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Background: Pneumocystis pneumonia (PCP) is an opportunistic fungal infection, which is frequently observed in immunocompromised patients. Although T-cell immunity is classically related to Pneumocystis defense, recent data support roles for B lymphocytes in the development of PCP in animals, and we have observed several cases of PCP in patients receiving rituximab. These observations prompted a systematic review and meta-analysis of our experience to see the efficacy of PCP prophylaxis (TMP-SMX) in lymphoma patients receiving rituximab. The efficacy of PCP prophylaxis in this population remains a subject of clinical interest. Research Question: To evaluate the effect of PCP prophylaxis compared to no prophylaxis on the risk of developing PCP in lymphoma patients receiving rituximab. Methods: We conducted meta-analysis including six retrospective cohort studies that compared the incidence of PCP in lymphoma patients receiving rituximab with and without prophylaxis. The cohort studies with incept up to January 2023 were retrieved from databases including PubMed, Google Scholar, EMBASE, PLOS ONE, Cochrane, and ClinicalTrials.gov. Data extraction was done using a spreadsheet, and data analysis was done using RevMan 5.4.1 for meta-analysis. Results: The analysis included 2304 patients, with 571 receiving PCP prophylaxis and 1733 did not receive prophylaxis. Studies reporting results of PCP prophylaxis were included. Enrolled studies were quality assessed with Newcastle-Ottawa Scale. The incidence of PCP was significantly lower in the prophylaxis group (3 out of 571) compared to the no prophylaxis group (67 out of 1733). The pooled risk ratio (RR) was 0.23 [95% CI, 0.09 to 0.58], indicating a 77% reduction in the risk of PCP with prophylaxis. Conclusion: The clinical course of cases of PCP in patients treated with rituximab can be quite fulminant, with significant mortality. Primary prophylaxis should be considered in patients at risk. PCP prophylaxis significantly decrease the risk of PCP in lymphoma patients receiving rituximab-based therapies, with a pooled risk ratio of 0.23.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Background: Osteochondritis dissecans (OCD) of the knee is a focal idiopathic alteration of subchondral bone and/or its precursor with risk for instability and disruption of adjacent cartilage. Treatment options focused on preventing premature osteoarthritis vary depending on multiple patient and lesion characteristics, including lesion mobility. Purpose: To differentiate lesion mobility before arthroscopy using a multivariable model that includes patient demographic characteristics and physical examination findings. Study Design: Cohort study (Diagnosis); Level of evidence, 2. Methods: Demographic, preoperative physical examination, and radiographic data were collected from a multicenter national prospective cohort of patients with OCD of the knee. Inclusion criteria included patients <19 years of age and patients with arthroscopically confirmed mobility status based on the Research on Osteochondritis Dissecans of the Knee arthroscopy classification. Multivariable logistic regression analysis using stepwise model selection was used to determine factors associated with the likelihood of a mobile versus an immobile lesion. A 75% partition of the data was used for model training, and 25% was used as a validation cohort. Quantitative model fit statistics were computed using the holdout data, including sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC), along with the corresponding 95% CI. Results: A total of 407 patients in the prospective cohort met inclusion criteria, and 62% were male. The mean ± SD age was 13.7 ± 2.2 years, height 161.8 ± 5.3 cm, and weight 59.2 ± 42.2 kg. Arthroscopic evaluation yielded 235 immobile and 172 mobile lesions. Multivariable analysis determined that the best model to predict lesion mobility included chronologic age ≥14 years ( P < .001), effusion on physical examination ( P < .001), and any loss of range of motion on physical examination ( P = .07), while controlling for male sex ( P = .38) and weight >54.4 kg ( P = .12). In the 25% holdout validation sample (n = 102), a sensitivity of 83%, a specificity of 82%, and an AUC of 0.89 (95% CI, 0.82-0.95) were achieved with these predictive factors. Conclusion: Age, effusion, and loss of motion can predict knee OCD lesion mobility at the time of arthroscopy. Education about lesion mobility can help with surgical planning and patient and family counseling.

Background: Antithrombotic regimens play a pivotal role in averting complications and ischemic incidents post-percutaneous coronary intervention (PCI) in MI (myocardial infarction) patients. Bivalirudin stands as a viable alternative to unfractionated heparin in this cohort, demonstrating the efficacy and safety profiles. Aim: We aimed to compare the efficacy and safety of bivalirudin versus unfractionated heparin in post-percutaneous coronary intervention (PCI) in MI (myocardial infarction) patients. Research Question : What is the efficacy and safety of Bivalirudin compared to unfractionated heparin in patients with MI undergoing PCI, specifically in terms of major bleeding, cardiovascular mortality, and other major adverse cardiovascular events? Methods: We systematically searched PubMed, including MEDLINE, Embase, Cochrane Library, Google Scholar, ClinicalTrials.gov, and EBSCOhost/CINAHL, from January 1, 2000, through May 29, 2024, for randomized controlled trials (RCTs) that evaluated Bivalirudin versus unfractionated heparin and with a study population of patients with MI undergoing PCI. Data extraction was done using a spreadsheet, and data analysis was done using RevMan 5.4.1 for meta-analysis. The primary efficacy and safety endpoints were major bleeding, major cardiovascular events, cardiovascular mortality, all-cause mortality, myocardial infarction, stent thrombosis, and stroke. Results: Our analysis included 11 RCTs, encompassing a total of 40,919 participants. When compared with unfractionated heparin, bivalirudin was associated with a significant reduction in major bleeding events (RR 0.66 [0.55 to 0.80]; p < 0.0001) and cardiovascular mortality (RR 0.79 [0.67 to 0.92]; p < 0.003). However, there were no significant differences between Bivalirudin and unfractionated heparin in terms of major adverse cardiovascular events (RR 1.02 [0.91 to 1.13]; p = 0.76), all-cause mortality (RR 0.89 [0.78 to 1.01]; p = 0.08), MI (RR 0.99 [0.85 to 1.15]; p = 0.90), stent thrombosis (RR 1.12 [0.53 to 2.40]; p = 0.76), or stroke (RR 0.96 [0.73 to 1.26]; p = 0.75). Conclusion: Our meta-analysis indicates that in patients with MI undergoing PCI, Bivalirudin is associated with lower rates of major bleeding and cardiovascular mortality compared to unfractionated heparin. However, there were no significant differences observed in major adverse cardiovascular events, all-cause mortality, MI, stroke, or stent thrombosis between the two treatment groups.

Background: Persistent atrial fibrillation (AF) presents a significant management challenge, particularly in patients with concurrent heart failure. The effectiveness of catheter ablation compared to medical therapy for these patients remains under debate. Aim: This meta-analysis aims to evaluate the outcomes of catheter ablation versus medical therapy for managing persistent AF. Research Question: How does catheter ablation compare to medical therapy in managing persistent AF considering outcomes like arrhythmia recurrence, hospitalizations, cardiac function, exercise capacity, and mortality? Methods: We performed a meta-analysis of randomized controlled trials (RCTs) comparing catheter ablation with medical therapy in patients with persistent AF. Data sources included PubMed, Embase, Cochrane Library, Clinicaltrial.gov, Google Scholar, and CINAHL/EBSCOHOST, with studies selected based on predefined inclusion criteria. Primary outcomes assessed were recurrence of atrial arrhythmias, hospitalizations, changes in left ventricular ejection fraction (LVEF), changes in 6-minute walk test (6MWT) distance, and all-cause mortality. The data extraction was done using a spreadsheet, and the data analysis was done using RevMan 5.4.1: for meta-analysis Results: A total of 10 RCTs involving 1812 patients were included in the analysis. Compared to medical therapy, catheter ablation significantly reduced the recurrence of atrial arrhythmias (risk ratio [RR] = 0.43, 95% confidence interval [CI]: 0.29-0.63, P < 0.0001). Hospitalization rates due to heart failure were also lower in the ablation group (RR = 0.57, 95% CI: 0.44-0.73, P < 0.001). Improvements in LVEF were observed with a mean difference (MD) of 5.98% (95% CI: 3.81% to 8.15%, P < 0.00001). The performance on the 6MWT was better in the catheter ablation group, with an MD of 28.83 meters (95% CI: 8.61 to 49.05 meters, P = 0.005). Additionally, catheter ablation was associated with a reduction in all-cause mortality (RR = 0.60, 95% CI: 0.45-0.80, P = 0.00006). Conclusion: This meta-analysis demonstrates that catheter ablation is superior to medical therapy in managing persistent atrial fibrillation. Catheter ablation offers significant benefits in reducing atrial arrhythmia recurrence, lowering hospitalization rates, improving cardiac function and exercise capacity, and reducing mortality. These findings support the consideration of catheter ablation as a preferred treatment strategy for patients with persistent AF.

Background: Heart failure (HF) is a heterogeneous syndrome with high mortality. Previous work characterizing HF subgroups primarily relied on clinical data to cluster patients, an approach constrained by the boundaries of documented clinical features. Clustering based on biomarker data, such as proteomics, may provide insights into underlying molecular processes. However, few studies have used this approach, and all used targeted cardiovascular proteomics panels and a restricted HF ejection fraction group. Hypothesis: We used unsupervised clustering analysis to characterize molecular phenogroups in a population-based HF cohort using a large-scale array of circulating plasma proteins. We hypothesized that distinct proteomic-defined phenogroups would exhibit differences in clinical characteristics, mortality, and protein expression. Methods: We measured 7151 SOMAmers (Slow off-rate modified aptamers) targeting human proteins via the SomaLogic 7K SomaScan assay in 1351 HF patients. After feature selection, 831 SOMAmers were used in k-means clustering of patients via R package “ConsensusClusterPlus.” Phenogroups were compared for clinical characteristics, all-cause mortality, and protein expression. Results: Three phenogroups were identified, exhibiting different clinical characteristics ( Table 1 ) and survival probabilities (5-year survival probability in phenogroup 1: 65% [61%, 68%], phenogroup 2: 45% [40%, 51%], and phenogroup 3: 26% [22%, 30%]). In covariate-adjusted Cox models, membership in phenogroups 2 and 3 was significantly associated with increased rate of mortality compared to phenogroup 1. Phenogroups did not differ by ejection fraction or New York Heart Association class. Pathway overrepresentation analysis of differentially expressed SOMAmers identified pathways associated with inflammatory response and immune cell trafficking. Conclusions: Unsupervised clustering analysis using large-scale proteomics data identified three HF phenogroups with different proteomic signatures, clinical characteristics, and outcomes. Future work is necessary to elucidate how molecular differences contribute to heterogeneity in HF to improve risk stratification beyond current recommended clinical guidelines.

Abstract BACKGROUND Yttrium-90 (Y90) microsphere treatment is an FDA-approved endovascular radiotherapy for Hepatocellular Carcinoma; however, extra-hepatic experience is limited. The FRONTIER trial (NCT05303467) is a first-in-human study conducted under an IDE from the FDA evaluating the safety and feasibility of intra-arterial Y90 endovascular radiotherapy in patients with recurrent glioblastoma (rGBM). METHODS The primary endpoint is the incidence of treatment-related limiting toxicities through 30 days, in 12 patients with rGBM. Eight subjects (50% male) with non-dominant hemisphere rGBM have been enrolled to date, with 6 patients reported herein. The treatment region, encompassing the recurrent lesion, excluding eloquent regions, and defined using cerebral angiography-MRI fusion, was selectively targeted with 40±4Gy. Immediate post-treatment imaging included MRI to evaluate acute treatment-related effects and Y90-PET to evaluate the absorbed dose distribution. Neurological assessments were performed pre- and post-treatment. Analysis of post-contrast T1w enhancing tissue volume (T1wvol) inside and outside the treated region was performed longitudinally. RESULTS All patients tolerated the procedure well and were discharged the following day. No decrease in neurological function and no limiting toxicities were reported through 30 days. Post-treatment MRI revealed no device-related acute ischemia or hemorrhage. Mean absorbed dose to the treatment region was 42.1±2.4Gy, within 3% of the targeted value, suggesting technical feasibility. Mean tumor absorbed dose within the treatment region was 65.1±22.6Gy most likely due to increased tumor perfusion in the treatment region. A reduction in T1wvol at 2m was observed in 4/6 patients, with the remaining 2 patients showing increased T1wvol. Disease progression by T1wvol occurred more rapidly outside the treatment region than within. All patients received subsequent therapy, with 2 patients receiving surgery 82 and 120 days post Y90 treatment. CONCLUSION Interim results in this first-in-human feasibility study demonstrated technical feasibility and no limiting toxicities through 30 days. Enrollment is ongoing. These data warrant additional investigation.

Abstract Glioblastoma (GBM) presents as a highly aggressive and malignant brain tumor with limited treatment options. Despite the availability of existing therapies, the invasive characteristics of GBM frequently result in tumor recurrence and poor prognosis. We previously developed a B-cell-based therapy (BVax) that has shown promising results in its ability to induce therapeutic responses in preclinical models of GBM. Our research revealed potency of BVax can be attributed to its robust antigen-presenting capability, cognate antigen specificity with T cells, and ability to generate tumor-reactive antibodies. The present study aims to characterize the unique antigenic reactivity of BVax-derived antibodies by evaluating their immunological effects and therapeutic potential in both murine models and GBM patient-specific samples. Leveraging CD45.1 and CD45.2 congenic mouse models, we first revealed that BVax preferentially migrated to glioma-bearing brains upon intravenous injection, resulting in a CD38+CD20-CD19+ plasmablast phenotype. To further characterize the reactivity of BVax-derived immunoglobulins (Ig), we utilized proteomic analysis and identified preferential targets of Gelsolin, Fibronectin, Versican, Fibrinogen, and collagen type IV alpha, commonly associated with cell motility and the extracellular matrix. Microdialysis data confirmed the increased presence of many of these BVax-derived Igs-recognized antigens in tumor regions compared to normal brain regions in GBM patients. Utilizing purified BVax-derived antibodies from patient specimen, in vitro cell motility assays demonstrated a significant prevention of the invasion and migration of cell lines from patient derived xenograft (PDX). In this study, we concluded that BVax elicits antitumor activity through targeted migration to tumor-bearing regions, differentiation into plasmablasts, and robust secretion of specific Igs that retain the ability to inhibit functionalities associated with cell invasion and migration. Here, we present the first in-depth study that characterizes GBM patients’ antibody reactivity, specifically a subset of inflammatory B cells (BVax) with therapeutic effects that offer an indication for a new direction of immunotherapies.

AbstractBackgroundIsolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in‐transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first‐line ILI/ILP, ICI, and TVEC.MethodsRetrospective review from 12 international institutions included patients treated from 1990 to 2022 with first‐line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM.ResultsA total of 551 patients were treated, with ILI/ILP (n = 356), ICI (n = 125), and TVEC (n = 70) with median follow‐up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p = .002). Breslow thickness was lowest with TVEC (p = .007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p = .01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p = .029) and a longer local progression‐free survival (PFS) (hazard ratio [HR], 0.40; p = .003). ILI/ILP had shorter local PFS (HR, 1.72; p = .012), PFS (HR, 1.79; p < .001), distant metastasis‐free survival (DMFS) (HR, 1.75; p = .014), overall survival (HR, 1.82; p = .009), and melanoma‐specific survival (HR, 2.29; p = .004). Stage IIIB disease had longer DMFS (HR, 0.24; p < .001) compared to IIIC/D.ConclusionsTVEC as first‐line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first‐line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.

Objective To further evaluate a genomic classifier (GC) in a cohort of patients undergoing radical cystectomy (RC), as long non‐coding RNA (lncRNA)‐based genomic profiling has suggested utility in identifying a distinct tumour subgroup corresponding to a favourable prognosis in patients with bladder cancer. Patients and Methods Transcriptome‐wide expression profiling using Decipher Bladder was performed on transurethral resection of bladder tumour samples from a cohort of patients with high‐grade, clinically organ‐confined (cTa–T2N0M0) urothelial carcinoma (UC) who subsequently underwent RC without any neoadjuvant therapy ( n = 226). The lncRNA‐based luminal favourable status was determined using a previously developed GC. The primary endpoint was overall survival (OS) after RC. Secondary endpoints included cancer‐specific mortality and upstaging at RC. Results In the study, 134 patients were clinical non‐muscle‐invasive bladder cancer (cTa/Tis/T1) and 92 patients were cT2. We identified 60 patients with luminal favourable subtype, all of which showed robust gene expression patterns associated with less aggressive bladder cancer biology. On multivariate analysis, patients with the luminal favourable subtype (vs without) were significantly associated with lower odds of upstaging to pathological (p)T3+ disease (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.12–0.82; P = 0.02), any upstaging (OR 0.41, 95% CI 0.20–0.83; P = 0.01), and any upstaging and/or pN+ (OR 0.50, 95% CI 0.25–1.00; P = 0.05). Luminal favourable bladder cancer was significantly associated with better OS (hazard ratio 0.33, 95% CI 0.15–0.74; P = 0.007). Conclusions This study validates the performance of the GC for identifying UCs with a luminal favourable subtype, harbouring less aggressive tumour biology.