Perineural Invasion in Papillary Thyroid Cancer: A Rare Indicator of Aggressive Disease.

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.

Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma.

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.

Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration.

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.

Metagenomic Sequencing of the Gallbladder Microbiome: Bacterial Diversity Does Not Vary by Surgical Pathology.

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.

Proposed Risk Stratification and Patterns of Radioactive Iodine Therapy in Malignant Struma Ovarii.

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.

Exposure to Polybrominated Diphenyl Ether Flame Retardants Causes Deoxyribonucleic Acid Damage in Human Thyroid Cells In Vitro.

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.

Quantifying physiologic parameters of the gastroesophageal junction during re-operative anti-reflux surgery.

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) mm2 and DI 1.1 (IQR - 2.4, - 0.6) mm2/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.

Evaluation of post-operative dysphagia following anti-reflux surgery.

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) mm2/mmHg. There was no difference in post-operative DI between procedures [Hill: 0.9 (IQR 0.7-1.1) mm2/mmHg, Nissen: 1.0 (IQR 0.7-1.4) mm2/mmHg, Toupet: 1.2 (IQR 0.8-1.5) mm2/mmHg, Linx: 1.0 (IQR 0.7-1.2) mm2/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) mm2/mmHg and 1.2 (IQR 1.0-1.8) mm2/mmHg, respectively, and that of those who did not was 2.5 (IQR 1.6-4.0) mm2/mmHg and 1.0 (IQR 0.7-1.4) mm2/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.

The impact of pneumoperitoneum on esophagogastric junction distensibility during anti-reflux surgery.

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 mm2/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.

CSPG4 Is a Potential Therapeutic Target in Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATC-derived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4+ T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting ∼10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC.

Can general surgery interns accurately measure their own technical skills? Analysis of cognitive bias in surgical residents' self-assessments.

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.

Association of medicaid expansion of the Affordable Care Act with the stage at diagnosis and treatment of papillary thyroid cancer: A difference-in-differences analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Medicaid expansion has resulted in a smaller uninsured population in PTC patients, but without earlier disease presentation nor change in RAI treatment.

The Use and Benefit of Adjuvant Radiotherapy in Parathyroid Carcinoma: A National Cancer Database Analysis.

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.

Hypertension resolution after adrenalectomy for primary hyperaldosteronism: Which is the best predictive model?

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.

Impact of multikinase inhibitor approval on survival and physician practice patterns in advanced or metastatic medullary thyroid carcinoma.

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.

Not all laparoscopic adrenalectomies are equal: analysis of postoperative outcomes based on tumor functionality.

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.

Does Aggressive Variant Histology Without Invasive Features Predict Overall Survival in Papillary Thyroid Cancer?: A National Cancer Database Analysis.

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.

Association of Adrenal Venous Sampling With Outcomes in Primary Aldosteronism for Unilateral Adenomas.

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.

Chimeric Antigen Receptor T Cell Therapy Targeting ICAM-1 in Gastric Cancer.

Cancer therapy utilizing adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated remarkable clinical outcomes in hematologic malignancies. However, CAR T cell application to solid tumors has had limited success, partly due to the lack of tumor-specific antigens and an immune-suppressive tumor microenvironment. From the tumor tissues of gastric cancer patients, we found that intercellular adhesion molecule 1 (ICAM-1) expression is significantly associated with advanced stage and shorter survival. In this study, we report a proof-of-concept study using ICAM-1-targeting CAR T cells against gastric cancer. The efficacy of ICAM-1 CAR T cells showed a significant correlation with the level of ICAM-1 expression in target cells in vitro. In animal models of human gastric cancer, ICAM-1-targeting CAR T cells potently eliminated tumors that developed in the lungs, while their efficacy was more limited against the tumors in the peritoneum. To augment CAR T cell activity against intraperitoneal tumors, combinations with paclitaxel or CAR activation-dependent interleukin (IL)-12 release were explored and found to significantly increase anti-tumor activity and survival benefit. Collectively, ICAM-1-targeting CAR T cells alone or in combination with chemotherapy represent a promising strategy to treat patients with ICAM-1+ advanced gastric cancer.