Citations

Introduction/Objective: Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer. Radiation therapy (RT) combined with ICIs and PI3K inhibition may enhance anti-tumor immune activity. Methods: RT-induced cytosolic double-stranded DNA (dsDNA) was measured in human and mouse prostate cancer cell lines as the surrogate upstream marker consistent with cGAS–STING engagement. In a syngeneic mouse model for castration-resistant prostate cancer (Myc-CaP in FVB mice), triple therapies were studied: (1) anti-CTLA-4, anti-PD-1, and RT, and (2) PIM kinase inhibitor PIM447, anti-PD-1, and RT. Mass cytometry (CyTOF) was used to measure the tumor-immune profile. Results: The peak induction of cytosolic dsDNA was at an RT dose of 13 Gy. In the mouse model, triple therapy with anti-CTLA-4, anti-PD-1, and RT doubled the median survival compared to monotherapy (32 days vs 11 to 22 days, p<0.006). Triple therapy with the PIM kinase inhibitor PIM447, anti-PD-1, and RT nearly tripled the median survival compared to PIM447 monotherapy (82 days vs 29 days, p=0.002). Mass cytometry analysis revealed that the combination of anti-PD-1 and RT reduced myeloid-derived suppressor cells and tissue-associated macrophages and enhanced CD8+ T-cell infiltration. Discussion: Although prostate cancer is an immunocold entity, RT can trigger immune activation, consistent with engagement of the cGAS–STING signaling pathway (cytosolic dsDNA serving as a surrogate upstream marker). In triple therapy, RT can enhance the efficacy of ICI and PI3K-targeted drug therapy, significantly improving overall survival in a mouse model of CRPC. Conclusions: A combination of RT, ICIs, and PIM kinase inhibition may help overcome immune resistance in prostate cancer. This combination therapy approach supports further preclinical validation and careful clinical evaluation and warrants further clinical investigation to optimize treatment strategies for CRPC.

Background Recent studies have disputed the association between bisphenol A (BPA) and endometriosis. This updated meta-analysis was conducted to investigate the impact of BPA exposure on endometriosis. Methods This study evaluated BPA exposure and endometriosis risk, analyzing studies from Web of Science, PubMed, Embase, Cochrane Library, and Chinese databases (CNKI, CBM, Wanfang, VIP) through August 2025. Methodological quality was assessed via the Newcastle-Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality Tool (AHRQ). Heterogeneity was quantified using I 2 statistics. Pooled odds ratios (ORs) and 95% CIs were calculated using fixed- or random-effects models according to heterogeneity. Subgroup analysis, sensitivity analysis, and publication bias assessment were supplemented to validate the overall finding. Results Seven studies comprising 2,488 participants were included in quantitative synthesis. The meta-analyses demonstrated that BPA exposure was associated with a statistically significant increase in endometriosis risk (OR = 1.36, 95% CI = 1.13–1.63, p = 0.008). Additionally, subgroup analysis indicated that BPA exposure may further elevate endometriosis risk in cases with different regions, populations, and measurement methods. Sensitivity analysis confirmed that the results of these meta-analyses were relatively robust. No publication bias was detected. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251019552 , identifier PROSPERO (CRD420251019552).

ABSTRACT Background Platelet factor 4‐polyanion enzyme‐linked immunosorbent assays (ELISAs) are considered highly sensitive for diagnosing heparin‐induced thrombocytopenia (HIT), such that current practice guidelines recommend use of ELISA‐negative results to exclude HIT. Once HIT is ruled out, alternative, non‐heparin‐based anticoagulant treatments are ceased, and heparin reintroduction frequently occurs. Methods Antigen‐based and PF4‐dependent functional testing were used to study PF4/polyvinylsulfonate ELISA‐negative platelet‐activating antibodies in HIT‐suspected patients. Results Three patients with clinical presentations consistent with HIT tested negative in an ELISA using PF4‐polyvinylsulfonate (PF4/PVS), an antigenic target very commonly used for HIT antibody screening. All three patients demonstrated PF4‐dependent platelet activation in functional testing that was sensitive to blockade of platelet FcγRIIa receptors and inhibited by high concentrations of heparin, consistent with pathogenic HIT antibodies. Functional testing‐based screening of 500 ELISA‐negative patients identified three additional patients whose sera activated platelets in a PF4‐ and FcγRIIa‐dependent manner and had clinical histories consistent with HIT. Five of the six ELISA‐negative HIT patients were re‐exposed to heparin, which precipitated a decrease in platelet counts in all re‐exposed patients, and one patient developed a new thrombus. Conclusions Recognition of ELISA‐negative HIT is critical to avoid harm due to the cessation of alternative anticoagulation therapy and re‐exposure of these patients to heparin.

Abstract Background Community-acquired pneumonia (CAP) is a significant public health concern associated with increased rates of hospital admissions and mortality. The purpose of the current study was to compare beta-lactam plus azithromycin or doxycycline vs fluoroquinolones in adults hospitalized with CAP. Methods We searched several databases from inception to 10 June 2024. Two reviewers independently screened, selected, and extracted data. Disagreements were resolved by consensus or a third reviewer. Study quality was assessed in duplicate with the Cochrane Risk of Bias 2 for randomized studies and the Newcastle-Ottawa Scale for nonrandomized studies. Meta-analysis was conducted by a random effect model when feasible. Network meta-analysis was performed to compare direct and indirect evidence. The GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) was followed to rate the certainty of evidence. Results Twenty studies were included (20 beta-lactam + azithromycin, 7 beta-lactam + doxycycline, 12 levofloxacin, and 4 moxifloxacin): 6 were randomized, enrolling 861 participants (mean age, 61.8 years; 43.2% women), and 14 were nonrandomized, enrolling 185 928 participants (mean age, 65.2 years; 42.9% women). Direct comparison and network meta-analysis results showed no statistically significant differences and likely equal effectiveness between beta-lactam + azithromycin and beta-lactam + doxycycline in terms of in-hospital mortality, need for intensive care unit admission or invasive mechanical ventilation, or safety outcomes including Clostridioides difficile infection and QT prolongation. Conclusions The current evidence demonstrated no likely difference in outcomes between azithromycin and doxycycline in adults hospitalized with CAP receiving beta-lactam. Head-to-head randomized clinical trials are needed to validate these results.

PURPOSE Although outcomes for nonmetastatic cancers have improved since the 1970s, it remains uncertain whether long-term survival has improved among patients presenting with de novo metastatic disease, defined as cancer presenting with distant metastases at the time of initial diagnosis. This study evaluated changes in 5-year survival among patients with de novo metastatic cancer diagnosed in 1976 versus 2015, with a minimum 5-year follow-up through 1981 and 2020, respectively. METHODS Population-based data were obtained from the SEER database. Patients diagnosed with de novo metastatic cancer in 1976 (n = 11,864) and 2015 (n = 26,324) were included. Five-year overall survival (OS) was compared between cohorts, and multivariable logistic regression identified demographic and clinical factors associated with survival. RESULTS The 5-year OS increased significantly from 10.6% in 1976-1981 to 23.6% in 2015-2020 ( P < .001). Survival gains were largest in breast cancer (12.6%-34.2%; P < .001), ovarian cancer (14.4%-32.5%; P < .001), colorectal cancer (3.7%-15.0%; P < .001), and hematologic malignancies (24.3%-53.9%; P < .001). Minimal improvement occurred in pancreatic cancer (0.25%-1.6%; P = .007) and small cell lung cancer (0.8%-3.1%; P = .008). Multivariable analysis demonstrated that older age, male sex, and Black race were associated with lower odds of 5-year survival (all P < .01) CONCLUSION Over the past four decades, long-term survival among patients with de novo metastatic cancer has more than doubled; however, progress remains uneven across cancer types. Gains appear concentrated in malignancies with substantial therapeutic advances, whereas others show persistently poor outcomes. Continued efforts are needed to address disparities and improve survival in resistant cancer types.

Abstract Osteochondral lesions of the knee, particularly in patients with early osteoarthritic changes, remain a clinical challenge. The Agili‐C implant (CartiHeal, Smith & Nephew), an aragonite‐based osteochondral scaffold, offers a single‐stage, off‐the‐shelf solution designed to regenerate both cartilage and subchondral bone. Unlike cell‐based therapies, Agili‐C eliminates the need for cell harvesting, culturing, or bioreactors, and avoids the morbidity associated with autografts and allografts. Recent multicenter randomized controlled trials have showed superior functional outcomes and pain reduction with Agili‐C compared to microfracture and debridement, even in patients with early osteoarthritis (Kellgren‐Lawrence grades 0‐3). This Technical Note describes the surgical technique for Agili‐C implantation and highlights key technical pearls to optimize outcomes.

Abstract Spatial transcriptomics links gene expression to tissue architecture, providing a mechanistic view of cellular organization. Yet existing datasets cover few donors and miss the complexity of human disease. Experimental costs remain prohibitive, and large-scale profiling is impractically slow for population-level studies. Accurate computational methods are urgently needed. Predicting gene expression from standard histology, however, remains an open problem, as current approaches transfer poorly to unseen cohorts and diseases. Here, we present Phoenix, a (latent) flow matching generative model that infers pan-cancer spatially resolved single-cell gene expression with high accuracy. Phoenix analyzes treatment response in silico: Applied to 763 head and neck cancer patients, it identified three new spatial biomarkers that we validated across two cancers (breast cancer, n = 84; ovarian cancer, n = 157) and treatment regimens (platinum, trastuzumab). Phoenix generalizes beyond carcinomas: In a large sarcoma cohort (802 tissue microarray cores), it accurately predicted cell-type-specific signatures in held-out samples and captured chemotherapy-induced immune remodeling. Phoenix also extends across species: In a mouse model, it accurately predicted the expression of pancreatic cancer lineage markers and the mutant mKras^G12D allele in silico. In total, we evaluated Phoenix on over 10,000 patients. Our results establish virtual spatial transcriptomics as a scalable framework for studying tissue organization, therapeutic response, and disease mechanisms.

Objectives This study aims to compare the reliability and accuracy of three large language models (LLMs) (Claude, Gemini and GPT) in assessing the risk of bias of nonrandomised studies using the ROBINS-I tool. Methods and analysis We conducted a secondary analysis of 171 nonrandomised studies previously assessed with Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool by two independent human review teams. Only studies with concordant human domain-level ratings were included. Each study was independently assessed twice by Claude, Gemini and Generative Pre-trained Transformer (GPT) using agent-based structured implementations of the ROBINS-I tool. Reliability (agreement between two runs of the same LLM) was evaluated using percent agreement and Gwet’s AC1. Accuracy (agreement with human reviewers) was assessed only for studies with consistent LLM ratings, using the same metrics. Results Claude demonstrated high reliability across all domains (79.5–98.0% agreement, AC1=0.729–0.975). Gemini showed moderate-to-high reliability (agreement 76.7–100%, AC1=0.680–1.0). GPT exhibited lower reliability overall, though domain-level agreement ranged from 70.9–95.6% (AC1=0.596–0.944). In terms of accuracy, Claude showed overall poor agreement with human reviewers (14.4–68.5% agreement; low AC1 values). Gemini demonstrated moderate-to-high accuracy in several domains, including deviations from intended interventions (79.6%, AC1=0.848) and measurement of outcomes (73.9%, AC1=0.702), with the highest overall agreement (40.0%, AC1=0.672). GPT showed variable accuracy, with the highest in measurement of outcomes (62.8%, AC1=0.571) and classification of interventions (57.8%, AC1=0.498), but poor performance in selection (14.3%, AC1 = −0.041) and overall agreement (23.0%, AC1=0.267). Conclusions Claude was internally consistent but poorly aligned with human reviewers. Gemini achieved both high reliability and moderate-to-high accuracy, whereas GPT had lower reliability and mixed accuracy. Current off-the-shelf LLMs cannot reliably perform ROBINS-I risk of bias assessments.

ABSTRACT Our study aimed to develop a novel, reproducible, minimally invasive turkey knee osteoarthritis (OA) model and evaluate whether intra‐articular hyaluronan (HA) alone or combined with purified exosome product (PEP) attenuates OA‐related functional and structural deterioration. OA was induced arthroscopically by transection of the anterior and posterior cruciate ligaments with resection of the anterior horn of the medial meniscus. Animals received intra‐articular injections of saline, HA, or PEP + HA at postoperative 2–5 weeks. Gait was assessed at 4, 8, and 12 weeks, and cartilage degeneration, subchondral bone sclerosis, osteophyte formation, synovial fibrosis, heterotopic ossification, and meniscal integrity were evaluated by quantitative CT and histology at week 12. Compared with saline, HA improved lameness, preserved cartilage glycosaminoglycan content, and reduced meniscal rupture, subchondral bone sclerosis, and periarticular heterotopic ossification. PEP + HA provided additional benefits, including prolonged stance phase, reduced synovial fibrosis, and greater chondroprotection than HA alone, while plantar pressure variables, subchondral bone remodeling, and patellar osteophytes did not differ between HA and PEP + HA. This turkey model reliably produces human‐like OA changes and enables longitudinal functional and structural assessment. Intra‐articular HA mitigated OA progression, and the addition of PEP conferred incremental joint protection.