Developing a predictive model for metastatic potential in pancreatic neuroendocrine tumor.

CONTEXT: Pancreatic neuroendocrine tumors (PNETs) exhibit a wide range of behavior from localized disease to aggressive metastasis. A comprehensive transcriptomic profile capable of differentiating between these phenotypes remains elusive. OBJECTIVE: Use machine learning to develop predictive models of PNET metastatic potential dependent upon transcriptomic signature. METHODS: RNA-sequencing data were analyzed from 95 surgically-resected primary PNETs in an international cohort. Two cohorts were generated with equally balanced metastatic PNET composition. Machine learning was used to create predictive models distinguishing between localized and metastatic tumors. Models were validated on an independent cohort of 29 formalin-fixed, paraffin-embedded samples using NanoString nCounter®, a clinically-available mRNA quantification platform. RESULTS: Gene expression analysis identified concordant differentially expressed genes between the two cohorts. Gene set enrichment analysis identified additional genes that contributed to enriched biologic pathways in metastatic PNETs. Expression values for these genes were combined with an additional 7 genes known to contribute to PNET oncogenesis and prognosis, including ARX and PDX1. Eight specific genes (AURKA, CDCA8, CPB2, MYT1L, NDC80, PAPPA2, SFMBT1, ZPLD1) were identified as sufficient to classify the metastatic status with high sensitivity (87.5% - 93.8%) and specificity (78.1% - 96.9%). These models remained predictive of the metastatic phenotype using NanoString nCounter® on the independent validation cohort, achieving a median AUROC of 0.886. CONCLUSIONS: We identified and validated an eight-gene panel predictive of the metastatic phenotype in PNETs, which can be detected using the clinically-available NanoString nCounter® system. This panel should be studied prospectively to determine its utility in guiding operative versus non-operative management.

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.

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.

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.

Timing to Surgery and Lymph Node Upstaging in Gastric Cancer: An NCDB Analysis.

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

Impedance planimetry (EndoFLIPTM) and surgical outcomes after Hill compared to Toupet fundoplication.

INTRODUCTION: Endoluminal functional lumen imaging probe (EndoFLIP) provides a real-time assessment of gastroesophageal junction (GEJ) compliance during fundoplication. Given the limited data on EndoFLIP measurements during the Hill procedure, we investigated the impact of the Hill procedure on GEJ compliance compared to Toupet fundoplication. METHODS: Patients who underwent robotic Hill or Toupet fundoplication with intraoperative EndoFLIP between 2017 and 2022 were included. EndoFLIP measurements of the GEJ included cross sectional surface area (CSA), intra-balloon pressure, high pressure zone length (HPZ), distensibility index (DI), and compliance. Subjective reflux symptoms, gastroesophageal reflux disease-health related quality of life (GERD-HRQL) score, and dysphagia score were assessed pre-operatively as well as at short- and longer-term follow-up. RESULTS: One-hundred and fifty-four patients (71.9%) had a Toupet fundoplication while sixty (28%) patients underwent the Hill procedure. The CSA [27.7 ± 10.9 mm2 vs 42.2 ± 17.8 mm2, p < 0.0001], pressure [29.5 ± 6.2 mmHg vs 33.9 ± 8.5 mmHg, p = 0.0009], DI [0.9 ± 0.4 mm2/mmHg vs 1.3 ± 0.6 mm2/mmHg, p = 0.001], and compliance [25.9 ± 12.8 mm3/mmHg vs 35.4 ± 13.4 mm3/mmHg, p = 0.01] were lower after the Hill procedure compared to Toupet. However, there was no difference in post-fundoplication HPZ between procedures [Hill: 2.9 ± 0.4 cm, Toupet: 3.1 ± 0.6 cm, p = 0.15]. Follow-up showed no significant differences in GERD-HRQL scores, overall dysphagia scores or atypical symptoms between groups (p > 0.05). CONCLUSION: The Hill procedure is as effective to the Toupet fundoplication in surgically treating gastroesophageal reflux disease (GERD) despite the lower CSA, DI, and compliance after the Hill procedure. Both procedures led to DI < 2 mm2/mmHg with no significant differences in dysphagia reporting (12-24) months after the procedure. Further studies to elucidate a cutoff value for DI for postoperative dysphagia development are still warranted.

Gastric development of pancreatic acinar cell metaplasia after Vonoprazan therapy in rats.

BACKGROUND: Vonoprazan is a new acid-suppressing drug that received FDA approval in 2022. It reversibly inhibits gastric acid secretion by competing with the potassium ions on the luminal surface of the parietal cells (potassium-competitive acid blockers or P-CABs). Vonoprazan has been on the market for a short time and there are many clinical trials to support its clinical application. However, medical experience and comprehensive clinical data is still limited, especially on how and if, gastric histology is altered due to therapy. METHODS: A 12-week experiment trial with 30 Wistar rats was to assess the presence of gastrointestinal morphologic abnormalities upon administration of omeprazole and vonoprazan. At six weeks of age, rats were randomly assigned to one of 5 groups: (1) saline as negative control group, (2) oral omeprazole (40 mg/kg), as positive control group, (3) oral omeprazole (40 mg/kg) for 4 weeks, proceeded by 8 weeks off omeprazole, (4) oral vonoprazan (4 mg/kg), as positive control group, and (5) oral vonoprazan (4 mg/kg) for 4 weeks, proceeded by 8 weeks off vonoprazan. RESULTS: We identified non-inflammatory alterations characterized by parietal (oxyntic) cell loss and chief (zymogen) cell hyperplasia and replacement by pancreatic acinar cell metaplasia (PACM). No significant abnormalities were identified in any other tissues in the hepatobiliary and gastrointestinal tracts. CONCLUSION: PACM has been reported in gastric mucosa, at the esophagogastric junction, at the distal esophagus, and in Barrett esophagus. However, the pathogenesis of this entity is still unclear. Whereas some authors have suggested that PACM is an acquired process others have raised the possibility of PACM being congenital in nature. Our results suggest that the duration of vonoprazan administration at a dose of 4 mg/kg plays an important role in the development of PACM.

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.

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.

Long-term potassium-competitive acid blockers administration causes microbiota changes in rats.

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

Transoral incisionless fundoplication for recurrent symptoms after laparoscopic fundoplication.

BACKGROUND: Revision of a failed laparoscopic fundoplication carries higher risk of complication and lower chance of success compared to the original surgery. Transoral incisionless fundoplication (TIF) may be an endoscopic alternative for select GERD patients without need of a moderate/large hiatal hernia repair. The aim of this study was to assess feasibility, efficacy, and safety of TIF 2.0 after failed laparoscopic Nissen or Toupet fundoplication (TIFFF). METHODS: This is a multicenter retrospective cohort study of patients who underwent TIFFF between September 2017 and December 2020 using TIF 2.0 technique (EsophyX Z/Z+) performed by gastroenterologists and surgeons. Patients were included if they had (1) recurrent GERD symptoms, (2) pathologic reflux based upon pH testing or Grade C/D esophagitis or Barrett's esophagus, and (3) hiatal hernia ≤ 2 cm. The primary outcome was improvement in GERD Health-Related Quality of Life (GERD-HRQL) post-TIFFF. The TIFFF cohort was also compared to a similar surgical re-operative cohort using propensity score matching. RESULTS: Twenty patients underwent TIFFF (median 4.1 years after prior fundoplication) and mean GERD-HRQL score improved from 24.3 ± 22.9 to 14.75 ± 21.6 (p = 0.014); mean Reflux Severity Index (RSI) score improved from 14.1 ± 14.6 to 9.1 ± 8.0 (p = 0.046) with 8/10 (80%) of patients with normal RSI (< 13) post-TIF. Esophagitis healed in 78% of patients. PPI use decreased from 85 to 55% with 8/20 (45%) patients off of PPI. Importantly, mean acid exposure time decreased from 12% ± 17.8 to 0.8% ± 1.1 (p = 0.028) with 9/9 (100%) of patients with normalized pH post-TIF. There were no statistically significant differences in clinical efficacy outcomes between TIFFF and surgical revision, but TIFFF had significantly fewer late adverse events. CONCLUSION: Endoscopic rescue with TIF is a safe and efficacious alternative to redo laparoscopic surgery in symptomatic patients with appropriate anatomy and objective evidence of persistent or recurrent reflux.

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.

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.

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.

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.

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.