Case report: Parsonage-turner syndrome in a melanoma patient treated by BRAF/MEK inhibitors after immune checkpoint inhibitors

IntroductionCombination molecular BRAF/MEK inhibitors targeted therapy has been shown to improve overall survival in patients with BRAF V600 mutated unresectable or metastatic melanoma. Most patients treated with BRAF/MEK inhibitors will experience adverse events but neurological adverse events (nAEs) remain rare.Case reportA 42-year-old woman diagnosed with metastatic melanoma presented with an intense pain in the left shoulder 7 days after the beginning of encorafenib/binimetinib after immune checkpoint inhibitors (ICI) combination. No other triggering factors were identified. Electromyogram performed one month after the pain onset revealed a left brachial plexopathy suggestive of a Parsonage-Turner syndrome. The weakness slowly improved with intensive rehabilitation and targeted therapies were continued.ConclusionWe report the first case of Parsonage-Turner syndrome in a melanoma patient treated with encorafenib/binimetinib following checkpoint inhibitors combination.We cannot rule out the implication of ICI in the development of this syndrome but the rapid onset of the symptoms after the beginning of targeted therapies makes their involvment more likely.Given the increased use of BRAF/MEK inhibitors in managing of stage III and IV melanoma, as well as the development in stage II, clinicians should be aware of this potential side effect

EULAR points to consider for the development, evaluation and implementation of mobile health applications aiding self-management in people living with rheumatic and musculoskeletal diseases

Background: Mobile health applications (apps) are available to enable people with rheumatic and musculoskeletal diseases (RMDs) to better self-manage their health. However, guidance on the development and evaluation of such apps is lacking. Objectives: The objective of this EULAR task force was to establish points to consider (PtC) for the development, evaluation and implementation of apps for self-management of RMDs. Methods: A systematic literature review of app content and development strategies was conducted, followed by patient focus group and an online survey. Based on this information and along with expert opinion, PtC were formulated in a face-to-face meeting by a multidisciplinary task force panel of experts, including two patient research partners. The level of agreement among the panel in regard to each PtC was established by anonymous online voting. Results: Three overarching principles and 10 PtC were formulated. Three PtC are related to patient safety, considered as a critical issue by the panel. Three were related to relevance of the content and functionalities. The requirement for transparency around app development and funding sources, along with involvement of relevant health professionals were also raised. Ease of app access across ages and abilities was highlighted, in addition to considering the cost-benefit of apps from the outset. The level of agreement was from 8.8 to 9.9 out of 10. Conclusion: These EULAR PtC provide guidance on important aspects that should be considered for the development, evaluation and implementation of existing and new apps

Multidisciplinary collaboration among young specialists: results of an international survey by the emerging EULAR network and other young organisations

Background: Multidisciplinary collaboration is defined as a collective work involving multiple disciplines and is common in clinical care and research. Our aim was to describe current clinical and research collaboration among young specialists and to identify unmet needs in this area. Methods: An online survey was disseminated by email and social media to members of the EMerging EUlar NETwork, the Young Nephrologists’ Platform, the Paediatric Rheumatology European Society Emerging Rheumatologists and Researchers and the European Academy of Allergy and Clinical Immunology Junior Members. Results: Of 303 respondents from 36 countries, 61% were female, 21% were aged below 30 years and 67% were aged 31–40 years. Young rheumatologists were the most represented (39%), followed by young nephrologists (24%), young paediatricians (20%), young allergologists (11%) then young internists (3%) and 3% other specialities. Collaborations were reported frequently by phone and email, also by various combined clinics while common local multidisciplinary meetings were uncommon. 96% would like to develop clinical research collaborations and 69% basic research collaborations. The majority of young specialists would be interested in online (84%) and/or 1–2 days (85%) common courses including case discussion (81%) and training workshops (85%), as well as webinars recorded with several specialists on a specific disease (96%). Conclusions: This collaborative initiative highlighted wishes from young specialists for developing (1) regular local multidisciplinary meetings to discuss complex patients, (2) clinical research collaboration with combined grants and (3) multidisciplinary online projects such as common courses, webinars and apps

Etude du microenvironnement immunitaire dans les sarcomes : pourrait-il y avoir une place pour l'immunothérapie dans la stratégie thérapeutique ?

Local control with adequate surgery is the cornerstone of sarcoma treatment. However, most sarcoma lack effective systemic therapies in case of advanced disease, emphasizing an unmet medical need for new therapeutic targets. The recent success of immunotherapy in epithelial malignancies raises the question whether such therapies, and which ones, would be applicable in sarcomas. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in three sarcoma subtypes potentially candidate to immunotherapy: 1) In chondrosarcoma, PD-L1 expression was exclusively found in nearly 50% of the dedifferentiated subtype, in association with immune-infiltrating cells and HLA class I expression. These data provide rationale for including such patients in clinical trials with PD-1/PD-L1-targeted therapies. 2) In osteosarcoma, we observed a high density of tumor-infiltrating T cells in metastatic lesions compared to primary tumors and local relapses. Furthermore, PD-L1 positivity in almost half of metastases while mainly negative in the associated primary tumors, emphasises the dynamics of an adaptive mechanism of immune escape. Enhancing the preexisting immune response in metastatic lesions using T-cell-based immunotherapy may offer clinical benefit. 3) In leiomyosarcoma, HLA class I molecules were strongly upregulated and PD-L1 expression found in 30% of high-grade tumors, which were also highly infiltrated with CD163+ immunosuppressive macrophages. CD163+ was found to be an independent poor prognostic factor for overall survival, indicating the need for assessing a macrophage-targeted approach in this tumor type, as single agent or in combination with anti PD-1/PD-L1agents.La chirurgie est la pierre angulaire du traitement curatif des sarcomes, lorsqu’elle est possible. En revanche, en cas de maladie avancée ou métastatique, les traitements systémiques ont une efficacité assez limitée avec un réel besoin de nouvelles options thérapeutiques. Le récent succès de l’immunothérapie dans les tumeurs épithéliales soulève donc la question de la possibilité d’une telle approche dans les sarcomes, et surtout pour quels sous-types histologiques. L’objectif de ce travail de thèse était d’obtenir des données précliniques en caractérisant le microenvironnement immunitaire au sein de trois types de sarcomes potentiellement candidats à l’immunothérapie, prérequis indispensable avant d’envisager une application clinique : 1) Dans le chondrosarcome, l’expression de PD-L1 a été retrouvée exclusivement dans près de 50% des chondrosarcomes dédifférenciés, et s’associait à une infiltration lymphocytaire T et l’expression des molécules HLA de classe I. Ces données incitent donc à inclure les patients avec ce sous type de chondrosarcome dans des essais cliniques évaluant un traitement anti PD-1/PD-L1. 2) Dans l’ostéosarcome, un infiltrat lymphocytaire T était observé de façon bien plus importante dans les lésions métastatiques que dans lésions primitives ou rechutes locales. De plus, l’expression de PD-L1 était retrouvée dans presque 50% des métastases mais pas ou peu dans la tumeur primitive correspondante, traduisant ici une dynamique d’échappement au système immunitaire lors de la progression de la maladie. Une stratégie ciblée sur les lymphocytes T visant à amplifier et potentialiser cette réponse immune préexistante dans les lésions métastatiques pourrait donc offrir un bénéfice clinique. 3) Dans le léiomyosarcome, les molécules HLA de classe I étaient fortement exprimées et l’expression de PD-L1 retrouvée dans 30% des tumeurs de haut grade, également très infiltrées par des macrophages immunosuppresseurs CD163+. Une importante infiltration de macrophages CD163+ était un marqueur indépendant de mauvais pronostic pour la survie, indiquant l’intérêt de d’une approche ciblée visant les macrophages dans ce type de sarcome, éventuellement en association avec un traitement anti PD-1/PD-L1

Defining the immune microenvironment in sarcoma : could immunotherapy be part of the treatment strategy in sarcoma patients ?

La chirurgie est la pierre angulaire du traitement curatif des sarcomes, lorsqu’elle est possible. En revanche, en cas de maladie avancée ou métastatique, les traitements systémiques ont une efficacité assez limitée avec un réel besoin de nouvelles options thérapeutiques. Le récent succès de l’immunothérapie dans les tumeurs épithéliales soulève donc la question de la possibilité d’une telle approche dans les sarcomes, et surtout pour quels sous-types histologiques. L’objectif de ce travail de thèse était d’obtenir des données précliniques en caractérisant le microenvironnement immunitaire au sein de trois types de sarcomes potentiellement candidats à l’immunothérapie, prérequis indispensable avant d’envisager une application clinique : 1) Dans le chondrosarcome, l’expression de PD-L1 a été retrouvée exclusivement dans près de 50% des chondrosarcomes dédifférenciés, et s’associait à une infiltration lymphocytaire T et l’expression des molécules HLA de classe I. Ces données incitent donc à inclure les patients avec ce sous type de chondrosarcome dans des essais cliniques évaluant un traitement anti PD-1/PD-L1. 2) Dans l’ostéosarcome, un infiltrat lymphocytaire T était observé de façon bien plus importante dans les lésions métastatiques que dans lésions primitives ou rechutes locales. De plus, l’expression de PD-L1 était retrouvée dans presque 50% des métastases mais pas ou peu dans la tumeur primitive correspondante, traduisant ici une dynamique d’échappement au système immunitaire lors de la progression de la maladie. Une stratégie ciblée sur les lymphocytes T visant à amplifier et potentialiser cette réponse immune préexistante dans les lésions métastatiques pourrait donc offrir un bénéfice clinique. 3) Dans le léiomyosarcome, les molécules HLA de classe I étaient fortement exprimées et l’expression de PD-L1 retrouvée dans 30% des tumeurs de haut grade, également très infiltrées par des macrophages immunosuppresseurs CD163+. Une importante infiltration de macrophages CD163+ était un marqueur indépendant de mauvais pronostic pour la survie, indiquant l’intérêt de d’une approche ciblée visant les macrophages dans ce type de sarcome, éventuellement en association avec un traitement anti PD-1/PD-L1.Local control with adequate surgery is the cornerstone of sarcoma treatment. However, most sarcoma lack effective systemic therapies in case of advanced disease, emphasizing an unmet medical need for new therapeutic targets. The recent success of immunotherapy in epithelial malignancies raises the question whether such therapies, and which ones, would be applicable in sarcomas. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in three sarcoma subtypes potentially candidate to immunotherapy: 1) In chondrosarcoma, PD-L1 expression was exclusively found in nearly 50% of the dedifferentiated subtype, in association with immune-infiltrating cells and HLA class I expression. These data provide rationale for including such patients in clinical trials with PD-1/PD-L1-targeted therapies. 2) In osteosarcoma, we observed a high density of tumor-infiltrating T cells in metastatic lesions compared to primary tumors and local relapses. Furthermore, PD-L1 positivity in almost half of metastases while mainly negative in the associated primary tumors, emphasises the dynamics of an adaptive mechanism of immune escape. Enhancing the preexisting immune response in metastatic lesions using T-cell-based immunotherapy may offer clinical benefit. 3) In leiomyosarcoma, HLA class I molecules were strongly upregulated and PD-L1 expression found in 30% of high-grade tumors, which were also highly infiltrated with CD163+ immunosuppressive macrophages. CD163+ was found to be an independent poor prognostic factor for overall survival, indicating the need for assessing a macrophage-targeted approach in this tumor type, as single agent or in combination with anti PD-1/PD-L1agents

Les limites des inhibiteurs de points de contrôle immunitaire et la gestion de leur toxicité

L’immunothérapie représente désormais un des piliers de la prise en charge du cancer, notamment avec l’arrivée des inhibiteurs de points de contrôle (checkpoint) immunitaire (ICI, immune checkpoint inhibitors). Ces anticorps thérapeutiques ciblent ces co-signaux inhibiteurs entre cellules tumorales ou cellules présentatrices d’antigènes et lymphocytes T, activant ou réactivant ainsi une immunité cellulaire T anti-tumorale. Mais la survenue d’une toxicité immunologique, qui peut concerner tous les organes, représente le facteur limitant dans le développement clinique de ces anticorps. La gestion de cette toxicité nécessite une collaboration étroite entre oncologues et spécialistes d’organe, et repose sur l’utilisation de corticoïdes et/ou d’autres immunosuppresseurs, avec l’objectif de contrôler la dysimmunité induite sans perdre l’efficacité anti-tumorale

Additional file 1: of Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis

Figures S5 to S7 Global immune-related adverse events (irAEs) with ipilimumab all dosage, 3 mg/kg, and 10 mg/kg for all grades and high grade. Figures S8 to S27 Organ-specific irAEs (endocrine, skin, gastrointestinal, and hepatic) for ipilimumab all dosage, 3 mg/kg, and 10 mg/kg and Tremelimumab, for all grades and high grade. Figures S28 to S31 Risk ratio of developing irAEs with ipilimumab at 10 mg/kg comparing with 3 mg/kg for organ-specific irAEs (gastrointestinal, skin, endocrine, and hepatic). Table S2 General characteristics of patients receiving anti-CTLA4 antibodies described in case reports. Table S3 Organ-specific irAEs. Table S4 Quality assessment. (DOCX 12329 kb