Citations

Abstract Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and perinatal morbidity, yet modifiable environmental risk factors remain poorly characterized. Prior studies typically have only examined a limited number of exposures and have rarely distinguished HDP subtypes (ie, gestational hypertension, preeclampsia, eclampsia, and chronic hypertension with or without superimposed preeclampsia) or accounted for residential mobility during pregnancy. To address these gaps, we conducted a spatial and contextual exposome study of HDP using linked electronic health records (EHR) and vital statistics data in Florida. We analyzed 686 412 singleton pregnancies conceived between 2013 and 2018, using computable phenotyping to distinguish HDP subtypes. A total of 245 spatial and contextual exposome measures spanning natural, built, and social environments were linked to residential histories from conception through gestational week 19. Using a two-phase double machine learning (DML) framework with exposure-specific, directed acyclic graph-guided confounder adjustment, we conducted discovery and replication analyses, followed by multi-treatment DML to estimate effect sizes. In Phase 1, 26 exposome measures replicated for gestational hypertension and 34 for overall HDP. In Phase 2, 12 measures remained associated with gestational hypertension and 11 with overall HDP, including air toxicants, meteorological factors, ultraviolet radiation, neighborhood crime indicators, environmental noise, and proximity to coastline. No exposures passed multiple-comparison thresholds for preeclampsia or eclampsia. These findings demonstrate that the spatial and contextual exposome contributes to HDP in a subtype-specific manner. Integrating EHR-linked phenotyping, residential mobility, and causal machine-learning methods offers a scalable framework for identifying environmental factors relevant to HDP prevention.

This cohort study evaluates the reduction in risk of high-grade serous carcinoma among women undergoing opportunistic bilateral salpingectomy in Canada.

Abstract Radiation therapy (RT) has long been included in the treatment of glioblastoma (GBM). However, radioresistance in cancer cells as well as toxicity in normal tissues are major obstacles to clinical efficacy. Improved understanding of the mechanisms of tumor microenvironment-induced radioresistance during and after radiation therapy can provide fundamental insights to improve clinical outcomes in GBM. Here, using three-dimensional engineered hydrogel models in vitro, we report the influence of extracellular matrix, hypoxia, and adjacent neuronal cells in radiotherapeutic sensitivity. We find that mechanical cues and oxygen availability regulate cellular response to radiation, with softer matrices allowing for more DNA damage. Hyaluronan fragments from the extracellular matrix also modulate rapid metabolic response to radiation, especially in hypoxic environments. We show that neuronal networks influence tumor metabolic activity and the inflammatory response. Overall, we demonstrate here that alternative radiation strategies, such as low dose rate radiation therapy and microenvironmental regulation, have the potential to be more effective in a specific subset of radiosensitive GBM tumors.

TPS611 Background: GPC3 is an oncofetal protein expressed in up to 75% of hepatocellular carcinomas (HCCs) and associated with poor prognosis. Its selective expression in tumor and not in normal tissue makes it a promising target for radiopharmaceutical imaging and therapy (theranostics). The GPC3-selective diagnostic RYZ811 ([ 68 Ga]Ga-RAYZ-8009) and therapeutic α particle-emitting RYZ801 ([ 225 Ac]Ac-RAYZ-8009) are a theranostic pair. Previous studies show high uptake of RYZ811 in intrahepatic and extrahepatic HCCs, with low normal liver background uptake. In GPC3+ HCC mouse models, single administrations of RYZ801 significantly inhibited tumor growth. Methods: RYZ801-101 is a single-arm, open-label, phase 1/1b study of RYZ811 and RYZ801 in previously treated patients with GPC3+ unresectable HCC. The study has two parts: dose escalation (part 1) and dose expansion (part 2). Each part consists of two stages: RYZ811 imaging and RYZ801 treatment. The aim of imaging is to determine if RYZ811 safely and adequately identifies patients with GPC3+ tumors. The aim of treatment is to determine the safety, pharmacokinetics (PK), recommended phase 2 dose (RP2D; part 1), and preliminary antitumor activity (part 2) of RYZ801. Key eligibility criteria are: confirmed HCC; Barcelona Clinic Liver Cancer stage B or C; Child-Pugh A; ≥1 RECIST v1.1-measurable lesion (treatment stage); and disease progression after ≥1 systemic therapy in part 1 and 1 prior line in part 2. In part 1, approximately 60 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 30 of these will receive escalating doses of RYZ801 (2.6–5.5 MBq × 4 doses) in the treatment stage. In part 2, approximately 80 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 40 of these will receive RYZ801 at the RP2D in the treatment stage. Primary RYZ811 objectives are to assess the safety/tolerability and biodistribution of RYZ811. Secondary objectives are to determine absorbed doses (ADs) to organs and tissues and any association between RYZ811 uptake and RYZ801 efficacy. Primary RYZ801 objectives are to identify the RP2D and safety/tolerability of RYZ801. Secondary objectives are to assess PK, ADs to critical organs and tumors, and preliminary antitumor activity. Enrollment for Part 1 is ongoing in the USA. Clinical trial information: NCT06726161 .

566 Background: FGFR inhibitors (FGFRi) have an established role in treating FGFR2-altered (alt) cholangiocarcinoma (CCA). Tinengotinib, a novel FGFRi, has shown promising activity overcoming acquired resistance to prior FGFRi. We present biomarker analyses evaluating tinengotinib’s ability to overcome prior FGFRi resistance and to elucidate mechanism of resistance to tinengotinib. Methods: Eligible patients (pts) with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy were treated with tinengotinib 10 mg daily across 4 Cohorts: A1: FGFR2 fusion (fus) with primary progressive disease (PD) on prior FGFRi; A2: FGFR2 fus with PD after prior response to FGFRi; B: FGFR alt without FGFR2 fus; C: FGFR wild-type. Efficacy was assessed by RECIST v1.1. All pts underwent liquid biopsy for circulating tumor DNA (ctDNA) at baseline; additional timepoints include cycle 3 day 1 (C3D1), time of PD, and end of treatment (EOT). Samples were analyzed using FoundationOne Liquid panel. Results: 27 out of 55 enrolled pts had biomarker samples collected at baseline and C3D1. Among them, pts in A1 (n=10, 107 mutations (mut)), B (n=8, 90 mut) and C (n=5, 74 mut) showed a significant decrease in short variant allele frequencies (VAF) from baseline to C3D1 by a median relative VAF reduction of 100% (p<0.0001) for each of the three cohorts. Although a median relative VAF reduction of 33.3% was seen in A2 (n=4, 15 mut), this was not significant (p=0.6093) likely due to low baseline mutation burden. A ≥50% reduction in ctDNA was associated with improved progression free survival (p<0.0014). Additionally, 100% of median relative reductions in FGFR2 kinase domain (KD) mut were seen in A1 and B (p<0.0001, 95% CI 100-100% and p=0.0156, 95% CI 83.6-100%, respectively), with 92% and 57% clearance of initial FGFR2 KD mut by C3D1. In a subgroup of 10 pts with biomarker sampling at baseline and EOT, 3 pts in A1 with acquired resistance showed emergence of novel FGFR2 mut, loss of FGFR-sensitive mut and new mut in alternate pathways (e.g., AKT, EGFR, RAS/MAPK) while retaining the original FGFR2 fus. 1 pt from B developed resistance due to new FGFR2 rearrangements and FGFR2 mut. 4 FGFR wild-type pts from C developed resistance involving mut in TP53, KRAS, and other oncogenic drivers. Conclusions: These findings provide genomic evidence that tinengotinib may overcome resistance to prior FGFRi treatment in FGFR2 fus-positive CCA, as reflected by significantly reductions in ctDNA VAFs and frequent clearance of FGFR2 KD mutations. The emergence of resistance alterations including de novo FGFR2 mutations and bypass pathways activations indicates acquired resistance that may limit long-term benefit. These results support further investigation with expanded biomarker sampling to better characterize resistance evolution and guide therapy optimization in an ongoing Phase 3 trial. Clinical trial information: NCT04919642 .

ABSTRACT Aims To investigate whether the association between the nitrite‐generating capacity of the subgingival microbiome and early cardiometabolic risk biomarkers varies by dietary nitrate intake. Materials and Methods Cross‐sectional data from 668 participants (mean age 31 ± 9 years, 73% women) were analysed. Dietary nitrate intake was calculated from food frequency questionnaires. Subgingival 16S rRNA sequencing (Illumina, MiSeq) and PICRUSt2 estimated microbial genes. The Microbiome‐Induced Nitric Oxide Enrichment Score (MINES) was calculated as a ratio of microbial gene abundances representing enhanced net capacity for NO generation. Adjusted multivariable linear models regressed cardiometabolic risk biomarkers (HbA1c, glucose, insulin, insulin resistance (HOMA‐IR), blood pressure) on nitrate intake and MINES together with a MINES × nitrate intake interaction term. Results Mean nitrate intake was 190 ± 171 mg/day. Significant interactions of MINES and nitrate intake were observed for insulin and HOMA‐IR ( p < 0.05). Among participants with a low MINES, higher nitrate intake was associated with lower HOMA‐IR (1.2 [1.1–1.4] vs. 1.5 [1.3–1.6]; p = 0.002), but levels were similar in those with high MINES ( p = 0.84). Conclusions A biomarker of higher microbial NO‐generating capacity in subgingival plaque is associated with lower insulin and insulin resistance among individuals with lower dietary nitrate intake. Future trials evaluating the cardiometabolic benefits of nitrate‐rich diets should incorporate measures of the entire oral microbiome.

Background Many guidelines list migraine with aura (MwA) as a contraindication to estrogen-containing combined hormonal contraceptives (CHCs) due to vascular risks. However, current evidence is based on small sample studies with potential influence by confounding factors. Additionally, few studies have examined the vascular risk associated with modern CHCs with lower dose estrogen, particularly in relation to aura status. The present study aims to investigate the vascular risk of modern CHCs in women with migraine with and without aura. Methods We used a de-identified electronic medical record database with 120 million patients across multiple health systems in the United States of America. We included female patients aged 18–45 years who received a migraine diagnosis code, had at least three office visits within three years, and were prescribed at least one migraine-specific medication within 6 months following the first outpatient visit. All data after 2010 were included. Patients with prior cardiovascular events were excluded. Our composite endpoint consisted of acute ischemic stroke, acute myocardial infarction, deep vein thrombosis/pulmonary embolism and intravenous thrombolytic administration. We stratified our analysis according to CHC exposure and aura status and compared the incidence of the endpoint with high-dimensional propensity score-matching between CHC users and non-users in (i) the overall cohort, (ii) MwA and (iii) migraine without aura (MwoA); between MwA and MwoA in (iv) patients prescribed CHCs; and in (v) those without CHC prescriptions. Results We included 5535 patients who received CHC prescriptions and 21,520 who did not. 114 (2.06%) of CHC users and 547 (2.54%) of CHC non-users had at least one vascular event. With propensity score-matched comparison, the composite endpoint did not significantly differ between CHC and non-CHC in the overall migraine group, those with MwA and the MwoA group. In those prescribed CHC, MwA and MwoA did not differ in all the outcomes. For CHC non-users, MwA was associated with a higher incidence of acute ischemic stroke (hazard ratio = 2.45; 95% confidence interval = 1.58–3.78; p < 0.001; n = 6201 in each group) and the composite endpoint (hazard ratio = 1.34; 95% confidence interval = 1.08–1.67; p = 0.008). Conclusions Our real-world study showed that exposure to modern CHC was not associated with a significant increase in vascular risk in women aged 18–45 years with migraine, MwA or MwoA who have no prior cardiovascular events. However, in those who never received CHC, MwA was associated with higher vascular risks compared to MwoA. While limitations exist using large scale electronic medical record databases for analysis, our results suggest that carefully designed prospective studies should be conducted to reassess the vascular risk associated with CHC use in women with migraine, especially MwA.

BACKGROUND: Metachronous cancer risk varies by mismatch repair mutation in patients with hereditary nonpolyposis colorectal cancer. Total colectomy offers decreased risk of metachronous colorectal cancers but decreased quality of life compared with segmental colectomy. OBJECTIVE: Compare segmental versus total colectomy for colon cancer via a mutation-specific Markov decision model. DESIGN: Simulated survival and colorectal metachronous occurrence among patients with MLH1, MSH2 , or MSH6 mutations undergoing either segmental or total colectomy. SETTINGS: National databases, literature review. PATIENTS: Simulated patients with hereditary nonpolyposis colorectal cancer. MAIN OUTCOME MEASURES: Overall survival, quality-adjusted life years based on procedure-specific utility states (segmental colectomy 0.99, total colectomy 0.95). RESULTS: Among patients aged 25 years, total colectomy offered less than 1 year of increased mean survival compared with segmental resection across all mutations ( MLH1: 0.8 years, MSH2: 0.9, MSH6: 0.3). This difference in survival decreased with increasing age. Segmental resection offered a small increase in quality-adjusted life years compared with total colectomy across all ages. This difference was highest for MSH6 (0.9 years vs MLH1 : 0.6 and MSH2 : 0.4 at age 25), particularly at younger ages of diagnosis. In a sensitivity analysis, lower total colectomy utility states resulted in greater increases in quality-adjusted life years with segmental colectomy across all mutations. LIMITATIONS: Metachronous cancer risk data do not distinguish between colon and rectal cancers and is extrapolated beyond age 70 years. CONCLUSIONS: Segmental and total colectomy offer similar survival and quality-adjusted life year outcomes. With decreased risk of metachronous cancers, patients with MSH6 mutations across all ages may prefer segmental resection owing to higher quality-adjusted life years and lower survival benefits from total colectomy compared with MLH1 and MSH2 patients. Operative strategy in patients with hereditary nonpolyposis colorectal cancer should be individualized, and this study shows that mutation-specific differences in survival and quality-adjusted life years are small. See Video Abstract . MODELO DE DECISIÓN ESPECÍFICO PARA LA MUTACIÓN EN LA COLECTOMÍA ABDOMINAL SEGMENTARIA FRENTE A LA COLECTOMÍA ABDOMINAL TOTAL EN EL CÁNCER COLORRECTAL HEREDITARIO NO POLIPOSO ANTECEDENTES: El riesgo de cáncer metacrónico varía según la mutación de reparación de desajustes en pacientes con cáncer colorrectal hereditario no poliposo. La colectomía total ofrece un menor riesgo de cánceres colorrectales metacrónicos, pero una menor calidad de vida en comparación con la colectomía segmentaria. OBJETIVO: Comparar la colectomía segmentaria con la colectomía total para el cáncer de colon mediante un modelo de decisión de Markov específico para mutaciones. DISEÑO: Simulación de la supervivencia y la aparición metacrónica de cáncer colorrectal en pacientes con mutaciones MLH1, MSH2 o MSH6 sometidos a colectomía segmentaria o total. ENTORNO: Bases de datos nacionales, revisión de la literatura. PACIENTES: Pacientes simulados con cáncer colorrectal hereditario no poliposo. PRINCIPALES MEDIDAS DE RESULTADO: Supervivencia global, años de vida ajustados por calidad basados en estados de utilidad específicos del procedimiento (colectomía segmentaria 0,99, colectomía total 0,95). RESULTADOS: Entre los pacientes de 25 años, la colectomía total ofreció menos de un año de aumento de la supervivencia media en comparación con la resección segmentaria en todas las mutaciones ( MLH1: 0,8 años, MSH2: 0,9, MSH6: 0,3). Esta diferencia en la supervivencia disminuyó con el aumento de la edad. La resección segmentaria ofreció un pequeño aumento en los años de vida ajustados por calidad en comparación con la colectomía total en todas las edades. Esta diferencia fue mayor para MSH6 (0,9 años frente a MLH1 : 0,6 y MSH2 : 0,4 a los 25 años), especialmente en las edades más jóvenes de diagnóstico. En un análisis de sensibilidad, los estados de utilidad más bajos de la colectomía total dieron lugar a mayores aumentos en los años de vida ajustados por calidad con la colectomía segmentaria en todas las mutaciones. LIMITACIONES: Los datos sobre el riesgo de cáncer metacrónico no distinguen entre cánceres de colon y recto y se extrapolan más allá de los 70 años. CONCLUSIONES: La colectomía segmentaria y la colectomía total ofrecen resultados similares en cuanto a la supervivencia y los años de vida ajustados por calidad. Con la disminución del riesgo de cánceres metacrónicos, los pacientes con mutaciones MSH6 de todas las edades pueden preferir la resección segmentaria debido a los mayores años de vida ajustados por calidad y los menores beneficios de supervivencia de la colectomía total en comparación con los pacientes MLH1 y MSH2 . La estrategia quirúrgica en pacientes con cáncer colorrectal hereditario no poliposo debe individualizarse, y este estudio muestra que las diferencias específicas de la mutación en la supervivencia y los años de vida ajustados por calidad son pequeñas. ( AI-generated translation )

Key Points Health care utilization rates in elderly kidney transplant were no different between the high kidney donor profile index and low kidney donor profile index group. Number of readmissions and surgical interventions in elderly kidney transplant was no different between the high kidney donor profile index and low kidney donor profile index group. Death censored graft loss was higher in the high kidney donor profile index group, whereas the patient survival was no different between the high kidney donor profile index and low kidney donor profile index groups. Background High kidney donor profile index (KDPI) kidneys (KDPI >85%) are often associated with increased risks of post-kidney transplant (KT) complications and greater health care utilization (HCU), particularly in elderly recipients with multiple comorbidities. These concerns frequently lead to underutilization of high KDPI kidneys in older transplant candidates, thereby limiting their access to transplantation despite potential clinical benefits. The aim of this study was to compare post-KT HCU between elderly recipients of high versus low KDPI deceased donor kidneys. The primary outcome included differences in hospital readmissions, surgical interventions, and outpatient service use at multiple post-transplant time points. Secondary outcome included graft function, graft survival, and patient survival. Methods A retrospective analysis of elderly solitary KT recipients (age ≥65 years) between January 1, 2011, and December 31, 2020. Patients were stratified into high KDPI (>85%, n =160) and low KDPI (≤85%, n =453) groups. We assessed inpatient and outpatient HCU, including readmissions at 30, 90, and 365 days post-transplant, surgical interventions, and outpatient visits (emergency department, transplant clinic, endocrine clinic, and ambulatory infusion units). Results There were no statistically significant differences between high and low KDPI groups in rates of hospital readmissions, surgical interventions, or outpatient visits (all P > 0.05). Delayed graft function rates were also similar ( P = 0.61). The low KDPI group had significantly higher eGFR at 4 months, 1, 2, and 3 years post-transplant (all P < 0.001). However, days alive and out of the hospital within 90 and 365 days post-transplant were comparable between the groups (all P > 0.05). Overall patient survival was similar ( P = 0.08), although death-censored graft loss was significantly higher in the high KDPI group ( P = 0.001). Conclusions Among elderly KT recipients, high KDPI kidney recipients had comparable post-transplant HCU and overall survival with those receiving low KDPI kidneys, despite lower long-term graft function. These findings suggest that high KDPI kidneys remain a viable option for older patients, offering timely access to transplantation.

Abstract Pyroptosis is a form of programmed cell death characterized by the cleavage of the gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and the release of proinflammatory cytokines. In this study, we performed immunohistochemistry for cleaved gasdermin D (GSDMD), gasdermin E (GSDME) N-terminus, and gasdermin C (GSDMC) in 2 different cohorts of diffuse large B-cell lymphoma (DLBCL) and analyzed the impact of GSDM expression on prognosis and immunity. The results showed frequent cleaved GSDMD (N-terminal) expression. Only cytoplasmic GSDMD N-terminal expression correlated with significantly better patient survival in the 2 cohorts. In contrast, GSDME was mainly expressed in the vascular endothelium, and correlated with significantly adverse prognostic effect. Correlating with the multiplex fluorescent immunohistochemistry results, we found that cytoplasmic GSDMD N-terminal expression was associated with increased CD38+ (activated) M1 macrophages in both cohorts, cognate interactions between live DLBCL cells and activated M1 macrophages (and T cells), and lower PD-1/PD-L1 expression in the analyzed cases. In contrast, T-cell pyroptosis, lymphoma cell-resistance to cell death, and phagocytosis by M2 macrophages were observed in tissues with predominantly nuclear GSDMD N-terminal expression. Bulk gene expression profiling and deconvolution analysis revealed associations of cytoplasmic GSDMD N-terminal expression with downregulation of “Don’t eat me”–signaling genes, upregulation of many RNA genes, decreased frequency of “inflammatory” lymphoma microenvironment subtype, increased frequencies of prognostically favorable cell states and ecotypes, and decreased frequency of T-cell exhaustion state. In summary, this study showed distinct cellular and subcellular patterns of 3 GSDM proteins and their associated immune response phenotypes and prognostic effects, with implications for novel therapeutic strategies for B-cell lymphoma.