Citations

Refractory angina affects patients’ quality of life around the world. Coronary sinus reducer (CSR) is a new therapeutic approach that has been investigated in recent years. We aimed to investigate the efficacy and safety of CSR for refractory angina. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) from PubMed, Web of Science, Scopus, Embase, and CENTRAL searches until May 2024. Dichotomous data were pooled using risk ratio (RR), and continuous data were pooled using mean difference (MD), both with a 95% confidence interval (CI), using (R version 4.3). With the inclusion of three RCTs, our cohort comprised a total of 180 patients. Compared with the control group, after 6 months, CSR was significantly associated with a decreased mean change of Canadian Cardiovascular Society (CCS) class [MD: −0.54 with 95% CI (−0.80 to −0.27), P < 0.01], a decreased number of patients in the CCS class III/IV [RR: 0.56 with 95% CI (0.38–0.84), P < 0.01], and increased exercise time [MD: 50.46 with 95% CI (9.47–91.45), P = 0.02]. However, there was no significant difference between CSR and the control group in double products, all Seattle Angina Questionnaire domains, and safety outcomes. CSR has been shown to reduce angina severity by lowering CCS class scores and increasing exercise time. Large-scale RCTs are needed to confirm its effectiveness in patients with refractory angina.

ABSTRACTBackgroundPreventive strategies for cytomegalovirus (CMV) in the posttransplant period have changed the pattern of CMV infections, now more commonly manifesting as late‐onset occurrences known as post‐prophylaxis delayed‐onset CMV disease (PPDOC). We conducted a survey to investigate provider practices in managing PPDOC.MethodsA web‐based provider survey on the management of PPDOC was developed using Research Electronic Data Capture (REDCap). It was distributed to the online forums of the American Society of Transplantation communities of practice (COP) for Infectious Diseases (IDCOP), Kidney and Pancreas (KPCOP), Liver and Intestinal (LICOP), and Thoracic and Critical Care (TCCOP). The survey was posted twice within a span of a month.ResultsFifty‐six respondents, comprising 50 (89%) transplant physicians and 6 (11%) transplant pharmacists, from 46 distinct transplant centers, completed the survey. Universal antiviral prophylaxis (UAP) was the predominant preventive approach for both high‐risk (85%) and moderate‐risk (85%) transplant recipients. Out of 56, 51 respondents completed the questions regarding management of PPDOC. Regular surveillance with nucleic acid amplification tests (NAAT) (88%) was the most commonly used approach in high‐risk recipients, while symptom monitoring (73%) was the most common strategy in moderate‐risk recipients. Immunologic monitoring was used only by a few respondents who found it moderately useful in high‐risk recipients.ConclusionManagement of PPDOC was highly variable among providers and strategies differed based on patient risk profile. These findings could help shape future studies and guidelines to harmonize CMV management.

Abstract Introduction: Immune checkpoint inhibitors (ICI) are an essential systemic therapy for advanced melanoma. However, most melanomas develop resistance to ICI. Tumor-derived soluble PD-L1 (sPD-L1) and other soluble immunosuppressive factors drive checkpoint inhibitor resistance and correlate with inferior survival. We previously showed that therapeutic plasma exchange (TPE) removes sPD-L1 from circulation. Thus, we hypothesized that TPE-mediated removal of sPD-L1 and other immunosuppressive factors could overcome immunotherapy resistance in refractory melanoma. Methods: In this clinical trial (NCT04581382), we prospectively enrolled eighteen (18) patients with widely metastatic melanoma with progression despite anti-PD-1 ICI and elevated sPD-L1 by ELISA (≥1.7ng/mL). Each patient received radiotherapy to between one and three metastatic lesions (at least two unirradiated lesions) followed by three TPE sessions on consecutive days and re-challenge with checkpoint inhibitor. The primary safety and efficacy endpoints of the study were adverse events (AEs) and sPD-L1 reduction by TPE, respectively. Secondary endpoints included RECIST-based response in unirradiated lesions and overall survival. Correlative studies included kinetics of sPD-L1 and soluble immonsuppressive factors and dynamics of peripheral immune cell phenotypes. Results: Mean age was 62 (SD 13) and seven of eighteen (39%) were female. Mean baseline sPD-L1 was 26.31 ng/mL (40.01). The treatment was well-tolerated with one (6%) patient with grade 3 and 4 adverse events from a central line infection after TPE. Levels of sPD-L1 were significantly reduced by TPE (mean 80.2% reduction, p<0.0001). Two patients (11.1%) experienced complete response (CR), one (5.6%) partial response, three (16.7%) stable disease, and 12 (66.7%) progressive disease. In one case, immunotherapy was discontinued after two years due to no detectable lesions. Changes in tumor-reactive (TTR) GZMB+/CX3CR1+/CD11ahigh and other peripheral immune cell populations predicted overall survival in this cohort. In addition to sPD-L1, other soluble mediators of ICI resistance were also reduced by TPE and predicted overall survival in this cohort. Summary/Conclusion: sPD-L1 and other soluble immunoregulatory signaling molecules are important mediators of ICI resistance. SBRT and TPE can resensitize ICI-refractory melanoma by removing these factors. Patients with persistently elevated or rapid rebound of sPD-L1 following TPE experienced poor response and overall survival. Serial monitoring of sPD-L1 may predict response to ICI and multiple courses of TPE may be necessary. Our findings may apply in other ICI-resistant cancers with elevated sPD-L1. ClinicalTrials.gov registration: NCT04581382, ReCIPE-M1 (Rescuing Cancer Immunotherapy with Plasma Exchange in Melanoma 1).

ImportanceImproving patients’ health status is a key goal of treating tricuspid regurgitation (TR). The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a heart failure disease-specific health status measure used to capture the health status impact of TR and the benefit of transcatheter tricuspid valve intervention (TTVI), but its validity in this clinical setting is unknown.ObjectiveTo evaluate the psychometric properties of the KCCQ in patients with TR.Design, Setting, and ParticipantsData were pooled from patients with severe TR enrolled in 11 manufacturer-sponsored trials of TTVI. The data were transferred to the US Food and Drug Administration to harmonize and anonymize prior to analysis by an independent center. Data were collected from December 2015 to April 2023, and data analysis was performed from July to October 2023.Main Outcomes and MeasuresPrespecified analyses included evaluation of internal consistency, reproducibility, responsiveness, construct validity, and predictive validity. Outcomes were determined using Cronbach α, score comparisons, intraclass correlation, Cohen d, Spearman correlations with best available reference measures, and association of scores and changes in scores with risk of subsequent clinical events.ResultsThe study cohort was composed of 2693 patients enrolled in either single-arm (n = 1517) or randomized (n = 1176) investigations of TTVI. Mean (SD) patient age was 78.6 (8.0) years, 1658 of 2693 patients (61.6%) were female, and the mean (SD) baseline KCCQ Overall Summary (KCCQ-OS) score was 50 (23). There was strong internal consistency within individual domains (Cronbach α, .77-.83). Among clinically stable patients between 1 and 6 months, there were small mean changes in KCCQ domain and summary scores (differences of −0.1 to 1.9 points), demonstrating reproducibility. In contrast, domain and summary scores of patients who underwent TTVI showed large improvements at 1 month after treatment (mean changes, 12.1-21.4 points), indicating excellent perceived responsiveness. Construct validity was moderately strong when domains were compared with best available reference measures (Spearman correlations, 0.47-0.69). In both cross-sectional and longitudinal analyses, the KCCQ-OS was associated with clinical events, with lower scores associated with an increased risk of mortality (hazard ratio, 1.34 per 10-point decrement; 95% CI, 1.22-1.47) and heart failure hospitalization (hazard ratio, 1.24 per 10-point decrement; 95% CI, 1.17-1.31).Conclusions and RelevanceIn this cohort study, the KCCQ had strong psychometric properties in patients with severe TR, including reliability, responsiveness, and validity. These data support use of the KCCQ in patients with severe TR as a measure of their symptoms, function, and quality of life and also for assessing the impact of interventions, such as TTVI, in rigorously controlled trials.

Epithelial ovarian neoplasms are commonly observed in older patients, while germ cell tumors (GCTs) typically present in young individuals. When GCTs are detected in patients over 35 yrs old, they often have an associated epithelial component, a phenomenon known as somatically derived GCTs. We report a unique case of mixed GCT involving bilateral ovaries with a background of high-grade serous carcinoma, including a yolk sac tumor and choriocarcinoma in the mixed GCT component. Somatically derived GCTs are rare with only 45 cases of ovarian carcinoma with somatic yolk sac tumor reported to date. Pathologists face diagnostic challenges in identifying somatically derived GCTs, as they can mimic high-grade epithelial neoplasms. Somatically derived GCTs have poor outcomes, therefore, precise diagnosis is crucial for prognostic and therapeutic considerations.

ABSTRACT Ledaborbactam (formerly VNRX-5236), a bicyclic boronate β-lactamase inhibitor with activity against class A, C, and D β-lactamases, is under development as an orally bioavailable etzadroxil prodrug (VNRX-7145) in combination with ceftibuten for the treatment of urinary tract infections. At ceftibuten breakpoints of ≤1 mg/L (EUCAST) and ≤8 mg/L (CLSI), 92.5% and 99.0%, respectively, of 200 carbapenem-resistant Klebsiella pneumoniae isolates, predominantly K. pneumoniae carbapenemase producing, were susceptible to ceftibuten-ledaborbactam (ledaborbactam tested at a fixed concentration of 4 mg/L) compared to 4.5% and 30.5%, respectively, to ceftibuten alone.