Citations

10030 Background: CABO is a multi-targeted kinase inhibitor of VEGFR2, c-MET, AXL and RET and has shown clinical evidence of activity in two prior studies of adult and pediatric patients with advanced OS. We report results of a feasibility cohort of CABO + MAP chemotherapy in patients with newly diagnosed high-risk OS. Methods: Patients <40 years, body surface area ≥ 0.8 m 2 and new diagnosis of high-grade OS with metastatic disease and resectable primary tumor were eligible. Patients were enrolled to two CABO dose levels (Dose Level 1 (DL1) 25 mg/m 2 /day, maximum 40 mg/day; Dose Level 2 (DL2) 35 mg/m 2 /day; maximum 60 mg/day) using a modified IQ 3+3 design. CABO was orally administered concomitantly with six 35-day cycles of MAP (cisplatin 60 mg/m 2 on days 1-2 (cycles 1-4), doxorubicin 37.5 mg/m 2 on days 1-2 (with dexrazoxane), methotrexate 12 g/m 2 on days 22, 29) and for 24 weeks as maintenance monotherapy. CABO was held after 7 weeks and resumed during 4 th MAP cycle to allow for primary tumor resection and metastatic surgeries. Dose-limiting toxicities (DLT) were assessed during weeks 1-6 of treatment; additional monitoring for post-surgical complications was conducted through completion of 4 th MAP cycle. The primary endpoint for this cohort was feasibility of combination therapy. Results: Ten patients (median age 11.5 years, 70% male) were enrolled and treated with CABO + MAP (DL1, n=4; DL2, n=6). Median cumulative doses of all MAP agents were maintained throughout treatment with no dose reductions. Concomitant dosing of CABO with MAP was tolerated with no protocol-specified DLTs occurring during the evaluation period. DL2 (35 mg/m 2 ) was established as the recommended dose for further study of combination therapy. Commonly reported adverse events included hematologic toxicities, febrile neutropenia, and alanine/aspartate aminotransferase (AST/ALT) elevation. Interruption of CABO was required in 6 patients for Grade 3+ AST/ALT elevation following methotrexate (n=3), wound complications (n=3), and Grade 3 pneumothorax (n=1). Wounds included two Grade 3 port site events and one Grade 1 primary tumor resection site; two patients later resumed CABO after healing without wound recurrence. Dose reduction of CABO was required in one patient for Grade 4 amylase elevation. Conclusions: The combination of CABO + MAP is feasible with no protocol-specified DLTs during the evaluation period. Generalizability is limited based on cohort size. Further evaluation of CABO + MAP is ongoing in a phase II/III randomized efficacy study in newly diagnosed standard and high-risk patients using CABO dose of 35 mg/m 2 /day (max 60 mg), with delayed initiation of CABO in patients with port placement and early safety monitoring for wound-related events, as well as full study monitoring of dose delivery, wound complications and systemic toxicity. Clinical trial information: NCT05691478 .

Abstract Purpose Crisis periods—defined as sustained disruptions to the clinical environment resulting in increased workload, exposure to high-acuity patient care, or limited access to coping resources—can lead to posttraumatic stress disorder (PTSD) among residents and fellows (trainees). By examining self-reported pandemic-related PTSD symptoms, associated risk factors, and their consequences, this study aims to identify vulnerable groups and inform institutional strategies to support trainee well-being during and after crisis events. Method A multi-institutional cross-sectional survey was conducted at 3 U.S. academic medical centers between April and May 2022. Measures included the Primary Care PTSD Screen for DSM-5 (range 0 to 5, scores ≥4 indicate probable PTSD), 4-item PROMIS Social Isolation scale (normed T-score range 0 to 100 scale with higher scores indicating greater isolation), items exploring intent to stay at one’s institution, and demographics. Multivariable analysis adjusted for demographics, specialty, and postgraduate year. Results Of 6,057 eligible trainees, 3,185 (53%) participated in the survey, with 3,109 completing the PTSD screening. A total of 190 (6%) trainees screened positive for self-reported PTSD symptoms. Multivariable analysis revealed that female trainees had a higher odds of screening positive for self-reported PTSD symptoms compared to males (odds ratio [OR] 1.45; 95% confidence interval [CI], 1.03-2.04; P = .03). Greater social isolation was independently associated with increased PTSD risk (OR 1.09; 95% CI, 1.07-1.11; P &lt; .001). Additionally, trainees who did not intend to remain at their institution after training were more likely to screen positive for PTSD (OR 1.74; 95% CI, 1.17-2.58; P = .01). Conclusions Female gender, greater social isolation, and reduced intention to remain at one’s institution are independently associated with self-reported PTSD symptoms in trainees. Recognizing these relationships may enable health care leaders to proactively identify trainees at higher risk during crisis periods and to implement targeted, evidence-based interventions that promote well-being and workforce retention.

ABSTRACT Reversion mutations (REVs) restore homologous recombination repair (HRR) and confer resistance to PARP inhibitors (PARPi) in HR-deficient cancers. Yet, their prevalence, mechanisms, and biological constraints remain undefined. We analyzed genomic profiling of 609,464 tissue and liquid biopsy samples across multiple cancer types to delineate the pan-cancer landscape of REVs. REVs were identified in eight HRR genes, most frequently BRCA2 and BRCA1 and notably never in ATM or CHEK2 . REVs exclusively impacted truncating pathogenic variants, predominantly through large in-frame and exon-level deletions, associated with repetitive sequences. Conserved functional domains are relatively depleted of REVs. Structural modeling and functional studies support that exon-level deletions preserve critical domain architecture and confer PARPi resistance. The study establishes HRR reversion as a structurally permissive, yet evolutionarily constrained, resistance mechanism with implications on response, monitoring, and therapeutic strategy. One Sentence Summary Homologous recombination reversion evolves through structurally tolerated, microhomology-driven alterations that restore DNA repair under therapeutic selection across cancers.

ABSTRACT Richter transformation of Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) into classic Hodgkin lymphoma (CHL-RT) is rare and remains incompletely understood. Two histologic subtypes are recognized: type 1 (CLL/SLL with scattered Hodgkin/Reed-Sternberg (HRS) cells) and type 2 (HRS cells within a polymorphous inflammatory background). In this multi-institutional study of 77 patients with CHL-RT (27 type 1 and 50 type 2), we characterized immune evasion markers, PD-L1 / PD-L2 copy number alterations, tumor microenvironment, and performed targeted next-generation sequencing on 37 CLL/SLL samples. HRS cells in CHL-RT displayed immune-evasion phenotypes similar to de novo CHL, though PD-L1 expression was lower in type 1 cases. PD-L1/PD-L2 gain/polysomy were frequent (83.3%). CLL/SLL with CHL-RT harbored increased mutations in XPO1, FBXW7, BIRC3, TRAF3 , and HLA-A versus reference CLL/SLL. Similar mutational profiles, demographics, and survival outcomes support a biological continuum between type 1 and type 2 CHL-RT, with distinct genetic features in CLL/SLL predisposing to CHL transformation. STATEMENT OF SIGNIFICANCE Classic Hodgkin lymphoma-type Richter transformation arises from convergent Hodgkin-like immune evasion on a genetically primed CLL/SLL background. Through integrated genomic and tumor microenvironment analyses in a large multicenter cohort, we establish this as a biologically coherent entity and provide rationale for PD-L1/PD-L2-directed therapeutic strategies.

Abstract Background Lung transplantation remains the accepted treatment modality of choice for life-threatening advanced lung disease due to established benefits of improving survival and functional status of the patients. However, the annual mortality of lung waitlist candidates remains high, reflecting ongoing donor-recipient mismatches and prolonged wait times. Modalities such as extracorporeal membrane oxygenation (ECMO) have been effectively used as a “bridge to transplant” (BTT) in high-risk patients on waitlist. Objective To evaluate trends in ECMO utilization, waitlist dynamics, and outcomes among lung transplant candidates between 2018 and 2024, with emphasis on the use of ECMO as a bridge to transplantation. Methods We conducted a retrospective chart review of all ECMO runs performed between 2018 to 2024 at the Mayo Clinic Florida Hospital. Among these, patients who underwent evaluation for lung transplantation were identified, and their waitlisting patterns, transplant outcomes, and peri-transplant ECMO status were described. Results Between 2018 and 2024, a total of 348 ECMO runs were recorded among 293 patients. Annual ECMO runs increased steadily from 17 in 2018 to 83 in 2024 (2019: 33, 2020: 30, 2021: 61, 2022: 56, 2023: 68, 2024: 83). Out of these patients, 142 underwent evaluation for lung transplantation and 133 (93.67%) were placed on the waitlist. Among waitlisted patients, 105 (78.9%) were listed before ECMO initiation, 23 (17.3%) during ECMO, and 5 (3.8%) after decannulation. Waitlist outcomes included 116 (87.2%) transplanted, 16 (12.0%) deaths before transplant, and 1 (0.8%) clinical improvement precluding transplant. Among 116 transplanted patients, 36 patients (31.03%) received ECMO as a bridge to lung transplantation. The annual patients bridged with ECMO demonstrated a progressive rise: 1 (2019), 3 (2020), 9 (2021), 6 (2022), 9 (2023), and 8 (2024). Among these 36 patients, 29 (80.56%) remained on ECMO support in the immediate post-transplant period. At the latest follow-up, mortality among BTT recipients was 9 (25%). Conclusion ECMO utilization has expanded substantially over the past several years reflecting its expanding role in supporting critically ill patients. There has been increased utilization of ECMO as a bridge to lung transplantation in order to support high risk candidates awaiting donor organs. The post-transplant mortality among BTT recipients was 25%, which highlights the importance of peri-transplant management to optimize long-term outcomes in this high-risk cohort. This abstract is funded by: None

ABSTRACT Early-life nutrition profoundly influences long-term metabolic health, and breast milk not only provides nutrients but also conveys maternal signals shaping infant metabolic development. While postpartum exercise by lactating women benefits maternal health, its impact on milk-borne signaling remains largely undefined. Small extracellular vesicles (sEVs) in breast milk are key mediators of maternal–infant communication because of their selectively packaged bioactive cargo and resistance to infant digestive enzymes and acids, enabling delivery of their cargo to peripheral tissues. Here, we show that a single session of moderate-intensity postpartum aerobic exercise robustly increases human breast milk sEV concentration, which persists for multiple post-exercise milk collections. Exercise enriches breast milk with sEVs containing regulatory metabolic cargo (proteins, miRNAs, and metabolites), which translates into enhanced mitochondrial capacity in neonatal-stage cells. These findings implicate sEVs as an exercise-responsive signaling compartment in breast milk capable of connecting postpartum maternal physical activity to beneficial infant metabolic programming. Highlights Acute moderate-intensity exercise increases human breast milk sEV concentration The exercise-mediated sEV increase lasts for multiple subsequent milk expressions Exercise coordinates a multi-omic enrichment of sEVs in breast milk Exercised breast milk sEVs enhance mitochondrial respiration in UC-MSCs

Abstract M.D.-Ph.D. programs in the United States have traditionally followed a “2- n -2” curricular model, with the graduate phase occurring between the pre-clerkship and clerkship portions of medical training. While well established, this format can limit trainee autonomy in shaping their physician-scientist training trajectories. In response, some programs have introduced a “3- n -1” model, allowing students to complete clerkships before beginning Ph.D. training. Our institution implemented multiple flexible curricula in 2017. Understanding why trainees choose one pathway is important as programs consider implementing more adaptable training structures. To investigate these factors, we surveyed M.D.-Ph.D. students at our institution, which offers multiple flexible curricular alternatives, about contributions to their curricular decisions. Responses supported that trainees weigh considerations across medical education, scientific development, and integrated physician-scientist training domains. Although the traditional pathway was a popular option, most students pursued one of the flexible pathways. Our findings suggest that introducing flexibility in the timing of undergraduate medical education and graduate training can support diverse educational, logistical, and personal priorities while maintaining the rigor of physician-scientist training. Offering multiple pathways empowers trainees to design trajectories that best fit their needs. Continued longitudinal studies are needed to assess the long-term impacts of flexible curricula on physician-scientist career outcomes.

By 2045, more than three quarters of global cancer deaths are projected to occur in low- and middle-income countries (LMICs); however, the global availability of cancer care remains constrained by high costs and inequitable access. Value-based frameworks that integrate clinical benefit with affordability, feasibility, and equity are essential to better guide research prioritization, resource allocation, and regulatory policies in LMICs. A key component of a value-based approach is the generation of high-quality, locally relevant data to support evidence-based implementation of cancer prevention and control strategies. Herein, we provide three contemporary examples from JCO Global Oncology which demonstrate how economic evaluation in cancer research can address locally relevant, health system–specific questions.