Citations

Abstract Purpose: Homozygous deletion of the 9p21 locus, containing CDKN2A/B and MTAP [CDKN2A/MTAP deletion (CMdel)], underlies emerging therapeutic strategies, including PRMT5/MAT2A inhibition. The clinicogenomic context and treatment outcome associations of CMdel in non–small cell lung cancer (NSCLC) remain incompletely defined. Experimental Design: We analyzed Tempus Lens records with paired DNA (xT) and RNA (xR) sequencing. After quality filtering (purity ≥40%), 16,947 patients were included in the primary dataset, and 10,996 were included in the validation dataset and stratified by deletion status [CMdel vs. CM wild-type (CMwt)]. IFN status was defined by IFN-kappa (IFNK) expression [log2(TPM + 1)] using the 25th percentile of CMwt as the threshold. Immune composition was inferred by quanTIseq. First-line regimens were grouped as immune checkpoint inhibitor (ICI) monotherapy, ICI chemotherapy, chemotherapy, or tyrosine kinase inhibitors (TKI). Best response and time to next treatment (TTNT) with risk-set adjustment and 18-month truncation were assessed. Results: CMdel occurred in 11.7% (n = 1,991) and 15% (n = 1,676), respectively, and was enriched in mucinous histology, stage IV disease, and never smokers. CMdel was associated with EGFR, TERT, and SMARCA4 alterations, whereas CMwt was associated with RB1, SETD2, and ARID2. More than 50% of CMdel tumors harbored targetable coalterations, enriched in EGFR/ALK/RET and relatively depleted in KRAS. CMdel tumors exhibited lower PD-L1, mutation burden, and immune infiltration. TTNT did not differ by CM status for ICI monotherapy or TKI but was shorter in CMdel for ICI chemotherapy and chemotherapy. Discordant and broad deletions were less common and had weaker TTNT association. IFNK-low expression marked immune-excluded subgroups with worse treatment outcomes. Conclusions: CDKN2A/MTAP loss defines a prevalent, genomically distinct NSCLC subset enriched in actionable drivers. CMdel associates with worse outcomes to ICI/chemotherapy-containing regimens. These findings highlight convergent biology at 9p21 and support biomarker-guided development of PRMT5/MAT2A inhibitors in MTAP-deleted NSCLC.

Abstract Background The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP‐MSA) have not been prospectively validated. Objective To evaluate the diagnostic performance of the PP‐MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. Methods Seventy‐six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP‐MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. Results Thirty‐eight participants met PP‐MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%–97%) and PPV (53%–83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. Conclusions The PP‐MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials. © 2026 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

BACKGROUND: Improved cleaning in the anesthesia workspace is important for surgical site infection prevention. We sought to identify high-priority cleaning targets to guide post-induction surface disinfection and use of a triangular ultraviolet-C (UV-C) configuration involving placement of one emitter at the head and one on each side of the surgical bed. METHODS: The 20 sites most frequently touched by anesthesia practitioners, previously identified via video-based workflow analysis, were filtered to remove disposable (eg, stopcocks) and transient (eg, the patient bed) sites, leaving durable cleaning targets amenable to repeated surface disinfection and UV-C irradiation within and/or between cases. Inequality in the distribution of cleaning target touches was quantified using the Gini coefficient, and uncertainty was estimated using bootstrap resampling (10,000 iterations). We then assessed residual contamination after standard terminal cleaning across three operating rooms and 171 sites to evaluate the difficulty of cleaning high-touch surfaces and the efficacy of UV-C disinfection. Simulations using medical devices composed of materials representative of cleaning targets contaminated with high-level Clostridium difficile were conducted to evaluate generalizability to more resistant pathogens. RESULTS: There were 13 of 20 frequently touched sites that were considered durable cleaning targets. Touches were relatively equal among the 13 cleaning targets (Gini coefficient 0.16, 95% confidence interval [CI], 0.12–0.20). Cleaning targets included components of the anesthesia cart (first and second drawer handles); anesthesia machine (reservoir bag, circuit ventilator control, oxygen dial, vaporizer dial, adjustable pressure-limiting valve), monitoring equipment (screen buttons/knob, electrocardiogram leads); and room infrastructure (intravenous pole, operating room table and chair). Residual contamination after cleaning was identified at 4% (7/171) of sites, mostly (6/7) within the anesthesia workspace, involving the anesthesia cart (N = 2), machine (N = 3), and monitor (N = 1). Only one site outside of the anesthesia workspace, the circulating nurse’s mouse, had residual contamination. Triangular UV-C reduced mean (standard deviation [SD]) colony-forming units (CFU) from 60.47 (542.22) to 0.12 (1.08), achieving a 2.7-log reduction. Simulation with high-level C. difficile contamination demonstrated ≥3-log reductions on surfaces representative of high-touch sites, confirming applicability to resistant pathogens. CONCLUSIONS: Thirteen durable cleaning targets in the anesthesia workspace are largely equivalent in terms of risk of touch. They are amenable to UV-C augmentation of surface disinfection in the real-world clinical environment. These findings can guide targeted post-induction cleaning and use of triangular UV-C, particularly for surfaces with substantial contamination or resistant pathogens.

Abstract Background: Immune checkpoint inhibitors (ICIs) have improved survival in non-small-cell lung cancer (NSCLC), yet only a subset of patients benefits, and biomarkers like PD-L1 remain limited. Here, we introduce a deep learning-based pathomics framework that utilizes routine H&E-stained slides to predict therapeutic response and survival outcomes in ICI-treated metastatic NSCLC. Methods: The study included 797 ICI-treated NSCLC patients from MD Anderson, with external validation in 280 patients from Mayo Clinic, Gustave Roussy, and the Phase III ICI-naïve LUSC Lung-MAP S1400I trial receiving nivolumab with or without ipilimumab. Path-IO (Pathology-Driven Immunotherapy Optimization) comprised of four major steps: (1) pathologist-verified tissue classifier segmented WSIs into eight compartments—Background, Bronchi, Immune, Lung, Necrosis, Stroma, Tumor, and Vessel—and was validated on TCGA and CPTAC dataset; (2) a survival prediction module generating patient-level risk scores in the MD Anderson cohort and validated across external datasets; (3) integration of Path-IO risk scores with radiomics and clinical features to improve prognostic accuracy; and (4) biological interpretability analyses correlating Path-IO risk immune contexture from multiplex immunofluorescence and transcriptomic signatures from NanoString profiling. Results: Path-IO effectively stratified patients into high and low-risk groups with significant survival differences. In the MD Anderson cohort, it achieved HR = 2.11 (p < 0.001) and HR = 2.51 (p < 0.001) for OS in the discovery and validation sets, and HR = 2.34 (p < 0.001) and HR = 1.87 (p < 0.001) for PFS, respectively. In the multicenter Phase III Lung-MAP S1400I trial, Path-IO achieved HR = 1.78 (p = 0.016) for OS and HR = 2.76 (p = 0.006) for PFS. In external validation, it predicted outcomes in the Gustave Roussy (OS = 1.97, p = 0.003; PFS = 1.51, p = 0.046) and Mayo Clinic (OS = 2.46, p = 0.007; PFS = 2.45, p = 0.027) cohorts. Path-IO outperformed PD-L1 and remained an independent predictor in multivariate analysis (p < 0.001). It enabled data-driven frontline selection between anti-PD-1 monotherapy and chemo-immunotherapy, offering guidance toward more personalized treatment decisions. Integration with radiomics and clinical features further improved predictive accuracy (OS 0.63→0.75; PFS C-index 0.58→0.70), while high Path-IO risk scores correlated with immune-cold phenotypes identified by multiplex immunofluorescence and NanoString transcriptomics. Conclusions: Path-IO demonstrates that deep learning models rooted in histopathologic architecture can generate interpretable and biologically informed survival predictions in NSCLC treated with ICIs. By integrating pathology, radiology, and clinical data, Path-IO provides complementary predictive value beyond established biomarkers such as PD-L1. Citation Format: Rukhmini Bandyopadhyay, Linghzi Hong, Mihaela Aldea, Shenduo Li, Lodovica Zullo, Frank R. Rojas, Maliazurina B. Saad, Maricel C. Marin, Muhammad Waqas, Jiexin Zhang, Eman Showkatian, Claudio A. Arrechedera, Xiaoyu Han, Yuliya Kitsel, Sherif Ismail, Muhammad Aminu, Bo Zhu, Carol C. Wu, Brett W. Carter, Joe Y Chang, Zhongxing Liao, Maria R. Ghigna, Davide Soldato, Hai T. Tran, Xiuning Le, Tina Cascone, Bingnan Zhang, Haniel A. Araujo, Mehmet Altan, Simon Heeke, David Jaffray, Don L. Gibbons, Ara Vaporciyan, J Jack Lee, Neda Kalhor, Cara Haymaker, Ignacio Wistuba, John V. Heymach, Yanyan Lou, Natalie Vokes, Luisa M. Solis Soto, Jianjun Zhang, Jia Wu. Path-IO: A deep learning pathomics framework for personalized immunotherapy selection and outcome prediction in metastatic non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4003.

Abstract Specialized immune niches located in the stroma-tumor junction promote interactions between tumor-resident antigen-presenting cells and effector lymphocytes that are required for immunotherapy efficacy. We have hypothesized that this stromal-based immune crosstalk may be regulated by provisional extracellular matrix signals, analogous to the early-stages of wound healing where provisional matrix hosts robust immune activity. A cardinal provisional matrix remodeling event, the regulated proteolysis of the large proteoglycan versican (VCAN) generates an immunomodulatory fragment (matrikine), versikine, that engages adaptive immunity. We have previously shown that VCAN proteolysis correlates with T-cell infiltration across multiple solid and liquid cancers with the most immune-evasive cancers showing low to negligible rates of VCAN proteolysis (e.g., 0% in pancreatic adenocarcinoma). A recent clinical trial generated informative prospective data linking VCAN proteolysis with immunotherapy outcomes: patients whose metastatic colorectal tumors categorized as VCAN proteolysis-weak (VPW, 60% of cases) demonstrated inferior responses to checkpoint inhibition (CPI, pembrolizumab) and worse outcomes compared to VCAN proteolysis-predominant (VPP, 40%) cases. Leveraging these prospective trial data, we hypothesized that versikine therapy may rationally reverse the immunosuppression associated with the prevalent VPW phenotype. To tailor versikine therapy to specific human biomarker-stratified tumor phenotypes, we studied experimental models replicating partially T-permissive VPW-VCANlo human cancers and poor-prognosis, immune-exclusionary VPW-VCANhi cancers. Across VPW-like tumors, versikine promoted the stromal accumulation of CD40lghiIcoshiFoxp3neg Tfh-like CD4+ T cells that engaged dendritic cells (DC) and CD8+ T cells in “immune triads” even at baseline (prior to CPI), concurrently with the intratumoral expansion of activated CD8+ T cells expressing cytolytic molecules (granzymes, perforin). In VPW-VCANlo tumors, versikine delivered as LNP-mRNA or recombinant protein demonstrated monotherapy activity, dependent on Batf3-lineage DC and CD8+ T cells. When combined with single-agent CPI, versikine cured most VPW-VCANlo tumors with memory to tumor re-challenge. In VPW-VCANhi tumors, versikine synergized with combination immunotherapy modulating “mature DCs enriched in immunoregulatory molecules” (mregDC). Our data provide mechanistic rationale for the biomarker-stratified, therapeutic restoration of a provisional matrix-regulated immune signaling network to reverse resistance to CPI. Moreover, the data highlight the need to reevaluate prior approaches to globally disrupt tumor stroma in favor of biomarker-driven, pathway-focused harnessing of stromal signals that modulate anti-tumor immunity. Citation Format: Daniel J. Lagal, Duncan Hong, Athanasios Papadas, Emma Geatches, George Yacu, Surabhi Naik, Alicia Gibbons, Alexander Cicala, Kersi Pestonjamasp, Peter Toth, Kristina Matkowskyj, Dustin A. Deming, Fotis Asimakopoulos. Biomarker-driven restoration of tumor provisional matrix signaling network reverses resistance to checkpoint inhibition immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6746.

ABSTRACT Objective To determine the test performance of cutaneous phosphorylated alpha‐synuclein (P‐SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. Methods This is the first subgroup analysis of the Synuclein‐One study, a prospective, blinded study evaluating P‐SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control ( N = 151) and DLB ( N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P‐SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40–99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. Results After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P‐SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. Interpretation In this prospective, blinded, cross‐sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P‐SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P‐SYN detected. These results support a role for skin biopsy detection of P‐SYN in patients with DLB. Trial Registration NCT04700722

ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin &amp;lt;3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

e13890 Background: Many oncology practices have reported continued use of telemedicine since onset of the COVID-19 pandemic. However, the future sustainability of telemedicine within oncology practices remains unclear, particularly because federal policies that enabled adoption in response to the public health emergency (PHE) have not been made permanent. Understanding similarities and differences in telemedicine utilization at high-volume oncology centers is crucial for shaping evidence-based policy that enables equitable access to oncology care across varying geographies. Methods: This is a cross-sectional, year-over-year, retrospective cohort analysis of trends in telemedicine utilization across all medical oncology clinical appointments conducted among adult patients (age >18) from January 2019 to December 2023 at Stanford Medicine Cancer Center (SM) – comprising multiple campuses in the California Bay Area – and the Mayo Clinic Comprehensive Cancer Center (MC) – a multiregional cancer practice with tertiary referral campuses in Minnesota, Florida, and Arizona, as well as community-based clinics throughout the Upper Midwest. Results: Both institutions exhibited a similar trend in telemedicine adoption over time. This was characterized by an initial surge in utilization following the PHE declaration in March 2020, followed by sustained utilization rates from 2021 to 2023. However, telemedicine use as a proportion of the overall practice differed significantly between institutions. At SM, the rate of telemedicine visits as a proportion of overall clinical practice was 60.3% (49,136/ 81,502) in 2021, 59.9% (52,247/ 87,215) in 2022, and 57.2% (55,007/ 96,163) in 2023. At MC, the proportion of telemedicine utilization was 12.8% in 2021 (23,873/186,086), 14.7% in 2022 (28,985/196,777), and 14.0% in 2023 (30,208/215,941). Deployment in the setting of new versus return visits also differed between institutions. In 2023, telemedicine accounted for 53.7% (6,440/11,998) of new and 57.7% (48,567/84,165) of return visits at SM, compared to 15.5% (3,359/21,728) and 13.8% (26,849/194,213) at MC. Additionally, while video visits were the predominant modality used to conduct telemedicine visits at both institutions from 2021 onward, in 2023 phone visits still made up 17.9% (5,394/30,208) of all telemedicine visits at MC, compared to just 5.4% (2,990/55,007) at SM. Conclusions: Stanford Medicine and Mayo Clinic exhibited a pattern of initial growth of telemedicine adoption in 2020, followed by sustained utilization from 2021-2023. We observed unique differences in the overall proportion, visit type deployment, and modality of telemedicine utilization between institutions. However, this study confirms telemedicine visits have remained a fixture of medical oncology care for many patients at these institutions since the COVID-19 pandemic.