Citations

Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8 + T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8 + T cells (T RM ) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain T RM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain T RM via peripheral infection prior to depletion of circulating memory T cells (T CIRCM ) and subsequent brain tumor challenge. Tumor-specific brain T RM durably protected mice against intracranial malignancy even in the absence T CIRCM . These brain T RM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain T RM that controlled tumor growth. Altogether, this work points to the utility of brain T RM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

Abstract Background NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT‐Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). Methods Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease‐free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6–8 weeks post‐CRT; one‐sided α = 0.05, using a χ 2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5‐, 2‐, and 2‐point increases, respectively, from baseline to 6–8 weeks post‐CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. Results From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6–8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6–8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different ( p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non‐pCR patients, respectively, having improved 1‐year ECS scores. Conclusions The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

Abstract Background Neuroendocrine tumors (NETs) are rare, heterogeneous neoplasms associated with prolonged survival and substantial symptom burden. However, patient-reported outcomes across NET subtypes remain poorly characterized, particularly in real-world settings. This study describes baseline health-related quality of life (HRQoL) and care experiences among patients with gastroenteropancreatic and lung NETs, examining differences by tumor site and time since diagnosis. Methods The Neuroendocrine Tumors–Patient Reported Outcomes study is a prospective, multi-institutional US cohort of adults (aged 18 years and older) with incident small intestinal, pancreatic, gastroenteropancreatic, or lung NETs diagnosed from January 2018 through September 2024, identified via a validated electronic medical record–based computable phenotype. Baseline surveys assessed HRQoL, symptoms, care experiences, and clinical characteristics using validated instruments. Descriptive statistics and standardized mean differences compared responses by NET site and time since diagnosis. Results Among 2367 participants (mean age = 57.8 years; 57.3% female), 1974 had gastroenteropancreatic NETs (659 small intestinal NET, 555 pancreatic NET) and 393 had lung NETs. Fatigue (mean = 33.0), insomnia (mean = 32.5), and diarrhea (mean = 25.7) were the most burdensome symptoms. Lung NET patients reported worse dyspnea (standardized mean difference = 0.58, P < .001) and lower physical, role, and global QoL scores than those with gastroenteropancreatic NETs, while pancreatic NET patients reported better functioning. Diarrhea worsened over time, especially in small intestinal NETs. Most rated care highly (75.3%) but cited concerns about treatment side effects (80.4%), costs (60.7%), and travel burden (58.8%). Conclusions This large US cohort reveals persistent symptom burden and HRQoL variation by tumor site and disease duration, underscoring the need for longitudinal HRQoL assessment in NET care.

514 Background: Poly(ADP-ribose) polymerase 1 (PARP1) senses single strand DNA damage and catalyzes repair mechanisms. PARP inhibitor (PARPi) suppresses PARP1 activity and promotes cell death in BRCA1 or BRCA2 mutated cancers that are homologous recombination repair deficient (HRD) via a phenomenon known as “synthetic lethality”. Utility of PARPi in HRD-negative (HRDn) cancers remain uncertain, although in a preclinical study overexpression—but not endogenous levels—of BRCA2 in mouse hybridoma cells led to HRD and increased sensitivity to DNA crosslinking agents, suggesting potential sensitization to PARPi. In renal cell carcinoma (RCC), HRD mutations are rare and the role of PARPi remains investigational. In this study, PARP1 and BRCA1/2 expression and overall survival (OS) in high risk of recurrence localized clear cell-type renal carcinoma (hrr-ccRCC) were explored. Methods: Batch-corrected bulk mRNA profile (RNA Seq V2 RSEM) and clinical data of HRDn stages II grade 4-only (n = 4) and III (n = 100) ccRCC from The Cancer Genome Atlas Pan-Cancer project were reviewed. Gene expression was classified “high” if mRNA level is higher than median, otherwise it was classified “low”. Survival analyses were Log-rank Kaplan-Meier. Group comparisons were two-tailed Mann-Whitney test. Results: In HRDn hrr-ccRCC (n = 104), BRCA1 and BRCA2 were upregulated by median fold change (mFC) of 1.6 and 3.7, respectively, whereas PARP1 was downregulated by mFC 0.8 compared to normal control (n = 72, all p < 0.0001). BRCA1 and BRCA2 levels were positively correlated (R 2 = 0.71). Median duration of follow-up for OS was 36.5 months (IQR 20.9-60.0). High BRCA2 (n = 54) was associated with superior OS compared to low BRCA2 (n = 50) with hazard ratio (HR) for death at 0.34 (95% CI 0.19-0.63, p = 0.0008). When high BRCA2 group was further stratified by PARP1 level, those with concomitant low PARP1 (n = 16) trended towards a superior OS compared to those with high PARP1 (n = 38) with HR 0.19 (95% CI 0.06-0.60, p = 0.067). Similarly, high BRCA1 (n = 53) was associated with superior OS compared to low BRCA1 (n = 51) with HR 0.53 (95% CI 0.29-0.96, p = 0.04). However, no differential OS was seen when high BRCA1 group was stratified by PARP1 level. No differential OS was seen when low BRCA1 or low BRCA2 groups were stratified by PARP1 level. Conclusions: In this retrospective analysis of HRDn hrr-ccRCC, high BRCA2 was associated with superior OS which was more pronounced with concomitant low PARP1 . High BRCA1 was also associated with superior OS, but PARP1 levels had no influence. The findings of this study may imply a potential therapeutic value of PARP1 suppression with PARPi by mimicking low PARP1 expression in treating HRDn hrr-ccRCC with BRCA2 overexpression. Further investigation is warranted.

Abstract Background Pembrolizumab is approved for advanced cutaneous melanoma (aCM). Cabozantinib, an oral multi‐tyrosine kinase inhibitor, has demonstrated antitumor activity as monotherapy or in combination with anti‐PD‐1 therapy in malignancies. The objective of this study was to determine the safety and efficacy of cabozantinib and pembrolizumab for patients with aCM. Methods This phase 1b/2 study enrolled 28 patients with unresectable aCM. In phase 1b, escalating dose levels of cabozantinib (20 mg, 40 mg, and 60 mg) were administered concurrently with pembrolizumab 200 mg intravenously every 3 weeks using a 3 + 3 design to determine recommended phase 2 dose (RP2D). In phase 2, patients received cabozantinib at RP2D in combination with pembrolizumab using a Simon 2 stage design. Primary end point of phase 2 was overall response rate (ORR). Secondary end points included disease control rate, progression‐free survival (PFS), and overall survival (OS). Results Phase 1b enrolled eight patients, cabozantinib 40 mg daily dose level was selected as RP2D. Response rate in stage 1 exceeded predefined criteria for proceeding to expansion phase; however, phase 2 was terminated after 20 patients due to low accrual in the setting of evolving standard of care. Among all treated patients, the most common grade ≥3 toxicities were hypertension ( n = 10, 36%), hypokalemia ( n = 5, 18%), hypophosphatemia ( n = 4, 14%), and ALT elevation ( n = 4, 14%). Among 20 patients treated in phase 2, ORR was 45%, median PFS was 6.6 months, and median OS was 29.5 months. Conclusions Cabozantinib and pembrolizumab combination was explored in treatment‐naive aCM. Toxicity was consistent with known profiles, but discontinuation rates were notable.

Abstract Histones variant composition and post-translational modifications (PTMs) of core and linker histones jointly orchestrate chromatin architecture and tissue-specific gene regulation. However, capturing the full complexity of the “histone code” in native human tissues remains challenging. Here we present a human cardiac histone proteoform atlas—comprising intact histone variants with combinatorial PTMs—enabled by a streamlined top‑down proteomics workflow. In a single one‑dimensional reversed‑phase liquid chromatography (LC)-mass spectrometry (MS) run, we achieve baseline separation of all four core histone families (H2A, H2B, H3, and H4) together with the linker histone H1 directly from human myocardium. Notably, this intact-protein analysis preserves the connectivity of co-occurring PTMs to individual histone molecules to reveal the combinatorial histone code, enabling proteoform‑level quantification of histone‑variant composition and PTM stoichiometry at the chromatographic scale. Targeted MS/MS directly resolves co-occurring PTM combinations and distinguishes highly homologous histone isoforms. Using this approach, we assemble the first comprehensive cardiac histone proteoform atlas and uncover previously unobserved histone proteoforms. More broadly, this top-down proteomics workflow provides a robust framework for proteoform-resolved analysis of histone variants and PTMs in complex biological systems.

Abstract Background Hairy cell leukemia (HCL) is a rare, indolent B-cell malignancy accounting for ~1% of all lymphoid neoplasms. While purine analogs remain the standard first-line therapy, the increasing use of combination regimens and targeted agents has expanded the therapeutic landscape. Data on long-term outcomes in real-world practice remain limited. Methods This is a retrospective, multicenter cohort study. We included 104 patients aged ≥18 years with a diagnosis of HCL who had at least one oncology visit from January 1, 2010, to July 17, 2025. Patients diagnosed prior to 2010 were left-truncated to account for survivorship bias. Data were abstracted from electronic medical records. Key outcomes included treatment patterns, response rates, overall survival (OS), and progression-free survival (PFS). Results The median age at diagnosis was 56.9 years (range 32.1–83.8), and 80% were male. Most patients (77%) were diagnosed during or after 2010. The most frequent frontline therapies were cladribine (63%), cladribine with rituximab (12%), rituximab monotherapy (9.7%), vemurafenib-based regimens (7.7%), splenectomy with or without interferon (3.8%), interferon monotherapy (2.9%), and other (1.9%). The overall complete response (CR) rate to first-line therapy was 63%, with 15% achieving a partial response (PR) and 22% having stable or no response. For patients receiving cladribine with rituximab first-line (n = 12), 92% had a CR. For patients receiving cladribine monotherapy first-line (n = 65), 63% had a CR and 12% had a PR. For patients receiving rituximab monotherapy first-line (n = 10), 50% had a CR and 20% had a PR. For patients receiving vemurafenib-based regimens first-line (n = 8), 75% had a CR. Among the 39 patients who received second-line therapy, the most common regimens included cladribine (31%), rituximab (26%), cladribine plus rituximab (18%), and vemurafenib-based regimens (13%). The CR rate after second-line therapy was 72%. For patients receiving cladribine with rituximab second-line (n = 7), 86% had a CR and 14% had a PR. For patients receiving cladribine monotherapy second-line (n = 12), 67% had a CR. For patients receiving rituximab monotherapy second-line (n = 10), 80% had a CR and 10% had a PR. For patients receiving vemurafenib-based regimens second-line (n = 5), 40% had a CR and 20% had a PR. Among the 17 patients who received third-line therapy, the most common regimens included rituximab (41%), cladribine (18%), and vemurafenib-based regimens (18%). The CR rate after third-line therapy was 50%. For patients receiving rituximab monotherapy third-line (n = 7), 43% had a CR and 14% had a PR. For patients receiving cladribine monotherapy third-line (n = 3), 33% had a CR. For patients receiving vemurafenib-based regimens third-line (n = 3), 67% had a CR and 33% had a PR. Overall, treatment-related hospitalizations for first-line therapy occurred in 27% of patients. 50% of patients receiving first-line cladribine with rituximab had treatment-related hospitalizations. 25% of patients receiving first-line vemurafenib-based treatment had treatment-related hospitalizations. 23% of patients receiving first-line cladribine monotherapy had treatment-related hospitalizations. 20% of patients receiving first-line rituximab monotherapy had treatment-related hospitalizations. Overall, after a median follow-up of 6.6 years (range 0.1–46), estimated OS was 96.6% at 5 years, 85.7% at 10 years, and 80.3% at 15 years. The median OS was 24.5 years [95% CI: 18.3, not reached]. Estimated PFS was 95.1% at 1 year, 89.9% at 3 years, 74.8% at 5 years, and 50.8% at 10 years. Median PFS was 12.2 years [95% CI: 7.0, not reached]. Estimated OS for first-line cladribine monotherapy was 100% at 5 years and 86.5% at 10 years. Estimated OS for first-line vemurafenib-based treatment was 85.7% at 5 years and 85.7% at 10 years. Conclusions This large real-world cohort provides important insights into the long-term management of HCL. Cladribine-based regimens remain the predominant first-line approach, with high response rates and durable remissions. However, treatment-related toxicity is common. Outcomes in later lines remain favorable, particularly with re-treatment using purine analogs or combination regimens. These findings underscore the importance of individualized treatment planning and the continued need for real-world evidence to inform care in rare hematologic malignancies.

Abstract Purpose: AXL, a receptor tyrosine kinase related to oncogenic processes, is aberrantly expressed in various cancers and associated with treatment resistance. Enapotamab vedotin (EnaV), a novel anti-AXL human IgG1 and monomethyl auristatin E antibody–drug conjugate, demonstrated antitumor activity in preclinical models, including non–small cell lung cancer (NSCLC). This phase 1/2 study assessed the safety and preliminary efficacy of EnaV in solid tumors. Patients and Methods: This study comprised dose-escalation and dose-expansion phases; both phases investigated EnaV once every 3 weeks (Q3W) and EnaV on days 1, 8, and 15 of a 28-day cycle (3Q4W). Primary objectives determined the maximum tolerated dose (dose escalation) and safety (dose expansion). Pharmacokinetic profile, antitumor activity, and AXL expression were also assessed. Results: During dose escalation, 32 patients received EnaV Q3W; 15 received EnaV 3Q4W. The maximum tolerated dose and recommended phase 2 dose were 2.2 mg/kg in Q3W and 1.0 mg/kg in 3Q4W schedules. In dose expansion, 189 patients received EnaV Q3W; 70 received EnaV 3Q4W. Common adverse events in dose expansion included fatigue, constipation, nausea, decreased appetite, and diarrhea. Overall response rates ranged from 4.5% to 12.5% with Q3W dose schedule and from 9.1% to 11.5% with 3Q4W dose schedule. Disease control rates for NSCLC cohorts were 40.9% to 50.0%. NSCLC subset analysis demonstrated correlation between radiomics signature and disease control. The relationship between clinical activity and AXL expression was not apparent. Conclusions: EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued. Significance: EnaV, an anti-AXL human IgG1 and monomethyl auristatin E antibody–drug conjugate, showed single-agent antitumor activity in preclinical models. This phase 1/2 study of EnaV demonstrated a manageable safety profile and antitumor activity in selected tumor types. Further studies exploring alternative targeting modalities, patient selection, and/or combinations are needed.