Skin fragility with mottled pigmentation by transport protein Slac2-b anomaly

Epidermolysis bullosa (EB) caused by EXPH5 mutations, is an recently identified and extremely rare subtype. We describe a novel homozygous nonsense mutation in the EXPH5 gene in a 15-year-old woman. EXPH5 encodes the vesicle transport protein &amp;#39;synaptotagmin-like homologue lacking C2 domains B&amp;#39; (Slac2-b, also known as exophilin- 5) and is involved in epidermolysis bullosa simplex with cleavage in the basal cell layer. The phenotype of this case was characterized by mottled pigmentation (MP), which developed when the patient was ten years old. By means of electron microscopy image analysis, we propose a hypothesis for the pigmentary changes associated with Slac-2b anomaly. This patient that we have described is one of the oldest with EXPH5 mutations reported up to now, which possibly allowed for the &amp;#39;lateonset&amp;#39; MP.</p

Single-arm trials supporting the approval of anticancer medicinal products in the European Union: contextualization of trial results and observed clinical benefit

Background: Single-arm trials (SATs) can sometimes be used to support marketing authorization of anticancer medicinal products in the European Union. The level and durability of antitumor activity of the product as well as context are important aspects to determine the relevance of trial results. The aim of this study is to provide details on the contextualization of trial results and to evaluate the magnitude of benefit of medicinal products approved based on SATs. Materials and methods: We focused on anticancer medicinal products for solid tumors approved on the basis of SAT results (2012-2021). Data were retrieved from European public assessment reports and/or published literature. The benefit of these medicinal products was evaluated via the European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). Results: Eighteen medicinal products were approved based on 21 SATs—few medicinal products were supported by >1 SAT. For the majority of clinical trials, a clinically relevant treatment effect was (pre)specified (71.4%) and most often an accompanying sample size calculation was provided. For 10 studies, each testing a different medicinal product, a justification for the threshold for a clinically relevant treatment effect could be identified. At least 12 out of 18 applications included information to facilitate the contextualization of trial results, including six supportive studies. Of the pivotal SATs analyzed (n = 21), three were assigned an ESMO-MCBS score of 4, which corresponds to ‘substantial’ benefit. Conclusions: The clinical relevance of the treatment effects shown by medicinal products for solid tumors tested in SATs is dependent on the effect size and context. To better facilitate regulatory decision making, prespecifying and motivating a clinically relevant effect and aligning the sample size to that effect is important. External controls may facilitate in the contextualization process, but the associated limitations must be addressed

Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer

Background: This study aimed to provide insights into the real-world use of palbociclib, dose reductions, and drug effectiveness in (older) patients with advanced breast cancer (BC). Patients and methods: Patients with advanced BC treated with palbociclib from 2017 to 2020 were included. The Kaplan-Meier method was used to calculate time to next treatment (TTNT) and overall survival (OS) for patients with or without dose reductions. These clinical outcomes were also compared in subgroup analyses for older patients (≥70 years) and younger patients (<70 years) and for patients discontinuing palbociclib early (<4 administrations). Results: A total of 598 patients with advanced BC were included, with a median age of 64 years. Palbociclib dose reductions occurred in 33% of all patients. Early discontinuation of palbociclib without dose reductions occurred in 23% of the patients. Patients who required a palbociclib dose reduction were older (median age 67 years vs. 63 years). Patients with dose reductions had a significantly higher TTNT of 16.9 vs. 11.4 months (p < 0.001) and median OS of 29.7 vs. 21.9 months (p = 0.003) compared to patients without dose reductions. The TTNT in older patients was significantly longer (16.9 vs. 11.6 months, p = 0.013) than younger patients, but OS was similar (20.7 vs. 26.7 months, p = 0.051). Conclusion: Palbociclib dose reductions occurred in real-world practice similarly to the PALOMA-3 trial. Patients with dose reductions had no poorer outcomes compared to patients not requiring a dose reduction. Older patients treated with palbociclib had more frequent dose reductions, but this did not appear to affect OS

Therapeutic prospects of exon skipping for epidermolysis bullosa

Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes

Effectiveness of the blended-care lifestyle intervention 'PerfectFit': A cluster randomised trial in employees at risk for cardiovascular diseases

Background: Web-based lifestyle interventions at the workplace have the potential to promote health and work productivity. However, the sustainability of effects is often small, which could be enhanced by adding face-to-face contacts, so-called 'blended care'. Therefore, this study evaluates the effects of a blended workplace health promotion intervention on health and work outcomes among employees with increased cardiovascular risk. Methods: In this multicentre cluster-randomised controlled trial (PerfectFit), 491 workers in 18 work units from military, police, and a hospital with increased cardiovascular risk were randomised into two intervention groups. The limited intervention (n = 213; 9 clusters) consisted of a web-based Health Risk Assessment with advice. In the extensive intervention (n = 271; 8 clusters), coaching sessions by occupational health physicians using motivational interviewing were added. One cluster dropped out after randomisation but before any inclusion o

Huidfragiliteit met vlekkige pigmentatie door transporteiwit Slac2-b-afwijkingen

Epidermolysis bullosa (EB) caused by EXPH5 mutations, is an recently identified and extremely rare subtype. We describe a novel homozygous nonsense mutation in the EXPH5 gene in a 15-year-old woman. EXPH5 encodes the vesicle transport protein &#39;synaptotagmin-like homologue lacking C2 domains B&#39; (Slac2-b, also known as exophilin- 5) and is involved in epidermolysis bullosa simplex with cleavage in the basal cell layer. The phenotype of this case was characterized by mottled pigmentation (MP), which developed when the patient was ten years old. By means of electron microscopy image analysis, we propose a hypothesis for the pigmentary changes associated with Slac-2b anomaly. This patient that we have described is one of the oldest with EXPH5 mutations reported up to now, which possibly allowed for the &#39;lateonset&#39; MP

Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer

Background: This study aimed to provide insights into the real-world use of palbociclib, dose reductions, and drug effectiveness in (older) patients with advanced breast cancer (BC). Patients and methods: Patients with advanced BC treated with palbociclib from 2017 to 2020 were included. The Kaplan-Meier method was used to calculate time to next treatment (TTNT) and overall survival (OS) for patients with or without dose reductions. These clinical outcomes were also compared in subgroup analyses for older patients (≥70 years) and younger patients (<70 years) and for patients discontinuing palbociclib early (<4 administrations). Results: A total of 598 patients with advanced BC were included, with a median age of 64 years. Palbociclib dose reductions occurred in 33% of all patients. Early discontinuation of palbociclib without dose reductions occurred in 23% of the patients. Patients who required a palbociclib dose reduction were older (median age 67 years vs. 63 years). Patients with dose reductions had a significantly higher TTNT of 16.9 vs. 11.4 months (p < 0.001) and median OS of 29.7 vs. 21.9 months (p = 0.003) compared to patients without dose reductions. The TTNT in older patients was significantly longer (16.9 vs. 11.6 months, p = 0.013) than younger patients, but OS was similar (20.7 vs. 26.7 months, p = 0.051). Conclusion: Palbociclib dose reductions occurred in real-world practice similarly to the PALOMA-3 trial. Patients with dose reductions had no poorer outcomes compared to patients not requiring a dose reduction. Older patients treated with palbociclib had more frequent dose reductions, but this did not appear to affect OS