Citations

Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60–73) and median two (range 1–4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2–11.8) and 1.5 months (95% CI 0.9–4.4), respectively. Prolonged survival (range 10.2–27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA.

Abstract Background Emerging evidence suggests that premature ventricular contractions (PVCs) may influence atrial electrophysiology and remodeling, potentially leading to higher rates of atrial fibrillation (AF) recurrence. However, existing data is limited to small-scale studies. Therefore, we conducted a retrospective study to evaluate the potential association between PVCs and AF ablation outcomes, which may suggest the need for more aggressive management of ventricular ectopy in this population. Objective This study aims to assess the 5-year outcomes of catheter ablation for AF in patients with and without a diagnosis of PVCs. Methods Using the TriNetX Analytics Research Network, we included patients aged ≥ 18 years who underwent AF catheter between January 1, 2014, and January 1, 2020. Patients were further categorized into two groups based on the presence of a diagnosis of PVCs. Propensity score matching (PSM) was performed using patient demographics, left ventricular ejection fraction (LVEF), cardiac comorbidities, and medications. Study outcomes included all-cause mortality & hospitalization, acute heart failure (HF), and rhythm control interventions during a 5-year follow-up. Results A total of 15,987 patients with PVCs and 40,605 patients without PVCs were identified. After PSM, 15,152 patients from each group were included for further analysis. Compared to control group, patients with PVCs had significantly higher odds of all-cause mortality (odds ratio [OR], 1.138; 95% confidence interval [CI], 1.034–1.253), all-cause hospitalization (OR, 1.300; 95% CI, 1.243–1.360), acute heart failure (HF) (OR, 1.223; 95% CI, 1.162–1.287), and cardiogenic shock (OR, 2.059; 95% CI, 1.751–2.420) following catheter ablation for AF at 5-year follow-up. Additionally, higher odds of AF requiring cardioversion (OR, 1.135; 95% CI, 1.074–1.199) or repeated ablation (OR, 1.164; 95% CI, 1.085–1.249) were observed in the PVCs group. Conclusion Premature ventricular contractions were associated with poorer clinical outcomes and a higher odds of requiring additional rhythm control intervention following catheter ablation for AF. These findings suggest that PVCs may be a marker for worse outcomes after AF ablation.

ABSTRACT Delayed onset muscle soreness (DOMS) is a musculoskeletal condition that typically follows unaccustomed exercise or muscle overload, most common after loaded eccentric contractions. This soreness manifests within 24–48 hours postexercise and can last several days, impacting muscle performance and recovery. Increased levels of anxiety may prolong the perception of soreness and discomfort. Evidence suggests that recovery times for DOMS vary because of multiple factors, which include psychological influences such as anxiety. This manuscript highlights the interplay between psychological states and the DOMS recovery sequelae. Although further studies are needed to fully understand the mechanisms by which anxiety influences DOMS and to confirm the efficacy of anxiety-reducing treatments, a deeper understanding of this relationship could offer strength and conditioning professionals new pathways for optimizing recovery strategies in individuals experiencing DOMS.

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Cancer-associated venous thromboembolism (CA-VTE) is a leading, severe, and potentially life-threatening complication in patients with malignancy. Low–molecular-weight heparin has historically been the standard of care; however, direct oral anticoagulants, particularly direct factor Xa inhibitors, have emerged as effective alternatives. These agents offer the convenience of oral administration, predictable pharmacokinetics, elimination of routine laboratory monitoring, and improved adherence. Despite the expanding role of direct oral anticoagulants in CA-VTE management, concerns regarding bleeding risk—particularly in patients with gastrointestinal and genitourinary malignancies—remain central to clinical decision-making. In this narrative review, we evaluate the efficacy, safety, and clinical applicability of apixaban for the treatment and prophylaxis of CA-VTE. Current evidence from randomized controlled trials, including CARAVAGGIO and AMPLIFY, demonstrates that apixaban has noninferior efficacy compared with low–molecular-weight heparin and conventional anticoagulation strategies, with comparable or lower rates of recurrent venous thromboembolism. In addition, apixaban appears to have a favorable safety profile, with no statistically significant increase in major bleeding in selected cancer populations, including those without active gastrointestinal lesions. Apixaban’s pharmacokinetic properties, including limited renal clearance and stable drug exposure, further enhance its clinical utility in oncologic populations. However, evidence supporting apixaban use across all cancer subtypes remains limited and heterogeneous, highlighting the need for additional comparative and real-world studies.

Abstract Background Myocardial strain derived from cardiovascular magnetic resonance (CMR) using feature tracking (FT) offers incremental prognostic value beyond traditional imaging markers. However, its broader clinical application is hindered by the lack of population-specific reference ranges. This study establishes age-, sex-, and ethnicity-specific normative data for FT-CMR-derived myocardial strain metrics from the Healthy Hearts Consortium (HHC). Methods The HHC is a large, international, multicohort initiative comprising CMR data from 9,088 rigorously screened healthy adults across six centers. The cohort spans the full adult age range and includes greater ethnic diversity than any comparable dataset. CMR scans were acquired using standardized protocols. Image analysis followed pre-specified standard operating procedures and was performed by two experienced readers using two commercial platforms (CVI42®, Circle Cardiovascular Imaging; suiteHEART®, Neosoft). Metrics extracted included: (i) global longitudinal, circumferential, and radial FT strain for both ventricles and atria; (ii) strain rate; (iii) annular plane systolic excursion (MAPSE, TAPSE); and (iv) rapid strain metrics (long-axis, junctional strain) for the left ventricle and atria. Comprehensive quality control involved visual review and exclusion of biologically implausible or extreme outlier values. Reference ranges were calculated using the 95% prediction interval method, stratified by age deciles (20–80 years), sex, and ethnicity (White, Black, Chinese, South Asian, Mixed/Other). The impact of technical factors—scanner vendor, field strength (1.5T vs 3.0T), and software platform—was also assessed. Results The study included 4,452 men (49%) and 4,636 women (51%), aged 18 to 83 years (mean 61 ± 13). The cohort was ethnically diverse: White (81.7%), South Asian (5.6%), Mixed/Other (5.3%), Black (3.7%), and Chinese (3.7%). Women consistently exhibited higher absolute strain values than men. A clear age-related decline in strain was observed, particularly in left ventricular global circumferential and longitudinal strain. Ethnic differences were most pronounced between White and Black, and White and Chinese individuals for RV and LV strain metrics; in contrast, RA, LA, and rapid strain metrics showed minimal ethnic variation. Conclusion This study delivers the most comprehensive age-, sex-, and ethnicity-specific reference ranges to date for FT-CMR-derived myocardial strain. These normative values support improved clinical interpretation, aiding diagnosis and risk stratification in diverse populations. The findings mark a pivotal advancement towards the routine integration of myocardial strain assessment in cardiovascular imaging practice.

Abstract Deep learning models enable the prediction of clinical endpoints from whole-slide images (WSIs), but many such models function as “black boxes”, lacking transparency about whether and which histomorphological patterns drive their predictions, hindering interpretability and clinical adoption. Here we propose a human-in-the-loop explanation framework, MorphoXAI, which provides both local and global interpretability for deep learning models by incorporating human-expert interpretations. At the global level, it reveals the histomorphological patterns on which the model consistently relies to distinguish between classes of WSIs, as well as the patterns associated with confusion between classes. At the local level, it indicates which of these patterns are used in the prediction of an individual WSI and which regions within the slide correspond to such patterns. We validated our method on a deep learning model trained for ovarian tumor histologic subtype prediction. The results show that our framework generates explanations that accurately reflect the histomorphology underlying the model’s predictions at both global and local levels. For interpretability and clinical utility in diagnostic contexts, human evaluation results showed that our explanations were easy to interpret, rich in diagnostic features, and directly helpful for diagnostic decision-making, thereby enhancing pathologist-AI collaboration. Our work highlights that unifying global and local explanations and grounding them in expert-interpreted morphology enhances the interpretability and verifiability of deep learning models, thereby facilitating the transparent deployment of such models in clinical practice.

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

Objective: Patent foramen ovale (PFO) closure is recommended for patients younger than 60 years with embolic stroke of undetermined source (ESUS) or cryptogenic stroke, but it’s role in patients older than 60 years remains unclear. We aim to investigate the benefit of closure in patients older than 60 with ESUS or cryptogenic stroke. Methods: Patients older than 60 years with ESUS or cryptogenic stroke from several large tertiary hospitals were recruited, who received a PFO closure after multidisciplinary brain-heart case conference, compared to age-matched cohort patients with ESUS or cryptogenic stroke. The primary outcome included recurrent ischemic stroke that occurred up to a median follow up of 5 years following PFO closure between two groups. The safety outcome was the occurrence of any complications after PFO closure, including new onset atrial fibrillation (AF). Results: A total of 102 patients (Table 1) were included (mean age 66±4), 56 male (55%), who received a PFO closure. Procedure-related complications, including new onset transient AF were low (1%). After following patients up to 5 years, patients with PFO closure demonstrated a relatively low incidence of recurrent ischemic stroke (3.9%, 4/102), compared to age-matched control cohort with a total of 97 patients (mean age 67±4), which had higher incidence of stroke recurrency (8.2%, 8/97) (Table 2). Kaplan-Meier event curve (Figure 1) reveals a trend of reducing recurrent stroke in patients with PFO closure but not achieved statistical significance. Conclusions: In patients with cryptogenic stroke or ESUS who are older than 60 years, PFO closure demonstrated safety profiles with a noticeable trend of reducing recurrent ischemic stroke compared to their age-matched counterparts. Prospective randomized trials are warranted in this young-older population.