BACKGROUND:Partial rotator cuff tears (RCTs) are a common cause of shoulder pain and functional limitation, often affecting daily activities and quality of life. Platelet-rich plasma (PRP), owing to its high concentration of growth factors, has emerged as a biological treatment option aimed at enhancing tendon healing and reducing inflammation. AIM:The objective of the study is to evaluate the clinical efficacy of ultrasound-guided PRP injections in partial RCTs. MATERIALS AND METHODS:A prospective study was conducted on 58 patients with magnetic resonance imaging-confirmed partial RCTs. Patients received two ultrasound-guided PRP injections (5 mL each) at a 3-week interval. Outcomes were assessed using the Visual Analog Scale (VAS) and the university of california-los angeles shoulder score (UCLA shoulder score) at baseline and 6, 12, and 24 weeks. RESULTS:Significant improvement was observed in VAS and UCLA scores at all follow-ups (P < 0.05). Maximum improvement occurred by 12 weeks and was sustained at 24 weeks. CONCLUSION:Ultrasound-guided PRP injections are an effective, minimally invasive modality for symptomatic partial RCTs, showing significant pain relief and functional improvement. Further large-scale randomized studies are required to establish its long-term efficacy and optimal treatment protocols.
Purpose To compare the extent of intravascular hemolysis, quantified by red blood cell microparticles (RBCµs), between patients undergoing pulsed-field ablation (PFA) for atrial fibrillation (AF) with a variable-loop circular catheter (VLCC) and those treated with a pentaspline catheter (PSC). Methods This prospective, single-center observational study included three cohorts of patients undergoing first-time AF ablation: (1) pulmonary vein isolation (PVI) by the PSC (PSC PVI), (2) PVI plus posterior wall and/or mitral isthmus by the PSC (PSC PVI+), and (3) PVI plus posterior wall by the VLCC (VLCC PVI+). Blood samples were collected at baseline, immediately post-ablation, and 24 hours after the procedure to measure RBCµs and other biochemical markers. Results The study included 77 patients (64.2 ± 9.5 years, 42.9% female): 22, 25 and 30 in the PSC PVI, PSC PVI+, and VLCC PVI + groups, respectively. All groups exhibited a significant transient rise in RBCµs concentration immediately after ablation (p < 0.001), returning to baseline within 24 hours. Peak RBCµs levels were highest in the PSC PVI + group, followed by PSC PVI and VLCC PVI+ (all pairwise comparisons p < 0.001). The total number of applications was highest in the PS PVI + group and lowest in the VLCC PVI + group, correlating with the magnitude of hemolysis. Conclusions The VLCC used in persistent AF ablation was linked to lower levels of intravascular hemolysis compared to the PS catheter employed in cases of paroxysmal and persistent AF.
The combination of venetoclax (VEN) and hypomethylating agents (HMA) is the standard of care in acute myeloid leukemia (AML) for elderly patients unfit for intensive chemotherapy. Despite its clinical success, most patients eventually relapse, creating an urgent need for effective therapeutic alternatives. In this study, we aimed to evaluate the potential of romaciclib, a first-in-class CDK8/CDK19 inhibitor, in combination with VEN to overcome stroma-mediated and primary/acquired VEN-resistance. We assessed the efficacy of RVU120+VEN combination in both sensitive and resistant AML cell lines and primary patient-derived models. Our finding demonstrated that romaciclib synergizes with VEN in AML cell lines and in 8 out of 11 patient-derived cell samples. The proteomic and functional studies demonstrated that combination induced apoptosis through caspase-dependent cleavage of MCL-1. In vivo studies confirmed the efficacy of RVU120+VEN, showing eradication of leukemic cells and bone marrow recovery. Importantly, the combination effectively overcame both stroma-mediated and transcriptionally dependent VEN-resistance. Mechanistic studies, focusing on transcriptomic analyses, identified key resistance-associated pathways, including IL6/JAK/STAT3, TGF-β, PI3K/AKT/MTOR, and inflammatory signaling, being suppressed by combination treatment. Furthermore, an in vivo study using a VEN-resistant patient-derived xenograft (PDX) model confirmed the efficacy of the combination, demonstrating a significant reduction in leukemia burden and a decreased proportion of leukemia initiating cells (LIC) following treatment. These findings prove the highly synergistic mechanism of action of RVU120+VEN combination and the potential to overcome primary/acquired VEN resistance in relapse/refractory AML disease. Altogether, the presented results support ongoing clinical studies evaluating romaciclib and VEN in VEN/HMA-refractory patients ( NCT06191263 ) and provide a basis for future exploration as a frontline therapy in VEN-naïve patients.
The randomized, multicenter, prospective Phase 3 trial (NCT02777736) evaluated central nervous system (CNS) prophylaxis using either intravenous (i.v.) or intrathecal (i.t.) methotrexate (MTX) in diffuse large B-cell lymphoma (DLBCL). Treatment consisted of six cycles of R-CHOP + 2xR or DA-EPOCH-R + 2xR. Patients with intermediate or high-risk CNS International Prognostic Index (CNS-IPI) were randomized to receive CNS prophylaxis with either 2 doses of MTX 3 g/m2 i.v. (arm A) or 6 doses of MTX 12 mg i.t. (arm B). Patients with low-risk CNS-IPI did not receive MTX prophylaxis (arm C). The primary objective was to compare the cumulative incidence of CNS relapse between arms A and B. Secondary objectives included evaluation of overall response rate (ORR), complete remission rate (CRR), progression-free survival (PFS), overall survival (OS), and treatment-related safety across all arms. Between 7/2015 and 5/2024, a total of 100 patients were enrolled: 30 in arm A, 31 in arm B, and 39 in arm C. ORR did not differ among arms (p = 0.20). During a median follow-up of 54.9 months, CNS relapses were observed in three patients who had received MTX prophylaxis-one in arm A and two in arm B. The 5-year cumulative incidence of CNS relapse was 0% in arm A and 8.7% in arm B (p = 0.72). However, due to the small sample size, the primary endpoint results are inconclusive. Median PFS was comparable between arms A and B (HR 0.66, p = 0.20). MTX i.v. was associated with a significantly higher grade ≥ 3 neutropenia (p = 0.0003) and infection (p = 0.0063). The higher infection rate contributed to a worse 5-year OS in arm A versus B (47.2% vs. 72.4%, HR 0.46, p = 0.04). Conclusion: our trial faced limitations due to a low number of randomized participants, making the interpretation of results challenging. A larger, international randomized trial is necessary to determine the benefit of CNS prophylaxis.
Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.
