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e15682 Background: Small cell carcinoma (SCC) of gastrointestinal tract is a highly aggressive rare malignancy with an estimated prevalence of 0.1% to 1% of all GI neoplasms. Treatment and survival outcomes data are very limited. Here we present an analysis of outcomes of patients with intestinal SCC using data from the Survival, Epidemiology, and End Result (SEER) database. Methods: SEER (2000-2020) was used to identify patients with SCC involving of the small intestine, colon and rectum. Variables included age, race, site, stage, chemotherapy (chemo), radiation therapy (RT) and surgery. Cox regression was used to model survival outcomes based on site, stage, and treatment received in the overall group and stage subgroups. Results: 1,169 patients with SCC of the small intestine, colon, and rectum were identified. Median age was 65 (24-90). 631 (54%) were male; majority of patients were white (989; 85%), followed by black (128; 11%) and other races (50; 4.3%). Colon (569; 49%) and rectum (514; 44%) were the predominant sites while small intestine only comprised 7.4% of the patients. Distant, regional and local diseases were reported in 55%, 17% and 7.5% of the patients. Median overall survival (mOS) of the entire group was 8 months (m). Primary tumor sites of small intestine and rectum were significantly associated with lower mortality rate in comparison to colon (11 m and 9 m vs 5 m, p < 0.001 for both). Patients with localized disease had the lowest mortality rate when compared with those with regional or distant metastatic diseases (38 m vs. 16 m and 5 m, p < 0.001 for both). Receiving surgery (HR: 0.458, p < 0.001), chemo (HR: 0.473, p < 0.001), and RT (HR: 0.733, p = 0.003) were all significantly associated with lower mortality rate (Table). These differences remained significant in each stage-based subgroup except for chemotherapy in localized disease subgroup, which encompassed only 87 patients. Conclusions: Intestinal SCC has poor prognosis, with SCC of the colon being most prevalent and with the highest mortality. Majority of patients presented with distant metastatic disease which led to high mortality. Multimodality treatment may improve survival for these patients. Number of cases (%) HR (CI) p-value mOS (months) vs reference Site (ref: colon) Rectum 514 (44%) 0.750 (0.648-0.867) <0.001 9 (ref: 5) Small intestine 86 (7.4%) 0.574 (0.44-0.749) <0.001 11 (ref: 5) Stage (ref: localized) Regional 201 (17%) 2.087 (1.507-2.891) <0.001 16 (ref: 38) Distant 639 (55%) 4.222 (3.110-5.733) <0.001 5 (ref: 38) Unknown/unstaged 242 (21%) 1.639 (1.160-2.315) 0.005 8 (ref: 38) Chemo (ref: none/unknown) Yes 590 (50%) 0.473 (0.404-0.553) <0.001 10 (ref:3) RT (ref: none/unknown) Yes 175 (15%) 0.733 (0.598-0.897) 0.003 12 (ref: 7) Surgery (ref: no surgery) Yes 363 (31%) 0.458 (0.385-0.546) <0.001 12 (ref: 6) Unknown 138 (12%) 0.717 (0.549-0.936) 0.01 7.5 (ref: 6)

Abstract Chronic overlapping pain conditions (COPCs) affect a wide population and incur a substantial disease burden including comorbid mental disorders. Although these comorbidities have been extensively documented, the longitudinal trajectories of their onset, particularly for those with three or more conditions, have been rarely studied. We conducted retrospective cohort studies to identify statistically significant COPCs and mental health trajectories in the All of Us Research Program (AoU v8, 338,170 persons) and the Mayo Data Warehouse (3,957,444 individuals). For each trajectory, cases were matched with controls by demographic factors. Logistic regression was then applied to assess the increased likelihood of the final condition given the prior conditions in that sequence. The significant trajectories were visualized as a “pain forest.” More than 88% of trajectories identified from AoU (Male: 78, Female: 361) were reproducible in the Mayo Data Warehouse data (Male: 361, Female: 1286), with female trajectories encompassing more than 96% of the male trajectories. The findings indicate that chronic low back pain generally occurs earlier than other conditions, while fibromyalgia tends to follow other COPCs. Endometriosis seems to be associated with an increased prevalence of COPCs in women. In addition, longer trajectories are associated with a greater risk of developing additional COPC or mental condition. The results offer new insights into the progression of COPCs and associated mental conditions, which may inform healthcare providers and patients in managing and preventing exacerbation of these conditions.

Abstract Background Optimal treatment for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma remains unclear due to limited head-to-head comparisons among chemotherapy and chemoradiation regimens. This network meta-analysis aimed to determine the relative efficacy of available multimodality treatment regimens in these patients. Methods MEDLINE, EMBASE, Scopus, Web of Science, and CENTRAL were searched till September 20, 2024. Phase 3 randomized trials evaluating perioperative/neoadjuvant systemic therapy ± radiation in resectable gastric/GEJ adenocarcinoma were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Frequentist network meta-analysis was conducted to compare hazard ratios (HRs) and 95% confidence intervals (CIs). Results Fifteen trials (8072 patients) were analyzed. pFLOT (perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel) ranked highest for DFS in the overall population (P-score 91%), achieving significant improvements compared to surgery alone (HR 0.48, 95% CI, 0.38-0.60) and nCROSS (neoadjuvant paclitaxel, carboplatin, and radiotherapy) (0.67, 0.56-0.81). For OS, nPLF + nCRT(EP) (neoadjuvant cisplatin, leucovorin, and fluorouracil for induction, followed by etoposide, cisplatin, and radiotherapy) (P-score 90%) and pFLOT (P-score 87%) were the top regimens. pFLOT significantly outperformed surgery alone (0.57, 0.45-0.72) and nCROSS (0.73, 0.60-0.89). Based on the limited data available, adding neoadjuvant chemoradiation to pFLOT provided no additional OS (1.14, 0.76-1.72) or DFS (1.22, 0.83-1.82) benefit. Similarly, adding pembrolizumab to perioperative chemotherapy (cisplatin and fluorouracil/capecitabine) was not superior to pFLOT (DFS: 1.10, 0.71-1.69; OS: 1.09, 0.69-1.72). Conclusions pFLOT demonstrated superior efficacy in resectable gastric/GEJ adenocarcinoma, outperforming surgery alone, nCROSS, and alternative perioperative regimens. The additive role of immunotherapy requires further investigation to optimize patient selection and outcomes.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

AbstractStandard of care first‐line systemic treatment for advanced biliary tract cancer includes chemo‐immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo‐immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo‐immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty‐eight patients were included in this study. Two hundred twenty‐seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first‐line chemo‐immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil‐to‐lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.

ABSTRACTMost discussions about discrimination and bias in anatomical research papers have been limited to terminology relating to race/ethnicity and gender/sex. However, as editors of anatomical journals, the authors of this article have frequently observed broader instances of potential discrimination and bias within anatomical research. These often stem from differences among authors' backgrounds, traditions, cultures, religions, provenance/origins, and workplace affiliations. In view of the limited discourse on this topic, we seek in this article to establish a consensus among editors of anatomical journals and to propose new Guidelines Against Discrimination and Bias in Anatomical Research Papers (GDBARP). We have identified multiple factors that can contribute to discrimination and bias, underscoring the need for greater awareness and proactive measures. It is imperative in anatomical research to respect authors, reviewers, and editors regardless of their background, culture, traditions, sex, ethnicity, language, religion, or ethical perspectives.

Abstract Rationale: SARS-CoV-2 infection may be associated with new or worsening respiratory symptoms that, if persistent, may contribute to “Long COVID.” Research is needed on the prevalence and risk determinants of Long COVID and related respiratory symptoms in adults with and without pre-existing obstructive lung disease or smoking history. Methods: C4R is a prospective, observational study that collected information on SARS-CoV-2 infection using standardized methods across 14 NIH-funded cohorts. The third wave of C4R questionnaires, administered June 2023 to January 2025, assessed self-reported Long COVID via the question, “Do you think that you are experiencing, or have ever experienced, what has been called “long COVID,” or symptoms related to COVID at least a month after your infection?” Questionnaires also assessed the presence (vs absence) of 22 symptoms that have been linked to Long COVID, including cough, shortness of breath, and post-exertional malaise. Pre-pandemic obstructive lung disease (COPD or asthma) and smoking status (ever/never) were harmonized from self-reported data collected at the most recent pre-pandemic cohort exam. Poisson regression was used to assess prevalence ratios (PRs) adjusting for age, sex, BMI, education, and pre-pandemic hypertension, diabetes, cardiovascular disease, and depressive symptoms. PRs for respiratory symptoms were tested according to self-reported Long COVID and history of non-hospitalized or hospitalized infection; effect modification by pre-pandemic lung disease and smoking was assessed by multiplicative interaction terms and in fully stratified models. Results: Among 23,434 questionnaire respondents, 1,484 (6.3%) self-reported Long COVID, including 246/1,262 (19.5%) with pre-pandemic lung disease and 664/4,018 (16.5%) with smoking history. The adjusted PR for Long COVID was 1.17 (95%CI:0.99-1.39;P=0.06) comparing participants with/without lung disease and 1.17 (95%CI:1.04-1.32;P=0.01) comparing participants with/without smoking history. Respiratory symptoms were more prevalent in those with self-reported Long COVID, as well as in those with a history of hospitalized or non-hospitalized infection (Table). Associations were generally stronger in participants without pre-pandemic lung disease (p-interaction&lt;0.05 for all comparisons). Respiratory symptoms were also more prevalent with a history of repeated, and pre-Omicron infections, and were less prevalent among participants vaccinated prior to their first infection; findings were similar even after excluding participants with self-reported Long COVID. Conclusions: Long COVID is common, particularly in adults with pre-existing COPD or asthma or smoking history. Long COVID and history of SARS-CoV-2 infection, including non-hospitalized infections, was associated with greater respiratory symptom burden. Whether SARS-CoV-2 infection or Long COVID are associated with development or progression of obstructive lung diseases warrants future studies.

Abstract INTRODUCTION While cardiac comorbidities or factors predisposing infection are common in patients with ESRD, one less common cause for pleural effusion in peritoneal dialysis (PD) patients is pleuroperitoneal communication. We present herein a case of a PD patient with large, right-sided pleural effusion one year after starting PD. CASE REPORT An 82-year-old female with ESRD managed on home continuous cycling peritoneal dialysis (CCPD) for 1 year presented to the Emergency Department (ED) with new-onset dyspnea. She recently completed a course of vancomycin for bacterial peritonitis secondary to PD catheter infection. She also reported that her home CCPD machine was not draining the fill amount in recent weeks. She was afebrile and hemodynamically stable on arrival. CT at the ED showed a large, right-sided pleural effusion. She underwent thoracentesis with pending fluid analysis, and experienced subsequent improvement in her dyspnea. She was then hospitalized and wished to continue PD over pursuing intermittent hemodialysis (iHD) while workup was pending, despite clinical suspicion for pleuroperitoneal fistula (PPF). She started inpatient CCPD, and drains following each dwell showed less than expected volumes with no additional output on manual drains. She reported worsening dyspnea the next morning, and bedside POCUS confirmed reaccumulation of her pleural effusion. Fluid analysis revealed a transudative pleural fluid profile, with pleural glucose of 583mg/dL and serum glucose of 80mg/dL. Given her recent peritonitis, suspicion was greatest for PPF. The patient was transitioned from PD to iHD to allow time for the suspected fistula to heal, and subsequent imaging obtained during her hospitalization did not show reaccumulation of her unilateral pleural effusion. DISCUSSION Pleuroperitoneal communication may occur due to congenital or acquired diaphagmatic defects, or insults such as the case in our patient with recent peritonitis. In fact, diaphragmatic blebs from age related degeneration and chronic increased intraabdominal pressure have been reported to cause hydrothorax in patients undergoing PD. Diagnosis of PD-associated pleural effusions is based on clinical suspicion, with pleural studies showing high pleural fluid to serum glucose gradient, and imaging commonly showing unilateral right-sided pleural effusions. Recent peritoneal dialysis with low drainage further supports PD as the etiology. Most cases of PD-associated pleural effusions occur soon after PD initiation, but cases occurring years after initiation have been reported. Management involves halting PD and thoracentesis for symptomatic relief. Patients may need transitioning to iHD indefinitely, or may resume PD after a pause if the cause of communication is reversible.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non–small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration is prognostic for disease progression and integrate additional pre-CRT risk factors, including radiomics, into a combined model that improves outcome prediction. Our results suggest that tumor features, radiomics, and mid-CRT ctDNA analysis are complementary and can identify patients at high and low risk of progression to potentially enable response-adapted therapies. Significance: This study demonstrates that combining tumor features, radiomics, and ctDNA analysis improves outcome prediction in NSCLC treated with CRT therapy. Our integrated model could enable personalized and response-adapted therapies to reduce toxicity and improve outcomes in patients. See related commentary by Anagnostou and Aggarwal, p. 1534