Citations

Introduction: Resistant and uncontrolled hypertension pose persistent clinical and public health challenges. Renal denervation, a catheter-based procedure targeting renal sympathetic nerves, has emerged as a promising approach to lower blood pressure by reducing sympathetic overactivity. Hypothesis: A systematic review and meta-analysis of sham-controlled trials investigated whether renal denervation results in sustained blood pressure reduction across short-, medium-, and long-term follow-up. Methods: We searched PubMed, Embase, CENTRAL, and Web of Science through March 2025. The protocol was registered in PROSPERO (CRD420251015937). Randomized, sham-controlled trials of renal denervation in resistant/uncontrolled hypertension were included. Primary outcomes were ambulatory blood pressure (daytime, nighttime, and 24-hour); secondary outcomes included office and home blood pressure measurements. Follow-up durations were categorized into three groups: less than 6 months, 6–12 months, and greater than 12 months. Risk of bias was assessed using RoB-2. Results: Twenty trials (25 reports) with 2,167 RDN patients and 1,744 sham controls were included. Most trials had a low risk of bias. RDN significantly reduced 24-hour SBP (–3.29 mmHg, 95% CI: –5.91 to –0.67) and DBP (–1.42 mmHg, 95% CI: –2.29 to –0.55), despite high heterogeneity (I2 > 90%). Daytime DBP showed a significant reduction (–2.90 mmHg, 95% CI: –4.39 to –1.41), while other BP measures were less consistent. Home SBP was significantly reduced (–5.04 mmHg, 95% CI: –8.50 to –1.58). At 6–12 months, 24-hour SBP reduction persisted (–3.36 mmHg, 95% CI: –5.71 to –1.01), but DBP effects were nonsignificant. Long-term follow-up revealed nonsignificant changes in systolic blood pressure and diastolic blood pressure. Conclusions: Renal denervation modestly lowers BP in the short term (<6 months). Mid-term SBP reduction persists, but diastolic and long-term effects are inconsistent. These findings highlight the need for refined patient selection, optimized techniques, and longer follow-up trials.

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.

Cholangiocyte pathophysiological activation was examined in a model of murine cholestasis. CX3CR1 + macrophages are recruited to the periportal region, likely mediated by cholangiocyte expression of CX3CL1. Cholangiocyte transcriptomics from cholestatic mice display activation of a “pathogen-induced cytokine storm” pathway, and exhibit activation of the transcription factor NF-Y. In human cholangiocytes, NF-Y promotes expression of the profibrogenic ligand TGFβ1. These observations provide insights into the cholestatic cholangiocyte pathobiology contributing to periductal inflammation and fibrosis.

We describe the first use of phage therapy in Canada for the treatment of a life-threatening periprosthetic joint infection (PJI), with successful outcome. PJI is a devastating complication of joint replacement surgery, with high morbidity and mortality. Our patient presented with early sepsis from a chronic recalcitrant multidrug-resistant (MDR) Staphylococcus epidermidis hip PJI which had repeatedly failed standard therapy. She had previously undergone 10 operations of the right hip, and only three weeks after completing a prolonged course of daptomycin following her most recent hip revision, she developed a draining sinus tract. Given the high burden of disease, inability to achieve surgical source control, and lack of antibiotic treatment options for long-term suppressive therapy, bacteriophage (phage) therapy was pursued. The patient underwent irrigation and debridement with complex flap reconstruction: intraoperative tissue cultures again yielded MDR S. epidermidis. We developed a novel phage therapy protocol for this patient, with twice daily, intra-articular and intravenous (7 × 109 PFU/dose) phage delivery over a planned 14-day course. Complete healing of the wound with cessation of drainage occurred within one month after treatment. A marked improvement in right hip pain and mobility occurred within three months after treatment. Twelve months following phage treatment, there is normalization of serum inflammatory markers with diminished pain, increased mobility, and no recurrent surgery. Our patient continues to improve and is currently living independently at home, with sustained clinical control of infection.