Optimizing targeted therapy for metastatic melanoma: a combination of encorafenib and trametinib beyond standard protocols

Only three combinations of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) targeted therapies are marketed for the treatment of BRAF-mutated metastatic melanoma. The use of these combinations can be limited by the occurrence of severe adverse events (AEs) that may lead to discontinuation of treatment or contraindication. We present the case of a 45-year-old male diagnosed with stage III melanoma of the left thigh, as classified by the 8th edition of the American Joint Committee on Cancer (AJCC), exhibiting rapid recurrence of inguinal lymph node metastasis following complete surgical resection. Molecular biology revealed a mutated BRAFV600E status, indicating treatment associated with BRAFi/MEKi. First-line treatments were introduced successively with dabrafenib-trametinib and then encorafenib-binimetinib, both stopped for fever and severe digestive AEs. After the failure of a third line with an immune checkpoint inhibitor, a new rechallenge of targeted therapy (TT) was introduced with encorafenib-trametinib to increase tolerance. This unusual and innovative combination allowed a spectacular tolerance and complete oncological response for 39 months after the failure of the usual combinations. This is the first case in the literature to show the potential efficacy of a non-standard combination of encorafenib and trametinib, which are commercialized in two different market combinations. A pharmacological evidence-based analysis was performed to understand these good clinical results

The VASCERN-VASCA working group diagnostic and management pathways for lymphatic malformations

Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds.The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members.The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.Peer reviewe

The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations.

UNLABELLED To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations. METHODS VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings. RESULTS The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies. CONCLUSION The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/)

The VASCERN-VASCA working group diagnostic and management pathways for severe and/or rare infantile hemangiomas

The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular dis-eases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus state -ments on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-facePeer reviewe

Establishment of D-dimer level as the first biomarker for differential diagnosis of vascular anomalies and evaluation of the efficacy and the safety of a new sclerosing agent

Les anomalies vasculaires sont des maladies rares, prises en charge au sein d’équipes pluridisciplinaires. Les malformations veineuses sont des anomalies vasculaires à bas débit qui représentent la majorité des consultations des centres multidisciplinaires. Au cours de cette thèse nous avons essayé d’avancer dans la connaissance clinique, biologique et moléculaire de ces malformations vasculaires. Le but final est d’améliorer le diagnostic et le traitement des malformations veineuses. Les malformations veineuses sont des lésions de la peau et du tissu cellulaire sous-cutané qui s’étendent souvent aux muscles, tendons, nerfs, os, articulations et muqueuses. Elles sont divisées en malformations veineuses cutanéo-muqueuses héréditaires (VMCM), malformations veineuses sporadiques uni ou focales (VM), et malformations glomuveineuses (GVM). Elles peuvent aussi être associées à d’autres anomalies vasculaires (malformation capillaro-veineuse, malformation capillaro-lymphatico-veineuse), ou faire partie de syndromes (syndrome de Klipper-Trénaumay ou de Maffucci). Lorsque ce travail à débuté, l’éthiopathogénie des VMCM et des GVM était déjà élucidée. Deux mutations génétiques activant les gènes TIE2 avaient été identifiées dans 4 familles VMCM et des mutations génétiques avec perte d’activation du gène glomulin étaient associées aux GVM. Ces mutations germinales n’expliquaient pas pourquoi ces anomalies vasculaires étaient essentiellement rencontrées dans la peau et le tissu sous-cutané, ni pourquoi leur nombre et leur taille étaient variables d’un patient à l’autre. Consécutivement, une autre étude a découvert au sein d’une GVM une mutation somatique. Cette double atteinte suggérait que les GVM sont la conséquence d’une perte complète de fonction du locus et donc une hérédité paradominante. A partir de cette découverte, une étude récente à démontré que des mutations somatiques sont la cause de 50% des malformations veineuses sporadiques. Environ 90% d’entre elles avaient la même mutation qui n’a jamais été observée comme mutation germinale dans les VMCM, suggérant le caractère délétaire de cette mutation qui deviendrait létale lorsqu’elle est héritée. Ces résultats sont une avancée majeure dans la découverte des mécanismes biologiques qui génèrent les malformations veineuses, les plus fréquentes parmi les malformations vasculaires. Parallèlement aux études génétiques, nous avons réalisé des études cliniques avec les patients des 2 centres multidisciplinaires de Caen et de Bruxelles. Comme nous avions malheureusement en quelques hémorragies sévères au cours d’interventions chirurgicales de malades présentant des malformations veineuses, nous avons étudié les désordres de la coagulation pouvant expliquer ces complications. Nous avons démontré que l’atteinte musculaire, la grande taille et la présence de phlébolithes palpables étaient associés de façon significative avec une Coagulation Intravasculaire Localisée caractérisée par une élévation du taux des D-dimères plasmatiques. Nous avons proposé un traitement par Héparine de Bas Poids Moléculaire (HBPM) pour prévenir les hémorragies pendant les interventions chirurgicales et pour soulager la douleur associée à la thrombose intralésionnelle. Comme cette activation de la coagulation est probablement liée à une stagnation sanguine dans les vaisseaux déformés, nous avons vérifié si l’élévation du taux des D-dimères était spécifique d’une malformation veineuse. Nous avons démontré que le dosage des D-dimères est utile pour diagnostiquer une atteinte veineuse au sein d’une anomalie vasculaire, avec une spécificité de 96.5%. Les maladies présentant des malformations glomuveineuses, lymphatiques, capillaires, et à haut débit ainsi que les syndromes de Maffucci avaient toujours un taux de D-dimères normal. De plus, les malformations combinées haut et bas débit pouvaient être mieux séparés (syndrome de Klippel-Trénaumay versus syndrome de Parkes Weber) et ce dosage permettait aussi de différentier les GVM des autres malformations veineuses multifocales. Ce marqueur biologique simple et peu coûteux doit donc être utilisé en pratique quotidienne lors de l’évaluation d’un malade présentant une anomalie vasculaire. La sclérothérapie est le traitement de choix pour la plupart des VM car l’exérèse chirurgicale complète de la lésion est rarement réalisable. L’alcool absolu est l’agent le plus efficace mais avec des complications locales et générales qui peuvent être sévères. Nous avons développé un nouvel alcool gélifié pour le traitement des malformations veineuses. Nous avons démontré que l’alcool éthylcellulose radioopaque est efficace, même avec des petites doses d’alcool, car le contact avec les cellules vasculaires endothéliales est plus prolongé. Cela augmente la sécurité de cet agent. Nous n’avons jamais observé de complications systématiques et toutes les complications locales étaient mineures, situées sur le visage, les mains ou les pieds. Ainsi donc, la sclérothérapie devient le traitement de référence pour les malformations veineuses, et les indications peuvent être élargies à des zones sensibles et dangereuses, en utilisant l’alcool-éthycellulose à des doses très faibles. (0.1 – 0.3cc). Ce travail commun a été très fructueux car il a permis d’inclure un grand nombre de malades dans des études prospectives mais aussi d’échanger nos différentes expériences dans les 2 centres multidisciplinaires. Le travail ca se produire afin de mieux diagnostiquer et prendre en charge les malformations combinées et syndromiques. Les modèles animaux élaborés à partir des mécanismes génétiques qui ont été découverts vont permettre de développer des traitements spécifiquesVascular anomalies are rare diseases which need interdisciplinary management. Venous malformations are slow-flow vascular lesions, which account for the majority of the consultations in interdisciplinary centers for vascular anomalies. The aim of this thesis was to advance our knowledge of these malformations at clinical, biological and molecular level. The goal was to improve the diagnosis and treatment of venous malformations. Venous malformations involve the skin, the subcutis, and often extend into muscles, tendons, nerves, bones, joints and mucosa. They are divided into inherited cutaneomucosal venous malformations (VMCM), sporadic uni and multifocal venous malformations (VM) and glomuvenous malformations (GVM). They can also be combined with other vascular anomalies (capillaro-venous malformation, capillaro-lymphatico-venous malformation), or part of syndromes (Klippel-Trenaunay and Maffucci syndrome). When this work started, the etiopathological cause of VMCM and GVM had already been defined. Two activating mutations located on the TIE2 gene had been identified in 4 VMCM families and loss-of-function mutations in glomulin were associated with GVM. These germline mutations did not explain why these vascular anomalies occcured mainly in the skin and subcutaneous tissue, and why their number and size varied between patients. Subsequently, another study showed that on a resected GVM a somatic mutation was present. This double-hit suggested that GVMs result from complete localized loss of function and the inheritance is paradominant. Based on this, a recent study discovered that somatic mutations in TIE 2 cause 50% of sporadic VMs. Almost 90% of them had the same mutation, which was never observed as a germline change in VMCM, suggesting it to be too deleterious for survival when inherited. This study is a major discovery of the biological mechanism of these malformations which are the most frequent anomalies in veins. In parallel to the genetic studies, we initiated clinical studies with the patients of the 2 centers for vascular anomalies (Caen and Brussels). We studied the coagulation disorders associated with venous malformations, as we noted that some patients experienced severe bleeding during surgical procedures. We demonstrated that muscle involvement, large size of lesions and presence of palpable phleboliths were significantly associated with localized intravascular coagulopathy (Gutierrez S et al) characterized by elevated D-dimer levels. We proposed a treatment with Low Molecular Weight Heparin to prevent hemorrhages during surgical procedures and to relieve pain associated with intralesional thrombosis (Publication I). As this activation of coagulation is probably due to blood stagnation in the enlarged venous channels, we evaluated if elevated D-dimer levels were specific for venous malformation, and hence a biomarker helpful for diagnosis. We demonstrated that D-dimer test is a useful tool for diagnosing a venous component of a vascular malformation with a high specificity (96.5%). Patients with glomuvenous, lymphatic, capillary and fast-flow malformations as well as Maffucci syndrome had always normal D-dimer levels. Furthermore, combined fast and slow-flow lesions may be more easily separated (Klippel-Trenaunay syndrome versus Parkes Weber syndrome) and this tool helps in differentiating GVMs from other multifocal venous lesions. Thus, this easy and cheap biomarker should be used as a routine test in clinical evaluation of vascular anomaly patients (Publication II). Sclerotherapy is the treatment used for most VMs, as complete surgical excision is rarely possible. Absolute ethanol is the best sclerosing agent but it can induce serious local and systemic side effects. We developped a new modified ethanol sclerosing agent for the treatment of venous malformations. We demonstrated that radio-opaque ethylcellulose-ethanol is an efficient sclerosing agent even with a low dose of ethanol, as prolonged intralesional endothelial contact is induced. This increases safety. We never observed systemic complications and all local complications were minor, and observed on the face, hands and feet. These are problematic or even contra-indicated regions for the use of absolute ethanol. Therefore, sclerotherapy is becoming the gold-standard treatment for venous malformations, and indications can be widened to sensitive and dangerous areas, using ethylcellulose-ethanol at very small doses (0.1-0.3cc) (Publication III). This collaborative work has been most fruitful, as it has allowed to include larger number of patients in the prospective studies and also to exchange and discuss the different experiences in the two interdisciplinary centers. Work will continue to better diagnose combined and syndromic lesions. The animal models being generated on the basis of the genetic mechanisms that have been discovered will provide novel tools for development of specific treatments.Thèse de doctorat en sciences médicales (anomalies vasculaires) (MED 3)--UCL, 200

Atteinte muqueuse dans la papulose lymphomatoïde (quatre cas)

CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Le lymphome centrofolliculaire cutané primitif (étude rétrospective de 1993 à 2005 dans les services de dermatologie du CHU de Caen et de Rouen)

CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Complications et prise en charge des hémangiomes péri-oculaires, en dehors des urgences thérapeutiques

CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

La pemphigoïde gestationis (une dermatose spécifique de la grossesse)

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF

Cohorte bas-normande d'hémangiomes infantiles (HI) traités par propranolol (proposition d un schéma thérapeutique)

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF