Efficacy of vinblastine in central nervous system Langerhans cell histiocytosis: a nationwide retrospective study

<p>Abstract</p> <p>Background</p> <p>Vinblastine (VBL) is the standard treatment for systemic Langerhans cell histiocytosis (LCH), but little is known about its efficacy in central nervous system (CNS) mass lesions.</p> <p>Methods</p> <p>A retrospective chart review was conducted. Twenty patients from the French LCH Study Group register met the inclusion criteria. In brief, they had CNS mass lesions, had been treated with VBL, and were evaluable for radiologic response.</p> <p>Results</p> <p>The median age at diagnosis of LCH was 11.5 years (range: 1-50). Intravenous VBL 6 mg/m²was given in a 6-week induction treatment, followed by a maintenance treatment. The median total duration was 12 months (range: 3-30). Eleven patients received steroids concomitantly. Fifteen patients achieved an objective response; five had a complete response (CR: 25%), ten had a partial response (PR: 50%), four had stable disease (SD: 20%) and one patient progressed (PD: 5%). Of interest, four out of the six patients who received VBL without concomitant steroids achieved an objective response. With a median follow-up of 6.8 years, the 5-year event-free and overall survival was 61% and 84%, respectively. VBL was well-tolerated and there were no patient withdrawals due to adverse events.</p> <p>Conclusion</p> <p>VBL, with or without steroids, could potentially be a useful therapeutic option in LCH with CNS mass lesions, especially for those with inoperable lesions or multiple lesions. Prospective clinical trials are warranted for the evaluation of VBL in this indication.</p

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Pain and neurophysiological characterization of small fiber involvement in peripheral neuropathies

L'objectif de notre travail était dans un premier temps d'étudier les liens entre l'altération des fibres nerveuses de petit diamètre et la présence de douleurs chez des patients ayant une neuropathie périphérique. Notre deuxième objectif était d'évaluer la pertinence de certaines techniques neurophysiologiques pour mettre en évidence l'atteinte de ces petites fibres nerveuses. Notre première étude réalisée sur une large cohorte de patients présentant divers types de neuropathie a montré, grâce à une étude quantifiée de la sensibilité, qu'il n'y avait pas de corrélation entre la perte ou perte de fonction des fibres nerveuses de petit diamètre et la présence de douleurs. Ceci a été confirmé par notre deuxième étude portant sur une population plus homogène de patients ayant une neuropathie amyloïde familiale et étudiés avec une batterie neurophysiologique plus large. Ainsi, les douleurs neuropathiques des patients présentant une neuropathie périphérique sont probablement dues à la combinaison de facteurs d'hyperexcitabilité périphérique et de sensibilisation centrale et non directement liée à la perte en petites fibres. Il reste cependant pertinent de développer des techniques objectives d'exploration de ces petites fibres notamment dans un but de diagnostic clinique. Notre troisième étude a montré que certaines méthodes neurophysiologiques étaient particulièrement sensibles dans ce cadre en prenant pour exemple la détection d'anomalies précoces d'atteinte des petites fibres au cours de la neuropathie amyloïde familiale. Une batterie de tests comprenant l'enregistrement des potentiels évoqués laser, la mesure du seuil de détection du chaud et de la conductance cutanée, s'est avérée être la combinaison la plus pertinente, comme l'a montré notre quatrième étude sur une grande cohorte de patients susceptibles de présenter une neuropathie des petites fibres.The aim of our work was initially to study the relationship between alterations in small diameter nerve fibers and the presence of pain in patients with peripheral neuropathy. Our second objective was to assess the relevance of some neurophysiological tests to characterize these alterations in small nerve fibers. Our first study of a large cohort of patients with various types of neuropathy showed, using quantitative sensory testing, that there was no correlation between the loss or loss of function of small nerve fibers and the presence of pain. This was confirmed by our second study focused on a more homogeneous population of patients with familial amyloid neuropathy and studied with a larger neurophysiological battery. Thus, neuropathic pain in patients with peripheral neuropathy is probably due to a combination of factors of peripheral hyperexcitability and central sensitization and not directly related to the loss of small nerve fibers. However, it remains relevant to develop techniques of objective investigation of these small nerve fibers for a purpose of clinical diagnosis. Our third study showed that some neurophysiological methods were particularly sensitive in this context, taking the example of the detection of early alteration of small nerve fibers in familial amyloid neuropathy. A battery of tests, including laser evoked potential recording, warm detection threshold and electrochemical skin conductance measurement, proved to be the most appropriate combination for this diagnostic purpose, as shown by our fourth study on a large cohort of patients likely to have a small fiber neuropathy

Pain and neurophysiological characterization of small fiber involvement in peripheral neuropathies

L'objectif de notre travail était dans un premier temps d'étudier les liens entre l'altération des fibres nerveuses de petit diamètre et la présence de douleurs chez des patients ayant une neuropathie périphérique. Notre deuxième objectif était d'évaluer la pertinence de certaines techniques neurophysiologiques pour mettre en évidence l'atteinte de ces petites fibres nerveuses. Notre première étude réalisée sur une large cohorte de patients présentant divers types de neuropathie a montré, grâce à une étude quantifiée de la sensibilité, qu'il n'y avait pas de corrélation entre la perte ou perte de fonction des fibres nerveuses de petit diamètre et la présence de douleurs. Ceci a été confirmé par notre deuxième étude portant sur une population plus homogène de patients ayant une neuropathie amyloïde familiale et étudiés avec une batterie neurophysiologique plus large. Ainsi, les douleurs neuropathiques des patients présentant une neuropathie périphérique sont probablement dues à la combinaison de facteurs d'hyperexcitabilité périphérique et de sensibilisation centrale et non directement liée à la perte en petites fibres. Il reste cependant pertinent de développer des techniques objectives d'exploration de ces petites fibres notamment dans un but de diagnostic clinique. Notre troisième étude a montré que certaines méthodes neurophysiologiques étaient particulièrement sensibles dans ce cadre en prenant pour exemple la détection d'anomalies précoces d'atteinte des petites fibres au cours de la neuropathie amyloïde familiale. Une batterie de tests comprenant l'enregistrement des potentiels évoqués laser, la mesure du seuil de détection du chaud et de la conductance cutanée, s'est avérée être la combinaison la plus pertinente, comme l'a montré notre quatrième étude sur une grande cohorte de patients susceptibles de présenter une neuropathie des petites fibres.The aim of our work was initially to study the relationship between alterations in small diameter nerve fibers and the presence of pain in patients with peripheral neuropathy. Our second objective was to assess the relevance of some neurophysiological tests to characterize these alterations in small nerve fibers. Our first study of a large cohort of patients with various types of neuropathy showed, using quantitative sensory testing, that there was no correlation between the loss or loss of function of small nerve fibers and the presence of pain. This was confirmed by our second study focused on a more homogeneous population of patients with familial amyloid neuropathy and studied with a larger neurophysiological battery. Thus, neuropathic pain in patients with peripheral neuropathy is probably due to a combination of factors of peripheral hyperexcitability and central sensitization and not directly related to the loss of small nerve fibers. However, it remains relevant to develop techniques of objective investigation of these small nerve fibers for a purpose of clinical diagnosis. Our third study showed that some neurophysiological methods were particularly sensitive in this context, taking the example of the detection of early alteration of small nerve fibers in familial amyloid neuropathy. A battery of tests, including laser evoked potential recording, warm detection threshold and electrochemical skin conductance measurement, proved to be the most appropriate combination for this diagnostic purpose, as shown by our fourth study on a large cohort of patients likely to have a small fiber neuropathy