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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.

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.

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.

Do patient-reported outcome measures differ among clinical T4 patients undergoing mastectomy with and without reconstruction?Neither reconstruction nor timing of reconstruction were associated with superior outcomes for breast satisfaction, physical well-being of the chest, or psychosocial well-being at any timepoint.

When needle core biopsies (NCBs) of the breast reveal radial scar or complex sclerosing lesions (RSLs), excision is often recommended despite a low risk of malignancy in the modern era. The optimal management of NCBs revealing RSLs is controversial, and understanding of the natural history of unresected RSLs is limited. We retrospectively analyzed pathology and imaging data from 148 patients with NCB revealing RSL without atypia from 2015 to 2019 to determine the prevalence of malignancy and the behavior of RSLs undergoing active surveillance (AS). The mean age of patients was 52 years, and most lesions were screen-detected (91%). The median lesion size was 6.0 mm (range 2–39). Most patients (66%, n = 98) underwent immediate surgery, while 34% (n = 50) of patients underwent AS, with a median follow-up of 16 months (range 6–51). Of the excised RSLs, 99% (n = 97) were benign and 1% (n = 1) revealed ductal carcinoma in situ (DCIS). In 17% (n = 17) of cases, additional high-risk lesions were discovered upon excision. Among the 50 patients undergoing AS, no lesions progressed on interval imaging. In this cohort, 99% of RSLs undergoing excision were benign, 1% revealed DCIS, and there were no invasive cancers. In the first study of patients with RSLs undergoing AS, we found that all lesions either remained stable or resolved. We propose that the vast majority of patients with RSL on NCB can be safely offered AS, and that routine excision is a low-value intervention.

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.

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.

Background The majority of papillary thyroid cancers are driven by acquired mutations typically in the BRAF or RAS genes that aberrantly activate the mitogen-activated protein kinase pathway. This process leads to malignant transformation, dedifferentiation, and a decrease in the expression of the sodium-iodide symporter (NIS; SLC5A5), which results in resistance to radioactive iodine therapy. We sought to determine whether inhibition of aberrant mitogen-activated protein kinase-signaling can restore NIS expression. Methods We prospectively developed cultures of papillary thyroid cancers derived from operative specimens and applied drug treatments for 24 hours. Samples were genotyped to identify BRAF and RAS mutations. We performed quantitative PCR to measure NIS expression after treatment. Results We evaluated 24 patient papillary thyroid cancer specimens; BRAFV600E mutations were identified in 18 out of 24 (75.0%); 1 patient tumor had an HRAS mutation, and the remaining 5 were BRAF and RAS wildtype. Dual treatment with dabrafenib and trametinib increased NIS expression (mean fold change 4.01 ± 2.04, P Conclusion Dual treatment with BRAF and MEK inhibitors upregulated NIS expression, suggesting that this treatment regimen may increase tumor iodine uptake. The effect was greatest in tumor cells from younger patients.

The incidence of papillary thyroid microcarcinoma (PTMC) has increased over the past decade. The American Thyroid Association (ATA) suggests that these patients may undergo either thyroid lobectomy or active surveillance. It remains unclear whether there exists a subgroup of PTMC patients who may benefit from more aggressive treatment due to increased risk of recurrence. We retrospectively reviewed 357 patients with PTMC who underwent surgery at a single institution from 2004 to 2016. Patients were classified according to 2015 ATA risk stratification for structural disease recurrence. Demographic, oncologic, and clinicopathologic data were compared between groups. Out of 357 patients, 246 were classified as low-risk PTMC, 93 were intermediate-risk, and 18 were high-risk. There were more male patients in the high-risk group (38.9%) than the intermediate- (31.2%) or low-risk groups (15.4%) (p

Laparoscopic adrenalectomy (LA) is the treatment of choice for aldosteronomas and other adrenal tumors. Despite evidence that surgical cure of aldosteronomas is superior to medical treatment, reluctance remains to refer patients for LA. Here we compared the safety profile of LA to laparoscopic cholecystectomy (LC), a commonly performed laparoscopic procedure.Patients undergoing LA or LC from 2012 to 2015 were selected from the National Surgical Quality Improvement Program. Patients who had an LA for an adrenal adenoma or aldosteronoma were compared to those who had LC for biliary colic or cholelithiasis. Multivariable logistic regressions were used to analyze postoperative outcomes between the two groups, controlling for patient factors.A total of 19,315 patients met inclusion criteria (n = 1458 LA, n = 17,857 LC). Patients undergoing an LA were older (median 53 versus 46 y old, P 0.001), with a higher rate of American Society of Anesthesiologists score ≥3 (65.6% versus 25.0%, P 0.001) and modified frailty index score ≥ 1 (78.5% versus 33.6%, P 0.001). Overall mortality was 0.1% with no difference between the two cohorts (P = 0.426). Incidence of at least one postoperative complication was higher in the LA cohort (3.6% versus 2.2%, P 0.001). However, when adjusting for demographics, comorbidities, and operative time, adrenalectomy was not associated with an increased risk of postoperative complications (OR 0.83 (0.6-1.2), P = 0.268).After comparing postoperative outcomes between patients undergoing LA and LC, operation type was not independently associated with an increased incidence of complications. Therefore, physicians should consider LA as having a similar overall risk profile to LC when deciding whether to refer patients to surgery.

Primary squamous cell carcinoma of the thyroid (ThySCC) is a rare cancer, primarily described only in case reports. We aimed to characterize the prognosis of ThySCC and compare its oncologic behavior to other thyroid malignancies. The National Cancer Database was queried to identify patients with ThySCC, papillary, tall cell variant, poorly differentiated (PDTC), and anaplastic (ATC) subtypes of thyroid cancer treated from 2004 to 2015. Demographics, tumor characteristics, and treatments were compared by tumor type and assessed to identify independent predictors of overall survival (OS). Of 123,684 patients included, 314 had ThySCC. ThySCC patients had a 5-year OS of 17.7%, more closely resembling ATC (8.3%) than PDTC or PTC. ThySCC and ATC patients had similar demographics, except ThySCC patients who were younger (68.0 vs. 70.2 years, p

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.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.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.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.

The optimal management of intraductal papillomas (IPs) without atypia diagnosed on needle core biopsy (NCB) is unclear. This study analyzed the malignancy risk of immediately excised IPs and characterized the behavior of IPs under active surveillance (AS). We retrospectively reviewed the pathology and imaging records of patients diagnosed with IPs without atypia on NCB during a 10-year period (1999–2019). The malignancy upgrade rate was assessed in patients who had an immediate surgical excision, and the rates of both radiographic progression and development of malignancy were assessed in a cohort of patients undergoing AS. The inclusion criteria were met in 152 patients with 175 IPs with a mean age of 51 ± 13 years. The average size of the IPs on initial imaging was 8 ± 4 mm. Most of the lesions (57%, n = 99) were immediately excised, whereas 76 (43%) underwent AS with interval imaging with a median follow-up period of 15 months (range, 5–111 months). Among the immediately excised IPs, surgical pathology revealed benign findings in 97% (n = 96) and ductal carcinoma in situ in 3% (n = 3). In the AS cohort, 72% (n = 55) of the IPs remained stable, and 25% (n = 19) resolved or decreased in size. At 2 years, 4% had increased in size on imaging and were subsequently excised, with ductal carcinoma in situ (DCIS, n = 1) and benign pathology (n = 1) noted on final pathology. In a large series of breast IPs without atypia, no invasive carcinoma was observed after immediate excision, and 96% of the lesions had not progressed on AS. This suggests that patients with IP shown on NCB can safely undergo AS, with surgery reserved for radiographic lesion progression.

The Affordable Care Act's (ACA) Medicaid expansion has increased insurance coverage and improved various cancer outcomes. Its impact in papillary thyroid cancer (PTC) remains unclear.Non-elderly patients (40-64 years-old) with PTC living in low-income areas either in a 2014 expansion, or a non-expansion state were identified from the National Cancer Database between 2010 and 2016. Insurance coverage, stage at diagnosis, and RAI administration were analyzed using a difference-in-differences analysis.10,644 patients were included. Compared with non-expansion states, the percentage of uninsured patients (adjusted-DD -2.6% [95%-CI -4.3to-0.8%],p = 0.004) and patients with private insurance decreased, and those with Medicaid coverage increased (adjusted-DD 9.7% [95%-CI 6.9-12.5%],p 0.001) in expansion states after ACA implementation. The percentage of patients with pT1 did not differ between expansion and non-expansion states; neither did the use of RAI.Medicaid expansion has resulted in a smaller uninsured population in PTC patients, but without earlier disease presentation nor change in RAI treatment.

Population-based analyses of 30-day outcomes after parathyroidectomy for renal secondary hyperparathyroidism are limited. We sought to identify risk factors associated with prolonged length of stay (LOS) and readmission in this patient population. Patients with secondary hyperparathyroidism who underwent parathyroidectomy were reviewed in the ACS-NSQIP database (2011–2016). Patients were identified by ICD codes specific to secondary hyperparathyroidism of renal origin and the ACS-NSQIP variable for current preoperative dialysis. Multivariable logistic regression was used to identify independent factors associated with prolonged LOS and 30-day readmission after parathyroidectomy. The cohort included 1846 patients with secondary hyperparathyroidism on dialysis who underwent parathyroidectomy. There were 416 (22.5%) patients classified under the prolonged LOS group. On multivariable analysis, factors associated with prolonged LOS included elevated preoperative alkaline phosphatase [OR 3.13 (95%-CI 2.09–4.70), p

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 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).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.

When needle core biopsies (NCBs) of the breast reveal fibroepithelial lesions (FELs), excision is often performed to rule out a phyllodes tumor (PT), despite low malignancy rates. Consequently, the natural history of observed FELs is not well described. We analyzed the malignancy risk in excised FELs and the natural history of FELs undergoing active surveillance (AS). We retrospectively studied the pathology and imaging records of 215 patients with FELs (n = 252) diagnosed on NCB. Incidence of growth was determined by Kaplan–Meier method. Of 252 FELs, 80% were immediately excised and 20% underwent AS. Of the excised FELs, 198 (98%) were benign: fibroadenoma (FA) or benign breast tissue in 137 (68%), benign PT in 59 (29%), or LCIS in 2 (1%). Borderline PT or malignant lesions were found in 4 (2%). On ultrasound, malignant and borderline PTs were larger than benign lesions [median 3.9 vs 1.3 cm, p = 0.006]. Fifty FELs underwent AS, with a median follow-up of 17 (range 2–79) months. The majority remained stable or decreased in size: at 2 years, only 35% increased in volume by ≥ 50%. Of those tumors undergoing AS that were later excised (n = 4), all were benign. Almost all FELs (98%) were benign on surgical excision, and the majority undergoing AS remained stable, with benign pathology if later excised. Most FELs on NCB can be safely followed with US, with surgery reserved for patients with FELs that are large, symptomatic, or growing. This could spare most women with FELs unnecessary surgery.

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.

Background: Health insurance has been shown to be a key determinant in cancer care, but it is unknown as to what extent insurance status affects treatments provided to papillary thyroid cancer (PTC...

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.

BRAFV600E is the most common driver mutation in anaplastic thyroid cancer, and BRAF inhibitors are increasingly being used in the treatment of this disease. However, the therapeutic benefit of BRAFV600E inhibitors, such as vemurafenib, has been limited in thyroid cancer due to rapid development of drug resistance in clinical practice. Here, we characterize a targetable mechanism of vemurafenib resistance by studying vemurafenib-resistant clones derived from BRAFV600E mutant anaplastic thyroid cancer cell lines (8505C and FRO), and propose a drug combination to overcome resistance. Vemurafenib resistance in these established clones was verified by persistent activation of ERK1/2 after vemurafenib treatment by western blot analysis. RNA-sequencing and subsequent ingenuity pathway analysis (IPA) was used to identify differences in pathway activation after vemurafenib treatment in parental and vemurafenib-resistant cell lines. Treatment of parental cells with vemurafenib resulted in differential gene expression correlating with upstream activation of the IFNγ-STAT1-IRF1 pathway (All FDR < 0.05). Furthermore, parental cells treated with vemurafenib demonstrated higher HLA-II and HLA-A2 expression than untreated cells when analyzed by flow cytometry, implying the activation of IFNγ signaling pathway. In the IPA of a vemurafenib-resistant clone (8505C Res1), IFNγ, STAT1 and IRF1 expression was upregulated compared to their respective untreated parental cell line (All FDR < 0.05). Increased IRF1 expression in 8505C Res1 compared to parental cells was also demonstrated by qPCR, supporting innate IFNγ activation in the resistant clone. Inhibition of the IFNγ pathway with increasing concentrations of neutralizing anti-IFNγ antibody sensitized resistant thyroid cancer cells to vemurafenib. Pharmacologically blocking the IFNγ downstream pathway in resistant clones with AZD1480 (JAK2 inhibitor) or fludarabine (STAT1 inhibitor), resulted in decreased cell viability in combination treatment groups compared to vemurafenib treatment only (cell viability: 92% vemurafenib vs 19% fludarabine combination, p < 0.05) (cell viability: 73% vemurafenib vs 37% AZD1480 combination, p < 0.05). These results demonstrate that activation of the IFNγ pathway is a potential mechanism for the development of resistance of anaplastic thyroid cancer to BRAFV600E inhibitors. Our study suggests that blockade of the IFNγ pathway may potentiate the therapeutic benefit of vemurafenib treatment in this disease. Citation Format: Jessica Limberg, Katherine D. Gray, Mandeep Singh, Timothy M. Ullmann, Brian Wyrwas, Weibin Wang, Zachary Lowenstein, Steve El Eshaky, Heng Liang, Wei Li, Tuo Zhang, Jenny Xiang, Dessislava Stefanova, Rasa Zarnegar, Thomas J. Fahey, Irene M. Min. The role of the IFNγ pathway in the development of vemurafenib resistance in BRAFV600E mutant thyroid carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1895.

In an attempt to prevent overly aggressive treatment of low-risk thyroid cancers, the American Thyroid Association changed guideline recommendations in late 2015 to state that either hemithyroidectomy or total thyroidectomy are acceptable operations for these patients. We hypothesized that surgeons would increasingly perform hemithyroidectomy after the release of these guidelines.The database of the National Surgery Quality Improvement Program was queried to identify all patients with thyroid cancer who were undergoing thyroidectomy between 2009 and 2017. Patients treated before the release of the 2015 American Thyroid Association guidelines were compared with those treated afterward. Temporal trends in operative rates were assessed quarterly using interrupted time series analyses.A total of 35,291 patients were included in the study. Of those, 26,882 (76.2%) were female and 25,193 (71.3%) were white. After the release of the American Thyroid Association guidelines, there was an increase in hemithyroidectomy rate for patients with cancer from 17.3% to 22.0% (P.001). Interrupted time series analysis controlling for patient factors demonstrated that quarterly growth in the hemithyroidectomy rate accelerated almost 10-fold (P.001) after publication of the revised guidelines. Of note, there was no corresponding increase in the completion thyroidectomy rate (8.3% versus 7.9%, respectively, P = .213). Patients treated with hemithyroidectomy were more likely to be managed as outpatients (70.8% versus 57.1%, P.001), had fewer surgical site infections (0.3% versus 0.5%, P = .050), and had fewer unplanned reintubations (0.2% versus 0.4%, P = .005).In hospitals participating in the National Surgery Quality Improvement Program, the hemithyroidectomy rate increased significantly after the release of the 2015 American Thyroid Association guidelines. Surgeons at hospitals that participate in the National Surgery Quality Improvement Program may be changing practice patterns in response to these guidelines.

Appendicitis remains the most common cause for emergency abdominal surgery in children. Immediate appendectomy in complicated, perforated appendicitis can be hazardous and nonoperative therapy has been gaining use as an initial therapy in children. Previous studies have reported failure rates in nonoperative therapy in such cases ranging from 10% to 41%. Factors leading to treatment failures have been studied with various and disparate results. We reviewed our institutional experience in treated complicated appendicitis, with focus on those initially managed nonoperatively. Methods Records of all children admitted with the diagnosis of perforated appendicitis to NYU Langone Medical Center and Bellevue Hospital Center from January 1, 2003 to December 31, 2013 were reviewed. The diagnosis was made with ultrasound and/or computed tomography scan. Those with abscesses amenable to drainage underwent aspiration and drain placement by an interventional radiologist. Broad spectrum intravenous (IV) antibiotics were given until the patient became afebrile, pain free and tolerating a regular diet. Oral antibiotics were continued for an additional week and interval appendectomy was done eight weeks later. The primary outcome measure was treatment response with failure defined as those who did not improve or required readmission for additional IV antibiotics and/or early appendectomy. Multiple patient and treatment related variables, including those previously reported as predicting failure in nonoperative therapy, were studied. Continuous variables were reported as means ± standard error and compared using 2-tailed unpaired t tests; nonparametric variables were analyzed by Mann–Whitney U tests. Categorical variables were reported as medians ± interquartile ranges and compared using Chi-square testing. Statistical significance was accepted for p Results Sixty-four patients were identified as undergoing initial nonoperative therapy. Fifty-two (81%) were categorized as treatment successes being treated nonoperatively and 12 (19%) were failures. Variables showing no significance in predicting treatment failures included duration of symptoms, presence of appendicolith, presence of phlegmon, presence of abscess, initial white blood cell count, and SIRS (Systemic Inflammatory Response Syndrome) positive. The variables that predicted failure of nonoperative therapy vs. successes were presence of bandemia (75% vs. 40%, p=0.052) and small bowel obstruction on imaging (42% vs. 15%, p=0.052) and presence of bandemia ≥15% which was highly predictive of failure (67% vs. 4%, p Conclusions Predicting which patients with complicated perforated appendicitis will respond well to nonoperative therapy may allow us to more effectively treat patients with complicated perforated appendicitis. In our study the presence of small bowel obstruction and bandemia, especially ≥15% correlated with treatment failure; this suggests that these select patients may need a modified treatment strategy.

Background The effect of perforated appendicitis on the adnexa is an issue of concern and controversy. Long-term fertility studies have been conflicting. Case We present the case of a patient with chronic pelvic infections, salpingitis, and hydrosalpinx after perforated appendicitis. Summary and Conclusion Magnetic resonance imaging was helpful in diagnosing a chronically obstructed fallopian tube, likely secondary to the dense adhesions from her previously treated perforated appendicitis. Salpingectomy relieved her symptoms of chronic pain and recurrent infections.