Benzon M. Dy

Does BRAF V600E Mutation Predict Aggressive Features in Papillary Thyroid Cancer? Results From Four Endocrine Surgery Centers

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.

Operative intervention for recurrent adrenocortical cancer

INTRODUCTION Adrenocortical cancer (ACC) recurs despite apparent complete resection. We examined the survival and palliative benefit of resection for recurrent ACC. METHODS A review of all patients undergoing operation for ACC between 1980 and 2010 at our institution was performed in which we compared resection with nonoperative therapy. RESULTS Overall, 164 patients underwent operation for ACC, 125 of whom underwent a complete resection (R0). Recurrence occurred in 93 R0 patients (median, 15 months; range, 1.5-150 months). Symptoms at recurrence were present in 71% (66/93), including pain (34%) and hormone excess (43%). There were 67 patients who underwent reoperation for recurrence. Forty-eight of 67 patients underwent R0 resection for recurrence. Operative patients had a greater overall operative versus nonoperative management or no therapy (65 months vs 6 months, P < .01). Median survival for nonoperatively managed patients (226 days) and those undergoing no therapy (179 days) was less than for debulking (1,272 days, P = .002). R0 for recurrence (P = .005) and a disease-free interval >6 months (P < .001) were associated with survival after operation, whereas original tumor size (P = .47), grade (P = .8), and stage (P = .23) were not. Pain and hormonal symptoms improved in 84% of operative patients versus 29% of nonoperatively managed patients (P = .005). Debulking had similar symptomatic improvement to R0 resection (P = .52). CONCLUSION Patients with recurrent ACC can benefit from operative intervention with improvement in survival and symptoms. Patients with a disease-free interval >6 months and complete resection are likely to benefit from resection of the recurrence, but the near universal improvement in symptoms may expand the criteria for operation in recurrent ACC.

Changes in bone mineral density after surgical intervention for primary hyperparathyroidism

BACKGROUND Patients with primary hyperparathyroidism often lack classic symptoms but can have reductions in bone mineral density and increased fracture risk. We sought to determine bone mineral density improvement after successful surgery and associated factors. METHODS A review of patients with osteopenia or osteoporosis with curative parathyroidectomy and both pre- and postoperative dual-energy X-ray absorptiometry bone mineral density scans was conducted. We compared patients with declining (<0%), moderate improvement (0.1-5%), and significant improvement (>5%) on dual-energy X-ray absorptiometry bone mineral density scans. RESULTS We identified 420 patients who underwent a dual-energy X-ray absorptiometry bone mineral density scan preoperatively and within 36 months postoperatively. At the most affected site, 38% had significant improvement, 31% moderate improvement, and 31% declining bone mineral density. Patients who significantly improved were younger (P = .01), had lesser preoperative dual-energy X-ray absorptiometry (P = .001), and had greater preoperative levels of parathyroid hormone (P = .04), serum calcium (P = .03), and preoperative urinary calcium. There was no difference in outcomes between sex and with preoperative bisphosphonate use. Average hip and spine bone mineral density had similar responses to surgery. CONCLUSION Bone mineral density improves in up to 75% of patients after curative parathyroidectomy for primary hyperparathyroidism. The hip and lumbar spine responded similarly. Younger patients and those with severe primary hyperparathyroidism may derive the most skeletal benefits from parathyroidectomy, but the uniform positive response supports parathyroidectomy in patients with osteoporosis and possibly osteopenia.

Association of BRAFV600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers

BACKGROUND Studies have demonstrated an association of the BRAF(V600E) mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAF(V600E) mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM). METHODS Between January 2012 and June 2013, 237 consecutive patients underwent total thyroidectomy and prophylactic central lymph node dissection (CLND) at four endocrine surgery centers. All tumors were tested for the presence of the BRAF(V600E) mutation and miR-21, miR-146b-3p, miR-146b-5p, miR-204, miR-221, miR-222, and miR-375 expression. Bivariate and multivariable analyses were performed to examine associations between molecular markers and aggressive clinicopathologic features of PTC. RESULTS Multivariable logistic regression analysis of all clinicopathologic features found miR-146b-3p and miR-146b-5p to be independent predictors of CLNM, while the presence of BRAF(V600E) almost reached significance. Multivariable logistic regression analysis limited to only predictors available preoperatively (molecular markers, age, sex, and tumor size) found miR-146b-3p, miR-146b-5p, miR-222, and BRAF(V600E) mutation to predict CLNM independently. While BRAF(V600E) was found to be associated with CLNM (48% mutated in node-positive cases vs. 28% mutated in node-negative cases), its positive and negative predictive values (48% and 72%, respectively) limit its clinical utility as a stand-alone marker. In the subgroup analysis focusing on only classical variant of PTC cases (CVPTC), undergoing prophylactic lymph node dissection, multivariable logistic regression analysis found only miR-146b-5p and miR-222 to be independent predictors of CLNM, while BRAF(V600E) was not significantly associated with CLNM. CONCLUSION In the patients undergoing prophylactic CLNDs, miR-146b-3p, miR-146b-5p, and miR-222 were found to be predictive of CLNM preoperatively. However, there was significant overlap in expression of these miRs in the two outcome groups. The BRAF(V600E) mutation, while being a marker of CLNM when considering only preoperative variables among all histological subtypes, is likely not a useful stand-alone marker clinically because the difference between node-positive and node-negative cases was small. Furthermore, it lost significance when examining only CVPTC. Overall, our results speak to the concept and interpretation of statistical significance versus actual applicability of molecular markers, raising questions about their clinical usefulness as individual prognostic markers.

Primary aldosteronism: Making sense of partial data sets from failed adrenal venous sampling-suppression of adrenal aldosterone production can be used in clinical decision making

Background. It has been suggested that accurate clinical decisions may be made in patients with primary aldosteronism (PA) in the setting of failed cannulation of an adrenal vein, thereby utilizing only data from either right or left adrenal venous sampling (AVS) alone. Methods. Retrospective analysis was performed for all patients with PA who underwent successful bilateral AVS. Adrenal vein/inferior vena cava index (AV/IVC index) was calculated by dividing aldosterone/cortisol ratio of the adrenal vein by aldosterone/cortisol ratio in the inferior vena cava, as described in a previously published study. We examined the rates of inappropriate adrenalectomy and failure to recognize unilateral disease when previously published cutoffs are used. Results. Inclusion criteria were met in 150 patients; 61 with bilateral and 89 with unilateral disease. AV/IVC index cutoff of ≤0.5 to predict contralateral disease would have not led to any inappropriate adrenalectomies and would have missed 19% of patients with unilateral disease; AV/IVC index cutoff of ≥5.5 to predict ipsilateral unilateral disease would have resulted in inappropriate adrenalectomy in 18% of patients (95% CI 8–34%, P < .01) and would have not recognized 55% of patients with unilateral disease (P < .01). Conclusion. The cortisol‐corrected adrenal vein/inferior vena cava aldosterone index with a cutoff value of ≤0.5 performed well in identifying patients with contralateral unilateral disease. AV/IVC index of ≥5.5 cannot be used to reliably diagnose ipsilateral unilateral disease because 18% of patients undergoing adrenalectomy based on this cutoff would have bilateral disease.

Assimilating endocrine anatomy through simulation: a pre-emptive strike!

BACKGROUND We sought to determine if endocrine anatomy could be learned with the aid of a hands-on, low-cost, low-fidelity surgical simulation curriculum and pre-emptive 60-second YouTube video clip. METHODS A 3-hour endocrine surgery simulation session was held on back-to-back Fridays. A video clip was made available to the 2nd group of learners. A comprehensive 40-point test was administered before (pre-test) and after (post-test) the sessions. RESULTS General surgery interns (n = 26) participated. The video was viewed 19 times by 80% (12 of 15) of interns with access. Viewers outperformed nonviewers on subsequent post-testing (mean [SD], 29.7 [1.3] vs 24.4 [1.6]; P = .015). Mean scores on the anatomy section of the post-test were higher among viewers than nonviewers (mean [SD] 14.2 [.9] vs 10.3 [1.0]; P = .012). CONCLUSIONS Low-cost simulation models can be used to teach endocrine anatomy. Pre-emptive viewing of a 60-second video may have been a key factor resulting in higher post-test scores compared with controls, suggesting that the video intervention improved the educational effectiveness of the session.

Treatment of lateral neck papillary thyroid carcinoma recurrence after selective lateral neck dissection

Background: There is a paucity of data regarding optimal treatment options and outcomes for recurrent disease after lateral neck dissection in patients with papillary thyroid carcinoma. Methods: Retrospective review of patients who underwent either percutaneous ethanol injection or surgery for first‐time ipsilateral recurrences after ipsilateral lateral neck dissection for papillary thyroid carcinoma was performed. Results: Follow‐up data were available for 54 patients with recurrences in 57 lateral necks treated by either percutaneous ethanol injection (n = 32) or surgery (n = 25). Tumor burden at the time of lateral neck recurrence differed between the groups including the largest lymph node diameter (mean: 13 mm vs 18 mm, P < .01) and the mean number of metastatic lymph nodes identified on ultrasound (1.3 vs 1.9, P = .04). Each modality alone achieved similar estimated rates of disease control at 36 months (75% for percutaneous ethanol injection and 74% for surgery, P = .8) with similar number of reinterventions (1.8 for percutaneous ethanol injection, 1.6 for surgery, P = .6). Conclusions: Both ethanol ablation and surgery can achieve disease control in the majority of patients with recurrences after ipsilateral lateral neck dissection for papillary thyroid carcinoma. Ethanol ablation, when used for treatment of a single small lymph node, can result in outcomes that are similar to reoperative surgery for larger and multiple lymph nodes.

J. Aidan Carney

Prior to genetic testing, the understanding of genetic endocrinopathies required the commitment and interest of astute clinicians treating patients with an interest in associating rare diseases. Conditions may have been described in only a single patient with a rare combination of diseases that required persistent and ongoing interest. Few have made contributions as important as J. Aidan Carney, M.D., Ph.D., in the field of endocrine surgery.