowship-trained surgeons were more likely to perform IOC (57%) versus non-fellowship trained surgeons (20%) (p<0.0001). The conversion rate for the fellowship-trained group was significantly lower than for the non-fellowship trained group (1.7% vs 8.5%, p=0.0004). The intraoperative and postoperative complication rates for the fellowship-trained group were not significantly different. The operative time was slightly longer in the non-fellowship trained group compared to the fellowship-trained group (104 min vs 111 min, p=0.04)., Discussion: Our data demonstrate that advanced laparoscopic fellowship training decreases conversion rates of laparoscopic cholecystectomy for acute biliary pathology. Moreover, given the lower conversion rates, patients may have experienced shorter hospitalizations., Conclusions: Formal advanced laparoscopic fellowship training may decrease length of stay among patients presenting with acute biliary pathology who undergo laparoscopic cholecystectomy., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Genomic diagnostics in cancer has evolved since the completion of the Human Genome Project and the advancements made in diagnosis and therapy in chronic myelogenous leukemia. Among the diseases to achieve limited success or potentially benefit from diagnostic genetic testing are thyroid cancer, Burkitt's lymphoma, gastrointestinal stromal tumors, adrenocortical carcinoma, and colorectal cancer. With increased understanding of genomics, genetic tests should improve diagnosis and help guide medical and surgical management., (© 2014 Wiley Periodicals, Inc.)

Background: Altered miRNA expression and down-regulation of Dicer has been shown in various cancers. We investigated Dicer expression and global miRNA environment in correlation with malignant features of thyroid tumors., Methods: Dicer gene expression was assessed for 22 normal thyroids, 16 follicular adenomas, 28 papillary thyroid cancers (PTCs), 10 tall-cell variants of PTC, 11 follicular variants of PTC, as well as the four thyroid cell lines BCPAP, TPC1, KTC1, and TAD2 via quantitative polymerase chain reaction. BRAF((V600E)) mutation screening was completed for 31 neoplasms. Next-generation sequencing was performed on a subset of PTC and normal thyroid. Protein levels were assessed via Western blotting and immunohistochemistry., Results: Dicer mRNA was down-regulated in malignant thyroid samples and cell lines compared with normal tissues, benign neoplasms, and the fetal cell line TAD2. Decreased Dicer gene expression in malignant tissues was correlated greatly with aggressive features: extrathyroidal extension, angiolymphatic invasion, multifocality, lymph node and distant metastasis, recurrence, and BRAF((V600E)) mutation. Conversely, increased levels of Dicer protein were observed in malignant tissues and cell lines. Sequencing yielded 19 differentially expressed miRNAs. Eight samples had a nonsignificant a global down-regulation in malignant tissues., Conclusion: Dysregulation of Dicer and possibly altered expression of miRNAs are associated with aggressive features in thyroid cancers. These findings suggest that disruption in normal miRNA processing involving Dicer may play a role in thyroid cancer progression., (Published by Elsevier Inc.)

Background: Well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors with varying metastatic potential. The underlying molecular basis for metastasis by GEP-NETs remains undefined., Methods: Quantitative PCR and immunohistochemistry (IHC) staining for ubiquitin carboxyl-terminal esterase L1 (UCHL1) gene and protein expression was performed on a group of localized and metastatic well-differentiated GEP-NET samples acquired from a prospectively maintained tissue bank. The ability of extent of UCHL1 IHC staining to differentiate localized and metastatic tumors was compared with Ki-67 index., Results: Among 46 total samples, UCHL1 expression at both the gene and protein level was significantly greater among localized GEP-NETs compared with metastatic tumors and metastases (p < 0.001). Hypermethylation of the UCHL1 promoter was commonly observed among metastatic primary tumors and metastases (those with the lowest UCHL1 expression) but not among localized tumors (p < 0.001). Poor staining (<50 %) for UCHL1 was observed in 27 % of localized tumors compared with 87 % of metastatic tumors (p = 0.001). The presence of <50 % staining for UCHL1 was 88 % sensitive and 73 % specific for identifying metastatic disease. In contrast, there was no association between Ki-67 index and metastatic disease. In multivariable analysis, only UCHL1 staining <50 % [odds ratio (OR) 24.5, p = 0.035] and vascular invasion (OR 38.4, p = 0.03) were independent risk factors for metastatic disease at the time of initial surgery., Conclusions: Loss of UCHL1 expression by CpG promoter hypermethylation is associated with metastatic GEP-NETs. Extent of UCHL1 staining should be explored as a potentially clinically useful adjunct to Ki-67 index in evaluating GEP-NETs for aggressive features.

Background: The Aldosteronoma Resolution Score (ARS) takes into consideration four, readily available, preoperative clinical parameters in predicting the likelihood of resolution of hypertension in patients 6 months after undergoing unilateral adrenalectomy for aldosterone-producing adenoma (APA). We sought to determine the durability of this predictive model after 1 year., Methods: Sixty patients who underwent unilateral adrenalectomy for APA at a single institution between 2004 and 2013 were reviewed retrospectively. Patients who were normotensive without any antihypertensive medication requirement at greater than 1-year follow-up were considered to have complete resolution of hypertension., Results: Forty-seven patients had data available for analysis. Median follow-up was 1,135 days (371-3,202). Forty-five percent of patients had complete resolution, 45% had improvement, and 10% had no improvement in hypertension. Applying the ARS, we found there was complete resolution of hypertension in 73% of patients with ARS 4-5, 53% of patients with ARS 2-3, and 24% of patients with ARS 0-1 compared with 75% (P = .9), 46% (P = .66), and 28% (P = .76), respectively, in the original cohort used to create the ARS., Conclusion: Most patients (90%) have long-term improvement or complete resolution of hypertension after unilateral adrenalectomy for APA. The ARS predicts accurately a patient's likelihood of complete resolution of hypertension beyond 1 year., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Alpha-blockade is the standard management preoperatively to prevent intraoperative hemodynamic instability (IHD) during resection of a pheochromocytoma. Calcium channel blockers also have been shown to lessen the risk of IHD. We aim to determine differences between these classes of antihypertensive agents in minimizing IHD., Methods: This was a retrospective analysis from a tri-institutional database. Inclusion criteria were unilateral transabdominal adrenalectomy for pheochromocytomas between 2002 and 2012. IHD was defined as at least one systolic blood pressure (SBP) measurement >160 mm Hg and at least one episode of mean arterial pressure 60 mm Hg., Results: A total of 155 patients were included: 110 receiving calcium channel blockers, 41 alpha-blockade, and 4 no medication. Intraoperatively, mean maximal SBP was less after alpha-blockade (P < .0001) as well as the incidence and duration of episodes of SBP >200 mm Hg (P < .01); however, severe hypotensive episodes (MAP <60 mm Hg) were more frequent (P < .001) and longer (P < .0001) with alpha-blockade. Consequently, intraoperative vasoactive drugs were used more frequently (P = .03), and mean fluid volume infused was larger (P < .001). Fifty-four patients had IHD, but these were independent of type of preoperative medication used. Familial disease was the only independent predictor of IHD., Conclusion: IHD was independent of type of preoperative medical management but was dependent on familial disease. These findings broaden options for clinicians in the preoperative management of pheochromocytoma., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Obesity has historically been a positive predictor of surgical morbidity, especially in the morbidly obese. The purpose of our study was to compare outcomes of obese patients undergoing laparoscopic cholecystectomy (LC)., Methods: We reviewed 1382 consecutive patients retrospectively who underwent LC for various pathologies from January 2008 to August 2011. Patients were stratified based on the World Health Organization definitions of obesity: nonobese (body mass index [BMI] < 30 kg/m(2)), obesity class I (BMI 30-34.9 kg/m(2)), obesity class II (BMI 35-39.9 kg/m(2)), and obesity class III (BMI ≥ 40 kg/m(2)). The primary end points were conversion rates and surgical morbidity. The secondary end point was length of stay., Results: There were significantly more females in the obesity II and III groups (P = 0.0002). American Society of Anesthesiologists scores were significantly higher in the obesity I, II, and III groups compared with the nonobese (P < 0.05; P < 0.01; and P < 0.0001, respectively). Independent predictors of conversion on multivariate analysis (MVA) included age (P = 0.01), acute cholecystitis (P = 0.03), operative time (P < 0.0001), blood loss (P < 0.0001), and fellowship-trained surgeons (P < 0.0001). Independent predictors of intraoperative complications on MVA included age (P = 0.009), white patients (P = 0.009), previous surgery (P = 0.001), operative time (P < 0.0001), and blood loss (P = 0.01). Independent predictors of postoperative complications on MVA included American Society of Anesthesiologists score (P < 0.0001), acute cholecystitis (P < 0.0001), and a postoperative complication (P < 0.0001). BMI was not a predictor of conversions or surgical morbidity. Length of stay was not significantly different between the four groups., Conclusions: This study demonstrates that overall conversion rates and surgical morbidity are relatively low following LC, even in obese and morbidly obese patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: This study was to evaluate the clinicopathological and prognostic features of follicular thyroid carcinoma (FTC) in our institute over a 15-year period., Methods: The clinical features, management and outcome of 134 consecutive patients were analyzed according to the time of diagnosis: Group I (1997-2001), Group II (2002-2006), and Group III (2007-2011)., Results: As time advanced, the ratio of FTC to papillary thyroid carcinoma decreased from 8.7% in group I to 4.3% in group III (p = 0.000). The percentage of patients undergoing total thyroidectomy seemed to be more commonly used in the later periods - from 10.5% in group I to 21.8% in group II and 18.9% in group III. The median diameter of tumors in group I was 4.2 cm and it showed a sharp decrease to 2.8 cm in group II and 2.9 cm in group III respectively. There was a trend towards a higher stage in patients from Group I vs. patients from Groups II and III (stage IV, 15.8% vs. 2.2% and 4.3%, p = 0.072). The outcome was improved in terms of disease-free survival (DFS). The 3-year DFS rate improved from 77.8% in group I to 93.7% in group II and 100% in group III (p = 0.008)., Conclusions: The clinical features, management and outcome of FTC patients changed over 15-year period. Patients diagnosed after 2001 had a better prognosis. This improvement was probably related to earlier diagnosis with smaller tumor size and presentation at earlier tumor stage., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: The most cost-effective diagnostic algorithm for gastroesophageal reflux disease (GERD) remains controversial. We hypothesized that prompt referral for esophageal pH monitoring is more cost-effective than prolonged empiric courses of proton-pump inhibitors (PPIs)., Discussion: A cost model was created based on a cohort of 100 patients with possible GERD who underwent pH monitoring. The additional costs incurred from pH monitoring were compared to the potential savings from avoiding unnecessary PPI usage in patients with a negative pH study. The costs of PPI therapy reach equivalence with pH monitoring after 6.4 to 23.7 weeks, depending on the PPI regimen. A total of 21,411 weeks of PPIs were prescribed beyond the recommended 8-week trial, of which 32 % were for patients who had a negative 24-h pH monitoring study. If the sensitivity of pH monitoring was 96 %, early referral for pH monitoring would have saved between $1,197 and $6,303 per patient over 10 years. This strategy remains cost-effective as long as the sensitivity of pH monitoring is above 35 %. Prompt referral for pH monitoring after a brief empiric PPI trial is a more cost-effective strategy than prolonged empiric PPI trials for patients with both esophageal and extraesophageal GERD symptoms.

Background: The tall cell (TC) variant of papillary thyroid carcinoma (PTC) is more aggressive than classic PTC, but the percentage of TC necessary to diagnose this variant has been debated. We aimed to better determine what percentage of TC correlates with a more aggressive phenotype., Methods: Cases from 2005 to 2010 that were the TC variant of PTC or PTC with TC features were identified and compared with classic PTCs. All cases were reviewed to determine what percent, if any, of the tumors consisted of TC., Results: One hundred forty-one cases of PTC were reviewed. Eighty-three cases had some TC component, and 58 cases had none. There were no differences in patient demographics. Tumors with ≥10% TC had more extrathyroidal extension, angiolymphatic invasion, positive surgical margin, and lymph node involvement than classic PTC. There were more recurrences in patients with ≥10% TC, but this was not significant. Similar findings were also observed with increasing percentages of TC., Conclusion: The aggressive features conferred by the presence of TC in PTCs occur with as little as 10% TC and are maintained with increasing percentages. Therefore, TC in a PTC should be reported if they comprise at least 10% of the tumor., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: It has been speculated that the Bethesda Classification System for thyroid fine-needle aspirate (FNA) may be used to predict aggressive features among histologically proven malignancies. We sought to evaluate whether malignancies that were characterized as Bethesda category V or VI have more aggressive features than malignancies that were category III or IV., Methods: A prospectively maintained database was reviewed to identify thyroid malignancies treated at a single center from 2004 to 2009. Only cancers that could be definitively matched to a preoperative FNA were included. Associations between Bethesda category, patient demographics, histopathologic findings, and outcomes were examined., Results: A total of 360 cancers were analyzed: 73 (20 %) were Bethesda category III or IV and 287 (80 %) were category V or VI. The majority of Bethesda III and IV cancers were follicular variants of papillary thyroid carcinoma (fvPTC), whereas the majority of Bethesda V and VI cancers were classic PTC (52 and 67 %, respectively, p < 0.01). Extrathyroidal extension (30 vs. 16 %, p = 0.02), lymph node metastases (50 vs. 31 %, p = 0.05), and multifocality (51 vs. 37 %, p = 0.03) were more common among Bethesda V and VI nodules. However, when Bethesda III or IV classic PTC and fvPTC were compared to Bethesda V or VI cancers of the same histologic subtype, there were no differences in any features. Recurrence and overall survival were the same in all groups., Conclusions: Bethesda category may help to predict the most likely histologic subtype of thyroid cancer, but it does not have any prognostic significance once the histologic diagnosis is known.

Background: Existing evidence is controversial regarding the association between BRAF mutation status and aggressive features of papillary thyroid cancer (PTC). Specifically, no study has incorporated multiple surgical practices performing routine central lymph node dissection (CLND) and thus has patients who are truly evaluable for the presence or absence of central lymph node metastases (CLNMs)., Methods: Consecutive patients who underwent total thyroidectomy and routine CLND at 4 tertiary endocrine surgery centers were retrospectively reviewed. Descriptive and bivariable analyses examined demographic, patient, and tumor-related factors. Multivariable analyses examined the odds of CLNM associated with positive BRAF status., Results: In patients with classical variant PTC, bivariate analysis found no significant associations between BRAF mutation and aggressive clinicopathologic features; multivariate analysis demonstrated that BRAF status was not an independent predictor of CLNM. When all patients with PTC were analyzed, including those with aggressive or follicular subtypes, bivariate analysis showed BRAF mutation to be associated with LNM, advanced American Joint Committee on Cancer (AJCC) stage, and histologic subtype. Multivariable analyses showed BRAF, age, size, and extrathyroidal extension to be associated with CLNM., Conclusion: Although BRAF mutation was found to be an independent predictor of central LNM in the overall cohort of patients with PTC, this relationship lost significance when only classical variant PTC was included in the analysis. The usefulness of BRAF in predicting the presence of LNM remains questionable. Prospective studies are needed before BRAF mutation can be considered a reliable factor to guide the treatment of patients with PTC, specifically whether to perform prophylactic CLND.

Indeterminate thyroid lesions are diagnosed in up to 30% of fine needle aspirations. These nodules harbor malignancy in more than 25% of cases, and hemithyroidectomy or total thyroidectomy has therefore been advocated in order to achieve definitive diagnosis. Recently, many molecular markers have been investigated in an attempt to increase diagnostic accuracy of indeterminate fine needle aspiration cytology and thereby avoid unnecessary complications and costs associated with thyroid surgery. Somatic mutation testing, mRNA gene expression platforms, protein immunocytochemistry and miRNA panels have improved the diagnostic accuracy of indeterminate thyroid nodules, and although no test is perfectly accurate, in the authors' opinion, these methods will most certainly become an important part of the diagnostic tools for clinicians and cytopathologists in the future.

Background: The BRAF(V600E) mutation is present in 62% of radioactive iodine-resistant thyroid tumors and is associated with downregulation of the sodium-iodide symporter (NIS) and thyroid stimulating hormone receptor (TSHr). We sought to evaluate the combined effect of BRAF inhibition and TSH supplementation on (131)I uptake of BRAF(V600E)-mutant human thyroid cancer cells., Materials and Methods: WRO cells (a BRAF(V600E)-mutant follicular-derived papillary thyroid carcinoma cell line) were transfected with small interfering RNA targeting BRAF for 72 h in a physiological TSH environment. NIS and TSHr expression were then evaluated at three levels: gene expression, protein levels, and (131)I uptake. These three main outcomes were then reassessed in TSH-depleted media and media supplemented with supratherapeutic concentrations of TSH., Results: NIS gene expression increased 5.5-fold 36 h after transfection (P = 0.01), and TSHr gene expression increased 2.8-fold at 24 h (P = 0.02). NIS and TSHr protein levels were similarly increased 48 and 24 h after transfection, respectively. Seventy-two hours after BRAF inhibition, (131)I uptake was unchanged in TSH-depleted media, increased by 7.5-fold (P < 0.01) in physiological TSH media, and increased by 9.1-fold (P < 0.01) in supratherapeutic TSH media., Conclusions: The combined strategy of BRAF inhibition and TSH supplementation results in greater (131)I uptake than when either technique is used alone. This represents a simple and feasible approach that may improve outcomes in patients with radioactive iodine-resistant thyroid carcinomas for which current treatment algorithms are ineffective., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Preoperative B-type Raf kinase Val600Glu mutation, or BRAF(V600E), analysis has been proposed as a tool to guide initial surgery for indeterminate thyroid nodules. This study sought to determine if cytologic markers of malignancy are associated with the BRAF(V600E) mutation and if preoperative BRAF(V600E) testing would alter the initial management of patients with indeterminate nodules., Methods: Patients who underwent surgery for a thyroid nodule between 2003 and 2012 at a tertiary care center were prospectively enrolled. Stored nodule samples were retrospectively genotyped for the BRAF(V600E) mutation. BRAF(V600E) status, demographics, cytologic and histopathologic findings, and choice of initial surgery were examined., Results: A total of 960 patients were enrolled, of which 310 (32%) had an indeterminate nodule. The BRAF(V600E) mutation was identified in 13 patients (4%), 12 of whom had either cytologic atypia or were Bethesda category V. Three percent of Bethesda category III or IV nodules that were malignant harbored the mutation compared with 42% of Bethesda category V malignancies. Nuclear grooves (P = .030), pseudoinclusions (P < .001), and oval nuclei (P = .022) were all more common among BRAF(V600E) mutants. The sensitivities of using BRAF testing alone, cytologic atypia/Bethesda category V classification, or both, were 15%, 73%, and 76%, respectively. Twelve of the 13 BRAF(V600E) mutants had total thyroidectomies initially due to worrisome cytologic features, and therefore the initial management of only one patient would have been altered if BRAF(V600E) testing had been performed preoperatively., Conclusions: Preoperative mutation screening for BRAF(V600E) does not meaningfully improve risk stratification and is unlikely to alter the initial management of patients with indeterminate nodules., (Copyright © 2012 American Cancer Society.)

Background: Gastroesophageal reflux disease (GERD) affects nearly 25 % of adults; however, an objective diagnosis is rarely established. We hypothesized that patients' symptoms and response to acid-reducing therapy are poor predictors of the outcome of 24-h esophageal pH monitoring., Methods: A review of 24-h esophageal pH monitoring studies performed at an ambulatory tertiary care center between 2004 and 2011 was performed. Demographics, type of GERD symptoms, and duration and response to acid-reducing medications before referral for pH monitoring were collected. DeMeester score, symptom sensitivity index (SSI), and symptom index (SI) were tabulated and compared with the patients' symptoms and response to medical therapy., Results: One hundred patients were included. Of all reported symptoms, only heartburn was more common in patients with positive DeMeester scores, but there were no correlations between any symptoms and SSI or SI scores. Sixty-nine percent of patients with esophageal symptoms had a positive DeMeester score compared with only 29 % of patients with extraesophageal symptoms (P < 0.01). Esophageal symptoms and endoscopic evidence of GERD significantly increased the likelihood of having a positive DeMeester score, but they had no influence on SSI or SI scores. There was no correlation between response to acid-reducing medications and DeMeester, SSI, or SI scores. A total of 536 person-years of acid-reducing medications were prescribed to the study population, of which 151 (28 %) were prescribed to patients who had a negative pH study., Conclusions: Extraesophageal symptoms and response to empiric trials of acid-reducing medications are poor predictors of the presence of GERD and the DeMeester score is more likely to identify GERD in patients who met other empiric diagnostic criteria than SSI or SI. Early referral for 24-h esophageal pH monitoring may avoid lengthy periods of unnecessary medical therapy.

Context: Paragangliomas are a type of neuroendocrine tumor that has been reported to be present in patients with cyanotic congenital heart disease. This report documents the first case of a patient with successful resection of a sympathetic paraganglioma in the setting of unrepaired tetralogy of Fallot, the most common cause of cyanotic heart disease, with pulmonary atresia., Objective: We present a 33-yr-old woman with hypertensive crises from a paraganglioma who presented for surgical resection., Patient and Methods: The patient's preoperative workup was consistent with a functioning sympathetic paraganglioma. Preoperative transesophageal echocardiogram displayed normal ventricular function, moderate-severe right ventricular hypertrophy, severe right ventricular hypertension, an overriding aorta, bidirectional shunting, pulmonary atresia, and aortopulmonary collaterals., Results: The patient underwent a successful laparoscopic resection of a functioning 7-cm paraganglioma after careful preoperative preparation and intraoperative monitoring. Pathology returned as a well-defined, partially hemorrhagic mass measuring 7.0 × 4.5 × 4.5 cm adjacent to and compressing the adrenal gland., Conclusion: Surgical resection of paraganglioma tumors in rare patients such as this one is appropriate; however, surgery requires meticulous perioperative management with a multidisciplinary approach. Future studies are needed to determine whether there is a link between neuroendocrine tumors and cyanotic congenital heart disease.

Background: The aim of this study was to determine the predictive value of the preoperative three-dimensional reconstructed volume (3D volumetry) for outcomes of laparoscopic splenectomy. The impact of splenomegaly on the feasibility of laparoscopic splenectomy is still debated. We hypothesized that splenic volumetry may accurately estimate splenic volume preoperatively and be used by surgeons to select patients for laparoscopic splenectomy., Methods: We performed a retrospective review of 88 patients seen at a tertiary referral center undergoing laparoscopic or open splenectomy between 2001 and 2010. Patients included in the study underwent elective splenectomy without associated procedures and had preoperative imaging available at our institution. We evaluated clinical, demographic characteristics and perioperative imaging as predictors of outcome. Study endpoints included conversion to open splenectomy, operating time, estimated blood loss (EBL), length of stay (LOS), postoperative complications, and mortality., Results: In all, 53 procedures were started laparoscopically. Among them, 7 (13.2 %) were converted to open splenectomy and 7 (13.2 %) to hand-assisted laparoscopic splenectomy. The conversion group was matched with 35 patients who underwent open splenectomy to determine differences in outcomes between these groups. There were no conversions in spleens measuring <1100 cc, whereas spleens of 1100 to 2700 cc had a conversion rate of 41 %. Spleen volume >2700 cc was associated with an 87.5 % conversion rate. Spleen 3D volumetry >2700 cc was the only independent predictor of surgical conversion on multivariate analysis (odds ratio 38.0, confidence interval 4.02-358.75, p = 0.001). Patients who underwent open splenectomy had shorter operating times (160.3 vs. 253.0 min, p = 0.001) than those converted from laparoscopic to open splenectomy., Conclusions: A 3D reconstructed splenic volume of >2700 cc is a predictor of conversion from laparoscopic to open splenectomy. For spleens measuring <2700 cc, laparoscopic splenectomy may be performed by experienced surgeons with low to moderate rates of conversion. For spleens with a 3D reconstructed volume >2700 cc, laparoscopic splenectomy is associated with high rates of conversion to open surgery.

Background: This study presents a cost analysis of the standard cervical, gasless transaxillary endoscopic, and gasless transaxillary robotic thyroidectomy approaches based on medical costs in the United States., Methods: A retrospective review of 140 patients who underwent standard cervical, transaxillary endoscopic, or transaxillary robotic thyroidectomy at 2 tertiary centers was conducted. The cost model included operating room charges, anesthesia fee, consumables cost, equipment depreciation, and maintenance cost. Sensitivity analyses assessed individual cost variables., Results: The mean operative times for the standard cervical, transaxillary endoscopic, and transaxillary robotic approaches were 121 ± 18.9, 185 ± 26.0, and 166 ± 29.4 minutes, respectively. The total cost for the standard cervical, transaxillary endoscopic, and transaxillary robotic approaches were $9,028 ± $891, $12,505 ± $1,222, and $13,670 ± $1,384, respectively. Transaxillary approaches were significantly more expensive than the standard cervical technique (standard cervical/transaxillary endoscopic, P < .0001; standard cervical/transaxillary robotic, P < .0001; and transaxillary endoscopic/transaxillary robotic, P = .001). The transaxillary and standard cervical techniques became equivalent in cost when transaxillary endoscopic operative time decreased to 111 minutes and transaxillary robotic operative time decreased to 68 minutes. Increasing the case load did not resolve the cost difference., Conclusion: Transaxillary endoscopic and transaxillary robotic thyroidectomies are significantly more expensive than the standard cervical approach. Decreasing operative times reduces this cost difference. The greater expense may be prohibitive in countries with a flat reimbursement schedule., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Differentiation is central to development, while dedifferentiation is central to cancer progression. Hence, a quantitative assessment of differentiation would be most useful. We propose an unbiased method to derive organ-specific differentiation indices from gene expression data and demonstrate its usefulness in thyroid cancer diagnosis. We derived a list of thyroid-specific genes by selecting automatically those genes that are expressed at higher level in the thyroid than in any other organ in a normal tissue's genome-wide gene expression compendium. The thyroid index of a tissue was defined as the median expression of these thyroid-specific genes in that tissue. As expected, the thyroid index was inversely correlated with meta-PCNA, a proliferation metagene, across a wide range of thyroid tumors. By contrast, the two indices were positively correlated in a time course of thyroid-stimulating hormone (TSH) activation of primary thyrocytes. Thus, the thyroid index captures biological information not integrated by proliferation rates. The differential diagnostic of follicular thyroid adenomas and follicular thyroid carcinoma is a notorious challenge for pathologists. The thyroid index discriminated them as accurately as did machine-learning classifiers trained on the genome-wide cancer data. Hence, although it was established exclusively from normal tissue data, the thyroid index integrates the relevant diagnostic information contained in tumoral transcriptomes. Similar results were obtained for the classification of the follicular vs classical variants of papillary thyroid cancers, that is, tumors dedifferentiating along a different route. The automated procedures demonstrated in the thyroid are applicable to other organs.

Objective: This study aims to determine the efficacy of calcimimetics in improving bone mineral density (BMD) in patients with primary hyperparathyroidism (pHPT) and compare those results to patients undergoing parathyroidectomy., Background: Parathyroidectomy has been shown to improve BMD in pHPT, but calcimimetics have recently been advocated as a medical alternative to parathyroidectomy for pHPT., Materials and Methods: We identified 17 patients that were treated with calcimimetics for pHPT. Seventeen patients with pHPT who underwent parathyroidectomy served as surgical controls. Serum calcium level, parathyroid hormone (PTH) level, and femur and spine BMD T scores were compared before and 1 year after therapy., Results: Both groups were demographically matched. Calcium levels normalized in 70.6% of medically versus 100% of surgically treated patients (P = 0.026). PTH levels normalized in 35% of patients treated with calcimimetics versus 76% of surgical patients (P = 0.036). Femur BMD improved in 18.8% of medically treated patients versus 58.8% of surgical patients (P = 0.032). Spine BMD improved in 70.6% of medically treated patients versus 82.4% of surgical patients (P = 0.69). Further analysis demonstrated that regardless of treatment, normalization of PTH was associated with significant improvement in femur (P = 0.03) and spine BMD (P < 0.001). Normalization of calcium without normalization of PTH did not impact BMD., Conclusions: Parathyroidectomy results in greater normalization of serum calcium and PTH levels and significantly improves cortical BMD compared to calcimimetics. Regardless of treatment, normalization of PTH is associated with significant improvement in spine and femur BMD, suggesting that the superior effects of surgery may be mediated by better control of PTH.

Purpose: Indeterminate thyroid lesions on fine needle aspiration (FNA) harbor malignancy in about 25% of cases. Hemi- or total thyroidectomy has, therefore, been routinely advocated for definitive diagnosis. In this study, we analyzed miRNA expression in indeterminate FNA samples and determined its prognostic effects on final pathologic diagnosis., Experimental Design: A predictive model was derived using 29 ex vivo indeterminate thyroid lesions on FNA to differentiate malignant from benign tumors at a tertiary referral center and validated on an independent set of 72 prospectively collected in vivo FNA samples. Expression levels of miR-222, miR-328, miR-197, miR-21, miR-181a, and miR-146b were determined using reverse transcriptase PCR. A statistical model was developed using the support vector machine (SVM) approach., Results: A SVM model with four miRNAs (miR-222, miR-328, miR-197, and miR-21) was initially estimated to have 86% predictive accuracy using cross-validation. When applied to the 72 independent in vivo validation samples, performance was actually better than predicted with a sensitivity of 100% and specificity of 86%, for a predictive accuracy of 90% in differentiating malignant from benign indeterminate lesions. When Hurthle cell lesions were excluded, overall accuracy improved to 97% with 100% sensitivity and 95% specificity., Conclusions: This study shows that that the expression of miR-222, miR-328, miR-197, and miR-21 combined in a predictive model is accurate at differentiating malignant from benign indeterminate thyroid lesions on FNA. These findings suggest that FNA miRNA analysis could be a useful adjunct in the management algorithm of patients with thyroid nodules., (©2012 AACR.)

Background: Intercellular adhesion molecule-1 (ICAM-1) is implicated in carcinogenesis. In this study we examined the expression of ICAM-1 in papillary thyroid cancer (PTC). We hypothesized that ICAM-1 correlates with indicators of tumor aggressiveness in PTC., Methods: Thirty-five primary and metastatic PTCs, five follicular adenomas, five Hashimoto thyroiditis, five nodular hyperplasia, and eight normal thyroid tissue samples were analyzed for ICAM-1 gene expression using quantitative reverse-transcription polymerase chain reaction (RT-PCR). ICAM-1 gene expression was analyzed at protein level by immunohistochemistry (IHC) using a semiquantitative score. Gene expression and intensity levels were correlated with markers of tumor aggressiveness including BRAF V600E mutation, tumor size, extrathyroidal extension (ETE), angiolymphatic invasion, and lymph node metastasis., Results: ICAM-1 gene expression was higher in PTC (p = 0.01) and lymph node metastases (p = 0.03) when compared with benign tumors and Hashimoto's. Furthermore, PTCs exhibiting BRAF V600E mutation (p = 0.01), ETE (p < 0.01), and lymph node metastasis (p = 0.02) were associated with higher ICAM-1 levels. Gene expression correlated with protein levels on IHC. Additionally, poorly differentiated thyroid carcinoma had a higher ICAM-1 intensity score compared with well-differentiated carcinoma (p = 0.03)., Conclusions: ICAM-1 expression is upregulated in papillary thyroid carcinoma. Furthermore, ICAM-1 upregulation correlated with aggressive tumor features such as BRAF V600E mutation, ETE, and lymph node metastasis, suggesting that ICAM-1 plays a role in thyroid cancer progression.

Background: The clinical significance of synchronous bilateral papillary thyroid carcinoma (SBiPTC) has not been fully defined, and the prevalence of BRAF (V600E) mutation in SBiPTC remains unknown. The purpose of this study is to compare the clinical outcomes and BRAF (V600E) mutation incidence of SBiPTC patients with those of unilateral papillary thyroid carcinoma (UiPTC) patients., Methods: From 1997 to 2008, a total of 903 patients with papillary thyroid cancer were treated at a single institution. Of 891 studied patients, 177 (19.9%) had SBiPTC and 714 had UiPTC. SBiPTC was defined as cancer diagnosed in both thyroid lobes at the same time or within a period of 3 months. The mean follow-up time was 6 years, ranging from 2.5 to 13.5 years. Rates of disease-free survival (DFS) and overall survival (OS) were calculated and compared. BRAF (V600E) mutation was determined by polymerase chain reaction (PCR) amplification and DNA sequencing., Results: Compared with UiPTC patients, patients with SBiPTC were more likely to have larger tumor size, extrathyroidal invasion, lymph node metastasis, and more advanced stage. The 5-year DFS rate was 86.0% for SBiPTC patients and 94.0% for UiPTC patients (p = 0.013). The prevalence of BRAF (V600E) mutation in the SBiPTC group was significantly higher than that in the UiPTC group (65.7% vs. 50.4%; p = 0.038)., Conclusions: Patients with SBiPTC present with more advanced tumor stage and have shorter disease-free survival than UiPTC patients. Poorer outcomes of these patients may be at least partially explained by the high incidence of BRAF (V600E) mutation.

Background: Mutation analysis is potentially a powerful tool to enhance the diagnostic accuracy of thyroid fine-needle aspiration (FNA) biopsy specimens. However, some clinicians may rely on a negative mutation panel to exclude malignancy. We aimed to determine the malignancy rate in indeterminate lesions with negative mutation analysis., Methods: A literature review established a mutation analysis model using the prevalence of BRAF, RET, RAS, and PAX8/peroxisome proliferator-activated receptor-γ mutations in indeterminate lesions. This model was applied retrospectively to a study cohort of 466 consecutive indeterminate lesions that underwent hemi- or total thyroidectomy for definitive diagnosis, to evaluate its accuracy for identifying malignancy., Results: Of 466 indeterminate lesions in the study, 30% (139) were malignant. These included 66 cases of papillary thyroid cancer, 45 cases of follicular variant of papillary thyroid cancer, 18 cases of follicular thyroid cancer, and 10 others. The risk of malignancy was 42% when cytologic atypia was present vs 17% without. The mutation analysis model would correctly identify only 48 of 139 (34%) of malignant indeterminate lesions. Therefore, when mutation analysis is negative, the overall risk of malignancy would be 23%. When atypia is present, the risk of malignancy would be 31% vs 13% in lesions without., Conclusion: Indeterminate lesions with a negative mutation analysis still carry a significant risk of malignancy, especially in the presence of atypia, requiring surgery for definitive diagnosis., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background: Fine-needle aspiration (FNA) biopsies are the most accurate method for diagnosis of thyroid nodules. Unfortunately, biopsies are indeterminate 15-30% of the time and surgery is thus required for a definitive diagnosis. We aimed to determine whether specific descriptors of cytologic atypia mentioned in indeterminate FNA reports were associated with malignancy on final histopathology., Methods: Retrospective review of 1000 surgery patients identified 466 indeterminate FNA lesions that underwent either a hemi- or total thyroidectomy between 1998 and 2009. We screened FNA reports for specific descriptors of nuclear atypia. Univariate and multivariate analyses were performed to evaluate the independent effect of cytologic atypia descriptors on the risk of malignancy., Results: Nuclear atypia on FNA conferred a risk of malignancy of 42% (P < 0.0001). Risk of malignancy increased from 17% for zero descriptors to 81.2% when four or more descriptors of atypia were described. Nuclear grooves and inclusions together conferred a risk of malignancy, specificity, and false positive rate of 79.3%, 98.2% and 1.8% respectively., Conclusions: The presence of four or more descriptors of cytologic atypia or the presence of both nuclear inclusions and grooves together confers a high risk of malignancy on final histopathology and a low false positive rate. These findings should be taken into consideration when interpreting FNA reports and total thyroidectomy should be considered for those patients at higher risk.

The management of papillary thyroid carcinoma continues to evolve. Although the debate over the extent of thyroidectomy has largely faded, the role of elective neck dissection in the surgical management of papillary thyroid cancer has become a topic of contention. The current standard of care for patients with papillary thyroid cancer includes total thyroidectomy and a therapeutic lymph node dissection for patients presenting with clinically evident nodal disease. However, many surgeons advocate prophylactic central neck lymph node dissections in patients who present with no clinical or radiographic evidence of lymph node involvement. Proponents of prophylactic central compartment neck dissection argue that the incidence of central neck metastases is high and the sensitivity of preoperative ultrasound is low. Furthermore, central neck dissection advocates argue that clearing the central neck at the initial operation improves staging accuracy, assists in deciding on postoperative radioactive iodine treatment, and potentially avoids a higher-risk reoperative central neck dissection. Selective lateral neck dissections, as well as modified radical neck dissections, are accepted as necessary therapy in patients with clinically or radiographically positive lateral compartment disease. An essential component of any discussion on the extent of lymphadenectomy is whether patients derive any additional benefit from having a lymphadenectomy with total thyroidectomy and whether this can be done without significantly increasing the morbidity of the operation. Here we discuss the surgical options for approaching lymphadenectomy in patients presenting with papillary thyroid carcinoma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The impact of large vessel extension (LVE) as a prognostic factor for adrenocortical carcinoma (ACC) is not fully understood. This study aimed to assess outcome of ACC in the presence and absence of LVE., Methods: A retrospective review of 57 patients undergoing curative intent resection for ACC over 10 years is presented comparing those with and without LVE. LVE was defined as vascular wall invasion or intraluminal extension of the neoplasm into the inferior vena cava or renal vein. Preoperative diagnostics, operative details, pathology, overall survival (OS), and recurrence-free survival (RFS) were analyzed., Results: Multivariable regression analysis showed a significant association for decreased survival with Stage III and IV disease and LVE. Patients with LVE had more functional neoplasms, greater preoperative serum hormone levels, and more positive margins than those without LVE. Median OS was 6 years and RFS 3 years. Kaplan-Meier analysis demonstrated a significant decrease in OS and RFS with LVE. Median OS with and without LVE was 18 vs 111 months and median RFS was 11 vs 64 months. Three-year OS with and without LVE were 29% vs 93% and 3 year RFS was 15% vs 67%., Conclusion: In addition to systemic and lymph node metastases, LVE is associated with poorer OS and RFS., (Copyright © 2010 Mosby, Inc. All rights reserved.)

The use of molecular markers for thyroid cancer diagnosis, prognosis, and surveillance have been an exciting area of study and change. Recent investigative focus on promising new markers will very likely lead to improvements in the diagnostic utility of fine needle aspiration biopsy (FNAB) in predicting malignancy, as well as provide more accurate prognostic information pre- and postoperatively. The 2010 Annual Meeting of the American Association for Endocrine Surgeons featured a symposium dedicated to molecular marker testing in thyroid cancer and its potential clinical applicability., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Background: The effectiveness of prophylactic central neck dissection (pCND) in the treatment of patients with papillary thyroid carcinoma (PTC) to prevent local recurrence is controversial. We performed a meta-analysis to assess the effect of pCND on local recurrence in PTC., Methods: Exhaustive search of online search engines identified five retrospective studies that compared the local recurrence rates of PTC in patients without clinically detectable nodal disease in patients undergoing thyroidectomy + pCND (group A) to those undergoing thyroidectomy alone (group B). A meta-analysis was performed by the fixed effects method. Recurrence was documented by imaging, thyroglobulin detection, or reoperation. Location of recurrence was identified in either the central or lateral neck compartment., Results: A total of 1264 patients were included, 396 in group A and 868 in group B. Follow-up ranged from 6 months to 27 years. The overall recurrence rate was 2.02% in group A versus 3.92% in group B (odds ratio [OR] = 1.05, 95% confidence interval [95% CI] 0.48-2.31). The recurrence rate in the central neck compartment in group A was 1.86% compared to 1.68% in group B (OR = 1.31, 95% CI 0.44-3.91). The recurrence rate in the lateral neck compartment in group A was 3.73% compared to 3.79% in group B (OR = 1.21, 95% CI 0.52-2.75). There was no statistically significant difference in the OR in the local recurrence between the two groups., Conclusions: This meta-analysis indicates that pCND does not greatly reduce local recurrence in thyroid cancer. However, the available studies have substantial limitations and a prospective multicenter study to determine the indications for pCND is warranted.

Papillary thyroid carcinoma usually presents as a multifocal disease; and tumors often recur in the contralateral thyroid lobe, raising questions concerning their clonal origins. The clonality of tumors appearing simultaneously in both lobes or recurring in the contralateral lobe remains unknown. Accordingly, we examined 25 pairs of bilateral papillary thyroid carcinomas (synchronous or metachronous) and 15 matched metastatic lymph nodes. BRAF gene mutation analysis combined with X-chromosome inactivation was used to evaluate these tumors' clonal origins. Genomic DNA was prepared from paraffin-embedded tissues after microdissection. In total, 62 tumors yielded DNA of adequate quality. Eighteen (18/21, 85.7%) of 21 informative cases showed concordant BRAF status in tumors from both thyroid lobes, being either BRAF mutation positive (12 patients) or BRAF mutation negative (6 patients). Metastatic lymph nodes in 12 patients (12/15, 80%) had a complete concordance of BRAF state with their primaries. Of the 18 studied female patients, 11 were suitable for X-chromosome inactivation assay. Nine cases (9/11, 81.1%) showed the same pattern of inactivation in bilateral tumors. A close correlation was found between BRAF mutation and X-chromosome inactivation analysis. In conclusion, our data provide evidence that bilateral, recurrent, and metastatic papillary thyroid carcinomas often arise from a single clone and that intrathyroidal metastasis may play an important role in the development of bilateral tumors, as well as in the recurrence of this malignancy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Microarray technology provides a new opportunity to improve the diagnostic accuracy of fine needle aspiration (FNA) in evaluating thyroid nodules. Here, we evaluate whether ex vivo FNA and tissue samples can be used interchangeably in microarray and whether the method of acquisition affects the precision of the gene list that is generated. To assess whether FNA samples provide adequate material for reliable gene expression analysis, paired tissue and FNA samples were collected from 13 thyroid nodules; 7 malignant, 6 benign. RNA was extracted from each specimen, converted to complimentary DNA and hybridized to AffymetrixU-133 GeneChips. Cluster analysis was then performed using 61 genes predetermined to differentiate benign from malignant nodules. Clustering patterns were evaluated using 2-group K-means and hierarchical analysis. Twelve concordant pairs were used to generate differentially expressed genes between the sampling methods. Twenty-five of 26 samples clustered concordantly with the pathologic diagnosis. The sensitivity, specificity, and accuracy were 100%, 100%, and 100% for FNA and 85.7%, 100%, and 92.3% for tissue, respectively. Two-group K-means revealed an adjacent grouping for 12 of 13 pairs. Hierarchical analysis clustered 8 of 13 pairs together. Sixty-seven genes were differentially expressed between FNA and the tissue sampling methods. These genes predominantly represented stromal components and were upregulated in the tissue compared with FNA samples. We conclude that FNA is a reliable alternative to tissue samples in predicting malignancy with microarray.

Selenium (Se) supplementation is reported to decrease the incidence and total mortality of cancer. Whereas in vitro and in vivo studies have shown a decrease in prostate, lung, and liver cancers, this has not been shown in thyroid cancer. ARO (anaplastic), NPA (BRAF positive papillary), WRO (BRAF negative papillary), and FRO (follicular) cells treated with 150 microM seleno-l-methionine (SM) were assessed for viability at 24, 48, and 72 h. Treated FRO cells were examined for cell cycle using flow cytometry, for apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and for gene expression using microarray. Genes identified as upregulated were confirmed by real-time PCR (RT-PCR) and proteins by Western blot analysis. SM treatment significantly decreased the proliferation of all cell lines. TUNEL assay showed no evidence of apoptosis, and flow cytometry showed a significant cell-cycle arrest in S (271% increase, P = 0.006) and G2/M (61% increase, P = 0.002) compared to control. Microarray revealed 21 differentially expressed genes with greater than twofold change. A relative overexpression of growth arrest and DNA damage inducible (GADD)34 and GADD153 in treated cells was confirmed with RT-PCR and Western blot. SM inhibits thyroid cancer cell proliferation through a time dependent upregulation of the GADD family of genes and arrest in S and G2/M phases of the cell cycle. This is the first report of selenium induced inhibition of thyroid cancer cell growth.

Background: Patients are relying on the Internet with greater frequency to learn about diseases and make medical decisions. We hypothesized that there is a disparity between the perceptions of patients and those of surgeons regarding the quality of information about primary hyperparathyroidism on the Internet., Methods: Patients (n = 62) with primary hyperparathyroidism seen in endocrine surgery clinics in France and the United States responded to a survey regarding their use of the Internet to prepare for upcoming parathyroid surgery. A panel of endocrine surgeons reviewed the top "hits" retrieved from Web sites related to parathyroid disease. Sites were rated using a previously validated Web site quality scoring system., Results: A total of 75% of the American cohort and 53% of the French cohort used the Internet to prepare for parathyroid surgery. The majority of these patients reported that the information was "somewhat to very accurate." The panel of surgeons gave the Web sites an overall average qualitative score of 8.6 (53%)., Conclusion: Surgeons and patients have different perceptions as to what constitutes a high-quality Web site. As patients depend more on the Internet to prepare for parathyroid surgery, there is an opportunity and a clear need to create comprehensive, high-quality, patient-oriented Web sites on this topic.

Background: A subset of follicular lesions of the thyroid is encapsulated similar to follicular adenomas but with partial nuclear features suggestive of papillary thyroid carcinoma (PTC), raising the possibility of biologically borderline tumors., Methods: Gene expression profiling and advanced significance analyses were performed on 50 histologically unequivocal benign and malignant tumors, and a list of 61 differentially expressed genes was generated. By using this 61-gene list, unsupervised hierarchical and K-means cluster analyses were performed on 40 additional tumors, including 15 histologically borderline tumors, 11 benign tumors, and 14 PTCs., Results: Analysis revealed 3 distinct tumor groups-benign, malignant, and intermediate. Tumors in the intermediate group (n = 15) were mostly histologic borderline tumors and had an expression profile overlapping with the benign and malignant groups. Twenty-seven genes were expressed differentially between the benign and intermediate groups, including the cyclic AMP response element-binding protein/p300-interactivator with glutamic acid/aspartic acid-rich carboxy-terminal domain 1 or CITED1 gene and the fibroblast growth factor receptor 2 or FGFR2 gene. Fourteen genes were expressed differentially between the intermediate group and malignant tumors, notably overexpression of the met proto-oncogene and of the high-mobility group adenine/thymine-hook 2 or HMGA2 gene in malignancies. Mutations of the v-raf murine sarcoma viral oncogene homolog B1 or BRAF gene were identified in 4 of 14 malignant tumors but not in benign or intermediate tumors. Patients who had either histologically or molecularly borderline tumors did not have metastasis or recurrences., Conclusions: Gene expression profiling supported the finding that encapsulated thyroid follicular lesions with partial nuclear features of PTC are biologically borderline tumors that are distinct molecularly from benign and malignant tumors., ((c) 2009 American Cancer Society.)

Although fine-needle aspiration biopsy (FNA) remains the mainstay of the preoperative workup of thyroid nodules, it does not provide a diagnosis in up to 20% of nodules. This group of indeterminate lesions, including lesions with cellular atypia, suspicious cytology, and demonstrating a follicular pattern, provides one of the greatest challenges to researchers in thyroid cancer today. Over the last 2 decades, considerable work has been done to find molecular markers to resolve this diagnostic dilemma. This article explores some of the markers including galectin-3, HBME-1, BRAF, RET/PTC, PAX8-PPARgamma, hTERT, telomerase, miRNA, and microarray and multigene assays. Although no one marker has proven to be a panacea, several combinations of markers have shown great promise as an adjunct to FNA.

Objective: Many patients undergoing thyroidectomy for papillary thyroid carcinoma (PTC) have subclinical nodal disease at the time of surgery. Prophylactic bilateral central neck dissection (CND) is gaining acceptance in the treatment of PTC as studies have shown nodal disease increases the rate of local recurrence and may alter postsurgical radioactive iodine dosing. Given the potential complications of bilateral CND, we undertook a prospective study to determine the adequacy of prophylactic ipsilateral CND for PTC., Methods: A total of 116 patients with PTC underwent total thyroidectomy and routine prophylactic CND at a tertiary referral center. Of these, 45 had right and left central neck lymph node basins submitted separately for pathologic examination. We examined the laterality of positive lymph nodes based on tumor location and size., Results: Overall, positive lymph nodes were found in 45% of patients. Of the patients having a lateralized CND, 33% had ipsilateral positive nodes only, while 20% had bilateral positive nodes. None of the patients with tumor size <=1 cm had bilateral positive lymph nodes compared with 31% of patients with tumors >1 cm (P = 0.02). Multifocality did not affect lymph node metastasis in tumors <=1 cm. Parathyroids were found in the pathology specimen of 34% of patients, 40% had parathyroids autotransplanted, 47% had temporary hypocalcemia, and 0% had permanent hypocalcemia. Rates of temporary and permanent recurrent laryngeal nerve injury were 5% and 0% respectively., Conclusions: Ipsilateral CND appears to be sufficient in patients with tumors <=1 cm. In tumors >1 cm, bilateral CND should be considered as these patients are more likely to have bilateral positive nodes. If tumor size is used as criteria for prophylactic CND, approximately one-third of patients can be spared a bilateral CND.

Background: The clinical significance of papillary thyroid microcarcinoma (PTMC) tumors < or =1 cm is widely debated. The objective of this study was to compare conventional papillary thyroid carcinoma (PTC) (tumors >1 cm) to PTMC and assess for differences in tumor characteristics and patient outcome., Methods: A retrospective chart review of patients with PTC or PTMC who were followed for a minimum of 3 years postoperatively and managed at a single academic institute was performed., Results: Of 202 patients in the study, 66 (32.7%) had PTMC and 136 (67.3%) had conventional PTC. Patient and tumor characteristics including tumor multifocality, extrathyroidal extension, angiolymphatic invasion, and lymph node metastasis were similar between both groups. Twenty-one percent of the PTMC tumors were discovered incidentally. Patients with conventional PTC were significantly more likely to undergo treatment with radioactive iodine therapy compared to PTMC patients (86.4% vs. 66.7%, respectively, p < 0.003). Disease recurrence was observed in 40 patients and was not statistically different between the two groups; 11 (16.7%) in PTMC and 29 (21.3%) in conventional PTC, p = 0.57. Within the PTMC group, tumors of patients that recurred were significantly larger than those who remained disease free (8.1 mm vs. 6.4 mm, p < 0.05). None of the patients with incidental PTMC had disease recurrence. Angiolymphatic invasion was the only significant prognostic indicator of recurrence on multivariate analysis (p < 0.02)., Conclusions: Nonincidental PTMC can have aggressive tumor features and disease recurrence similar to conventional PTC. These tumors should be managed like any other papillary thyroid malignancy.

Background: The aim of this study was to analyze the utility of preoperative thin cut (2.5 mm) computed tomography (CT) in patients with primary hyperparathyroidism (PHPT) and negative sestamibi scans., Methods: A retrospective review of patients with PHPT was conducted from the prospective parathyroid registries of 2 tertiary referral centers. Of 482 patients, 63 with negative sestamibi scanning underwent thin cut CT of the neck and were included in the final analysis., Results: CT was 85% sensitive and 94% specific for correctly lateralizing the side(s) of diseased glands and 66% sensitive and 89% specific for predicting exactly the location of diseased glands. Sixty-six percent of patients underwent focused explorations, and 87% of patients underwent parathyroidectomy under local anesthesia. Pathology revealed a single adenoma in 83%, multigland disease in 14%, carcinoma in 1%, and no pathology in 2%. Average operative time was 73 minutes overall, but only 55 minutes in patients with precise CT localization (P = .02)., Conclusion: Thin cut CT is a helpful adjunct to preoperative workup in PHPT patients who have negative sestamibi localization and permits a focused neck exploration in a high percentage of those patients.

Background: Extrathyroidal extension (ETE) is a risk factor for recurrence of papillary thyroid carcinoma (PTC). Although initial data supporting this was based on gross ETE noted at surgery, current treatment regimens group patients with microscopic ETE-identified only on histopathology-similarly to those with macroscopic (gross) ETE. This study was designed to assess the influence of microscopic ETE on disease recurrence., Methods: Retrospective analysis of 212 patients undergoing thyroidectomy for PTC between 1995 and 2004 with minimum 3-year follow-up was conducted., Results: Of 212 patients, 71 had ETE; 32% were macroscopic and 68% microscopic. Patient demographics, tumor variables, and adjuvant therapy were similar between both ETE groups. Recurrence rates were 52% for macroscopic ETE, 21% for microscopic ETE, and 13% without ETE. On multivariate analysis, patients with macroscopic ETE had a 6.4-fold increased relative risk of recurrence compared with patients with microscopic ETE (P < .02; 95% confidence interval, 1.6-25.9) and a significantly decreased disease-free survival (DFS). Furthermore, patients with microscopic ETE had neither a significantly increased risk of recurrence nor different DFS compared with patients without ETE., Conclusion: Macroscopic ETE has a higher incidence of disease recurrence than microscopic ETE, implying they should be considered separately when devising adjuvant treatment regimens. The significance of microscopic ETE is undetermined.

Background: Functional chemokine receptors are expressed in many malignant tumors, including papillary thyroid carcinoma (PTC). These receptors promote tumor growth and metastasis in response to endogenous chemokines. The purpose of this study was to examine the expression of two chemokine receptors-CXCR4 and CCR7-in a series of PTCs. We hypothesized that CXCR4 and CCR7 would correlate with indicators of tumor aggressiveness, including tumor size, extrathyroidal extension (ETE), angiolymphatic invasion (ALI), and lymph node metastasis., Methods: CXCR4 and CCR7, as well as their specific chemokine ligands (CXCL12 and CCL21, respectively), were assessed in 88 PTCs from 65 patients using a semiquantitative measure of immunohistochemical (IHC) staining intensity for each molecule. Staining intensity was compared with clinicopathologic features including patient age, gender, tumor size, multifocality, ETE, ALI, and lymph node metastasis. Differences in CXCR4 and CCR7 mRNA levels were sought in a subset of tumors using gene microarrays and quantitative RT-PCR. [, Statistics: t test, Mann-Whitney U test; P < .05]., Results: High-intensity IHC staining for CXCR4 was associated with larger tumor size (P = .02), while PTCs exhibiting ETE, ALI, or lymph node metastasis showed higher-intensity IHC staining for CCR7 than those without (P = .01, .03, and .01, respectively). CCR7 mRNA levels were also higher in tumors with ALI (P = .04)., Conclusion: Expression of CXCR4 and CCR7 by PTCs is associated with indicators of tumor aggressiveness, including tumor size, ETE, ALI, and lymph node metastasis. Further studies are necessary to define the mechanisms underlying this association and to determine its potential prognostic and therapeutic implications.

MicroRNA (miRNA) microarray analysis has consistently found altered expression of miRNAs in thyroid tumors, suggesting their roles in thyroid carcinogenesis. To explore whether this differential expression can be used as a diagnostic tool in surgical pathology and fine-needle aspirate (FNA) specimens, the expression of selected miRNA was evaluated by quantitative RT-PCR, using total RNA from 84 formalin-fixed paraffin-embedded tissues and 40 ex vivo aspirate specimens. miRNA from all paraffin-embedded tissues and all but one FNA sample were found to be analyzable, with paraffin sections yielding better miRNA quality. Preliminary analysis of 6 miRNAs in 10 papillary thyroid carcinoma and 10 follicular adenoma identified significant overexpression of miR-146b, -221, and -222 in papillary thyroid carcinoma (P<0.02), but not miR-146a, -155, or -187 (P>0.08). The expression of these first three miRNAs was examined in a series of 5 normal thyroid, 11 hyperplastic nodules, 24 follicular adenoma, 27 classical papillary thyroid carcinoma, 5 follicular variant papillary thyroid carcinoma, 2 follicular carcinoma, and 10 encapsulated follicular lesions with partial nuclear features of papillary carcinoma. Results showed miR-146b to be most consistently overexpressed in both classical papillary carcinoma and follicular variants, whereas all other groups showed lower expression at a similar level (P<0.001 for pair-wise comparisons between papillary carcinoma and all other groups). Follicular lesions with partial features of papillary carcinoma all showed low miR-146b levels similar to other non-papillary carcinoma groups, suggesting that they are biologically distinctive from papillary carcinoma. miR-221 and miR-222 also showed higher expression in papillary carcinoma, but with substantial overlaps with the other groups. When applied to 40 FNA samples of various lesions, only miR-146b and miR-222 persisted as distinguishing markers for papillary carcinoma. We concluded that miRNAs, particularly miR-146b, might potentially be adjunct markers for diagnosing papillary thyroid carcinoma in both FNA and surgical pathology specimens.

Background: Benign thyroid tumors account for most nodular thyroid disease. Determination of whether a thyroid nodule is benign or malignant is a major clinical dilemma and underlies the decision to proceed to surgery in many patients. Although the accuracy of thyroid nodule fine-needle aspiration (FNA) has reduced the need for surgery over the years, questions regarding how to follow FNA-designated benign nodules remain unresolved. This is true at least in part because of uncertainty over whether some benign nodules harbor malignant potential., Methods: An evidence-based review of recent clinical, pathologic, and molecular data is presented. A summary of data and observations from our own experience is also provided., Results: Review of our recent 10-year experience indicates that 2% of thyroid malignancies arise within a preexisting benign thyroid nodule. In addition, both cytologic and molecular tumor markers, including Gal-3, CITED1, HBME-1, Ras, RET/PTC, and PAX8/PPAR gamma, have been identified in some histopathologically classified benign nodules. Gene expression profiling suggests that follicular adenomas and Hürthle cell adenomas have similarities to both benign and malignant tumors, suggesting that some of these tumors are premalignant. In addition, 10% of surgically excised follicular tumors are encapsulated follicular lesions with nuclear atypia, which have been termed "well-differentiated tumors of uncertain malignant potential." The data available suggest that these tumors could be precursors to carcinoma., Conclusion: Some benign thyroid nodules have malignant potential. Further molecular testing of these tumors can shed light on the pathogenesis of early malignant transformation.

Background: Substernal thyroidectomy (ST), as compared to conventional, cervical thyroidectomy, is a technically demanding procedure that is associated with increased morbidity and mortality. We tested the hypothesis that outcomes following ST are improved at centers that perform a high volume of thyroidectomies., Methods: Patients who underwent ST from 1998 to 2004 were extracted from the New York State Statewide Planning and Research Cooperative System database. Hospital volume of thyroidectomies was divided into low (<33 per year), middle (33-99 per year), and high (>or=100 per year) volumes. Outcome variables included hospital length of stay (LOS), recurrent laryngeal nerve (RLN) injury, hypoparathyroidism, postoperative bleeding, respiratory failure, blood transfusion, and mortality., Results: A total of 1153 STs were analyzed; 372 (32.2%) were performed at low-volume centers, 388 (33.7%) at middle-volume centers, and 393 (34.0%) at high-volume centers. Linear associations were observed between increasing hospital volume of thyroidectomies and decreasing age (p=0.003), increasing co-morbidity (p<0.0001), increased likelihood of total versus subtotal thyroidectomy (p<0.0001), and increased likelihood of thyroid malignancy (p<0.0001). Despite this, increasing hospital volume of thyroidectomies predicted a decreased likelihood of overall complications (p=0.005), postoperative bleeding (p=0.01), blood transfusion (p=0.04), respiratory failure (p=0.04) and mortality (p=0.004), as well as a trend toward a decreased LOS (p=0.06). The overall complication rate and the mortality rate remained significantly associated with volume group by multivariate analysis., Conclusion: Despite more extensive surgery on patients with greater co-morbidity, LOS, morbidity, and mortality were all decreased when ST occurred at hospitals that perform a high volume of thyroidectomies.

Background: Although recent single-institution series have reported low morbidity and zero mortality after substernal thyroidectomy, a direct comparison of outcomes between substernal thyroidectomy and conventional cervical thyroidectomy has not been performed. We hypothesized that substernal thyroidectomy would be associated with higher morbidity and mortality as compared with cervical thyroidectomy., Study Design: Data were extracted from the New York State Statewide Planning and Research Cooperative System database for the years 1998 to 2004. The primary predictor variable was substernal as compared with cervical thyroidectomy. Outcomes variables included postoperative complications, length of stay, and mortality. Multiple logistic regression was used to access the independent effects of substernal thyroidectomy on postoperative outcome., Results: A total of 33,930 patients underwent thyroidectomy, 1,153 (3.4%) of whom underwent substernal thyroidectomy. Compared with patients who underwent cervical thyroidectomy (n=32,777), patients who underwent substernal thyroidectomy were older (p<0.0001), more likely to have a comorbid condition (p<0.0001), more likely to be men (p<0.0001), more likely to lack private insurance (p<0.0001), more likely to undergo total thyroidectomy (p<0.0001), less likely to undergo thyroidectomy for malignancy (p<0.0001), and less likely to undergo thyroidectomy at a high-volume center (p=0.001). After controlling for these covariates, patients who underwent substernal thyroidectomy were considerably more likely to experience recurrent laryngeal nerve injury (p=0.0002), postoperative bleeding (p=0.004), deep venous thrombosis (p=0.0002), and respiratory failure (p<0.0001), and were more likely to receive a red blood cell transfusion (p<0.0001). Patients who underwent substernal thyroidectomy also had a considerably increased length of stay (p<0.0001), and more than an eightfold increase in likelihood of mortality (p<0.0001)., Conclusions: Substernal thyroidectomy, as compared with cervical thyroidectomy, is associated with a markedly increased likelihood of both postoperative complications and mortality.