Shariq, Omair A.

Abstract Acute appendicitis is a common surgical emergency, most often caused by luminal obstruction from fecaliths. Rarely, foreign body ingestion can lead to appendicitis, particularly when small objects like lead shot become lodged in the appendix. We present the case of a 30-year-old man with chronic intermittent right lower quadrant pain who presented with an acute exacerbation. Imaging revealed two metallic densities in the appendix without overt signs of inflammation. He underwent laparoscopic appendectomy, which confirmed the presence of two retained lead pellets and histologic evidence of acute appendicitis. The patient had a history of frequent game meat consumption. This case underscores a rare but important etiology of appendicitis and the potential for systemic lead exposure from retained foreign bodies. In patients with relevant social histories and suggestive imaging, clinicians should consider this diagnosis and proceed with timely surgical management to prevent complications.

Abstract O.A. Shariq: None. K.E. Lines: None. K.A. English: None. I. Rioja: Employee; Self; GlaxoSmithKline. A. Selberherr: None. H. Ferry: None. A.L. Oberg: None. R. Prinjha: Employee; Self; GlaxoSmithKline. D. Richards: None. R.V. Thakker: None. Background: Effective treatments for metastatic pancreatic neuroendocrine tumors (PNETs) are scarce. We previously showed that inhibiting bromodomain and extra-terminal (BET) epigenetic reader proteins via non-selective targeting of their two bromodomains (BD1 and BD2) reduces proliferation in preclinical PNET models. However, the clinical relevance of BET proteins in PNETs and functional differences between BD1/BD2 are unclear. Here, we characterised BET expression in human PNETs and performed efficacy and mechanistic studies using next-generation BD1- (BD1i) and BD2-selective (BD2i) BET inhibitors. Methods: BET expression was evaluated by immunohistochemistry in functioning and non-functioning human PNETs (n=52) vs normal adjacent islets (n=18). RNA sequencing (RNA-seq) and gene set enrichment analyses (GSEA) were performed in an independent PNET cohort (n=46) to identify biological pathways upregulated in metastatic vs non-metastatic tumors. Effects of BD1i and BD2i on viability, apoptosis, and cell cycle progression were assessed in three PNET cell lines (BON1, QGP1, MIN6). Early (6h) and late (48h) transcriptional responses to BET inhibition were examined in vitro using nascent RNA-seq (SLAM-seq) and standard RNA-seq, respectively. Epigenomic responses were explored using chromatin immunoprecipitation sequencing (ChIP-seq) for the histone mark H3K27ac. Effects of BD1i and BD2i on viability were evaluated in ex vivo neoplastic pancreatic islets derived from Men1L/L/RIP2-Cre mice. Results: BET proteins (BRD2, BRD3 and BRD4) were overexpressed by 1.5-2.5-fold in human PNETs vs islets (p<0.01). GSEA showed enrichment of BET-regulated gene sets in metastatic tumors (normalized enrichment score 1.31, adjusted p=0.04). BD2i marginally affected cell viability (IC50 55-90 µM), apoptosis, and cell cycle profile, while BD1i had a moderate impact on all phenotypes (IC50 1-1.5 µM). Synergistic effects were observed when BD1i+BD2i were combined (IC50 0.2-0.5 µM). RNA-seq and SLAM-seq revealed transcriptional changes that were minimal with BD2i (n=73 and n=10 differentially expressed genes, respectively), modest with BD1i (n=354 and n=60 genes), and greatest with BD1i+BD2i combined (n=1739 and n=375 genes). ChIP-seq showed a reduction in H3K27ac enrichment at promoters and super-enhancers of genes involved in BET protein-regulated pathways (e.g. cell cycle progression), with the greatest decrease observed with BD1i+BD2i combined. In ex vivo cultured neoplastic islets, viability was reduced by <30% with BD2i (p<0.005), ∼40% with BD1i (p<0.0001), and ∼60% with BD1i+BD2i (p<0.0001). Conclusions: Our studies confirm BET proteins as clinically-relevant targets in human PNETs and show that dual (BD1+BD2) inhibition has synergistic efficacy. These findings have important implications for the clinical application of next-generation epigenetic modulators. Sunday, June 2, 2024

Abstract Pancreatic neuroendocrine neoplasm (panNEN) is a rare malignancy and the second most common type of pancreatic cancer after pancreatic ductal adenocarcinoma (PDAC), but its etiology is poorly understood. We investigated whether the risk factors of panNEN are concordant with those known for PDAC. We performed the largest case-control study to date on panNENs, comprising 927 sporadic nonfunctional panNEN cases and 1807 frequency-matched controls, using data from the Mayo Clinic Biospecimen Resource for Pancreas Research. We assessed associations for obesity, first-degree family history of pancreatic cancer, cigarette smoking, overall type II diabetes mellitus (T2DM), new-onset T2DM (<1 year before panNEN diagnosis), longstanding T2DM (≥5 years), alcohol intake and aspirin use. Multivariable logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). Our results show that overall T2DM (OR = 1.71, 95% CI: 1.37–2.14) and new-onset T2DM (OR = 2.65, 95% CI: 1.92–3.69) are associated with higher odds of panNEN, but not longstanding T2DM (OR = 1.29, 95% CI: 0.94–1.75). A non-significant elevated odds of panNEN was observed among participants with a positive family history of pancreatic cancer (OR = 1.44, 95% CI: 0.96–2.14). Alcohol use was inversely related to panNEN (OR = 0.52, 95% CI: 0.42–0.66, ever-vs-never). No association was observed for smoking, obesity or aspirin use. These findings indicate that overall T2DM and new-onset T2DM are associated with higher odds of panNEN. Unlike PDAC, alcohol use was inversely related to panNEN, and we found no associations for cigarette smoking, obesity or aspirin use. These results indicate differences in the risk factor profiles of panNEN and PDAC.

AbstractGastroenteropancreatic neuroendocrine tumours (GEP‐NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non‐secreting (also known as non‐functioning NETs) are associated with severe morbidity and have a median overall survival of 75–124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP‐NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled‐receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP‐NET subtypes. Using RNA‐Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non‐functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP‐NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC‐seq analyses in the pancreatic NET cell line QGP‐1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP‐1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP‐NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.

Abstract Disclosure: S. Mohan: None. O.A. Shariq: None. J.C. Andrews: None. W.F. Young: None. Background: Adrenal vein sampling (AVS) is performed in patients with primary aldosteronism (PA) to subtype surgically curable unilateral disease. During AVS, iodinated contrast is used to confirm catheterization of adrenal veins for accurate sampling. However, in patients with severe contrast allergy, the optimal method of safely and effectively confirming localization is debatable. Premedication with oral corticosteroids has raised concern for suppression of cortisol and confounding of AVS results. We therefore investigated our experience of AVS after corticosteroid premedication in patients with PA and iodine contrast allergy. Methods: Patients with PA who underwent AVS at our center under continuous cosyntropin infusion (50 mcg/hr started 30 minutes before sampling) between September 1990 - October 2023 were identified. Individuals with documented allergy to iodinated contrast who received corticosteroid premedication were matched 1:1 for age and sex with control patients without contrast allergy or premedication. Baseline demographics, biochemical variables, AVS results, and follow-up data were compared between groups. Results: 1273 AVS studies were performed in 1255 patients with PA and 35 (2.8%) patients received corticosteroid premedication for contrast allergy. Methylprednisolone was used in 32 (91.4%) patients while dexamethasone was used in the rest. No patients experienced a severe breakthrough allergic reaction. Mean age was similar in cases vs. controls (53.9 vs. 54.1 years, P=0.92) with 16 females (45.7%) per group. There were no significant differences in baseline aldosterone-to-renin ratios (57.7 vs. 49.3, P=0.57) or daily defined doses of antihypertensives (5.5 vs. 4.4, P=0.21) between the two groups. Absolute cortisol levels (mcg/dL) from both adrenal veins (AV) and the inferior vena cava (IVC) were similar between cases and controls (right AV: 752.5 vs. 813.7, P=0.48; left AV: 527.2 vs. 462.7, P=0.33; IVC: 23.1 vs. 24.5, P=0.18). The ratio of cortisol in the corresponding AV to the IVC (selectivity index) was >5 in all patients, confirming appropriate cannulation, with similar mean selectivity indices between groups (right AV: 33.0 vs. 33.7, P=0.86; left AV: 22.8 vs. 19.0 P=0.17). Unilateral disease (indicated by a lateralization index >4) was present in 20 (57.1%) patients who received premedication compared with 16 (45.7%) controls (P=0.34). Surgery for unilateral disease was performed in 16 cases and 12 controls, with similar post-op day 1 aldosterone levels in both groups (3.8 vs. 3.3, P=0.36), consistent with surgical cure. Conclusion: In patients with PA and iodine contrast allergy, premedication with corticosteroids prior to cosyntropin-stimulated AVS does not significantly suppress cortisol levels or affect interpretation of AVS results, with comparable rates of disease subtyping and surgical outcomes when compared to a control group. Presentation: 6/3/2024

Background: Despite numerous potential benefits of outpatient surgery, there is currently a lack of national benchmarking data available for hospitals and surgeons to compare their own outcomes as they transition toward outpatient surgery. Materials and methods: Patients who underwent 14 common general surgery operations from 2016 to 2020 were identified in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Operations were selected based on frequency and the ability to be performed both inpatient and outpatient. Postoperative complications and readmissions were compared between patients who underwent inpatient vs outpatient surgery. After adjusting for patient comorbidities, multivariable models assessed the effect of patient characteristics on the odds of experiencing postoperative complications. A separate multi-institutional study of 21 affiliated hospitals assessed practice variation. Results: In 13 of the 14 studied procedures, complications were lower for patients who were selected for outpatient surgery (all P<0.01); minimally invasive (MIS) adrenalectomy showed no difference (P=0.61). Multivariable analysis confirmed these findings; the odds of experiencing any adverse events were lower following outpatient surgery in all operations but MIS adrenalectomy (OR 0.97; 95% CI: 0.47–2.02). Analysis of institutional practices demonstrated variation in the rate of outpatient surgery in certain breast, endocrine, and hernia repair operations. Conclusions: Institutional practice patterns may explain the national variation in the rate of outpatient surgery. While the present data does not support the adoption of outpatient surgery to less optimal candidates, addressing unexplained practice variations could result in improved utilization of outpatient surgery.

Abstract Disclosure: O.A. Shariq: None. T.J. McKenzie: None. W.F. Young: None. Background: Multiple endocrine neoplasia type 2B (MEN2B) is most commonly caused by a germline methionine-to-threonine substitution at codon 918 (M918T) of the RET proto-oncogene. The syndrome is characterized by medullary thyroid carcinoma, pheochromocytoma, and extra-endocrine manifestations (intestinal ganglioneuromas, mucosal neuromas, and skeletal and ophthalmic abnormalities). We describe a patient with MEN2B and bilateral pheochromocytomas, in whom the slow-growing nature of the lesions, and previous history of an extra-endocrine manifestation, precluded the typical approach to surgical resection. Clinical Case: A 58-year-old-male with MEN2B, diagnosed at age 15, presented with a 6-month history of episodic palpitations and labile blood pressures. His past surgical history included a total abdominal colectomy and ileorectal anastomosis at age 7 years for megacolon, secondary to intestinal ganglioneuromatosis. He subsequently required multiple laparotomies and adhesiolysis procedures for recurrent small bowel obstructions. During his most recent laparotomy at age 44, he was noted to have a ‘frozen’ abdomen with dense adhesions involving the small bowel. CT abdomen revealed bilateral adrenal masses, measuring 2.9 cm and 1.5 cm on the right and left, respectively. Review of previous imaging revealed that the right adrenal mass had been present 16 years prior, measuring 1.0 cm at that time, while the left-sided mass was not seen. Biochemical workup was negative previously, but now showed elevated plasma metanephrine (4.1 nmol/L [N&lt;0.5 nmol/L ]) and normetanephrine 2.3 nmol/L [N&lt;0.9 nmol/L ]) levels. In the setting of extensive intra-abdominal adhesions and the slow-growing nature of both masses, the decision was made to perform a unilateral right adrenalectomy through a retroperitoneoscopic, rather than a transabdominal, approach. Pathology confirmed a 4.4 cm pheochromocytoma. The patient was discharged on postoperative day 1 and was symptom free at 1 year follow-up. His most recent plasma metanephrine and normetanephine levels were 0.7 nmol/L and 0.5 nmol/L, respectively. Clinical Lessons: Patients with MEN2B have a 50% lifetime risk of developing pheochromocytoma. Unlike medullary thyroid cancer, which exhibits an aggressive phenotype in this syndrome, MEN2B-associated pheochromocytomas may be slow growing, thereby avoiding the need for an initial bilateral adrenalectomy. Many patients with MEN2B develop gastrointestinal manifestations, including megacolon during infancy, for which multiple surgical interventions may be required. These procedures carry a risk of adhesion formation, which presents a challenge if further abdominal surgery is required later in life for pheochromocytoma. Retroperitoneoscopic adrenalectomy provides a safe approach in such patients, as the need to perform risky adhesiolysis and mobilize adjacent organs is obviated. Presentation: Saturday, June 17, 2023

Background: Gastrojejunal (GJ) anastomotic stenosis is a well-described complication after Roux-en-Y gastric bypass (RYGB); however, its impact on weight loss outcomes is not well elucidated. Methods: We performed a retrospective cohort study of adult patients who underwent RYGB at our institution between 2008 and 2020. Propensity score matching was used to match 30 patients who developed GJ stenosis within the first 30 days post-RYGB with 120 control patients who did not develop this outcome. Short and long-term complications and mean percentage of total body weight loss (TWL) were recorded at 3 months, 6 months, 1 year, 2 years, 3 to 5 years, and 5 to 10 years postoperatively. Hierarchical linear regression modeling was used to analyze the association between early GJ stenosis and the mean percentage of TWL. Results: Patients who developed early GJ stenosis had a 13.6% increase in the mean percentage of TWL when compared with controls in the hierarchical linear model [P < 0.001 (95% CI: 5.7; 21.5)]. These patients were also more likely to present to an intravenous infusion center (70% vs 4%; P < 0.01), require readmission within 30 days (16.7% vs 2.5%; P < 0.01), and/or develop an internal hernia (23.3% vs 5.0%) postoperatively. Conclusions: Patients who develop early GJ stenosis after RYGB have a greater degree of long-term weight loss compared with patients who do not develop this complication. Although our findings support the key contribution that restrictive mechanisms play in maintaining weight loss after RYGB, GJ stenosis remains a complication associated with significant morbidity.

ImportanceThe American College of Surgeons (ACS) has advocated for the expansion of outpatient surgery to conserve limited hospital resources and bed capacity, while maintaining surgical throughput, during the COVID-19 pandemic.ObjectiveTo investigate the association of the COVID-19 pandemic with outpatient scheduled general surgery procedures.Design, Setting, and ParticipantsThis multicenter, retrospective cohort study analyzed data from hospitals participating in the ACS National Surgical Quality Improvement Program (ACS-NSQIP) from January 1, 2016, to December 31, 2019 (before COVID-19), and from January 1 to December 31, 2020 (during COVID-19). Adult patients (≥18 years of age) who underwent any 1 of the 16 most frequently performed scheduled general surgery operations in the ACS-NSQIP database were included.Main Outcomes and MeasuresThe primary outcome was the percentage of outpatient cases (length of stay, 0 days) for each procedure. To determine the rate of change over time, multiple multivariable logistic regression models were used to assess the independent association of year with the odds of outpatient surgery.ResultsA total of 988 436 patients were identified (mean [SD] age, 54.5 [16.1] years; 574 683 women [58.1%]), of whom 823 746 underwent scheduled surgery before COVID-19 and 164 690 had surgery during COVID-19. On multivariable analysis, the odds of outpatient surgery during COVID-19 (vs 2019) were higher in patients who underwent mastectomy for cancer (odds ratio [OR], 2.49 [95% CI, 2.33-2.67]), minimally invasive adrenalectomy (OR, 1.93 [95% CI, 1.34-2.77]), thyroid lobectomy (OR, 1.43 [95% CI, 1.32-1.54]), breast lumpectomy (OR, 1.34 [95% CI, 1.23-1.46]), minimally invasive ventral hernia repair (OR, 1.21 [95% CI, 1.15-1.27]), minimally invasive sleeve gastrectomy (OR, 2.56 [95% CI, 1.89-3.48]), parathyroidectomy (OR, 1.24 [95% CI, 1.14-1.34]), and total thyroidectomy (OR, 1.53 [95% CI, 1.42-1.65]). These odds were all greater than those observed for 2019 vs 2018, 2018 vs 2017, and 2017 vs 2016, suggesting that an accelerated increase in outpatient surgery rates in 2020 occurred as a consequence of COVID-19, rather than a continuation of secular trends. Despite these findings, only 4 procedures had a clinically meaningful (≥10%) overall increase in outpatient surgery rates during the study period: mastectomy for cancer (+19.4%), thyroid lobectomy (+14.7%), minimally invasive ventral hernia repair (+10.6%), and parathyroidectomy (+10.0%).Conclusions and RelevanceIn this cohort study, the first year of the COVID-19 pandemic was associated with an accelerated transition to outpatient surgery for many scheduled general surgical operations; however, the magnitude of percentage increase was small for all but 4 procedure types. Further studies should explore potential barriers to the uptake of this approach, particularly for procedures that have been shown to be safe when performed in an outpatient setting.

AbstractBackgroundBilateral idiopathic hyperaldosteronism (IHA) is responsible for 60% of primary aldosteronism (PA) cases. Medical management is standard of care for IHA. Unilateral adrenalectomy (UA) with the intent of debulking total aldosterone production as a palliative measure remains controversial.MethodsSingle‐center retrospective review (2010–2020) of patients undergoing UA with a diagnosis of PA due to IHA (lateralization index [LI] on adrenal venous sampling [AVS] < 4). Demographic, pre‐operative, intra‐operative, and post‐operative variables were assessed. Hypertensive regimens were converted to the WHO Defined Daily Dose (DDD).ResultsTwenty‐four patients were identified, 14, 58% male and mean age 52 ± 10 years. Preoperative hypokalemia was present in 22, 92% of patients. Median number of antihypertensives taken was 3 (interquartile range [IQR], 2–4) and median DDD was 4 (IQR, 3–5.3). Median lateralization index on AVS was 3.52 (range, 1.19–3.88). All operations were performed in minimally invasive fashion. There were no conversions to open procedure, ICU admissions, or post‐operative complications. Median follow‐up was 10.5 months (range, 1–145 months). Hypokalemia resolved in 17, 76% of patients at last follow‐up. Post‐operative median number of antihypertensives taken was 1 (IQR, 1–3) and median DDD was 2 (IQR, 0.5–2.75) from 4, P = 0.003. Three (%) patients required continuation of mineralocorticoid receptor antagonists post‐operatively. Blood pressure control improved in 65% of patients.ConclusionUnilateral adrenalectomy in the setting of bilateral hyperaldosteronism can improve blood pressure control and stabilize potassium levels in selected patients. Further prospective studies in larger cohorts will be necessary to further define the role of unilateral adrenalectomy in the setting of PA due to bilateral adrenal disease.