Citations

Abstract Rationale: Current guidelines recommend a short course of antibiotic therapy for ventilator-associated pneumonia (VAP) caused by non-fermenting gram-negative bacilli (NF-GNB). However, this approach has been associated with an increased risk of pneumonia recurrence. This meta-analysis aims to address inconsistencies in the literature and evaluate the efficacy of short-course versus long-course antibiotic therapy for VAP, particularly in cases due to NF- GNB. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing short versus long courses of antibiotic therapy in patients with VAP. The primary outcomes were the risk of all-cause mortality and pneumonia recurrence. Data were analyzed using RevMan 5.4, with risk ratio (RR) and mean difference (MD) as effect measures. Results: Our pooled analysis included seven RCTs. There was no significant difference in all- cause mortality between short- and long-course antibiotic regimens (RR 1.02; 95% CI: 0.88-1.18; Figure 1). However, a short course of antibiotics increased the incidence ofpneumonia recurrence, particularly in patients with VAP due to NF-GNB (RR 1.64; 95% CI: 1.18-2.29; Figure 1). There were no significant differences between the two regimens regarding the duration of mechanical ventilation (MD 0.01 days; 95% CI: -0.51 to 0.53 days), ICU (MD 0.10 days; 95% CI: -1.00 to 1.20 days) and hospital stay (MD -0.63 days; 95% CI: -3.18 to 1.91 days), or subsequent infection with or acquisition of resistant organisms (RR 0.89; 95% CI: 0.63-1.24). Conclusions: Our meta-analysis suggests that while a short course of antibiotics increases the risk of pneumonia recurrence in NF-GNB VAP, it does not impact mortality compared to a longer course. The clinical significance of the increased recurrence of pneumonia remains uncertain, as it did not result in worse clinical outcomes. A practical approach incorporating validated clinical criteria and biomarker thresholds to guide the duration of antibiotic therapy may be more effective for patients with NF-GNB VAP. Larger RCTs are needed to drawdefinitive conclusions in this population.

Abstract Background: Effective treatments (Tx) are needed for MTAP-del cancers (10-15% of all cancers). BMS-986504 (formerly MRTX1719) is a potential first-in-class MTA-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor that selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP-del but not MTAP-wild-type cells. In the first-in-human phase 1/2 CA240-0007 study, BMS-986504 was well tolerated and showed clinical activity in heavily pretreated pts across multiple advanced solid tumors with homozygous MTAP-del. Here, we report results of exploratory PD analyses of PRMT5 inhibition with BMS-986504 in CA240-0007. Methods: Pts with advanced, unresectable or metastatic solid tumors with homozygous MTAP-del received BMS-986504 (50 to 800 mg) in 3-wk cycles. Symmetric dimethylarginine (SDMA) and intron retention are known PD BMs of PRMT5 inhibition. Therefore, PD effects of BMS-986504 were assessed via changes in plasma and tumor SDMA levels (mass spec and IHC), intron retention, and gene expression (RNASeq) based on samples collected at baseline (BL) and cycle 2 day 1 (C2D1). Additional analyses correlating efficacy outcomes with PD results and select mutations at BL were performed in clinically evaluable pts as of 19-SEP-24. Results: Robust PD modulation of the PRMT5 pathway was observed with BMS-986504. Among pts with matched samples (n = 63), median plasma SDMA levels were reduced by 56% from BL (122.6 ng/mL) to C2D1 (53.8 ng/mL). There were dose-dependent reductions in median plasma SDMA with the greatest reductions at 400 mg QD (59.7% [n = 20]), 400 mg BID (61.9% [n = 9]) and 600 mg QD (59.1% [n = 14]). These PD effects were corroborated in the tumor. Median tumor SDMA levels decreased from an HScore of 285 at BL to 0 at C2D1. Consistent with the SDMA decreases, increased intron retention was observed in 9/11 pts with matched samples. BMS-986504 led to downregulation of several gene pathways including DNA repair and mitotic spindle formation, and MYC and E2F targets, as assessed by RNASeq. There was no significant change in expression of MAT2A, PRMT5, or other PRMT genes, suggesting a lack of compensation for PRMT5 inhibition through these genes. Responses were observed with BMS-986504 across EGFR, KRAS, and TP53 mutation subgroups. Additional correlative analyses among BMs and efficacy outcomes will be presented. Conclusions: BMS-986504 demonstrated robust PD effects across multiple doses and solid tumors which is consistent with the proposed mechanism of action. There was a trend of increasing plasma SDMA reduction across doses, with the greatest reductions observed at 400 mg QD and above. Together these results support further investigation of BMS-986504 at 400 mg QD and higher doses as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP-del. Citation Format: Jordi Rodón, Tyler Simpson, Ben George, Pasi A. Jänne, Kathryn C. Arbour, Konstantinos Leventakos, Kyriakos P. Papadopoulos, Melissa L. Johnson, Alexander I. Spira, Cesar A. Perez, Hani M. Babiker, Richard Zuniga, Candace L. Haddox, Tapsi Kumar, Yidi Qin, Wen-Chi Chou, Peter Olson, Kenna Anderes, Alice Wozniak, Curtis Chin, Ming Lei, Jason T. Henry. Pharmacodynamic (PD) and exploratory biomarker (BM) analysis of the PRMT5 inhibitor BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT079.

Abstract Introduction DISTINCT is a randomized controlled trial evaluating passive recharge burst SCS compared with CMM in improving pain and pain‐related physical function in patients suffering from chronic back pain without prior lumbar surgery, and for whom corrective surgery is not an option. Sub‐analyses of outcome measures are presented for a subset implanted with paddle leads at both 6 and 12 months. Objective To investigate the treatment effect of using BurstDR‐capable SCS in nonsurgical low back pain (NSLBP) patients with paddle leads. Methods An independent board‐certified spine surgeon reviewed each case, confirming a lack of corrective surgical options. Out of 29 sites and 115 implants, 10 sites implanted 50 patients with paddle leads. Primary and secondary endpoints assessed improvements in low back pain intensity (NRS), low back pain‐related disability (ODI), pain catastrophizing (PCS), and patient global impression of change (PGIC). Results Data for patients with NSLBP and implanted with paddle leads are available for 47 and 44 patients at 6 and 12 months, respectively. Patients reported significant reductions in pain relief at 6 and 12 months, decreasing from 7.8 ± 1.2 at baseline to 2.0 ± 1.6 and 2.2 ± 2.2, respectively ( p < 0.0001). Disability was substantially reduced (> 20 points) from severe to mild at 6 and 12 months; ODI reduced from 54.4 ± 15.0 at baseline to 19.9 ± 14.1 and 22.1 ± 13.6, respectively ( p < 0.0001). Pain catastrophizing improved to reflect the average of a non‐chronic pain population; decreased from 27.6 ± 13.1 at baseline to 8.1 ± 8.2 and 7.8 ± 9.9 ( p < 0.0001). 93.2% of patients reported a moderately better‐much‐improved outcome on PGIC. Ten complications occurred in 9 patients, 3 being severe device‐related events. Two explants were required; one due to infection and one due to persistent pain at the IPG site, and one lead‐related event was resolved by surgical repositioning. Conclusions Passive recharge burst using paddle leads provides substantial relief to patients suffering from severe, debilitating, NSLBP. Patients report significant improvements in pain, function, and pain‐related emotional distress. In addition, the rate of adverse events is low, supporting a favorable safety profile.

ABSTRACT Ventricular arrhythmias (VA), including ventricular tachycardia and fibrillation, are critical cardiac conditions that are often managed by catheter ablation among those unresponsive to pharmacologic therapy. The choice of anesthesia and sedation regimens for VA ablations may impact arrhythmia inducibility and hemodynamic stability, which can affect procedural success and complication rates. This systematic review and meta-analysis aimed to compare the efficacy and safety of sedation versus general anesthesia (GA) among patients undergoing VA ablation. The review was prospectively registered on PROSPERO (CRD42023441553). Database searches were conducted across five major databases from inception to March 9, 2024 to identify randomized trials or observational studies including adult patients undergoing ablations for VA. Screening and data extraction were completed in duplicate. Risk-of-bias assessments were conducted using ROBINS-I as all included studies were observational, and the quality of evidence was evaluated using the GRADE framework. Six observational studies (N = 16,435) were included. No significant differences were found between sedation and GA for total procedure time (MD: −14.16 minutes; 95%CI: −38.61 to 10.29 minutes), arrhythmia non-inducibility (RR: 0.73; 95% CI: 0.33–1.58), acute ablation success (RR: 1.06; 95% CI: 0.65–1.71), or procedural complications (RR: 0.72; 95% CI: 0.28–1.85). However, sedation was associated with significantly lower intraprocedural hemodynamic instability (RR: 0.28; 95% CI: 0.12–0.70). These findings indicate that while sedation and GA have comparable outcomes, sedation may be associated with less hemodynamic instability during VA ablation. However, more high-quality studies are needed to confirm these results.

Abstract Objectives In an effort to maintain the technical aspects of traditional prosthetic surgical aortic valve replacement (AVR) while reducing invasiveness and facilitate options for concomitant operations, transaxillary lateral mini-thoracotomy endoscopic robotic-assisted aortic valve replacement (RAVR) has been introduced. The present data highlight the contemporary international collaborative experience. METHODS All consecutive patients undergoing standardized RAVR across 10 international sites (1/2020–7/2024) were evaluated using a central database with 1 year follow-up. RESULTS A total of 300 patients were analysed with a median predicted risk of 1.6% with aortic stenosis in 85.7%, nearly half with bicuspid valves. Biological prostheses were implanted in 220 (73.3%) with a median valve size 23 mm, 10% receiving aortic root enlargement, with 17% of all patients undergoing concomitant procedures. Median cross-clamp 120 min with no conversions to sternotomy. Median length of stay was 5 days, 4.3% with prolonged ventilation, 1.7% renal failure, 1.0% stroke and 8.3% required re-thoracotomy for evacuation of haemothorax. There were two 30-day operative mortalities (0.7%). The new permanent pacemaker rate for the full cohort was 2.6%. Of 163 patients with complete 1-year clinical and echocardiographic follow-up, mean aortic valve gradient was 10 mmHg and all but 2 patients (1.2%) had trace to no prosthetic or paravalvular insufficiency. CONCLUSIONS RAVR is safe and effective, providing the reproducible benefits of surgical AVR while affording a less invasive approach that permits the opportunity for concomitant procedures. For low and intermediate risk patients with aortic valve disease, RAVR is a potential reproducible alternative for patients and heart teams.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Central Nervous System Cancers provide multidisciplinary diagnostic workup, staging, and treatment recommendations for diffuse high-grade gliomas and medulloblastomas in children and adolescents. This article summarizes the studies and panel discussion that serve as the rationale for comprehensive care recommendations included in the NCCN Guidelines for Pediatric Central Nervous System Cancers.