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A subset of thyroid cancers, recurrent differentiated thyroid cancers and anaplastic thyroid cancer (ATC), are difficult to treat by thyroidectomy and systemic therapy. A common mutation in thyroid cancer, BRAFV600E, has targetable treatment options; however, the results have been disappointing in thyroid cancers compared with BRAFV600E melanoma, as thyroid cancers quickly become resistant to BRAFV600E inhibitor (BRAFi). Here, we studied the molecular pathway that is induced in BRAFV600E thyroid cancer cells and patient-derived tumor samples in response to BRAFi, vemurafenib, using RNA-sequencing and molecular analysis. Both inducible response to BRAFi and acquired BRAFi resistance in BRAFV600E thyroid cancer cells showed significant activation of the JAK/STAT pathway. Functional analyses revealed that the combination of BRAFi and inhibitors of JAK/STAT pathway controlled BRAFV600E thyroid cancer cell growth. The Cancer Genome Atlas data analysis demonstrated that potent activation of the JAK/STAT signaling was associated with shorter recurrence rate in patients with differentiated thyroid cancer. Analysis of tumor RNA expression in patients with poorly differentiated thyroid cancer and ATC also support that enhanced activity of JAK/STAT signaling pathway is correlated with worse prognosis. Our study demonstrates that JAK/STAT pathway is activated as BRAFV600E thyroid cancer cells develop resistance to BRAFi and that this pathway is a potential target for anticancer activity and to overcome drug resistance that commonly develops to treatment with BRAFi in thyroid cancer. Implications: Dual inhibition of BRAF and JAK/STAT signaling pathway is a potential therapeutic treatment for anticancer activity and to overcome drug resistance to BRAFi in thyroid cancer.

BackgroundThe 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.MethodsAmerican 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.ResultsTwelve 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, χ2= 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).ConclusionAlthough 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.

ImportanceAdrenalectomy 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.ObjectiveTo develop evidence-based recommendations to enhance the appropriate, safe, and effective approaches to adrenalectomy.Evidence ReviewA 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.FindingsPatients 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 RelevanceTwenty-six clinically relevant and evidence-based recommendations are provided to assist surgeons with perioperative adrenal care.

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.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, BRAFOf the 327 patients who underwent initial surgery for PTC during the study period, 192 (58.7%) had BRAFPatients with RET-driven PTCs had higher rates of extrathyroidal extension, multifocal disease, and distant metastases than patients whose tumors had BRAF

S1. BRAFV600E mutation identified in thyroid cancer cell lines analyzed by RNA-seq.S2. STR analysis in thyroid cancer cell lines used in this study.S3. Gene expression of thyroid-specific genes in thyroid cancer cell lines analyzed by RNA-seq.S4. Dose-dependent toxicity of vemurafenib in BRAFV600E thyroidcancer cells.S5. Vemurafenib dose-dependent curves of vemurafenib-resistantBRAFV600E thyroid cancer cells.S6. Vemurafenib induces apoptosis in 8505C cells.S7. Predicted activators and inhibitors in Vem-resistant BRAF mutant thyroid cancer cells.

Supplementary Table 1. Gene expression changes in 8505C after vemurafenib treatment.Supplementary Table 2. Gene expression changes in WRO after vemurafenib treatment.Supplementary Table 3. Gene expression changes in 8505C -Vem-Res 1 relative to parental 8505C.Supplementary Table 4. Gene expression changes in WRO -Vem-Res 6 relative to parental WRO.Supplementary Table 5. Clinical features of thyroid tumors used in Fig. 5.

A subset of thyroid cancers, recurrent differentiated thyroid cancers and anaplastic thyroid cancer (ATC), are difficult to treat by thyroidectomy and systemic therapy. A common mutation in thyroid cancer, BRAFV600E, has targetable treatment options; however, the results have been disappointing in thyroid cancers compared with BRAFV600E melanoma, as thyroid cancers quickly become resistant to BRAFV600E inhibitor (BRAFi). Here, we studied the molecular pathway that is induced in BRAFV600E thyroid cancer cells and patient-derived tumor samples in response to BRAFi, vemurafenib, using RNA-sequencing and molecular analysis. Both inducible response to BRAFi and acquired BRAFi resistance in BRAFV600E thyroid cancer cells showed significant activation of the JAK/STAT pathway. Functional analyses revealed that the combination of BRAFi and inhibitors of JAK/STAT pathway controlled BRAFV600E thyroid cancer cell growth. The Cancer Genome Atlas data analysis demonstrated that potent activation of the JAK/STAT signaling was associated with shorter recurrence rate in patients with differentiated thyroid cancer. Analysis of tumor RNA expression in patients with poorly differentiated thyroid cancer and ATC also support that enhanced activity of JAK/STAT signaling pathway is correlated with worse prognosis. Our study demonstrates that JAK/STAT pathway is activated as BRAFV600E thyroid cancer cells develop resistance to BRAFi and that this pathway is a potential target for anticancer activity and to overcome drug resistance that commonly develops to treatment with BRAFi in thyroid cancer.Implications:Dual inhibition of BRAF and JAK/STAT signaling pathway is a potential therapeutic treatment for anticancer activity and to overcome drug resistance to BRAFi in thyroid cancer.

Purpose: Indeterminate thyroid lesions on fine needle aspiration (FNA) harbor malignancy in about 25% of cases. Hemi- or total thyroidectomy has, therefore, been routinely advocated for definitive diagnosis. In this study, we analyzed miRNA expression in indeterminate FNA samples and determined its prognostic effects on final pathologic diagnosis.Experimental Design: A predictive model was derived using 29 ex vivo indeterminate thyroid lesions on FNA to differentiate malignant from benign tumors at a tertiary referral center and validated on an independent set of 72 prospectively collected in vivo FNA samples. Expression levels of miR-222, miR-328, miR-197, miR-21, miR-181a, and miR-146b were determined using reverse transcriptase PCR. A statistical model was developed using the support vector machine (SVM) approach.Results: A SVM model with four miRNAs (miR-222, miR-328, miR-197, and miR-21) was initially estimated to have 86% predictive accuracy using cross-validation. When applied to the 72 independent in vivo validation samples, performance was actually better than predicted with a sensitivity of 100% and specificity of 86%, for a predictive accuracy of 90% in differentiating malignant from benign indeterminate lesions. When Hurthle cell lesions were excluded, overall accuracy improved to 97% with 100% sensitivity and 95% specificity.Conclusions: This study shows that that the expression of miR-222, miR-328, miR-197, and miR-21 combined in a predictive model is accurate at differentiating malignant from benign indeterminate thyroid lesions on FNA. These findings suggest that FNA miRNA analysis could be a useful adjunct in the management algorithm of patients with thyroid nodules. Clin Cancer Res; 18(7); 2032–8. ©2012 AACR.

A model for ICAM1-CAR T and anti-PD1 antibody activities in advanced thyroid cancers.

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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.

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Figure S1. PTCs with BRAFV600E mutations are associated with ICAM-1 Overexpression; Figure S2. Tumor tissue morphology in ATC patients.; Figure S3. ICAM-1-overexpressing ATC cell lines are more proliferative.; Figure S4. ICAM-1 CAR T cell phenotype characterization; Figure S5. Validation of ICAM-1 CAR T cells used in vivo experiments.; Figure S6. Organ weight changes in ATC xenografted mice after ICAM-1 CAR T treatment.; Figure S7. CAR T cells in ICAM-1 CAR T treated and ATC xenografts.; Figure S8. Establishment of ATC patient-derived xenografts.; Figure S9. CAR T activity is detectable throughout the body.; Figure S10. Correlation between ICAM-1 overexpression in TCGA cancer patient tumor tissues and overall survival.

Expression of ICAM1 and PD-L1 in anaplastic thyroid tumor cell lines.

PD1 inhibition enhances survival benefit of CAR T treatment in KHM-5M xenografts.

Purpose: Poorly differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors, including papillary thyroid cancer (PTC) and ATC, are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1–targeting agents for the treatment of aggressive cancer. We developed a third-generation chimeric antigen receptor (CAR) targeting ICAM-1 to leverage adoptive T-cell therapy as a new treatment modality.Experimental Design: ICAM-1 CAR T cells were applied to multiple malignant and nonmalignant target cells to investigate specific target cell death and “off-tumor” toxicity in vitro. In vivo therapeutic efficacy of ICAM-1 CAR T cells was examined in ATC mouse models established from a cell line and patient-derived tumors that rapidly develop systemic metastases.Results: ICAM-1 CAR T cells demonstrated robust and specific killing of PTC and ATC cell lines in vitro. Interestingly, although certain ATC cell lines showed heterogeneous levels of ICAM-1 expression, addition of cytotoxic CAR T cells induced increased ICAM-1 expression such that all cell lines became targetable. In mice with systemic ATC, a single administration of ICAM-1 CAR T cells mediated profound tumor killing that resulted in long-term remission and significantly improved survival. Patient-derived ATC cells overexpressed ICAM-1 and were largely eliminated by autologous ICAM-1 CAR T cells in vitro and in animal models.Conclusions: Our findings are the first demonstration of CAR T therapy against both a metastatic, thyroid cancer cell line and advanced ATC patient-derived tumors that exhibit dramatic therapeutic efficacy and survival benefit in animal studies. Clin Cancer Res; 23(24); 7569–83. ©2017 AACR.

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.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 aged65.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.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.

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.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.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 indices75th percentile) improved less than more accurate residents (median 5 vs 16 points, P.05). All residents with a deviation index75 percentile underestimated their performance.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.

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.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.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.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.

We aimed to quantify the contribution of pneumoperitoneum on compliance of the esophagogastric junction (EGJ) during anti-reflux surgery. 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. 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. 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 mm2/mmHg, p = 0.002). 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.

This study aimed to identify whether multikinase inhibitor approval for medullary thyroid carcinoma was associated with changes in systemic therapy administration or overall survival.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.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).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.

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.

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.

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.

OBJECTIVE To quantify the contribution of key steps in antireflux surgery on compliance of the EGJ. BACKGROUND The lower esophageal sphincter and crural diaphragm constitute the intrinsic and extrinsic sphincters of the EGJ, respectively. Interventions to treat reflux attempt to restore the integrity of the EGJ. However, there are limited data on the relative contribution of critical steps during antireflux procedures to the functional integrity of the EGJ. METHODS Primary antireflux surgery was performed on 100 consecutive patients with pathologic reflux. Intraoperative EGJ measurements including distensibility index (DI), cross-sectional area (CSA), and HPZ length were collected using EndoFLIP. Data was acquired pre-repair, post-diaphragmatic re-approximation with sub-diaphragmatic EGJ relocation, and post-sphincter augmentation. RESULTS Patients underwent Nissen (45%), Toupet (44%), or LINX (11%). After diaphragmatic re-approximation, DI decreased by a median 0.77 mm2/mm Hg [95%-confidence interval (CI): -0.99, -0.58; P < 0.0001], CSA decreased 16.0 mm2 (95%-CI: -20.0, -8.0; P < 0.0001), whereas HPZ length increased 0.5 cm (95%-CI: 0.5, 1.0; P < 0.0001). After sphincter augmentation, DI decreased 0.14 mm2/mm Hg (95%-CI: -0.30, -0.04; P = 0.0005) and CSA decreased 5.0 mm2 (95%-CI: -10.0, 1.0; P = 0.0.0015), whereas HPZ length increased 0.5 cm (95%-CI: 0.50, 0.54; P < 0.0001). Diaphragmatic re-approximation had a higher percent contribution to distensibility (79% vs 21%), CSA (82% vs 18%), and HPZ (60% vs 40%) than sphincter augmentation. CONCLUSION Dynamic intraoperative monitoring demonstrates that diaphragmatic re-approximation and sub-diaphragmatic relocation has a greater effect on EGJ compliance than sphincter augmentation. As such, antireflux procedures should address both for optimal improvement of EGJ physiology.

Laparoscopic adrenalectomy is known to have a low complication rate; however, the influence of functional tumor subtype on postoperative outcomes is not well defined. 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. 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

Simulation assessments are not yet standardized among surgical programs. We instituted a 5-task simulation program to assess surgical technical skills longitudinally during internship.First-year residents completed 5 simulation tasks: suturing, knot-tying, vascular anastomosis, and the peg-transfer and the intracorporeal suturing of the Fundamentals of Laparoscopic Skills. Assessments occurred just before residency, mid-year, and at the completion of the intern year.This study involved 19 residents: 8 categorical, 4 urology, 3 interventional radiology, 2 plastics, and 2 non-designated preliminary interns. Mean completion times improved in both the Fundamentals of Laparoscopic Skills peg-transfer (145 ± 50, 111 ± 47, and 95 ± 28 seconds) and suturing (526 ± 92, 392 ± 131, and 351 ± 158 seconds; each P.001) tasks, and decreased variability was noted in the former. Total scores trended to improve (P = .013). Interns underwent similar training; 95% completed at least 1 core rotation by mid-year. Surgical specialty was associated with total scores during the first knot-tying session, with plastics residents scoring highest; however, all scores progressed toward the group median over time.Technical skills of beginning surgery residents were assessed longitudinally with the institution of a 5-task curriculum. Periodic assessments showed improvement in each task. Furthermore, as residents were exposed to equal surgical training, the variability in resident scores showed the greatest decrease in simpler motor tasks.

Objective:To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy.Background:Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in th

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; [Formula: see text]] and 0.67 (SE = 0.05; [Formula: see text]) 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; [Formula: see text]), which was higher than the AUC of a commercially available molecular testing platform (AUC = 0.81, SE = 0.11; [Formula: see text]). 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.