Citations

Background Youth-onset diabetes mellitus (DM) is an increasing public health concern, especially among adolescents facing socioeconomic challenges. Food insecurity (FI), a key social determinant of health, has been linked to adverse metabolic outcomes, but its association with youth-onset DM and the role of preventive care remain unclear. Methods Using repeated cross-sectional data from the National Survey of Children’s Health (2016–2021), we examined the association between FI status (food secure, mild FI and moderate-to-severe FI) and youth-onset DM among adolescents aged 10–17 years. We also evaluated whether usual preventive care modified this association. Propensity score weighting (PSW) was used to reduce the imbalance of measured confounders across FI groups. These weights were applied in the least absolute shrinkage and selection operator logistic regression for variable selection and in the final multivariable logistic regression models. Results In the PSW analysis of 66 560 adolescents, 432 had youth-onset DM. Moderate-to-severe FI was associated with higher odds of DM than food-secure adolescents (OR 1.55, 95% CI 1.35 to 1.77; p<0.0001), whereas mild FI was not associated with youth-onset DM. Among adolescents with preventive care visits, both mild FI (OR 1.19, 95% CI 1.04 to 1.37; p=0.0126) and moderate-to-severe FI (OR 1.67, 95% CI 1.46 to 1.92; p<0.0001) were associated with higher odds of DM. Among those without preventive care visits, FI was associated with lower odds of having a reported DM diagnosis, especially in the moderate-to-severe FI group (OR 0.11, 95% CI 0.03 to 0.35; p=0.0002). Conclusions Moderate-to-severe FI was associated with youth-onset DM, and this relationship varied by access to preventive care. Adolescents with FI who lack regular preventive care may have fewer opportunities for DM diagnosis. Public health strategies should integrate FI screening, equitable access to preventive services and culturally responsive approaches to chronic disease prevention.

Abstract Background Multiplexed immunofluorescence (MxIF) enables high-dimensional immune cell phenotyping and detailed characterization of the tumor immune microenvironment (TIME), but complex cyclic staining can introduce signal degradation and uncertainty in cell-level measurements. In routine practice, pathologists rely on hematoxylin and eosin (H&E) staining as the primary reference for tissue morphology and frequently cross-reference H&E to interpret MxIF findings. Methods We present a framework for aligning H&E and MxIF images at the tissue microarray (TMA) core level to support cross-modal analysis. Cell nucleus detections from each modality are used as anchor points, formulating the task as a point-set alignment problem. Coherent Point Drift (CPD) is applied for global alignment, followed by graph-matching–based refinement to improve local consistency. Evaluation on ovarian TMAs demonstrates consistent alignment performance for both restained and serial sections. We further explore the use of restained H&E as a reference for MxIF interpretation and investigate virtual H&E generation from MxIF data as a complementary approach when restained H&E is unavailable. Results The aligned images enable quantitative assessment of cross-modal feature concordance between MxIF-derived measurements and H&E morphology. The generated virtual H&E demonstrated similar cell population compared to the real H&E. Conclusions Cell-centric alignment can facilitate integrative multimodal histopathology analysis for TMA cores in spatial co-localization, cell feature validation, and virtual H&E generation.

Abstract Purpose: The addition of MEK inhibition (MEKi) to programmed cell death ligand 1 (PD-L1) blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer. Although MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance antitumor immunity in this combination. Patients and Methods: We conducted a randomized, phase II trial evaluating atezolizumab (840 mg, intravenously, days 1 and 15) in combination with the CD27 costimulatory monoclonal antibody [CDX-1127/varlilumab (3 mg/kg, intravenously, days 1 and 15)], with/without the addition of an MEK inhibitor [cobimetinib (60 mg, orally, daily, days 1–21, off days 22–28)] in unresectable biliary tract cancer following at least one metastatic therapy. Overall response rate (ORR) and PFS were coprimary endpoints. Treatment-related changes in CD8+ tumor-infiltrating lymphocytes (TIL) were the primary correlative outcomes. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled [n = 29 in the cobimetinib + atezolizumab + varlilumab (CAV) arm; n = 28 in the atezolizumab + varlilumab (AV) arm]. A majority (67%) had intrahepatic cholangiocarcinoma, and 32% were immunotherapy experienced. Both regimens were well tolerated without new safety signals. Objective responses were rare [0% (CAV); 3.8% (AV)]. The median PFS (mPFS) was 2.40 (CAV) and 1.84 (AV) months [hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.38–1.18]. Among immunotherapy-experienced patients, the mPFS was 3.62 (CAV) and 1.84 (AV) months (HR, 0.54; 95% CI, 0.18–1.62). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. Conclusions: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe, but neither meaningfully improved outcomes in biliary tract cancer treated in the later lines. Correlative tissue studies validated preclinical work that MEKi increases CD8+ TILs.

Abstract Background In children with non-metastatic atypical teratoid/rhabdoid tumor (ATRT), proton therapy is increasingly utilized worldwide due to the radiosensitivity of afflicted young patients. General questions persist, however, surrounding dose and volume of radiotherapy. Methods Between 2009-2024, 39 children from a single institution with non-metastatic intracranial ATRT received focal proton therapy at a median age of 2.4 years (range 0.7-19). Twenty-two patients had supratentorial tumors and 27 had gross/near total resection prior to radiation. Most common chemotherapy regimens were ACNS0333 and SJYC07 (n = 10 each) and Dana-Farber (n = 6). Four patients received consolidative high-dose chemotherapy after radiation. The median radiation dose was 50.4 Gy (range, 50.4-54). The cumulative incidence method assessed freedom from selected endpoints.The Fine-Gray method assessed the level of statistical significance between levels of selected prognostic factors. Results With a median followup of 5.2 years (range 0.5-16.2), the 5-yr overall survival, progression-free survival, and local control was 63%, 64%, and 97%, respectively. Thirteen patients developed isolated leptomeningeal failure as first site of recurrence. Only subtotal resection was significantly associated with local recurrence (100% vs 92%, p &lt; 0.05). Patient age, tumor site, extent of resection, radiation dose, and chemotherapy regimen were otherwise not significantly associated with disease control or survival. Four patients experienced symptomatic radiation necrosis, including 1 death: Three of 4 cases received 54 Gy and consolidative intrathecal methotrexate (n = 2) or high dose ACNS0333 intravenous chemotherapy (n = 1, fatal) after radiation. The other patient received 50.4 Gy and necrosis was immediately preceded by ventriculoperitoneal shunt failure. Six patients developed hearing loss requiring aids. One patient developed radiation-induced meningioma a decade following treatment. Conclusion This represents the largest experience reporting 5-year outcomes following focal radiation in children with non-metastatic intracranial ATRT. When applied with a variety of modern chemotherapy regimens in real-world settings, focal proton therapy at a dose of 50.4 Gy may offer the best therapeutic ratio but does not eliminate serious toxicity. If avoidance of craniospinal radiation remains an ongoing priority, further improvement in survival will depend upon systemic therapy.

Abstract Rationale Seralutinib is an investigational, first-in-class tyrosine kinase inhibitor designed for inhalation and selective for PDGFRα, PDGFRβ, CSF1R, and cKIT, targeting proliferation, inflammation, and fibrosis ─ three core drivers of pulmonary vascular remodeling in PAH. The phase 2 TORREY trial of seralutinib added to standard-of-care treatment in adults with PAH WHO FC II or III met its primary endpoint of a statistically significant reduction in pulmonary vascular resistance (PVR) vs. placebo at 24 weeks. Methods PROSERA (NCT05934526), a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, evaluated the efficacy and safety of inhaled seralutinib in PAH patients treated for up to 48 weeks. Eligible patients (WHO Group 1 PH, FC II or III; REVEAL Lite 2 Risk Score ≥5 or NT-proBNP ≥300 ng/L or PVR ≥800 dyne•s/cm5) on standard background therapy were randomized 1:1 to seralutinib 90 mg or placebo delivered by dry powder inhaler twice daily. The primary endpoint was change in six-minute walk distance (6MWD) from baseline to week 24 in the seralutinib treatment group vs. placebo. Key secondary endpoints included: time to clinical worsening (TTCW), proportion of patients with clinical improvement at week 24, change in NT-proBNP from baseline to week 24, and proportion of patients with ≥1-point decrease from baseline in REVEAL Lite 2 Risk Score at week 24. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs). Patients who completed blinded treatment could be eligible to participate in an open-label extension study. Preliminary Blinded Results 390 patients were randomized at 132 sites worldwide. At baseline, mean age was 50.0 years. PAH etiologies included 61.0% idiopathic, 9.7% heritable, and 22.3% associated with connective tissue disease. 25.6% of patients were WHO FC II and 74.4% FC III. Mean time from diagnosis was TBD years. Most patients were receiving 2 (39.2%) or ≥ 3 (54.6%) PAH medications, 29.2% were receiving parenteral prostacyclin. Baseline PVR was 798.4 dyne•s/cm5, 6MWD was 373.7 m, and NT-proBNP was 986.8 ng/L. The difference in 6MWD from baseline to week 24 between seralutinib and placebo was TBD [SD] m (p=TBD). Secondary endpoints of TTCW, clinical improvement, NT-proBNP, and REVEAL Lite 2 Risk Score will be reported. The most common AEs were TBD (x%) and TBD (y%). SAEs and discontinuations related to AE will be reported. Conclusions The PROSERA study demonstrates⋯ [to be updated following unblinding of the data]. Funding Gossamer Bio, Inc. This abstract is funded by: Gossamer Bio, Inc.

Introduction The introduction of the purpose‐built single‐port (SP) robotic platform has allowed for the advent of regionalized minimally invasive surgical approaches for robotic radical prostatectomy (RARP), including the extraperitoneal and transvesical techniques. This study sought to develop a best practice consensus on the key principles, patient selection, surgical techniques, expected clinical outcomes, and learning curves pertaining to SP‐RARP. Methods A modified Delphi consensus was developed by a panel of experts, consisting of a 33‐item questionnaire, with each statement rated using a binary Likert scale (‘agree’ or ‘disagree’). The survey was distributed via email to all practicing SP‐RARP surgeons across the USA and Europe. Consensus was defined as ≥75% agreement on a given statement. Results A total of 53 surgeons participated in the Delphi Consensus across the two rounds. Of 33 statements, 28 (84.8%) reached agreement in the first round. The remaining consensus was achieved in the second round, involving 35 surgeons, and with one additional statement. The panel agreed that, although are no absolute contraindications to SP‐RARP, the preference towards specific SP‐RARP techniques should remain guided by the individual patients and surgical expertise. Although the SP extraperitoneal technique is recommended to pursue pelvic lymph node dissections, the panel agreed that transvesical SP‐RARP showed promise in promoting shorter hospital stay, faster recovery of urinary continence, and utility in patients with extensive prior abdominal surgery. Consensus was also reached on the need for a structured training pathway, with most recommending beginning with extraperitoneal SP‐RARP before advancing to the transvesical approach. Conclusion This Delphi consensus demonstrates broad agreement among experienced SP surgeons in the USA and Europe, forming the foundation for future research on the clinical utility and necessary training pathways for SP‐RARP. Nevertheless, empirical validation based on clinical data from large cohort studies remains important.

LBA10509 Background: The MCED test (Galleri) detects a shared cancer signal from cell-free DNA in blood and predicts a cancer signal origin (CSO) to guide diagnostic (dx) workup. PF2 (NCT05155605) is a large, prospective, multicenter, interventional study of the MCED test’s performance and safety in a diverse US intended-use population. Methods: PF2 enrolled participants aged ≥50y without clinical suspicion of cancer or cancer diagnosis/treatment within 3y of enrollment. Primary objectives were MCED performance and safety in terms of dx testing triggered by a positive (cancer signal detected) MCED test result. Participants with a positive MCED test underwent targeted dx workup guided by the predicted CSO(s). Participant-reported anxiety was assessed with the State Trait Anxiety Inventory. Results: PF2 enrolled 35,878 participants; 32,007 with a 12m cancer assessment were analyzable for performance. Of 287 (0.9%) with a positive MCED test, 173 were diagnosed with cancer within 12m, for a cancer detection rate of 0.5% (95% CI 0.5-0.6%) and positive predictive value of 60.3% (54.5-65.8%). Specificity was 99.6% (99.6-99.7%). 12m episode sensitivity was 69.8% (62.8-76.0%) in a prespecified subgroup of 12 cancers responsible for ⅔ of US cancer deaths, 66.2% (55.1-75.8%) in a subgroup of 6 aggressive cancers with low 5y survival, and 39.3% (34.9-44.0%) across all cancers. Overall CSO prediction accuracy was 91.3% (86.2-94.7%) across all cancers. The MCED test detected 151 new primary and 22 recurrent cancers; additional cancers detected by screening were those with USPSTF A/B (n=31) and C (n=60) recommended screening. Of 151 MCED-detected new primaries, 80 (53.0%) were clinical stage I-II; 107 (70.9%) were stage I-III. Of 80 MCED-detected stage I-II cancers, 71.2% had no USPSTF A/B screening recommendation. Of 35,335 participants analyzable for safety, 213 (0.6%) had invasive procedure(s) to evaluate a positive MCED test result, of which 90% were nonsurgical and 1.8x more likely for participants with vs without cancer diagnosis. Most (87.6%) had a CSO-guided dx evaluation. There were 5 study-related adverse events during the time of dx workup; none were serious. Anxiety temporarily increased for participants with a positive MCED test and cancer diagnosed, and returned to baseline by 12m. Of participants with a positive MCED test, median time from test result to dx resolution was 48d (95% CI 43-56). Few participants (7/63 [11.1%]) had cancer found by dx PET/CT after a targeted dx workup that did not reveal cancer. Conclusion: The MCED test demonstrated robust performance with a favorable safety profile. When MCED testing was added to USPSTF A/B screening, 6.5x more cancers were detected by screening, most at early stages. The diverse, representative PF2 participant population supports the generalizability of these findings to the US intended-use population. Clinical trial information: NCT05155605 .

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.