Citations

Abstract Background: Spatial cellular ecosystems in the tumor microenvironment (TME) form dynamic signaling hubs that critically influence cancer disease progression and response to therapy, including response to immune checkpoint inhibitors (ICIs). However, tumor sampling bias and the impracticality of acquiring serial tumor biopsies have made it challenging to profile the TME clinically. To address this challenge, we developed Liquid EcoTyper, a multi-analyte AI framework to quantify TME spatial cellular ecosystems—termed spatial ecotypes (SEs)—noninvasively from cell-free DNA (cfDNA) methylation data. Methods: In previous work, we discovered nine spatial ecotypes, including SEs associated with ICI response (e.g., SE7 with benefit, SE4 with resistance), and quantified them from 1,249 bulk tumor RNA-seq profiles of melanoma, non-small cell lung cancer (NSCLC), and bladder cancer (BC) patients (Cancer Res (2025) 85 (8_Supplement_1): 153). Here we trained Liquid EcoTyper, an interpretable deep learning model, to transfer SE profiling to cell-free DNA using CpG methylation profiles. Performance was quantified using simulated and real data, including methylation profiles (EM-seq) of plasma cfDNA paired with tumor biopsy-derived SE levels determined by EM-seq (n=20 pairs) or 10x Visium (n=15 pairs). Clinical outcome prediction was evaluated using pretreatment plasma from patients treated with ICI alone (n=78 melanoma pts), chemotherapy and ICI (n=25 NSCLC pts), and enfortumab vedotin and ICI (n=10 localized muscle-invasive BC (MIBC) pts). Tumor mutational burden (TMB), tumor PD-L1, or circulating tumor DNA (ctDNA) were profiled as a comparator where possible. Results: We observed striking concordance between plasma-derived SE levels and tumor biopsy-confirmed SE levels from the same patients, demonstrating that liquid biopsy analysis of cfDNA methylomes can recapitulate TME spatial biology. Underscoring specificity, no reliable SE signal was detectable from peripheral blood mononuclear cells. In pre-ICI plasma, liquid SE levels were significantly associated with ICI-based response (SE7) versus resistance (SE4) in patients with melanoma, NSCLC, and MIBC, with a mean cross-cancer area under the curve (AUC) of 0.87 for SE7 (range 0.8-0.97) and 0.81 for SE4 (range 0.76-0.85)—far surpassing TMB, tumor PD-L1, and ctDNA in evaluable patients, both in binary analyses of response and multivariable models of survival. Our results also showed potential to predict pathologic complete response in the neoadjuvant setting. Conclusion: Liquid EcoTyper is a scalable noninvasive AI-based framework for spatiotemporal assessment of the TME. By enabling TME-informed risk stratification without surgical biopsies, Liquid EcoTyper has potential to enable more precise and actionable decision making in patients with solid tumors. Citation Format: Erin L. Brown, Wubing Zhang, Abul Usmani, Noah Earland, Ayesha Hashmi, Chibuzor Olelewe, Anushka Viswanathan, Pradeep S. Chauhan, Minji Kang, Chloé B. Steen, Hyun Soo Jeon, Susanna Avagyan, Irfan Alahi, Nicholas P. Semenkovich, Matteo Bergsagel, Janella C. Schwab, Chloe M. Sachs, Faridi Qaium, Peter K. Harris, Antonella Bacchiocchi, Qingyuan Cai, Andrew J. Gentles, Rondell P. Graham, Peter C. Lucas, Ryan C. Fields, Jacob J. Orme, Aaron S. Mansfield, Mario Sznol, Ruth Halaban, David Y. Chen, Aaron M. Newman, Aadel A. Chaudhuri. Liquid biopsy profiling of the tumor microenvironment to determine response to immunotherapy regimens across solid tumors [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 94.

Abstract Hypoxia constrains cerebral oxygen availability and challenges brain function and stability. Although hypoxia-responsive functional connectivity (HR-FC) reorganizes rapidly with declining arterial oxygen partial pressure, its relationship to local neurovascular activity remains unclear. We examined time-resolved amplitude of low-frequency fluctuations (ALFF) in blood-oxygenation-level dependent (BOLD) fMRI during graded acute hypoxia in healthy adults, performing a continuous cognitive test (Go/No-go task) with concurrent physiological monitoring. Dynamic ALFF and functional connectivity were estimated using a sliding-window approach and analyzed across large-scale brain networks defined by Schaefer’s 17-network parcellation. Severe hypoxia elicited temporally dissociated responses across modalities. Functional connectivity increased monotonically, whereas ALFF exhibited pronounced nonlinear modulation, including phase-dependent divergence across networks. During hypoxic decompensation, the default mode network (DefaultA) showed marked ALFF suppression, whereas a ventral secondary somatosensory-dominant network (SomMotB) exhibited preferential preservation despite similar engagement in HR-FC. Together, these findings indicate that network-level ALFF captures a distinct yet complementary layer of functional dynamics, with a temporal profile distinct from functional connectivity. Spontaneous BOLD dynamics during acute hypoxia reflect structured network-level modulation rather than a uniform suppression attributable solely to reduced oxygen availability. These findings support a conceptual framework of cerebral oxygen budgeting , in which metabolic constraints reshape functional dynamics across brain networks.

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.

Purpose To use publicly available injured list (IL) data to 1) describe Major League Baseball injury trends from 2010 to 2024; 2) analyze injury types and body regions affected to report the highest impact injuries; and 3) report the financial implications of time lost due to injury over this 15‐year period. Methods IL data for every Major League Baseball player (pitchers and position players) from the 2010 to 2024 regular seasons were collected using publicly available sources, including player demographics, IL placements, body part injured, and length of each IL stay. Player salaries were compiled to determine the “financial loss” per injury. Results Across 15 seasons, 8078 players were placed on the IL, totaling 478,085 days. The mean IL placements/year was 634, and the annual number increased by an additional 27 injuries/year ( P < .001). Mean total IL days/season was 31,872, and this increased year‐over‐year ( P = .008). Shoulder injuries represented the most IL placements (n = 1555), followed by elbow (n = 1344) and upper leg (n = 769). Elbow injuries averaged the most days missed/IL placement (mean: 93, median: 74) and the greatest total days missed (129,610), followed by shoulder (95,189). Pitchers comprised 55% of IL placements and most commonly injured their shoulder or elbow. Infielders and outfielders accounted for 21% and 16% of IL placements, respectively. A total financial loss of $9,636,753,291 was accumulated over 15 seasons. Financial loss increased season‐to‐season (+$32,309,178/year, P = .002). Elbow injuries accounted for the highest financial loss at $1,932,048,168 ($1,379,049 lost/injury). In 2024, $2,220,432 was lost/elbow injury, $1,110,573/shoulder injury, $1,397,322/any injury, and $952,973,760 total for the season. Conclusions This study observed that the number of players, IL placements, days spent on the IL, and financial loss due to injury increased steadily each year. Pitchers were the most frequently injured players with shoulder and elbow injuries being most common. Over the 15‐season study period, there was a total financial loss of nearly $9.7 billion due to salary paid to injured players, with elbow injuries contributing the highest loss at just under $2 billion. Clinical Relevance Injury trends and financial data from Major League Baseball highlight the growing burden of shoulder and elbow injuries, particularly in pitchers. These findings underscore the need for orthopaedic surgeons to focus on prevention, early intervention, and optimized surgical management of high‐impact injuries to reduce long‐term morbidity and associated financial costs at the elite level.

Background: Femoroacetabular impingement (FAI) is a common injury experienced by basketball players. Surgical management with arthroscopic labral repair and femoral osteochondroplasty can lead to successful outcomes for athletes whose nonoperative management fails. Recent studies have demonstrated that athletes undergoing hip arthroscopy in the setting of FAI had favorable return-to-sport (RTS) and sport continuation outcomes. Purpose: To evaluate patient-reported outcome measures (PROMs) and RTS rates at minimum 5-year follow-up in basketball players after hip arthroscopy for FAI. Study Design: Case series; Level of evidence, 4. Methods: All active basketball players at the recreational, high school, and collegiate levels who underwent primary hip arthroscopy with labral repair for FAI between August 2009 and December 2019 were identified. Postoperative RTS, revision rates, and surgery satisfaction at final follow-up were evaluated. PROMs were also analyzed as follows: visual analog scale, Tegner Activity Scale, modified Harris Hip Score, Hip Outcome Score–Activities of Daily Living, and Hip Outcome Score–Sport. Results: Fifty-three patients (64 hips) were included with a mean ± SD age of 21.2 ± 6.0 years. Most athletes played recreational or high school basketball (85%), while 15% played college basketball. Forty-three patients attempted to return to basketball. Of these patients, 35 (81%) returned to basketball after surgery, with 32 (91%) returning to the same level of play. Patients who returned to basketball had significantly improved outcomes on the modified Harris Hip Score ( P = .006), Hip Outcome Score–Activities of Daily Living ( P = .007), Hip Outcome Score–Sport ( P = .004), Tegner Activity Scale ( P = .010), and visual analog scale with use ( P = .041) as compared with those who did not return. High school athletes had decreased odds of RTS when compared with recreational athletes ( P = .01). There was significant improvement in all PROMs from baseline to minimum 5-year follow-up ( P < .05). Conclusion: At minimum 5-year follow-up, basketball players demonstrated durable improvements in PROMs and an RTS rate of 81% after hip arthroscopy for FAI. The majority of athletes returned to the same level of competition. There were significantly improved PROMs in patients who returned to sport versus those who did not. High school athletes had decreased odds of RTS when compared with recreational athletes. However, body mass index, sex, age, alpha angle, and basketball position did not significantly correlate with RTS outcomes.

Background: Frequent pivoting, rotation, and deep hip flexion place football players at high risk for femoroacetabular impingement (FAI), a leading cause of hip pain in this population. Previous studies have primarily focused on professional National Football League athletes undergoing mixed surgical techniques, including labral debridement. Limited data exist on outcomes in younger, amateur players treated with labral repair. Purpose: To report return to sport (RTS) rates and functional outcomes at a minimum 5-year follow-up in primarily active high school and college football players undergoing primary hip arthroscopy with labral repair for FAI. Study Design: Case series, Level of evidence, 4. Methods: All football players who underwent primary hip arthroscopy with labral repair for FAI between 2010 and 2019 were identified from an institutional database. Collected data included descriptive data, radiographic parameters, surgical details, and reoperations. At a minimum 5-year follow-up, RTS outcomes and patient-reported outcome measures (PROMs), such as the Modified Harris Hip Score (mHHS) and Hip Outcome Score (HOS), were evaluated. Results: A total of 36 hips in 27 male athletes (mean age, 18 years; body mass index, 28.1 kg/m 2 ) were included. The majority of athletes competed at the high school (70%) or collegiate level (26%). Mean preoperative radiographic measurements were as follows: lateral center-edge angle, 31.6°; Tönnis angle, 4.1°; and alpha angle, 61.4°. Femoroplasty and acetabuloplasty were performed in 100% and 86% of cases, respectively. Also, 84% of players returned to football, all at the same or higher level than before surgery. At a mean follow-up of 9.8 years, all PROMs improved significantly from baseline ( P < .002). Outcome scores at follow-up were as follows: mHHS 90.5; HOS-Activities of Daily Living, 94.5; HOS-Sports-Specific Subscale, 91.1; and visual analog scale (VAS) pain with use, 2.3/10; VAS pain at rest, 1.3/10; and surgical satisfaction, 8.5/10. No patients required revision surgery. However, 2 patients (7%) underwent reoperations—including 1 for heterotopic ossification excision and 1 for periacetabular osteotomy. Conclusion: American football players who underwent primary hip arthroscopy with labral repair for FAI achieved excellent long-term outcomes, with high RTS rates at the same or higher levels, and improvements in PROMs and patient satisfaction. Despite favorable outcomes, nonmedical factors, such as graduation, may influence RTS in competitive athletes, particularly at the high school and collegiate levels.

Abstract Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

88 Background: The VISION (NCT03511664) and PSMAfore (NCT04689828) clinical trials have demonstrated the effectiveness of 177 Lu-PSMA-617 in patients with mCRPC who have previously received androgen receptor pathway inhibitors (ARPIs) with or without taxane-based chemotherapy. Sipuleucel-T is used for treatment of mCRPC in routine clinical practice, particularly among community urologists; however, to date, there are no data available to understand the effectiveness of 177 Lu-PSMA-617 in patients previously treated with sipuleucel-T. Methods: This was a retrospective, observational study of adult patients with a diagnosis of mCRPC who received 177 Lu-PSMA-617 between March 23, 2022, and June 27, 2025, and had a history of treatment with sipuleucel-T. Data were obtained from the PRECISION data platform, a harmonized dataset of patients with advanced prostate cancer in the US that integrates electronic health records and claims data from community, academic, urology, and medical oncology settings. The index date was the date of 177 Lu-PSMA-617 initiation. Patient characteristics and prostate-specific antigen (PSA) response rates were evaluated descriptively. Progression-free survival (PFS), defined as the time from 177 Lu-PSMA-617 initiation to disease progression or death, was analyzed using Kaplan–Meier curves. Results: A total of 290 patients met the inclusion criteria, of whom 72% were White and 12% were Black. At index, 32% of patients were treated in urology and 68% in oncology settings. The median age was 74 years, the median baseline PSA was 35.3 ng/mL (interquartile range [IQR] 10.0–99.2 ng/mL), and 57% of patients had a Gleason score of ≥8. In addition to sipuleucel-T, prior to 177 Lu-PSMA-617, 97% of patients had received ≥1 ARPI and 79% had received ≥1 taxane. The median follow-up for this cohort was 9.4 months (IQR 5.3–17.5 months). Among 144 patients with available PSA values both before and during 177 Lu-PSMA-617 treatment (representing 50% of the cohort), PSA response rates were as follows: a ≥50% reduction in PSA from baseline (PSA50) was observed in 60%, PSA80 in 42%, and PSA90 in 33% of patients. Overall, the median PFS was 15.2 months (95% confidence interval [CI] 11.6–19.4 months). Conclusions: In this real-world analysis of patients who received 177 Lu-PSMA-617 after sipuleucel-T treatment, the median PFS was similar to that observed in clinical trials, suggesting that 177 Lu-PSMA-617 can be sequenced after sipuleucel-T treatment in appropriate patients.

81 Background: In the PSMAfore clinical trial, 177 Lu-PSMA-617 achieved a PSA50 (defined as a ≥50% reduction in prostate-specific antigen [PSA] from baseline) response rate in 58%, a median radiographic progression-free survival (PFS) of 12 months, and a median overall survival (OS) of 25 months among taxane-naïve patients with mCRPC who had received one prior androgen receptor pathway inhibitor (ARPI). The aim of the present study was to evaluate the real-world effectiveness of 177 Lu-PSMA-617 in taxane-naïve patients with mCRPC who had received one or more prior ARPIs. Methods: This retrospective, observational study included taxane-naïve adults with mCRPC initiating 177 Lu-PSMA-617 between March 23, 2022, and June 27, 2025, after ≥1 prior ARPI. All data for the study were extracted from the PRECISION data platform, a harmonized dataset of patients with advanced prostate cancer in the US treated in a variety of clinical settings. The index date was the date of 177 Lu-PSMA-617 initiation. Patient characteristics and PSA response rates were evaluated descriptively. PFS, defined as the time from 177 Lu-PSMA-617 initiation to progression or death, was estimated using Kaplan–Meier methodology. Results: A total of 500 patients were included. The median age was 75 years, 75% of patients were White and 8% Black, and 18% were treated in urology centers while 82% were treated in oncology centers. The most common site of metastasis was bone (77%), followed by lymph node (21%), visceral (12%), and unknown (5%). Overall, 51% had received 1 previous ARPI while 49% had received ≥2. The median baseline PSA was 26.7 ng/mL (interquartile range [IQR] 10−105 ng/mL) and the median time from mCRPC diagnosis to 177 Lu-PSMA-617 initiation was 23.6 months. The median number of 177 Lu-PSMA-617 cycles received was 4 (IQR 2−6). Among 219 patients with available PSA measurements both before and during 177 Lu-PSMA-617 treatment (representing 44% of the cohort), PSA response rates were as follows: PSA50 in 137 (63%), PSA80 in 86 (39%), and PSA90 in 56 (26%) patients. Overall, the median PFS was 13.5 months (95% confidence interval 11.7–14.7 months). Conclusions: The effectiveness of 177 Lu-PSMA-617 as a standard-of-care treatment in real-world, taxane-naïve patients with mCRPC who had received prior treatment with ≥1 ARPI is consistent with results from the PSMAfore trial, confirming the applicability of those findings to the real-world population now eligible for 177 Lu-PSMA-617. Further research on sequencing 177 Lu-PSMA-617 after one or more prior ARPIs in taxane-naïve patients with mCRPC is needed to guide optimal treatment sequencing in clinical practice.