Progression of nodular thyroid disease in Familial Adenomatous Polyposis syndrome: refined surveillance recommendations.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) have an increased risk of thyroid nodular disease. Previous studies demonstrated that screening thyroid ultrasound (US) will allow detection of nodules in 38% and thyroid cancer in 2.6% of patients. The aim of this study is to define the value of serial US evaluation at identifying disease progression in patients with FAP. METHODS: Retrospective review from 2008-2023 at a single referral center. All patients with FAP and screening thyroid US were included. Patient demographics, initial US characteristics, follow-up regarding the development of new nodules and cancer were assessed using a Kaplan-Meier analysis. RESULTS: A total of 556 patients underwent screening. 51% were male. Median age at first screening was 38 years old. 81% underwent longitudinal follow-up for a median length of 7 years. At initial screening, 169 patients (30%) had nodules. For patients with normal baseline US, 14% developed a nodule overtime. A total of 20 patients (3.6%) were diagnosed with thyroid cancer. The cumulative incidence of initial and subsequent cancer was 4% by 5-years and 6% by 10-years, while the cumulative incidence of thyroid nodules was 40% and 48%, respectively. CONCLUSIONS: Based on the Kaplan-Meier analysis, ongoing longitudinal screening is warranted for patients with FAP as they are prone to thyroid cancer and nodule development overtime even when presenting with a baseline normal US. Additionally, these data demonstrate a slow development of thyroid cancer from a normal US, thus it is reasonable to consider selectively extending the screening interval for this population.

Comparison of incidental parathyroid tissue detection rates on pathology after total thyroidectomy performed with or without near-infrared autofluorescence imaging.

BACKGROUND: Near-infrared autofluorescence imaging is an adjunct to parathyroid identification. As it does not show perfusion, it is important to study its impact during thyroidectomy by measuring quantifiable data on parathyroid detection rather than function. The aim of this study was to compare incidental parathyroidectomy rates in patients undergoing total thyroidectomy with or without near-infrared autofluorescence. METHODS: Retrospective study of patients who underwent total thyroidectomy between 2014 and 2022 at one center. Clinical parameters, including rates of incidental parathyroid tissue on pathology reports, were compared between near-infrared autofluorescence and non-near-infrared autofluorescence groups. Near-infrared autofluorescence was used to guide dissection (identification) and/or to confirm tissue as parathyroid (confirmation). Statistical analysis was done with Wilcoxon rank sum test and χ2 analysis. RESULTS: There were 300 patients in the near-infrared autofluorescence and 750 patients in the non-near-infrared autofluorescence group. The rate of incidental parathyroid tissue detection on final pathology was 13.3% (n = 40) in the near-infrared autofluorescence and 23.2% (n = 174) in the non-near-infrared autofluorescence group (P < .001). The rate of incidental parathyroid tissue detected on pathology with near-infrared autofluorescence decreased when used for identification and confirmation of parathyroid tissue (30.0% to 13.4%, P < .001), but not when used for confirmation only (19.6% to 18.5%, P = .89). Impact of near-infra red autofluorescence in decreasing the rate of incidental parathyroid tissue was more profound for early (38.5% to 17.1%) versus mid-late career surgeons (20% to 13%). CONCLUSION: Our results suggest that the use of near-infrared autofluorescence may help decrease the rate of incidental parathyroid tissue detected on final pathology if used for both identification and confirmation of parathyroid glands during thyroidectomy.

Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.

Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD). Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS. Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023. Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews. Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population. Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001). Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

Adolescent exposure to low-dose Δ9-tetrahydrocannabinol depletes the ovarian reserve in female mice.

Cannabis use by adolescents is widespread, but its effects on the ovaries remain largely unknown. Δ9-tetrahydrocannabinol (THC) exerts its pharmacological effects by activating, and in some conditions hijacking, cannabinoid receptors (CBRs). We hypothesized that adolescent exposure to THC affects ovarian function in adulthood. Peripubertal female C57BL/6N mice were given THC (5 mg/kg) or its vehicle, once daily by intraperitoneal injection. Some mice received THC from postnatal day (PND) 30-33 and their ovaries were harvested PND34; other mice received THC from PND30-43, and their ovaries were harvested PND70. Adolescent treatment with THC depleted ovarian primordial follicle numbers by 50% at PND70, 4 weeks after the last dose. The treatment produced primordial follicle activation, which persisted until PND70. THC administration also caused DNA damage in primary follicles and increased PUMA protein expression in oocytes of primordial and primary follicles. Both CB1R and CB2R were expressed in oocytes and theca cells of ovarian follicles. Enzymes involved in the formation (N-acylphosphatidylethanolamine phospholipase D) or deactivation (fatty acid amide hydrolase) of the endocannabinoid anandamide were expressed in granulosa cells of ovarian follicles and interstitial cells. Levels of mRNA for CBR1 were significantly increased in ovaries after adolescent THC exposure, and upregulation persisted for at least 4 weeks. Our results support that adolescent exposure to THC may cause aberrant activation of the ovarian endocannabinoid system in female mice, resulting in substantial loss of ovarian reserve in adulthood. Relevance of these findings to women who frequently used cannabis during adolescence warrants investigation.

The Role of ERα and ERß in Castration-Resistant Prostate Cancer and Current Therapeutic Approaches.

Castration-resistant prostate cancer, or CRPC, is an aggressive stage of prostate cancer (PCa) in which PCa cells invade nearby or other parts of the body. When a patient with PCa goes through androgen deprivation therapy (ADT) and the cancer comes back or worsens, this is called CRPC. Instead of androgen-dependent signalling, recent studies show the involvement of the estrogen pathway through the regulation of estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) in CRPC development. Reduced levels of testosterone due to ADT lead to low ERß functionality in inhibiting the proliferation of PCa cells. Additionally, ERα, which possesses androgen independence, continues to promote the proliferation of PCa cells. The functions of ERα and ERß in controlling PCa progression have been studied, but further research is needed to elucidate their roles in promoting CRPC. Finding new ways to treat the disease and stop it from becoming worse will require a clear understanding of the molecular processes that can lead to CRPC. The current review summarizes the underlying processes involving ERα and ERß in developing CRPC, including castration-resistant mechanisms after ADT and available medication modification in mitigating CRPC progression, with the goal of directing future research and treatment.

Risk Factors Associated With Recurrence and Death in Patients With Tall Cell Papillary Thyroid Cancer: A Single-Institution Cohort Study With Predictive Nomogram.

Importance: Tall cell morphology (TCM) is a rare and aggressive variant of papillary thyroid carcinoma (PTC) that has been associated with poor outcomes; however, the risk factors for worse survival are not well characterized. Objective: To identify prognostic factors associated with cancer recurrence and death in patients with PTC-TCM. Design, Setting, and Participants: All patients treated for PTC-TCM at a single tertiary-level academic health care institution from January 1, 1997, through July 31, 2018, were included. Tall cell variant (TCV) was defined as PTC with TCM of 30% or more; and tall cell features (TCF) was defined as PTC with TCM of less than 30%. Patients with other coexisting histologic findings and/or nonsurgical management were excluded. Clinicopathologic features associated with worse outcomes were identified using Kaplan-Meier and Cox proportional-hazards model. Data were analyzed from March 1, 2018, to August 15, 2018. Main Outcomes and Measures: Locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and overall survival (OS) after surgery. Results: A total of 365 patients (median [range] age, 51.8 [15.9-91.6] years; 242 [66.3%] female) with PTC-TCM (TCV, 32%; TCF, 68%) were evaluable. Total thyroidectomy was performed in 336 (92%) patients; 19 (5.2%) received radiotherapy; and 15 (4.1%) received radioactive iodine. Clinical features were pT3 or T4, 65%; node-positive, 53%; and positive surgical margins, 24%. LRRFS at 1-, 3-, 5-, and 10-year was 95%, 87%, 82%, and 73%, respectively. On multivariable analysis, male sex and age were not independent predictors of inferior 5-year LRRFS, whereas positive surgical margins (HR, 3.5; 95% CI, 2.0-6.3), positive lymph nodes (HR, 2.8; 95% CI, 1.4-5.8), and primary tumor size of 3 cm or more (HR, 3.3; 95% CI, 1.4-7.8) were strongly associated with worse LRRFS. Age 55 years or older (HR, 3.2; 95% CI, 1.5-7.0), male sex (HR 4.5; 95% CI, 2.1-10.0), positive surgical margins (HR, 2.7; 95% CI, 1.2-6.0), nodal positivity (HR, 3.1; 95% CI, 1.3-7.7), tumor diameter of 1.5 cm or more (HR, 20.6; 95% CI, 2.8-152.1), and TCV vs TCF (HR, 3.1; 95% CI, 1.5-6.7) were associated with worse DRFS. Male sex (HR, 3.1; 95% 1.4-6.8) and tumor diameter of 1.5 cm or more (HR, 2.8; 95% CI, 1.0-7.4) were associated with worse OS. A findings-based nomogram was constructed to predict 10-year LRRFS (C index, 0.8). Conclusions and Relevance: This retrospective cohort study found that in patients with PTC-TCM, positive surgical margins, node positive disease, and tumor size of 3 cm or more were risk factors for worse LRRFS. Intensified locoregional therapy, including adjuvant radiation, may be considered for treating these patients.

A multicenter evaluation of near-infrared autofluorescence imaging of parathyroid glands in thyroid and parathyroid surgery.

BACKGROUND: The usefulness of incorporating near-infrared autofluorescence into the surgical workflow of endocrine surgeons is unclear. Our aim was to develop a prospective registry and gather expert opinion on appropriate use of this technology. METHODS: This was a prospective multicenter collaborative study of patients undergoing thyroidectomy and parathyroidectomy at 7 academic centers. A questionnaire was disseminated among 24 participating surgeons. RESULTS: Overall, 827 thyroidectomy and parathyroidectomy procedures were entered into registry: 42% of surgeons found near-infrared autofluorescence useful in identifying parathyroid glands before they became apparent; 67% correlated near-infrared autofluorescence pattern to normal and abnormal glands; 38% of surgeons used near-infrared autofluorescence, rather than frozen section, to confirm parathyroid tissue; and 87% and 78% of surgeons reported near-infrared autofluorescence did not improve the success rate after parathyroidectomy or the ability to find ectopic glands, respectively. During thyroidectomy, 66% of surgeons routinely used near-infrared autofluorescence to rule out inadvertent parathyroidectomy. However, only 36% and 45% felt near-infrared autofluorescence decreased inadvertent parathyroidectomy rates and improved ability to preserve parathyroid glands during central neck dissections, respectively. CONCLUSION: This survey study identified areas of greatest potential use for near-infrared autofluorescence, which can form the basis of future objective trials to document the usefulness of this technology.

Laparoscopic versus robotic adrenalectomy in severely obese patients.

BACKGROUND: Over the last 20 years, the prevalence of severe obesity (body mass index ≥ 35 kg/m2) has almost doubled. This condition increases the challenge of laparoscopic adrenalectomy (LA) by creating problems with instrument reach, adequate exposure, and visualization. The aim was to compare perioperative outcomes of laparoscopic versus robotic adrenalectomy (RA) in severely obese patients. METHODS: This was an institutional review board-approved retrospective study. Prospectively collected clinical parameters of patients who underwent LA versus RA between 2000 and 2021 at a single center were compared using Mann-Whitney U, ANOVA, Chi-square, and multivariate regression analysis. Continuous data are expressed as median (interquartile range). RESULTS: For lateral transabdominal (LT) adrenalectomies, skin-to-skin operative time (OT) [164.5 (71.0) vs 198.8 (117.0) minutes, p = 0.006] and estimated blood loss [26.2 (15.0) vs 72.6 (50.0) ml, p = 0.010] were less in RA versus LA group, respectively. Positive margin rate, hospital stay and 90-day morbidity were similar between the groups (p = NS). For posterior retroperitoneal (PR) approach, operative time and perioperative outcomes were similar between LA and RA groups. Multivariate analysis demonstrated robotic versus laparoscopic technique (p = 0.006) to be an independent predictor of a shorter OT. CONCLUSION: There was a benefit of robotic over the laparoscopic LT adrenalectomy regarding OT and estimated blood loss. Although limited by the small sample size, there was no difference regarding perioperative outcomes between RA and LA performed through a PR approach.

Development and Progression of Thyroid Disease in PTEN Hamartoma Tumor Syndrome: Refined Surveillance Recommendations.

Background: PTEN hamartoma tumor syndrome (PHTS) is associated with a high prevalence and early onset of differentiated thyroid cancer and benign thyroid disease. However, a consensus on the time of initiation and frequency of thyroid cancer surveillance has not yet been reached. Most commonly, guidelines recommend annual thyroid ultrasounds, but vary widely in the time of initiation, ranging from shortly after birth to 18 years of age. Minimal data are available on the development and progression of thyroid disease over time in this population. This study aimed to target this knowledge gap by investigating the time to develop thyroid nodules and thyroid cancer from an initial ultrasound in 76 PHTS patients. Methods: The electronic records of 281 prospectively accrued PHTS patients were retrospectively reviewed between 2005 and 2021, and 76 patients were identified as having at least two thyroid ultrasounds. Time-to-event analyses were performed, determining the probability of developing thyroid nodules and thyroid cancer over time. Results: We demonstrated that PHTS patients with an initial thyroid ultrasound without nodules (n = 41) had >90% likelihood of remaining free of a clinically actionable nodule at 3 years and an 85% likelihood at 6 years. None of these patients developed thyroid cancer over the entire follow-up period (mean 4.6 years). In patients with a clinically nonactionable nodule, defined as not meeting criteria for fine needle aspiration or thyroidectomy (n = 14), we demonstrated that 80% will not have an actionable nodule at 3 years, and none developed thyroid cancer over the entire follow-up period. Conclusions: Our observations suggest stratifying surveillance intervals based on thyroid ultrasound result, and support extending surveillance intervals in PHTS patients without nodules on ultrasound to 3-5 years, and patients with clinically nonactionable nodules to 2-3 years, in contrast to the current recommendation of annual ultrasounds. This change in practice would decrease the burden of frequent ultrasounds, especially in young children and adolescents who are more likely to have a normal or nonactionable ultrasound result.

Quantifying disease-specific symptom improvement after parathyroid and thyroid surgery using patient-reported outcome measures.

BACKGROUND: Patient-reported outcome measures for parathyroid and thyroid disease (PROMPT) is a 30-question, previously validated, survey assessing symptoms on a scale from 0 to 100. Using PROMPT, we aimed to assess symptom improvement for patients undergoing thyroidectomy and parathyroidectomy. METHODS: Single-center prospective study in which PROMPT was used to assess symptom improvement in patients undergoing parathyroidectomy or thyroidectomy. A postoperative assessment was performed approximately 6 months after surgery and compared to its baseline preoperative assessment. RESULTS: A total of 144 patients completed both assessments (71 parathyroidectomy, 73 thyroidectomy). Parathyroidectomy patients demonstrated significant improvements in all hyperparathyroidism domains (38.2-28.3, p < 0.001) regardless of preoperative calcium and parathyroid hormone levels. Thyroidectomy patients experienced improvement in their compressive symptoms (25.6-16.5, p < 0.001). CONCLUSIONS: PROMPT objectively demonstrates the clinical effectiveness of parathyroidectomy and thyroidectomy in alleviating subjective patient symptoms. PROMPT offers promising use as a standardized metric to assess quality of life improvement within endocrine surgery.

Exposure to environmentally relevant concentrations of ambient fine particulate matter (PM2.5) depletes the ovarian follicle reserve and causes sex-dependent cardiovascular changes in apolipoprotein E null mice.

BACKGROUND: Fine particulate matter (PM2.5) exposure accelerates atherosclerosis and contains known ovotoxic chemicals. However, effects of exposure to PM2.5 on the finite ovarian follicle pool have hardly been investigated, nor have interactions between ovarian and cardiovascular effects. We hypothesized that subchronic inhalation exposure to human-relevant concentrations of PM2.5 results in destruction of ovarian follicles via apoptosis induction, as well as accelerated recruitment of primordial follicles into the growing pool. Further, we hypothesized that destruction of ovarian follicles enhances the adverse cardiovascular effects of PM2.5 in females. RESULTS: Hyperlipidemic apolipoprotein E (Apoe) null ovary-intact or ovariectomized female mice and testis-intact male mice were exposed to concentrated ambient PM2.5 or filtered air for 12 weeks, 5 days/week for 4 h/day using a versatile aerosol concentration enrichment system. Primordial, primary, and secondary ovarian follicle numbers were decreased by 45%, 40%, and 17%, respectively, in PM2.5-exposed ovary-intact mice compared to controls (P < 0.05). The percentage of primary follicles with granulosa cells positive for the mitosis marker Ki67 was increased in the ovaries from PM2.5-exposed females versus controls (P < 0.05), consistent with increased recruitment of primordial follicles into the growing pool. Exposure to PM2.5 increased the percentages of primary and secondary follicles with DNA damage, assessed by γH2AX immunostaining (P < 0.05). Exposure to PM2.5 increased the percentages of apoptotic antral follicles, determined by TUNEL and activated caspase 3 immunostaining (P < 0.05). Removal of the ovaries and PM2.5-exposure exacerbated the atherosclerotic effects of hyperlipidemia in females (P < 0.05). While there were statistically significant changes in blood pressure and heart rate variability in PM2.5-compared to Air-exposed gonad-intact males and females and ovariectomized females, the changes were not consistent between exposure years and assessment methods. CONCLUSIONS: These results demonstrate that subchronic PM2.5 exposure depletes the ovarian reserve by increasing recruitment of primordial follicles into the growing pool and increasing apoptosis of growing follicles. Further, PM2.5 exposure and removal of the ovaries each increase atherosclerosis progression in Apoe-/- females. Premature loss of ovarian function is associated with increased risk of osteoporosis, cardiovascular disease and Alzheimer's disease in women. Our results thus support possible links between PM2.5 exposure and other adverse health outcomes in women.

Risk of malignancy in cytologically indeterminate thyroid nodules harboring thyroid stimulating hormone receptor mutations.

Objectives: To evaluate the frequency and risk of malignancy of TSHRpI568T mutations discovered in indeterminate thyroid nodules (ITN) within the Veracyte CLIA laboratory undergoing Afirma® Genomic Sequencing Classifier (GSC) testing, and to evaluate a broader cohort of TSHR variants and their categorization as Afirma GSC benign (GSC-B) or suspicious (GSC-S). Finally, we seek to assess the risk of malignancy (ROM) of this group of TSHR mutated ITN in the GSC-S category. Methods: ITN submitted to Veracyte for Afirma GSC testing between October 2017 and February 2022 were analyzed for TSHR variants and rates of GSC-B and GSC-S were calculated based upon BIII or IV cytology, by TSHR variant codon amino acid (AA) substitution, age, and gender. For GSC-S samples, surgical pathology reports were requested, and the rate of malignancy was calculated. Results: Five percent of the ITN samples harbored an isolated TSHR variant and 5% of those were classified as GSC-S. Among TSHRpI568T samples, 96% were GSC-B and of the GSC-S samples, 21% were malignant. Among an unselected group of TSHR, absent TSHRpI568T mutations, 16.3% of GSC-S samples were malignant, all but one with codon mutations in the transmembrane subdomains of the TSHR. This prompted a dedicated evaluation of transmembrane codons which revealed a malignancy rate of 10.7% among GSC-S nodules. In total, 13/85 (15.3%) TSHR mutated ITN with Afirma GSC-S results were found to be malignant. Conclusions: TSHR variants are rare in ITN, and most are categorized as benign under Afirma GSC testing which carries a < 4% risk of malignancy. For GSC-S ITN with TSHR mutations, the risk of malignancy is ≥= 15%, which is clinically meaningful and may alter treatment or monitoring recommendations for patients.

Preoperative Calcium and Parathyroid Hormone Values Are Poor Predictors of Gland Volume and Multigland Disease in Primary Hyperparathyroidism: A Review of 2000 Consecutive Patients.

OBJECTIVE: Calcium and parathyroid hormone (PTH) values are believed to have a linear relationship in patients with primary hyperparathyroidism and correlate with parathyroid gland size, with higher values predicting single-gland disease. In this modern series, these preoperative values were correlated with operative findings to determine their utility in predicting the gland involvement at parathyroid exploration. METHODS: Two thousand consecutive patients who underwent initial surgery for sporadic primary hyperparathyroidism from 2000 to 2014 were reviewed. All patients underwent a 4-gland exploration. Relationships between preoperative calcium and PTH values with the total gland volume of each patient were examined and stratified using the number of involved glands: single adenoma (SA), double adenoma (DA), and hyperplasia (H). RESULTS: There were 1274 (64%) SA, 359 (18%) DA, and 367 (18%) H cases. There was a poor correlation between preoperative calcium and PTH values (R = 0.37) and both poorly correlated with the total gland volume (R < 0.40). Similarly, subgroup analysis using the number of involved glands showed poor correlation. The mean total gland volume was similar among all subgroups (SA = 1.28 cm3, DA = 1.43 cm3, and H = 1.27 cm3; P = .52), implying that individual glands were smaller in multigland disease. SA was found in 271 (53%) of patients with calcium levels of ≤10.5 mg/dL and 122 (78%) with levels of ≥12 mg/dL (P < .001). CONCLUSION: This is the largest series correlating preoperative calcium and PTH values with operative findings of gland size and number of diseased glands. Although a lower calcium value predicts somewhat more multigland disease, the overall poor correlation should make the parathyroid surgeon aware that gland size and multigland disease cannot be predicted by preoperative laboratory testing.

A critical analysis of laparoscopic and open approaches to sporadic pancreatic insulinoma resection in the modern era.

BACKGROUND: A single center experience with sporadic pancreatic insulinoma was analyzed to develop an algorithm for modern surgical management. METHODS: Thirty-four patients undergoing surgery from 2001 to 2019 were reviewed. RESULTS: The majority underwent enucleation (10 laparoscopic, 15 open). Laparoscopy was performed in 22 patients with conversion to open in 11, mostly related to the proximity of the tumor to the pancreatic duct (n = 4). Tumors on the anterior and posterior surface of the pancreas in all anatomic locations were completed with laparoscopic enucleation. Overall, the clinically-relevant postoperative pancreatic fistula (CR-POPF) rate was 21%, with no difference between laparoscopic versus open enucleation (10% vs 20%, p = 0.50) or enucleation versus resection (16% vs 33%, p = 0.27). Laparoscopic enucleation had shorter median hospital length of stay (LOS) compared with open (4 vs 7 days, p = 0.02). CONCLUSIONS: Laparoscopic enucleation does not increase the CR-POPF risk and provides an advantage with a shorter hospital LOS in select patients. Tumor location and relationship to the pancreatic duct guide surgical decision-making. These findings highlight tumor-specific criteria that would benefit from a minimally invasive approach.

Thyroid nodule molecular profiling: The clinical utility of Afirma Xpression Atlas for nodules with Afirma Genomic Sequencing Classifier-suspicious results.

BACKGROUND: The Afirma Genomic Sequencing Classifier uses whole transcriptome RNA sequencing to identify thyroid nodules as benign or suspicious. The Afirma Xpression Atlas became available in 2018 and reports findings across 593 genes, including 905 variants and 235 fusions. When an alteration is identified, its risk of malignancy and associated neoplasm type is listed. We report the results of Afirma Xpression Atlas testing at our institution during its first 2 years of clinical use. METHODS: All patient charts with indeterminate thyroid nodules and Afirma Xpression Atlas results at our institution were reviewed. Thyroid nodule characteristics, cytology, Afirma Genomic Sequencing Classifier results, Afirma Xpression Atlas results, and final histopathology were reported. RESULTS: Afirma Xpression Atlas was performed on 136 indeterminate nodules since May 2018, and 103 met inclusion criteria. Forty-three nodules had positive Afirma Xpression Atlas results, and of these, 83.7% were follicular cell-derived thyroid cancer on surgical histopathology. This is similar to the overall 82.5% positive predictive value among Afirma Genomic Sequencing Classifier-suspicious indeterminate nodules during the same time period. Of the 60 nodules with negative Afirma Xpression Atlas, 73.3% were follicular cell-derived thyroid cancer on surgical histopathology. CONCLUSION: Afirma Xpression Atlas positivity is predictive of follicular cell-derived thyroid cancer, but its positive predictive value is similar to that of Genomic Sequencing Classifier-suspicious results alone at our institution, which is higher than previously published. Specific mutations likely predict follicular cell-derived thyroid cancer with higher accuracy, but our current sample size of any given mutation is too small to evaluate this further. Larger studies are needed to determine whether Afirma Xpression Atlas results predictably inform the risk of malignancy and tumor characteristics in thyroid nodules.

Standardization of thyroid fine needle aspiration procedure and outcomes within an endocrine surgery department.

BACKGROUND: Fine needle aspiration (FNA) biopsy is an essential procedure for thyroid nodules. Although, the efficacy of surgeon-performed thyroid FNA biopsies has been demonstrated in the literature, there are insufficient data regarding how to establish an efficient program with a low insufficiency rate within a group practice. METHODS: An endocrine surgery thyroid FNA biopsy program was established in 2000 by one surgeon, with training of additional partners during fellowship and upon recruitment. The results within 18 years were analyzed. The FNA biopsies were performed by endocrine surgeons under ultrasound guidance without on-site pathologist review. RESULTS: A total of 5,469 FNA biopsies were performed by 7 surgeons. The total number of FNA biopsies performed by each surgeon varied between 291-1,378. FNA biopsies were performed in 2 passes using 22-gauge needles under constant suction. The overall insufficiency rate was 4.3%, with individual surgeon rates ranging between 2.7% and 7.2%. The insufficiency rate for the whole team ranged between 3.3% and 5% when examined in 5-year blocks. CONCLUSIONS: This study shows that an establishment of a highly efficient thyroid FNA biopsy program within a group practice is possible with a structured endocrine surgical training and adoption of a standard technique.

Selective parathyroid venous sampling in reoperative parathyroid surgery: A key localization tool when noninvasive tests are unrevealing.

BACKGROUND: Preoperative localization studies are essential for parathyroid re-exploration. When noninvasive studies do not regionalize the abnormal parathyroid gland, selective parathyroid venous sampling may be employed. We studied the utility of parathyroid venous sampling in reoperative parathyroid surgery and the factors that may affect parathyroid venous sampling results. METHODS: Patients with hyperparathyroidism and previous cervical surgery undergoing evaluation for reoperative parathyroidectomy over a 20-year period were identified. Patients with indeterminate or negative noninvasive studies underwent parathyroid venous sampling. Parathyroid hormone values were mapped with a ≥2-fold increase above peripheral signifying positive parathyroid venous sampling. These results were correlated with reoperative findings. RESULTS: Parathyroid venous sampling was positive in 113 of 140 (81%). Re-exploration occurred in 75 (66%). Parathyroid venous sampling correctly detected the region of abnormal glands in 58 (77%). With 1 gradient, 1 abnormal gland was found in 81%. With multiple gradients, 1 abnormal gland was found in 78%, most often at the site with the largest gradient. Eighty percent of patients who underwent reoperative parathyroidectomy were biochemically cured. CONCLUSION: Parathyroid venous sampling can guide parathyroid re-exploration when noninvasive localizing studies are indeterminate. Expectation of 1 versus multiple remaining glands was key in interpreting the results.

Need for Completion Thyroidectomy in Patients Undergoing Lobectomy for Indeterminate and High-Risk Nodules: Impact of Intra-Operative Findings and Final Pathology.

INTRODUCTION: Current guidelines increasingly suggest the use of thyroid lobectomy for indeterminate (Bethesda 3 and 4) and high-risk (Bethesda 5 and 6) thyroid nodules; however, the clinical reality is often very different. MATERIALS AND METHODS: The aim of this study was to determine the rate of completion thyroidectomy (CTx) for indeterminate and high-risk thyroid nodules which are pre-operatively classified as suitable for unilateral resection (lobe eligible) based on current guidelines. Seven hundred consecutive patients with thyroid nodules and FNA cytology over four years (2015-2018) were reviewed. RESULTS: Distribution of the dominant nodules by Bethesda was: non-diagnostic 3.9%, benign 28.1%, atypia of unknown significance 19.0%, follicular neoplasm 23.6%, suspicious for malignancy 6.1% and malignancy 19.3%. Of 298 indeterminate nodules, 68.8% (205/298) had relative but independent indications for a total thyroidectomy (TTx) and the remainder were candidates for lobectomy. For these lobe eligible patients, the overall risk of ultimately needing a TTx was 19.4% (18/93), comprising 4.3% (4/93) from intra-operative findings and 15.7% (14/89) from final pathology. Similarly, of 170 high-risk nodules, 63.5% (108/170) had upfront indications for a TTx and the remaining 62 nodules were lobe eligible. Of the patients taken to the operating room for a lobectomy, 21.0% (13/62) were upgraded to a TTx intra-operatively and 26.5% (13/49) post-operatively. The lobe success rate for indeterminate nodules was 25.2% and for high-risk nodules was 21.2%. The rate of CTx, or the proportion of patients needing a second operation was 15.7% (14/89) and 26.5% (13/49), respectively. CONCLUSIONS: In counselling a patient for surgery, the risk of needing a more radical initial procedure or second surgery needs to be accurately explained. There are three points of care that can influence operative strategy, pre-operatively by way of high-risk clinical factors, intra-operatively via anatomical findings and post-operatively in response to unrecognized pathological features. Additionally, the patient's personal value judgment and level of risk aversion should be taken into consideration.

Thyroglobulin washout from cervical lymph node fine needle aspiration biopsies in patients with differentiated thyroid cancer: an analysis of different expressions to use in post-total thyroidectomy follow-up.

INTRODUCTION: Although frequently used as an adjunct to cytology in patients with differentiated thyroid cancers, interpretation of thyroglobulin washout remains unclear. We aim to compare the utility of different analytic tools to develop recommendations for use in post-total thyroidectomy follow-up. METHODS: This is an institutional review board-approved retrospective study of patients who underwent lymph node fine needle aspiration biopsy with thyroglobulin washout between 2012 and 2018, during the post-total thyroidectomy follow-up of differentiated thyroid cancer. The utilities of thyroglobulin washout concentration, thyroglobulin washout/serum thyroglobulin ratio, and absolute thyroglobulin content were compared. RESULTS: Sixty-four patients underwent 79 fine needle aspirations with thyroglobulin washout of cervical lymph nodes. Fifty-two lymph nodes were found to be metastatic and 27 benign. One patient had a pathologically confirmed lymph node metastasis despite a thyroglobulin washout of 0. The optimal cutoffs of thyroglobulin washout, thyroglobulin washout/serum thyroglobulin ratio, and absolute thyroglobulin content to predict metastatic involvement were 2.5 ng/ml (94% sensitive, 100% specific), 0.1 (100% sensitive and specific), and 12.5 (94% sensitive, 100% specific), respectively. The second measure lacked utility in patients with undetectable serum thyroglobulin. CONCLUSION: The use of thyroglobulin washout concentration or thyroglobulin washout/serum thyroglobulin ratio has drawbacks based on variations in technique and clinical scenario. Absolute thyroglobulin content is an alternative that may be a more objective expression of thyroglobulin washout.

Recognition of primary hyperparathyroidism: Delayed time course from hypercalcemia to surgery.

BACKGROUND: Under recognition of primary hyperparathyroidism can lead to delays in diagnosis and surgical management. We aimed to establish a time course for primary hyperparathyroidism from initial hypercalcemia to surgery and evaluate the impact of guidelines for surgical referral on this time course. METHODS: A retrospective review was conducted on all patients undergoing parathyroidectomy for primary hyperparathyroidism in 2013 at the Cleveland Clinic. Patients were stratified by adherence to 2008 indications for surgery guidelines, age, calcium values, osteoporosis, history of nephrolithiasis, 24-hour urinary calcium values, and estimated glomerular filtration rate. RESULTS: 219 patients with sporadic primary hyperparathyroidism underwent initial surgery. Twenty-three (10.5%) normocalcemic patients were excluded. Time course from initial hypercalcemia to surgery was 3.9 years for 137 (70%) patients who met objective guideline criteria versus 3.8 years for 59 (30%) patients who did not meet objective guideline criteria (P = .87). Stratification by age <50 years and calcium value >11.5 mg/dL revealed earlier times to surgery. However, osteoporosis, nephrolithiasis, 24-hour urinary calcium values, and estimated glomerular filtration rate had no impact. CONCLUSION: There is a delayed time course for patients with sporadic primary hyperparathyroidism from initial hypercalcemia to surgery. Despite published objective criteria, one third of the patients who underwent surgery did not meet criteria, signifying the importance of clinician and patient decision making. Furthermore, patients with osteoporosis and nephrolithiasis who can significantly benefit from surgical cure have no apparent impact on the time to surgery. Overall, the objective guideline criteria have no effect in referral patterns suggesting a call for revision.