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Esophageal squamous cell carcinoma (ESCC) remains a significant global health challenge, being the sixth leading cause of cancer mortality with pronounced geographic variability. The incidence rates range from 125 per 100,000 in northern China to 1–1.5 per 100,000 in the United States, driven by environmental and lifestyle factors such as tobacco and alcohol use, dietary habits, and pollution. Major modifiable risk factors include tobacco and alcohol consumption, with a synergistic risk increase when combined. Nonmodifiable risk factors include previous diagnoses of head and neck squamous cell carcinoma (H&N SCC), achalasia, and prior radiotherapy. Prevention strategies must be tailored to specific regional burdens to efficiently allocate medical and financial resources. Gastrointestinal endoscopy is crucial in reducing ESCC burden through early detection and characterization of neoplastic changes, such as high‐grade dysplasia. Early diagnosis significantly improves survival rates, while endoscopic resection of noninvasive dysplasia can prevent ESCC onset, reducing treatment burden for advanced disease. Postresection surveillance can detect high‐risk metachronous lesions. Despite these benefits, endoscopic prevention faces challenges, including the lack of high‐level evidence supporting its efficacy, opportunity costs, the need for specialized training and techniques, and the requirement for advanced technology investments. This Position Statement from the World Endoscopy Organization (WEO) aims to address these challenges, supplying recommendations for the exploitation of endoscopic resources regarding the possible role of screening, quality, and training for the detection, characterization, resection, and surveillance of ESCC.

Purpose: We report the first multicenter, prospective, randomized noninferiority controlled trial of steerable ureteroscopic renal evacuation (SURE) for nephrolithiasis treatment. Materials and Methods: Candidates for laser lithotripsy ≥18 years with ≥1 renal stone ≥7 mm and 7–20 mm stone burden were randomized 1:1 SURE vs ureteroscopy (URS). SURE was performed using the CVAC Aspiration System, a novel steerable irrigation–aspiration catheter. The primary efficacy end point was noninferiority in stone-free rate (SFR) based on zero residual fragments (RFs) 30 days postprocedure on noncontrast computed tomography. Secondary end points were superiority tests, stone clearance (percent stone volume reduction), residual stone volume (RSV), SFR (no RF >2 mm), and SFR (no RF >4 mm) 30 days postprocedure. Results: Of the subjects, 123 were randomized and 101 qualified for efficacy analysis (SURE 46 vs URS 55). Despite randomization, baseline URS stone volume was higher (SURE 485.0 ± 432.5 mm 3 vs URS 713.3 ± 558.5 mm 3 ). The primary noninferiority end point was achieved (SURE SFR 48% vs URS SFR 49%, p = 0.027, −1.3% [90% confidence interval; −18%, 15%]). Stone clearance was significantly higher for SURE vs URS subjects (SURE 96.9 ± 5.6% vs URS 92.9 ± 11.6%, p = 0.036); RSV was significantly lower (SURE 14.3 ± 3 0.9 mm 3 vs URS 70.2 ± 144.9 mm 3 , p = 0.012). SURE stone clearance and RSV were independent of baseline stone volume, but for URS degraded with increasing baseline stone volume. Safety was comparable between groups. Conclusions: SFR for SURE subjects was noninferior compared with URS subjects; stone clearance and RSV were significantly better with SURE, independent of baseline stone volume.

Abstract Introduction Incorporation of mammographic density to breast cancer risk models could improve risk stratification to tailor screening and prevention strategies according to risk. Robust evaluation of the value of adding mammographic density to models with comprehensive information on questionnaire-based risk factors and polygenic risk score is needed to determine its effectiveness in improving risk stratification of such models. Methods We used the Individualized Coherent Absolute Risk Estimator (iCARE) tool for risk model building and validation to incorporate density to a previously validated literature-based model with questionnaire-based risk factors and a 313-variant polygenic risk score (PRS). The model was evaluated for calibration and discrimination in three prospective cohorts of European-ancestry women (1,468 cases, 19,104 controls): US-based Nurses’ Health Study (NHS I and II) and Mayo Mammography Health Study (MMHS); and Sweden-based Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) study. Analyses were done separately for women younger (NHS II, KARMA) and older than 50 years (NHS I, MMHS, KARMA). Improvements in terms of risk stratification and reclassification proportions were assessed among European-ancestry women aged 50–70 years in US and Sweden. Results For women younger and older than 50 years, the model with questionnaire-based risk factors, PRS and density was generally well calibrated across risk with some evidence of miscalibration at the extremes of the risk distribution. Incorporation of density led to modest improvements risk discrimination beyond the model with questionnaire-based risk factors and PRS: the area under the curve (AUC) among younger women was 67.0% (95% CI: 63.5–70.6%) vs. 65.6% (95% CI: 61.9–69.3%) for models with and without density; and 66.1% (95% CI 64.4–67.8%) vs. 65.5% (95% CI: 63.8–67.2%) among older women. The model with density identified 18.4% of US women 50–70 years old ≥ 3% 5-year predicted risk (threshold used for recommending risk-reducing medication in the US), with 42.4% of future cases expected to occur in this group. At this threshold, 7.9% of US women were reclassified by adding density to the model, resulting in the identification of 2.8% of additional future cases. The model with density identified 10.3% of Swedish women ≥ 3% 5-year predicted risk, with 29.4% of future cases expected to occur in this group. At this threshold, 5.3% of women were reclassified with the addition of density, leading to the identification of an additional 4.4% of future cases. Conclusion Integrating density with questionnaire-based risk factors and PRS could potentially identify more women of European-ancestry with elevated risk of breast cancer in the United States and Sweden. Further investigations of the integrated model in non-European ancestry populations are needed prior to considering clinical applications.

Background: Myeloproliferative neoplasms (MPNs) are chronic leukemias with increased thrombotic risk. Venous thrombosis in MPN often occurs in atypical sites, such as splanchnic vein thrombosis (SVT), defined by thrombosis in the portal, hepatic, mesenteric, or splenic veins. Data to guide anticoagulation management of SVT in MPN patients is lacking. Objectives: The purpose of this study is to evaluate outcomes as well as the safety and efficacy of different anticoagulation strategies in MPN patients with SVT. Methods: A retrospective cohort study of MPN patients with SVT from 10 international centers was conducted. All centers performed systematic identification of adults with a World Health Organization 2016 diagnosis of an MPN (polycythemia vera [PV], essential thrombocythemia [ET], myelofibrosis [MF], prefibrotic MF, MPN-unclassifiable [MPN-U]) and confirmed SVT. Inclusion criteria were met if first SVT occurred after or within one year before MPN was diagnosed. The primary outcome was 1-year cumulative incidence of recurrent venous (VT) or arterial thrombosis (AT). Secondary outcomes included 1-year cumulative incidence of (1) major and clinically relevant non-major bleeding (CRNMB) by International Society on Thrombosis and Hemostasis criteria, (2) SVT recanalization; and (3) 1-year overall survival. Death as a competing risk was used for cumulative incidence analyses of recurrence and bleeding. Results: 486 MPN patients (median age at first SVT 51 years; 62.3% female) were identified. MPN diagnosis preceded SVT in 35.2% of patients (median time 4.8 years) and occurred simultaneously or within 1 year of first SVT in 64.8% of patients. 43.8% of patients had PV, 23.7% ET, 14.2% MF, 3.1% prefibrotic MF and 13.2% MPN-U. The most common driver mutation was in JAK2 (90.7%) followed by CALR (4.4%) and MPL (1.6%). SVT localization was isolated to portal (25.7%), hepatic (15.4%), mesenteric (1.9%), and splenic veins (4.3%), and in 51.2% of cases SVT occurred in multiple vessels. Prior VT or AT occurred in 8.8% and 4.1% of subjects, respectively. Cytoreduction (most commonly hydroxyurea [36.9%], interferon [9.6%] or JAK inhibitor [6.8%]) was started after SVT in 58.7% of newly diagnosed MPN patients and 40.6% of those with known MPN. 57.6% of patients were anticoagulated, 3.5% of patients were treated with an antiplatelet agent, and 11.7% were treated with both. The most common initial anticoagulants were vitamin K antagonists (VKA) (29.2%), direct oral anticoagulants (DOAC; 20.4%), and low-molecular-weight heparin (LMWH; 10.5%). DOACs were more commonly used in the USA and Asia than Europe (21.2%, 52%, and 13.5%; p<0.001). The median duration of anticoagulation was 23.9 months, with 62.8% still on anticoagulation after 3 years or at last follow-up. 1-year cumulative incidence of recurrent VT and AT was 14% (95% CI 11-18) (5.8% for recurrent SVT [95% CI 3.9-8.3]; 6.3% for other VT [95% CI 4.3-8.8]; 2.4% for AT [95% CI 1.3-4.2]), with an overall time to event 89 (IQR 34-193) days. Thrombosis incidence was similar in patients initially treated with VKA (13%), DOAC (15%) or LMWH (16%) (p=0.93); in comparison, individuals not treated with anticoagulation had 1-year thrombosis incidence of 13% (p=0.22). 1-year major and CRNMB cumulative incidence in all patients was 5.8% (95% CI 3.9-8.2) and 8.5% (95% CI 6.1-11), with median time to event 68 (IQR 13-150) days. Incidence of major bleeding was similar in VKA, DOAC, and LMWH-treated patients (5.9%, 6.6%, and 4.0%; p=0.89). 1-year cumulative incidence of SVT (partial) recanalization was 13% (95% CI 9.8-16) in all patients, with a median time to recanalization of 127 (IQR 40-323) days; recanalization rates were similar in anticoagulated and non-anticoagulated patients (p=0.76). There was a trend toward higher recanalization rates in patients treated with DOAC (26.9%) than with VKA (21.5%) or LMWH (13.6%; p=0.28). 1-year overall survival was 94.2% (95% CI 91.8-96.1) and similar between treatment groups (VKA 96.7%, DOAC 95.6%, LMWH 89.7%; p=0.11) and for no anticoagulation (82.3%; p=0.32). Conclusions: This is the largest contemporary cohort of MPN patients with SVT. MPN patients with SVT remain at risk for short-term thrombosis and bleeding complications regardless of treatment. We found no significant differences in outcomes between anticoagulation strategies, including in patients treated with DOACs compared to VKA or LMWH.

Background. Study of myeloid neoplasms (MN) has been rapidly transformed by genome characterization. Gene mutations have been reported to influence disease phenotype and risk of disease progression, and the evaluation of mutational status can provide valuable insights to improve the decision-making process. In this international study, we evaluated the clinical impact of mutational screening in patients with CMML, which is characterized by significant clinical and genomic heterogeneity, including a substantial proportion of patients with poor outcomes and unmet needs. Currently, only limited molecular information has been incorporated into CMML classification and prognostication. Methods. We retrospectively collected 3182 CMML patients. We used MOSAIC, an AI-based framework for multimodal analysis in rare cancers (PMID: 38875514) to develop innovative, molecular-based tools for classification and prognostication. An independent validation of the results on 516 prospectively collected patients was performed. Results. Bayesian Networs and Hierarchical Dirichlet Processes were used to identify genomic associations and define a CMML molecular classification. We identified 11 clusters with distinct clinical and genomic features, including splicing machinery, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures (i.e., AML-like and TP53 mutations). Up to 15% of patients showed clear genomic overlap with other MN. Importantly, extensive multi-color flow cytometry on T lymphocytes, NK and myeloid cells (BD FACSymphony A5 Cell Analyzer) revealed specific immunologic and inflammation signatures associated with molecular subgroups. We then integrated molecular and clinical information to build an international CMML Prognostic Scoring System (iCPSS). We assessed the performance of different statistical and AI-based methods; L1-penalized Cox Model resulted as the best performing method. Selected features included hematological parameters (WBC, Hb, PLT and marrow blasts), cytogenetic abnormalities, and mutations in 10 genes (ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SETBP1, STAG2, TET2, TP53, U2AF1). By Bayesian thresholds optimization, we identified 5 risk classes (i.e., very-low, low, intermediate, high and very-high) with median overall survival (OS) ranging from 99 to 9 months (P<.001), and median leukemia-free survival (LFS) ranging from 210 to 18 months (P<.001). iCPSS provided better patient discrimination across all clinical endpoints compared to currently available prognostic tools, with a Concordance Index (CI) for OS of 0.75 versus 0.62-0.64, respectively. Notably, compared to available scoring systems, up to 40% of patients were reassigned to higher or lower risk classes by the iCPSS. External validation on an independent prospective cohort confirmed that the performance of iCPSS is superior to existing prognostic models (CI for OS 0.71 vs 0.54-0.61, respectively) To demonstrate the clinical utility of iCPSS, we focused on 753 patients who underwent allogeneic stem cell transplantation (HSCT). In multivariable analysis, iCPSS stratified the probability of OS post-HSCT (P<.001) and identified groups of patients with different probabilities of disease relapse, ranging from 9% to 62% (P<.001). We employed a clinical- and genomic-based decision support system (PMID: 38723212) to determine the optimal timing of HSCT. Preliminary analyses indicated that higher-risk patients according to iCPSS (i.e., intermediate, high, and very high) benefit from an immediate HSCT strategy. Lower-risk patients (i.e., very low and low) had life expectancy maximized with delayed HSCT. Modeling decision analysis using iCPSS compared to conventional scores, resulted in a change in transplantation policy for a significant proportion of patients (up to 25%). Conclusion. Molecular information significantly improves the classification of CMML patients, providing a basis for refining diagnostic boundaries with other MN and for a more rational inclusion of patients in clinical trials. The iCPSS demonstrated superior performance over currently available scoring systems and improved HSCT decision making process.

Background Short-term outcomes after pancreatoduodenectomy (PD) are well-studied, but long-term reoperation rates and their indications remain poorly characterized. Methods A single-center retrospective chart review was performed on patients who underwent PD for pancreatic adenocarcinoma between 1/2011 and 12/2021. Reoperations occurring >90 days after PD were dichotomized to being related or unrelated to the index PD or pancreatic adenocarcinoma. The Kaplan-Meier analysis estimated the incidence of long-term reoperation at 1 and 5 years postoperatively. Results Six-hundred twenty-eight patients were included. The 5-year incidence of any additional operation >90 days after PD was 30.0% (95% CI 23.2-36.2%), and the 5-year incidence of any long-term related reoperation was 21.2% (95% CI 15.0-26.8%). The most common indications for reoperations by 5-year incidence were cancer recurrence (12.8%, 95% CI 7.6-17.7%), incisional hernia (6.2%, 95% CI 2.6-9.7%), small bowel obstruction (1.3%, 95% CI 0.2-2.4%), and leak, fistula, or infection (1.0%, 95% CI 0.1-2.0%). Of the examined risk factors, only 90-day reoperation was found to be predictive of long-term related reoperations ( P = 0.02). Additionally, the 5-year incidence of endoscopic or interventional radiology procedures was 20.2% (95% CI 14.5-25.4%). However, 40.9% (95% CI 33.6-47.3%) of patients required additional surgery or procedures of any kind between 90 days and 5 years after PD. Discussion Within 5 years of PD, one in three patients required additional surgery, and one in five had operations for related indications. Related reoperative indications included recurrence, hernia, PD-specific complications, and small bowel obstruction. However, the rates of each of these reoperations were relatively low.

Abstract Background The recognition of autoimmune causes of encephalitis has led to epidemiological shifts in the worldwide characteristics of encephalitis. N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis leads to well-established complex neuropsychiatric manifestations. In low- and middle-income countries, including Vietnam, its relative incidence, especially in children, is unknown and most neurologists currently consider infectious encephalitis prior to autoimmune etiologies. Methods The study was prospectively conducted at Children's Hospital 1 in Ho Chi Minh City between March 2020 and December 2022. Any child admitted to the Department of Infectious Diseases and Neurology fulfilling the case definition of encephalitis was eligible to participate. Cerebrospinal fluid samples were collected alongside meta-clinical data for analysis. Results We recruited 164 children with a clinical diagnosis of encephalitis. Etiologies were determined as NMDAR antibody encephalitis in 23 of 164 cases (14.0%), Japanese encephalitis virus in 14 of 164 (8.5%), and herpes simplex virus in 4 of 164 (2.4%). Clinical categorizations suggested idiopathic viral encephalitis in another 71 (43.3%), and autoimmune encephalitis of unknown origin in the remaining 52. Factors including demographics, specific clinical features, cerebrospinal fluid and electroencephalogram findings, and length of hospital stay were significantly different between NMDAR antibody encephalitis and Japanese encephalitis. Conclusions At a tertiary children's hospital in Vietnam, the prevalence of NMDAR antibody encephalitis exceeds that of Japanese encephalitis, the most common infectious encephalitis cause in Southeast Asia. NMDAR antibody encephalitis is associated with long hospital stay and poor outcomes. These findings should change pediatric diagnostics, to earlier consider autoimmune treatments in this clinical setting.

ABSTRACT. Encephalitis is a significant global health problem, especially in children. Knowledge of its economic burden is essential for policymakers in prioritizing the development and implementation of interventions but remains limited. An observational study was prospectively conducted at a major children’s hospital in Ho Chi Minh City, Vietnam from 2020 to 2022. Data on direct medical costs, direct nonmedical costs, and productivity costs were collected alongside demographic information, clinical features, diagnosis, severity, and outcomes of study participants. This was used to undertake a cost of illness analysis from a societal perspective. Data were collected from a total of 164 pediatric patients. The median cost of illness was estimated at US $1,859 (interquartile range [IQR]: US $1,273–$3,128). The direct costs were the main cost driver, accounting for 83.9% of the total cost of illness (US $1,560; IQR: US $975–$2,460). The productivity costs accounted for a median of US $275 (IQR: US $154–$474). The cost of illness was higher in more severe patients, patients with sequelae, patients with morbidities, and ventilated patients. Most direct medical costs were attributed to hospitalization and resulted in out-of-pocket payments from the patient’s family (30.2%; US $316). The results showed that the cost of illness of encephalitis in children is considerable and will be useful for policymakers in prioritizing resources for the development and implementation of intervention strategies to reduce the burden of pediatric encephalitis.

Background: Gain-of-function mutations in the canonical transient receptor potential 6 (TRPC6) channel contribute to heart failure (HF) and focal segmental glomerulosclerosis in humans. Our GWAS results indicated that the TRPC6 A404V variant, having a minor allele frequency of 12% in the population, is associated with doxorubicin-induced cardiotoxicity. However, the underlying ionic mechanisms of this variant have not been fully examined. Methods: Combining patch clamp recording, site-directed mutagenesis, and in-silico analysis, we evaluated the TRPC6 A404V variant function. Results: Whole-cell TRPC6 currents were elicited in HEK293 cells using a voltage ramp protocol from -100 mV to +100 mV with a holding potential of -60 mV, 48 hours after transfection with TRPC6 WT or A404V cDNAs. The inward-current densities at -100 mV and the outward-current densities at +100 mV for TRPC6 WT and A404V variant were similar at baseline. However, after exposure to 50 μM 1-oleoyl acetyl-sn-glycerol (OAG, a TRPC6 activator), these current densities were significantly increased by 2.6-fold and 4.5-fold respectively in the WT (n=20 cells), and by 8.4-fold and 8.9-fold respectively in the A404V variant (n=12 cells, p<0.05 vs. WT). The OAG effects were abolished by superfusion with 1 μM BI-749327 (a specific TRPC6 inhibitor). Moreover, a 24-hour treatment with 0.5 μM doxorubicin (DOX) further amplified the effects of OAG, increasing the total inward- and outward-current densities by 7.2-fold and 9.5-fold respectively in TRPC6 WT (n=11 cells), and by 13.9-fold and 14.7-fold respectively in the A404V variant (n=13 cells, p<0.05 vs. WT). In comparison, the OAG effects on TRPC6 WT and A404V channels were not potentiated by treatment with 0.5 μM doxorubicinol (DOXol, a metabolite of DOX) for 24 h (n=10-12 cells, p=N.S.). Molecular docking studies showed that OAG had a lower binding energy (-5.60 kcal/mol) and a smaller apparent equilibrium constant (Kd) of 0.079 mM with the A404V variant, compared to those of -4.49 kcal/mol and 0.511 mM respectively with TTRPC6 WT. Conclusion: TRPC6 A404V is a gain-of-function variant with a higher binding affinity to OAG. Treatment with DOX but not DOXol greatly enhances TRPC6 WT and A404V channel activation by OAG. Thus, cancer patients carrying the TRPC6 A404V variant may be more vulnerable to develop HF upon treatment with anthracycline.

Abstract Background and Aims Individuals with inflammatory bowel disease (IBD) experience a high symptom burden, including abdominal pain, fatigue, anxiety, depression, and sleep disturbances; yet, little is known regarding the relationship between sex and gender on symptoms. We sought to report symptom severity for cisgender men, cisgender women, and transgender and gender-diverse (TGD) individuals. In addition, we used network analysis to identify core symptoms and explore if symptoms and their relationships differ between cisgender men and cisgender women. Methods This was a cross-sectional study. We recruited adults with IBD online through ResearchMatch. Individuals responded to Patient-Reported Outcomes Measurement Information symptom questionnaires, as well as demographic and clinical questionnaires. Network analysis was used to identify the core symptoms driving the symptom structure. Results One-hundred and fifty-seven (63.3%) participants identified as cisgender women, 84 (33.9%) as cisgender men, and 7 (2.8%) as TGD. Cisgender men (M = 61.8) and TGD (M = 61.3) groups reported higher abdominal pain levels compared with cisgender women (M = 57.8; P = .02). Transgender and gender-diverse individuals reported higher depression levels (M = 64.8) compared with cisgender men (M = 56.7) and cisgender women (M = 54.4; P = .01). Using a network analysis approach, anxiety and fatigue emerged as core symptoms for the entire sample (clinically active and inactive disease), and among only those with active clinical disease. Fatigue was a top core symptom for cisgender women; anxiety emerged as a top core symptom for cisgender men. Conclusions This study highlights that fatigue and anxiety are core symptoms among individuals with IBD and demonstrates a potential sex and/or gender difference in core symptoms. Replication of this study is needed with further consideration of inclusion of TGD patients.