Annals of Oncology

IMPORTANCE: A recent meta-analysis showed that chemoimmunotherapy was associated with improved overall survival (OS) compared with immune checkpoint inhibitor (ICI) monotherapy for programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) [&ge;] 50% advanced non-small-cell lung cancer (NSCLC). However, whether this benefit reflects chemotherapy effect or ICI heterogeneity remains unclear. OBJECTIVE: To reassess the survival benefit of adding chemotherapy to ICI monotherapy using agent-stratified comparisons anchored to chemotherapy. DATA SOURCES: The 24 phase 3 randomized clinical trials included in the original meta-analysis (search date, August 3, 2025). DATA EXTRACTION AND SYNTHESIS: Hazard ratios (HRs) for OS and progression-free survival (PFS) were extracted from each trial in the original meta-analysis. Two analytic frameworks were used: within-agent comparisons (same ICI in both chemoimmunotherapy and monotherapy) and across-agent comparisons (ICI in one treatment strategy only). For within-agent comparisons, a two-stage random-effects meta-analysis was conducted. In stage 1, ICI-specific HRs for chemoimmunotherapy and ICI monotherapy versus chemotherapy were pooled and their ratio was calculated (RHR = HRchemoimmuno/HRmono; RHR < 1 favors chemoimmunotherapy). The RHRs were pooled in stage 2. For across-agent comparisons, RHR was derived from pooled HRs by treatment strategy. MAIN OUTCOMES AND MEASURES: Endpoints were OS and PFS. RESULTS: In within-agent comparisons (4 ICIs; 13 trials; N = 3252), pooled RHR was 0.94 (95% CI, 0.78-1.13; P = .48; I2 = 0.0%) for OS and 0.85 (95% CI, 0.68-1.06; P = .14; I2 = 0.0%) for PFS. In across-agent comparisons (7 ICIs; 11 trials; N = 2231), RHR favored chemoimmunotherapy for OS (0.68; 95% CI, 0.50-0.92; P = .01) and PFS (0.46; 95% CI, 0.37-0.58; P < .001). In a sensitivity analysis restricted to trials of NCCN-recommended regimens, pooled RHR was 1.02 (95% CI, 0.81-1.28; P = .87) for OS. CONCLUSIONS AND RELEVANCE: In the within-agent comparisons, adding chemotherapy to ICI monotherapy did not improve OS or PFS in patients with PD-L1 TPS [&ge;] 50% advanced NSCLC. The benefit in the original meta-analysis appears driven by across-ICI heterogeneity. These findings are consistent with ICI monotherapy as a standard first-line option and underscore the need for agent-level stratification in across-trial comparisons.

Purpose/Objective There is paucity of data reporting outcomes of breast cancers with initial internal mammary nodal involvement and no visceral metastases, treated with curative hypofractionated radiotherapy . We report the outcomes from a tertiary centre alongside spatial patterns of recurrences in the above group Material/Methods For this retrospective cross-sectional study, consecutive patients contoured as per the ESTRO 2013 guidelines, treated between 2016-2022 were eligible if their diagnostic imaging demonstrated involvement of the internal mammary nodes. Radiotherapy (40 Gy/15#/3 weeks) was delivered to the residual breast / thoracic wall, SCF region corresponding to the ESTRO lymph node level 4 and internal mammary chain nodes. Residual IMN/ level 4 nodes received a boost of 10Gy/5#. Spatial mapping of sites of recurrence at the local site and three nodal sites (axilla, SCF and IMN) was performed using deformable image registration. Sites of recurrence at the local site and three nodal levels were contoured separately. Volumetric intersection of the recurrent gross tumour volume (GTV_recurrence) with treated clinical target volume (CTV) was calculated. Actuarial overall (OS), disease free survival (DFS) & cumulative incidence of local (LR), regional (RR) and loco-regional recurrence(LRR) were calculated using Kaplan Meier method. Univariate comparison of outcomes with or without residual disease was performed using the log rank test. Results The median age of the 61 eligible women was 49 years. 77% received neoadjuvant chemotherapy and the rest adjuvant chemotherapy. 82% patients had a mastectomy. Axillary lymph node dissection was done in 96.7%. Boosts to residual IMN and SCF nodes were delivered to 21(34.4%) and 2 (3.3%) respectively. Median follow up was 3.6 years. Out of the 61 patients, 42 patients were disease free with an estimated 3 year disease free survival of 75% (95% CI 64, 88%). Spatial mapping of locoregional recurrence was possible in all but 1 patient with local (only) recurrence who was lost to follow-up after mammogram only. Among the patients with loco regional recurrence 1 had recurrence in local site + SCF +axilla, 3 had recurrence in the SCF+axilla, 2 in the SCF+IMN and 1 in the axilla+SCF+IMN. Only one patient had isolated axillary recurrence or isolated SCF recurrence. There were no IMN only recurrences. Among the 8 patients with nodal recurrence, a total of 27 individual GTV_recurrence were identified in the axilla(n=11), SCF(n=11) and IMN (n=5). IMN recurrences showed complete or partial overlap with CTV. SCF recurrences were a mix with predominantly in-field recurrences while axillary recurrences occurred outside the treated volume.Four (6.6%) patients had Grade 2 lymphoedema as documented late side effect. Conclusion Aggressive treatment of IMN disease with adjuvant radiation is effective with good locoregional control. Systemic recurrences are common and may benefit from intensification strategies.

Introduction: There is an unmet need for effective topical anti-pruritic medications for acute itch, as there are only a few over-the-counter products that have a direct effect on itch. Tripelennamine is a first-generation antihistamine that would be useful in treating histamine-induced pruritus, however, supportive robust clinical data is lacking. Objectives: The efficacy of tripelennamine (TPA) compared to diphenhydramine (DPH) and a vehicle control cream base on histamine-induced pruritus was evaluated as the primary endpoint. Histamine-induced urticaria served as the secondary endpoint. Methods: Thirty-six healthy participants completed this single-center, double-blinded, placebo-controlled crossover clinical study. Following pretreatment with TPA1%, DPH 1% or vehicle control creams, histamine challenge occurred via iontophoresis and a visual analog scale (VAS) for pruritus was used to determine extent of itch (AUC-VAS), peak itch, and duration of itch. Results: Compared to the vehicle control, TPA reduced histamine-induced extent of itch (AUC-VAS), peak itch, and itch duration by 59%, 38% and 43%, respectively (p<0.01 all). DPH did not significantly affect these responses and TPA was superior in reducing extent of itch (48% reduction, p<0.05) and duration (38% shorter, p<0.05). TPA, but not DPH, also reduced histamine induced flare and wheal responses (secondary endpoints) by 53% and 27%, respectively. The reduction in flare responses by TPA was superior to that of DPH (45% reduction, p<0.05). Conclusion: TPA significantly attenuated histamine-induced pruritus and urticaria in a human histamine-challenge model and demonstrated greater efficacy than DPH. These findings provide strong evidence of the antipruritic activity of topical TPA and support further clinical investigation of TPA as a treatment for histaminergic itch and related dermatologic conditions.

Chemoradiotherapy (CRT) is the standard-of-care therapy for many solid malignancies, yet predictive biomarkers of treatment response remain limited. We identified a germline single nucleotide polymorphism (SNP) in an intrinsically disordered region of the lysine demethylase KDM3C/JMJD1C (p.S464T) that is associated with CRT outcomes in locally advanced rectal cancers (LARC) and head and neck squamous cell carcinoma (LA-HNSCC). In silico modeling with AlphaFold predicted S464T substitution influenced interaction between phosphorylated KDM3C and RNF8 FHA domain. In cellular models, conversion of S464 to T464 increased sensitivity to DNA-damaging agents. S464T substitution impaired damage-induced MDC1-RAP80 signaling and downstream RAP80-BRCA1 colocalization. SNP carrying cells impaired DNA repair causing genotoxic stress that is associated with increased cGAS-cGAMP innate immune signaling and increased apoptosis. Population analyses with the SNP highlighted an increase incidence of UV-induced skin and other cancers, linking inherited variation in the chromatin regulatory gene KDM3C to genome instability, cancer risk, and therapeutic vulnerability.

Importance: Immune checkpoint inhibitors (ICIs) produce diverse immune toxicities, but whether checkpoint blockade also modifies associations between other drugs and adverse events is poorly understood. Objective: To define ICI-associated toxicity organization and determine whether drug-associated adverse events and onset vary with ICI exposure and checkpoint pathway. Design and Setting: Cross-sectional analysis of deduplicated FAERS reports from 2016 through 2025; analyses performed in 2026. Participants: Among 13,701,106 deduplicated reports, 2,365,269 were cancer associated and 256,940 contained an ICI. Median age among cancer reports with observed age was 66 years (IQR, 56-75 years); 1,031,999 (43.6%) were female and 1,003,154 (42.4%) were male. Exposures: ICI exposure in any reported drug role, individual primary-suspect drugs, and checkpoint-pathway exposure. Main Outcomes and Measures: Reporting odds ratios (ORs), cross-organ adverse-event communities, adjusted primary-suspect drug x ICI interaction ORs for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), interstitial nephritis, drug-induced liver injury (DILI), and vomiting (VOM), and accelerated failure-time model time ratios for documented onset. Results: Of 3001 eligible Preferred Terms in cancer-associated reports, 2091 differed at a false discovery rate (FDR) less than .05. Four cross-organ toxicity communities were identified. Of 138 eligible drug-phenotype pairs, 65 had FDR-significant interactions, including moxifloxacin-SJS/TEN amplification (interaction OR, 101.72; 95% CI, 39.11-264.55), enfortumab vedotin-SJS/TEN attenuation (interaction OR, 0.17; 95% CI, 0.13-0.23), and omeprazole-interstitial nephritis amplification (interaction OR, 10.35; 95% CI, 7.62-14.05). Among 60,324 reports contributing to temporal analyses, ICI exposure was associated with longer adjusted documented time to onset for 5 of 6 phenotypes (time ratios, 1.37-1.59) but not AGEP (time ratio, 0.99; 95% CI, 0.67-1.46). Temporal associations also differed across checkpoint pathways. Conclusions and Relevance: ICIs were associated with a structured cross-organ toxicity landscape, phenotype-specific modification of drug-associated adverse events, and distinct temporal patterns across checkpoint pathways. These findings support checkpoint blockade as a modifier of drug-associated toxicity and motivate longitudinal and mechanistic validation.

Background: Prostate cancer enzalutamide treatment is approved at a standard dose of 160 mg daily. Concerns for real-world patients -- older and more fragile than those enrolled in clinical trials -- have prompted consideration of initiating treatment with lower doses, but the long-term efficacy of this approach remains unknown. We evaluate the long-term survival and longevity in patients treated with standard versus upfront low-dose enzalutamide. Methods: Retrospective analysis of 151 patients treated with enzalutamide (102 receiving 160 mg; 49 receiving [&le;]80 mg) between 2014--2021 at the Centre Hospitalier Universitaire de Martinique, with complete follow-up through end of life (98.7% completeness of follow-up). Primary outcomes were overall survival (OS), progression-free survival (PFS), and longevity (attained age). Results: Doses [&le;]80 mg were associated with longer median OS (36.3 vs. 20.7 months), improved restricted mean OS (difference of 0.7 years, p=0.05), and enhanced longevity (median 82.5 vs. 78.3 years, p=0.004). PSA response rate at 12 weeks was higher with lower-dose (71.4% vs. 48.8%, p=0.016). In multivariable models adjusted for prognostic factors, [&le;]40 mg compared with 160 mg was non-inferior regarding OS (HR=0.61, 95% CI 0.36--1.06), superior regarding PFS (HR=0.59, 95% CI 0.35--0.99), and superior regarding longevity (HR=0.48, 95% CI 0.28--0.84). Bone metastasis, poor performance status, PSA response, time to PSA nadir, and disease duration were independent predictors of outcomes. A post-hoc analysis revealed a strong association between dose and physician-prescribing profiles, ranging from "endorse-lowest-dose" to "never-deviate-from-full-dose". Conclusions: Lower doses of enzalutamide were non-inferior to full-dose. Dose-adapted strategies warrant further investigation.

Background Conversion surgery for stage IV gastric cancer is supported by a pooled overall survival hazard ratio of 0.36 (95% confidence interval 0.32-0.40) and, in the largest international cohort, median survival of 36.7 versus 12.5-13.8 months on chemotherapy. Survival is measured from diagnosis; the median diagnosis-to-gastrectomy interval is 124 days, which patients must survive to be counted surgical. Methods We simulated cohorts of 3,177 stage IV gastric cancer patients from published parameters: background median survival 14.5 months; median diagnosis-to-surgery interval 124 days (category-specific 92-174 days). Surgery had no effect (true hazard ratio 1.00 by construction). Data were analysed as the literature analyses them (exposure fixed at baseline, follow-up from diagnosis), and by time-varying Cox and landmark analysis. Confounding by indication was added in a second scenario. Results Under immortal time bias alone the naive analysis returned a hazard ratio of 0.794 (95% simulation interval 0.743-0.851), median survival 16.8 versus 12.8 months. Time-varying Cox recovered 1.000 and landmark analysis 1.000-1.004. Bias scaled with the interval: 0.849 at 92 days, 0.715 at 174 days. Adding confounding, the naive estimate fell to 0.601 (0.560-0.644) at strength 0.5 and 0.356 (0.323-0.385) at strength 1.5, overlapping the published estimate; median survival 21.9 versus 8.7 months. Correcting immortal time alone left residual bias (hazard ratio 0.439). Conclusions The reported survival advantage of conversion surgery is reproducible where the operation does nothing; published estimates cannot distinguish benefit from bias. Resolving this requires individual patient data analysed with methods that assign person-time correctly, or completion of JCOG2301.

Background: Many at-risk patients lack access to genetic services due to a genetic counselor (GC) workforce shortage. Little is known about how digital alternatives impact patients with and without cancer who meet criteria for genetic testing. Methods: eREACH2 is a randomized 4-arm non-inferiority trial where pre-test (visit 1) and/or return of results (visit 2) GC counseling was replaced with a patient-centered digital intervention. Arms include: A (GC/GC), B (GC/digital), C (digital/GC) and D (digital/digital). Primary outcomes were non-inferiority in uptake of genetic services and change in genetic knowledge and general anxiety from baseline to post-disclosure of results (T0-T2). Secondary cognitive and affective outcomes were assessed using non-inferiority ANOVAs and equivalency chi-squared tests in intention-to-treat and per-protocol analyses. Findings: 773 participants were recruited nationwide; 46.6% from rural areas. Mean age was 51 years (range 20-87), 13% male, 12% non-white, 29% had less than a college education, and 33% had a personal history of cancer. 584 (76%) patients completed testing (14% had a positive result, 16% had a VUS). In the primary ITT analyses, we met the non-inferiority for uptake of genetic services and anxiety, but results were inconclusive for knowledge. Secondary outcomes were heterogeneous across arms. Arm C demonstrated consistently favorable effects, while Arms B and D showed less favorable outcomes in select domains (e.g. satisfaction and MICRA). Patients who received positive or VUS results via digital disclosure had significantly higher MICRA scores - indicating greater negative response to testing. Interpretation: In this large, randomized trial of patients with and without cancer, the eREACH intervention was effective for pre-test counseling, but inconclusive for digital disclosure of results. Exploratory analyses suggest that digital delivery could be a reasonable alternative for individuals receiving negative results, while those receiving positive or VUS results may derive some short-term psychosocial benefit from GC disclosure.

Next-generation sequencing (NGS) for the detection of somatic variants has become the method of choice in a variety of molecular oncology fields and in the clinic. Its use ranges from sequencing entire tumor genomes and transcriptomes to targeted clinical diagnostic gene panels. The NYU Langone Genome PACT (Profiling of Actionable Cancer Targets, LG-PACT) assay is a qualitative in vitro diagnostic test that uses targeted next generation sequencing (NGS) of formalin-fixed paraffin-embedded (FFPE) tumor tissue matched with normal specimens from patients to detect gene alterations in a targeted panel covering 606 genes and the TERT promoter. Indications for testing are cancer (solid tumors and hematological malignancies) where a mutational profile from multiple genes would be informative for disease stratification, prognosis, or treatment options including targeted therapies and eligibility for clinical trials. The test is intended to provide information on somatic mutations including point mutations, small insertions/deletions (indels), and copy number aberrations for diagnostic and treatment decisions. LG-PACT is a United States Food and Drug Administration (FDA) cleared diagnostic test (510K: K202304). The clinical interpretation of sequencing data of molecular tumor markers from NGS encompasses automated variant calling tools with human interpretation. This final mostly manual review of data step is intensive, involving highly trained scientists, encompassing literature review, interpretation and clinical tier classification by pathologists, who then provide a complete molecular diagnostic report to the treating oncologists. We provide analysis of 1339 clinical genomic profiles from 31 different cancers and their subtypes, comprising of central nervous system (CNS) 792 (59%) cases (incl. meningioma, glioma and glioblastoma), with 267 (20%) cases predominantly of lung, pancreatic and colorectal and 280 of others (21%). Here, we present the technical challenges of validating an NGS oncological diagnostic targeted assay for clinical grade accuracy and sensitivity for patient care. We show how copy number alterations provide a more comprehensive description of the tumors genomic profile. We then outline the utility of targeted panel sequencing based on certified pathologist selection of reportable variants for our current patient cohort. Where analysis of variant detection has led to 49.4% (661/1339) of our clinical tumor samples containing mutations in known therapy targeted genes, 35.6% (477/1339) with mutation detected in other genes, and 15% (201/1339) cases being negative.

Background: Primary malignant cardiac tumors (PMCTs) are rare and histologically heterogeneous. Objective: To compare demographics, specific ICD-O-3 morphologies, first-course treatment patterns, annual registered case counts, and unadjusted overall survival between soft-tissue and hematologic PMCTs. Methods: We identified 730 PMCT cases diagnosed from 2000 to 2021 in SEER 18 (ICD-O-3 topography C38.0). Histologic lineage was assigned from ICD-O-3 morphology. Comparative analyses included soft-tissue (n=458) and hematologic (n=212) tumors. First-course variables were primary-site surgery, chemotherapy (yes versus no/unknown), and radiotherapy (radiation versus none/unknown). Groups were compared with chi-square tests. Overall survival was estimated with Kaplan-Meier methods; follow-up was truncated at 120 months. Results: Soft-tissue PMCTs occurred predominantly at ages 45-64 years (67.9%), whereas hematologic PMCTs occurred predominantly at age [&ge;]65 years (63.2%; p<0.001). Men comprised 59.9% of hematologic and 49.3% of soft-tissue cases (p=0.014). The leading soft-tissue morphology was hemangiosarcoma/angiosarcoma (ICD-O-3 9120/3; 201/458, 43.9%); synovial sarcoma accounted for 20/458 cases (4.4%). Diffuse large B-cell lymphoma, NOS, accounted for 131/212 hematologic tumors (61.8%). Any primary-site surgery was recorded in 66.6% of soft-tissue versus 15.6% of hematologic cases (p<0.001). Chemotherapy was recorded in 67.5% versus 51.1% (p<0.001), and radiotherapy in 9.0% versus 20.5% (p<0.001). In exploratory Kaplan-Meier analyses, hematologic patients with recorded chemotherapy had higher unadjusted 120-month overall survival than those without recorded chemotherapy (42.0% versus 12.2%; log-rank p=7.5x10-). Radiation-associated survival differences were not statistically significant in either lineage. Conclusions: Soft-tissue and hematologic PMCTs have distinct age distributions, named histologies, and first-course treatment patterns in SEER. These findings describe registry coding and do not establish treatment effectiveness or population incidence.

Background: Pressure ulcers often develop complex three-dimensional morphologies that extend beyond the visible wound surface. Subsurface extensions such as tunneling and undermining create hidden cavities that complicate clinical assessment and wound management. Despite their clinical relevance, the prevalence and spatial characteristics of these subsurface wound morphologies have not been well characterized at scale. Methods: We performed a registry-based analysis using data from the LIFT-OFF Pressure Ulcer Registry, which captures longitudinal clinical documentation of pressure ulcers treated in routine care. The registry included approximately 18,000 patients with 32,000 documented pressure ulcers. Spatial characteristics of tunneling and undermining were analyzed using measurements recorded during routine wound assessments, including tract length, direction, and circumferential extent. Directional and circumferential distributions of subsurface defects were examined to characterize wound geometry. Results: Tunneling was present in 764 of 14,700 full-thickness pressure ulcers (5.2%), whereas undermining occurred in 2,293 wounds (15.6%). Tunneling tracts were typically short and exhibited directional clustering relative to the wound bed. In contrast, undermining demonstrated broader circumferential distributions and frequently involved larger subsurface separations beneath the wound margin. Both morphologies demonstrated distinct spatial patterns across anatomical locations and wound stages. Conclusion: Tunneling and undermining are common subsurface features of pressure ulcers and exhibit distinct spatial geometries. Whereas tunneling manifests as directional tract-like extensions, undermining more frequently produces circumferential tissue separation beneath wound margins. Improved characterization of subsurface wound architecture may enhance assessment of wound complexity and provide information not captured by surface measurements alone. Future studies should evaluate whether these features contribute to wound severity assessment, prognosis, and risk stratification.

Klebsiella pneumoniae (Kp) is a WHO high-priority pathogen for vaccine development, yet previous efforts failed largely because key protective immune mechanisms remain unclear. Here we show that protective immunity conferred by mucosal mRNA vaccines (but not parenteral) require neither serum IgG nor airway secretory IgA, but instead depends on a previously unrecognized lung-resident CD8IL-17 T-cells (Tc17) that rapidly recruits neutrophils/macrophages to eliminate bacteria. To therapeutically harness this paradigm, we developed INSPIRE, a machine learning-engineered exosome platform incorporating donor-screened, miRNA-bioactive backbones (miR-21-mediated airway barrier penetration and miR-155-associated dendritic-cell activation through SOCS1/Inpp5d axis) and computationally designed peptides that boosts 11.6-fold mRNA encapsulation and 3-fold dendritic-cell cross-presentation. Intranasal INSPIRE-mRNA vaccination confers near-complete protection against clinically relevant Kp strains while intramuscular counterparts fail (below ~30% survival). Leveraging pIgR-/- and IL-17-/- mice coupled with T-cell depletions, we demonstrate the protection is Tc17-dependent. This work overturns the antibody-centric dogma and redefines a non-canonical Tc17-correlate for extracellular bacterial pneumonia.

Background: Evidence suggests chronic distress influences ovarian cancer (OC) etiology and metabolomic profiles. Here, we evaluated the association of a metabolite-based distress score (MDS) and OC risk. Methods: We included two matched case-control studies nested within the Nurses' Health Studies (N=584) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N=348). Metabolites were measured 3-27 years before diagnosis using liquid-chromatography tandem mass spectrometry. We examined the association of quintiles of MDS and 19 constituent metabolites with OC risk using unconditional logistic regression and stratified by tumor histotype, menopausal status, and age at diagnosis. Results: We observed women in the highest versus lowest quintile of MDS had an increased OC risk (OR=1.62,95%CI=1.03-2.54,ptrend=0.07), and type 2 tumors (OR=1.71,95%CI=1.03-2.83,ptrend=0.11). Associations were suggestively stronger for premenopausal and <69-year-old women, and driven by pseudouridine, and N2,N2-dimethylguanosine. Conclusion: Our findings suggest chronic distress-associated metabolic dysregulation may represent a novel OC risk factor, especially among younger women.

Prognostic models in oncology are developed one cancer at a time, from that cancer's own labelled outcomes, and fail where prognostic information is scarcest. Rare cancers account for roughly a fifth of diagnoses and most paediatric malignancies, yet seldom supply enough events for a reliable time-to-event model. We therefore asked whether a representation learned without outcome labels can supply what those cohorts cannot. A Transformer encoder was pretrained by masked field-value modelling on 9425135 tumour records from the SEER 17 registries, diagnosed in 2000 to 2023. Only diagnosis-time fields passing a fail-closed coding-verification gate were admitted, and each record was emitted as an era-specific and a harmonised view, keeping two decades of recoding auditable. The encoder was then frozen and read by a linear Cox head for overall survival. Nine rare cancers were removed from the pretraining corpus entirely, each requiring an independent pretraining run. On a sealed test partition, all nine exceeded an architecture-identical random frozen encoder in Harrell concordance by +0.0034 to +0.0368, every lower confidence limit above zero. At 256 labelled patients, all 67 cancers favoured the pretrained representation over budget-matched Cox regression, median difference +0.0283. The advantage was bounded: given the entire training set, Cox regression was favoured in seven of nine rare cancers. The encoder did not outperform a field-frequency baseline on its own objective, so upstream reconstruction did not predict downstream transfer. Outcome-agnostic registry pretraining carries prognostic signal into cancers it has never seen, and is most useful where labels are fewest, without establishing clinical utility.

Outcomes for high-grade pediatric brain tumor patients remain poor, but there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. We present the results from a phase I clinical trial of IL13BBz-CAR T cells infused weekly into the cerebral ventricles in pediatric and young adult patients with recurrent or refractory brain tumors. The trial met its primary objectives of feasibility, safety, and tolerability, with one dose-limiting toxicity. 8 of 16 patients evaluable for response experienced radiographic size decreases consistent with biologic activity and with an anti-tumor response. Two patients met protocol criteria for response. Median survival for patients receiving lymphodepletion was 20.5 months from diagnosis and 6.9 months from treatment for patients with midline glioma, and 187 months from diagnosis and 7.5 months from treatment for patients with ependymoma. Importantly, patients who did not receive lymphodepletion developed anti-CAR humoral and cellular immune responses detectable in the CSF and peripheral blood, whereas patients receiving lymphodepletion had no evidence of CSF anti-CAR immunity. Taken together, these findings demonstrate the safety, tolerability, and biological activity of locoregionally-delivered IL13BBz-CAR T cells for children and young adults with CNS tumors. Moreover, we show that anti-CAR immune responses arise in patients not receiving lymphodepletion, but not in the CSF of patients receiving systemic lymphodepletion. Further investigation of adoptive cellular therapies combined with immunosuppression is warranted in this patient population. ClinicalTrials.gov registration: NCT04510051.

Abstract Background: Cytolytic activity (CYT), a widely used transcriptomic surrogate of anti-tumor immune cytotoxicity derived from GZMA (granzyme A) and PRF1 (Perforin 1) expression, is associated with clinical outcomes across cancers. MicroRNAs (miRNAs) are key post-transcriptional regulators of tumor immunity, yet their pan-cancer roles in modulating cytolytic activity remain incompletely understood. Objective: This study aimed to identify conserved miRNA regulators of tumor cytolytic activity and their downstream gene-mediated networks across diverse cancer types, while evaluating their clinical and therapeutic relevance. Methods: Matched miRNA and mRNA expression profiles from 9,288 primary tumors across 31 TCGA cancer types were analyzed. A multi-stage framework was applied: per-cancer Spearman correlations (|{rho}| >= 0.30, FDR < 0.05) identified recurrent CYT-associated miRNAs (at least 3 cancer types); these were integrated with TargetScan-predicted targets and subjected to pan-cancer and cross-cancer triple filtering (miRNA-gene and gene-CYT associations). All associations underwent tumor purity adjustment using Consensus Purity Estimate (CPE), with LUMP (Leukocytes Unmethylation for Purity) as sensitivity analysis. Candidates were further prioritized by random forest modeling with bootstrap stability, cancer-type-adjusted Cox regression, mediation analysis, immune cell deconvolution, k-means molecular subtyping, pathway enrichment, and DGIdb-based drug-target prioritization. Results: The analysis converged on 38 high-confidence miRNA-gene-CYT regulatory triplets involving 9 conserved miRNAs and 31 target genes after stringent purity adjustment and multi-layer validation. All nine miRNAs exhibited complete bootstrap stability. Mediation analysis confirmed significant gene-level mediation in 37 of 38 triplets (FDR < 0.01), with mediated proportions up to 94%. The final miRNA signature defined two distinct pan-cancer immune subtypes (immune-hot vs. immune-cold) with significantly different cytolytic activity and overall survival (OS) (HR = 0.754, FDR = 1.12 x 10^-4). The network was enriched for T-cell activation and lymphocyte differentiation pathways and highlighted multiple druggable targets, including CTLA4 and CD274 (PD-L1), nominating 124 candidate compounds. Conclusions: In conclusion, this tumor purity-adjusted pan-cancer study defines a compact, reproducible, and clinically relevant miRNA network that regulates cytolytic activity across diverse malignancies. By linking miRNA biology to immune subtyping and actionable therapeutic targets, the present work provides a valuable foundation for advancing precision immuno-oncology.

Background Late-stage cancer incidence is being considered as an earlier endpoint in cancer-screening trials, but its trial-level association with cancer-specific mortality may depend on evidence selection and endpoint harmonization. We evaluated the robustness of this association to source-verified additions. Methods We reconstructed the PubMed corpus underlying a 41-comparison review. Gemini 3.1 Pro Preview was used only to prioritize reports for blinded human reassessment. Reviewers determined eligibility, linked reports from the same trial, harmonized endpoints, and verified comparison-level data. We recalculated unweighted Pearson correlations overall and by cancer type after adding earliest-compatible trial comparisons. Results Among 1209 candidate records, 996 PDFs were assessed. Thirty-three reports absent from the source review were prioritized; 26 were eligible, representing 18 trials, and 8 provided compatible comparisons. Adding these comparisons increased the dataset from 41 to 49 and attenuated the overall correlation from 0.73 (95% confidence interval [CI] = 0.55 to 0.85) to 0.59 (95% CI = 0.37 to 0.75). Updated correlations were 0.49 (95% CI = -0.26 to 0.87) for breast, -0.23 (95% CI = -0.71 to 0.40) for colorectal, and 0.83 (95% CI = 0.54 to 0.95) for lung cancer. One sparse-event comparison influenced the colorectal estimate. Conclusions The overall association was sensitive to evidence composition, and cancer-specific stability varied. Late-stage incidence should be evaluated by cancer type and with prespecified sensitivity analyses for evidence selection and endpoint definitions. Model-assisted prioritization cannot replace human eligibility review, trial reconciliation, and source verification.

To evaluate the cost-utility and 5-year budget impact of first-line olaparib plus abiraterone versus abiraterone alone for metastatic castration-resistant prostate cancer (mCRPC) in China after the eleventh round of volume-based procurement (VBP). The intention-to-treat (ITT) population was assigned primary decision-analytic weight; the prespecified BRCA1/2-mutated (BRCAm) subgroup was a supporting analysis.

Background: Biochemical recurrence (BCR) occurs in 20-40% of men after radical prostatectomy. Existing postoperative recurrence risk tools based on PSA and pathology are clinically useful but show only moderate and variable discrimination, highlighting the need for biomarkers that improve risk stratification and consequent treatment decisions. We hypothesized that the prostate microenvironment, including both the tumor and non-cancerous adjacent tissue, may contain prognostic features associated with adverse postoperative PSA outcomes. Methods: We assembled a cohort of matched tumor-adjacent benign and tumor prostate tissue from 243 men across three institutions to establish a discovery cohort (n=123; 43 postoperative PSA events, 35%) and validation cohort (n=120; 46 events, 38%). For primary binary analyses, a postoperative PSA event included BCR, defined as two consecutive postoperative PSA values >=0.2 ng/mL, or PSA persistence. We performed RNA sequencing of matched tumor-adjacent benign and tumor tissues, quantified immune signatures, and developed an integrated model combining the adjacent-tissue B-cell signature, preoperative PSA, and radical prostatectomy Gleason score (BRIGADE). CAPRA-S-adjusted Cox analyses excluding recurrence-time-0 cases evaluated time to BCR, and CD19 multiplex immunofluorescence provided tissue-level confirmation (n=10). Results: In prostatectomy specimens, tumors from patients without a postoperative PSA event were enriched for B-cell transcriptional programs, whereas tumors from event-positive patients showed elevated proliferation signatures. B-cell-related transcriptional programs were correlated between tumor and adjacent tissue. Tumor-adjacent benign B-cell scores were higher in no-event cases and discriminated postoperative PSA-event status in PCBN discovery (AUC 0.63) and BM validation (AUC 0.81) cohorts, outperforming numerous other immune-related signatures. In CAPRA-S-adjusted Cox sensitivity analyses excluding recurrence-time-0 cases, higher adjacent-tissue B-cell activity was associated with reduced recurrence risk in PCBN (HR 0.42, 95% CI 0.19-0.94; BH-adjusted p=0.035) and BM (HR 0.54, 95% CI 0.30-0.95; BH-adjusted p=0.034). Tissue-based validation showed that CD19+ B-cell density in adjacent benign tissue was higher in no-event than event-positive patients (median 0.1145 vs 0.0471; p=0.008). BRIGADE achieved an AUC of 0.68 in cross-validation and 0.83 in independent validation, compared to AUCs of 0.54-0.63 and 0.44-0.78 for the tested clinical predictors, respectively. At the fixed classification threshold, the validation-cohort odds ratio for BRIGADE was 2.75. The adjacent B-cell score remained associated with lower odds of a postoperative PSA event after adjustment for PSA and Gleason score. Conclusions: B-cell infiltration in tumor-adjacent benign prostate tissue may complement existing clinicopathologic models for stratifying adverse postoperative PSA outcomes and subsequent BCR after radical prostatectomy. The transcriptomic signal was recapitulated by CD19-based tissue staining, supporting further development of a pathology-based assay.

Patients with history of neck radiation for Human Papilloma Virus (HPV)-associated head and neck cancer experience rapid progression of carotid artery stenosis. The present study sought to determine whether screening and treating asymptomatic carotid artery stenosis in patients with a history of neck radiation is cost-effective. This study is a cost-utility analysis using a probabilistic Markov model over a thirty-year time horizon assessing carotid screening and treatment to avoid neurologic consequences of neck radiation for HPV-associated head and neck cancer. A strategy of no carotid surveillance was associated with a 14.8% cumulative risk of stroke and a strategy of ultrasound surveillance and treatment with TCAR was associated with a 3.0% cumulative risk of stroke. The latter had a median incremental cost of $1.04 million USD and provided a median 39.1 additional QALYs, resulting in a median incremental cost-effectiveness ratio of $26,556 per QALY. In conclusion, this study suggests that ultrasound surveillance and treatment with TCAR for asymptomatic carotid artery stenosis is likely to be cost-effective for patients who have been successfully treated with radiation therapy for HPV-associated head and neck cancer.