Ongoing Trials Research Articles

Treated obstructive sleep apnoea and incident arrhythmias

Abstract Background Obstructive sleep apnoea (OSA) is prevalent in approximately 15% of western populations. Cardiovascular disease and arrhythmia are extremely common in this group with significant morbidity overlap. Whilst treatment of OSA with continuous positive airways pressure (CPAP) appears to reduce hypertension, bradycardia and recurrence of atrial fibrillation (AF), large randomised control trials and meta-analyses do not demonstrate a significant reduction of incident tachyarrhythmias such as atrial fibrillation or sudden cardiac death. Some smaller studies suggest that AF may have up to 20% incidence. Analysis of these studies suggest that there may be significant heterogeneity in both CPAP usage and OSA phenotype, confounding the results. Furthermore, standard arrhythmia detection often underestimates paroxysmal arrhythmias. This on-going trial investigates a treated OSA population using CPAP monitoring and implantable loop recorders (ILR). Purpose This study aims to identify the incidence of arrhythmia in a treated OSA population with comprehensive arrhythmia monitoring and CPAP usage. It also explores the mechanisms linking OSA and arrhythmia such as heart rate variability and turbulence and cardiac biomarkers in order to identify at risk sub populations. Methods Continuous moderate-to-severe OSA patients were recruited from a major UK sleep centre after ECG and medical history confirmed the absence of arrhythmia. Each patient was then randomised to receive either standard-care or standard-care with an ILR with 24-hour heart rate variability/turbulence measurements, echocardiography (where possible) and cardiac biomarkers at baseline and 12 months. All patients had remote CPAP usage monitoring (where possible). The trial ended at 36 months after enrolment. Results 200 patients were recruited to the trial. Current mean average follow-up is 28 months in this on-going trial. Mean age and apnoea hypopnea index at enrolment was 53 years and 43.8 respectively. To date we have diagnosed atrial fibrillation in 15% of the ILR group compared to 2% in the standard care group. Other arrhythmias detected in the ILR group include two with supraventricular tachycardia and 2 with significant pauses but not requiring further treatment. Final analysis of arrhythmia incidence with CPAP usage and heart rate variability/turbulence, and cardiac biomarkers is ongoing with final results due by the time of final submission. Conclusion Arrhythmias, particularly AF, are highly incident in OSA despite CPAP treatment. This study may determine if heterogenous CPAP usage confounds the above observation and whether there may be predictors of arrhythmia that may indicate a need for arrhythmia screening in the OSA population.

Pulmonary Arterial Hypertension and TGF-β Superfamily Signaling: Focus on Sotatercept.

Pulmonary arterial hypertension (PAH) is a rare and progressive disease that continues to remain highly morbid despite multiple advances in medical therapies. There remains a persistent and desperate need to identify novel methods of treating and, ideally, reversing the pathologic vasculopathy that results in PAH development and progression. Sotatercept is a first-in-class fusion protein that is believed to primarily inhibit activin signaling resulting in decreased cell proliferation and differentiation, though the exact mechanism remains uncertain. Here, we review the currently available PAH therapies, data highlighting the importance of transforming growth factor-β (TGF-β) superfamily signaling in the development of PAH, and the published and on-going clinical trials evaluating sotatercept in the treatment of PAH. We will also discuss preclinical data supporting the potential use of the fusion protein KER-012 in the inhibition of aberrant TGF-β superfamily signaling to ameliorate the obstructive vasculopathy of PAH.

The impact of heterogeneity on the analysis of platform trials with normally distributed outcomes

BackgroundA platform trial approach allows adding arms to on-going trials to speed up intervention discovery programs. A control arm remains open for recruitment in a platform trial while intervention arms may be added after the onset of the study and could be terminated early for efficacy and/or futility when early stopping is allowed. The topic of utilising non-concurrent control data in the analysis of platform trials has been explored and discussed extensively. A less familiar issue is the presence of heterogeneity, which may exist for example due to modification of enrolment criteria and recruitment strategy.MethodWe conduct a simulation study to explore the impact of heterogeneity on the analysis of a two-stage platform trial design. We consider heterogeneity in treatment effects and heteroscedasticity in outcome data across stages for a normally distributed endpoint. We examine the performance of some hypothesis testing procedures and modelling strategies. The use of non-concurrent control data is also considered accordingly. Alongside standard regression analysis, we examine the performance of a novel method that was known as the pairwise trials analysis. It is similar to a network meta-analysis approach but adjusts for treatment comparisons instead of individual studies using fixed effects.ResultsSeveral testing strategies with concurrent control data seem to control the type I error rate at the required level when there is heteroscedasticity in outcome data across stages and/or a random cohort effect. The main parameter of treatment effects in some analysis models correspond to overall treatment effects weighted by stage wise sample sizes; while others correspond to the effect observed within a single stage. The characteristics of the estimates are not affected significantly by the presence of a random cohort effect and/ or heteroscedasticity.ConclusionIn view of heterogeneity in treatment effect across stages, the specification of null hypotheses in platform trials may need to be more subtle. We suggest employing testing procedure of adaptive design as opposed to testing the statistics from regression models; comparing the estimates from the pairwise trials analysis method and the regression model with interaction terms may indicate if heterogeneity is negligible.

Effect of Red Blood Cell Transfusion on Central Venous-to-Arterial Carbon Dioxide Difference in Anemic Surgical Patients – A Pilot Study

Background: Biochemical markers for monitoring adequacy of cardiac output and tissue perfusion such as blood lactate and central venous oxygen saturation (ScvO2) are meanwhile well established in clinical routine. In addition, in recent years, the central venous-to-arterial carbon dioxide difference (dCO2) has been evaluated as a further marker, and studies meanwhile have demonstrated the validity of an increased dCO2 to identify capillary perfusion mismatches. However, results from animal studies suggest that dCO2 may be influenced by altered hemoglobin values during severe bleeding. It was the aim of our study to evaluate if dCO2 changes upon Red Blood Cell (RBC) transfusion in humans. Methods: Patients of the ongoing LIBERAL trial were prospectively evaluated. Participants were aged ≥70 years and scheduled for elective intermediate or high risk orthopedic or trauma surgery with the clinical need for invasive blood pressure monitoring and central venous catheterization. During surgery, drop of hemoglobin triggered administration of one single RBC unit, together with arterial and central venous blood analysis immediately before as well as after transfusion. Results: In total, 46 patients were analyzed. Baseline median hemoglobin before RBC transfusion was 8.35 (7.48–8.73)g/dl, while dCO2 was 6.2 (3.4–9.6)mmHg. According to Spearman correlation, there was a linear association between pre-transfusion dCO2 and ScvO2. Transfusion of one RBC unit resulted in a significant increase of median hemoglobin by 1.2 (0.7–1.63)g/dl (p<0.0001), and hemoglobin increase was more pronounced when pre-transfusion hemoglobin was low, as evidenced by a significant negative association between both parameters (r=-0.61, p <0.0001). Neither lactate nor ScvO2 nor dCO2 were significantly influenced by transfusion. When the whole cohort was divided according to pre-transfusion dCO2 levels using a cut-off value of 6 mmHg, median dCO2 decreased significantly more pronounced following RBC transfusion when pre-transfusion values were high (>6 mmHg), compared to those patients with a pre-transfusion dCO2 below 6 mmHg. Conclusions: The results of our study suggest that crude dCO2 is not influenced by moderate hemoglobin increases in orthopedic and trauma surgery patients. However, including dCO2 into the decision whether to administer RBC or not may be an interesting reasonable approach for further investigations on the way towards more individualized transfusion regimens.

#1437 Renal expression pattern of the relaxin receptor, RXFP1, and effects of the RXFP1 agonist, AZD5462, on renin in non-human primates and humans

Abstract Background and Aims RXFP1 is a G protein-coupled receptor (GPCR) for the pregnancy hormone, relaxin. While preclinical studies, performed primarily in rodent, describe beneficial effects of this pleiotropic peptide across several organ systems, there has been a disappointing lack of success in translating these observations into clinical benefit. To provide a potential pharmacological explanation accounting for this translational gap, the aim of this study was thus to thoroughly evaluate RXFP1 expression across species and tissues as well as to evaluate the renal-intrinsic effects of the RXFP1 agonist, AZD5462. Method Unbiased bioinformatic analysis of several gene expression databases was used as a first approach to compare RXFP1 tissue-level expression between rodent and human. Experimental validation was subsequently performed using scRNAseq, RNAscope and immunohistochemistry on mouse, rat, non-human primate (NHP) and human kidney. The putative renal target engagement effects of RXFP1 agonism were assessed by determining the acute and chronic effects of the RXFP1-selective small molecule agonist, AZD5462, on plasma renin concentrations in both NHPs and in a Phase 1 randomized, single-blind, placebo-controlled study in healthy humans. Results RXFP1 was identified as one of the most highly expressed GPCRs in human and NHP kidney glomeruli. Specifically, by multiple assays, we identified glomerular endothelial cells as the principal cell type expressing RXFP1. This observation is in stark contrast to mouse and rat kidney, where RXFP1 was not readily detected. AZD5462 administered orally to NHPs and healthy human participants elicited an early and sustained dose-dependent increase in plasma renin concentration, and in humans an additional decline in serum creatinine. Conclusion Human RXFP1 kidney glomerular expression is conserved with NHPs but not rodent, thus highlighting the translational and pharmacological challenges in studying RXFP1/relaxin biology across species. The concordant ability of AZD5462 to induce elevations in renin and reduction in serum creatinine, together with relaxin's reported renal-hemodynamic activity in humans, may underlie a previously unappreciated renal-intrinsic RXFP1 target engagement mechanism driving its hemodynamic and renal effects. The potential therapeutic benefits of RXFP1 agonism are the subject of on-going clinical trials in heart failure patients.

#1647 Clinical insights into incremental hemodialysis: a retrospective analysis of patient persistence and outcomes

Abstract Background and Aims Incremental haemodialysis has been proposed as an alternative to standard thrice-weekly haemodialysis for incident patients with significant residual kidney function. Definition is not unique, but it is mostly intended as twice weekly dialysis. Its diffusion is not known since there are no public registers in Europe, but it is adopted in some dialysis facilities, while in others is not, with geographical differences. In our centre incremental haemodialysis in adopted for some patients, based on the clinical judgement, without a strict protocol. We retrospectively analysed clinical outcomes of the incident patients of the last 36 months, to understand which patients may benefit more from this approach, how long it is viable and the clinical outcomes. Method Retrospective observational analysis of incident patients of the last 36 months, without serious rapidly evolving disease. Focus was on persistence in twice-weekly dialysis, nutritional parameters, residual kidney function, hospital admissions and economic considerations. 36 patients started haemodialysis with a 2-times per week schedule while 13 with full dose dialysis. At baseline, there were no significant differences on age, sex, serum albumin or vascular access. 5 patients in full dose group were anuric for bilateral nephrectomy or rapidly progressive kidney disease, while all patients in incremental group had significant residual kidney function (average creatinine clearance: 7.1 ml/min). Results During the follow up period, 19/36 patients’ weekly dialysis sessions were incremented to three after a median time of 280 days, and 17/36 were still on 2-dialysis with a median follow-up time of 228 days. The reason for transition to three dialysis per week was residual kidney function loss except for a case of pericarditis. Persistence in incremental dialysis was >80% at 6 months and 44% at 1 year (Fig. 1a). We observed a significantly reduced persistence in patients with low ultrafiltration at 2nd month of dialysis (<1.7% of weight per session – 1 kg for a 60 kg patient-) and a reduced persistence with pre-dialysis systolic blood pressure <150 mmHg at 2nd month (Fig. 1b-c). Persistence was not different in more frail patients (elderly, dialyzed with a central venous line or with lower baseline albumin). Serum albumin increase was higher in patients in incremental haemodialysis at 6 months, with a borderline statistically significant difference, and similar at 1 year (Fig. 2a-b). The average weight was stable in both groups (Fig. 2). Hospital admissions were lower in the incremental group, and number of days of hospitalization per 1000 patients’ days were lower (24 vs 41 days). Thanks to the incremental approach, about 1600 dialysis sessions were avoided for the patients included in the analysis, with significant reduction of economic impact for the public healthcare and the possibility to treat more patients. Data was insufficient to make conclusions on kidney function preservation. Conclusion Incremental approach is valid in our experience. These data give useful information on how long we can expect patients to persist in 2-weekly dialysis and on which patients might benefit more and longer of this approach. The patients with better volume control, which reflect in adequate blood pressure control and low ultrafiltration rate, show a significantly longer persistence in incremental dialysis. The approach is valid also for frail patients. We also found better albumin and lower hospital admission rates that could be related with a reduced health-care exposition and better overall patients’ well-being, with adequate uremic symptoms control. The reduction on the hospital admissions has been already observed, while the albumin better rise is a new finding and should be confirmed in a randomized or at least larger study. Waiting for the results of the on-going randomized clinical trials, incremental haemodialysis might be the new standard-of-care for a subset incident haemodialysis patients.

Delivery Strategies, Structural Modification, and Pharmacological Mechanisms of Honokiol: A Comprehensive Review.

Honokiol (HK) is a traditional Chinese herbal bioactive compound that originates mainly from the Magnolia species, traditionally used to treat anxiety and stroke, as well as alleviation of flu symptoms. This natural product and its derivatives displayed diverse biological activities, including anticancer, antioxidant, anti-inflammatory, neuroprotective, and antimicrobial activities. However, its poor bioavailability and pharmacological activity require primary consideration in the development of HK-based drugs. Recent innovative HK formulations based on the nanotechnology approach allowed for improvement in both bioavailability and therapeutic efficacy. Chemical derivation and drug combination are also effective strategies to ameliorate the drawbacks of HK. In recent years, studies on HK derivatives and compositions have made great progress in the treatment of cancer, inflammation, bacterial infection, cardiovascular, and cerebrovascular diseases, demonstrating better activity than HK. The objective of this review is an examination of the recent developments in the field of pharmacological activity of HK and its drug-related issues, and approaches to improve its physicochemical and biological properties, including solubility, stability, and bioavailability. Recent patents and the ongoing clinical trials in HK are also summarized.

Abstract PO5-18-06: On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit the the in vitro and in vivo action of human PGRN/GP88 has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. The presentation will provide an update on the number of patients enrolled in this on-going phase 1A trial. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS. Citation Format: Katherine Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine Scilla, Nancy Tait, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-06.

New Insights into the Relationship between Nutrition and Neuroinflammation in Alzheimer's Disease: Preventive and Therapeutic Perspectives.

Neurodegenerative diseases are progressive brain disorders characterized by inexorable synaptic dysfunction and neuronal loss. Since the most consistent risk factor for developing neurodegenerative diseases is aging, the prevalence of these disorders is intended to increase with increasing life expectancy. Alzheimer's disease is the most common cause of neurodegenerative dementia, representing a significant medical, social, and economic burden worldwide. Despite growing research to reach an early diagnosis and optimal patient management, no disease-modifying therapies are currently available. Chronic neuroinflammation has been recognized as a crucial player in sustaining neurodegenerative processes, along with pathological deposition of misfolded proteins, including amyloid-β and tau protein. Modulating neuroinflammatory responses may be a promising therapeutic strategy in future clinical trials. Among factors that are able to regulate neuroinflammatory mechanisms, diet, and nutrients represent easily accessible and modifiable lifestyle components. Mediterranean diet and several nutrients, including polyphenols, vitamins, and omega-3 polyunsaturated fatty acids, can exert antioxidant and anti-inflammatory properties, impacting clinical manifestations, cognitive decline, and dementia. This review aims to provide an updated overview of the relationship between neuroinflammation, nutrition, gut microbiota, and neurodegeneration. We summarize the major studies exploring the effects of diet regimes on cognitive decline, primarily focusing on Alzheimer's disease dementia and the impact of these results on the design of ongoing clinical trials.

Dopaminergic Cell Replacement for Parkinson's Disease: Addressing the Intracranial Delivery Hurdle.

Parkinson's disease (PD) is an increasingly prevalent neurological disorder, affecting more than 8.5 million individuals worldwide. α-Synucleinopathy in PD is considered to cause dopaminergic neuronal loss in the substantia nigra, resulting in characteristic motor dysfunction that is the target for current medical and surgical therapies. Standard treatment for PD has remained unchanged for several decades and does not alter disease progression. Furthermore, symptomatic therapies for PD are limited by issues surrounding long-term efficacy and side effects. Cell replacement therapy (CRT) presents an alternative approach that has the potential to restore striatal dopaminergic input and ameliorate debilitating motor symptoms in PD. Despite promising pre-clinical data, CRT has demonstrated mixed success clinically. Recent advances in graft biology have renewed interest in the field, resulting in several worldwide ongoing clinical trials. However, factors surrounding the effective neurosurgical delivery of cell grafts have remained under-studied, despite their significant potential to influence therapeutic outcomes. Here, we focus on the key neurosurgical factors to consider for the clinical translation of CRT. We review the instruments that have been used for cell graft delivery, highlighting current features and limitations, while discussing how future devices could address these challenges. Finally, we review other novel developments that may enhance graft accessibility, delivery, and efficacy. Challenges surrounding neurosurgical delivery may critically contribute to the success of CRT, so it is crucial that we address these issues to ensure that CRT does not falter at the final hurdle.

Improving Clinical Trials of Antioxidants in Alzheimer's Disease.

Maintaining diversity in drug development in research into Alzheimer's disease (AD) is necessary to avoid over-reliance on targeting AD neuropathology. Treatments that reduce or prevent the generation of oxidative stress, frequently cited for its causal role in the aging process and AD, could be useful in at-risk populations or diagnosed AD patients. However, in this review, it is argued that clinical research into antioxidants in AD could provide more useful feedback as to the therapeutic value of the oxidative stress theory of AD. Improving comparability between randomized controlled trials (RCTs) is vital from a waste-reduction and priority-setting point of view for AD clinical research. For as well as attempting to improve meaningful outcomes for patients, RCTs of antioxidants in AD should strive to maximize the extraction of clinically useful information and actionable feedback from trial outcomes. Solutions to maximize information flow from RCTs of antioxidants in AD are offered here in the form of checklist questions to improve ongoing and future trials centered around the following dimensions: adhesion to reporting guidelines like CONSORT, biomarker enrichment, simple tests of treatment, and innovative trial design.

Effectiveness of erector spinae plane block for rib fracture analgesia: a systematic review protocol.

This systematic review will investigate the effectiveness of the ultrasound-guided erector spinae plane block as an analgesic technique for patients with rib fractures compared with all other standard management techniques. Comparisons will be made with both nerve blocks (neuraxial techniques and peripheral nerve blocks) and systemic treatment (with patient-controlled analgesia and/or per required need analgesia for breakthrough pain). Erector spinae plane block is a well-established rescue analgesia option for patients with rib fractures. The use of ultrasound-guided erector spinae plane block in clinical practice has been largely based on observational data, with recent randomized controlled trials examining it against several other options for analgesic management. This review will compare the erector spinae against all other management techniques used in practice for rib fractures to determine whether this is the most effective analgesic technique. The review will include all randomized controlled and pseudo-randomized controlled trials examining ultrasound-guided erector spinae plane block for the analgesic management of traumatic rib fractures. All other study designs will be excluded. MEDLINE (PubMed), Embase (Ovid), CINAHL (EBSCOhost), the Cochrane Central Register of Controlled Trials, the Australian and New Zealand Clinical Trials Registry (ANZCTR), ClinicalTrials.gov, and the ISRCTN registry will be searched to identify all relevant ongoing clinical trials. Study selection, critical appraisal, and data extraction will be performed by 2 independent reviewers. Data will be extracted into software for statistical analysis (including meta-analysis where possible). PROSPERO CRD42023414849.

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation.

Cancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.

Quantitative or qualitative biomolecular changes in blood serum composition induced by childhood obesity: A Fourier transform infrared examination

Childhood obesity (CO) negatively affects one in three children and stands as the fourth most common risk factor of health and well-being. Clarifying the molecular and structural modifications that transpire during the development of obesity is crucial for understanding its progression and devising effective therapies. The study was indeed conducted as part of an ongoing CO treatment trial, where data were collected from children diagnosed with CO before the initiation of non-drug treatment interventions. Our primary aim was to analyze the biochemical changes associated with childhood obesity, specifically focusing on concentrations of lipids, lipoproteins, insulin, and glucose. By comparing these parameters between the CO group (n = 60) and a control group of healthy children (n = 43), we sought to elucidate the metabolic differences present in individuals with CO. Our biochemical analyses unveiled lower LDL (low-density lipoproteins) levels and higher HDL (high-density lipoproteins), cholesterol, triglycerides, insulin, and glucose levels in CO individuals compared to controls. To scrutinize these changes in more detail, we employed Fourier transform infrared (FTIR) spectroscopy on the serum samples. Our results indicated elevated levels of lipids and proteins in the serum of CO, compared to controls. Additionally, we noted structural changes in the vibrations of glucose, β-sheet, and lipids in CO group. The FTIR technique, coupled with principal component analysis (PCA), demonstrated a marked differentiation between CO and controls, particularly in the FTIR region corresponding to amide and lipids. The Pearson test revealed a stronger correlation between biochemical data and FTIR spectra than between 2nd derivative FTIR spectra. Overall, our study provides valuable insights into the molecular and structural changes occurring in CO.

Exploring Molecular Genetic Alterations and RAF Fusions in Melanoma: A Belvarafenib Expanded Access Program in Patients with RAS/RAF-Mutant Melanoma.

Melanoma incidence is on the rise in East Asia, yet studies of the molecular landscape are lacking in this population. We examined patients with melanoma who underwent next-generation sequencing (NGS) at a single tertiary center in South Korea, focusing on patients harboring NRAS or RAF alterations who received belvarafenib, a pan-RAF dimer inhibitor, through the Expanded Access Program (EAP). Data were collected from 192 patients with melanoma who underwent NGS between November 2017 and May 2023. Variant call format data were obtained and annotated. Patients in the EAP received 450 mg twice daily doses of belvarafenib. Alterations in the RAS/RTK pathway were the most prevalent, with BRAF and NRAS alteration rates of 22.4% and 17.7%, respectively. NGS enabled additional detection of fusion mutations, including 6 BRAF and 1 RAF1 fusion. Sixteen patients with NRAS or RAF alterations received belvarafenib through the EAP, and disease control was observed in 50%, with 2 patients demonstrating remarkable responses. Our study highlights the value of NGS in detecting BRAF, NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib.

Evolution of European prostate cancer screening protocols and summary of ongoing trials.

Population-based organised repeated screening for prostate cancer has been found to reduce disease-specific mortality, but with substantial overdiagnosis leading to overtreatment. Although only very few countries have implemented a screening programme on a national level, individual prostate-specific antigen (PSA) testing is common. This opportunistic testing may have little favourable impact, while stressing the side-effects. The classic early detection protocols as were state-of-the-art in the 1990s applied a PSA and digital rectal examination threshold for sextant systematic prostate biopsy, with a fixed interval for re-testing, and limited indication for expectant management. In the three decades since these trials were started, different important improvements have become available in the cascade of screening, indication for biopsy, and treatment. The main developed aspects include: better identification of individuals at risk (using early/baseline PSA, family history, and/or genetic profile), individualised re-testing interval, optimised and individualised starting and stopping age, with gradual invitation at a fixed age rather than invitation of a wider range of age groups, risk stratification for biopsy (using PSA density, risk calculator, magnetic resonance imaging, serum and urine biomarkers, or combinations/sequences), targeted biopsy, transperineal biopsy approach, active surveillance for low-risk prostate cancer, and improved staging of disease. All these developments are suggested to decrease the side-effects of screening, while at least maintaining the advantages, but Level 1 evidence is lacking. The knowledge gained and new developments on early detection are being tested in different prospective screening trials throughout Europe. In addition, the European Union-funded PRostate cancer Awareness and Initiative for Screening in the European Union (PRAISE-U) project will compare and evaluate different screening pilots throughout Europe. Implementation and sustainability will also be addressed. Modern screening approaches may reduce the burden of the second most frequent cause of cancer-related death in European males, while minimising side-effects. Also, less efficacious opportunistic early detection may be indirectly reduced.

Treatment Options for Alopecia Areata in Children and Adolescents.

Alopecia areata (AA) lifetime incidence is around 2%, with many patients first experiencing symptoms during childhood. However, ritlecitinib is the only FDA-approved treatment for pediatric patients 12 years and older. This review outlines reported topical, injectable, and oral treatment options for pediatric patients with AA. Clinical studies were obtained via a PubMed search using the following search terms: alopecia areata, areata, universalis, or totalis and medication, therapy, treatment, drug, or management. Only studies with pediatric patients were included in this review. Commonly used therapies, including corticosteroids, methotrexate, and minoxidil, newer promising medications, such as Janus kinase inhibitors, and less frequently used topical and systemic treatments are included. A summary of the drug development pipeline and ongoing interventional clinical trials with pediatric patients is provided. Treatments demonstrate variable efficacy, and many patients require combination therapy for maximal response. More robust clinical data is needed for many of the medications reviewed in order to provide better care for these patients.

COVID-19, a self-limiting disease – A case report of a severe COVID-19 pneumonia patient with multiple comorbidities successfully treated without antivirals

COVID-19 pneumonia is a communicable disease with no definite therapy. Therapeutic recommendations are still evolving based on ongoing studies and clinical trials. Patients with comorbidities, such as obesity and diabetes, are at risk for developing more severe diseases with higher mortality rates. A number of antivirals, such as oseltamivir, favipiravir, and remdesivir, have been proposed as a treatment for COVID-19, especially in severe diseases. However, the World Health Organization (WHO) initially does not recommend any antiviral therapy.

Cardiac ECMO: changing role in times of Impella and ventricular assist devices?

Mortality in infarct-related as well as heart failure-associated cardiogenic shock remains high, reaching 40-50% depending on the etiology and severity of cardiogenic shock. Percutaneous active mechanical circulatory support devices including veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and microaxial left ventricular mechanical circulatory support devices are rapidly evolving in their use. However, evidence of VA-ECMO therapy has only recently emerged and showed no benefit for mortality, with an associated higher complication rate. Evidence for microaxial left ventricular mechanical circulatory support devices such as the Impella pump (Abiomed, Danvers/MA, USA) is limited. The current article aims to give an overview of the basics of VA-ECMO therapy and microaxial left ventricular mechanical circulatory support devices, the current evidence, ongoing trials, patient selection, and potential complications. This article is freely available.

Immunomodulatory Effects of Vitamin D and Zinc on Viral Infection.

Several nutrients are crucial in enhancing the immune system and preserving the structural integrity of bodily tissue barriers. Vitamin D (VD) and zinc (Zn) have received considerable interest due to their immunomodulatory properties and ability to enhance the body's immune defenses. Due to their antiviral, anti-inflammatory, antioxidative, and immunomodulatory properties, the two nutritional powerhouses VD and Zn are crucial for innate and adaptive immunity. As observed with COVID-19, deficiencies in these micronutrients impair immune responses, increasing susceptibility to viral infections and severe disease. Ensuring an adequate intake of VD and Zn emerges as a promising strategy for fortifying the immune system. Ongoing clinical trials are actively investigating their potential therapeutic advantages. Beyond the immediate context of the pandemic, these micronutrients offer valuable tools for enhancing immunity and overall well-being, especially in the face of future viral threats. This analysis emphasizes the enduring significance of VD and Zn as both treatment and preventive measures against potential viral challenges beyond the current health crisis. The overview delves into the immunomodulatory potential of VD and Zn in combating viral infections, with particular attention to their effects on animals. It provides a comprehensive summary of current research findings regarding their individual and synergistic impacts on immune function, underlining their potential in treating and preventing viral infections. Overall, this overview underscores the need for further research to understand how VD and Zn can modulate the immune response in combatting viral diseases in animals.