Citations

Abstract Background Isocitrate dehydrogenase-1 (IDH-1) inhibitor ivosidenib and dual-IDH1/2 inhibitor vorasidenib have demonstrated clinical activity in the treatment of IDH-mutant gliomas. We evaluated the efficacy of vorasidenib in patients with prior exposure to ivosidenib. Methods Retrospective review of patients with IDH-mutant glioma treated with vorasidenib who had prior treatment with ivosidenib. Previous treatments, radiographic response, and adverse events were collected and analyzed descriptively. Results Twenty-nine patients (median age 42, 34% female) were evaluated. Tumor types included IDH-mutant astrocytoma (grade 2 n = 9, 31%; grade 3 n = 3, 10%; grade 4 n = 3, 10%) and oligodendroglioma (grade 2 n = 10, 34%; grade 3 n = 4, 14%). Treatments received prior to ivosidenib included surgical resection (n = 23, 79%), radiation (n = 16, 55%), temozolomide (n = 15, 52%), procarbazine, lomustine, vincristine (PCV, n = 2, 7%), bevacizumab (n = 3, 10%), lomustine (n = 2, 7%), and pembrolizumab (n = 1, 3%). Four patients received additional treatment in between ivosidenib and vorasidenib treatment. Ten of 16 (63%) patients who experienced disease progression on ivosidenib achieved stable disease and remain on vorasidenib, while 6 (37%) had continued progression. Eleven patients with stable disease on ivosidenib transitioned to vorasidenib following FDA approval and remained without progression. Two patients who transitioned to vorasidenib due to ivosidenib-related adverse effects (diarrhea and fatigue) experienced symptom resolution and maintained disease stability. Conclusions Vorasidenib demonstrated clinical efficacy in patients with IDH-mutant gliomas previously treated with ivosidenib. Notably, stable patients who transitioned maintained disease stability, while some of those with progressive disease achieved stabilization with vorasidenib. These findings support vorasidenib as a viable therapeutic option following ivosidenib exposure.

Abstract The lung, one the largest branching organs in our body and vital for survival at first breath, is commonly known as the gas-exchange organ. Recent novel findings on lung sensing cells, molecules, and lung-brain crosstalk in the emerging discipline of interoception have highlighted the consideration of the lung as a sensory organ. Acknowledging the central importance of lung sensing to human health and disease, NHLBI convened a workshop to synthesize the past, current, and future of lung sensing research, with in-person presentations by ∼20 interdisciplinary experts and a large virtual audience. Here, we highlight the key topics discussed and summarize a blueprint for the future in this important field.

BACKGROUND: Performance and transferability of contemporary polygenic risk scores (PRS) for atherosclerotic cardiovascular disease phenotypes may vary across PRS methods, training data, and trait ascertainment. METHODS: We aimed to investigate the performance and transferability of contemporary PRS for atherosclerotic cardiovascular disease subtypes: coronary heart disease (CHD), abdominal aortic aneurysm (AAA), ischemic stroke (IS), and peripheral artery disease (PAD), using the All of Us Workbench, which consists of a large, diverse cohort with whole-genome sequence data. We also developed and evaluated a multi-trait PRS for each subtype. Performance of PRS for 4 atherosclerotic cardiovascular disease subtypes was compared across genetic similarity groups in 245 388 All of Us participants. Groups genetically similar to European, African, admixed American, and remaining groups (combined as other) were used to assess PRS for CHD, IS, AAA, PAD, and multi-trait. RESULTS: PRS for CHD and AAA performed better than IS and PAD. For CHD, CHD PGS003725 performed the best (hazard ratio per SD increase [95% CI]), across genetic ancestry groups, European, and African (1.72 [1.67–1.78], 1.23 [1.17–1.29]), with CHD PGS004696 being best for admixed American (1.91 [1.70–2.15]), and CHD PGS003356 for other (1.75 [1.58–1.95]). The best performing PRS for AAA was AAA Multi for European, other, and admixed American (1.71 [1.52–1.92], 1.59 [1.07–2.37], 1.50 [0.90–2.52]) and AAA PGS003972 for African (1.39 [1.19–1.63]). For IS, IS Multi performed best for other and European (1.49 [1.17–1.89], 1.33 [1.25–1.42]), and IS PGS000039 performed best in admixed American and African (1.17 [1.07–1.27], 1.09 [1.04–1.15]). For PAD, PAD Multi performed best for all groups (other, 1.51 [1.19–1.92]; European, 1.32 [1.24–1.41]; admixed American, 1.23 [1.05–1.45]; and African, 1.18 [1.04–1.34]). CONCLUSIONS: Multi-trait and multi-ancestry PRS performed better than individual trait and/or single ancestry PRS for each atherosclerotic cardiovascular disease phenotype across ancestrally diverse and admixed individuals, with minimal change including adjustment for conventional risk factors.

Background. Pancreas transplantation (PT), historically limited to patients with type 1 diabetes (T1D), is currently performed successfully in selected patients with type 2 diabetes (T2D). However, contemporary practice patterns and eligibility criteria for PT in T2D remain incompletely characterized. Methods. The International Pancreas and Islet Transplant Association Pancreas Transplant Interest Group developed an electronic survey to assess center-level approaches to patient phenotyping, candidacy, and peri- and posttransplant management for PT in patients with T2D. The survey was distributed to international transplant professionals during an International Pancreas and Islet Transplant Association Pre-Congress meeting on June 15, 2025. Results. Thirty-seven participants completed the survey. Most respondents’ programs offer PT for T2D only when a kidney transplant is also indicated. Fewer respondents’ programs also offer PT alone (10%), evaluate T2D candidates on a case-by-case basis (3%), or do not offer PT to patients with T2D (10%). Total daily insulin requirement and body mass index (BMI) were the most selected factors in determining eligibility. Considerable variability existed in metabolic thresholds: 62% of programs reported no C-peptide cutoff, whereas nearly half required a BMI of <30 kg/m 2 for C-peptide-positive candidates. Respondents frequently recommend weight-optimization strategies, including lifestyle modification, glucagon-like peptide-1 receptor agonists, and bariatric surgery for candidates exceeding acceptable BMI thresholds. Surgical technique, induction, and maintenance immunosuppression and early posttransplant glycemic management were largely uniform between T2D and T1D recipients. Conclusions. International practice reflects broad but heterogeneous adoption of PT for T2D, with most participants restricting its use to candidates requiring kidney transplantation and emphasizing integrated clinical phenotyping approaches.

Abstract Metabolic vulnerabilities in cancer have been targeted primarily to suppress tumor growth, but less is known about the metabolic requirements for tumor cell invasion. Here we report that lipid catabolism by cytosolic and lysosomal lipases supports pancreatic cancer cell invasion through both overlapping and distinct functional and metabolic mechanisms. Lysosomal acid lipase (LAL)-dependent lipid droplet catabolism promotes invadopodia formation and stabilization, enabling extracellular matrix degradation. In addition to modulating cellular energetics, lipidomics revealed that lipid droplet catabolism regulates cholesterol and membrane phospholipid levels. Using spatially resolved biosensors and cholesterol imaging, we found that lysosomal lipid catabolism occurs at invadopodia and sustains local ATP and membrane cholesterol. These findings identify spatially organized lipid catabolism as a mechanism that couples local energetics and membrane remodeling during the earliest steps of pancreatic cancer cell invasion.