Citations

Abstract Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor (CAR) T-cell therapy approved for relapsed and refractory multiple myeloma (RRMM). Out-of-specification (OOS) CAR T cells not meeting criteria for commercial release are considered an investigational product; the expanded access protocol (EAP) allows release of OOS product for administration. The manufacturing analysis of capability, reliability, and timely delivery of ide-cel in the United States over >3 years since its approval included patients with RRMM who underwent leukapheresis for ide-cel treatment after ≥2 prior lines of therapy between 23 February 2021 and 1 November 2024. Additionally, the BB2121-EAP-001 study evaluated safety and efficacy of OOS ide-cel and included patients who had undergone leukapheresis for commercial ide-cel treatment not meeting commercial release specifications, most commonly due to high CD137 activation or low-infused dose. Primary end point was safety. Secondary end points were overall response rate (ORR) and complete response rate (CRR). At data cutoff (1 November 2024), the manufacturing success rate of ide-cel improved from 95.3% in 2021 to 96.8% in 2024. Turnaround time also improved from 31 days in 2021 to 24 days in 2024. In BB2121-EAP-001, 68 (72.3%) patients experienced ≥1 cytokine release syndrome event (mostly grade 1/2) and 15 (16.0%) had neurological toxicities (2 grade 3, 13 grade 1/2). ORR was 75.4% (95% confidence interval [CI], 63.1-85.2), and CRR was 35.4% (95% CI, 23.9-48.2). The manufacturing success of ide-cel is reliable and consistently high, and when OOS ide-cel products emerged, they demonstrated consistent clinical efficacy and safety. The BB2121-EAP-001 study was registered at www.clinicaltrials.gov as NCT04771078.

Importance Adjuvant chemotherapy regimens may be administered after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMNs), although the evidence supporting their use is limited. Objective To evaluate the survival benefit associated with contemporary adjuvant chemotherapy regimens after resection in A-IPMNs between 2017 and 2023. Design, Setting, and Participants This retrospective cohort study was an international, multicenter study with 69 participating centers across Europe, North America, South America, and the Asia-Pacific region. Patients undergoing resection for A-IPMNs were included. Data were analyzed from May to August 2025. Intervention Contemporary adjuvant chemotherapy regimens, such as gemcitabine-capecitabine (GemCap); 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), modified FOLFIRINOX (mFOLFIRINOX), and S-1. Main Outcome and Measure Overall survival (months). Results Among 1321 patients (median [IQR] age 70 [63 to 76] years; 713 males [54.0%] and 608 females [46.0%]), 781 patients (59.1%) received adjuvant chemotherapy, while in 181 patients (13.7%) it was omitted due to poor patient fitness. Of patients who received adjuvant chemotherapy, 568 patients (72.6%) received contemporary regimens, including GemCap (232 patients [29.7%]), FOLFIRINOX (176 patients [22.5%]), mFOLFIRINOX (71 patients [9.1%]), and S-1 (70 patients [9.0%]). The median (IQR) follow-up for the cohort was 64.2 (40.4 to 85.0) months, and the median overall survival was 73.8 months (95% CI, 66.4 to 81.9 months). After 90-day landmark analysis and exclusion of patients ineligible for chemotherapy, adjuvant chemotherapy vs no adjuvant chemotherapy (propensity score–matched populations, 243:243 patients) was not associated with improved overall survival (median, 82.3 months; 95% CI, 78.2 months to not applicable [NA] vs not reached; 95% CI, 75.3 months to NA; P = .58). Contemporary regimens vs no adjuvant chemotherapy (propensity score–matched populations, 309:309 patients) was not associated with longer survival, and a mean survival benefit greater than 4.2 months over 5 years was excluded (difference in restricted mean survival, 1.26 months; 95%, −1.72 to 4.24 months). Treatment outcomes did not vary by chemotherapy regimen or disease characteristic (eg, N stage or carbohydrate antigen 19-9 level). Conclusions and Relevance In this study, contemporary adjuvant chemotherapy was not associated with improved overall survival in A-IPMNs, and a randomized clinical trial is indicated.

ABSTRACT Purpose Malignant rhabdoid tumor of the kidney (MRTK) is a rare, aggressive tumor seen in young children. The optimal timing of resection for locally advanced tumors is not well‐defined. The purpose of this study is to evaluate modern oncologic outcomes and the impact of surgical timing. Methods A multicenter retrospective review was performed by institutions participating in the Pediatric Surgical Oncology Research Collaborative. Children younger than 21 years old with MRTK diagnosed between 2000 and 2022 were included. Results Sixty‐nine patients were identified with MRTK and met the inclusion criteria. Median age of diagnosis was 10.1 months. Overall survival (OS) at 1, 5, and 10 years was 49%, 32%, and 19%, respectively. Patients with local Stage III disease who underwent upfront resection ( n = 18) compared to those who had delayed resection after NAT ( n = 15) had a similar OS, median OS greater than 60 months versus 14.6 months, respectively; p = 0.396. The surgical timing groups were balanced in terms of the presence of metastasis, length of follow‐up, and tumor characteristics. There was one occurrence of primary intraoperative tumor spill and two occurrences of organ injury in the upfront resection group compared to none in the delayed resection group. Conclusion MRTK carries a poor prognosis despite multimodal treatment. Histologic diagnosis may not be confirmed at presentation, and MRTK cannot be reliably distinguished from Wilms tumor on imaging alone. As overall survival is similar, the decision regarding surgical timing in locally advanced tumors should be individualized based on perceived resectability, balancing the risk of intraoperative complications against the possibility of tumor progression during neoadjuvant therapy.

Background: Sinonasal malignancies (SNM) are rare cancers associated with poor prognosis and impaired quality of life (QOL). The 22-question Sino-Nasal Outcome Test (SNOT-22) has been used to assess QOL in patients with SNM. Objective: To determine the minimal clinically important difference (MCID) for the SNOT-22 in patients with SNM. Methods: About 264 patients with SNM were drawn from a prospective, longitudinal, multi-institutional study. SNOT-22 scores were collected at pre-treatment baseline and follow-up through 5 years post-treatment. Cronbach’s alpha was used to assess the internal consistency of the SNOT-22. Distribution-based approaches were used to estimate the MCID. Multivariable regression identified factors associated with SNOT-22 improvement exceeding the determined MCID. Results: Cronbach’s alpha was >.85. The estimated MCIDs were: 1.44 (Cohen’s effect size), 1.32 (standard error of the mean), 10.45 (1/2 of baseline standard deviation), and 3.67 (minimum detectable change). The mean MCID across methods was 4.22. Multivariable regression demonstrated higher odds of clinically meaningful improvement from baseline in patients with early-stage disease (odds ratio (OR) 3.510, P = .035), no neck irradiation (OR 11.050, P = .014), and neoadjuvant therapy (OR 16.667, P = .047). Conclusions: The SNOT-22 MCID was estimated as 4.22 in a large multi-center cohort of patients with SNM, suggesting that relatively small QOL changes are clinically relevant. When applying the MCID to the current cohort, advanced stage, treatment of neck disease, and not requiring neoadjuvant therapy were predictive of worse QOL.

Normothermic regional perfusion (NRP) adoption for donation after circulatory death (DCD) liver transplantation in the United States has been growing, but there remains a higher rate of non-utilization of NRP DCD liver grafts as compared with donation after brain death liver grafts. Six transplant centers and 1 organ procurement organization (OPO) with substantial NRP liver procurement experience performed retrospective reviews of all NRP procurement attempts from September 1, 2021, until March 1, 2024, identifying opportunities for utilization. Five of the 6 transplant centers had prospectively collected data on all accepted livers with NRP intent. The transplant center's intention to utilize DCD donors included 329 livers accepted for transplantation before withdrawal, 252 (76.6%) potential donors expired within the hospital timeframe for donation, and 168 (66.7%) livers were transplanted. Fifty-seven opportunities for utilization were identified by transplant centers, plus 11 from the OPO: most were due to exceeding a functional warm ischemic time limit (n=26), other reasons (n=17), and functional assessment (n=16). The lessons learned by centers in this study provide guidance for newer NRP centers and for OPOs in identifying opportunities for utilization of NRP DCD grafts that have historically been declined.

Abstract Reported prevalence estimates of Lewy body pathology (LBP) vary widely, often without considering brain regional distributions or demographic influences. Large, population-representative autopsy cohorts are needed to provide estimates and clarify the distribution and clinical implications of LBP. Neuropathological, genetic, and clinical data were pooled from nine community- or population-based brain autopsy cohorts in the USA (n=6), Brazil, Austria, and Finland (n=7309 total; 59% women; mean age of death 84.2 years). Cognitive status was available for 6166 participants: dementia (38.5%), mild cognitive impairment (14.8%), and cognitively unimpaired (47.0%). Frequency of LBP was examined by anatomical distribution (neocortical, limbic, brainstem, amygdala, olfactory) and stratified by covariates. Prevalence was calculated in meta-analysis, and mixed-effect logistic regression examined associations with sex, cognitive status, Alzheimer’s disease neuropathological change (ADNC), and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-pathology. Overall, 27.3% of participants had LBP: neocortical 8.4%, limbic 6.8%, brainstem 4.8%, amygdala 3.7%, and olfactory 3.6%. Neocortical LBP was associated with dementia (present in 15%; OR=4.06 [95%CI 3.24-5.10]) and with increased odds of ADNC (OR=2.30 [95%CI 1.88–2.81]) and LATE-NC (OR=2.03 [95%CI 1.69-2.44]). Sex differences were not observed in the frequencies of neocortical or limbic LBP. However, amygdala-predominant LBP was more frequent in women (OR=1.53 [95%CI 1.06-2.21]) whereas brainstem-predominant LBP was more common in men (OR=0.64 [95%CI 0.49-0.84]). Additionally, amygdala-predominant LBP was associated with increased odds of comorbid ADNC (OR=12.7 [95%CI 5.30–30.6]) while brainstem-predominant LBP was not associated with greater odds of ADNC co-pathology (OR=0.88 [95%CI 0.67–1.16]). Pooling data from large, international community-based autopsy cohorts allows for more robust estimates of region-specific LBP prevalence and their associations with cognitive status. The observed sex- and co-pathology–specific differences in brainstem and amygdala-predominant LBP highlight potential biological heterogeneity and suggest that distinct disease pathways may underlie these patterns.

Background: Successful applications of artificial intelligence (AI) in healthcare have increased interest in how it could be integrated into orthopaedic surgery. However, orthopaedics surgeons’ current use of AI and attitudes toward its incorporation remain largely unexplored. The 2025 American British Canadian Travelling Fellowship Survey on AI in Orthopaedic Surgery aimed to assess AI use, knowledge, training, and attitudes among orthopaedic surgeons. Methods: The survey was administered from May 7 to September 4, 2025 to orthopaedic surgeons across Australia, New Zealand, the United Kingdom, and North America. Questions addressed demographics, AI training and use, and attitudes toward AI. Descriptive statistics summarized responses, chi-square tests compared AI use by geography and attitudes by career stage, and linear regression explored associations between demographics, AI behaviors, and outlook on AI. Results: Among 350 participants, most were trainees (45.1%) and from North America (42.9%). AI use exceeded training, and 79.9% rated their AI knowledge as average or poor. Trainees reported significantly more favorable attitudes toward AI than late-career respondents. Higher self-rated AI knowledge and AI use in clinical and research settings were associated with a more positive outlook on the future of AI in orthopaedics. Conclusions: These findings highlight the need for formal AI education, as use is widespread despite limited training, particularly among later-career surgeons. Future studies should reduce self-selection and career-stage imbalance and include additional demographic variables to improve generalizability. Level of Evidence: III . See Instructions for Authors for a complete description of levels of evidence.

Abstract In many cancers, a major barrier to effective immunotherapy is the dominance of tumor-associated myeloid cells (TAMs), which establish a profoundly immunosuppressive tumor microenvironment (TME). This challenge is particularly pronounced in glioblastoma (GBM), where myeloid cells represent the predominant immune population and actively suppress antitumor immunity. Identifying targets that can reprogram TAMs from an immunosuppressive state toward a pro-inflammatory, antigen-presenting phenotype remains a critical unmet need. Here, we identify the voltage-gated proton channel Hv1 as an immune-restricted regulator of glioma-associated macrophage function. Hv1 is notable not only for its immune-specific expression but also for its established roles in central nervous system (CNS) pathologies, where Hv1 depletion alters microglial and macrophage polarization, reduces myeloid accumulation, dampens inflammatory cytokine production, and limits secondary tissue damage. However, Hv1’s role in shaping the GBM immune landscape—particularly in vivo—has remained poorly understood due to low Hvcn1 transcript abundance and the lack of reliable antibodies and genetic tools. Given the dominance of myeloid cells in GBM and their central role in tumor immune regulation, we sought to define Hv1 function within this highly immunosuppressive brain TME. Analysis of patient datasets revealed that elevated Hv1 expression correlates with poor clinical prognosis. Consistently, Hv1 loss significantly prolonged survival in multiple murine glioma models. Using in vivo two-photon imaging and spectral flow cytometry, we show that Hv1 depletion reprograms TAMs toward an anti-tumor phenotype characterized by enhanced tumor cell phagocytosis, improved antigen presentation, and increased T cell infiltration. By generating new Hv1 reporter and conditional mouse lines, we further demonstrate that tumor-associated microglia and infiltrating macrophages are the principal sources of Hv1 and markedly upregulate its expression in response to glioma. Notably, selective deletion of Hv1 in infiltrating macrophages phenocopied the survival benefit observed with global Hv1 loss. Mechanistically, using mass spectrometry and genetic models, we identify the Stimulator of Interferon Genes (STING) as a previously unrecognized binding partner of Hv1, placing Hv1 within the STING signaling pathway, a central regulator of innate and adaptive immune responses. Together, these findings fill a critical gap in understanding myeloid Hv1 function in GBM and identify Hv1 as a promising target for reprogramming the tumor immune microenvironment. Citation Format: Jiaying Zheng, Lingxiao Wang, Shunyi Zhao, Katayoun Ayasoufi, Meijie Wang, Praveen N. Pallegar, Peter R. Strege, Langni Liu, Yushan Wan, Wenjing Zhang, Emma N. Goddery, Manling Xie, Arthur Beyder, Aaron J. Johnson, Long-Jun Wu. Myeloid Hv1-STING axis tunes glioma immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A016.

Background: ASCO recommends extended venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs) following cancer surgery. However, these recommendations were based on trials using routine venography, which detects asymptomatic VTEs, and real-life efficacy is not well studied. We aimed to assess the association of extended VTE prophylaxis with the incidence of clinically significant VTE after elective cancer surgery. Patients and Methods: In this retrospective, population-based cohort study, we identified patients who underwent surgical resection for lung, breast, esophageal, gastric, pancreas, and colon cancer from 2010 to 2017 using the SEER–Medicare linked dataset. Patients were divided into 1 of 2 main groups for comparative analyses: those who received extended VTE prophylaxis after cancer surgery and those who did not. Patients who received extended VTE prophylaxis after cancer surgery were identified as those prescribed prophylactic doses of LMWH or a DOAC within 7 days of discharge, as captured in Medicare Part D files. Results: A total of 113,739 Medicare beneficiaries were identified, of whom 1,570 (1.4%) received extended VTE prophylaxis. There was a year-over-year increase in the use of extended VTE prophylaxis during the study period, rising from 0.6% in 2010 to 3.3% in 2017. The overall incidence of VTE was 1.6% at 1 month, 4.3% at 6 months, 5.7% at 12 months, with significant differences observed across cancer types ( P <.001). However, patients who received extended VTE prophylaxis had a higher 1-year cumulative incidence of postoperative VTE compared with those who did not (11.4% vs 5.3%; P <.001), an association that was consistent across cancer sites. In adjusted analyses, extended VTE prophylaxis was independently associated with an increased risk of VTE (hazard ratio, 1.6; 95% CI, 1.3–2.0; P <.001). Extended prophylaxis was also associated with a higher 1-year incidence of bleeding events compared with patients who did not receive prophylaxis (12.0% vs 8.5%; P <.001). Conclusions: The utilization of extended VTE prophylaxis after cancer surgery remains low, although it has increased every year. Paradoxically, patients who received extended VTE prophylaxis had higher incidences of clinically significant VTE and bleeding compared with those who did not, likely reflecting patient selection and surveillance bias after surgery. In light of these findings, national guidelines recommending postoperative extended VTE prophylaxis, and its use as a surrogate for quality of care, should continue to be re-examined.

Abstract Lentigo maligna (LM) is a subtype of cutaneous melanoma in situ that develops on chronically sun‐damaged skin in elderly individuals. Its diagnosis and management remain challenging due to its slow progression, frequent occurrence on cosmetically sensitive areas in frail individuals, and tendency for subclinical peripheral extension. Despite its potential for invasive transformation, the natural history of LM remains incompletely understood and evidence‐based management strategies for this specific entity remain limited. This work aims to bridge the gap between scarce high‐quality evidence and the clinicians' need for practical guidance on LM management by formulating evidence‐based and expert consensus‐driven recommendations for diagnosis, treatment and follow‐up. Under the coordination of the International Dermoscopy Society, a global, multidisciplinary consortium of 53 experts—including dermatologists, dermato‐oncologists, dermatologic surgeons, radiologists, radiotherapists, pathologists and epidemiologists—formulated recommendations through structured consensus, informed by a comprehensive review of current scientific evidence and clinical practice standards. Optimal management of LM requires accurate diagnosis and individualized treatment planning. Non‐invasive skin imaging techniques, especially dermoscopy and reflectance confocal microscopy, aid in diagnosis, biopsy orientation, lesion delineation and post‐treatment monitoring. Multiple partial biopsies help confirm diagnosis and rule out invasion. Complete surgical excision remains the first treatment option. No definitive safety margins can be recommended for standard surgery; margin‐controlled techniques are preferable for large or ill‐defined lesions. Topical imiquimod and radiotherapy are effective alternatives where surgery is unsuitable. Topical imiquimod is useful as primary, adjuvant or neoadjuvant therapy. Blind destructive methods should be avoided. Close clinical and imaging follow‐up is needed. Patient‐centred care, shared decision‐making, and a multidisciplinary approach are critical for optimal outcomes. These international consensus recommendations summarize current best practices for LM management, offering practical, evidence‐informed guidance to clinicians while acknowledging the potential of future research in refining these conclusions.