Chronic Lymphocytic Thyroiditis May Limit the Utility of Molecular Testing in AUS/FLUS Thyroid Nodules.

INTRODUCTION: Chronic lymphocytic thyroiditis (CLT) may increase the likelihood of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) results in thyroid nodules by fine needle aspiration (FNA). Gene expression classifier (GEC) and Thyroid Sequencing (ThyroSeq) may better stratify rate of malignancy (ROM) of AUS/FLUS thyroid nodules. This study compares the utility of molecular tests in determining malignancy in surgical patients with concomitant AUS/FLUS thyroid nodules and CLT. METHODS: A retrospective review of 1648 patients with index thyroid nodules who underwent FNA and thyroidectomy at a single institution was performed. Patients with concomitant AUS/FLUS thyroid nodules and CLT were subdivided into three diagnostic groups: FNA only, FNA with GEC, and FNA with ThyroSeq. Patients with AUS/FLUS thyroid nodules without CLT were subdivided into similar groups. Final histopathology of the cohorts was further stratified into benignity and malignancy and analyzed using Chi-squared statistics. RESULTS: Of 463 study patients, 86 had concomitant AUS/FLUS thyroid nodules and CLT with a 52% ROM, and the difference of ROM among FNA only (48%), suspicious GEC (50%), or positive ThyroSeq (69%) was not significant. In 377 patients with AUS/FLUS thyroid nodules without CL, ROM was 59%. ROM among these patients was significantly higher when molecular testing was used (FNA only 51%, suspicious GEC 65%, and positive ThyroSeq 68%; P < 0.05). CONCLUSIONS: Molecular tests may have limited value in predicting malignancy in surgical patients with concomitant AUS/FLUS thyroid nodules and CLT.

A >50% Intraoperative Parathyroid Hormone Decrease Into Normal Reference Range Predicts Complete Excision of Malignancy in Patients With Parathyroid Carcinoma.

INTRODUCTION: The mainstay of successful treatment for parathyroid carcinoma remains complete surgical excision. Although intraoperative parathyroid hormone (ioPTH) monitoring is a useful adjunct during parathyroidectomy for benign primary hyperparathyroidism, its utility for parathyroid carcinoma remains unclear. METHODS: A retrospective review of 796 patients who underwent parathyroidectomy with ioPTH monitoring for primary hyperparathyroidism revealed 13 patients with parathyroid carcinoma on final pathology from two academic institutions. A systematic review yielded 5 additional parathyroid carcinoma patients. Complete excision of malignancy, or operative success (eucalcemia ≥6 mo. after parathyroidectomy); operative failure (persistent hypercalcemia <6 mo. after parathyroidectomy); and perioperative complications were evaluated. Comparison of the >50% ioPTH decrease alone to >50% ioPTH decrease into normal reference range was analyzed using Chi-squared, Kolmogorov-Smirnov, Kruskal-Wallis tests. RESULTS: All 18 parathyroid carcinoma patients achieved a >50% ioPTH decrease, and 14 patients also had a final ioPTH level decrease into normal reference range. 93% of patients who met normal parathyroid hormone reference range had operative success, whereas only two of the four (50%) patients with parathyroid carcinoma with a >50% ioPTH decrease alone demonstrated operative success. CONCLUSIONS: Parathyroidectomy guided by a >50% ioPTH decrease into normal reference range may better predict complete excision of malignant tissue in patients with parathyroid carcinoma compared to >50% ioPTH decrease alone. IoPTH monitoring should be used in conjunction with clinical judgment and complete en bloc resection for optimal treatment and success.

Sex Differences in Papillary Thyroid Cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is three times more common in women than men. However, PTC in men appears to be associated with poorer outcomes than in women. This study compares the clinical presentation and pathologic features of men and women with PTC. MATERIALS AND METHODS: A retrospective review of prospectively collected data for patients with PTC who underwent fine needle aspiration (FNA) of a solitary thyroid nodule and thyroidectomy at a single institution was performed. Factors including age, ultrasound features, FNA results, extent of surgical operation and final histopathology were compared between male and female patients. Descriptive statistics using chi-square and t-test statistics compared outcomes by sex. RESULTS: Of the 851 patients with PTC, 158 (19%) were men and 693 (81%) were women. Mean age and standard deviation (SD) of patients was 48 (± 14) years, and most were of Hispanic origin (69%). Men had a significantly higher rate of radiation exposure relative to women, respectively (8% vs. 2%, P<0.01). There were no ultrasonographic or FNA cytologic differences among sexes. Men had more aggressive pathologic features including lymphovascular invasion (LVI) (47% vs. 34%, P<0.01) and positive lymph nodes (LN) (36% vs. 27%, P<0.05) compared to women. Thyroid lobectomy with isthmusectomy was more commonly performed among men compared to women (24% vs. 13%, P<0.01). CONCLUSION: Men with PTC have higher rates of radiation exposure associated with more aggressive disease with LVI and LN involvement on final histopathology compared to women. Total thyroidectomy with possible central neck dissection should further be considered when counseling men with PTC.

Morbidity Associated With Surgical Removal of Substernal Thyroid Goiters.

INTRODUCTION: Surgical excision of substernal thyroid goiters (STG) can be challenging while minimizing postoperative morbidity. Postoperative complication rates associated with transcervical and transthoracic approaches (i.e., partial or total sternotomy) for STG compared to multinodular goiters (MNG) limited to the neck (i.e., non-substernal) remains unclear. This study examines postoperative morbidity related to surgical approaches in the removal of STG and MNG. METHODS: A retrospective review of prospectively collected data of 988 patients with STG and non-substernal MNG from a single institution between 2010 and 2021 was performed. Patients were stratified by STG and conventional non-substernal MNG limited to the neck excised by transcervical and transthoracic approach. Postoperative complications including neck hematoma requiring return to the operating room, permanent recurrent laryngeal nerve injury and hypocalcemia, and transient or temporary recurrent laryngeal nerve injury and hypocalcemia were identified. Demographics including age, sex, and race, among others, were analyzed. RESULTS: Of the 988 cases, there were 887 (90%) MNG and 101 (10%) STG. Of the STG cohort, 11 (11%) required a partial sternotomy and 4 (4%) required a total sternotomy. Permanent complication rates for non-substernal MNG and STG patients were 1.5% and 0.9%, respectively. Only transient or temporary hypocalcemia rates were statistically different between the STG and MNG cohorts (9.9% versus 3.8%, P < 0.001). CONCLUSIONS: Regardless of transcervical or transthoracic approach, postoperative complications associated with the surgical removal of STG are low in the hands of experienced, high-volume thyroid surgeons.

Transient Hypocalcemia After Total Thyroidectomy: The Obesity Paradox at Work?

INTRODUCTION: With increasing rates of obesity worldwide, a correlation between high body mass index (BMI) and postoperative morbidity after thyroid surgery remains unclear. Postoperative transient hypocalcemia is common after total thyroidectomy due to interruption of parathyroid function. This study examines the relationship between BMI and hypocalcemia after total thyroidectomy. MATERIALS AND METHODS: A retrospective review of prospectively collected data for 1135 patients who underwent total thyroidectomy for cancer, multinodular goiter (MNG), or Graves' disease between June 2009 and November 2020 at a single institution was performed. BMI groups followed the World Health Organization classification. Hypocalcemia was defined as serum calcium ≤8 mg/dL. Calcium levels measured on postoperative day 0 and the following morning were compared between the BMI groups. RESULTS: Of 1135 total thyroidectomy patients, 85% were women. The mean age and standard deviation of patients was 49 (± 13) y, with most of Hispanic origin (64%). Overall, 41.5% of patients had cancer, 45% nontoxic MNG, 5.8% toxic MNG, and 12% Graves' disease. Stratified by BMI, 27% of patients were normal, 34% overweight, and 39% obese. Overall, overweight and obese patients experienced less transient hypocalcemia at both time points compared to normal patients postoperatively (P = 0.01 and P = 0.009). Furthermore, overweight and obese patients with Graves' disease experienced less transient hypocalcemia at both time points (P = 0.04 and P = 0.05). There was no statistical difference in other groups. CONCLUSIONS: A protective role of higher BMI or "obesity paradox" for postoperative hypocalcemia may exist in those obese patients after total thyroidectomy.

Telemedicine During COVID-19 Pandemic: Endocrine Surgery Patient Perspective.

INTRODUCTION: In response to the COVID-19 pandemic, many medical providers have turned to telemedicine as an alternative method to provide ambulatory patient care. Perspectives of endocrine surgery patients regarding this mode of healthcare delivery remains unclear. The purpose of this study is to evaluate the opinions and perspectives of endocrine surgery patients regarding telemedicine. METHODS: The first 100 adult patients who had their initial telemedicine appointment with two endocrine surgeons were contacted at the conclusion of their visit. The survey administered assessed satisfaction with telemedicine, the provider, and whether attire or video background played a role in their perception of the quality of care received using a 5-point Likert scale. Differences in responses between new and returning patients were also evaluated. RESULTS: Telemedicine endocrine surgery patients stated excellent satisfaction with their visit (4.89 out of 5) and their provider (4.96 out of 5). Although there was less consensus that telemedicine was equivalent to in-person or face-to-face clinic visits (4.15 out of 5), patients would recommend a telemedicine visit to others and most agreed that this modality made it easier to obtain healthcare (4.7 out of 5). Attire of the provider and video background did not influence patient opinion in regard to the quality of care they received. Returning patients were more likely to be satisfied with this modality (4.94 versus 4.73, P = 0.02) compared to new patients. CONCLUSIONS: This study shows that telemedicine does not compromise patient satisfaction or healthcare delivery for patients and is a viable clinic option for endocrine surgery.

Intraoperative parathormone monitoring to predict operative success in patients with normohormonal hyperparathyroidism.

BACKGROUND: It is unclear whether parathyroidectomy guided by intraoperative parathormone (PTH) monitoring is predictive of operative success in patients with normohormonal hyperparathyroidism (nhHPT), a variant of primary hyperparathyroidism (pHPT) in which patients develop clinical manifestations similar to those of pHPT. This study examined intraoperative PTH monitoring in patients undergoing parathyroidectomy for nhHPT. METHODS: We performed a retrospective review of prospectively collected data from adult (age > 18 yr) patients who underwent parathyroidectomy for pHPT at 1 of 2 North American medical centres (in Calgary, Alberta, Canada, or Miami, Florida, United States) between 2007 and 2015. In patients with nhHPT, we used the criterion of an intraoperative decrease of more than 50% in PTH after abnormal gland excision. We defined operative success as continuous eucalcemia more than 6 months after parathyroidectomy. RESULTS: Of 333 patients, 38 (11.4%) had nhHPT, with mean preoperative calcium and PTH levels of 2.7 mmol/L and 53 pg/dL, respectively. An intraoperative decrease of more than 50% in PTH level was seen in 27 patients (71.0%) with nhHPT and 265 patients (89.8%) with classic pHPT at 5 minutes (p < 0.001); the corresponding values at 20 minutes were 35 (92.1%) and 286 (96.9%). Although 5 patients (13.2%) with nhHPT did not reach this criterion until 20 minutes, the rate of operative success was still 97.0% at long-term follow-up (mean 13 mo, range 6-67 mo). Of the 38 patients, 3 (7.9%) did not have an intraoperative decrease of more than 50% in PTH level by 20 minutes. Two of the 3 achieved operative success and remained normocalemic, and 1 developed recurrent disease at 12 months. CONCLUSION: Parathyroidectomy guided by intraoperative PTH monitoring accurately predicted operative success in patients with nhHPT. Intraoperative PTH monitoring may also help identify multiglandular disease in patients with nhHPT, using criteria similar to those in classic pHPT, with comparable operative success.

Molecular Testing Has Limited Utility in the Surgical Evaluation of Bethesda III Thyroid Nodules.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology has 6 diagnostic categories, each with an implied cancer risk of malignancy (ROM). Bethesda III, defined as atypia or follicular lesions of undetermined significance (AUS/FLUS) on fine needle aspiration (FNA), has an indeterminate ROM. This study investigates the utility of Afirma Gene Expression Classifier (GEC) and Thyroid Sequencing (ThyroSeq) molecular testing to predict malignancy in AUS/FLUS thyroid nodules. METHODS: A retrospective review of prospectively collected data of 1457 patients with index thyroid nodules who underwent FNA and thyroidectomy at a single academic institution was performed. Use of GEC or ThyroSeq for AUS/FLUS thyroid nodules was examined. GEC testing was reported benign or suspicious for malignancy whereas ThyroSeq testing was reported on a spectrum of low, intermediate or high ROM. Descriptive statistics were utilized to compare the ROM among AUS/FLUS thyroid nodules. RESULTS: Of 1457 patients with FNA thyroid cytology, 359 (25%) corresponded to AUS/FLUS results. There were 132 (37%) patients with GEC testing and 88 (24%) had ThyroSeq testing. ROM without GEC or ThyroSeq testing was 49%, whereas ROM with suspicious GEC was 55%. ROM with positive ThyroSeq was 73%. Among ThyroSeq patients, 43 had intermediate-risk mutations with 60% malignancy, and 23 had high-risk mutations with 96% malignancy (P < 0.01). CONCLUSION: Surgical patients with AUS/FLUS thyroid nodules have a high ROM. High-risk ThyroSeq testing may have some utility in predicting malignancy, but GEC and intermediate-risk TGC results have limited value. Surgeons should carefully consider the utility of molecular tests to determine surgical resection.

Increased Incidental Thyroid Cancer in Patients With Subclinical Chronic Lymphocytic Thyroiditis.

BACKGROUND: The autoimmune process and increased TSH associated with chronic lymphocytic thyroiditis (CLT) are factors that may promote development of thyroid cancer. When surgically removed, the cellular changes of CLT are commonly seen surrounding thyroid cancers. This study investigates the malignancy rate in CLT patients when compared with non-CLT patients after thyroidectomy. METHODS: A retrospective review of prospectively collected data for 1268 patients with index thyroid nodules who underwent thyroidectomy at a single institution was performed. Patients were excluded if they had previous thyroid surgery, known thyroid cancer, Graves' disease, family history of thyroid cancer, and history of radiation exposure. Patients were subdivided into CLT and non-CLT groups by final pathology. Final pathology was reviewed and grouped into cancer in the index thyroid nodule and incidental thyroid cancers. Chi-squared analyses were performed using SAS. RESULTS: Of 359 patients that met study criteria, 52 had CLT. Overall, the malignancy rate was 37% in both CLT patients (19/52) and non-CLT patients (114/307) (P = 0.86). However, incidental thyroid cancer was found in 15% (8/52) of CLT patients and 10% (31/307) of non-CLT patients (relative risk = 1.52) who had no index nodule cancer. The breakdown of incidental cancer subtype in CLT patients was classic variant papillary thyroid carcinoma (PTC), n = 3; follicular variant PTC, n = 5. CONCLUSIONS: Patients with CLT have a 1.5-fold increased risk of incidental PTC. CLT should be considered a risk factor for incidental thyroid cancer, and patients with this thyroid condition should be counseled and monitored periodically for underlying thyroid malignancy.

Chronic Lymphocytic Thyroiditis May Lower Accuracy of AUS/FLUS Cytopathology in Surgical Patients.

BACKGROUND: Chronic lymphocytic thyroiditis (CLT) increases cytologic atypia on fine-needle aspiration of thyroid nodules, and its effect on rate of malignancy in atypia of undetermined significance (AUS)/follicular lesions of undetermined significance (FLUS) thyroid nodules remains unclear. This study evaluates the effect of concomitant CLT on malignancy rates of AUS/FLUS thyroid nodules in surgical patients. METHODS: Retrospective review of 1061 patients who underwent thyroidectomy for a dominant thyroid nodule from a single institution was performed. Fine-needle aspiration was classified according to the Bethesda System for Reporting Thyroid Cytopathology. Patients with AUS/FLUS cytopathology were classified into two cohorts: AUS/FLUS with CLT and AUS/FLUS without CLT. Final pathology was reviewed, and the cohorts were further stratified into benign and malignant subgroups. When applicable, patients with gene expression classifier (GEC) testing were reviewed and the positive predictive value (PPV) was calculated. RESULTS: Of the entire surgical series, 293 (28%) patients had AUS/FLUS cytopathology with a rate of malignancy of 56% (163/293) on final pathology. Seventy-three (25%) patients had AUS/FLUS with CLT, of which 44% (n = 32) were malignant by final pathology. The remaining 75% (n = 220) had AUS/FLUS without CLT, 60% (n = 131) of which were malignant. GEC testing was performed in 36 of the AUS/FLUS with CLT patients, where of the 33 suspicious results, 17 were malignant on final pathology, yielding a PPV of 52%. CONCLUSIONS: The rate of malignancy for AUS/FLUS thyroid nodules is lower with coexisting CLT, and similar to previous studies, the PPV of GEC testing is approximately 50%. Cytologic atypia due to CLT may increase more AUS/FLUS results in thyroid nodules, which may lead to overestimation of malignancy rates in this patient population.

High Rates of Underlying Thyroid Cancer in Patients Undergoing Thyroidectomy for Hyperthyroidism.

BACKGROUND: The rate of thyroid cancer in patients with hyperthyroidism is reported to be rare, and patients with toxic thyroid nodules do not routinely undergo fine-needle aspiration (FNA) to evaluate for malignancy. However, higher rates of malignancy in hyperthyroid patients may exist than previously reported. This study examines the rate of malignancy in patients with hyperthyroidism who have undergone thyroidectomy. METHODS: A retrospective review of prospectively collected data of 138 patients with hyperthyroidism who underwent thyroidectomy at a single institution was performed. Patients were divided into three groups: Graves' disease (n = 80), toxic multinodular goiter (n = 46), and toxic solitary nodule (n = 12). Patients with previous thyroid surgery were excluded from the study. All patients had biochemical confirmation of hyperthyroidism with thyroid-stimulating hormone <0.1 mIU/L and clinical diagnosis by a referring physician. RESULTS: Of 138 patients, 22% (31/138) were found to have malignancy on final pathology. The breakdown of malignancy by hyperthyroid condition was as follows: 16% in Graves' disease, 24% in toxic multinodular goiter patients, and 50% in toxic solitary nodule patients. CONCLUSIONS: There is a clinically significant rate of malignancy seen in patients who undergo thyroidectomy for hyperthyroidism. Patients with distinct thyroid nodules in the presence of hyperthyroidism may have the highest rates of malignancy and should undergo appropriate workup with ultrasound and FNA to exclude underlying malignancy. In cases with suspicious ultrasound features and/or FNA cytopathology, surgical treatment should be considered as initial management.

Impact of Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features on Revised Bethesda System Malignancy Rates at a Single Institution.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) standardizes thyroid cytopathology reporting in six tier diagnostic categories. In recent years, noninvasive encapsulated follicular variant of papillary thyroid carcinoma was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This study examines the impact of NIFTP on the BSRTC risk of malignancy (ROM). METHODS: This was a retrospective review of prospectively collected data from 565 patients who underwent fine needle aspiration and thyroidectomy at a single institution. ROM for each Bethesda category was analyzed and calculated with NIFTP classified as a malignant and nonmalignant lesion. Absolute and relative differences between ROM were compared. RESULTS: Of 565 patients, 19 were Bethesda I, 159 were Bethesda II, 178 were Bethesda III, 46 were Bethesda IV, 42 were Bethesda V, and 121 were Bethesda VI. ROM differences with NIFTP classified as malignant versus nonmalignant for each class were as follows: Bethesda I, no change; Bethesda II, 18%-14%; Bethesda III, 55%-48%; Bethesda IV, 50%-35%; Bethesda V, 93%-91%; and Bethesda VI, 99%-98%. Absolute ROM differences for each category were as follows: Bethesda I, 0%; Bethesda II, 4%; Bethesda III, 7%; Bethesda IV, 15%; Bethesda V, 2%; and Bethesda VI, 1%. CONCLUSIONS: A decreasing trend in absolute and relative ROM was seen in Bethesda II, III, and IV categories; however, exclusion of NIFTP as a malignant lesion did not significantly alter the ROM of BSRTC categories. Surgeons should assess their respective institution's experiences with NIFTP and the BSRTC.

Inverse Relationship of BMI to TSH and Risk of Papillary Thyroid Cancer in Surgical Patients.

BACKGROUND: Obesity and thyroid cancer has increased in recent decades. Thyroid malignancy is linked with elevated thyroid-stimulating hormone (TSH) levels, which may have a positive association with body mass index (BMI). This study examines obesity and TSH level effect on papillary thyroid cancer (PTC) risk in a surgical population. METHODS: A retrospective review of prospectively collected data for 991 patients who underwent thyroidectomy at a single institution was performed. Patients were stratified according to BMI into three groups: nonobese (18.5-29.9 kg/m2), obese (30-39.9 kg/m2), and morbidly obese (≥40 kg/m2). Further subdivisions into benign and malignant outcomes based on final pathology were compared with preoperative TSH levels. Subanalyses according to sex were also performed. RESULTS: Of 517 patients with PTC, rate of malignancy (ROM) decreased (55% versus 48% versus 41%, P < 0.05) as BMI increased with a concomitant decrease in average TSH levels (1.75 versus 1.69 versus 1.41 mU/L), respectively. According to sex, decreased ROM (53% versus 44% versus 42%, P < 0.05) and TSH (1.79 versus 1.70 versus 1.33 mU/L), respectively, with increased BMI was identified in women. However, decrease of ROM was not significant in men with increasing TSH levels as BMI increased. Male sex was associated with increased PTC risk (OR, 1.916; 95% CI, 1.331-2.759), whereas obesity with reduced PTC risk (OR, 0.736; 95% CI, 0.555-0.976). CONCLUSIONS: Higher BMI correlates with decreased PTC rates and lower TSH levels and suggests other factors may be involved in thyroid tumorigenesis. Obese patients with thyroid cancer should not be managed differently compared with nonobese patients.

Additional 20-Minute Intraoperative Parathormone Measurement Can Minimize Unnecessary Bilateral Neck Exploration.

BACKGROUND: Parathyroidectomy guided by intraoperative parathormone (ioPTH) monitoring for primary hyperparathyroidism (pHPT) confirms removal of all hyperfunctioning parathyroid glands. This study evaluates the utility of an additional 20-min ioPTH measurement in patients who fail to meet the >50% ioPTH drop criterion. METHODS: A retrospective review of prospectively collected data of 706 patients with pHPT who underwent parathyroidectomy guided by ioPTH monitoring was performed. When a >50% ioPTH decrease from the highest either preincision or preexcision level was achieved after 10 min, parathyroidectomy was completed. If this criterion was not met, further exploration was performed or an additional 20-min ioPTH measurement was obtained. RESULTS: Of 706 patients, 72 (10%) patients did not meet the >50% ioPTH drop criterion at 10 min. Of these patients, 67% (48/72) underwent immediate bilateral neck exploration (BNE). For the other 33% of patients (24/72), a 20-min parathormone (PTH) measurement was drawn. Of patients with an additional 20-min PTH measurement, 46% (11/24) had a >50% ioPTH decrease at 20 min where BNE was avoided and parathyroidectomy completed, whereas 54% (13/24) did not. Compared to patients with insufficient ioPTH drop at 10 min and subsequent BNE, there was a statistically significant 46% reduction of BNE in patients with a 20-min PTH level (P < 0.01). CONCLUSIONS: A 20-min ioPTH measurement is useful in preventing unnecessary BNE in some patients who undergo focused parathyroidectomy with a delayed >50% ioPTH drop.

Protein structural and surface water rearrangement constitute major events in the earliest aggregation stages of tau.

Protein aggregation plays a critical role in the pathogenesis of neurodegenerative diseases, and the mechanism of its progression is poorly understood. Here, we examine the structural and dynamic characteristics of transiently evolving protein aggregates under ambient conditions by directly probing protein surface water diffusivity, local protein segment dynamics, and interprotein packing as a function of aggregation time, along the third repeat domain and C terminus of Δtau187 spanning residues 255-441 of the longest isoform of human tau. These measurements were achieved with a set of highly sensitive magnetic resonance tools that rely on site-specific electron spin labeling of Δtau187. Within minutes of initiated aggregation, the majority of Δtau187 that is initially homogeneously hydrated undergoes structural transformations to form partially structured aggregation intermediates. This is reflected in the dispersion of surface water dynamics that is distinct around the third repeat domain, found to be embedded in an intertau interface, from that of the solvent-exposed C terminus. Over the course of hours and in a rate-limiting process, a majority of these aggregation intermediates proceed to convert into stable ß-sheet structured species and maintain their stacking order without exchanging their subunits. The population of ß-sheet structured species is >5% within 5 min of aggregation and gradually grows to 50-70% within the early stages of fibril formation, while they mostly anneal block-wisely to form elongated fibrils. Our findings suggest that the formation of dynamic aggregation intermediates constitutes a major event occurring in the earliest stages of tau aggregation that precedes, and likely facilitates, fibril formation and growth.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features reclassification and its impact on thyroid malignancy rate and treatment.

BACKGROUND: The reclassification of noninvasive encapsulated follicular variant papillary thyroid carcinoma (FVPTC) to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) may have significant implications by changing overall malignancy rates and minimizing the extent of surgical treatment. METHODS: A retrospective review of 847 patients who underwent thyroidectomy at a single institution from January 2010 to April 2016 was performed. The subgroup with FVPTC (n = 181) was re-reviewed by endocrine pathologists for reclassification to NIFTP. The overall rate of malignancy (ROM) and within each Bethesda classification was determined before and after the reclassification of NIFTP. The extent of thyroidectomy among others in patients reclassified as NIFTP was further reviewed. RESULTS: Of 847 patients who underwent thyroidectomy, there was an overall ROM of 58% (n = 495), the majority being papillary thyroid cancer (PTC) (n = 454, 92%). In 181 patients with FVPTC, 146 underwent pathology re-review. There were 32 cases (22%) reclassified as NIFTP, reducing the overall ROM to 55%. ROM decreased across Bethesda categories I to V by the following: 3% Bethesda I, 8% Bethesda II, 8% Bethesda III, 10% Bethesda IV, and 3% Bethesda V. Among NIFTP patients, 16 underwent total thyroidectomy and 16 underwent thyroid lobectomy, of which 12 had completion thyroidectomies (75%). Twenty patients (63%) underwent central neck dissection, and nine underwent postoperative radioactive iodine ablation treatment (28%). CONCLUSIONS: A significant proportion of patients with FVPTC reclassified as NIFTP may decrease the overall institutional thyroid ROM. On final pathology, NIFTP should be regarded as an indolent tumor requiring no further surgical treatment.

Nationwide review of hormonally active adrenal tumors highlights high morbidity in pheochromocytoma.

BACKGROUND: Adrenal adenomas are benign tumors often discovered incidentally, and >70% are hormonally inactive. The remaining subset may produce excess aldosterone, cortisol, or catecholamine. Perioperative outcomes after adrenalectomy for such "hormonally active" tumors remain unclear. This study examines in-hospital outcomes after unilateral adrenalectomy for hormonally active tumors. METHODS: A retrospective review was performed using the Nationwide Inpatient Sample (2006-2011) to identify patients undergoing unilateral adrenalectomy for hormonally active or inactive tumors. Malignant adrenal tumors were excluded. Demographics, comorbidities, and postoperative complications were evaluated by univariate analysis, using two-tailed Chi-square and t-tests and multivariate logistic regression. RESULTS: Of 27,312 patients who underwent adrenalectomy, 78% (n = 21,279) had hormonally inactive and 22% (n = 6033) had hormonally active adrenal tumors. Among the latter, 65% (n = 4000) had primary hyperaldosteronism (Conn's syndrome), 33% (n = 1996) had hypercortisolism (Cushing's syndrome), and 1.4% (n = 85) had pheochromocytoma. Patients with pheochromocytoma had higher rate of comorbidities including congestive heart failure, chronic lung disease, and malignant hypertension compared with remaining hormonally active tumors (12% versus 4%, 18% versus 11%, 6% versus 2%; P < 0.01). For patients with pheochromocytoma versus other hormonally active tumors, mean length of stay was 5 versus 3 d and total in-hospital cost was $50,000 versus $41,000 (P < 0.01). On multivariate analysis, pheochromocytoma had an independently higher risk for intraoperative blood transfusion (4.2, 95% confidence interval [CI] 2.4-7.2), postoperative cardiac (7.6, 95% CI 2.8-20.2), and respiratory (1.9, 95% CI 1.0-3.3) complications. CONCLUSIONS: Patients with pheochromocytoma have high rates of preoperative comorbidities, postoperative cardiopulmonary complications, and longer and more costly hospitalizations. Such high-risk patients should undergo appropriate preoperative medical optimization in preparation for adrenalectomy.

High perioperative morbidity and mortality in patients with malignant nonfunctional adrenal tumors.

BACKGROUND: Both functional (hormone hypersecreting) and nonfunctional (nonhypersecreting) adrenal tumors can have benign or malignant pathology. This study compares perioperative in-hospital outcomes after adrenalectomy in patients with benign versus malignant nonfunctional primary adrenal tumors. METHODS: A retrospective cross-sectional analysis was performed using the Nationwide Inpatient Sample database (2006-2011) to identify patients who underwent unilateral open or laparoscopic adrenalectomy for nonfunctional primary adrenal tumors. Patients were subdivided by benign and malignant final pathology. Demographics, comorbidities, and perioperative complications were compared between groups using bivariate and multivariate logistic regression. RESULTS: Of 23,297 patients, 89.7% (n = 20,897) had benign tumors, whereas 10.3% (n = 2400) had malignant tumors. Those with malignant tumors had higher Charlson Comorbidity Index scores and were more likely to undergo adrenalectomy at high volume centers. For both laparoscopic and open approach, patients with malignant nonfunctional tumors had higher rates of intraoperative complications including vascular and splenic injury (P < 0.01), as well as postoperative complications including hematoma, shock, acute kidney injury, venous thromboembolism, and pneumothorax (P < 0.01). In addition, the malignant group had higher rates of blood transfusions, longer hospital stay, and higher in-hospital mortality (P < 0.05) than benign counterparts. On risk-adjusted multivariate analysis, malignant nonfunctional primary adrenal tumors were independently associated with increased risk of complications following adrenalectomy. CONCLUSIONS: Patients with malignant nonfunctional primary adrenal tumors have higher perioperative morbidity and mortality compared to patients with benign nonfunctional adrenal tumors. Such patients should be medically optimized before adrenalectomy, and surgeons must remain vigilant in preventing perioperative complications.

Clinically significant cancer rates in incidentally discovered thyroid nodules by routine imaging.

BACKGROUND: With widespread use of diagnostic imaging modalities, incidental thyroid nodules are frequently identified in patients for unrelated reasons. If underlying thyroid cancer risk in such patients is significant, further evaluation becomes imperative. This study evaluates the malignancy rate of incidentally discovered compared to clinically apparent thyroid nodules in surgical patients. METHODS: A retrospective review of prospectively collected data of 809 patients who underwent thyroidectomy at a tertiary referral center was performed. The association between incidental discovery of thyroid nodules, malignancy rates, and clinicopathologic characteristics was assessed. RESULTS: Of 809 patients, 12% (n = 98) had incidental thyroid nodules, where malignancy was found in 65 (66%) of these patients. The overall rate of malignancy identified incidentally by routine imaging was 14% (65/466). Most common imaging modalities leading to detection were ultrasound (32%), computed tomography (29%), and magnetic resonance imaging (23%). Of patients with incidental thyroid nodules harboring malignancy, follicular variant papillary thyroid cancer (PTC) (48%), classical variant PTC (18%), tall cell variant PTC (12%), and diffuse sclerosing variant PTC (12%) were most commonly found. Patients with malignant incidental thyroid nodules had more lymphovascular invasion and positive lymph nodes compared to nonincidental malignant thyroid nodules (53% versus 41% and 47% versus 33%, P < 0.05, respectively). CONCLUSIONS: Incidentally discovered thyroid nodules by imaging represent an important group of surgical patients with clinically significant rates of underlying malignancy. Patients with incidentally discovered thyroid nodules by imaging should undergo appropriate evaluation and counseling for further surgical treatment.

Location of abnormal parathyroid glands: lessons from 810 parathyroidectomies.

BACKGROUND: Primary hyperparathyroidism (pHPT) is commonly treated with targeted parathyroidectomy (PTX) guided by preoperative imaging and intraoperative parathormone monitoring. Despite advanced imaging techniques, failure of parathyroid localization still occurs. This study determines the anatomical distribution of single abnormal parathyroid glands, which may help direct the surgeon in PTX when preoperative localization is unsuccessful. METHODS: A retrospective review of prospectively collected data of 810 patients with pHPT who underwent initial PTX at a tertiary medical center was performed. All patients had biochemically confirmed pHPT and single-gland disease. Abnormal parathyroid gland localization was determined at time of operation, correlated with operative and pathology reports, and confirmed by operative success defined as eucalcemia for ≥6 mo after PTX. Patients with multiple endocrine neoplasia, secondary, tertiary, or familial hyperparathyroidism, multiglandular disease, parathyroid cancer, and ectopic glands were excluded. Data were analyzed by chi-square and Z-test analyses. RESULTS: Among 810 patients who underwent PTX for pHPT, single abnormal parathyroid glands were unequally distributed among the four eutopic locations (left superior, 15.7%; left inferior, 31.3%; right superior, 15.8%; right inferior, 37.2%; P < 0.01). Abnormal inferior parathyroid glands (68.5%) were significantly more common than abnormal superior glands (31.5%), respectively (P < 0.01). In men, the most common location for single abnormal parathyroid glands was the right inferior position (43.4%, P < 0.01). Overall, there was no significant difference in laterality. CONCLUSIONS: This large series of patients suggests that single eutopic abnormal parathyroid glands are more likely to be inferior. In men, moreover, if an abnormal parathyroid gland is not localized preoperatively, the right inferior location should be explored first. Nevertheless, successful PTX remains predicated on knowledge of parathyroid anatomy, experience, and judgment of the surgeon.