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Role and prognostic value of growth differentiation factor 15 in patient of heart failure with preserved ejection fraction: insights from the PURSUIT-HFpEF registry.
Sakamoto, D, Matsuoka, Y, Nakatani, D, Okada, K, Sunaga, A, Kida, H, Sato, T, Kitamura, T, Tamaki, S, Seo, M, et al
Open heart. 2025;(1)
Abstract
BACKGROUND Growth differentiation factor 15 (GDF15) is a cytokine responding to oxidative stress and inflammation, and it regulates appetite and energy balance. The association between GDF15 and clinical factors and its prognostic value in elderly multimorbid patients with heart failure with preserved ejection fraction (HFpEF) have not been well unknown. METHODS This exploratory analysis is part of the Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction study (N=1231), an ongoing, prospective, multicentre observational study of acute decompensated HFpEF (UMIN000021831). A predefined subcohort of 212 patients underwent multi-biomarker testing. Of these, we analysed 181 patients with available GDF15 data. The primary endpoint was a composite of all-cause death and hospitalisation for HF. RESULTS In this analysis population, the median age was 81 (75-85) years, with 48% male patients. GDF15 significantly correlated with cardiac burden, anaemia, renal dysfunction and inflammation. Notably, poor nutritional status was significantly associated with GDF15. GDF15 was linked to poor prognosis in this elderly multimorbid cohort with HFpEF (adjusted HR for log-transformed GDF15: 13.67, 95% CI: 2.78 to 67.22, p=0.001). Furthermore, GDF15 added significant incremental value to the MAGGIC risk score (net reclassification improvement=0.4955 (95% CI: 0.1367 to 0.8543), p=0.007; integrated discrimination improvement=0.0278 (95% CI: 0.0013 to 0.0543), p=0.040). CONCLUSIONS GDF15 was associated with anaemia, inflammation, renal dysfunction, cardiac burden and malnutrition. It demonstrated prognostic value in elderly multimorbid HFpEF patients, suggesting its potential role as a complementary marker for the prognostic risk assessment of HFpEF patients. TRIAL REGISTRATION NUMBER UMIN-CTR ID UMIN000021831.
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Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer.
Hoeppner, J, Brunner, T, Schmoor, C, Bronsert, P, Kulemann, B, Claus, R, Utzolino, S, Izbicki, JR, Gockel, I, Gerdes, B, et al
The New England journal of medicine. 2025;(4):323-335
Abstract
BACKGROUND The best multimodal approach for resectable locally advanced esophageal adenocarcinoma is unclear. An important question is whether perioperative chemotherapy is preferable to preoperative chemoradiotherapy. METHODS In this phase 3, multicenter, randomized trial, we assigned in a 1:1 ratio patients with resectable esophageal adenocarcinoma to receive perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus surgery or preoperative chemoradiotherapy (radiotherapy at a dose of 41.4 Gy and carboplatin and paclitaxel) plus surgery. Eligibility criteria included a primary tumor with a clinical stage of cT1 cN+, cT2-4a cN+, or cT2-4a cN0 disease, in which T indicates the size and extent of the tumor (higher numbers indicate a more advanced tumor), and N indicates the presence (N+) or absence (N0) of cancer spread to the lymph nodes, without evidence of metastatic spread. The primary end point was overall survival. RESULTS From February 2016 through April 2020, we assigned 221 patients to the FLOT group and 217 patients to the preoperative-chemoradiotherapy group. With a median follow-up of 55 months, overall survival at 3 years was 57.4% (95% confidence interval [CI], 50.1 to 64.0) in the FLOT group and 50.7% (95% CI, 43.5 to 57.5) in the preoperative-chemoradiotherapy group (hazard ratio for death, 0.70; 95% CI, 0.53 to 0.92; P = 0.01). Progression-free survival at 3 years was 51.6% (95% CI, 44.3 to 58.4) in the FLOT group and 35.0% (95% CI, 28.4 to 41.7) in the preoperative-chemoradiotherapy group (hazard ratio for disease progression or death, 0.66; 95% CI, 0.51 to 0.85). Among the patients who started the assigned treatment, grade 3 or higher adverse events were observed in 120 of 207 patients (58.0%) in the FLOT group and in 98 of 196 patients (50.0%) in the preoperative-chemoradiotherapy group. Serious adverse events were observed in 98 of 207 patients (47.3%) in the FLOT group and in 82 of 196 patients (41.8%) in the preoperative-chemoradiotherapy group. Mortality at 90 days after surgery was 3.1% in the FLOT group and 5.6% in the preoperative-chemoradiotherapy group. CONCLUSIONS Perioperative chemotherapy with FLOT led to improved survival among patients with resectable esophageal adenocarcinoma as compared with preoperative chemoradiotherapy. (Funded by the German Research Foundation; ESOPEC ClinicalTrials.gov number, NCT02509286.).
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Efficacy of tranilast in preventing exacerbating cardiac function and death from heart failure in muscular dystrophy patients with advanced-stage heart failure: a single-arm, open-label, multicenter study.
Matsumura, T, Fukudome, T, Motoyoshi, Y, Nakamura, A, Kuru, S, Segawa, K, Kitao, R, Watanabe, C, Tamura, T, Takahashi, T, et al
Orphanet journal of rare diseases. 2025;(1):13
Abstract
BACKGROUND Transient receptor potential cation channel subfamily V member 2 (TRPV2) functions as a stretch-sensitive calcium channel, with overexpression in the sarcolemma of skeletal and cardiac myocytes leading to detrimental calcium influx and triggering muscle degeneration. In our previous pilot study, we showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide levels in two patients with muscular dystrophy and advanced heart failure. Building on this, we performed a single-arm, open-label, multicenter study herein to evaluate the safety and efficacy of tranilast in the treatment of advanced heart failure in patients with muscular dystrophy. RESULTS This study involved 18 patients with muscular dystrophy who had brain natriuretic peptide levels > 100 pg/mL, despite receiving standard cardioprotective therapy. Tranilast was administered orally at a dose of 100 mg three times daily. Over the short-term period (28 weeks), the primary endpoint of change ratio in the logarithm of brain natriuretic peptide level from baseline to 28 weeks was not significant in the full analysis set but was lower in the per set protocol compared with data from a previous beta-blocker treatment study. All 15 patients who completed the short-term treatment consented to be enrolled in long-term therapy for an additional 116 weeks. After all participants completed the long-term treatment, we analyzed all data. TRPV2 expression on the peripheral blood mononuclear cell surfaces decreased throughout the study period, confirming that the TRPV2 inhibitory effect of tranilast was maintained over time. Despite the presence of progressive disease, cardiac indices such as brain natriuretic peptide level, human atrial natriuretic peptide level, and fractional shortening, remained stable, and only brain natriuretic peptide levels at 144 weeks showed significant changes. The survival rate was 80.7%, and no cardiac deaths were reported. Regarding safety, no serious adverse events associated with tranilast were noted, except for recurrent diarrhea during the short-term period in one case. CONCLUSIONS The findings suggest that tranilast can inhibit TRPV2 expression for an extended period and is effective in preventing the worsening of cardiac function and subsequent death from heart failure. CLINICAL TRIAL REGISTRATION DETAILS The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: http://www.umin.ac.jp/ctr/ ) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: https://jrct.niph.go.jp/ ) [November 12, 2021]. Patient registration was initiated on December 19, 2018.
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Clinical Outcomes of Patients With Cholesterol Crystal Embolism Accompanied by Lower Extremity Wound.
Hata, Y, Iida, O, Okamoto, S, Ishihara, T, Nanto, K, Tsujimura, T, Higashino, N, Toyoshima, T, Nakao, S, Fukunaga, M, et al
Angiology. 2025;(1):32-39
Abstract
Cholesterol crystal embolism (CCE) accompanied by a lower extremity wound is occasionally difficult to differentiate from chronic limb-threatening ischemia (CLTI) and treat. The present multi-center retrospective observational study investigated the clinical characteristics and prognosis of CCE with lower extremity wounds. Consecutive patients (n = 58) clinically diagnosed as CCE with lower extremity wounds between April 2010 and December 2019 were studied. CCE was diagnosed using histological findings, foot condition, renal impairment, and eosinophilia. The primary outcome was 1-year wound healing rate. Patients with CCE were compared with 1309 patients diagnosed with CLTI with tissue loss during the same study period. The CCE group had a significantly more severe Wound, Ischemia, and foot Infection (WIfI) classification compared with the CLTI group. After Kaplan-Meier analysis, the CCE group had a similar 1-year wound healing (55.1 vs 58.3%, P = .096) as the CLTI group. In multivariate stratified Cox regression analysis by WIfI stages, CCE was significantly associated with poor wound healing compared with CLTI [hazard ratio .36 (95% confidence interval .21-.62)]. In conclusion, among the similar WIfI clinical stages, wound healing was significantly worse in the CCE group than in the CLTI group.
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The Protocol for the Multi-Ethnic, multi-centre raNdomised controlled trial of a low-energy Diet for improving functional status in heart failure with Preserved ejection fraction (AMEND Preserved).
Bilak, JM, Squire, I, Wormleighton, JV, Brown, RL, Hadjiconstantinou, M, Robertson, N, Davies, MJ, Yates, T, Asad, M, Levelt, E, et al
BMJ open. 2025;(1):e094722
Abstract
INTRODUCTION Heart failure with preserved ejection fraction (HFpEF) is characterised by severe exercise intolerance, particularly in those living with obesity. Low-energy meal-replacement plans (MRPs) have shown significant weight loss and potential cardiac remodelling benefits. This pragmatic randomised trial aims to evaluate the efficacy of MRP-directed weight loss on exercise intolerance, symptoms, quality of life and cardiovascular remodelling in a multiethnic cohort with obesity and HFpEF. METHODS AND ANALYSIS Prospective multicentre, open-label, blinded endpoint randomised controlled trial comparing low-energy MRP with guideline-driven care plus health coaching. Participants (n=110, age ≥18 years) with HFpEF and clinical stability for at least 3 months will be randomised to receive either MRP (810 kcal/day) or guideline-driven care for 12 weeks. Randomisation is stratified by sex, ethnicity, and baseline Sodium Glucose Cotransporter-2 inhibitor (SGLT2-i) use, using the electronic database RedCap with allocation concealment. Key exclusion criteria include severe valvular, lung or renal disease, infiltrative cardiomyopathies, symptomatic biliary disease or history of an eating disorder. Participants will undergo glycometabolic profiling, echocardiography, MRI for cardiovascular structure and function, body composition analysis (including visceral and subcutaneous adiposity quantification), Kansas City Cardiomyopathy Questionnaire (KCCQ) and Six-Minute Walk Test (6MWT), at baseline and 12 weeks. An optional 24-week assessment will include non-contrast CMR, 6MWT, KCCQ score. Optional substudies include a qualitative study assessing participants' experiences and barriers to adopting MRP, and skeletal muscle imaging and cardiac energetics using 31Phosphorus MR spectroscopy. STATISTICAL ANALYSIS Complete case analysis will be conducted with adjustment for baseline randomisation factors including sex, ethnicity and baseline SGLT2-i use. The primary outcome is the change in distance walked during the 6MWT. The primary imaging endpoint is the change in left atrial volume indexed to height on cardiac MRI. Key secondary endpoints include symptoms and quality of life measured by the KCCQ score. ETHICS AND DISSEMINATION The Health Research Authority Ethics Committee (REC reference 22/EM/0215) has approved the study. The findings of this study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT05887271.
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Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma.
Wolchok, JD, Chiarion-Sileni, V, Rutkowski, P, Cowey, CL, Schadendorf, D, Wagstaff, J, Queirolo, P, Dummer, R, Butler, MO, Hill, AG, et al
The New England journal of medicine. 2025;(1):11-22
Abstract
BACKGROUND Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions. METHODS We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to BRAF mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response. RESULTS With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab. CONCLUSIONS The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
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Prognostic significance of peripheral blood biomarkers in patients with advanced renal cell carcinoma treated with nivolumab and ipilimumab-a polish multicenter, observational study.
Pacholczak-Madej, R, Drobniak, A, Grela-Wojewoda, A, Calik, J, Viegas, NV, Tusień-Małecka, D, Dobrzańska, J, Roman, A, Bidas, A, Szwiec, M, et al
Clinical and experimental medicine. 2025;(1):45
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Abstract
Immune checkpoint inhibitors have improved the treatment of metastatic renal cell carcinoma (RCC), with the combination of nivolumab (NIVO) and ipilimumab (IPI) showing promising results. However, not all patients benefit from these therapies, emphasizing the need for reliable, easily assessable biomarkers. This multicenter study involved 116 advanced RCC patients treated with NIVO + IPI across nine oncology centers in Poland. Blood markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), eosinophils, and monocytes were assessed at baseline, after three months, and before disease progression (PD). The prognostic significance of these parameters was analyzed using linear regression, Kaplan-Meier survival analysis, and Cox regression models. After a median follow-up of 11.8 months, the progression-free survival (PFS) was 12.8 months (95% confidence interval [CI] 5.7-28.1), while the overall survival (OS) was 27.3 months (95% CI 16-not reached). Patients with an NLR increase of ≥ 25% had a PFS of 8.2 (3.1-24.7) months compared to 17.5 (8.6-28.1) months in those with a rise in < 25% (p = 0.015). Similarly, a ≥ 25% increase in PLR was linked to a PFS of 6.8 (2.8-8.3) months compared to 17.4 (8.4-28.1) months (p < 0.001). Multivariate analysis confirmed PLR as an independent predictor of PFS (HR 2.9, 95% CI 1.5-5.6, p = 0.001), while elevated eosinophil levels were associated with a reduced risk of death (HR 0.2, 95% CI 0.04-0.9, p = 0.05). No other analysis was statistically significant. NLR, PLR, and eosinophil levels may serve as valuable biomarkers for predicting treatment response in RCC patients receiving NIVO + IPI.
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Effect of apixaban versus vitamin K antagonist and aspirin versus placebo on days alive and out of hospital: An analysis from AUGUSTUS.
Fanaroff, AC, Vora, AN, Wojdyla, DM, Mehran, R, Granger, CB, Goodman, SG, Aronson, R, Windecker, S, Alexander, JH, Lopes, RD
American heart journal. 2025;:60-69
Abstract
BACKGROUND Clinical trials of antithrombotic agents typically use separate time-to-event analyses for bleeding and ischemic events, but this framework has limitations. Days alive and out of hospital (DAOH) is an alternative that may provide additional insight. We assessed the utility of DAOH as a clinical trial endpoint among patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention METHODS AUGUSTUS, a randomized clinical trial, compared apixaban with warfarin and aspirin with placebo in 4614 patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention. We used Poisson regression with a robust variance estimate to compare DAOH by treatment group. RESULTS Mean (SD) DAOH was 168 (31); median (IQR) was 177 (169-180); 75% of patients neither died nor were hospitalized. Mean (SD) DAOH was 169 (28) with apixaban + placebo, 168 (29) with apixaban + aspirin, 168 (33) with warfarin + placebo, and 167 (33) with warfarin + aspirin. There were no significant differences in the rate ratio for DAOH for apixaban vs. warfarin (RR 1.00, 95% CI 0.99-1.01) or aspirin vs. placebo (RR 1.00, 95% CI 1.00-1.01). Compared with warfarin, apixaban increased the proportion of patients who neither died nor were hospitalized during follow-up (76.8 vs. 73.3%; OR 0.83, 95% CI 0.73-0.95). CONCLUSION In this analysis of AUGUSTUS, there was no difference in DAOH by treatment arm. These findings contrast with time-to-event analyses, which showed lower rates of major bleeding and hospitalization with apixaban and placebo. DAOH may not be very a useful measure of effects of antithrombotic therapies in this population. TRIAL REGISTRATION clinicaltrials.gov; NCT02415400; https://clinicaltrials.gov/study/NCT02415400.
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Epidemiological profile and clinical characteristics of ocular and periocular tumors in North and Central India.
Gupta, C, Patidar, N, Gaikwad, H, Mishra, M, Das, S
Indian journal of ophthalmology. 2025;(2):253-260
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Abstract
PURPOSE To describe the epidemiological profile and clinical characteristics of ocular and periocular tumors in patients presenting to three tertiary care referral centers in North and Central India. METHODS Hospital-based consortium study. SETTINGS AND DESIGN Retrospective, descriptive, observational study. RESULTS A total of 3184 patients were diagnosed with 3557 ocular and periocular tumors over 11 years from 2010 to 2021. Of these, 2395 (67.33%) were benign, 84 (2.36%) were premalignant, and 1078 (30.30%) were malignant. The most common location was the ocular surface (n = 1294, 37.09%), followed by the eyelid (n = 1185, 33.97%), intraocular (n = 624, 17.88%), and orbit (n = 454, 13.01%). The most common tumors were retinoblastoma (n = 483, 13.57%), ocular surface squamous neoplasia (OSSN) (n = 301, 8.46%), and dermoid cyst (n = 167, 4.69%). In the pediatric age group, retinoblastoma was the most common tumor (n = 483, 13.57%), while in adults, it was OSSN (n = 301, 8.46%). The stage at presentation for malignant tumors was divided into in-situ (57.14%), local spread (8.16%), and metastasis (32.83%). For specific tumor locations, the stages were 78.83%, 17.51%, and 2.18%, respectively, for eyelid tumors; 51.76%, 27.05%, and 17.64%, respectively, for orbital tumors; 88.37%, 5.81%, and 5.19%, respectively for ocular surface tumors; and 35.71%, 14.15%, and 50.28%, respectively, for intraocular tumors. CONCLUSIONS Identifying the epidemiological characteristics of ocular and periocular tumors will aid in early diagnosis and timely intervention. Intraocular tumors showed delayed diagnosis, advanced stages at presentation, and required patients to travel longer distances for treatment, indicating the need for strengthened diagnostic and treatment facilities to improve access to care.
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Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk.
Watts, GF, Rosenson, RS, Hegele, RA, Goldberg, IJ, Gallo, A, Mertens, A, Baass, A, Zhou, R, Muhsin, M, Hellawell, J, et al
The New England journal of medicine. 2025;(2):127-137
Abstract
BACKGROUND Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. METHODS In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis. RESULTS At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline. CONCLUSIONS Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.).