Fatal hymenoptera venom anaphylaxis by undetected clonal mast cell disorder: A better identification of high risk patients is needed.

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.

Efficacy of sonic hedgehog inhibitors rechallenge, after initial complete response in recurrent advanced basal cell carcinoma: a retrospective study from the CARADERM database.

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.

FDG PET biomarkers for prediction of survival in metastatic melanoma prior to anti-PD1 immunotherapy.

Our aim was to analyse whether biomarkers extracted from baseline 18F-FDG PET before anti-PD1 treatment contribute to prognostic survival information for early risk stratification in metastatic melanoma. Fifty-six patients, without prior systemic treatment, BRAF wild type, explored using 18F-FDG PET were included retrospectively. Our primary endpoint was overall survival (OS). Total metabolic tumoral volume (MTV) and forty-one IBSI compliant parameters were extracted from PET. Parameters associated with outcome were evaluated by a cox regression model and when significant helped build a prognostic score. Median follow-up was 22.1 months and 21 patients died. Total MTV and long zone emphasis (LZE) correlated with shorter OS and served to define three risk categories for the prognostic score. For low, intermediate and high risk groups, survival rates were respectively 91.1% (IC 95 80-1), 56.1% (IC 95 37.1-85) and 19% (IC 95 0.06-60.2) and hazard ratios were respectively 0.11 (IC 95 0.025-0.46), P = 0.0028, 1.2 (IC 95 0.48-2.8), P = 0.74 and 5.9 (IC 95 2.5-14), P < 0.0001. To conclude, a prognostic score based on total MTV and LZE separated metastatic melanoma patients in 3 categories with dramatically different outcomes. Innovative therapies should be tested in the group with the lowest prognosis score for future clinical trials.

Relevance of body mass index as a predictor of systemic therapy outcomes in metastatic melanoma: analysis of the MelBase French cohort data☆.

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.

[Stage III melanoma: Sentinel node biopsy, completion lymph node dissection and prospects of adjuvant therapy. A French national survey on current and envisaged practices]. / Mélanome au stade ganglionnaire : analyse du ganglion sentinelle, curage ganglionnaire, perspective des traitements adjuvants. Enquête nationale française sur les pratiques actuelles et envisagées.

BACKGROUND: The recent publication of randomized trials investigating the efficacy of adjuvant therapy and completion lymph node dissection at microscopic stage III melanoma calls for a reappraisal of melanoma management from different angles: indications for sentinel lymph node biopsy, indications for completion lymph node dissection in microscopic-stage disease, and adjuvant therapies. Our objective was to evaluate current practices and to question French onco-dermatologists about any changes they envisaged in their practices in the light of recent publications. METHODS: We conducted a national survey among members of the Cutaneous Oncology Group of the French Society of Dermatology in October 2017. RESULTS: Forty French health centers were included, and 53 individual responses were collected. Sentinel lymph node biopsy for melanoma was performed at 75 % of the centers. Before the summer of 2017 and the publication of MSLT-II (proving the absence of any therapeutic benefits for complete lymph node dissection in microscopic stage III melanoma), when a positive sentinel lymph node was diagnosed, immediate completion lymph node dissection was performed at 90 % of the centers. After the publication of MSLT-II, 45 % of the respondents considered stopping this practice. The risk-benefit ratio prompted prescription of nivolumab and of combined dabrafenib+trametinib as adjuvant therapy by respectively 96 % and 79 % of respondents, while the corresponding rates for interferon and ipilimumab were only 21 % and 15 %. CONCLUSION: Early melanoma management stands on the verge of major changes thanks to the arrival of efficient adjuvant therapies and a decrease in immediate completion lymph node dissections for patients with microscopic stage III is also anticipated.

Current opinions in immune checkpoint inhibitors rechallenge in solid cancers.

Immune checkpoint inhibitors (ICI) completely upset the therapeutic algorithm of several type of solid cancer conferring in some patients a long clinical benefit with an acceptable toxicity. ICI rechallenge is an attractive option being a palliative chemotherapy the only alternative treatment in most of cases. Despite this strategy recently entered into the clinical practice, no widely recognized recommendation is currently available to select the good candidates. Anti-Cytotoxic T Lymphocyte Antigen 4 (Anti-CTLA4) rechallenge and a sequential administration of anti-CTLA4 and anti-Programmed cell Death protein 1 (anti-PD1) or Anti-Programmed Death Ligand 1 (anti-PDL1) agents have been explored in melanoma patients in several clinical trials while the anti-PD1/anti-PDL1 rechallenge has been little investigated. Here we performed a literature revision about efficacy and tolerability of ICI rechallenge across solid tumors also focusing on inclusion criteria used into clinical trials.

[Reprint of: New guidelines for stage III melanoma (the French Cutaneous Oncology Group)]. / Republication de : Actualisation des données concernant le mélanome stade III : nouvelles recommandations du groupe français de cancérologie cutanée.

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.

[New guidelines for stage III melanoma (the French Cutaneous Oncology Group)]. / Actualisation des données concernant le mélanome stade III : nouvelles recommandations du groupe français de cancérologie cutanée.

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.

Update of survival and cost of metastatic melanoma with new drugs: Estimations from the MelBase cohort.

PURPOSE: Since 2011, significant progress was observed in metastatic melanoma (MM), with the commercialisation of seven immunotherapies or targeted therapies, which showed significant improvement in survival. In France, in 2004, the cost of MM was estimated at €1634 per patient; this cost has not been re-estimated since. This study provided an update on survival and cost in real-life clinical practice. METHODS: Clinical and economic data (treatments, hospitalisations, radiotherapy sessions, visits, imaging and biological exams) were extracted from the prospective MelBase cohort, collecting individual data in 955 patients in 26 hospitals, from diagnosis of metastatic disease until death. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. For live patients, survival and costs were extrapolated using a multistate model, describing the 5-year course of the disease according to patient prognostic factors and number of treatment lines. RESULTS: Since the availability of new drugs, the mean survival time of MM patients has increased to 23.6 months (95%confidence interval [CI] :21.2;26.6), with 58% of patients receiving a second line of treatment. Mean management costs increased to €269,682 (95%CI:244,196;304,916) per patient. Drugs accounted for 80% of the total cost. CONCLUSION: This study is the first that evaluated the impact of immunotherapies and targeted therapies both on survival and cost in real-life conditions. Alongside the introduction of breakthrough therapies in the first and subsequent lines, MM has been associated with a significant increase in survival but also in costs, raising the question of financial sustainability.

Real-world treatment patterns and clinical outcomes in advanced cutaneous melanoma patients in France.

BACKGROUND: Since 2011, the management of advanced melanoma has radically changed with the availability of new therapies (immunotherapy and BRAF-targeted therapy) and with BRAF testing. OBJECTIVES: Following the introduction of these new therapies, the objectives of this AMEL study were to describe treatment patterns and evaluate overall survival (OS) among unresectable stage III/IV melanoma patients, in a real-life setting in France. METHODS: The AMEL study is a multicentre retrospective record review study. Thirty-three physicians working in 33 unique treatment centres participated in the study. Two hundred and sixty-four patients diagnosed between 1 January 2012 and 31 October 2012 with unresectable stage III/IV melanoma were included in the study. RESULTS: 94.7% of the patients received a first-line antitumour drug treatment, 62.5% a second-line treatment while 26.9% received a third-line treatment with no significant differences between patients with a BRAF mutation (50.4%) and BRAF wild type (47.0%). First-line treatment differs according to the BRAF status: 74.8% of patients with a BRAF mutation received a BRAF inhibitor while 79.3% of the BRAF wild-type patients were treated with conventional chemotherapy. In second line and over, the treatment patterns were more heterogeneous, depending on the BRAF mutation, the treatment received previously, the speed of progression of the disease and the availability of immunotherapy at the time the treatment was initiated. CONCLUSION: Regardless of the BRAF mutation status, the median OS of patients was 16 months (95% CI = 14-18). Compared to a similar study conducted in 2007 (MELODY), a gain of 4 months is observed. The gain seems to be higher for patients with a BRAF mutation (18 months) than for those without a BRAF mutation (14 months). The OS of patients who sequentially received both a BRAF inhibitor and ipilimumab (28 months) highlights the benefit of this treatment sequence.

Mucosal melanoma: clinical, histological and c-kit gene mutational profile of 86 French cases.

BACKGROUND: Mucosal melanomas are rare and highly aggressive tumours. Few studies evaluated mucosal melanomas of locations other than the head and neck region, and other than those of the Asian population. OBJECTIVES: The objective of this study was to analyse the clinical and histological features, as well as the mutational status of c-kit and b-raf gene of mucosal melanoma in any localization in a French series. METHODS: We investigated clinical (sex, age, performance status, survival, treatment of the patients and lack of pigmentation of the tumours) and histopathological features (ulceration, Breslow's index, mitotic rate), as well as the mutational status of c-kit and b-raf of 86 mucosal melanomas diagnosed in 15 years in four French University Hospitals. RESULTS: Most melanomas affected women (72%) and the genital region (46.5%). A fifth of melanomas were amelanotic. 81% of melanomas had a Breslow's index ≥1, whereas all glans melanomas, and most vulvar melanomas had a Breslow index ≤1 mm. Overall survival was 54% at 3 years; 11.6% of the 43 tested mucosal melanomas were c-kit-mutated while the 15 tested genital melanomas were not. The c-kit gene mutation did not influence the overall survival. Age ≥ 50, amelanotic type and performance status ≥1 were not poor prognostic factors in our series. CONCLUSION: This study confirmed that mucosal melanomas are rare and could be difficult to diagnose being often amelanotic and in hidden sites. Most melanomas were thick at the diagnosis, but glans and vulvar melanomas were thinner probably because of their greater visibility. The frequency of the c-kit mutation varied depending on the initial tumour site. In our series, the prognosis was poor, independently from c-kit mutations and the patient's general health and age. The presence of metastasis at diagnosis was associated with a worse prognosis indicating the importance of an early diagnosis.

[Granulomatous periocular eruption]. / Dermatite périoculaire granulomateuse.

BACKGROUND: Herein, we report a case of atypical periorificial dermatitis in a patient that had been receiving treatment for some time for atopic dermatitis. The specific feature of this rash was its periocular predominance with no perioral involvement, its clinical aspect and its histological picture evocative of sarcoidosis. PATIENTS AND METHODS: A 33-year-old man was being treated for a atopic dermatitis limited to the face and poorly responsive to dermal corticosteroids. Treatment was initiated with topical tacrolimus 0.1%. After 4 years, dependence on this treatment was noted, with daily application being needed to control the lesions. One year later, symmetric lesions were seen on the eyelids and periorbital regions; these were erythematous, micropapular and poorly delineated in a setting of oedema. Biopsy revealed epithelioid granulomatous inflammation, and, to a lesser degree, sarcoidal giant-cell features without caseous necrosis. Staging tests to identify systemic sarcoidosis were negative. Treatment with hydroxychloroquine at 400mg per day and discontinuation of topical tacrolimus resulted in complete remission of the lesions within 2 months. Hydroxychloroquine was discontinued after 6 months, and no relapses had occurred after 2 years of follow-up. DISCUSSION: Three diagnostic hypotheses may be posited for these granulomatous facial lesions. We opted for a diagnosis of granulomatous periorificial dermatitis despite the fact that exclusively periorbital involvement is rare (this condition is generally associated with perioral dermatitis). The second was that of pure cutaneous sarcoidosis, but the topography and clinical appearance of the lesions did not correspond to any of the cutaneous forms classically described. The third was that of tacrolimus-induced granulomatous rosacea, but the histological picture is different. CONCLUSION: The present case underscores the fact that a histological appearance of sarcoidosis on skin biopsy may be associated with perioral dermatitis.

[Systemic treatment of melanoma brain metastases]. / Traitement systémique des métastases cérébrales de mélanome.

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).

[Recommendations for genetic testing and management of individuals genetically at-risk of cutaneous melanoma]. / Recommandations pour le diagnostic de prédisposition génétique au mélanome cutané et pour la prise en charge des personnes à risque.

Cutaneous melanoma is a multifactorial disease resulting from both environmental and genetic factors. Five susceptibility genes have been identified over the past years, comprising high-risk susceptibility genes (CDKN2A, CDK4, and BAP1 genes) and intermediate-risk susceptibility genes (MITF, and MC1R genes). The aim of this expert consensus was to define clinical contexts justifying genetic analyses, to describe the conduct of these analyses, and to propose surveillance recommendations. Given the regulatory constraints, it is recommended that dermatologists work in tandem with a geneticist. Genetic analysis may be prescribed when at least two episodes of histologically proven invasive cutaneous melanoma have been diagnosed before the age of 75 years in two 1st or 2nd degree relatives or in the same individual. The occurrence in the same individual or in a relative of invasive cutaneous melanoma with ocular melanoma, pancreatic cancer, renal cancer, mesothelioma or a central nervous system tumour are also indications for genetic testing. Management is based upon properly managed photoprotection and dermatological monitoring according to genetic status. Finally, depending on the mutated gene and the familial history, associated tumour risks require specific management (e.g. ocular melanoma, pancreatic cancer). Due to the rapid progress in genetics, these recommendations will need to be updated regularly.

[Remote dermatological advice: a survey in three French regions]. / Avis dermatologiques à distance : une enquête interrégionale.

BACKGROUND: General practitioners and specialists often seek advice from dermatologists based on digital pictures. This time-consuming activity is currently not valued nor well-established. We therefore conducted a survey to assess the extent and nature of such requests. PATIENTS AND METHODS: A questionnaire was sent to dermatologists working either at university hospitals or in private practice in three regions of France (Loire Atlantique, Rhone Alpes and Normandy). For two months, the dermatologists completed the same questionnaire for each specialized request. The following items were recorded: status of the dermatologist asked to provide a specialized opinion, region in which the request was made, status of the requesting practitioner, mode of request, type of disease, question asked, time taken to answer the request and result of the specialized advice. RESULTS: Thirty dermatologists, including 11 in private practice, participated in this study. We identified 287 requests. The majority of these requests came from general practitioners (30%) and dermatologists working in private practice (29%). These requests were sent by e-mail using a non-secure professional e-mail address in 49% of cases or via smartphone in 29% of cases. The purpose of the requests was either diagnostic/therapeutic (36%) or solely therapeutic (39%). Relevant requests concerned dermatological manifestations in paediatric or cancer patients (23% and 21% respectively), general dermatological diseases (21%) and wound management (14%). Nearly half of the specialized advice was provided in under 5minutes, and in 60% of cases a consultation with a dermatologist was avoided. CONCLUSION: Despite the small number of physicians taking part in the study, this non-exhaustive survey confirms the usefulness of remote dermatological reviews and consultations, and identifies the main intervening physicians involved in this type of procedure. The study also raises potential medico-legal issues regarding the lack of data security covering medical information. There is thus a need for dermatologists to organize their activity in order to respond to such requests without exposing themselves to medico-legal consequences.

[Mechanisms of resistance to anti-BRAF treatments]. / Mécanismes de résistance aux inhibiteurs de BRAF.

CONTEXT: In patients with melanoma positive for the BRAF V600 mutation, clinical response to specific BRAF inhibitors is usually rapid and striking, with significant benefits in terms of progression-free survival and overall survival. However, resistance to treatment almost invariably arises, typically within a median timeframe of 6 months. Indeed, very few patients exhibit long-lasting response to these targeted therapies. AIMS: It is essential to better understand the mechanisms of resistance to targeted anti-BRAF therapies in order to increase both response rates and the duration of clinical response to treatment. This literature review describes the signaling pathways involving BRAF and presents recent data from clinical trials with these molecules. Furthermore, we aim to describe the main resistance mechanisms linked with targeted anti-BRAF therapies. METHODS: The keywords (resistance, BRAF, melanoma, targeted therapy, vemurafenib, and dabrafenib) were used to extract relevant articles in the Medline/Pubmed database published before 31 January 2014. DISCUSSION: Improved knowledge and understanding of the mechanisms of resistance to targeted anti-BRAF therapies should enable the development of new therapeutic strategies in order to overcome such resistance and allow more significant and sustained response rates to be achieved among melanoma patients.