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ABSTRACT Background and Objectives Pancreatic neuroendocrine tumors (pNETs) account for 1%–2% of pancreatic tumors, with an increasing incidence. The safety of concurrent pancreas‐liver resections remains uncertain. This study evaluated the national outcomes of concurrent pancreatectomy and liver‐directed surgery for pNETs. Methods ACS‐NSQIP (2019–2023) was queried for adult patients who underwent pancreatectomy for pNETs. Concurrent liver‐directed procedures were identified by CPT code and classified as hepatectomy or ablation alone; patients were grouped as isolated pancreatectomy, concurrent hepatectomy, or concurrent ablation alone. Pre‐, intra‐, and postoperative characteristics were compared using inferential statistics. Multivariable logistic regression identified predictors of 30‐day morbidity, readmission, reoperation, and mortality, with Firth penalized likelihood used for rare outcomes. Results Of 4794 patients, 4587 (95.7%) underwent isolated pancreatectomy, 172 (3.6%) underwent concurrent hepatectomy, and 35 (0.7%) underwent concurrent ablation alone. Concurrent hepatectomy was parenchymal‐sparing in 163 of 172 patients (94.8%); only nine patients underwent a major hepatectomy. Overall morbidity was similar across groups (38.8%, 45.9%, and 42.9%; p = 0.154), as was serious morbidity (28.7%, 27.9%, 22.9%; p = 0.730) and 30‐day mortality (1.0%, 0.6%, 0%). On multivariable analysis, neither concurrent hepatectomy (OR 1.02, 95% CI 0.71–1.48) nor concurrent ablation (OR 0.94, 95% CI 0.46–1.93) was associated with morbidity. Pancreatoduodenectomy was associated with morbidity (OR 2.38, 95% CI 2.05–2.76), reoperation (OR 2.16, 95% CI 1.52–3.08), and mortality (OR 2.50, 95% CI 1.39–4.50), and a minimally invasive approach was associated with lower morbidity (OR 0.69, 95% CI 0.60–0.80). Conclusions Concurrent liver‐directed surgery was not associated with an increase in 30‐day morbidity or mortality after pancreatectomy for pNETs. These findings support the safety of concurrent hepatic resection in appropriately selected pNET patients.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Background Upstream regulators of the homologous recombination (HR) repair pathway are promising targets for overcoming temozolomide (TMZ) resistance. We investigated whether pharmacologic inhibition of Retinoblastoma Binding Protein 4 (RBBP4)/p300-mediated HR activity by CCS1477 or NEO2734 sensitizes glioblastoma (GBM) to TMZ. Methods Lentiviral-mediated shRNA was used to silence RBBP4 and EP300 (p300). A fluorescence-based multiplex flow-cytometric host cell reactivation assay was used to measure DNA repair activity, while TMZ-induced double-strand breaks (DSBs) were assessed using a comet assay and γ-H2AX foci formation. Cytotoxicity was monitored using an Incucyte device, and survival analysis was performed to evaluate efficacy in orthotopic tumor models. Drug distribution was assessed using liquid chromatography-mass spectrometry (LC-MS/MS) and acetylation of lysine 27 of histone H3 (H3K27Ac) immunofluorescence for target inhibition. Promoter occupancy was determined using chromatin immunoprecipitation. Results GBM patient-derived xenograft tumors with high RBBP4 expression showed elevated levels of 6 HR genes (RAD51, RAD50, BRCA1, BARD1, BRIP1, and FIGNL1), with RAD51 and BRIP1 correlating strongly with RBBP4 and p300. Silencing RBBP4 or p300 decreased HR and microhomologous-mediated end joining (MMEJ) activity and delayed repair of TMZ-induced DSBs. CCS1477 and NEO2734 suppressed RAD51 and MYC in a concentration-dependent manner, prolonged γ-H2AX foci, and enhanced TMZ sensitivity. Both compounds inhibited H3K27Ac and were detectable in orthotopic tumors by LC-MS/MS and significantly extended survival alone and in combination with TMZ. Conclusion These findings suggest that the RBBP4/p300-axis is a key regulator of HR-mediated repair of TMZ-induced DSBs, and inhibition by either CCS1477 or NEO2734 may be beneficial as monotherapy, but further studies are needed to determine the benefit of combining these agents with TMZ.

10513 Background: Prior reports of high frequency of BRCA1 and BRCA2 ( BRCA1/2 ) PVs among South Asian women from Bangladesh, India, Nepal, and Pakistan with breast or ovarian cancer require validation in large prospective unselected cohorts. Methods: Individual-level anonymized patient data from two prospective cohorts were pooled to evaluate the prevalence of germline PVs among South Asian women: the South Asian Regional Alliance for Hereditary Cancers (SARAH Consortium) in Bangladesh, Nepal, and Pakistan, and the previously reported Nurse-led Genetic Counseling and Awareness (NuGenA) expansion cohort in India. Both studies enrolled consecutive cases of histologically confirmed newly diagnosed breast or epithelial ovarian cancer irrespective of age at diagnosis or family history. In both studies, participants completed questionnaires on personal and family history (first-, second- or third-degree) and provided blood for germline genetic testing after written consent. PVs in cancer predisposition genes including ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MLH1, MSH2, MSH6, PALB2, RAD51C, RAD51D, and TP53 were identified as part of the studies utilizing a multigene panel and the results were returned to ordering clinicians. The data cutoff date for this analysis was November 30, 2025. Results: The analysis included 1,711 South Asian women with breast (n=1,210) or ovarian (n=501) cancer. A family history of breast or ovarian cancer was noted in 177 (10.3%). Among breast cancers, 94% were invasive, 84% were ductal, 35% were triple-negative and over two-thirds presented with nodal involvement. Germline PVs across 13 predisposition genes were observed in 17.7% of breast and 35.9% of ovarian cancers. Notably, BRCA1/2 PVs accounted for most of these PV (13.6% of breast and 28.3% of ovarian cancer cases) with PVs in all genes except BRCA1/2 under 1%. The frequency of BRCA1/2 PVs was 24.4% in triple-negative breast cancer and 8.0% in ER+/HER2-. BRCA1/2 PV carriers were diagnosed with breast cancer at a younger age than non-carriers (Median age: 42 vs 46 years, P<0.001), with no age difference observed in ovarian cancer (50 vs. 51 years, P=0.79). Notably, among the 306 BRCA1/2 PV carriers identified, 229 (74.2%) did not report a family history of breast or ovarian cancer. Conclusions: We confirm a high prevalence of BRCA1/2 PVs among unselected South Asian women with either breast or ovarian cancer. The observations of younger age at cancer diagnosis, and low rates of family history support the need for population-specific germline genetic testing and risk management strategies in South Asia.

Summary Achalasia is a motility condition defined by failure of relaxation of the lower esophageal sphincter and loss of peristalsis in the distal esophagus. Per-oral endoscopic myotomy (POEM) is a technique to reduce lower esophageal sphincter pressure. We performed a systematic review and meta-analysis to assess the association between POEM and the clinical outcomes. We performed a systematic review and a meta-analysis (CRD420251052240). Literature search was done on PubMed and Embase (up to 8 June 2025). Original studies involving achalasia patients who underwent esophageal POEM with impedance planimetry using 8-cm balloon at 30 or 40 mL filling volumes with 325 catheter only (not the 322-N catheter) were included. The outcomes of interest were the clinical response groups (responders’ Eckardt score [ES] &lt; 3 and non-responders’ ES &gt; 3), reflux esophagitis, cross-sectional area (CSA), distensibility index (DI), and diameter. Nineteen studies with 1215 patients were included. The responders (ES &lt; 3) showed a statistically significantly greater increase in DI due to POEM (post-op minus pre-op) (mean difference [MD] = 1.92 mm2/mmHg [0.32, 3.53], P = 0.02) as well as a higher postoperative DI (MD = 1.87 mm2/mmHg [0.04, 3.70], P = 0.05) (40 mL). Reflux esophagitis group had statistically significantly higher CSA and diameter values (CSA MD = 15.68 mm2 [6.91, 24.24], P = 0.0005) (diameter MD = 0.96 mm [0.58, 1.33], P &lt; 0.00001) but no statistically significant difference for DI as compared to the non-reflux esophagitis group (DI MD = 0.19 mm2/mmHg [−0.51, 0.89], P = 0.59). In achalasia patients undergoing esophageal POEM, a greater interval increase in the DI as well as a higher post-procedural DI absolute value predicts a favorable clinical response. Higher postoperative CSA and diameter were linked to reflux esophagitis.

Background: The medial femoral trochlea flap is used for treating recalcitrant scaphoid proximal pole nonunions. Although this requires resecting a substantial portion of the scapholunate interosseous ligament, the intercarpal angular relationships are preserved. Studies have demonstrated that lunate alignment is preserved despite loss of the scapholunate ligament because the scaphoid is reconstructed with an osteochondral flap that is larger than the resected nonunited proximal scaphoid. The technique of purposeful expansion of the scaphoid height has been termed scaphoid overstuffing . The purpose of this study is to characterize the effect of scaphoid overstuffing on force transmission across the scaphoid and lunate facets of the radius. Methods: Eleven fresh frozen cadaveric upper extremities without ligament instability were selected. The radiocarpal joint was exposed via a dorsal approach, and electronic pressure sensors were introduced. Three different states of the wrist were evaluated: native, scapholunate dissociation (SLD), and overstuffed (OS). Pressures were measured in 4 positions: 30° flexion, full wrist extension, 30° extension, and clenched fist. Pressures were measured in kPa and contact areas in mm 2 . Results: In all functional positions, the OS state had higher peak pressures across the scaphoid facet. This included 30° wrist flexion (OS 383 ± 221 kPa, P = .033), full wrist extension (OS 1068 ± 767 kPa, P = .022), 30° wrist extension (OS 880 ± 518 kPa, P < .001), and clenched fist (OS 1040 ± 736 kPa, P = .02). Conclusions: In functional wrist positions, overstuffing the scaphoid increases scaphoid facet peak contact pressures. Further study is needed to examine the long-term clinical consequences of these changes and the potential for accelerated cartilage degeneration.

Abstract Reactive arthritis is an immune-mediated arthropathy caused by a preceding remote infection. Typically, reactive arthritis affects the joints of the lower extremities but can occur in the upper extremity. There are a few case reports of reactive arthritis primarily involving the joints of the hand and wrist, necessitating surgical intervention. We describe the case of a 37-year-old, right-hand dominant female who presented with severe left wrist pain. After obtaining radiographs, she was diagnosed with severe erosive changes in the radiolunate joint and distal radioulnar joint (DRUJ) and secondary reactive gonococcal arthritis of the DRUJ. The patient failed conservative measures and ultimately underwent radioscapholunate (RSL) arthrodesis, distal ulna resection, and wrist denervation. Postoperatively, she had resolution of her pain and an excellent functional outcome. Refractory reactive arthritis of the DRUJ can cause concomitant adjacent joint erosive changes. Performing RSL arthrodesis and distal ulna resection can provide an excellent functional outcome and still allow motion to be preserved through the midcarpal joint. IV: Case report level IV or higher evidence.