Radioactive iodine administration is not associated with improved disease-specific survival in classic papillary thyroid carcinoma greater than 4 cm confined to the thyroid.

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

Patterns in the Reporting of Aggressive Histologic Subtypes in Papillary Thyroid Cancer.

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

Low Mitotic Activity in Papillary Thyroid Cancer: A Marker for Aggressive Features and Recurrence.

CONTEXT: The significance of low mitotic activity in papillary thyroid cancer (PTC) is largely undefined. OBJECTIVE: We aimed to determine the behavioral landscape of PTC with low mitotic activity compared to that of no- and high-mitotic activity. METHODS: A single-institution consecutive series of PTC patients from 2018-2022 was reviewed. Mitotic activity was defined as no mitoses, low (1-2 mitoses/2 mm2) or high (≥3 mitoses/2 mm2) per the World Health Organization. The 2015 American Thyroid Association risk stratification was applied to the cohort, and clinicopathologic features were compared between groups. For patients with ≥6 months follow-up, Cox regression analyses for recurrence were performed. RESULTS: 640 PTCs were included - 515 (80.5%) no mitotic activity, 110 (17.2%) low mitotic activity, and 15 (2.3%) high mitotic activity. Overall, low mitotic activity exhibited rates of clinicopathologic features including vascular invasion, gross extrathyroidal extension, and lymph node metastases in between those of no- and high-mitotic activity. PTCs with low mitotic activity had higher rates of intermediate- and high-risk ATA risk stratification compared to those with no mitotic activity (p < 0.001). Low mitotic activity PTCs also had higher recurrence rates (15.5% vs. 4.5%, p < 0.001). Low mitotic activity was associated with recurrence, independent of the ATA risk stratification (HR 2.96; 95% CI 1.28-6.87, p = 0.01). CONCLUSIONS: Low mitotic activity is relatively common in PTC and its behavior lies within a spectrum between no- and high-mitotic activity. Given its association with aggressive clinicopathologic features and recurrence, low mitotic activity should be considered when risk stratifying PTC patients for recurrence.

Malpractice claims after antireflux surgery and paraesophageal hernia repair: a population-based analysis.

BACKGROUND: The complication rate of modern antireflux surgery or paraesophageal hernia repair is unknown, and previous estimates have been extrapolated from institutional cohorts. METHODS: A population-based retrospective cohort study of patient injury cases involving antireflux surgery and paraesophageal hernia repair from the Finnish National Patient Injury Centre (PIC) register between Jan 2010 and Dec 2020. Additionally, the baseline data of all the patients who underwent antireflux and paraesophageal hernia operations between Jan 2010 and Dec 2018 were collected from the Finnish national care register. RESULTS: During the study period, 5734 operations were performed, and the mean age of the patients was 54.9 ± 14.7 years, with 59.3% (n = 3402) being women. Out of all operations, 341 (5.9%) were revision antireflux or paraesophageal hernia repair procedures. Antireflux surgery was the primary operation for 79.9% (n = 4384) of patients, and paraesophageal hernia repair was the primary operation for 20.1% (n = 1101) of patients. A total of 92.5% (5302) of all the operations were laparoscopic. From 2010 to 2020, 60 patient injury claims were identified, with half (50.0%) of the claims being related to paraesophageal hernia repair. One of the claims was made due to an injury that resulted in a patient's death (1.7%). The mean Comprehensive Complication Index scores were 35.9 (± 20.7) and 47.6 (± 20.8) (p = 0.033) for antireflux surgery and paraesophageal hernia repair, respectively. Eleven (18.3%) of the claims pertained to redo surgery. CONCLUSIONS: The rate of antireflux surgery has diminished and the rate of paraesophageal hernia repair has risen in Finland during the era of minimally invasive surgery. Claims to the PIC remain rare, but claims regarding paraesophageal hernia repairs and redo surgery are overrepresented. Additionally, paraesophageal hernia repair is associated with more serious complications.

Clinical utility of a microRNA classifier in cytologically indeterminate thyroid nodules with RAS mutations: A multi-institutional study.

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

Treatment of Secondary Hyperparathyroidism and Posttransplant Tertiary Hyperparathyroidism.

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

An Original Study: Is There an Optimal Time to Complete Dedicated Research During Surgical Residency? Twelve Years of Research Experience After PGY2 or PGY3.

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

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.

Coexisting Papillary and Anaplastic Thyroid Cancer: Elucidating the Spectrum of Aggressive Behavior.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare and lethal form of thyroid cancer. Overall prognosis is unclear when it arises focally in a background of papillary thyroid cancer (PTC). Clinicopathologic features and outcomes of tumors with coexisting PTC and ATC histologies (co-PTC/ATC) were categorized. METHODS: The National Cancer Database was queried for histologic codes denoting PTC, ATC, and co-PTC/ATC, defined as Grade 4 PTC, diagnosed from 2004 to 2017. Clinicopathologic features, OS, and treatment outcomes were analyzed by histologic type. RESULTS: A total of 386,862 PTC, 763 co-PTC/ATC, and 3,880 ATC patients were identified. Patients with co-PTC/ATC had clinicopathologic features in-between those of PTC and ATC, including rates of tumor size >4 cm, extrathyroidal extension, and distant metastases. On multivariable Cox proportional hazards modeling, age >55 years, Charlson-Deyo score ≥2, positive lymph nodes, lymphovascular invasion, distant metastases, and positive surgical margins were associated with worse OS, whereas radioactive iodine (RAI) and external beam radiation therapy (EBRT) were associated with improved OS, irrespective of margin status. OS was worse for co-PTC/ATC than for PTC but better than for ATC and differed based on the presence or absence of "aggressive" tumor features, including lymph node positivity, lymphovascular invasion, distant metastases, and positive surgical margins. CONCLUSIONS: Survival of patients with co-PTC/ATC is dependent on the presence of aggressive clinicopathologic features and lies within a spectrum between that of PTC and ATC. Adjuvant RAI and EBRT treatment may be beneficial, even after R0 resection.

Comparative Outcomes of Anti-Reflux Surgery in Obese Patients with Gastroesophageal Reflux Disease1.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) has been the preferred operation for obese patients with gastroesophageal reflux disease (GERD); however, some patients are hesitant to undergo bypass. Obese patients have a multifactorial predisposition to GERD, including lower esophageal sphincter (LES) dysfunction and aberrant pressure gradients across their diaphragmatic crura. Among non-obese patients, anti-reflux surgery (ARS) with hiatal hernia (HH) repair and LES augmentation has shown excellent long-term results. We aimed to determine whether patient satisfaction and GERD recurrence differed between obese and non-obese patients who underwent ARS. METHODS: Review of patients who underwent ARS between January 2012 and June 2021 was performed. Perioperative and postoperative characteristics were compared across three BMI groups: BMI < 30 kg/m2, 30 kg/m2 ≤ BMI < 35 kg/m2, and BMI ≥ 35 kg/m2. RESULTS: Four-hundred thirteen patients were identified, of which 294 (71.1%) had BMI < 30 kg/m2, 87 (21.1%) were 30 kg/m2 ≤ BMI < 35 kg/m2, and 32 (7.7%) had a BMI ≥ 35 kg/m2. Patients with BMI ≥ 35 kg/m2 had higher preoperative manometric and EndoFLIP™ intra-balloon pressure at the LES than those with lower BMIs. This value was increased to a similar level throughout ARS across the three cohorts. Post-operative GERD-specific satisfaction was similar across the three cohorts, as were rates of postoperative reflux and hiatal hernia recurrence on barium swallow; rates of reoperation were low. CONCLUSIONS: ARS with HH repair and LES augmentation may be appropriate for select patients across a range of BMIs, including those with a BMI ≥ 35 kg/m2 who are hesitant to undergo RYGB.

Prepubertal Children with Papillary Thyroid Carcinoma Present with More Invasive Disease Than Adolescents and Young Adults.

Introduction: Pediatric papillary thyroid carcinomas (PTCs) are more invasive than adult PTCs. No large, contemporary cohort study has been conducted to determine whether younger children are at higher risk for advanced disease at presentation compared to adolescents. We aimed to describe pediatric PTC and contextualize its characteristics with a young adult comparison cohort. Methods: The National Cancer Database was interrogated for pediatric and young adult PTCs diagnosed between 2004 and 2017. Clinical variables were compared between prepubertal (≤10 years old), adolescent (11-18 years old), and young adult (19-39 years old) groups. Multivariable logistic regression modeling for independent predictors of metastases was conducted. A subanalysis of microcarcinomas (size ≤10 mm) was performed. Results: A total of 4860 pediatric (prepubertal n = 274, adolescents n = 4586) and 101,159 young adult patients were included. Prepubertal patients presented with more extensive burden of disease, including significantly larger primary tumors, higher prevalence of nodal and distant metastases, and increased frequency of features such as lymphovascular invasion, and extrathyroidal extension (ETE). Prepubertal age was an independent predictor of positive regional nodes (adjusted odds ratio [AOR] = 1.36 [95% confidence interval {CI} 1.01-1.84], p = 0.04) and distant metastatic disease (AOR = 3.12 [CI 1.96-4.96], p < 0.001). However, there was no difference in survival between groups (p = 0.32). Prepubertal age independently predicted lymph node metastases for microcarcinomas (AOR = 2.19 [CI 1.10-4.36], p = 0.03). Prepubertal (n = 41) versus adolescent (n = 937) patient age was associated with gross ETE (p = 0.004), even with primary tumors ≤1 cm in size. Conclusions: Patients aged <11 years old present with more advanced disease than adolescents, with a higher likelihood of nodal and distant metastatic disease at time of diagnosis, although survival is high. Prepubertal children undergo more extensive treatment, likely reflective of more invasive disease at the outset, even in the setting of a subcentimeter primary tumor.

Quantifying physiologic parameters of the gastroesophageal junction during robotic sleeve gastrectomy and identifying predictors of post-sleeve gastroesophageal reflux disease.

BACKGROUND: Sleeve gastrectomy is among the most commonly-performed procedures for morbid obesity. However, patients occasionally develop post-sleeve gastroesophageal reflux disease (GERD). Identifying patients most at risk for this complication remains difficult. We aimed to correlate intra-operative physiologic measurements of the lower esophageal sphincter (LES) at the gastroesophageal junction (GEJ) during robotic sleeve gastrectomy in an attempt to identify predictors of post-sleeve GERD symptoms. METHODS: A retrospective chart review of a prospectively maintained database identified 28 patients in whom robotic sleeve gastrectomy was performed utilizing EndoFLIP™ technology between January and September 2021. Intraoperative LES measurements at the GEJ including cross-sectional area (CSA), distensibility index (DI), intra-balloon pressure, and high-pressure zone (HPZ length) were correlated with post-operative GERD. RESULTS: GEJ CSA, pressure, and DI increased over the course of the surgery (CSA pre-op: 31 (IQR 19.3-39.5) mm2 vs. post-op: 67 (IQR 40.8-95.8) mm2, p < 0.001; pressure: 25.8 (IQR 20.2-33.1) mmHg vs. 31.5 (IQR 28.9-37.0) mmHg, p = 0.007; DI 1.1 (IQR 0.8-1.8) mm2/mmHg vs. 2.0 (IQR 1.2-3.0) mm2/mmHg, p = < 0.001), whereas HPZ length decreased (2.5 (IQR 2.5-3) cm vs. 2.0 (IQR 1.3-2.5) cm, p = 0.022). Twenty-three patients (82.1%) completed a post-operative GERD questionnaire. Fifteen (65.2%) had no GERD symptoms before or after surgery; 5 (21.7%) reported new post-sleeve GERD symptoms; 3 (13.0%) reported exacerbation of pre-existing GERD symptoms. Patients with new or worsening GERD symptoms had higher post-sleeve DIs (3.2 (IQR 1.9-4.5) mm2/mmHg vs. 1.5 (IQR 1.2-2.4) mm2/mmHg, p = 0.024) and lower post-sleeve LES pressures (29.9 (IQR 26.3-32.9) mmHg vs. 35.2 (IQR 31.0-38.0) mmHg, p = 0.023) than those without. CONCLUSIONS: An increase in GEJ CSA, pressure, and DI, and a decrease in GEJ length can be expected during robotic sleeve gastrectomy. Patients with new or worsening post-sleeve GERD symptoms have higher post-sleeve DI and lower post-sleeve LES pressure than their asymptomatic counterparts.

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.

Sex-Based Clinicopathologic and Survival Differences Among Patients with Pancreatic Neuroendocrine Tumors.

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

Care Fragmentation in Patients with Differentiated Thyroid Cancer.

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

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.