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Background: The association of radioactive iodine (RAI) with disease-specific survival (DSS) is controversial in N1b papillary thyroid carcinoma (PTC). We aimed to evaluate whether RAI is associated with DSS in low-to-intermediate-risk N1b PTC., Methods: The Surveillance, Epidemiology, and End Results database was queried for pT1-3, N1b, M0/Mx classic PTC treated with total thyroidectomy. Multivariable Cox regression was performed to identify predictors of DSS. Subanalyses were conducted for age, intermediate-risk versus otherwise low-risk features, and positive lymph node ratio (LNR) > 0.17., Results: Radioactive iodine recipients were younger (43.0 vs. 44.0 years, p = 0.036) with increased capsular or local invasion (49.2% vs. 41.9%, p < 0.001) and median LNR (0.37 vs. 0.33, p = 0.001). Worse DSS was associated with age (adjusted-HR = 1.09, p < 0.001), tumor size (adjusted-HR = 1.02, p < 0.001), and local invasion (adjusted-HR = 1.86, p = 0.003). Radioactive iodine was associated with improved DSS in the whole cohort (adjusted-HR = 0.61, p = 0.014), in patients ≥ 55 years (adjusted-HR = 0.48, p = 0.001) and in patients ≥55 years with LNR > 0.17 (adjusted-HR = 0.45, p = 0.001) but not LNR ≤ 0.17. Radioactive iodine was not associated with a DSS benefit in patients < 55 years even when stratified by LNR 0.17. Radioactive iodine administered to patients with at least one intermediate-risk feature (> 5 pathologic LNs or any local invasion) was associated with improved DSS (adjusted-HR = 0.60, p = 0.019) but not those with otherwise low-risk features (adjusted-HR = 0.71, p = 0.502)., Conclusions: Radioactive iodine is associated with improved DSS in N1b PTC patients with intermediate-risk features, age ≥ 55 years, and LNR > 0.17 in older patients, but not in patients with otherwise low-risk features. These factors could help guide RAI utilization in N1b PTC., (© 2024. Society of Surgical Oncology.)

Background: Hiatal and paraesophageal hernia (HH/PEH) recurrence is the most common cause of failure after gastroesophageal anti-reflux surgery. Crural reinforcement with mesh has been suggested to address this issue, but its efficacy remains debated. In this study, we aimed to determine the impact of biosynthetic mesh reinforcement compared to suture cruroplasty on anatomic and symptomatic hernia recurrence., Method: Data of patients who underwent robotic HH/PEH repair with suture cruroplasty with or without biosynthetic mesh reinforcement between January 2012 and April 2024 were retrospectively reviewed. Gastroesophageal reflux disease symptoms and anatomic hernia recurrence were assessed at short-term (3 months to 1 year) and longer-term (≥ 1 year) follow-up. Symptomatic hernia recurrence was defined as having both anatomic recurrence and symptoms., Results: Out of the 503 patients in the study, 308 had undergone biosynthetic mesh repair, while 195 had suture-only repair. After the surgery, both groups demonstrated comparable improvements in symptoms. Short-term anatomic hernia recurrence rates were 11.8% and 15.6% for mesh and suture groups, respectively (p = 0.609), while longer-term rates were 24.7% and 44.9% (p = 0.015). The rates of symptomatic hernia recurrence in the same group were 8.8% and 14.6% in the short-term (p = 0.256), and 17.2% and 42.2% in longer-term follow-ups (p = 0.003). In the repair of medium and large-size hernias, mesh reinforcement resulted in a 50.0% relative risk reduction in anatomic hernia recurrences and a 59.2% reduction in symptomatic hernia recurrences at ≥ 1-year follow-up., Conclusion: After more than a year of follow-up, it has been found that using biosynthetic mesh for medium and large hiatal or paraesophageal hernia repair significantly reduces the likelihood of both anatomic and symptomatic recurrence compared to using only suture cruroplasty. These findings strongly support the use of biosynthetic mesh to manage larger hernias. However, further long-term multicenter randomized studies are needed to provide more conclusive evidence., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Obese patients represent a large proportion of patients experiencing recurrent reflux and re-operations after initial anti-reflux surgery. However, there is a limited data describing the impact of obesity on GERD recurrence following re-operative procedures., Methods: A review of patients who underwent re-operative anti-reflux surgery (Re-ARS) between 2012 and 2023. Peri-operative characteristics and post-operative Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) scores were compared across the three BMI categories: (BMI < 25 kg/m 2 , 25 ≤ BMI > 30 kg/m 2 , and BMI ≥ 30 kg/m 2 ) over 12 IQR (9-14.9) months follow-up. Impedance planimetry measurements were included when it was utilized intraoperatively., Results: Of 718 patients who underwent robotic ARS, 84 patients (11.6%) underwent Re-ARS, of which 29.7% had a BMI < 25 kg/m 2 , 35.7% were ≤ 25 BMI < 30 kg/m 2 , and 34.5% had a BMI ≥ 30 kg/m 2 . The lower esophageal sphincter distensibility decreased similarly between groups with no differences in post-induction [3.2 ± 2 vs 4.5 ± 3.1 vs 3.9 ± 2.5 mm 2 /mmHg, p = 0.44] or post-fundoplication values [1 ± 0.6 vs 1.3 ± 0.7 vs 1.2 ± 0.6 mm 2 /mmHg, p = 0.46]. There was a significant improvement in GERD-HRQL scores postoperatively compared to preoperative levels across the three BMI classes (BMI < 25 kg/m 2 : pre 17 IQR (12-22), post 7.5 (1.5-15), p = 0.04 vs ≤ 25 BMI < 30 kg/m 2 : pre 26 IQR (10-34), post 8 IQR (0-17), p < 0.01 vs BMI ≥ 30 kg/m 2 : pre 44 IQR (26-51), post 5 IQR (3.5-14.5), p < 0.001) during 12 IQR (9-14.9) months follow-up. The rates of hiatal hernia recurrence on barium swallow [5.2 vs 15.7 vs 13.7%, p = 0.32] during 7 IQR (5.2-9.2) months follow-up, and endoscopy [13.3 vs 16.6 vs 7.1%, p = 0.74] during 11.8 (IQR 5.6-17.1) months follow-up period were also similar between groups., Conclusion: GERD-HRQL scores in obese patients are expected to improve similarly compared to non-obese patients. Indicating that Re-ARS may be appropriate for patients across a range of BMIs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Dysphagia is a potential complication following anti-gastroesophageal reflux surgery (ARS), with challenging management. Endoscopic balloon dilation is recommended for patients with significant dysphagia from tight wraps or strictures. We aim to evaluate factors associated with the need for post-ARS dilation and the outcomes of balloon dilation. Additionally, we assessed the predictors of sustained clinical failure after dilation., Methods: A retrospective analysis was conducted on patients who underwent robotic or laparoscopic ARS between January 2012 and April 2023. Patients were divided based on whether they received balloon dilation using a through-the-scope wire-guided dilator. Excluded were those with pre-existing achalasia, other dilation devices, or inadequate follow-up., Results: Of 1002 patients, 69 underwent 94 postoperative dilations, and the remainder were controls. The dilation cohort was older (63.78 vs. 56.14 years, P = 0.032) and had more magnetic sphincter augmentations (MSA) (P = 0.004), a prior history of ARS (P = 0.039), and a higher rate of laparoscopic surgery (P = 0.009) compared to controls. Of all dilations, 54 (57.5%) patients reported immediate dysphagia improvement, and 39 (41.5%) had sustained improvement. Sixteen (23.2%) patients required reoperation, primarily for hiatal hernia recurrence or slipped wrap. Multivariable logistic regression showed that MSA (OR 0.04, 95% CI 0.01-0.46, P = 0.031) and requiring multiple dilations (OR 0.16, CI 0.03-0.68) predicted sustained dilation failure., Conclusions: Factors including older age, history of prior ARS, and MSA are correlated with higher post-ARS dilation rates. Although dilation improves symptoms in approximately half of patients initially, one-fourth may eventually require reoperation, mostly due to a slipped wrap or hernia recurrence. Thus, in cases of persistent dysphagia, consideration for surgical failure is important, and further imaging and workup are warranted. Patients who undergo MSA and those who have more than one dilation are more likely to experience dilation failure., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Reflux recurrence after fundoplication remains poorly understood, prompting an investigation into factors associated with it., Methods: A study was conducted to review patients who had primary fundoplication. The main focus was on identifying recurrent reflux confirmed by an abnormal DeMeester score of > 14.7. Risk factors were evaluated using multivariable logistic regression. Additionally, Impedance planimetry (EndoFLIP™) measurements were taken into account if performed during the operation., Results: Out of 137 patients who met inclusion criteria. 17 (12.4%) patients developed recurrent reflux, with 6.5% of them required secondary fundoplication. There were no significant differences in demographic, pre-operative or intra-operative characteristics between patients who developed recurrent reflux and those who did not (p > 0.05). However, in the subset of patients who underwent EndoFLIP™ monitoring during surgery (60%); patients who developed recurrent reflux had lower HPZ values post-wrap compared to those who did not [3.5 IQR (3-4) vs 2.5 IQR (1.8-3), p < 0.01]. Patient factors such as age, sex, BMI, and race were not found to be associated with recurrent reflux or reflux requiring surgical re-intervention in our analysis. However, having a low HPZ post-wrap was identified as a risk factor for recurrent reflux [0.15 95% CI (0.03-0.57)] and it showed a significant correlation with post-operative DeMeester score [r = - 0.28, p = 0.02]., Conclusion: No relationship was found between patient factors such as age, sex, race, and BMI and recurrent reflux following primary fundoplication. However, a Low HPZ post-wrap was a risk factor for recurrent reflux with a risk ratio of 0.15 (0.03-0.57) and a p value of 0.01. Larger studies are needed to evaluate the impact of HPZ on outcomes following fundoplication in order to develop guidelines for clinicians., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited treatment options. Although there have been recent advancements revealing genomic drivers of these tumors, it remains unclear which genomic signatures are associated with recurrence, particularly following R0 resection., Methods: Adrenocortical carcinoma patients treated with adrenalectomy in the Cancer Genome Atlas with recurrence data were identified using cBioPortal. Clinicopathologic variables, genomics, treatment patterns, and outcomes were retrospectively analyzed., Results: Among 92 adrenocortical carcinoma patients, 84 had recurrence data, with 52% experiencing tumor recurrence. Age and sex were not significantly different between recurrent and nonrecurrent groups. Nonrecurrent patients had a significantly longer overall survival (54 months vs 35 months, P = .0036). Adjuvant radiation was administered similarly in both groups (25.0% vs 16.2%, P = .4164). There were no differences in capsular or venous invasion or median tumor size. Sixty-two patients had R0 resection and 40.3% (n = 25/62) recurred. Multivariate logistic regression in this cohort, when controlling for vascular invasion, venous invasion, and capsular invasion, revealed that the WNT (odds ratio 4.43 [1.09-18.0], P = .034), PI3K (odds ratio 7.80 [1.33-45.65], P = .023), and cell cycle (odds ratio 6.81 [1.43-32.30], P = .016) pathways were significantly associated with recurrence. Median time to recurrence was 7.9 months; early recurrence (<7.9 months) was associated with MYC pathway alterations (40.9% vs 9.1%, P = .0339)., Conclusion: This study identified genomic signatures in the PI3K, WNT, and cell cycle pathways associated with adrenocortical carcinoma recurrence, including in those who underwent R0 resection. Investigations regarding the utility of these signatures as a prognostic tool to dictate adjuvant therapies or targeted treatment are warranted., Competing Interests: Conflict of Interest/Disclosure The authors have no relevant financial disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Integrating microRNA markers with next-generation sequencing panels may enhance risk assessment of cytologically indeterminate thyroid nodules. The ThyGeNEXT-ThyraMIRv1 multiplatform test version 1 demonstrated limited utility in risk-stratifying RAS-mutated indeterminate thyroid nodules. We sought to validate the updated ThyraMIRv2 platform in clinical practice., Methods: ThyGeNEXT/ThyraMIRv2, a 3-tiered microRNA classifier, were evaluated using a previously studied multi-institutional cohort of Bethesda III/IV nodules, with positive results having risk of malignancy ≥10%. In addition, ThyraMIRv2's clinical utility in RAS-mutated indeterminate thyroid nodules was assessed., Results: In 366 indeterminate thyroid nodules, ThyraMIRv2 platform yielded a 30.3% positive-call rate. ThyraMIRv2 platform + nodules had greater operative rates (63.9% vs 36.1%, P < .0001) and cancer/noninvasive follicular thyroid neoplasm with papillary-like nuclear features diagnosis (65.9% vs 25.0%, P < .0001) than ThyraMIRv2 platform nodules. Compared with multiplatform test version 1, ThyraMIRv2 platform's diagnostic testing parameters did not improve significantly. Among 68 RAS-mutated nodules, ThyraMIRv2 classified 36.8%, 55.9%, and 7.4% as positive, moderate, and negative, respectively. All moderate nodules had risk of malignancy ≥10% and were combined with the positive cohort. No significant differences existed in operative rate (81.0% vs 60.0%, P = .272) or cancer/noninvasive follicular thyroid neoplasm with papillary-like nuclear features diagnosis (47.6% vs 40.0%, P > .999) between RAS-mutated positive/moderate and negative groups. For RAS-mutated nodules, ThyraMIRv2 demonstrated improved sensitivity (93.8% vs 64.7, P = .003) and decreased specificity (4.5% vs 34.8%, P = .008) compared with ThyGeNEXT-ThyraMIRv1 multiplatform test version 1, with comparable negative predictive value (33.3% vs 40.0%, P = .731) and positive predictive value (58.8% vs 59.5%, P = .864)., Conclusion: ThyraMIRv2 platform does not improve indeterminate thyroid nodule malignancy stratification compared to ThyGeNEXT-ThyraMIRv1 multiplatform test version 1. ThyraMIRv2 improves malignant RAS-mutated nodule detection but increases false positives. Future studies encompassing a larger cohort of RAS-mutated with surgical pathology results are warranted to better characterize the performance parameters of this classifier., Competing Interests: Conflicts of Interest/Disclosure The authors have no potential conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: ATRX, DAXX, MEN1, and PTEN mutations are proposed drivers of pancreatic neuroendocrine tumor tumorigenesis and independent prognostic factors for metastasis and mortality. However, their implications after R0 resection remain debated. Thus, we sought to identify genomic signatures of pancreatic neuroendocrine tumor disease-specific mortality and recurrence after surgery for curative intent., Methods: Pancreatic neuroendocrine tumor patients who underwent whole exome sequencing with available survival data were identified using cBioPortal. Clinicopathologic variables, genomics, and outcomes were analyzed., Results: Seventy patients who underwent R0 resection were identified. Forty-five of 70 patients were disease free at last follow-up, whereas 25 of 70 patients had disease-specific mortality or recurrent disease and therefore were categorized as part of the recurrent cohort. There were no significant differences in age (P = .245), sex (P = .201), or median follow-up (38.9 vs 33.7 months, P = .122) between groups. Clinicopathologically, the recurrent cohort had significantly greater tumor size (median 5.0 cm vs 3.2 cm, P = .012) and were more likely to have vascular invasion (88% vs 40%, P = .000), positive lymph nodes (68.0% vs 35.6%, P = .013), and metastatic disease (44% vs 4.4%, P < .000). For both cohorts, most tumors were well or moderately differentiated. Tumor mutation burden was greater in the recurrent cohort (median 0.77 vs 0.43 mutations/Mb, P = .004). DAXX mutations were more frequent in the recurrent cohort (36% vs 11%, P = .026) and in those with vascular invasion (51% vs 92%, P = .010)., Conclusion: Our analysis demonstrated the prognostic significance of DAXX mutations after curative-intent surgery. Future studies investigating DAXX mutations as a biomarker for aggressive features to guide treatment are warranted., Competing Interests: Conflict of Interest/Disclosure Rasa Zarnegar has received consulting fees from Intuitive, BD, and Medtronic. Thomas J. Fahey has received consulting fees from Veracyte. All of the other authors have indicated that they have no conflicts of interest (or funding) regarding the content of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Dysphagia after anti-reflux surgery (ARS) is one of the most common indications for re-operative anti-reflux surgery and a leading cause of patient dissatisfaction. Unfortunately, the factors affecting its development are poorly understood. We investigated the correlation between pre-operative manometric and the intra-operative impedance planimetry (EndoFLIP™) measurements and development of post-operative dysphagia., Methods: A review of patients who underwent index robotic ARS in our institution. Patients who underwent pre-operative manometry and intra-operative EndoFLIP™ were included in our study. Dysphagia was assessed pre-operatively and at 3-month after surgery., Results: Fifty-five patients (26.9%) reported post-operative dysphagia, and 34 (16.6%) reported new or worsening dysphagia. On pre-operative manometry, patients with post-operative dysphagia had a lower distal contractile integral [868.7 (IQR 402.2-1447) mmHg s cm vs 1207 (IQR 612.1-2111) mmHg s cm, p = 0.006) and lower esophageal sphincter (LES) pressure [14.7 IQR (8.9-23.6) mmHg vs 20.7 IQR (10.2-32.6) mmHg, p = 0.01] compared to those without post-operative dysphagia. They were also found to have higher pre-operative cross-sectional surface area (CSA) [83 IQR (44.5-112) mm 2 vs 66 IQR (42-93) mm 2 , p = 0.02], and distensibility index (DI) [4.2 IQR (2.2-5.5) mm 2 /mmHg vs 2.9 IQR (1.6-4.6) mm 2 /mmHg, p = 0.003] compared to patients without post-operative dysphagia. Additionally, the decrease in CSA [- 34 (- 18.5, - 74.5) mm 2 vs - 26.5 (- 10.5, - 53.7) mm 2 , p = 0.03] and DI [- 2.3 (- 1.2, - 3.7) mm 2 /mmHg vs - 1.6 (- 0.7, - 3.3) mm 2 /mmHg, p = 0.03] measurements were greater in patients with post-operative dysphagia., Conclusion: Patients who developed dysphagia post-operatively had poorer pre-operative motility and a greater change in LES characteristics intra-operatively. This finding suggests the utility of pre-operative manometry and intra-operative EndoFLIP in identifying patients at risk of developing dysphagia post-operatively., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: As our population ages, older adults are being considered for anti-reflux surgery (ARS). Geriatric patients typically have heightened surgical risk, and literature has shown mixed results regarding postoperative outcomes. We sought to evaluate the safety and efficacy of robotic ARS in the geriatric population., Methods: We conducted a single-institution review of ARS procedures performed between 2009 and 2023. Patients ≥ 65 were assigned to the geriatric cohort. We compared operative details, lengths of stay (LOS), readmissions, reoperations, and complications between the two cohorts. The gastroesophageal reflux disease health-related quality of life (GERD-HRQL) survey and review of clinic notes were used to evaluate ARS efficacy., Results: 628 patients were included, with 190 in the geriatric cohort. This cohort had a higher frequency of diabetes (16.3% vs 5.9% p < 0.0001), hypertension (50.0% vs 21.5% p < 0.0001), and heart disease (17.9% vs 2.3% p < 0.0001). Geriatric patients were more likely to exhibit hiatal hernias on imaging (51.6% vs 34.2% p < 0.0001) and were more likely to have large hernias (30.0% vs 7.1% p < 0.0001). Older adults were more likely to undergo Toupet fundoplications (58.4% vs 41.3%, p < 0.0001), Collis gastroplasties (9.5% vs 2.7% p < 0.0001), and relaxing incisions (11.6% vs 1.4% p < 0.0001). Operative time was longer for geriatric patients (132.0 min vs 104.5 min p < 0.0001). There were no significant differences in LOS, readmissions, or reoperations between cohorts. Geriatric patients exhibited lower rates of complications (7.4% vs. 14.6%, p = 0.011), but similar complication grades. Both groups had significant reduction in symptom scores from preoperative values. There were no significant differences in the reported symptoms between cohorts at any follow-up timepoint., Conclusion: Geriatric robotic ARS patients tend to do as well as younger adults regarding postoperative and symptomatic outcomes, despite presenting with larger hiatal hernias and shorter esophagi. Clinicians should be aware of possible need for lengthening procedures or relaxing incisions in this population., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Anaplastic thyroid cancer (ATC) is highly aggressive with a poor prognosis. Adjuvant systemic therapy and radiation post-surgery are endorsed by NCCN and ATA guidelines. Our study aimed to identify those at risk of forgoing postoperative adjuvant treatment and to determine survival predictors., Methods: We used the National Cancer Database (NCDB) to identify ATC patients who underwent upfront thyroidectomy from 2010 to 2017, excluding those opting for palliative care. We compared demographics, characteristics, treatments, and outcomes between those who received adjuvant therapy and those who did not. Predictors of receiving adjuvant therapy were identified using logistic regression, while Cox regression identified survival factors., Results: Of 563 patients, 160 received no adjuvant treatment, 82 received radiation only, 16 received systemic therapy only, and 305 received combination therapy. Notably, over 75 ​% of patients who did not receive adjuvant treatment had it excluded from their treatment plan, not due to refusal. Older age (OR 0.92) and non-white race/ethnicity (OR 0.33) were significant predictors of not receiving adjuvant therapy. Undergoing a total thyroidectomy, an R0 or R1 resection, and radiation or combination therapy were associated with better survival, while non-metropolitan location, primary tumor size >7.5 ​cm, and stage IVC disease were negative factors., Conclusion: Total thyroidectomy, R0/R1 resection, and adjuvant therapy reduce mortality in ATC patients. However, older patients and minorities are less likely to receive adjuvant therapy, underscoring disparities in treatment adherence., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The tall cell, columnar, and diffuse sclerosing subtypes are aggressive histologic subtypes of papillary thyroid cancer (PTC) with increasing incidence, yet there is a wide variation in reporting. We aimed to identify and compare factors associated with the reporting of these aggressive subtypes (aPTC) to classic PTC (cPTC) and secondarily identify differences in outcomes., Methods: The National Cancer Database was utilized to identify cPTC and aPTC from 2004 to 2017. Patient and facility demographics and clinicopathologic variables were analyzed. Independent predictors of aPTC reporting were identified and a survival analysis was performed., Results: The majority of aPTC (67%) were reported by academic facilities. Compared to academic facilities, all other facility types were 1.4-2.0 times less likely to report aPTC (P < 0.05). Regional variation in reporting was noted, with more cases reported in the Middle Atlantic, despite there being more total facilities in the South Atlantic and East North Central regions. Compared to the Middle Atlantic, all other regions were 1.4-5 times less likely to report aPTC (P < 0.001). Patient characteristics including race and income were not associated with aPTC reporting. Compared to cPTC, aPTC had higher rates of aggressive features and worse 5-y overall survival (90.5% versus 94.5%, log rank P < 0.001)., Conclusions: Aggressive subtypes of PTC are associated with worse outcomes. Academic and other facilities in the Middle Atlantic were more likely to report aPTC. This suggests the need for further evaluation of environmental or geographic factors versus a need for increased awareness and more accurate diagnosis of these subtypes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Context: The significance of low mitotic activity in papillary thyroid cancer (PTC) is largely undefined., Objective: We aimed to determine the behavioral landscape of PTC with low mitotic activity compared to that of no- and high-mitotic activity., Methods: A single-institution consecutive series of PTC patients from 2018-2022 was reviewed. Mitotic activity was defined as no mitoses, low (1-2 mitoses/2 mm2) or high (≥3 mitoses/2 mm2) per the World Health Organization. The 2015 American Thyroid Association risk stratification was applied to the cohort, and clinicopathologic features were compared between groups. For patients with ≥6 months follow-up, Cox regression analyses for recurrence were performed., Results: 640 PTCs were included - 515 (80.5%) no mitotic activity, 110 (17.2%) low mitotic activity, and 15 (2.3%) high mitotic activity. Overall, low mitotic activity exhibited rates of clinicopathologic features including vascular invasion, gross extrathyroidal extension, and lymph node metastases in between those of no- and high-mitotic activity. PTCs with low mitotic activity had higher rates of intermediate- and high-risk ATA risk stratification compared to those with no mitotic activity (p < 0.001). Low mitotic activity PTCs also had higher recurrence rates (15.5% vs. 4.5%, p < 0.001). Low mitotic activity was associated with recurrence, independent of the ATA risk stratification (HR 2.96; 95% CI 1.28-6.87, p = 0.01)., Conclusions: Low mitotic activity is relatively common in PTC and its behavior lies within a spectrum between no- and high-mitotic activity. Given its association with aggressive clinicopathologic features and recurrence, low mitotic activity should be considered when risk stratifying PTC patients for recurrence., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Prior studies have shown tumor specificity on the impact of longer time interval from diagnosis to surgery, however in gastric cancer (GC) this remains unclear. We aimed to determine if a longer time interval from diagnosis to surgery had an impact on lymph node (LN) upstaging and overall survival (OS) outcomes among patients with clinically node negative (cN0) GC., Patients and Methods: Patients diagnosed with cN0 GC undergoing surgery between 2004-2018 were identified in the National Cancer Database (NCDB) and divided into intervals between time of diagnosis and surgery [short interval (SI): ≥ 4 days to < 8 weeks and long interval (LI): ≥ 8 weeks]. Multivariable regression analysis evaluated the independent impact of surgical timing on LN upstaging and a Cox proportional hazards analysis and Kaplan-Meier curves evaluated survival outcomes., Results: Of 1824 patients with cN0 GC, 71.8% had a SI to surgery and 28.1% had a LI to surgery. LN upstaging was seen more often in the SI group when compared to LI group (82% versus 76%, p = 0.004). LI to surgery showed to be an independent factor protective against LN upstaging [adjusted odds ratio = 0.62, 95% CI: (0.39-0.99)]. Multivariate Cox regression analysis indicated that time to surgery was not associated with a difference in overall survival [hazard ratio (HR) = 0.91, 95% CI: (0.71-1.17)], however uncontrolled Kaplan-Meier curves showed OS difference between the SI and LI to surgery groups (p = 0.037)., Conclusion: Timing to surgery was not a predictor of LN upstaging or overall survival, suggesting that additional medical optimization in preparation for surgery and careful preoperative staging may be appropriate in patients with node negative early stage GC without affecting outcomes., (© 2023. Society of Surgical Oncology.)

Introduction: Endoluminal functional lumen imaging probe (EndoFLIP) provides a real-time assessment of gastroesophageal junction (GEJ) compliance during fundoplication. Given the limited data on EndoFLIP measurements during the Hill procedure, we investigated the impact of the Hill procedure on GEJ compliance compared to Toupet fundoplication., Methods: Patients who underwent robotic Hill or Toupet fundoplication with intraoperative EndoFLIP between 2017 and 2022 were included. EndoFLIP measurements of the GEJ included cross sectional surface area (CSA), intra-balloon pressure, high pressure zone length (HPZ), distensibility index (DI), and compliance. Subjective reflux symptoms, gastroesophageal reflux disease-health related quality of life (GERD-HRQL) score, and dysphagia score were assessed pre-operatively as well as at short- and longer-term follow-up., Results: One-hundred and fifty-four patients (71.9%) had a Toupet fundoplication while sixty (28%) patients underwent the Hill procedure. The CSA [27.7 ± 10.9 mm 2 vs 42.2 ± 17.8 mm 2 , p < 0.0001], pressure [29.5 ± 6.2 mmHg vs 33.9 ± 8.5 mmHg, p = 0.0009], DI [0.9 ± 0.4 mm 2 /mmHg vs 1.3 ± 0.6 mm 2 /mmHg, p = 0.001], and compliance [25.9 ± 12.8 mm 3 /mmHg vs 35.4 ± 13.4 mm 3 /mmHg, p = 0.01] were lower after the Hill procedure compared to Toupet. However, there was no difference in post-fundoplication HPZ between procedures [Hill: 2.9 ± 0.4 cm, Toupet: 3.1 ± 0.6 cm, p = 0.15]. Follow-up showed no significant differences in GERD-HRQL scores, overall dysphagia scores or atypical symptoms between groups (p > 0.05)., Conclusion: The Hill procedure is as effective to the Toupet fundoplication in surgically treating gastroesophageal reflux disease (GERD) despite the lower CSA, DI, and compliance after the Hill procedure. Both procedures led to DI < 2 mm 2 /mmHg with no significant differences in dysphagia reporting (12-24) months after the procedure. Further studies to elucidate a cutoff value for DI for postoperative dysphagia development are still warranted., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: We aimed to evaluate the impact of radioactive iodine on disease-specific survival in intrathyroidal (N0M0) papillary thyroid carcinoma >4 cm, given conflicting data in the American Thyroid Association guidelines regarding their management., Methods: The Surveillance, Epidemiology, and End Results database was queried for N0M0 classic papillary thyroid carcinoma >4 cm. Kaplan-Meier estimates were performed to compare disease-specific survival between radioactive iodine-treated and untreated groups. A multivariable Cox regression was performed to identify predictors of disease-specific survival., Results: There were more patients aged ≥55 (41.7% vs 32.3%, P = .001) and fewer multifocal tumors (25.3% vs 30.6%, P = .006) in the no radioactive iodine group. Ten-year disease-specific survival was similar between the radioactive iodine treated and untreated groups (97.2% vs 95.6%, P = .34). Radioactive iodine was not associated with a significant disease-specific survival benefit (adjusted hazard ratio = 0.78, confidence interval [0.39-1.58], P = .49). Age ≥55 (adjusted hazard ratio = 3.50, confidence interval [1.69-7.26], P = .001) and larger tumor size (adjusted hazard ratio = 1.04, confidence interval [1.02-1.06], P < .001) were associated with an increased risk of disease-specific death. Subgroup analyses did not demonstrate improved disease-specific survival with radioactive iodine in patients ≥55 and in tumors >5 cm., Conclusion: Adjuvant radioactive iodine administration in classic papillary thyroid carcinoma >4 cm confined to the thyroid did not significantly impact disease-specific survival. Thus, these patients may not require routine treatment with adjuvant radioactive iodine., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Molecular testing guides the management of cytologically indeterminate thyroid nodules. We evaluated the real-world clinical benefit of a commercially available thyroid mutation panel plus microRNA risk classifier in classifying RAS-mutated nodules., Methods: We performed a subgroup analysis of the results of molecular testing of Bethesda III/IV nodules using the ThyGenX/ThyGeNEXT-ThyraMIR platform at 3 tertiary-care centers between 2017 and 2021, defining a positive result as 10% or greater risk of malignancy., Results: We identified 387 nodules from 375 patients (70.7% female, median age 59.3 years) who underwent testing. Positive nodules (32.3%) were associated with increased surgical intervention (74.4% vs 14.9%, P < .0001) and carcinoma on surgical pathology (46.4% vs 3.4%, P < .0001) compared to negative modules. RAS mutations were the most common mutations, identified in 71 of 380 (18.7%) nodules, and were classified as ThyraMIR- (28 of 71; 39.4%) or ThyraMIR+ (43 of 71; 60.6%). Among RAS-mutated nodules, there was no significant difference in operative rate (P = .2212) or carcinoma diagnosis (P = .6277) between the ThyraMIR+ and ThyraMIR- groups, and the sensitivity, specificity, negative predictive value, and positive predictive value of ThyraMIR were 64.7%, 34.8%, 40.0%, and 59.5%, respectively., Conclusion: Although testing positive is associated with malignancy in surgical pathology, the ThyraMIR classifier failed to differentiate between benign and malignant RAS-mutated nodules. Diagnostic lobectomy should be considered for RAS-mutated nodules, regardless of microRNA expression status., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Secondary hyperparathyroidism (sHPT) is prevalent in dialysis patients and can lead to tertiary hyperparathyroidism (tHPT) after kidney transplantation. We aimed to assess the association of pretransplant sHPT treatment on posttransplant outcomes., Methods: We reviewed kidney transplant patients treated with parathyroidectomy or cinacalcet for sHPT. We compared patients biochemical and clinical parameters, and outcomes based on sHPT treatment., Results: A total of 41 patients were included: 18 patients underwent parathyroidectomy and 23 patients received cinacalcet prior to transplantation. There were no significant differences between demographics, comorbidities, allograft characteristics or pre-sHPT intervention parathyroid hormone (PTH) and calcium levels. Patients that underwent parathyroidectomy were on dialysis for longer, although not significantly (71.9 versus 42.3 mo, P = 0.051). At time of transplantation, patients treated by parathyroidectomy had increased rates of controlled sHPT (88.9%; 16/18 versus 47.8%; 11/23, P = 0.008). Patients treated by parathyroidectomy had decreased development of tHPT (5.9%; 1/17; versus 42.1%; 8/19, P = 0.020) as well as decreased rates of posttransplant treatment with cinacalcet (11.1%; 2/18 versus 52.2%; 12/23, P = 0.008). Three patients treated with cinacalcet underwent parathyroidectomy after transplantation. Median PTH after transplant remained lower in patients treated by parathyroidectomy prior to transplant compared to those treated with cinacalcet (60.7 [interquartile range 39.7-133.4] versus 170.0 [interquartile range 128.4-292.7], P = 0.001). Allograft function and survival were similar for parathyroidectomy and cinacalcet, with median follow-up after transplantation of 56.7 and 34.2 mo, respectively., Conclusions: sHPT treated by parathyroidectomy is associated with controlled PTH levels at transplantation and decreased rates of tHPT. Long-term outcomes should be studied on a larger scale., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Vonoprazan is a new potassium-competitive acid blocker (P-CAB) that was recently approved by the FDA. It is associated with a fast onset of action and a longer acid inhibition time. Vonoprazan-containing therapy for helicobacter pylori eradication is highly effective and several studies have demonstrated that a vonoprazan-antibiotic regimen affects gut microbiota. However, the impact of vonoprazan alone on gut microbiota is still unclear.Please check and confirm the authors (Maria Cristina Riascos, Hala Al Asadi) given name and family name are correct. Also, kindly confirm the details in the metadata are correct.Yes they are correct.  METHODS: We conducted a prospective randomized 12-week experimental trial with 18 Wistar rats. Rats were randomly assigned to one of 3 groups: (1) drinking water as negative control group, (2) oral vonoprazan (4 mg/kg) for 12 weeks, and (3) oral vonoprazan (4 mg/kg) for 4 weeks, followed by 8 weeks off vonoprazan. To investigate gut microbiota, we carried out a metagenomic shotgun sequencing of fecal samples at week 0 and week 12.Please confirm the inserted city and country name is correct for affiliation 2.Yes it's correct., Results: For alpha diversity metrics at week 12, both long and short vonoprazan groups had lower Pielou's evenness index than the control group (p = 0.019); however, observed operational taxonomic units (p = 0.332) and Shannon's diversity index (p = 0.070) were not statistically different between groups. Beta diversity was significantly different in the three groups, using Bray-Curtis (p = 0.003) and Jaccard distances (p = 0.002). At week 12, differences in relative abundance were observed at all levels. At phylum level, short vonoprazan group had less of Actinobacteria (log fold change = - 1.88, adjusted p-value = 0.048) and Verrucomicrobia (lfc = - 1.76, p = 0.009).Please check and confirm that the author (Ileana Miranda) and their respective affiliation 3 details have been correctly identified and amend if necessary.Yes it's correct. At the genus level, long vonoprazan group had more Bacteroidales (lfc = 5.01, p = 0.021) and Prevotella (lfc = 7.79, p = 0.001). At family level, long vonoprazan group had more Lactobacillaceae (lfc = 0.97, p = 0.001), Prevotellaceae (lfc = 8.01, p < 0.001), and less Erysipelotrichaceae (lfc = - 2.9, p = 0.029)., Conclusion: This study provides evidence that vonoprazan impacts the gut microbiota and permits a precise delineation of the composition and relative abundance of the bacteria at all different taxonomic levels., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: We aimed to determine if there is an optimal time to complete dedicated research during surgical residency., Background: Research is an integral part of academic general surgical residency, and dedicated research usually occurs after the 2nd or 3rd post-graduate year (PGY). The timing of dedicated research and its association with resident productivity, self-assessed competency (including technical skills), and fellowship match is not known., Methods: PubMed was queried for publications resulting after dedicated research time for graduating surgical residents at a single institution from 2010 to 2021. Graduates were surveyed about their research experience and placed into 2 groups: research after PGY2 or PGY3., Results: Sixty-six of 91 (73%) graduating residents completed dedicated research (after PGY2, n=28; after PGY3, n=38). Median number of total and first author publications was similar between groups; however, research after PGY2 was associated with an increased number of basic science publications by fellowship application deadlines (PGY2: 1.0[0-13] vs PGY3: 0.0[0-6], p=0.02). With a 79% survey response rate, there were no differences in self-assessed competencies upon return from research between cohorts. Most surveyed residents matched at their top fellowship choice (PGY2:70% vs PGY3:62%, p=0.77)., Conclusions: Research after PGY2 or PGY3 had no association with residents' total number of publications, self-assessed competency, or rates of matching at first choice fellowship. As research after PGY2 had an increased number of basic science publications by time of fellowship application, surgical residents applying to fellowships that highly value basic science research may benefit from completing dedicated research after PGY2., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Perineural invasion (PNI) is associated with aggressive tumor behavior, increased locoregional recurrence, and decreased survival in many carcinomas. However, the significance of PNI in papillary thyroid cancer (PTC) is incompletely characterized., Methods: Patients diagnosed with PTC and PNI from 2010-2020 at a single, academic center were identified and matched using a 1:2 scheme to patients without PNI based on gross extrathyroidal extension (ETE), nodal metastasis, positive margins, and tumor size (±4 cm). Mixed and fixed effects models were used to analyze the association of PNI with extranodal extension (ENE)-a surrogate marker of poor prognosis., Results: In total, 78 patients were included (26 with PNI, 52 without PNI). Both groups had similar demographics and ultrasound characteristics preoperatively. Central compartment lymph node dissection was performed in most patients (71%, n = 55), and 31% (n = 24) underwent a lateral neck dissection. Patients with PNI had higher rates of lymphovascular invasion (50.0% vs. 25.0%, p = 0.027), microscopic ETE (80.8% vs. 44.0%, p = 0.002), and a larger burden [median 5 (interquartile range [IQR] 2-13) vs. 2 (1-5), p = 0.010] and size [median 1.2 cm (IQR 0.6-2.6) vs. 0.4 (0.2-1.4), p = 0.008] of nodal metastasis. Among patients with nodal metastasis, those with PNI had an almost fivefold increase in ENE [odds ratio [OR] 4.9 (95% confidence interval [CI] 1.5-16.5), p = 0.008] compared with those without PNI. More than a quarter (26%) of all patients had either persistent or recurrent disease over follow-up (IQR 16-54 months)., Conclusions: PNI is a rare, pathologic finding that is associated with ENE in a matched cohort. Additional investigation into PNI as a prognostic feature in PTC is warranted., (© 2023. Society of Surgical Oncology.)

Introduction: Roux-en-Y gastric bypass (RYGB) has been the preferred operation for obese patients with gastroesophageal reflux disease (GERD); however, some patients are hesitant to undergo bypass. Obese patients have a multifactorial predisposition to GERD, including lower esophageal sphincter (LES) dysfunction and aberrant pressure gradients across their diaphragmatic crura. Among non-obese patients, anti-reflux surgery (ARS) with hiatal hernia (HH) repair and LES augmentation has shown excellent long-term results. We aimed to determine whether patient satisfaction and GERD recurrence differed between obese and non-obese patients who underwent ARS., Methods: Review of patients who underwent ARS between January 2012 and June 2021 was performed. Perioperative and postoperative characteristics were compared across three BMI groups: BMI < 30 kg/m 2 , 30 kg/m 2  ≤ BMI < 35 kg/m 2 , and BMI ≥ 35 kg/m 2 ., Results: Four-hundred thirteen patients were identified, of which 294 (71.1%) had BMI < 30 kg/m 2 , 87 (21.1%) were 30 kg/m 2  ≤ BMI < 35 kg/m 2 , and 32 (7.7%) had a BMI ≥ 35 kg/m 2 . Patients with BMI ≥ 35 kg/m 2 had higher preoperative manometric and EndoFLIP™ intra-balloon pressure at the LES than those with lower BMIs. This value was increased to a similar level throughout ARS across the three cohorts. Post-operative GERD-specific satisfaction was similar across the three cohorts, as were rates of postoperative reflux and hiatal hernia recurrence on barium swallow; rates of reoperation were low., Conclusions: ARS with HH repair and LES augmentation may be appropriate for select patients across a range of BMIs, including those with a BMI ≥ 35 kg/m 2 who are hesitant to undergo RYGB., (© 2022. The Society for Surgery of the Alimentary Tract.)

Background: The COVID-19 pandemic profoundly impacted the delivery of care and timing of elective surgical procedures. Most endocrine-related operations were considered elective and safe to postpone, providing a unique opportunity to assess clinical outcomes under protracted treatment plans., Methods: American Association of Endocrine Surgeon members were surveyed for participation. A Research Electronic Data Capture survey was developed and distributed to 27 institutions to assess the impact of COVID-19-related delays. The information collected included patient demographics, primary diagnosis, resumption of care, and assessment of disease progression by the surgeon., Results: Twelve out of 27 institutions completed the survey (44.4%). Of 850 patients, 74.8% (636) were female; median age was 56 (interquartile range, 44-66) years. Forty percent (34) of patients had not been seen since their original surgical appointment was delayed; 86.2% (733) of patients had a delay in care with women more likely to have a delay (87.6% vs 82.2% of men, χ 2  = 3.84, P = .05). Median duration of delay was 70 (interquartile range, 42-118) days. Among patients with a delay in care, primary disease site included thyroid (54.2%), parathyroid (37.2%), adrenal (6.5%), and pancreatic/gastrointestinal neuroendocrine tumors (1.3%). In addition, 4.0% (26) of patients experienced disease progression and 4.1% (24) had a change from the initial operative plan. The duration of delay was not associated with disease progression (P = .96) or a change in operative plan (P = .66)., Conclusion: Although some patients experienced disease progression during COVID-19 delays to endocrine disease-related care, most patients with follow-up did not. Our analysis indicated that temporary delay may be an acceptable course of action in extreme circumstances for most endocrine-related surgical disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. The TMEs of localized and metastatic PNETs were investigated using an approach that combines RNA-Seq, cancer and T cell profiling, and pharmacologic perturbations. RNA-Seq analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared with localized tumors. T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigen-dependent activation, suggestive of an immune-permissive microenvironment. A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. Treatment of PNET cell lines with vorinostat increased chemokine CCR5 expression by NF-κB activation. Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, and this augmentation was substantiated in a mouse model of PNET. Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs.

Background: Among surgical patients, care fragmentation (CF) is associated with worse outcomes. However, oncologic literature documents an association between high surgical volume and improved outcomes, favoring centralized cancer-surgery centers and thus predisposing to CF in patients with surgically treated tumors. We aimed to identify features associated with CF and ascertain differences in overall survival (OS) among patients with differentiated thyroid cancer (DTC)., Methods: The National Cancer Database was queried for DTC patients diagnosed from 2009 to 2017. Patients experienced CF if part of their treatment was performed outside of the reporting facility or an associated office. A multivariable logistic regression analysis identified independent features associated with CF. A Cox multivariable regression analysis assessed the impact of CF on OS. A Kaplan-Meier analysis compared survival differences between patients experiencing CF or unified care (UC)., Results: A total of 131,620 patients were included. Among them, 70,204 (53.3%) experienced CF and 61,416 (46.7%) experienced UC. Age < 55, residing in high-income areas, and stage 3 and 4 tumors were features independently associated with CF, whereas uninsured patients were less likely to experience CF than the privately insured. The features most strongly associated with CF were treatment at highest thyroid cancer-surgery volume institutions and traveling in the top distance quartile. While patients with CF experienced minor delays in time from diagnosis to surgery, 5-year OS was improved among patients with CF compared to UC for those with Stage 1-3 disease., Conclusions: Among patients with DTC, CF is associated with treatment at a highest thyroid cancer surgery volume facility and improved OS in a setting of minor treatment delays., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: Incidence of venous thromboembolism (VTE) after adrenalectomy for adrenal cortical carcinoma (ACC) is unknown. Herein, we aim to identify the relative incidence and risk factors of VTE after adrenalectomy for ACC., Methods: The American College of Surgeons National Surgical Quality Improvement Program database was queried to identify patients who underwent adrenalectomy for ACC, Cushing syndrome (CS), and benign adrenal cortical syndromes (BACS). Univariable and multivariable analyses were used to determine clinical characteristics, 30-day postoperative VTE occurrences, and associated risk factors. Khorana oncologic risk score (KRS) for VTE was calculated and compared between groups., Results: A total of 5896 patients were analyzed: 576 ACC, 371 CS, and 4949 BACS. Postoperative VTE occurred 0.9%, with the highest rate occurring in ACC (2.6% ACC vs. 1.6% CS vs. 0.7% BACS, p < 0.001). Forty percent of VTEs in the ACC cohort were diagnosed postdischarge. ACC patients with KRS ≥ 2 had a 9.6% incidence of VTE (p = 0.007). Multivariable analysis identified increased age (p = 0.03), presence of adrenal cancer (p = 0.01), and KRS ≥ 2 (p = 0.005) as risk factors for VTE after adrenalectomy., Conclusions: Postoperative VTE after adrenalectomy occurs most frequently for ACC. ACC patients with increased age and/or Khorana score ≥2 should be considered for extended VTE prophylaxis., (© 2022 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Introduction: Sex-based differences in survival have emerged among patients with pancreatic neuroendocrine tumors (PNETs). Mechanisms driving these differences remain poorly understood. We aimed to further characterize sex-based clinicopathologic and survival differences among patients with PNETs and correlate divergent mutational signatures in these patients., Methods: The National Cancer Database (NCDB) was queried for PNET patients diagnosed 2004-2017 who underwent surgery. Clinicopathologic features were analyzed by sex. The overall survival (OS) of men and women by disease stage was compared using the Kaplan-Meier method. Differences in PNET mutational signatures were analyzed by querying the American Association for Cancer Research Genomics Evidence Neoplasia Information (AACR-GENIE) Cohort v11.0-public. Frequencies of mutational signatures were compared by Fischer's exact (FE) test, adjusting for multiple testing via the Benjamini-Hochberg correction., Results: About 15,202 patients met inclusion criteria from the NCDB; 51.9% were men and 48.1% were women. Men more frequently had tumors > 2 cm than women and more commonly had poorly or undifferentiated tumors. Despite this, lymph node positivity and distant metastases were similar. Differences in OS were only seen among those with early stage rather than stage 3 or 4 disease. MEN1 and DAXX mutations were more frequent among men with PNETs, whereas TP53 mutations were more frequent among women when assessed by FE test. However, neither of these mutational differences maintained statistical significance when adjusted for multiple testing., Conclusion: Compared to women, men have larger tumors but similar rates of distant metastases at time of surgery. OS differences appear to be driven by patients with early-stage disease without clearly identifiable differences in mutational signatures between the sexes., (© 2022. The Society for Surgery of the Alimentary Tract.)

Introduction: Alterations in the microbiome contribute to the pathogenesis of many gastrointestinal diseases. However, the composition of the microbiome in gallbladder disease is not well described., Methods: We aimed to characterize the biliary microbiome in cholecystectomy patients. Bile and biliary stones were collected at cholecystectomy for a variety of surgical indications between 2017 and 2019. DNA was extracted and metagenomic sequencing was performed with subsequent taxonomic classification using Kraken2. The fraction of bacterial to total DNA reads, relative abundance of bacterial species, and overall species diversity were compared between pathologies and demographics., Results: A total of 74 samples were obtained from 49 patients: 46 bile and 28 stones, with matched pairs from 25 patients. The mean age was 48 years, 76% were female, 29% were Hispanic, and 29% of patients had acute cholecystitis. The most abundant species were Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pasteurianus. The bacterial fraction in bile and stone samples was higher in acute cholecystitis compared to other non-infectious pathologies (p < 0.05). Neither the diversity nor differential prevalence of specific bacterial species varied significantly between infectious and other non-infectious gallbladder pathologies. Multivariate analysis of the non-infectious group revealed that patients over 40 years of age had increased bacterial fractions (p < 0.05)., Conclusions: Metagenomic sequencing permits characterization of the gallbladder microbiome in cholecystectomy patients. Although a higher prevalence of bacteria was seen in acute cholecystitis, species and diversity were similar regardless of surgical indication. Additional study is required to determine how the microbiome can contribute to the development of symptomatic gallbladder disease., (© 2022. The Society for Surgery of the Alimentary Tract.)

Introduction: The incidence of papillary thyroid cancer (PTC) in the United States has tripled in the past 30 y. Polybrominated diphenyl ethers (PBDEs) are flame retardants that were ubiquitously used over that time period, and exposure to PBDEs has been associated with PTC prevalence. They are potential carcinogens via their induction of reactive oxygen species (ROS) formation and resultant deoxyribonucleic acid (DNA) damage. We sought to determine the effects of PBDE and tris(2-chloroethyl) phosphate (TCEP), another flame retardant implicated in PTC incidence, on thyrocytes in vitro and measure PBDE levels in human thyroid tissue to determine their carcinogenic potential., Methods: Nthy-Ori, an immortalized benign human thyroid follicular cell line was used as a model of normal human thyroid. MTT assays were used to measure cell viability after exposure to PBDEs and TCEP. ROS levels and double-stranded and single-stranded DNA breaks were measured to determine genotoxicity. DNA damage response protein levels were measured with immunoblotting., Results: Exposure to 20μM PBDE or TCEP for 48 h had minimal effects on thyrocyte viability. There was no significant increase in intracellular ROS up to 6 h following PBDE or TCEP exposure in thyrocytes; however, cells exposed to PBDE 47 showed evidence of DNA single-stranded and double-stranded breaks. There was a dose-dependent increase in γH2AX levels following exposure to PBDEs 47 and 209 in Nthy-Ori cells but not with TCEP treatment., Conclusions: PBDE 47 and 209 demonstrated genotoxicity but not cytotoxicity in follicular thyrocytes in vitro. Therefore, PBDE 47 and 209 may be carcinogenic in human thyroid cells., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: Adrenalectomy is the definitive treatment for multiple adrenal abnormalities. Advances in technology and genomics and an improved understanding of adrenal pathophysiology have altered operative techniques and indications., Objective: To develop evidence-based recommendations to enhance the appropriate, safe, and effective approaches to adrenalectomy., Evidence Review: A multidisciplinary panel identified and investigated 7 categories of relevant clinical concern to practicing surgeons. Questions were structured in the framework Population, Intervention/Exposure, Comparison, and Outcome, and a guided review of medical literature from PubMed and/or Embase from 1980 to 2021 was performed. Recommendations were developed using Grading of Recommendations, Assessment, Development and Evaluation methodology and were discussed until consensus, and patient advocacy representation was included., Findings: Patients with an adrenal incidentaloma 1 cm or larger should undergo biochemical testing and further imaging characterization. Adrenal protocol computed tomography (CT) should be used to stratify malignancy risk and concern for pheochromocytoma. Routine scheduled follow-up of a nonfunctional adrenal nodule with benign imaging characteristics and unenhanced CT with Hounsfield units less than 10 is not suggested. When unilateral disease is present, laparoscopic adrenalectomy is recommended for patients with primary aldosteronism or autonomous cortisol secretion. Patients with clinical and radiographic findings consistent with adrenocortical carcinoma should be treated at high-volume multidisciplinary centers to optimize outcomes, including, when possible, a complete R0 resection without tumor disruption, which may require en bloc radical resection. Selective or nonselective α blockade can be used to safely prepare patients for surgical resection of paraganglioma/pheochromocytoma. Empirical perioperative glucocorticoid replacement therapy is indicated for patients with overt Cushing syndrome, but for patients with mild autonomous cortisol secretion, postoperative day 1 morning cortisol or cosyntropin stimulation testing can be used to determine the need for glucocorticoid replacement therapy. When patient and tumor variables are appropriate, we recommend minimally invasive adrenalectomy over open adrenalectomy because of improved perioperative morbidity. Minimally invasive adrenalectomy can be achieved either via a retroperitoneal or transperitoneal approach depending on surgeon expertise, as well as tumor and patient characteristics., Conclusions and Relevance: Twenty-six clinically relevant and evidence-based recommendations are provided to assist surgeons with perioperative adrenal care.

Introduction: Malignant struma ovarii (MSO) is a rare thyroid cancer arising within an ovarian teratoma. While surgical excision of the primary tumor is widely accepted as standard of care, recommendations for adjuvant treatment of MSO-whether or not to administer radioactive iodine (RAI)-are based largely on case reports and remain debated. In this study, we aimed to propose a risk stratification and analyze RAI utilization patterns in MSO cases. Methods: The National Cancer Database (NCDB) was queried for patients with MSO between 2004 and 2016. Demographic, oncological, and clinicopathologic data were compared between groups using Fisher's exact test. Kaplan-Meier curves were used to estimate overall survival (OS), and variables associated with OS were assessed via univariate Cox regression. We adapted the 2015 American Thyroid Association risk guidelines for MSO patients. We stratified patients into low-, intermediate-, and high-risk groups using metastasis, extraovarian extension, lymphovascular invasion, lymph node status, surgical margins, tumor size, and grade. Risk stratification, demographic, oncological, and clinicopathologic data were compared between the groups receiving and not receiving RAI therapy. We then queried the Surveillance, Epidemiology, and End Results (SEER) 18 registry for patients with MSO between 2000 and 2018 to confirm our risk stratification analysis. Results: In the NCDB analysis, a total of 158 patients were identified, and 19 received RAI. RAI therapy was associated with distant metastasis ( p  = 0.005) and lymph node status ( p  = 0.012). Twenty-one NCDB patients were stratified as high risk, and 30% of high-risk patients received RAI. High-risk stratification was associated with decreased OS via univariate Cox regression (hazard ratio = 4.0 [95% confidence interval 1.11-14.26], p  = 0.034). In our subsequent analysis using the SEER registry, there were 95 MSO patients, and 18 received RAI. Again, the majority of high-risk patients did not receive RAI, with only 41% of high-risk patients receiving RAI. Conclusions: MSO is a rare malignancy with apparently variable and inconsistent patterns of postoperative RAI administration. The risk stratification described here provides a framework to identify patients potentially at risk for mortality, and utilization of RAI in this group should be studied further.

Background: Hiatal hernia re-approximation during index anti-reflux surgery (ARS) contributes approximately 80% of overall change in distensibility index (DI) and, potentially, compliance of the gastroesophageal (GEJ), while sphincter augmentation contributes approximately 20%. Whether this is seen in re-operative ARS is unclear. We quantify the physiologic parameters of the GEJ at each step of robotic re-operative ARS and compare these to index ARS., Methods: Robotic ARS with hiatal hernia repair was performed on 195 consecutive patients with pathologic reflux utilizing EndoFLIP™, of which 26 previously had ARS. Intra-operative GEJ measurements, including cross-sectional area (CSA), pressure, DI, and high-pressure zone (HPZ) length were collected pre-repair, post-diaphragmatic re-approximation, post-mesh placement, and post-lower-esophageal sphincter (LES) augmentation., Results: Both cohorts were similar by sex and BMI and underwent similar procedures. The re-operative cohort was older (60.6 ± 15.3 vs. 52.7 ± 16.2 years, p = 0.03), had more frequent pre-operative dysphagia (69.2% vs. 42.6%, p = 0.01) and esophageal dysmotility on barium swallow (75.0% vs. 35.0%, p < 0.001) but lower rates of hiatal hernia on endoscopy (30.8% vs. 68.7%, p < 0.001) compared to index procedures. Among the re-operative cohort, the CSA decreased by 34 (IQR - 80, - 15) mm 2 and DI 1.1 (IQR - 2.4, - 0.6) mm 2 /mmHg (both p < 0.001). Pressure increased by 11.2 (IQR 4.7, 14.9) mmHg and HPZ by 1.5 (1,2) cm (both p < 0.001). These changes were similar to those seen in index ARS. Diaphragmatic re-approximation contributed to a greater percentage of overall change to the GEJ than did the augmentation procedure, with 72% of the change in DI occurring during hiatal closure, similar to that seen during index ARS., Conclusions: During re-operative ARS, dynamic intra-operative monitoring can quantify the effects of each operative step on GEJ physiologic parameters. Diaphragmatic re-approximation appears to have a greater effect on GEJ physiology than does LES-sphincter augmentation during both index and re-operative ARS., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Anti-reflux surgery (ARS) has known long-term complications, including dysphagia, bloat, and flatulence, among others. The factors affecting the development of post-operative dysphagia are poorly understood. We investigated the correlation of intra-operative esophagogastric junction (EGJ) characteristics and procedure type with post-operative dysphagia following ARS., Methods: Robotic ARS was performed on 197 consecutive patients with pathologic reflux utilizing EndoFLIP™ technology. Intraoperative EGJ measurements including distensibility index (DI), cross-sectional area (CSA), and high-pressure zone (HPZ) length were collected. Dysphagia was assessed pre-operatively and at 3 months post-operatively., Results: The median pre-operative DI for all procedures was 2.6 (IQR 1.6-4.5) mm 2 /mmHg. There was no difference in post-operative DI between procedures [Hill: 0.9 (IQR 0.7-1.1) mm 2 /mmHg, Nissen: 1.0 (IQR 0.7-1.4) mm 2 /mmHg, Toupet: 1.2 (IQR 0.8-1.5) mm 2 /mmHg, Linx: 1.0 (IQR 0.7-1.2) mm 2 /mmHg, p = 0.24], whereas post-operative HPZ length differed by augmentation type [Hill: 3 (IQR 2.8-3) cm, Nissen: 3.5 (IQR 3-3.5) cm, Toupet: 3 (IQR 2.5-3.5) cm, Linx: 2.5 (IQR 2.5-3) cm, p = 0.032]. Eighty-nine patients (45.2%) had pre-operative dysphagia. Thirty-two patients (27.6%) reported any dysphagia at their 3-month post-operative visit and 12 (10.3%) developed new or worsening post-operative dysphagia [Hill: 2/18 (11.1%), Nissen: 2/35 (5.7%), Toupet: 4/54 (7.4%), Linx: 4/9 (44.4%), p = 0.006]. The median pre-operative and post-operative DI of patients who developed new or worsening dysphagia was 2.0 (IQR 0.9-3.8) mm 2 /mmHg and 1.2 (IQR 1.0-1.8) mm 2 /mmHg, respectively, and that of those who did not was 2.5 (IQR 1.6-4.0) mm 2 /mmHg and 1.0 (IQR 0.7-1.4) mm 2 /mmHg (p = 0.21 and 0.16, respectively)., Conclusions: Post-operative DI was similar between procedures, and there was no correlation with new or worsening post-operative dysphagia. Linx placement was associated with higher rates of new or worsening post-operative dysphagia despite a shorter post-procedure HPZ length and similar post-operative DI when compared to other methods of LES augmentation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Thyroid autoimmunity is common in papillary thyroid carcinoma (PTC) and was believed to confer a better prognosis; however, controversy still remains. This study aimed to investigate the prognostic value of chronic lymphocytic thyroiditis (CLT) and preoperative thyroid peroxidase antibody (TPOAb) in PTC patients., Methods: A retrospective analysis was performed on 5,770 PTC patients who underwent surgical treatment with pathologically confirmed PTC in our institution between 2012 to 2016. The patients were divided into groups with respect to the coexistence of CLT or preoperative TPOAb levels. The clinicopathological characteristics and disease-free survival (DFS) rates were compared between the groups., Results: The coexistence of CLT was likely to have bilateral, multifocal tumors. Particularly, PTC patients with TPOAb++ (>1,000 IU/L) had a larger tumor size ( p = 0.007) and higher rates of bilaterality and multifocality than those with TPOAb- (TPOAb< 100 IU/L), while for lymph node metastasis and extrathyroidal extension, there is no statistical difference. Tumor recurrence was found in 15 of 425 (3.5%), 9 of 436 (2.1%), and 56 of 3,519 (1.6%) patients with TPOAb++, TPOAb+, and TPOAb-, respectively ( p = 0.017). On univariate analysis, TPOAb++ was correlated with tumor recurrence, with a hazard ratio of 2.20 [95% confidence interval (CI), 1.25-3.89], which remained as an independent risk factor at 1.98 (95% CI, 1.10-3.55) on multivariate analysis. PTC patients with TPOAb++ had the lowest DFS rates (96.5 vs. 97.9 vs. 98.4%, p = 0.020)., Conclusion: CLT is not a protective factor in PTC patients. We provide initial evidence that the preoperative TPOAb instead predicts recurrence in papillary thyroid carcinoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Wen, Chen, Su, Mao, Ding, Chen, Chen, Ruan, Yang, Zhou, Teng, Fahey, Li and Teng.)

Background : Ultrasound (US)-guided fine needle aspiration (FNA) cytology is the gold standard for the evaluation of thyroid nodules. However, up to 30% of FNA results are indeterminate, requiring further testing. In this study, we present a machine-learning analysis of indeterminate thyroid nodules on ultrasound with the aim to improve cancer diagnosis. Methods : Ultrasound images were collected from two institutions and labeled according to their FNA (F) and surgical pathology (S) diagnoses [malignant (M), benign (B), and indeterminate (I)]. Subgroup breakdown (FS) included: 90 BB, 83 IB, 70 MM, and 59 IM thyroid nodules. Margins of thyroid nodules were manually annotated, and computerized radiomic texture analysis was conducted within tumor contours. Initial investigation was conducted using five-fold cross-validation paradigm with a two-class Bayesian artificial neural networks classifier, including stepwise feature selection. Testing was conducted on an independent set and compared with a commercial molecular testing platform. Performance was evaluated using receiver operating characteristic analysis in the task of distinguishing between malignant and benign nodules. Results: About 1052 ultrasound images from 302 thyroid nodules were used for radiomic feature extraction and analysis. On the training/validation set comprising 263 nodules, five-fold cross-validation yielded area under curves (AUCs) of 0.75 [Standard Error (SE) = 0.04; P < 0.001 ] and 0.67 (SE = 0.05; P = 0.0012 ) for the classification tasks of MM versus BB, and IM versus IB, respectively. On an independent test set of 19 IM/IB cases, the algorithm for distinguishing indeterminate nodules yielded an AUC value of 0.88 (SE = 0.09; P < 0.001 ), which was higher than the AUC of a commercially available molecular testing platform (AUC = 0.81, SE = 0.11; P < 0.005 ). Conclusion: Machine learning of computer-extracted texture features on gray-scale ultrasound images showed promising results classifying indeterminate thyroid nodules according to their surgical pathology., (© 2022 Society of Photo-Optical Instrumentation Engineers (SPIE).)

Background: It is unclear if different genetic drivers in papillary thyroid cancer (PTC) confer different phenotypic tumor behavior leading to more aggressive disease. We hypothesized that RET-driven cancers are more aggressive., Patients and Methods: We reviewed records of consecutive patients treated for newly diagnosed PTC at this single institution from 2015 to 2016. Tumor samples from these patients were genotyped to identify RET-translocated, BRAF V600E mutant, and HRAS, KRAS, and NRAS mutant tumors. Patient demographic, clinicopathologic, and outcomes data were compared to identify genotype-specific patterns of disease., Results: Of the 327 patients who underwent initial surgery for PTC during the study period, 192 (58.7%) had BRAF V600E mutant tumors (BRAF), 14 (4.3%) had RET-rearranged tumors (RET), 46 (14.1%) had RAS mutant tumors (RAS), and 75 (22.9%) had BRAF, RET, and RAS wildtype tumors. RET-driven tumors were more likely to have extrathyroidal extension (50.0% versus 27.0% for BRAF and 2.2% for RAS, P < 0.001), multifocal disease (85.7% versus 60.3%, and 44.4%, respectively, P = 0.017), and distant metastases (14.3% versus 1.1%, and 0%, respectively, P = 0.019). RET and BRAF patients also had worse disease-free survival than RAS patients (Kaplan-Meier log rank, P = 0.027)., Conclusions: Patients with RET-driven PTCs had higher rates of extrathyroidal extension, multifocal disease, and distant metastases than patients whose tumors had BRAF V600E or RAS mutations. Patients with RET-rearranged tumors had similar disease-free survival to patients with BRAF V600E mutant tumors. RET rearrangement may confer an aggressive phenotype in PTC., (© 2022. Society of Surgical Oncology.)

Objective: We aimed to quantify the contribution of pneumoperitoneum on compliance of the esophagogastric junction (EGJ) during anti-reflux surgery., Background: Compliance of the EGJ is reduced with anti-reflux surgery. EndoFLIP® planimetry can be used to assess dynamic changes of EGJ compliance intraoperatively. It is unclear how pneumoperitoneum impacts intraoperative measurements by EndoFLIP® and the implications thereof on validity of the results. Therefore, determining variability in EndoFLIP® measurements based on pneumoperitoneum is warranted to establish guidelines to interpret clinical outcomes., Methods: Primary anti-reflux surgery was performed on 39 consecutive patients with pathologic reflux. Intraoperative EGJ measurements including distensibility index (DI), cross-sectional area (CSA), and intrabag pressure were collected using EndoFLIP® at 0, 10, and 15 mmHg of intraperitoneal pressure. Data were acquired pre-procedure, post-hiatal hernia repair, and post-LES augmentation with fundoplications., Results: Patients underwent Nissen (13.2%), Toupet (68.4%), LINX (10.5%), or Hill-fundoplications (7.9%). There was no difference between 0 and 10 mmHg of pneumoperitoneum in CSA, pressure, or DI measurements pre-procedure; however, there was a difference between 0 and 15 mmHg in pressure (p = 0.016) and DI (p = 0.023) measurements. After LES augmentation, 10 mmHg intraperitoneal pressure reduced DI, though the absolute difference is small (2.0 vs. 1.5 mm 2 /mmHg, p = 0.002)., Conclusion: Pneumoperitoneum affected EGJ distensibility at 15 mmHg, but not 10 mmHg, of insufflation prior to anti-reflux procedures. After anti-reflux surgery, there was a significant variance between 0 and 10 mmHg of pneumoperitoneum in pressure and distensibility. The change in pressure appears linear and needs to be considered if procedural modifications are performed based on intraoperative findings and when evaluating clinical outcomes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: Disparities exist in access to high-volume surgeons, who have better outcomes after thyroidectomy. The association of the Affordable Care Act's Medicaid expansion with access to high-volume thyroid cancer surgery centers remains unclear., Methods: The National Cancer Database was queried for all adult thyroid cancer patients diagnosed from 2010 to 2016. Hospital quartiles (Q1-4) defined by operative volume were generated. Clinicodemographics and adjusted odds ratios for treatment per quartile were analyzed by insurance status. An adjusted difference-in-differences analysis examined the association between implementation of the Affordable Care Act and changes in payer mix by hospital quartile., Results: In total, 241,448 patients were included. Medicaid patients were most commonly treated at Q3-Q4 hospitals (Q3 odds ratios 1.05, P = .020, Q4 1.11, P < .001), whereas uninsured patients were most often treated at Q2-Q4 hospitals (Q2 odds ratios 2.82, Q3 2.34, Q4 2.07, P < .001). After expansion, Medicaid patients had lower odds of surgery at Q3-Q4 compared with Q1 hospitals (odds ratios Q3 0.82, P < .001 Q4 0.85, P = .002) in expansion states, but higher odds of treatment at Q3-Q4 hospitals in nonexpansion states (odds ratios Q3 2.23, Q4 1.86, P < .001). Affordable Care Act implementation was associated with increased proportions of Medicaid patients within each quartile in expansion compared with nonexpansion states (Q1 adjusted difference-in-differences 5.36%, Q2 5.29%, Q3 3.68%, Q4 3.26%, P < .001), and a decrease in uninsured patients treated at Q4 hospitals (adjusted difference-in-differences -1.06%, P = .001)., Conclusions: Medicaid expansion was associated with an increased proportion of Medicaid patients undergoing thyroidectomy for thyroid cancer in all quartiles, with increased Medicaid access to high-volume centers in expansion compared with nonexpansion states., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: We aimed to characterize the association between differentiated thyroid cancer (DTC) patient insurance status and appropriateness of therapy (AOT) regarding extent of thyroidectomy and radioactive iodine (RAI) treatment., Methods: The National Cancer Database was queried for DTC patients diagnosed between 2010 and 2016. Adjusted odds ratios (AOR) for AOT, as defined by the American Thyroid Association guidelines, and hazard ratios (HR) for overall survival (OS) were calculated. A difference-in-differences (DD) analysis examined the association of Medicaid expansion with outcomes for low-income patients aged <65., Results: A total of 224,500 patients were included. Medicaid and uninsured patients were at increased risk of undergoing inappropriate therapy, including inappropriate lobectomy (Medicaid 1.36, 95% confidence interval [CI]: 1.21-1.54; uninsured 1.30, 95% CI: 1.05-1.60), and under-treatment with RAI (Medicaid 1.20, 95% CI: 1.14-1.26; uninsured 1.44, 95% CI: 1.33-1.55). Inappropriate lobectomy (HR 2.0, 95% CI: 1.7-2.3, P < .001) and under-treatment with RAI (HR 2.3, 95% CI: 2.2-2.5, P < .001) were independently associated with decreased survival, while appropriate surgical resection (HR 0.3, 95% CI: 0.3-0.3, P < .001) was associated with improved odds of survival; the model controlled for all relevant clinico-pathologic variables. No difference in AOT was observed in Medicaid expansion versus non-expansion states with respect to surgery or adjuvant RAI therapy., Conclusion: Medicaid and uninsured patients are at significantly increased odds of receiving inappropriate treatment for DTC; both groups are at a survival disadvantage compared with Medicare and those privately insured., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Accurate self-assessment of knowledge and technical skills is key to self-directed education required in surgical training. We aimed to investigate the presence and magnitude of cognitive bias in self-assessment among a cohort of surgical interns., Methods: First-year general surgery residents self-assessed performance on a battery of technical skill tasks (knot tying, suturing, vascular anastomosis, Fundamentals of Laparoscopic Skills peg transfer and intracorporeal suturing) at the beginning of residency. Each self-assessment was compared to actual performance. Bias and deviation were defined as arithmetic and absolute difference between actual and estimated scores. Spearman correlation assessed covariation between actual and estimated scores. Improvement in participant performance was analyzed after an end-of-year assessment., Results: Participants (N = 34) completed assessments from 2017 to 2019. Actual and self-assessment scores were positively correlated (0.55, P < .001). Residents generally underestimated performance (bias -4.7 + 8.1). Participants who performed above cohort average tended to assess themselves more negatively (bias -7.3 vs -2.3) and had a larger discrepancy between self and actual scores than below average performers (deviation index 9.7 + 8.2 vs 3.8 + 3.1, P < .05). End-of-year total scores improved in 31 (91.2%) participants by an average of 11 points (90 possible). Least accurate residents in initial self-assessments (deviation indices >75th percentile) improved less than more accurate residents (median 5 vs 16 points, P < .05). All residents with a deviation index >75 percentile underestimated their performance., Conclusion: Cognitive bias in technical surgical skills is apparent in first-year surgical residents, particularly in those who are higher performers. Inaccuracy in self-assessment may influence improvement and should be addressed in surgical training., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: We aimed to clarify whether aggressive histology of papillary thyroid cancer (PTC) impacts overall survival (OS)., Summary Background Data: Aggressive variants of PTC (AVPTC) are associated with invasive features. However, their behavior in the absence of these features is not well characterized., Methods: Patients treated from 2004 to 2015 for classic PTC (cPTC) or AVPTCs were identified from the National Cancer Database. Patients were further stratified based on presence of at least 1 invasive feature-extrathyroidal extension, multifocality, lymphovascular invasion, nodal or distant metastasis. Demographics, treatments, and OS were compared., Results: A total of 170,778 patients were included-162,827 cPTC and 7951 AVPTC. Invasive features were more prevalent in AVPTC lesions compared to cPTC (70.7% vs 59.7%, P < 0.001). AVPTC included tall cell/columnar cell (89.5%) and diffuse sclerosing (10.5%) variants. Patients with invasive features had worse OS irrespective of histology. Furthermore, when controlling for demographics, tumor size, and treatment variables in patients with noninvasive lesions, AVPTC histology alone was not associated with worse OS compared to cPTC (P = 0.209). In contrast, among patients who had at least 1 invasive feature, AVPTC histology was independently predictive of worse OS (P < 0.05) {TCV/Columnar hazard ratio [HR] 1.2; [95% confidence interval (CI) 1.1-1.3] and diffuse sclerosing HR 1.3; 95% CI 1.0-1.7]}. All invasive features, except multifocality, were independently associated with worse OS, with metastasis being the most predictive [HR 2.9 (95% CI 2.6-3.2) P < 0.001]., Conclusions: In the absence of invasive features, AVPTC histology has similar OS compared to cPTC. In contrast, diffuse sclerosing and tall cell/columnar variants are associated with worse OS when invasive features are present., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Laparoscopic adrenalectomy is known to have a low complication rate; however, the influence of functional tumor subtype on postoperative outcomes is not well defined., Methods: Patients undergoing laparoscopic adrenalectomy for benign adrenal tumors between 2009 and 2017 were selected from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. Patient demographics, postoperative outcomes, and length of stay were compared between tumor subtypes., Results: A total of 3946 patients underwent a laparoscopic adrenalectomy during the study period; 3214 (81.5%) were performed for non-functional adenomas, and 732 (18.6%) for functional tumors-467 (64%) aldosteronomas, 184 (25%) cortisol-producing adenomas, and 81 (11%) pheochromocytomas. The risk of any complication was highest for patients with Cushing's (6.5%) and lowest with Conn's syndrome (1.1%) compared to other lesions (3.7% pheochromocytoma, 5.3% adenoma, p < 0.001). Among the patients with functional tumors, those with cortisol-producing adenomas had the highest rates of both deep surgical site infection (1.6%, p = 0.026) and urinary tract infection (2.2%, p = 0.029), whereas myocardial infarction was most prevalent in patients with pheochromocytoma (2.5%, p = 0.012). When adjusted for demographic differences, BMI, and comorbidity scores, no tumor type was associated with increased complication rate; instead aldosteronoma (vs. benign adenoma) was independently predictive of fewer adverse events [0.3 (95% CI 0.1-0.7), p = 0.004] and a shorter length of hospital stay [0.6 (95% CI 0.4-0.8), p = 0.001]. The overall mortality rate was low at 0.4%, although significantly higher in Cushing's patients (2.2%, p = 0.015)., Conclusions: Laparoscopic adrenalectomy is a safe operation with low mortality and complication rates. However, postoperative risks differ between tumor subtype, so patients should be counseled accordingly.

Risk assessment is critical to determine the timing of elective surgeries and preserve valuable resources in time of pandemic. This study was undertaken to better understand the potential value of molecular testing to risk-stratify thyroid nodules with malignant cytology (Bethesda VI). Systematic review of the literature contributed 21 studies representing 2036 preoperative specimens. The BRAF p.V600E substitution was detected in 46% to 90% of cases with a pooled positivity rate of 70% (95% confidence intervals: 64%-76%). None of the studies used comprehensive oncogene panels. Retrospective analysis of 531 clinical specimens evaluated with the next-generation sequencing ThyGeNEXT Thyroid Oncogene Panel identified a total of 436 gene alterations. BRAF mutation rate was 64% in specimens tested as part of standard clinical care and 75% in specimens from cross-sectional research studies (P = .022). Testing for additional actionable gene alterations such as TERT promoter mutations or RET and NTRK gene rearrangements further increased the diagnostic yield to 78%-85% and up to 95% when including the ThyraMIR Thyroid miRNA Classifier. These data support the role of molecular cytopathology in surgical and therapeutic decision-making and warrant additional studies., (© 2020 The Authors. Diagnostic Cytopathology published by Wiley Periodicals LLC.)

Importance: Adrenal venous sampling is recommended prior to adrenalectomy for all patients with hyperaldosteronism; however, cross-sectional imaging resolution continues to improve, while the procedure remains invasive and technically difficult. Therefore, certain patients may benefit from advancing straight to surgery., Objective: To determine whether clinical and biochemical resolution varied for patients with primary aldosteronism with unilateral adenomas who underwent adrenal venous sampling vs those who proceeded to surgery based on imaging alone., Design, Setting, and Participants: Retrospective, international cohort study of patients treated at 3 tertiary medical centers from 2004 to 2019, with a median follow-up of approximately 6 months. A total of 217 patients were consecutively enrolled. Exclusion criteria consisted of unknown postoperative serum aldosterone level and imaging inconsistent with unilateral adenoma with a normal contralateral gland. A total of 125 patients were included in the analysis. Data were analyzed between October 2019 and July 2020., Exposures: Adrenal venous sampling performed preoperatively., Main Outcomes and Measures: The primary outcome measurements were the clinical and biochemical success rates of surgery for the cure of hyperaldosteronism secondary to aldosterone-producing adenoma., Results: A total of 125 patients were included (45 cross-sectional imaging with adrenal venous sampling and 80 imaging only). The mean (SD) age of the study participants was 50.2 (10.6) years and the cohort was 42.4% female (n = 53). Of those patients for whom race or ethnicity were reported (n = 80), most were White (72.5%). Adrenal venous sampling failure rate was 16.7%, and the imaging concordance rate was 100%. Relevant preoperative variables were similar between groups, except ambulatory systolic blood pressure, which was higher in the imaging-only group (150 mm Hg; interquartile range [IQR], 140-172 mm Hg vs 143 mm Hg, IQR, 130-158 mm Hg; P = .03). Resolution of autonomous aldosterone secretion was attained in 98.8% of imaging-only patients and 95.6% of adrenal venous sampling patients (P = .26). There was no difference in complete clinical success (43.6% [n = 34] vs 42.2% [n = 19]) or partial clinical success (47.4% [n = 37] vs 51.1% [n = 23]; P = .87) between groups. Complete biochemical resolution was similar as well (75.9% [n = 41] vs 84.4% [n = 27]; P = .35). There was no difference in clinical or biochemical cure rates when stratified by age, although complete clinical success rates downtrended in the older cohorts, and sample sizes were small., Conclusions and Relevance: Given the improved sensitivity of cross-sectional imaging in detection of adrenal tumors, adrenal venous sampling may be selectively performed in appropriate patients with clearly visualized unilateral adenomas without affecting outcomes. This may facilitate increased access to surgical cure for aldosterone-producing adenomas and will decrease the incidence of morbidities associated with the procedure.

Background: This study aimed to identify whether multikinase inhibitor approval for medullary thyroid carcinoma was associated with changes in systemic therapy administration or overall survival., Methods: The National Cancer Database was queried for advanced medullary thyroid carcinoma patients. Clinicopathologic comparisons were performed between premultikinase inhibitor (2005-2010) and postmultikinase inhibitor (2011-2016) approval groups. Multivariable logistic and Cox regressions were applied to assess predictors of systemic therapy and overall survival., Results: A total of 2,891 patients met the criteria. Postmultikinase inhibitor patients were less likely to undergo radiation (P = .02) and more likely to receive systemic therapy (P = .01). The rate of systemic therapy nearly doubled from 2010 to 2011 (8.1% to 13.8%, P = .04); it subsequently declined back toward preapproval rates. Before multikinase inhibitor approval, only metastases and radiation were associated with systemic therapy (P < .05). After multikinase inhibitor approval, patients with small tumors, extrathyroidal extension, positive lymph nodes, or metastases were more likely to receive systemic therapy (P < .05). The 5-year overall survival between pre and postmultikinase inhibitor groups, for those who received systemic therapy (n = 288), was similar (P = .58), even when restricted to patients with distant metastases (P = .55)., Conclusion: After approval of multikinase inhibitors, physicians broadened the criteria for systemic therapy. Prescription rates have since declined. Given the toxicities of these drugs and no improvement in overall survival since introduction, selective utilization may be warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: We aimed to compare the predictive performance of three distinct clinical models purported to predict the resolution of aldosteronoma-associated hypertension after adrenalectomy., Methods: A tri-institutional database of aldosteronoma patients who underwent adrenalectomy between 2004 and 2019 was retrospectively reviewed. The three models of interest incorporate various preoperative clinical factors, such as age and sex. The predictive accuracy, as measured by area under the curve of receiver operator characteristic, was estimated. Receiver operator characteristic was evaluated across the whole cohort, then stratified by treatment location., Results: A total of 200 patients were included (91 American, 109 French). The clinicodemographic variables between groups were similar; the French cohort had a lower mean body mass index (P = .02). The overall complete clinical resolution of hypertension after adrenalectomy for the entire data set was 45.5% (n = 91). The regression coefficients in the Utsumi et al (2014) Japanese model produced a superior overall area under the curve (0.78, 95% confidence interval [CI] [0.71-0.84]). This model also performed best when the cohort was stratified by treatment location (French area under the curve = 0.74, 95% CI [0.64-0.83], US area under the curve = 0.82, 95% CI [0.72-0.91])., Conclusion: When comparing three predictive models of aldosteronoma-associated hypertension resolution after adrenalectomy, the Utsumi et al model demonstrated the highest predictive validity across all cohorts. Counseling based on this model regarding probability of cure is recommended., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The routine use of external beam radiotherapy (EBRT) is not recommended for parathyroid carcinoma (PC). However, case series have demonstrated a potential benefit in preventing local recurrence with EBRT. We aimed to characterize the patient population treated with EBRT and identify any impact of EBRT on overall survival (OS) in parathyroid carcinoma., Methods: Patients who underwent surgery for PC from 2004 to 2016 were identified from the National Cancer Database. Clinicopathologic variables and OS were compared between patients based on treatment with EBRT. Multivariable logistic and Cox regression models were performed with propensity scores and inverse-probability-weighting (IPW) adjustment to reduce treatment-selection bias in the OS analysis., Results: A total of 885 patients met the inclusion criteria, with 126 (14.2%) undergoing EBRT. Demographics were similar between the two cohorts (EBRT vs. no EBRT). However, patients treated with EBRT had a higher frequency of regionally extensive disease, nodal metastases, and residual microscopic disease (all p < 0.05). On multivariable analysis, Black race, regional tumor extension, nodal metastasis, and treatment at an urban facility were independently associated with EBRT. The 5-year OS was 85.3% with a median follow-up of 60.8 months. EBRT was not associated with a difference in OS in crude, multivariable, or IPW models. More importantly, 10.5% of patients with completely resected localized disease (M0, N0 or Nx) underwent EBRT without a benefit in OS (p = 0.183)., Conclusions: EBRT is not associated with any survival benefit in the treatment of PC. Therefore, it may be overutilized, particularly in patients with localized disease and complete surgical resection.

Background: Indoleamine 2,3-dioxygenase 1 (IDO-1) is overexpressed in many human carcinomas and a successful target for therapy in mouse models. Prognosis of patients with advanced adrenocortical carcinoma (ACC) is poor due to the lack of effective treatments, and new therapies are therefore needed. Herein, we investigate whether IDO-1 is expressed in human ACC tissues., Methods: 53 tissue samples from patients with ACC, adrenal adenoma (AA), adrenocortical tumors (ACTs), and normal adrenal were identified. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded slides for IDO-1. Samples were scored for cytoplasmic staining as per intensity and the percent of positive cells and for stromal staining by percent of positive cells. Tumor characteristics, PD-L1, PDL-2, and CD-8+ T-lymphocyte expression were also determined., Results: Samples from 32 ACC, 3 ACT, 15 AA, and 3 normal adrenal were analyzed. IDO-1 was expressed in tumor tissue in 22 of 32 ACC samples, compared with 8 of 15 AA sample (P = 0.344). IDO-1 expression was significantly increased in stromal tissue of ACC samples (16 of 33), compared with AA samples (0 of 15) (P = 0.001). IDO-1 expression in ACC and AA samples was associated with PD-L2 expression (P = 0.034). IDO-1 expression in ACC stromal tissue was associated with CD8+ T-lymphocyte infiltration (P = 0.028)., Conclusions: IDO-1 is expressed in a majority of ACC samples. Its expression in tumor tissue is associated with PD-L2 expression, and expression in stroma is associated with CD8+ cell infiltration. IDO-1 inhibition, alone or in combination with PD-1 inhibition, could therefore be an interesting target in treatment of ACC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Advanced thyroid cancers, including poorly differentiated and anaplastic thyroid cancer (ATC), are lethal malignancies with limited treatment options. The majority of patients with ATC have responded poorly to programmed death 1 (PD1) blockade in early clinical trials. There is a need to explore new treatment options., Experimental Design: We examined the expression of PD-L1 (a ligand of PD1) and intercellular adhesion molecule 1 (ICAM1) in thyroid tumors and ATC cell lines, and investigated the PD1 expression level in peripheral T cells of patients with thyroid cancer. Next, we studied the tumor-targeting efficacy and T-cell dynamics of monotherapy and combination treatments of ICAM1-targeting chimeric antigen receptor (CAR) T cells and anti-PD1 antibody in a xenograft model of ATC., Results: Advanced thyroid cancers were associated with increased expression of both ICAM1 and PD-L1 in tumors, and elevated PD1 expression in CD8 + T cells of circulating blood. The expression of ICAM1 and PD-L1 in ATC lines was regulated by the IFNγ-JAK2 signaling pathway. ICAM1-targeted CAR T cells, produced from either healthy donor or patient T cells, in combination with PD1 blockade demonstrated an improved ability to eradicate ICAM1-expressing target tumor cells compared with CAR T treatment alone. PD1 blockade facilitated clearance of PD-L1 high tumor colonies and curtailed excessive CAR T expansion, resulting in rapid tumor clearance and prolonged survival in a mouse model., Conclusions: Targeting two IFNγ-inducible, tumor-associated antigens-ICAM1 and PD-L1-in a complementary manner might be an effective treatment strategy to control advanced thyroid cancers in vivo ., (©2020 American Association for Cancer Research.)