Comparison of 24-Month Clinical Outcomes after Prostatic Artery Embolization in Prostate Glands Larger versus Smaller than 80 mL: A Systematic Review.

PURPOSE: This review was undertaken to compare the clinical outcomes of prostatic artery embolization (PAE) in patients with >80 versus <80 mL prostatic volume (PV) at the 24-month follow-up to determine whether PV predicted the effectiveness or durability of PAE. MATERIALS AND METHODS: The PubMed/MEDLINE database was searched for articles published between 2010 and 2022 using the search term "(prostat∗ artery embolization) AND (long term OR follow-up OR 24-month)." Articles were included if they discussed PAE for benign prostatic hyperplasia (BPH) and reported a minimum follow-up of 24 months. Articles with <10 patients were excluded. A subgroup analysis was performed to evaluate for any difference in clinical outcomes at the 24-month post-PAE follow-up between studies with a mean PV of >80 mL and those with a mean PV of <80 mL. RESULTS: A total of 14 studies with 2,260 patients were included, all of which demonstrated significant reduction in symptoms at the 24-month follow-up after PAE. Four studies were included as part of the >80-mL PV subgroup (n = 467), and 10 studies were included as part of the <80-mL PV subgroup (n = 1,793). There was a statistically significant difference between the mean preprocedural PV (128.5 vs 64.0 mL; P = .015). At the 24-month follow-up, there were no significant differences between groups across any of the compared parameters. The collective incidence of major adverse events reported in the studies within this review was <1%. CONCLUSIONS: PAE is both safe and durable for patients suffering from BPH and can be effective across a wide range of baseline PVs.

Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma.

STAT3 is constitutively activated in many cancers and regulates gene expression to promote cancer cell survival, proliferation, invasion, and migration. In diffuse large B cell lymphoma (DLBCL), activation of STAT3 and its kinase JAK1 is caused by autocrine production of IL-6 and IL-10 in the activated B cell-like subtype (ABC). However, the gene regulatory mechanisms underlying the pathogenesis of this aggressive lymphoma by STAT3 are not well characterized. Here we performed genome-wide analysis and identified 2,251 STAT3 direct target genes, which involve B cell activation, survival, proliferation, differentiation, and migration. Whole-transcriptome profiling revealed that STAT3 acts as both a transcriptional activator and a suppressor, with a comparable number of up- and down-regulated genes. STAT3 regulates multiple oncogenic signaling pathways, including NF-κB, a cell-cycle checkpoint, PI3K/AKT/mTORC1, and STAT3 itself. In addition, STAT3 negatively regulates the lethal type I IFN signaling pathway by inhibiting expression of IRF7, IRF9, STAT1, and STAT2 Inhibition of STAT3 activity by ruxolitinib synergizes with the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL cells in vitro and in a xenograft mouse model. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate ruxolitinib or a specific JAK1 inhibitor combined with lenalidomide in ABC DLBCL.

PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cells.

PRMT5, which regulates gene expression by symmetric dimethylation of histones and non-histone target proteins, is overexpressed and plays a pathogenic role in many cancers. In diffuse large B cell lymphoma (DLBCL), the mechanisms of PRMT5 dysregulation and its role in lymphomagenesis remain largely unknown. Here we demonstrate that B cell receptor (BCR) signaling regulates PRMT5 expression in DLBCL cells. Immunohistochemical analysis reveals elevated levels of PRMT5 expression in DLBCL cases and in germinal center (GC) B cells when compared to naive B cells. PRMT5 can be induced in naive B cells by BCR stimulation. We discovered that BTK-NF-κB signaling induces PRMT5 transcription in activated B cell-like (ABC) DLBCL cells while BCR downstream PI3K-AKT-MYC signaling upregulates PRMT5 expression in both ABC and GCB DLBCL cells. PRMT5 inhibition inhibits the growth of DLBCL cells in vitro and patient derived xenografts. Genomic and biochemical analysis demonstrate that PRMT5 promotes cell cycle progression and activates PI3K-AKT signaling, suggesting a feedback regulatory mechanism to enhance cell survival and proliferation. Co-targeting PRMT5 and AKT by their specific inhibitors is lethal to DLBCL cell lines and primary cancer cells. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate PRMT5 and AKT inhibitors for DLBCL.