Multiple Clinical Trials Research Articles

New Bladder Preservation Strategies in Urothelial Carcinoma of the Bladder.

17 500 persons receive a new diagnosis of urothelial carcinoma of the bladder in Germany each year. Radical cystectomy is performed for muscle-invasive and for non-muscle-invasive, recurrent, high-risk tumors. Because this procedure carries a perioperative complication rate of 30-40% and impairs the patients' quality of life, options have been developed for intravesical and systemic bladder-preserving treatment. This review is based on pertinent publications (up to July 2024) on bladder-preserving treatment methods that were retrieved by a selective search in the PubMed, Web of Science, and Cochrane Library databases. Multiple clinical phase II-III trials and observational studies are available. Carefully selected patients with recurrent, non-muscle-invasive, high-risk urothelial carcinoma received bladder-preserving treatment of the following kinds: intravesical chemotherapy with or without hyperthermia (52-65% progression-free at 2-3 years); drug-coated carrier systems (complete remission, 50-83%); viral gene therapy (complete remission, 53%); systemic immunotherapy with checkpoint inhibitors (19-44% recurrence-free at 1 year). The rate of bladder preservation was 49-100%. No worsening of overall survival was observed. Treatments for muscle-invasive urothelial carcinoma included neoadjuvant chemotherapy followed by frequent follow-up, radical transurethral tumor resection, partial cystectomy, and trimodal radiochemotherapy (TMRT). Only TMRT yielded comparable long-term oncological results to those of cystectomy, with a 74% rate of freedom from metastases and an overall survival rate of 73%. Any type of bladder-preserving treatment requires meticulous long-term uro-oncological follow-up, with repeated cystoscopies, bladder biopsies, urine cytologies, and multiparametric bladder MRI. Bladder-preserving treatments should be considered part of the therapeutic armamentarium and should be critically discussed in an interdisciplinary setting.

Acupuncture for substance use disorders: a protocol of systematic review and meta-analysis of randomised controlled trials

IntroductionSubstance use disorders (SUDs) are common and highly disabling, causing serious long-term harm to people’s health. Despite the existence of evidence-based interventions for treating SUDs, many individuals remain symptomatic regardless...

Bringing Pain Neuroscience Into the Arena: A Call to Action in Sports Rehabilitation

SYNOPSIS: The study of pain continues to evolve by leaps and bounds. In the last 2 decades, multiple observational studies, clinical trials, and evidence syntheses have attempted to shed light on the relevance of the biopsychosocial model in musculoskeletal rehabilitation. In sports, pain is an area of significant interest for many researchers, sports clinicians, and, of course, athletes. Pain neuroscience is a constantly growing area of research, with important advances in musculoskeletal rehabilitation. We have information about the importance of some pain neuroscience-related mechanisms such as central sensitization, conditioned pain modulation, and temporal summation of pain in people with chronic pain. However, the number of studies evaluating different areas of pain neuroscience in athletes with chronic pain remains limited. We make a call for action to researchers to expand and improve the quality of research specifically addressing pain neuroscience-related mechanisms in athletes, to better understand and manage their pain experiences. JOSPT Methods 2025;1(2):1-4. Epub 23 April 2025. doi:10.2519/josptmethods.2025.0158

Recent advances in delivery systems of ginsenosides for oral diseases.

Recent advances in delivery systems of ginsenosides for oral diseases.

Myeloid-derived Suppressor Cells EN-RAGE Antitumor Immunity

Immune checkpoint inhibitors (ICI) have radically altered cancer therapy and enable delayed tumor progression and in some cases cures for some cancer patients. However, ICI efficacy is mixed depending on the type of cancer and individual cancer patients. Myeloid-derived suppressor cells (MDSCs) are potent inhibitory cells that are present in most cancer patients where they suppress T cell and NK cell-mediated antitumor immunity. They are likely to contribute to the lack of effect of ICI, and therefore, eliminating MDSCs may enhance the efficacy of ICI. MDSCs are activated by multiple proinflammatory mediators that are typically present in many cancers, and MDSCs are homeostatically regulated so that depletion of MDSCs in circulation or within solid tumors increases their rate of production from the bone marrow. Multiple clinical trials have been conducted using drugs targeting individual mediators that either eliminate MDSCs in the periphery or neutralize the suppressive activity of MDSCs. Unfortunately, the trials have been largely ineffective in limiting MDSCs and enhancing ICI-induced antitumor immunity. Given the homeostatic regulation of MDSCs and the variety of proinflammatory molecules in individual patients capable of inducing MDSC differentiation, optimal reduction of MDSCs will likely require blocking the relevant proinflammatory mediators and preventing the development of MDSCs in bone marrow. Signal transduction through The Receptor for Advanced Glycation Endproducts (RAGE) activates many of the pro-inflammatory mediators that are established activators of MDSC. Our studies in mice have established RAGE as a receptor on MDSC bone marrow progenitor cells and have demonstrated that blocking RAGE on murine bone marrow stem cells prevents the development of MDSC. Studies by others have demonstrated that RAGE inhibitors also directly suppress the growth of RAGE-expressing tumor cells. Therefore, we hypothesize that RAGE may be a key receptor on myeloid progenitor cells for driving the differentiation, accumulation, and function of MDSC, and that inhibitors of RAGE may be efficacious therapeutics for use in conjunction with ICI.

Extracellular vesicles and the lung: from disease pathogenesis to biomarkers and treatments.

Nanosized extracellular vesicles (EVs) are released by all cells to convey cell-to-cell communication. EVs, including exosomes and microvesicles, carry an array of bioactive molecules, such as proteins and RNAs, encapsulated by a membrane lipid bilayer. Epithelial cells, endothelial cells, and various immune cells in the lung contribute to the pool of EVs in the lung microenvironment and carry molecules reflecting their cellular origin. EVs can maintain lung health by regulating immune responses, inducing tissue repair, and maintaining lung homeostasis. They can be detected in lung tissues and biofluids such as bronchoalveolar lavage fluid and blood, offering information about disease processes, and can function as disease biomarkers. Here, we discuss the role of EVs in lung homeostasis and pulmonary diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis, and lung injury. The mechanistic involvement of EVs in pathogenesis and their potential as disease biomarkers are discussed. Finally, the pulmonary field benefits from EVs as clinical therapeutics in severe pulmonary inflammatory disease, as EVs from mesenchymal stem cells attenuate severe respiratory inflammation in multiple clinical trials. Further, EVs can be engineered to carry therapeutic molecules for enhanced and broadened therapeutic opportunities, such as the anti-inflammatory molecule CD24. Finally, we discuss the emerging opportunity of using different types of EVs for treating severe respiratory conditions.

The Microbiome and Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition wherein excessive fat accumulates in the liver, leading to inflammation and potential liver damage. In this narrative review, we evaluate the tissue microbiota, how they arise and their constituent microbes, and the role of the intestinal and hepatic microbiota in MASLD. The history of bacteriophages (phages) and their occurrence in the microbiota, their part in the potential causation of MASLD, and conversely, "phage therapy" for antibiotic resistance, obesity, and MASLD, are all described. The microbiota metabolism of bile acids and dietary tryptophan and histidine is defined, together with the impacts of their individual metabolites on MASLD pathogenesis. Both periodontitis and intestinal microbiota dysbiosis may cause MASLD, and how individual microorganisms and their metabolites are involved in these processes is discussed. Novel treatment opportunities for MASLD involving the microbiota exist and include fecal microbiota transplantation, probiotics, prebiotics, synbiotics, tryptophan dietary supplements, intermittent fasting, and phages or their holins and endolysins. Although FDA is yet to approve phage therapy in clinical use, there are multiple FDA-approved clinical trials, and this may represent a new horizon for the future treatment of MASLD.

Multiple sclerosis in China: the current state of diagnosis and management.

This comprehensive overview summarized the latest advances of multiple sclerosis (MS) in China, including the diagnostic and treatment challenges, research and future directions under health policy recommendations. Given the rising prevalence of MS in China during the past decades, it has emerged as a significant public health concern due to the extensive population and pronounced disparities between urban and rural areas. The clinical manifestations of MS patients in China can be various due to the nation's diversity and evolving environmental factors. Advances in diagnostic practices, including the advances under 7T MRI radiological assessments, have enhanced the precision of MS diagnosis. Despite the introduction of disease-modifying therapeutic agents and the support of healthcare policies offering patients a wider range of treatment options, multiple ongoing research efforts and clinical trials will provide additional evidence. The ongoing China National Registry of Neuro-Inflammatory Diseases study (NCT05154370) holds promise for further enhancing the management of MS patients in China. Improved recognition and management of MS in China have been facilitated, encompassing both prompt diagnosis and diverse treatment options. Simultaneously, research efforts and large-scale cohort studies have significantly advanced the overall status in this field.

Joint Associations of APOC3 and LDL-C–Lowering Variants With the Risk of Coronary Heart Disease

Despite substantial progress in low-density lipoprotein cholesterol (LDL-C)-lowering strategies, residual cardiovascular risk remains. Apolipoprotein C3 (APOC3) has emerged as a novel target for lowering triglycerides. Multiple clinical trials of small-interfering RNA therapeutics targeting APOC3 are currently underway. To investigate whether genetically predicted lower APOC3 is associated with a reduction in cardiovascular risk and if the combined exposure to APOC3 and LDL-C-lowering variants is associated with a reduction in the risk of coronary heart disease (CHD). This was a population-based genetic association study with 2 × 2 factorial mendelian randomization. Included were participants of European ancestry in the UK Biobank. Data were analyzed from November 2023 to July 2024. Genetic scores were constructed to mimic the effects of APOC3, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. Plasma lipid and lipoprotein levels, CHD, and type 2 diabetes (T2D). This study included 401 548 UK Biobank participants (mean [SD] age, 56.9 [8.0] years; 216 901 female [54.0%]). Genetically predicted lower APOC3 was associated with a lower risk of CHD (odds ratio [OR], 0.96; 95% CI, 0.93-0.98) and T2D (0.97; 95% CI, 0.95-0.99). Genetically lower APOC3 and PCSK9 were associated with a similar magnitude of risk reduction in CHD per 10-mg/dL decrease in apolipoprotein B (ApoB) level (APOC3: 0.70; 95% CI, 0.59-0.83; PCSK9: 0.71; 95% CI, 0.65-0.77). Combined exposure to genetically lower APOC3 and PCSK9 was associated with an additive lower risk of CHD (APOC3: 0.96; 95% CI, 0.92-0.99; PCSK9: 0.93; 95% CI, 0.90-0.97; combined: 0.90; 95% CI, 0.86-0.93). Genetically lower HMGCR was also associated with a lower risk of CHD, and the risk was further reduced when combined with APOC3 (0.93; 95% CI, 0.90-0.97). Genetically predicted lower APOC3 was associated with a reduced risk of CHD that is comparable with that associated with lower PCSK9 per unit decrease in ApoB. Combined exposure to APOC3 and LDL-C-lowering variants was associated with an additive reduction in CHD risk. Future studies are warranted to investigate the therapeutic potential of these combined therapies, particularly among high-risk patients who cannot achieve therapeutic targets with existing lipid-lowering therapies.

Real-World Evidence of Tralokinumab Effectiveness and Safety: A Systematic Review and Meta-analysis.

Tralokinumab, a first-in-class and second biologic approved for treating moderate-to-severe atopic dermatitis in adolescents and adults, has demonstrated consistent efficacy and safety across multiple clinical trials. We aimed to assess the real-world effectiveness and safety of tralokinumab by performing a systematic review and meta-analysis on the real-world evidence of tralokinumab. We systematically searched PubMed and EMBASE from inception until 28 July, 2024 for observational studies describing the effectiveness and safety of tralokinumab for the treatment of atopic dermatitis. The primary outcome was the proportion of patients achieving a ≥75% improvement in the Eczema Area and Severity Index (EASI-75) after 16 weeks and secondary outcomes included the proportion of patients achieving EASI-50 and EASI-90 and the proportion of patients experiencing adverse events. Nineteen unique studies encompassing 911 bio-naïve and bio-experienced patients with atopic dermatitis treated with tralokinumab were included. After 16 weeks of treatment, 82%, 59% and 26% of patients achieved EASI-50, EASI-75 and EASI-90, respectively, and the proportion of patients developing conjunctivitis was 3.2%. Tralokinumab demonstrates strong effectiveness and good tolerability in real-world settings, with a high proportion of patients achieving a clinical response and adverse events being observed only infrequently.

Advances in Therapy of Adult Patients with Acute Lymphoblastic Leukemia.

The landscape of adult acute lymphoblastic leukemia (ALL) is dramatically changing. With very promising results seen with novel immunotherapeutics in the setting of relapsed and refractory disease, the prospect of using these agents in first-line therapy has prompted the development of multiple clinical trials addressing this question. This review seeks to outline and expand the current standard of care, as well as new advances, in the treatment of adult patients with ALL and address future areas of research. We expect the frontline integration of immuno-oncology agents such as bispecific T-cell engagers, antibody-drug conjugates, and chimeric antigen receptor (CAR) T cells may maintain or improve outcomes in adults while also minimizing toxicity. Treatment of ALL will continue to evolve as we focus on personalized, patient-centered approaches.

Advances in the screening, diagnosis, and treatment of transthyretin amyloid cardiomyopathy: New insights and future directions.

Advances in the screening, diagnosis, and treatment of transthyretin amyloid cardiomyopathy: New insights and future directions.

Treatment options to break the cycle of recurrent pericarditis.

This review provides a contemporary, evidence-based update on the pathophysiological mechanisms and rapidly evolving therapeutic options for recurrent pericarditis. Recent studies have elucidated the pathogenesis of recurrent pericarditis, identifying autoinflammation as a key mechanism and interleukin-1 (IL-1) as a central modulator of the inflammatory cascade. Multiple clinical trials have investigated novel therapeutic approaches, particularly focusing on IL-1 inhibition. The recent FDA approval of IL-1 pathway blockade for recurrent pericarditis has revolutionized treatment, offering patients significantly improved quality of life and symptom management. The enhanced understanding of the autoinflammatory nature of recurrent pericarditis, coupled with groundbreaking advances in targeted therapies, has transformed the treatment landscape for affected patients. The emergence of IL-1 inhibitors as an effective therapeutic option promises substantial improvements in clinical outcomes and patient well being. Clinicians must familiarize themselves with these new treatments, their efficacy, and potential limitations to optimize patient care and guide therapeutic decision-making in this challenging condition.

Therapeutic Ketosis for Heart Failure: A State-of-the-Art Review.

Heart failure is characterized by an energy-deprived heart, and in recent years it has been found that the failing heart increases ketone body oxidation to meet its energy demands. Accumulating evidence suggests that this metabolic adaptation is cardioprotective, suggesting that interventions that boost blood ketone levels could aid the failing heart. Indeed, multiple small clinical trials with short-term follow up have demonstrated that supplying the failing heart with exogenous ketone bodies may improve myocardial function across various manifestations of heart failure. As such, therapeutic ketosis, which is a metabolic state in which blood ketone levels are mildly elevated, could have great potential to ameliorate heart failure. Therapeutic ketosis can be achieved endogenously via exercise or dietary practices, exogenously via supplementation with ketone bodies, or pharmacologically via treatment with a sodium-glucose cotransporter-2 inhibitor. Although ketosis-inducing practices cannot be routinely recommended to patients with heart failure at this time due to a lack of robust data regarding the long-term benefits and risks, anecdotal evidence suggests that some patients have begun to adopt ketosis-inducing practices, so it is important for clinicians to be aware of how to manage patients optimally when they are in therapeutic ketosis. In this review, we discuss myocardial ketone metabolism in heart failure, the current evidence for therapeutic ketosis in patients with heart failure, a framework to distinguish between therapeutic ketosis and the pathologic state of ketoacidosis, and practical considerations for managing patients adhering to ketosis-inducing practices.

The interplay between acute and late toxicity among patients receiving prostate radiotherapy: an individual patient data meta-analysis of six randomised trials.

The interplay between acute and late toxicity among patients receiving prostate radiotherapy: an individual patient data meta-analysis of six randomised trials.

Developing a cost-effective and efficient safety case management solution for data coordinating center projects.

Developing a cost-effective and efficient safety case management solution for data coordinating center projects.

Educational Review: Updates on Therapeutic Strategies for Gastric Cancer with Peritoneal Metastasis.

Gastric cancer (GC) commonly presents in advanced stages with metastatic spread to the peritoneal cavity, and outcomes associated with gastric cancer with peritoneal metastasis (GCPM) continue to carry a dismal prognosis. Persistent challenges in the detection of peritoneal metastasis (PM) have resulted in a relative paucity of high-quality data to inform management decisions. Several consensus groups have published recommendations to guide management, including most recently the National Comprehensive Cancer Network guidelines, which now include cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as a potential treatment modality in select patients with GCPM. Multiple clinical trials have investigated the use of CRS/HIPEC and other peritoneal-directed therapies, such as intraperitoneal chemotherapy (IPC) and pressurized intraperitoneal aerosolized chemotherapy (PIPAC). As high-volume centers work to incorporate such therapies into their practice, ongoing clinical trials are aimed at understanding their efficacy. Recent findings have improved understanding of the mechanisms and pathophysiology underlying GCPM while the discovery of novel targets offers potential for drug development and therapeutic strategies to overcome treatment resistance. This review highlights recent advancements and addresses the persistent challenges in managing GCPM while also offering a comprehensive summary of current guidelines and treatment strategies.

Timing of ctDNA Analysis Aimed at Guiding Adjuvant Treatment in Colorectal Cancer.

Multiple clinical trials are investigating ctDNA to guide adjuvant chemotherapy (ACT) in colorectal cancer. Timely ACT initiation necessitates early ctDNA testing, but the impact of postoperative cell-free DNA (cfDNA) and ctDNA dynamics remains unclear, particularly with cost-reducing input caps employed in some assays. This study investigates ctDNA detection at day 14 versus day 30, comparing whole-sample analysis with capping the cfDNA input, and evaluates single and dual timepoint assessments for ACT allocation. From 2019 to 2023, 611 patients with stage I to III colorectal cancer were enrolled. Blood was collected preoperatively and postoperatively on ∼day 14 and ∼day 30. The cfDNA levels were assessed using digital PCR, and ctDNA was assessed using tumor-informed digital PCR or targeted sequencing analyzing all cfDNA from 8 mL of plasma. Despite elevated cfDNA in 85% of day 14 samples, performance was comparable between the two timepoints (sensitivity, 31% vs. 32% and specificity, both 98%). A 50-ng cfDNA input cap reduced ctDNA detection probability, affecting 78% of day 14 samples and 65% of day 30 samples. At both timepoints, ctDNA detection was prognostic of recurrence (day 14; HR, 9.0, 95% confidence interval, 5.5-14.8 and day 30: HR, 12.5, 95% confidence interval, 7.6-20.4). In 74% of ctDNA-positive recurrence patients, both samples had ctDNA detected. An increase in the ctDNA level from day 14 to day 30 was associated with a shorter time to recurrence (Pearson R = -0.63, P = 0.003). Combining the timepoints would increase sensitivity (36%) and allow earlier ACT start in 80% of patients. Early ctDNA sampling is feasible and highly prognostic. Supplemental later testing may improve sensitivity while allowing early ACT initiation for most ctDNA-positive patients.

Clinical research progress of stem cell therapy for decompensated cirrhosis and liver failure

Chronic liver disease remains a severe threat to human health. Furthermore, if left untreated promptly and effectively, it may gradually develop into end-stage liver disease, including decompensated cirrhosis and liver failure. Currently, mesenchymal stem cell technology is acting as a kind of an emerging treatment method, and multiple clinical trials have confirmed its promising application prospects in the treatment of decompensated cirrhosis and liver failure. Hence, stem cell therapy may offer a novel therapeutic option for these patients. This article summarizes the clinical research progress of stem cell therapy for decompensated cirrhosis and liver failure and analyzes present challenges and application prospects.

Network Meta-Analysis With Individual Participant-Level Data of Time-to-Event Outcomes Using Cox Regression.

The accessibility of individual participant-level data (IPD) enhances the evaluation of moderation effects of patient covariates. It facilitates the provision of accurate estimation of intervention effects and confidence intervals by incorporating covariate correlations across multiple clinical trials. With a time-to-event outcome, Cox regression can be applied for network meta-analysis (NMA) using IPD. However, there lacks comprehensive reviews and comparisons of the specifications and assumptions of these Cox models and their impact on the interpretation of hazard ratios, effect moderation, and trial heterogeneity in IPD-NMA. In this paper, we examine various Cox models for IPD-NMA and compare different approaches to modeling trial, treatment, and covariate effects. We employ multiple graphical tools and statistical tests to assess proportional hazard assumptions and discuss their implications. Additionally, we explore the application of extended Cox models when the proportional hazard assumption is violated. Practical guidance on interpreting and reporting NMA results is provided. A simulation study is conducted to compare the performance of different models. We illustrate the methods to conduct IPD-NMA through a real data example.