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Background High‐risk non‐muscle‐invasive bladder cancer (HRNMIBC) has a variable prognosis, managed predominantly by local surgical resection and intravesical Bacillus Calmette–Guérin (BCG), or radical cystectomy (RC). Current treatments are poorly tolerated, have supply limitations and often fail to control the disease. Treatments overcoming these limitations are needed to improve HRNMIBC outcomes. Many novel agents have been approved in recent years (including systemic pembrolizumab, nogapendekin alfa inbakicept‐pmln, N‐803), but long‐term efficacy is unknown. Given advanced bladder cancer findings, we believe direct intravesical administration of atezolizumab may aid with managing HRNMIBC or muscle‐invasive bladder cancer in patients who are ineligible for cisplatin‐based neoadjuvant chemotherapy. Study design The INtraVESical immunoTherapy (INVEST) trial is a UK‐based, open‐label, non‐randomised, single‐centre, Phase Ib dose escalation, window of opportunity study exploring atezolizumab administration via intravesical routes (passive instillation and direct injection [sub‐urothelial]) in patients with bladder cancer with all stages undergoing RC. For both routes, an initial dose confirmation stage will determine toxicity and recommended atezolizumab dosage, followed by a dose expansion stage to further evaluate safety and toxicity at the recommended dose. Endpoints We aim to investigate safety (primary) and preliminary activity (secondary) of intravesical atezolizumab delivered by passive instillation and direct injection into the tumour/bladder wall in patients with bladder urothelial cell carcinoma prior to RC. Primary endpoints include dose limiting toxicities and adverse events. Secondary endpoints include progression‐free survival, pathological complete response rate and treatment compliance. Exploratory endpoints include pharmacokinetic profile (assessed by serum and urine concentrations at prespecified timepoints), spatial analysis of atezolizumab distribution within RC tissue by imaging mass spectrometry and overall survival. Patients and Methods Atezolizumab will be administered intravesically by either passive instillation or direct injection into the tumour/bladder wall. Cohorts will receive either 600 mg or 1200 mg doses administered as a single dose or as multiple doses (weekly for 3–6 weeks). Trial Registration International Standard Randomised Controlled Trial Number: ISRCTN15842444 , registered 2 December 2022.

Pediatric heart failure is a heterogeneous, high-risk clinical syndrome that differs fundamentally from adult heart failure in its etiologies, pathophysiology, and therapeutic responses. Although its absolute prevalence is lower, children experience disproportionate morbidity and mortality, with up to 40% of patients with symptomatic cardiomyopathy progressing to death or transplantation within 2 years of diagnosis. Congenital heart disease, cardiomyopathies, and genetic or metabolic disorders dominate the etiologic spectrum, while developmental differences in myocardial signaling, neurohormonal activation, and ventricular remodeling limit direct extrapolation of adult guideline-directed medical therapy. Evidence supporting pharmacologic treatment remains limited, and most therapies are symptom-modifying rather than outcome-modifying, particularly in single-ventricle physiology. Advances in mechanical circulatory support and heart transplantation have substantially improved survival, yet pose unique anatomic, physiological, and ethical challenges in children. This review synthesizes contemporary evidence across medical, device-based, and transplant therapies, highlights lesion- and age-specific considerations, and identifies critical research gaps needed to advance outcomes in pediatric heart failure.

Hypertension remains the leading modifiable risk factor for cardiovascular morbidity and mortality worldwide, yet blood pressure control rates remain suboptimal despite the availability of effective therapies. Contemporary guidelines increasingly recommend early use of combination therapy, recognizing that most patients require multiple agents to achieve target blood pressure. Widaplik, a recently Food and Drug Administration-approved fixed-dose, single-pill triple combination of telmisartan, amlodipine, and indapamide, represents the first triple therapy approved for initial treatment of hypertension in adults likely to need multidrug therapy. This review summarizes the pharmacologic rationale for low-dose triple therapy, highlighting complementary mechanisms targeting the renin-angiotensin-aldosterone system, vascular resistance, and sodium retention. We examine evidence from pivotal phase 3 trials demonstrating rapid, sustained blood pressure reductions, higher control rates compared with dual therapy, and favorable tolerability. We also discuss safety considerations, practical limitations, and gaps in evidence, including long-term cardiovascular outcomes. Widaplik represents a paradigm shift toward simplified, early combination therapy aimed at improving hypertension control and reducing cardiovascular risk.

Coronary microvascular dysfunction (CMD) is increasingly recognized as a central mechanism underlying myocardial ischemia, heart failure with preserved ejection fraction, and adverse cardiovascular outcomes in patients with and without obstructive coronary artery disease. The coronary microcirculation plays a critical role in regulating myocardial perfusion through tightly coordinated myogenic, metabolic, and endothelial pathways. Disruption of these mechanisms results in impaired vasodilatory capacity, abnormal coronary flow reserve, and microvascular ischemia. This review summarizes the anatomy and physiology of coronary microcirculation and examines the pathophysiologic mechanisms driving CMD, including endothelial dysfunction, structural remodeling, inflammation, and neurohormonal dysregulation. Contemporary diagnostic strategies are reviewed, with emphasis on invasive coronary function testing and advanced noninvasive imaging modalities such as positron emission tomography and cardiac magnetic resonance imaging. The clinical implications of CMD across diverse disease states, including ischemia with nonobstructive coronary arteries, heart failure, and cardiomyopathies, are discussed. Finally, current therapeutic approaches, prognostic considerations, and emerging research directions aimed at improving diagnosis and targeted treatment of CMD are highlighted.

Coronary artery spasm (CAS) is a dynamic vasomotor disorder characterized by transient, intense constriction of epicardial coronary arteries, leading to myocardial ischemia in patients with and without obstructive coronary artery disease. CAS plays a central role in vasospastic angina, ischemia with nonobstructive coronary arteries and myocardial infarction with nonobstructive coronary arteries, malignant arrhythmias, and sudden cardiac death. Its pathophysiology is multifactorial, involving endothelial dysfunction, vascular smooth muscle hyperreactivity, inflammation, oxidative stress, autonomic imbalance, and genetic susceptibility, with notable ethnic and sex-related differences. Diagnosis relies on integration of clinical features, electrocardiographic changes, and invasive coronary provocation testing using acetylcholine or ergonovine, supported by advanced imaging and functional assessment when microvascular involvement is suspected. Management is centered on calcium channel blockers and nitrates, aggressive risk factor modification, particularly smoking cessation, and individualized strategies for refractory or high-risk patients. Improved recognition and standardized diagnostic pathways are essential to optimize outcomes and reduce life-threatening complications associated with CAS.

Shock is a life-threatening state of circulatory failure characterized by inadequate tissue oxygen delivery and cellular hypoxia. Lactate has emerged as a central biomarker in the diagnosis, risk stratification, and management of shock, yet its interpretation is complex and context dependent. Although traditionally viewed as a marker of anaerobic metabolism and tissue hypoperfusion, hyperlactatemia in distributive shock, particularly sepsis, frequently reflects multifactorial mechanisms, including increased aerobic glycolysis, adrenergic stimulation, mitochondrial dysfunction, and impaired hepatic clearance. This review examines the pathophysiology and classification of shock, the biochemical basis of lactate production and clearance, and the prognostic significance of both static lactate levels and lactate kinetics. We synthesize evidence supporting lactate as a robust prognostic marker while highlighting limitations of lactate-targeted resuscitation strategies. Emerging data favor multimodal approaches integrating lactate trends with complementary perfusion markers such as capillary refill time and central venous oxygen saturation. Lactate should be interpreted as one component of a comprehensive physiological assessment rather than an isolated therapeutic target.

Sudden death in children and young adults, while uncommon, carries profound clinical and societal implications. Cardiac causes, particularly inherited arrhythmias and cardiomyopathies, account for most cases, though neurologic, toxicologic, traumatic, and infectious etiologies also contribute significantly. This review explores the epidemiology, classification, and pathophysiologic mechanisms of sudden death in this population, emphasizing early clinical warning signs and identifiable risk factors. We also outline diagnostic and preventive strategies, including electrocardiography, genetic testing, and postmortem evaluation. Despite guidelines advocating preparticipation screening, real-world implementation remains inconsistent. Advances in genomics and artificial intelligence offer new opportunities for early risk detection. Finally, we discuss public health interventions such as defibrillator access, cardiopulmonary resuscitation education, and school-based protocols as essential components of a broader prevention strategy.

Coronary artery disease (CAD) is the leading cause of death globally. Apolipoprotein A-1 (apoA-1), the primary protein component of high-density lipoprotein (HDL), facilitates reverse cholesterol transport and has emerged as a potential therapeutic target. While pharmacologic efforts to raise HDL-C levels have failed to reduce cardiovascular events, focus has shifted to HDL functionality, particularly cholesterol efflux capacity (CEC). ApoA-1 infusions have demonstrated antiatherogenic effects in preclinical models and early human trials by enhancing CEC and promoting cholesterol clearance. This review summarizes the rationale and evolving clinical trial landscape investigating apoA-1 infusions as a novel therapy for CAD prevention and treatment.

Abstract Introduction Synchronous carcinomas are second neoplasms that occur within 6 months of the primary lesion. After this period, they are considered metachronous neoplasms. Literature reported the incidence of synchronous and metachronous carcinoma in the oral cavity from 8% to 21% which is a poor prognostic factor with a subsequently poor overall survival rate. Case Report A 57-year-old male presented with ulcerative lesions in the oral cavity for the last 2 years. He had 25-year history of betel nut chewing. On examination, two ulcerative lesions noted in the oral cavity: on the right upper gingival area measuring approximately 1 x 1 cm with the exposed underlying bone, and another on the left lower gingival area measuring 2 x 2 cm from canine to premolar, subsequently confirmed with MRI. Biopsy confirmed squamous cell carcinoma (SCC). After discussion in the multidisciplinary meeting, he underwent right partial maxillectomy, left marginal mandibulectomy, bilateral neck dissection, and dental extractions, with uneventful post-operative recovery. Histopathology of right partial maxillectomy was moderately differentiated SCC (pT4a), Left marginal mandibulectomy; well-differentiated SCC in the canine area, as well as molar teeth area, and no involved lymph nodes (0/88). All resection margins were free of tumour. Radiotherapy was given to the right maxilla postoperatively. Conclusions To our knowledge, this is the first reported case of triple synchronous SCC oral cavity in our country. Detection of three Synchronous SCCs in the oral cavity follows the concept of field cancerization. A multidisciplinary treatment strategy in a high-volume cancer-dedicated centre is required to aggressively treat such tumours.

773 Background: BCG-unresponsive High-risk non-muscle invasive bladder cancer (HRNMIBC) tumours have an ominous prognosis and require effective, tolerable treatments. Uptake remains low for FDA approved agents (including systemic pembrolizumab, nogapendekin alfa inbakicept-pmln or N-803) due to toxicity concerns. We hypothesize direct intravesical administration of a PDL1 inhibitor could be effective with less systemic toxicity. However, it is unknown whether antibodies delivered via this route can reach tumor vasculature. INVEST is a phase Ib window of opportunity study investigating the safety and preliminary activity of passive instillation and direct injection of intravesical atezolizumab into the tumour/bladder wall. Methods: Eligible participants (ECOG performance status 0-2) are awaiting radical cystectomy (RC) for any stage urothelial cell carcinoma. Participants with muscle invasive bladder cancer, must be ineligible for/ refuse cisplatin based neo-adjuvant chemotherapy. Atezolizumab (600mg or 1200mg) is administered via direct injection into the tumour/bladder or by instillation into the bladder. The 3+3 design is utilised in the dose confirmation stages where participants receive either Single or Multiple (between 3 and 6) dose(s) of treatment before RC. Efficacy signals are derived from pathological complete response at RC and progression-free survival at 2 years. Primary endpoint, Dose confirmation stage: The number of dose-limiting toxicities (DLTs) observed from first dose of trial treatment to RC. Results: Enrolment began in May 2023. 13 participants were recruited to the single dose cohorts: 11 male, and 2 female. Age (Range; 43-86); median 70y, 9 NMIBC, 4 MIBC. 7 for direct injection (4 at 600mg and 3 at 1200mg dose) and 6 for passive instillation (3 at 600mg and 3 at 1200mg). Due to technical issues (syringe size) the first direct injection participant did not receive the full 600mg and were replaced. 12 participants received trial treatment as planned. There were no DLTs; 5 participants experienced non-trial treatment related SAEs (4 infections, 2 ileus, 2 renal impairment; 7/8 events occurred post-RC and all SAEs resolved). All participants underwent planned RC within the protocol stipulated timeline. Median time from last treatment to RC was18 days. 5 of 13 participants had downstaging of tumour in cystectomy specimen. Following independent Safety Review Committee review, recruitment is now open for the dose confirmation phase (Multiple 1200mg dose) in both treatment routes. Conclusions: Single dose atezolizumab treatment at a dose of 600mg and 1200mg in passive instillation and direct injection cohorts was well tolerated. Early efficacy data is encouraging. Multiple weekly doses of 1200mg in each treatment route are now being investigated within the INVEST trial. Clinical trial information: ISRCTN15842444 .