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Hymenoptera venom anaphylaxis is the most frequent cause of anaphylaxis and responsible for about 20% of all fatal anaphylaxis cases in adults. We report two cases of fatal hymenoptera venom anaphylaxis with undiagnosed underlying mastocytosis and review the risk factors for severe or fatal hymenoptera venom anaphylaxis, as well as the specificities of its association with mastocytosis. As hymenoptera venom allergic patients with underlying clonal mast cell disorder generally lack typical skin lesions of mastocytosis, its diagnosis can easily be missed, underscoring the importance and need for diagnostic strategies in order to correctly identify these patients. Predominant cardiovascular symptoms in the absence of urticaria or angioedema following an insect sting are suggestive of underlying clonal mast cell disorder, and should be distinguished from panic attack or vasovagal syncope. Similarly, an unexplained syncope or an "idiopathic" anaphylaxis might reveal mastocytosis or hereditary alpha-tryptasemia. Acute and basal serum tryptase measurements should always be integrated in the diagnostic work-up of an insect sting reaction or unexplained syncope or shock of any origin., (Copyright © 2021 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Background: Smoothened (SMO) inhibitors, blocking the sonic hedgehog pathway, have been approved for advanced basal cell carcinoma (aBCC). Safety analyses reveal a high rate of adverse events (AEs) and, most of the time, vismodegib is most commonly stopped when the best overall response is reached. The long-term evolution of aBCC after vismodegib discontinuation is poorly described. The aim of this study is to evaluate the efficacy and safety of the SMO inhibitors (SMOis) available (vismodegib and sonidegib) following rechallenge after complete response (CR) following an initial treatment by vismodegib., Materials and Methods: This real-life, retrospective, multicenter and descriptive study is based on an extraction from the CARADERM accredited database, including 40 French regional hospitals, of patients requiring BCC systemic treatment., Results: Of 303 patients treated with vismodegib, 110 achieved an initial CR. The vast majority of these patients (98.2%) stopped vismodegib, notably due to poorly tolerated AEs. The CARADERM database provided a median follow-up of 21 months (13.5-36.0 months) after CR. Of the 110 patients, 48.1% relapsed after a median relapse-free survival of 24 months (13.0-38.0 months). Among them, 35 patients were retreated by an SMOi and the overall response rate was 65.7% (34.3% of CR and 31.4% of partial response). The median duration of retreatment was 6.0 months (4.0-9.5 months)., Conclusion: Our real-life study, carried out on patients with complex clinical pictures, shows that after treatment discontinuation, 48.1% of patients achieved CR relapse within an average of 24 months (13.0-38.0 months). It emphasized that even though rechallenge can be considered as a therapeutic option, efficacy seems to decrease, suggesting the development of resistance mechanisms., Competing Interests: Disclosure EMN: Consulting or advisory role: Novartis, Pierre Fabre, Bristol-Myers Squibb, MSD. EM: Consulting or advisory role: MSD, Pierre Fabre, Novartis, Sanofi; research funding: MSD (Inst); travel, accommodations, expenses: MSD Oncology, Pierre Fabre, Novartis. NM: Consulting or advisory role or research funding: Bristol-Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Merck, Sanofi, Sun Pharmaceutical Industries. MB-B: Research funding: Roche; consulting or advisory role: Sun Pharmaceutical Industries. NB-S: Consulting or advisory role: Sanofi, Sun Pharmaceutical Industries. LM: Consulting or advisory role: Sanofi, Sun Pharmaceutical Industries, MSD Oncology, Bristol-Myers Squibb, Novartis. The remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy., Patients and Methods: This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out., Results: A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n = 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P = 0.88)/overall survival (P = 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI., Conclusion: The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution., Competing Interests: Disclosure StD reports institutional research funding from Roche; institutional research funding and nonfinancial support from Bristol-Myers Squibb (BMS); and an immediate family member who is employed by Sanofi and owns stock or other ownership interest in the company. LM reports personal fees and nonfinancial support from Roche, Novartis, BMS, and Merck Sharp & Dohme (MSD) outside the submitted work. OD reports personal fees and nonfinancial support from BMS, MSD, Pierre Fabre, Novartis, Leo Pharma, Genevrier, Kyowa Kirin, Recordati Rare Diseases outside the submitted work. SoD received research funding and travel costs covered by BMS and MSD. Travel costs covered by Pierre Fabre. CD reports personal fees from Roche, BMS, Novartis, MSD, and Pierre Fabre Laboratories outside the submitted work. PS reports research funding and personal fees from Roche; grants, personal fees, and nonfinancial support from BMS, MSD, Novartis, and Pierre Fabre Laboratories; and personal fees from Array, Sanofi, and Merck, all outside the submitted work. J-PA reports personal fees from BMS, grants from BMS, Novartis, and MSD, during the conduct of the study. EM reports grants, personal fees, and nonfinancial support from MSD; personal fees from Sanofi and Novartis; personal fees and nonfinancial support from BMS; and nonfinancial support from Pierre Fabre Laboratories, all outside the submitted work. JDQ reports nonfinancial support from BMS, MSD, and Janssen outside the submitted work. FA reports personal fees and nonfinancial support from Novartis, MSD, and Roche outside the submitted work. TL reports research funding and personal fees from Roche and personal fees from BMS, MSD, Novartis, Pierre Fabre Laboratories, and Incyte, all outside the submitted work. P-ES reports travel accomodations -meetings by BMS, Novartis, MSD, and Sanofi. J-JG reports personal fees and nonfinancial support from BMS, Roche, MSD, Novartis, Merck, Amgen, Pierre Fabre Laboratories, Sanofi, and Pfizer and nonfinancial support from Amgen, all outside the submitted work. CA reports travel accommodations-meetings by Roche, BMS, and Amgen. CL reports grants and personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Amgen, grants and personal fees from Roche, personal fees from Avantis Medical Systems, personal fees from Pierre Fabre, personal fees from Pfizer, personal fees from Incyte, personal fees from Merck Serono, personal fees from Sanofi, outside the submitted work. HM reports institutional research funding from LeoPharma; institutional research funding, personal fees, and nonfinancial support from BMS; personal fees from Pierre Fabre Laboratories and MSD; and nonfinancial support from Novartis, all outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Improved knowledge of sentinel node procedures coupled with the results of adjuvant clinical trials in stage III melanoma have prompted the French Cutaneous Oncology Group to propose new guidelines for the management of stage III melanoma. These guidelines comply with the principles of the evidence-based medicine., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase)., (Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The antifungal voriconazole was given its marketing authorization in 2002. Several kinds of adverse effects have been reported, including acute and chronic cutaneous adverse effects, mainly due to a phototoxicity mechanism. More recently, some authors have reported that voriconazole was involved in the occurrence of multiple and often-aggressive cutaneous squamous cell carcinomas if the treatment was maintained for a long time. According to safety data in studies assessing voriconazole effectiveness, 8% of outpatients may experience phototoxic events. An overview of the different types of phototoxicity and of the concerned population was given by the 61 published case reports of photo-induced voriconazole-related skin adverse events (including 18 cases of squamous cell carcinomas). The most likely mechanisms may be phototoxicity directly related to either voriconazole or to its N-oxide main metabolite, and an interaction with retinoid metabolism; moreover, immunodeficiency may enhance the risk of skin cancer. Several issues remain to be investigated, and studies are needed concerning the phototoxicity and photocarcinogenesis of voriconazole and the prognosis of chronic non-malignant skin lesions. Voriconazole prescription must be associated with strict photoprotection; in case of a phototoxic adverse event, another azole may be recommended., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The development of effective vaccines against cancer and viruses still remains a challenge. Many immunotherapeutic strategies have been developed but without sufficient therapeutic success. Plasmacytoid dendritic cells (pDC) play a crucial role in antitumor and antiviral responses. Despite their outstanding functional properties, their therapeutic potential has not yet been worked out. We propose a new immunotherapeutic strategy based on a pDC cell line irradiated and pulsed with tumor or viral antigens. GENiusVac allows the induction of multispecific and highly functional cytotoxic cell responses directed against viral or tumor targets. We demonstrated the potential of this strategy in vitro, its therapeutic efficacy in vivo in a humanized mouse model, and its clinical relevance ex vivo from melanoma patients' cells. GENiusVac highlights pDCs as potent vector of immunotherapy and provide a way to exploit them in cell therapy to fight cancer or chronic viral infections., (Copyright © 2010 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Rare squamous cell carcinoma (SCC) cases associated with voriconazole therapy have been reported, but this risk may not receive enough consideration from clinicians. We describe four patients presenting with multiple SCC while receiving prolonged (two to three years) voriconazole therapy. Three patients had underwent lung transplantation. SCC were preceded by photosensitization lesions, and predominated in photoexposed area, particularly the face. Therapy associated surgery, chemotherapy in one case, and voriconazole discontinuation; replacement by posaconazole or itraconazole did not trigger other photosensitive lesions. Once voriconazole withdrawn, preneoplastic lesions regressed. In conclusion, prolonged voriconazole therapy may enhance the risk of photoinduced SCC in immunocompromised patients, and skin monitoring is mandatory., (© 2010 The Author Clinical Microbiology and Infection © 2010 European Society of Clinical Microbiology and Infectious Diseases.)

Cell migration, growth, and survival is modulated by focal adhesions linking extracellular matrix proteins, cell adhesion molecules, and the cytoskeleton. Zyxin is a focal adhesion phosphoprotein that shares homology with Listeria ActA protein in promoting actin filament assembly; it also has specialized protein-protein interface domains implicating an important role in cell growth and differentiation. We investigated the distribution of zyxin in normal and migrating human keratinocytes in wounds in vitro and in situ using confocal laser microscopy. Zyxin expression in high-density nonmigrating keratinocytes versus low-density migrating keratinocytes was determined by western immunoblotting and time lapse image analysis. In normal epidermis, zyxin exhibited a punctate staining pattern throughout the cytoplasm and was excluded from the intercellular spaces. In wounds, the punctate staining also localized in the edge of the migrating keratinocyte sheets; however, intercellular spaces were absent. Likewise, in vitro keratinocytes showed punctate staining throughout the cytoplasm. Migrating cultured keratinocytes next to wounds, however, had large focal contacts in the cell periphery where actin bundles converged at focal adhesions. Western immunoblots and confocal experiments with protein synthesis inhibition by cycloheximide confirmed that this difference in distribution of zyxin in migrating versus nonmigrating keratinocytes is due to the redistribution and not upregulation of zyxin. The abundance of zyxin and its relative change in distribution from normal to migrating keratinocytes in wounds is consistent with its role in cytoskeletal organization of actin bundles.