Project description:As the prevalence of dementia and Alzheimer's disease (AD) increases worldwide, it is imperative to reflect on the major clinical trials in the prevention of dementia and the challenges that surround them. The pharmaceutical industry has focused on developing drugs that primarily affect the Aβ cascade and tau proteinopathy, while academics have focused on repurposed therapeutics and multi-domain interventions for prevention studies. This paper highlights significant primary, secondary, and tertiary prevention trials for dementia and AD, overall design, methods, and systematic issues to better understand the current landscape of prevention trials. We included 32 pharmacologic intervention trials and 9 multi-domain trials. Fourteen could be considered primary prevention, and 18 secondary or tertiary prevention trials. Major categories were Aβ vaccines, Aβ antibodies, tau antibodies, anti-inflammatories, sex hormones, and Ginkgo biloba extract. The 9 multi-domain studies mainly focused on lifestyle modifications such as blood pressure management, socialization, and physical activity. The lack of validated drug targets, and the complexity of the diagnostic frameworks, eligibility criteria, and outcome measurements for trials, make it difficult to show efficacy for both pharmacological and multi-domain interventions. We hope that this summative analysis of trials will stimulate discussion for scientists and clinicians interested in reviewing and developing preventative interventions for AD.
Project description:The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways. The contribution of the NRF2 pathway to organismal homeostasis is seen in many studies using cell lines and animal models, raising intense attention towards targeting its clinical promise. Over the last three decades, an expanding number of clinical studies have examined NRF2 inducers targeting an ever-widening range of diseases. Full understanding of the pharmacokinetic and pharmacodynamic properties of drug candidates rely partly on the identification, validation, and use of biomarkers to optimize clinical applications. This review focuses on results from clinical trials with four agents known to target NRF2 signaling in preclinical studies (dimethyl fumarate, bardoxolone methyl, oltipraz, and sulforaphane), and evaluates the successes and limitations of biomarkers focused on expression of NRF2 target genes and others, inflammation and oxidative stress biomarkers, carcinogen metabolism and adduct biomarkers in unavoidably exposed populations, and targeted and untargeted metabolomics. While no biomarkers excel at defining pharmacodynamic actions in this setting, it is clear that these four lead clinical compounds do touch the NRF2 pathway in humans.
Project description:Although most individuals recover from acute SARS-CoV-2 infection, a significant number continue to suffer from Post-Acute Sequelae of SARS-CoV-2 (PASC), including the unexplained symptoms that are frequently referred to as long COVID, which could last for weeks, months, or even years after the acute phase of illness. The National Institutes of Health is currently funding large multi-center research programs as part of its Researching COVID to Enhance Recover (RECOVER) initiative to understand why some individuals do not recover fully from COVID-19. Several ongoing pathobiology studies have provided clues to potential mechanisms contributing to this condition. These include persistence of SARS-CoV-2 antigen and/or genetic material, immune dysregulation, reactivation of other latent viral infections, microvascular dysfunction, and gut dysbiosis, among others. Although our understanding of the causes of long COVID remains incomplete, these early pathophysiologic studies suggest biological pathways that could be targeted in therapeutic trials that aim to ameliorate symptoms. Repurposed medicines and novel therapeutics deserve formal testing in clinical trial settings prior to adoption. While we endorse clinical trials, especially those that prioritize inclusion of the diverse populations most affected by COVID-19 and long COVID, we discourage off-label experimentation in uncontrolled and/or unsupervised settings. Here, we review ongoing, planned, and potential future therapeutic interventions for long COVID based on the current understanding of the pathobiological processes underlying this condition. We focus on clinical, pharmacological, and feasibility data, with the goal of informing future interventional research studies.
Project description:ObjectivesTo compare the efficacy and prognosis of one-stop hybrid surgery using the elephant trunk procedure for treatment of complex Stanford type B aortic dissection.MethodsWe retrospectively analyzed patients who underwent surgical treatment from January 2014 to July 2019. The patients were divided into those who underwent the elephant trunk procedure (n = 10) and those who underwent one-stop hybrid surgery (n = 10). The cardiopulmonary bypass time, mechanical ventilation time, length of hospital stay, and red blood cell usage were compared between the two groups. All patients' 3-month postoperative aortic computed tomography angiography (CTA) findings were also reviewed.ResultsThe cardiopulmonary bypass time, mechanical ventilation time, and length of hospital stay were significantly shorter and red blood cell usage was significantly lower in the one-stop hybridization group. The aortic cross-clamp time was not significantly different between the two groups. Aortic CTA review after hybrid surgery showed that the true lumen of the descending aorta was almost completely restored at 3 months.ConclusionOne-stop hybrid surgery effectively alleviated the occlusion of the aortic dissection, prevented the need for additional surgery, and expanded the indications for covered-stent endovascular repair.
Project description:IntroductionThere has been a growing recognition on the importance of diversity in clinical trials. Existing research has highlighted a significant demographic imbalance. Amidst this renewed focus on diversity, it is crucial to acknowledge that Asia comprises over half of the world's population. Given the region's demographic significance, we sought to compare various characteristics and growth rates for trials with sites in Asia against those without any sites in Asia.MethodsWe performed comprehensive analyses of industry-sponsored phase 2 and 3 oncology trials registered at Clinicaltrials.gov, using drugs or biologics as investigational agents and executed between 1 January 2018 and 31 December 2022. We applied the compound annual growth rate (CAGR) as an analytical tool to track the trial growth rates over this 5-year period.ResultsWe identified 894 industry-sponsored phase 2 and 3 cancer studies with available study location data. Out of these, 415 trials (46.42%) had study sites in Asia. Notably, these trials with sites in Asia were also more likely to be phase 3 trials (39.76% vs 6.47%, p < 0.001), include female and paediatric populations, and be randomised trials. Interestingly, lung and stomach cancers were more commonly studied in these trials, while myeloma was less commonly studied. The number of trial sites for liver cancer was not significantly higher for Asia, even though the incidence of the disease is much higher in this region. Despite an overall declining trend in the number of clinical trials in the last 5 years, we observed a transitional positive increase in the CAGR from 2020 to 2021 for trials with sites in Asia. However, East Asia, specifically China, exhibited a disproportionate overrepresentation in these trials.ConclusionsThere are notable characteristics of clinical trials with sites in Asia. Comprehending these disparities may aid in the strategic planning to enhance a balanced representation of ethnicities in trials.
Project description:The clinical development of systemic treatments for hepatocellular carcinoma (HCC) has gained significant momentum in recent years. After the unexpected failure of the phase 3 trials testing the PD1-inhibitors nivolumab and pembrolizumab as monotherapy in advanced HCC, a multitude of trials employing different agents in various combinations and at different disease stages have been initiated. The first positive results reported for the combination of atezolizumab and bevacizumab, as the first line treatment of advanced HCC, will bring lasting change to the management of HCC and has increased the odds of success for alternative combination therapies. This review article seeks to provide clarity on the complex and evolving landscape of clinical trials on systemic treatments of HCC. It covers current trials which test various systemic treatments (i) in the first and second line in advanced HCC, (ii) in intermediate HCC, (iii) as adjuvant as well as (iv) neoadjuvant strategies, and (v) including immune interventions other than immune checkpoint inhibition.
Project description:Medulloblastoma is an embryonal pediatric brain tumor and can be divided into at least four molecularly defined groups. The category non-WNT/non-SHH medulloblastoma summarizes medulloblastoma groups 3 and 4 and is characterized by considerable genetic and clinical heterogeneity. New therapeutic strategies are needed to increase survival rates and to reduce treatment-related toxicity. We performed a noncomprehensive targeted review of the current clinical trial landscape and literature to summarize innovative treatment options for non-WNT/non-SHH medulloblastoma. A multitude of new drugs is currently evaluated in trials for which non-WNT/non-SHH patients are eligible, for instance immunotherapy, kinase inhibitors, and drugs targeting the epigenome. However, the majority of these trials is not restricted to medulloblastoma and lacks molecular classification. Whereas many new molecular targets have been identified in the last decade, which are currently tested in clinical trials, several challenges remain on the way to reach a new therapeutic strategy for non-WNT/non-SHH medulloblastoma. These include the severe lack of faithful preclinical models and predictive biomarkers, the question on how to stratify patients for clinical trials, and the relative lack of studies that recruit large, homogeneous patient collectives. Innovative trial designs and international collaboration will be a key to eventually overcome these obstacles.
Project description:BackgroundClinical trials are essential for bringing new drugs, technologies and procedures to the market and clinical practice. Considering the design and the four-phase development, only 10% of them complete the entire process, partly due to the increasing costs and complexity of clinical trials. This low completion rate has a huge negative impact in terms of population health, quality of care and health economics and sustainability. Automating some of the process' tasks with artificial intelligence (AI) tools could optimize some of the most burdensome ones, like patient selection, matching and enrollment; better patient selection could also reduce harmful treatment side effects. Although the pharmaceutical industry is embracing artificial AI tools, there is little evidence in the literature of their application in clinical trials.MethodsTo address this issue, we performed a scoping review. Following the PRISMA-ScR guidelines, we performed a search on PubMed for articles on the implementation of AI in the development of clinical trials.ResultsThe search yielded 772 articles, of which 15 were included. The articles were published between 2019 and 2022 and the results were presented descriptively. About half of the studies addressed the topic of patient recruitment; 12 articles reported specific examples of AI applications; five studies presented a quantitative estimate of the effectiveness of these tools.ConclusionAll studies present encouraging results on the implementation of AI-based applications to the development of clinical trials. AI-based applications have a lot of potential, but more studies are needed to validate these tools and facilitate their adoption.
Project description:Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with a distinctive regional and racial prevalence. It is associated with Epstein-Barr virus infection and has a high propensity for regional and distant metastases, while it is very sensitive to radiation and chemotherapy. A common feature of Epstein-Barr virus-positive NPC is the dense infiltration of lymphocytes in the tumor stroma and positive programmed death-ligand 1 expression in tumor cells, making it an attractive target for immunotherapy, especially immune checkpoint inhibitors. As new immunotherapeutic agents are being rapidly adopted in many cancers, including head and neck cancer, the National Cancer Institute sponsored a clinical trial planning meeting to identify opportunities for developing phase II and III trials testing immunotherapy in different stages of NPC. The meeting started with the summary of the biology of the disease, current standards of care, and evidence of immunotherapy in this cancer. Three subcommittees were tasked to develop clinical trials: loco regionally advanced, nonmetastatic NPC; widely metastatic NPC; and either local recurrence after initial treatment or presenting with oligometastatic disease. This article summarizes the proceedings of this clinical trial planning meeting and provides a road map for future trials incorporating immune checkpoint inhibitors for therapeutic management of NPC. This road map, though specific for NPC, may also be applicable to other virally driven cancers that have similar ability to evade the host's immune system.
Project description:PurposeAdequate clinical services have yet to be established in the majority of African countries, where childhood cancer survival rates vary from 8.1% to 30.3%. The aim of this review is to describe the landscape of pediatric oncology trials in Africa, identify challenges, and offer future opportunities for research collaborations.MethodsThe study includes data from the International Pediatric Oncology Society (SIOP) global mapping survey, meta-research identifying trials in Africa in ClinicalTrials.gov, and a literature overview of publications on the subject of pediatric oncology clinical research supported by expert opinions on the current situation and challenges.ResultsThe SIOP global mapping survey received responses from 47 of 54 African countries, of which 23 have active clinical research programs. A preliminary search of ClinicalTrials.gov showed that only 105 (12.1%) of 868 African oncology studies included children and adolescents. Of these, 53 (50.5%) were interventional trials according to the registry's classification. The small number of African trials for children and adolescents included palliative care and leukemia trials. In African oncology journals and international pediatric oncology journals, < 1% of the pediatric oncology publications come from Africa. Services and research were strengthened by international collaboration. National studies focused on clinical needs, local challenges, or interventional priorities. Both the literature review and the expert opinions highlight the need to expand clinical research in Africa, despite ongoing regional instability and lack of resources.ConclusionWhile a low number of pediatric clinical treatment trials are open to African children and adolescents, clinical research of high quality is being done in Africa. Several initiatives are stimulating the development of the research capacity across the continent, which should increase the publication output.