Clinical trials in oncology are important tools to identify and establish new effective drugs for cancer treatment. Since the development of the concept of precision oncology, a huge number of multi-centric biomarker-driven clinical trials have been performed and promoted by either academic institutions or pharmaceutical companies. In this scenario, the role of pathologists is essential in multiple aspects, with new challenges that should be addressed. In this position paper of the European Society of Pathology, the role of pathologists as contributors to the design of the clinical trial, as local collaborators, or as members of central review laboratories is discussed. Moreover, the paper emphasizes the important role of pathologists in guiding methods and criteria of tissue biomarker testing in the biomarker-driven clinical trials. The paper also addresses issues regarding quality control, training, and the possible role of digital pathology.

• MeSH
• Clinical Trials as Topic * MeSH
• Pathology, Clinical standards   methods   MeSH
• Humans MeSH
• Biomarkers, Tumor * analysis   MeSH
• Neoplasms * pathology   drug therapy   MeSH
• Pathologists * MeSH
• Societies, Medical MeSH
• Research Design standards   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Geographicals
• Europe MeSH

BACKGROUND: Inflammation is associated with adverse cardiovascular events. Data from recent trials suggest that colchicine reduces the risk of cardiovascular events. METHODS: In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients who had myocardial infarction to receive either colchicine or placebo and either spironolactone or placebo. The results of the colchicine trial are reported here. The primary efficacy outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization, evaluated in a time-to-event analysis. C-reactive protein was measured at 3 months in a subgroup of patients, and safety was also assessed. RESULTS: A total of 7062 patients at 104 centers in 14 countries underwent randomization; at the time of analysis, the vital status was unknown for 45 patients (0.6%), and this information was most likely missing at random. A primary-outcome event occurred in 322 of 3528 patients (9.1%) in the colchicine group and 327 of 3534 patients (9.3%) in the placebo group over a median follow-up period of 3 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.16; P = 0.93). The incidence of individual components of the primary outcome appeared to be similar in the two groups. The least-squares mean difference in C-reactive protein levels between the colchicine group and the placebo group at 3 months, adjusted according to the baseline values, was -1.28 mg per liter (95% CI, -1.81 to -0.75). Diarrhea occurred in a higher percentage of patients with colchicine than with placebo (10.2% vs. 6.6%; P<0.001), but the incidence of serious infections did not differ between groups. CONCLUSIONS: Among patients who had myocardial infarction, treatment with colchicine, when started soon after myocardial infarction and continued for a median of 3 years, did not reduce the incidence of the composite primary outcome (death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization). (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.).

• MeSH
• C-Reactive Protein * analysis   MeSH
• Stroke prevention & control   MeSH
• Double-Blind Method MeSH
• Myocardial Infarction * prevention & control   mortality   MeSH
• Kaplan-Meier Estimate MeSH
• Colchicine * therapeutic use   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Recurrence MeSH
• Secondary Prevention MeSH
• Aged MeSH
• Spironolactone therapeutic use   adverse effects   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Mineralocorticoid receptor antagonists have been shown to reduce mortality in patients after myocardial infarction with congestive heart failure. Whether routine use of spironolactone is beneficial after myocardial infarction is uncertain. METHODS: In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients with myocardial infarction who had undergone percutaneous coronary intervention to receive either spironolactone or placebo and either colchicine or placebo. The results of the spironolactone trial are reported here. The two primary outcomes were a composite of death from cardiovascular causes or new or worsening heart failure, evaluated as the total number of events; and a composite of the first occurrence of myocardial infarction, stroke, new or worsening heart failure, or death from cardiovascular causes. Safety was also assessed. RESULTS: We enrolled 7062 patients at 104 centers in 14 countries; 3537 patients were assigned to receive spironolactone and 3525 to receive placebo. At the time of our analyses, the vital status was unknown for 45 patients (0.6%). For the first primary outcome, there were 183 events (1.7 per 100 patient-years) in the spironolactone group as compared with 220 events (2.1 per 100 patient-years) in the placebo group over a median follow-up period of 3 years (hazard ratio adjusted for competing risk of death from noncardiovascular causes, 0.91; 95% confidence interval [CI], 0.69 to 1.21; P = 0.51). With respect to the second primary outcome, an event occurred in 280 of 3537 patients (7.9%) in the spironolactone group and 294 of 3525 patients (8.3%) in the placebo group (hazard ratio adjusted for competing risk, 0.96; 95% CI, 0.81 to 1.13; P = 0.60). Serious adverse events were reported in 255 patients (7.2%) in the spironolactone group and 241 (6.8%) in the placebo group. CONCLUSIONS: Among patients with myocardial infarction, spironolactone did not reduce the incidence of death from cardiovascular causes or new or worsening heart failure or the incidence of a composite of death from cardiovascular causes, myocardial infarction, stroke, or new or worsening heart failure. (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.).

• MeSH
• Mineralocorticoid Receptor Antagonists * therapeutic use   adverse effects   MeSH
• Stroke mortality   MeSH
• Double-Blind Method MeSH
• Myocardial Infarction * mortality   drug therapy   MeSH
• Kaplan-Meier Estimate MeSH
• Cardiovascular Diseases mortality   prevention & control   MeSH
• Percutaneous Coronary Intervention MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Spironolactone * therapeutic use   adverse effects   MeSH
• Heart Failure * drug therapy   mortality   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Aveir DR (Abbott, Abbott Park, IL) is a dual-chamber leadless pacemaker (LP) system with distinct atrial and ventricular LPs (ALP, VLP) that communicate wirelessly to deliver atrioventricular synchronous pacing. Success rates of these implant-to-implant (i2i) transmissions have not been systematically evaluated. OBJECTIVE: This study aims to evaluate chronic i2i success rates in a clinical setting. METHODS: Patients meeting standard dual-chamber pacing indications were enrolled and implanted with dual-chamber LP systems as part of a prospective international clinical trial (Aveir DR i2i Study). The percent of successful i2i transmissions from ALP-to-VLP (A-to-V) and VLP-to-ALP (V-to-A) were interrogated from LPs in de novo patients using the device programmer at implant, discharge, and at 1, 3, and 6 months postimplant (1M, 3M, 6M). RESULTS: A total of 399 patients completed device implant and i2i diagnostic interrogation (62% male; age 69 years; 65% sinus node dysfunction, 32% atrioventricular [AV] block). Median A-to-V and V-to-A i2i success rates exceeded 90% of beats at all time-points from implant to 6M. The minority of patients with A-to-V or V-to-A i2i success in <70% of beats at implant (A-to-V: 19% of patients, V-to-A: 31% of patients) showed roughly 40% improvement by 1M, with this minority dropping to roughly 5% of patients by 6M. Improvement in i2i communication success may be attributed to reprogramming of i2i setting levels, natural changes in dominant posture, and device stabilization. CONCLUSION: Wireless implant-to-implant communication in the new dual-chamber leadless pacemaker system demonstrated successful transmissions in >90% of beats throughout the 6-month evaluation period. Communication success improved significantly over time postimplant for specific subgroups. CLINICAL TRIAL REGISTRATION: Aveir DR i2i Study, ClinicalTrials.gov ID NCT05252702.

• MeSH
• Wireless Technology MeSH
• Equipment Design * MeSH
• Cardiac Pacing, Artificial methods   MeSH
• Pacemaker, Artificial * MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Prospective Studies MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

OBJECTIVE: This study aimed to demonstrate the clinical equivalence of biosimilar QL1205 and reference ranibizumab, Lucentis, in patients with neovascular age-related macular degeneration (nAMD). DESIGN: This was a multicenter, double-masked, randomized, controlled phase III trial. PARTICIPANTS: Treatment-naive patients with active nAMD were randomly assigned to receive QL1205 or reference ranibizumab. METHODS: Patients received intravitreal injection of QL1205 or reference ranibizumab at a dose of 0.5 mg in the study eye once every 4 weeks for 48 weeks. MAIN OUTCOME MEASURES: The primary end point was change in best-corrected visual acuity (BCVA) by ETDRS letters at week 8 compared with baseline level. Biosimilarity of QL1205 to reference ranibizumab was assessed with an equivalence range for the difference in BCVA letters between -3.49 and +3.49. RESULTS: Between June 27, 2019 and June 8, 2021, 616 patients were randomized to the QL1205 group (n = 308) and the reference ranibizumab group (n = 308). The mean improvement of BCVA was +6.3 ± 9.13 ETDRS letters in the QL1205 group and +7.3 ± 8.82 ETDRS letters in the reference ranibizumab group at week 8. Both the 90% confidence interval (CI, -2.23 to 0.13) and 95% CI (-2.46 to 0.36) of the difference between the 2 treatment groups (P = 0.1434) were within the predefined equivalence range. Safety profiles were manageable in both groups. CONCLUSIONS: QL1205 was biosimilar to reference ranibizumab regarding clinical efficacy, ocular and systemic safety, as well as immunogenicity and pharmacokinetics profiles in the treatment of patients with nAMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

• MeSH
• Biosimilar Pharmaceuticals * administration & dosage   adverse effects   MeSH
• Double-Blind Method MeSH
• Angiogenesis Inhibitors administration & dosage   adverse effects   MeSH
• Intravitreal Injections MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Tomography, Optical Coherence MeSH
• Ranibizumab * administration & dosage   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Vascular Endothelial Growth Factor A antagonists & inhibitors   MeSH
• Wet Macular Degeneration * drug therapy   diagnosis   MeSH
• Treatment Outcome MeSH
• Dose-Response Relationship, Drug MeSH
• Visual Acuity * MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: This study examines the perspectives of individuals with coronary heart disease (CHD) on a nurse-led eHealth cardiac rehabilitation (NeCR) program, which included a website, tele-monitoring device, and social media chatroom. METHODS: Using a descriptive qualitative approach, semi-structured interviews were conducted with 18 participants to capture their feedback and experiences with the NeCR program. RESULTS: Participants found the NeCR program valuable in addressing gaps in cardiac rehabilitation services in China, empowering them to make behavioral changes and enhancing their social motivation. However, they also highlighted the need for a more user-friendly website, better symptom management during exercise, and stronger privacy protections in the peer networking chatroom. The study concludes that the NeCR program is feasible in providing accessible rehabilitative services at home post-discharge. Recommendations include improving the self-monitoring platform for ease of use, incorporating immediate symptom management guidance during exercise, and ensuring a secure environment for online peer support. CONCLUSIONS: These findings offer crucial insights for developing patient-centered eHealth cardiac rehabilitation services, emphasizing the importance of user-friendly design, effective symptom management features, and privacy protection in promoting participant engagement with e-platforms. TRIAL REGISTRATION: ChiCTR1800020411 (http://www.chictr.org.cn/showprojen.aspx?proj=33906).

• MeSH
• Adult MeSH
• Cardiac Rehabilitation * methods   MeSH
• Coronary Disease rehabilitation   nursing   MeSH
• Qualitative Research * MeSH
• Middle Aged MeSH
• Humans MeSH
• Interviews as Topic MeSH
• Aged MeSH
• Telemedicine * MeSH
• Feedback MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• China MeSH

PURPOSE OF REVIEW: This review explores the design and endpoints of perioperative platforms in clinical trials for muscle-invasive bladder cancer (MIBC). RECENT FINDINGS: The choice of clinical trial design in perioperative platforms for MIBC must align with specific research objectives to ensure robust and meaningful outcomes. Novel designs in perioperative platforms for MIBC integrate bladder-sparing approaches. Primary endpoints such as pathological complete response and disease-free survival are highlighted for their role in expediting trial results in perioperative setting. Incorporating patient-reported outcomes is important to inform healthcare decision makers about the outcomes most meaningful to patients. Given the growing body of evidence, potential biomarkers, predictive and prognostic tools should be considered and implemented when designing trials in perioperative platforms for MIBC. SUMMARY: Effective perioperative platforms for MIBC trials are critical in enhancing patient outcomes. The careful selection and standardization of study designs and endpoints in the perioperative platform are essential for the successful implementation of new therapies and the advancement of personalized treatment approaches in MIBC.

• MeSH
• Cystectomy methods   adverse effects   MeSH
• Neoplasm Invasiveness * MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Urinary Bladder Neoplasms * surgery   pathology   therapy   mortality   MeSH
• Perioperative Care methods   standards   MeSH
• Endpoint Determination MeSH
• Treatment Outcome MeSH
• Research Design MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

OBJECTIVES: This study quantified blood bicarbonate (HCO3-) kinetics and gastrointestinal upset to determine the gender-related ergogenic potential of sodium bicarbonate (0.15-, 0.25- and 0.35 gSB·kgFat-free mass (FFM)-1) in high intensity functional training. DESIGN: Double-blind randomized placebo-controlled crossover. METHODS: Thirty female and male athletes performed two bouts of the Wingate Anaerobic Test (WAnTPRE-HIFT and WAnTPOST-HIFT) interspaced with two 3-min bouts of Wall Balls and Burpees 120 min after ingestion of three sodium bicarbonate doses. Blood HCO3- was determined pre-ingestion, after supplementation and before/post exercise. Gastrointestinal upset was evaluated 120 min post-ingestion. Control (CTRL) measurements were performed. RESULTS: There were significant gender × treatment interactions for: changes in blood HCO3- at 60 min post-ingestion (p = 0.014; η2p = 0.104; at 0.15 gSB·kgFFM-1 males experienced higher increase than females); peak power (p = 0.015; η2p = 0.103) and average power (p = 0.005; η2p = 0.124) during WAnTPOST-HIFT, and changes in peak power between the Wingate Anaerobic Test bouts (p = 0.049; η2p = 0.081). Sodium bicarbonate compared to PLA had no significant impact on Wall Balls and Burpees performance. The dose of 0.35 gSB·kgFFM-1 resulted in higher less severe gastrointestinal symptoms compared to CTRL and 0.15 gSB·kgFFM-1 (p = 0.001; W = 0.178); and higher total gastrointestinal upset compared to CTRL, PLA and 0.15 gSB·kgFFM-1 (p < 0.001; W = 0.323). CONCLUSIONS: There were dose- and gender-related differences in extracellular buffering capacity and ergogenic potential of sodium bicarbonate. The study suggested a detrimental impact of gastrointestinal upset on performance.

• MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Sodium Bicarbonate * administration & dosage   pharmacology   blood   MeSH
• Cross-Over Studies * MeSH
• Performance-Enhancing Substances administration & dosage   pharmacology   MeSH
• Humans MeSH
• Young Adult MeSH
• Sex Factors MeSH
• Exercise Test MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

Cohort studies are a robust analytical observational study design that explore the difference in outcomes between two cohorts, differentiated by their exposure status. Despite being observational in nature, they are often included in systematic reviews of effectiveness, particularly when randomized controlled trials are limited or not feasible. Like all studies included in a systematic review, cohort studies must undergo a critical appraisal process to assess the extent to which a study has considered potential bias in its design, conduct, or analysis. Critical appraisal tools facilitate this evaluation. This paper introduces the revised critical appraisal tool for cohort studies, completed by the JBI Effectiveness Methodology Group, who are currently revising the suite of JBI critical appraisal tools for quantitative study designs. The revised tool responds to updates in methodological guidance from the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group and reporting guidance from PRISMA 2020, providing a robust framework for evaluating risk of bias in a cohort study. Transparent and rigorous assessment using this tool will assist reviewers in understanding the validity and relevance of the results and conclusions drawn from a systematic review that includes cohort studies. This may contribute to better evidence-based decision-making in health care. This paper discusses the key changes made to the tool, outlines justifications for these changes, and provides practical guidance on how this tool should be interpreted and applied by systematic reviewers.

• MeSH
• Cohort Studies MeSH
• Humans MeSH
• Research Design * standards   MeSH
• Bias * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: Ischemic complications account for significant patient morbidity following aneurysmal subarachnoid hemorrhage (aSAH). The Prevention and Treatment of Vasospasm with Clazosentan (REACT) study was designed to assess the safety and efficacy of clazosentan, an endothelin receptor antagonist, in preventing clinical deterioration due to delayed cerebral ischemia (DCI) in patients with aSAH. METHODS: REACT was a prospective, multicenter, randomized, double-blind, phase 3 study. Eligible patients had aSAH secured by surgical clipping or endovascular coiling, and had presented with thick and diffuse clot on admission CT scan. Patients were randomized (1:1 ratio) to 15 mg/hour intravenous clazosentan or placebo within 96 hours of the aSAH for up to 14 days, in addition to standard of care treatment including oral or intravenous nimodipine. The primary efficacy endpoint was the occurrence of clinical deterioration due to DCI up to 14 days after initiation of the study drug. The main secondary endpoint was the occurrence of clinically relevant cerebral infarction at day 16 after study drug initiation. Other secondary endpoints included clinical outcome assessed on the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) at week 12 post-aSAH. Imaging and clinical endpoints were centrally adjudicated. RESULTS: A total of 409 patients were randomized between February 2019 and May 2022 across 74 international sites. Three patients did not start study treatment and were not included in the analysis set. The occurrence of clinical deterioration due to DCI was 15.8% (32/202 patients) in the clazosentan group and 17.2% (35/204 patients) in the placebo group, and the difference was not statistically significant (relative risk reduction [RRR] 7.2%, 95% CI -42.6% to 39.6%, p = 0.734). A nonsignificant RRR of 34.1% (95% CI -21.3% to 64.2%, p = 0.177) was observed in clinically relevant cerebral infarcts treated with clazosentan (7.4%, 15/202) versus placebo (11.3%, 23/204). Rescue therapy was less frequently needed for patients treated with clazosentan compared to placebo (10.4%, 21/202 vs 18.1%, 37/204; RRR 42.6%, 95% CI 5.4%-65.2%). A nonsignificant relative risk increase of 25.4% (95% CI -10.7% to 76.0%, p = 0.198) was reported in the risk of poor GOSE and mRS scores with clazosentan (24.8%, 50/202) versus placebo (20.1%, 41/204) at week 12 post-aSAH. Treatment-emergent adverse events were similar to those reported previously. CONCLUSIONS: Clazosentan administered for up to 14 days at 15 mg/hour had no significant effect on the occurrence of clinical deterioration due to DCI. Clinical trial registration no.: NCT03585270 (ClinicalTrials.gov) EU clinical trial registration no.: 2018-000241-39 (clinicaltrialsregister.eu).

• MeSH
• Dioxanes * therapeutic use   adverse effects   MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Vasospasm, Intracranial etiology   prevention & control   drug therapy   diagnostic imaging   MeSH
• Brain Ischemia * prevention & control   etiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prospective Studies MeSH
• Pyridines * therapeutic use   adverse effects   administration & dosage   MeSH
• Pyrimidines * therapeutic use   adverse effects   administration & dosage   MeSH
• Aged MeSH
• Subarachnoid Hemorrhage * complications   diagnostic imaging   MeSH
• Sulfonamides * therapeutic use   adverse effects   administration & dosage   MeSH
• Tetrazoles * therapeutic use   adverse effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH