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Few satisfactory treatment options are available for widespread areas affected by multiple actinic keratoses (AKs). Our primary objective was to assess the response rate to weekly 5-fluorouracil (5-FU) chemowraps on widespread AK lesions, and secondarily to assess tolerability, the percentage of patients with recurrence and time to recurrence, the response rate for patients with associated Bowen's disease (BD), and the percentage of squamous cell carcinomas (SCCs) identified after treatment. We conducted an open study which included all the patients who had been treated with weekly 5-FU chemowraps in our department over the course of five years for areas of widespread AKs. The response rate for AKs was 60%, with 20% complete responses among 25 patients after an average of 9.6 sessions (1 to 64). The treatment had to be discontinued because of toxicity in four patients; one case of contact dermatitis, one case of erosive pustular dermatosis, and two cases of Grade 2 irritations. Invasive SCCs were identified in five patients after treatment cessation. The median recurrence-free survival was five months. A 64% response rate was achieved for associated BD. The weekly application of 5-FU under occlusion seems to be an interesting, well-tolerated therapeutic option for the treatment of widespread AKs.

Background The course of skin cancer after retransplantation in organ-transplant recipients who have already developed posttransplant skin cancer has not been assessed. Methods This retrospective multicentric study included 53 patients with a history of cutaneous squamous cell carcinoma (SCC) after a first kidney transplantation who received a second kidney transplantation. The primary endpoint was the occurrence of aggressive cutaneous SCC after the second transplantation. Secondary endpoints included the course of skin cancers over 3 periods (first transplantation, return to dialysis, second transplantation), the time to occurrence, and risk factors for aggressive SCC after retransplantation. Results The first SCC developed in 47 patients with a functional graft and in 6 after return to dialysis. After the first transplantation, 17 (33.3%) patients developed SCC in dialysis and 39 (73.6%) after the second transplantation, respectively. Twenty aggressive SCC developed over the study period. They occurred in 14 (26.4%) patients after retransplantation vs 5 (9.4%) after the first transplantation with a median delay of 50 months and were responsible for 5 deaths. Fair skin type, multiple tumors before retransplantation, treatment with azathioprine, T cell-depleting antibodies, and delayed revision of immunosuppression were associated with an increased risk of aggressive cutaneous SCC after retransplantation. Conclusions Candidates to retransplantation with a history of posttransplant SCC have a high risk of aggressive SCC. Our data suggest that the risk could be reduced by a tailored immunosuppression. A wait period may be required depending on the clinicopathological characteristics of the previous SCC and discussed on an individual patient basis.

The aims of this study were to determine the clinical and histological characteristics of melanoma in transplant recipients, the mutation profile (BRAF, NRAS and c-KIT genes), and the immune tolerance of the tumour microenvironment by immunohistochemical study of the expression of indoleamine 2,3-dioxygenase (IDO), PD1, PD-L1, CD8 and FoxP3. The study population comprised patients who had undergone a renal transplant in Nantes University Hospital who developed post-transplantation melanoma. Twenty cases of melanoma out of 4,663 transplant recipients were studied. The results differed from the usual data with respect to melanoma site: 40% were located on the face and were of the malignant lentigo type. The mutation profile was concordant with that of the immunocompetent population. IDO was expressed in all the sections tested, while CD8, FoxP3, PD1 and PD-L1 were poorly expressed. This reflected a highly immunodepressed tumour environment, raising the question of the inductive role of IDO on tumour immune tolerance in patients presenting with long-term immunodepression.

Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor–based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.

Tumor immune escape has recently been shown to be related to the development of an immune tolerance state of the microenvironment. Cytokines activating the immune system such as IFN-γ can be used to reverse the immune escape and thus to potentiate the efficacy of immunotherapy. A clinical study was conducted in 18 stage IIIc/IV melanoma patients treated with tumor-infiltrating lymphocytes (TILs) in combination with intratumoral TG1042 injection (adenovirus expressing IFN-γ). The primary objective was to investigate the safety of treatment. Secondary objectives were to study the clinical response and translational research. The treatment was well tolerated. Among the 13 patients evaluable for tumor response, 38.5 % had an overall objective response (OOR = CR + PR) and disease control rate (DCR = CR + PR + S) of 46 %. The clinical response of the 37 targeted lesions led to an OOR of 51 % and a DCR of 75 %. Translational research on predictive markers did not significantly differ between responder and non-responder patients. However, specifically regarding injected lesions, the clinical response correlated with CD3−/CD56+ NK cells which could be activated by TG1042. Further larger studies of this combined immunotherapy are needed to confirm our findings. Intralesional TG1042 combined with antigen-selected TILs should be discussed.

Merkel cell carcinoma (MCC) is a rare type of skin tumor that is derived from epidermal neuroendocrine cells. It is an aggressive tumor for which the 5-year survival rate is estimated at 64% for localized tumors, 39% in cases of regional invasion, and 18% for metastatic tumors.1 The standard treatment of the primary tumor is based on surgical resection with wide margins in conjunction with adjuvant radiotherapy. At the metastatic stage, in the absence of consensus, the most commonly proposed treatment is platinum/etoposide or doxorubicin chemotherapy, resulting in only a suspensive effect.2 We report the dramatic and sustained response to imatinib achieved in a patient with inoperable locally advanced Merkel cell tumor.

Vemurafenib is indicated for the treatment of patients with BRAF (V600)-mutant metastatic melanoma. We studied for the first time the characteristics of brain metastases developed during treatment with vemurafenib in real-life conditions. We included all patients treated over 3 years with vemurafenib in our department for metastatic melanoma without initial brain involvement. Our primary endpoint was to assess the incidence of brain metastases in these patients. Our secondary endpoints were to identify the risk factors for metastases occurrence and their characteristics and course. In our retrospective cohort of 86 patients, 20% had developed brain metastases on average 5.3 months after vemurafenib initiation. The median follow-up was 9 months (1-26 months). Radiological examinations revealed multiple brain metastases in 41% of patients. The only risk factor for metastasis occurrence identified was a high number of metastatic sites when initiating vemurafenib (p = 0.045). Metastasis development was associated with a trend toward a decrease in overall survival from 12.8 to 8.5 months (p = 0.07) and a significant decrease in progression-free survival from 7 to 5 months (p = 0.04). Among the patients who developed brain metastases, 82% died, of whom 64% within 3 months, versus 58% of patients without brain metastases over the same period. The extra-cerebral disease was well controlled in 59% of patients during brain progression. In vemurafenib-treated melanoma patients, brain metastases are frequent and associated with a particularly poor prognosis. Because of their high frequency in patients with controlled extra-cerebral disease, brain explorations should be systematically performed during treatment.

Background Basal cell carcinoma (BCC) is the most common cancer in humans. Vismodegib, a Hedgehog pathway inhibitor, has proved its effectiveness in treating non-resectable advanced BCC. Aim However, its action on squamous cell carcinoma (SCC) is unknown. We present three SCC cases developed into BCC in vismodegib-treated patients. Material and methods We have described three cases of patients developing SCC during treatment by vismodegib for BCC. Results Patient 1 was treated with vismodegib for five facial BCC. Due to the progression of one of the lesions at month 3 (M3), a biopsy was performed and showed SCC. Patient 2 was treated with vismodegib for a large facial BCC. A biopsy was performed at M2 on a BCC area not responding to treatment and showed SCC. Patient 3 was treated with vismodegib for a BCC on the nose. Due to vismodegib ineffectiveness, a biopsy was performed and showed SCC. Discussion Two similar cases have been described in the literature. This could be due to the appearance of the squamous contingent of a metatypical BCC or to the squamous differentiation of stem cells through inhibition of the hedgehog pathway. Conclusion In practice, any dissociated response of a BCC to vismodegib should be biopsied.

Rituximab is an anti-CD20 monoclonal antibody increasingly used in haematology and rheumatology, but also in internal medicine and dermatology. It has a good tolerance profile without known increased risk of cancer. We report a case of nodular melanoma with a 4.8 mm Breslow thickness that appeared after 2 years of rituximab in a 45-year-old patient with non-Hodgkin lymphoma. Fifteen additional rituximab-associated melanoma cases in 13 patients have been identified in the literature and in the EudraVigilance database. These patients were treated for various indications and had melanomas, often aggressive, initially diagnosed at a metastatic stage in 31% of cases. Our work raises the question of rituximab accountability in melanoma onset in these immunosuppressed patients. A dermatological monitoring seems necessary in patients treated with rituximab, especially in case of risk factors for melanoma. In case of individual melanoma history, the benefit/risk ratio of initiating rituximab therapy should be carefully assessed.

Temsirolimus belongs to the mammalian target of rapamycin (mTOR) inhibitors, targeted therapies for which indications are booming in oncology. While their tolerance is usually good, mucocutaneous toxicity is the most common, including stomatitis, rashes, edemas, pruritus, dry skin and nail disorders. The latter are common in clinical practice but have not yet been well characterized. We report 2 cases of patients who developed, after 6–7 months with temsirolimus, a dystrophy of the 20 nails with fragility, distal onycholysis, yellow discoloration, associated in 1 case with painful paronychia. Topical steroids improved the paronychia, without changing the nail dystrophy. To our knowledge, the occurrence of yellow nail discoloration with temsirolimus has never been reported before. We review the cutaneous and mucosal toxicities induced by temsirolimus and everolimus, two mTOR inhibitors used as anticancer agents and by their parent molecule sirolimus.

Resume Introduction La granulomatose lymphomatoide (GL) est une maladie lymphoproliferative tres rare, de type B, liee au virus d’Epstein Barr (EBV). Cette lymphoproliferation a une predilection pour trois organes : la peau, les poumons et le systeme nerveux central. Elle survient essentiellement chez des sujets immunodeprimes. Nous en rapportons ici un cas a revelation cutanee, survenu chez un sujet immunocompetent. Observation Un homme de 56 ans consultait pour des nodules erythemateux du tronc apparus dans un contexte de profonde alteration de l’etat general avec perte de 14 kg. En quelques jours, ces nodules evoluaient vers la constitution d’une necrose centrale. Deux semaines plus tard, une toux apparaissait et la tomodensitometrie (TDM) thoracique objectivait de multiples nodules parenchymateux pulmonaires. Les biopsies cutanees et pulmonaires mettaient en evidence un infiltrat constitue a la fois de lymphocytes T et B, avec presence d’elements lymphoides atypiques. La recherche d’EBV etait positive dans la peau et associee a une charge sanguine EBV elevee. Sur l’ensemble de ces elements, le diagnostic de GL etait pose. Malgre la mise en route d’une polychimiotherapie, le patient decedait rapidement. Discussion Le diagnostic de GL est souvent difficile. En effet, ce sont habituellement les signes generaux (alteration de l’etat general et perte de poids) qui sont au premier plan. Par ailleurs, l’analyse histologique des tissus preleves est souvent trompeuse du fait de l’infiltrat T reactionnel massif. Il est donc essentiel de savoir evoquer ce diagnostic sur l’association de manifestations cutanees et pulmonaires dans un contexte d’alteration de l’etat general, et de renouveler les biopsies si necessaire.

Regulatory T cells have already been associated with poor prognosis in various types of cancer. It was previously reported, in ovarian carcinoma, that quantification of Foxp3 identified a subgroup of patients characterized by a significantly worse prognosis in terms of overall survival (OS) and progression-free survival (PFS), suggesting that high expression levels of Foxp3 might represent a surrogate marker for an immunosuppressive microenvironment contributing to tumor immune escape. The main objective of the present study was to precise the prognostic value of Foxp3 regarding PFS and OS in stage III (AJCC) melanoma patients. Total RNA was isolated from 102 metastatic melanoma lymph nodes and from eight tumor-free lymph nodes. Real-time PCR for Foxp3 was performed and correlated with patients' outcome. Quantification of Foxp3 identified a patient subgroup (>90th percentile), which is characterized by a significantly worse prognosis in terms of PFS (P = 0.000271) but not in terms of OS (P = 0.11). In conclusion, quantification of Foxp3 expression using qPCR appears as an independent prognostic factor for PFS in stage III melanoma patients (AJCC). High Foxp3 expression might thus enable the identification of patients most at risk of relapse.

Background Primary melanoma ulceration is a factor of poor prognosis at the local and regional stage. The physiopathological mechanisms which explain its prognostic impact are still little known. However, two recent studies suggest that it could be a predictive factor of good response to a non-specific immunotherapy (interferon-alpha) and to an active immunotherapy (vaccine). Objective The aim of this study was to determine whether ulceration could be a factor of good prognosis in the context of an adoptive immunotherapy with tumour infiltrating lymphocytes (TIL) in stage III regional lymph node metastatic melanoma (sixth American Joint Committee on Cancer staging system) and whether it was associated with an improvement in the effectiveness of this treatment compared with the control group. Methods We have included all the patients treated in open prospective randomized TIL vs. control protocols in our unit from 1997 to 2009. Clinical data were derived retrospectively from patient files. Statistical analysis was performed using log-rank tests, Cox models and tests for interaction. Results A total of 144 patients were included. In the group of 80 patients treated with TIL, primary melanoma ulceration remained a pejorative factor for relapse-free and overall survival in univariate and multivariate analysis. The presence of ulceration did not change the effectiveness of TIL treatment in comparison with the control group with regards to relapse-free and overall survival. Conclusion Our study demonstrates that primary melanoma ulceration does not have any impact on the response to TIL adoptive immunotherapy and thus does not confirm its positive prognostic value suggested by two other immunotherapy approaches.

Please cite this paper as: Absence of modulation of CD4+CD25high regulatory T cells in CTCL patients treated with bexarotene. Experimental Dermatology 2010; 19: e95–e102. Abstract: Cutaneous T-cell lymphoma (CTCL) are a heterogeneous group of lymphoproliferative disorders, characterized by the infiltration of the epidermis by mature and activated malignant CD4+ T-lymphocytes. Retinoids such as retinoic acid and synthetic analogues have long been used alone or in combination with other therapies for CTCL. Bexarotene, the first synthetic highly selective RXR retinoid, was approved for the treatment of all stages of CTCL in patients refractory to at least one systemic therapy. Recently, six cases in which the initiation of bexarotene therapy for CTCL was associated with the progression of internal disease despite improvement of cutaneous signs and symptoms were reported. Moreover, it has been established that retinoids promote the generation of CD4+ Foxp3+ regulatory T cells, raising the question of an induction of regulatory T-cells by bexarotene. The aim of this work was to determine if bexarotene induces an increase of functional regulatory T cells which could play a role in the development of secondary extra-cutaneous lymphomas. Regulatory T cells were studied both in cutaneous biopsy specimens using an immunohistochemical analysis of CD4, CD25 and Foxp3 and in blood where proportion and functionality of circulating CD4+CD25high T-cells were determined. The study was performed in 10 patients [five patients with Sezary syndrome (SS) and five mycosis fungoides (MF)], treated for 6 months with bexarotene. Four healthy donors were used as controls for phenotypic and functional analysis on PBL. We found that the frequency of CD4+CD25high Treg cells was not significantly different before starting bexarotene and after 6 months of treatment in CTCL patients. However, we observed that the frequency of CD4+CD25high Treg cells before the beginning of the treatment was significantly increased compared to healthy donors. In addition, functional assays demonstrated that Foxp3 expressing CD4+CD25high T-cells were capable of suppressing autologous CD4 + CD25− T-cell proliferation. In the present work, we detected the presence of functional circulating CD4+CD25high Foxp3+ regulatory T-cells in CTCL patients, with an increased frequency compared to healthy donors. The treatment with bexarotene does not seem to affect the regulatory T-cell compartment.

Primary cutaneous B-cell lymphomas are a rare entity. They are included in the distinct classification of primary cutaneous lymphomas, the WHO-EORTC. In order to be confirmed, the primary nature of a cutaneous lymphoma requires that negative results of a CT scan of the chest, abdomen and pelvis and of a bone marrow biopsy (BMB) be obtained. Nevertheless, there is a question as to whether BMB should be performed routinely in view of the good prognosis of certain cutaneous B-cell lymphomas and the invasive nature of the examination. To answer that question, we studied retrospectively 62 cases of cutaneous B-cell lymphomas in which a BMB was performed. In 4 cases, lymph nodes, and in one case pancytopenia were identified during the initial evaluation performed at the same time as BMB and thus these patients were excluded from the analysis. Among the 57 patients, the BMB was positive in only 3 patients (5.2%). Interestingly, the positivity of the biopsy did not significantly affect the way that the treatment was given. In conclusion, this study demonstrates that it is not indispensable to perform a routine BMB for a Primary cutaneous B-cell lymphoma with cutaneous lesions on examination and with negative CT Scan and blood laboratory evaluations.

Ipilimumab is a monoclonal antibody blocking the inhibitory molecule CTLA4 expressed by activated T lympocytes, used for the treatment of metastatic melanoma. Recent studies have shown its potential efficacy on brain metastases. Objectives: To assess the development of brain metastases under ipilimumab and identify clinical, histological or evolving criteria related to the appearance of these metastases. A retrospective study was conducted in 52 patients treated with 4 cycles of ipilimumab 3 mg/kg every 3 weeks for unresectable stage III or stage IV melanoma between January 2011 and July 2013 in a Department of Dermato-Oncology. As no data has been find in the literature, the results were compared to our other cohort of patients treated with vemurafenib during the same period. Ten patients (21.7 %) developed brain metastases under ipilimumab in a median time of 6.58 months after treatment initiation. The multivariate analysis showed a lower rate of brain metastases in patients with acral lentiginous melanoma and melanoma of unknown primary site. The median survival after diagnosis of brain metastases was of 2.5 months. There was no significant difference with vemurafenib-treated patients in terms of incidence rate of brain metastasis, time of development and survival after diagnosis of cerebral metastases. This was the first study focused on the development of brain metastases under treatment with ipilimumab 3 mg/kg. Although ipilimumab is used for the treatment of brain metastases, it paradoxically did not seem to reduce the risk of developing brain metastases.

Vemurafenib is a BRAF inhibitor indicated in metastatic or unresectable melanoma in patients with BRAF mutations. Vemurafenib is frequently toxic, but the toxicity is often not serious. The third case of vemurafenib-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is reported herein. The case is unusual in that the onset was early, with symptoms emerging as of day 8 of treatment. Treatment of DRESS syndrome is not currently based on precise recommendations, but systemic corticosteroid therapy is effective in serious cases. Severe toxidermias under vemurafenib are exceptional; immediate discontinuation of treatment upon diagnosis is imperative. Switching from vemurafenib to dabrafenib then seems to constitute an interesting therapeutic alternative, since its efficacy is the same but with fewer cutaneous adverse reactions. This case highlights the importance of awareness of the risk of DRESS syndrome associated with vemurafenib and monitoring for warning signs from treatment initiation.

Background Vemurafenib, a BRAF inhibitor, is commonly associated with skin toxicity. The impact of severe forms is unknown. Objective To determine the rate of permanent vemurafenib discontinuation due to grade 3–4 skin toxicity, features of these toxicities, their recurrence rate after a switch to dabrafenib and their impact on overall survival. Methods Retrospective cohort study of 131 patients treated with vemurafenib for melanoma between November 2010 and December 2014. Data on skin toxicities, the need for vemurafenib adjustment and the impact of switching to dabrafenib were collected. Regarding survival analysis, a conditional landmark analysis was performed to correct lead-time bias. Results Among the 131 vemurafenib-treated patients, 26% developed grade 3–4 skin toxicity. Forty-four percent of them permanently discontinued their treatment, mainly due to rash and classic skin adverse reactions (Steven–Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms). Conversely, photosensitivity and carcinomas rarely required treatment adjustment. Grade 3–4 rashes were associated with clinical or biological abnormalities in 94% of patients. Among the 10 patients who subsequently switched to dabrafenib, skin toxicity recurred only in one patient. Overall survival was significantly prolonged in case of severe skin toxicity emerging within the first 4 (P = 0.014) and 8 weeks (P = 0.038) on vemurafenib, with only a trend at 12 weeks (P = 0.052). Median overall survival was also prolonged in case of severe rash. Conclusion In this study, vemurafenib was continued in 56% of patients with grade 3–4 skin toxicity, which was associated with prolonged overall survival when emerging within the first 4 and 8 weeks of treatment. While developing severe skin adverse reactions permanently contraindicates vemurafenib use, other rashes should lead to retreatment attempts with dose reduction. In case of recurrence, dabrafenib seems to be an interesting option. For other skin toxicities, including photosensitivity and cutaneous carcinoma, treatment adjustment is usually not needed.

Introduction La toxicite cutanee des traitements anticancereux est frequente. La classification actuelle de reference de leur grade est la NCI-CTCAE V4.0 (National Cancer Institute – Common Terminology Criteria for Adverse Events), peu adaptee en pratique quotidienne pour les toxicites cutanees. Cette difficulte d’utilisation s’est accentuee avec l’apparition des nouveaux traitements en cancerologie, responsables de toxidermies variees et nombreuses. Nous avons donc voulu creer un outil d’utilisation facile en pratique quotidienne pour identifier et grader les toxicites cutanees des traitements anticancereux et ainsi aboutir a une harmonisation de leur cotation. Materiel et methodes Creation d’un guide pratique des toxicites cutanees des traitements anticancereux les plus frequemment rencontrees. Celui-ci est base sur la CTCAE mais adapte aux lesions cutanees et inclut la description de nouvelles toxicites. Les differentes atteintes (items) ont ete regroupees en categories pour faciliter l’utilisation de l’outil. Chaque item a ete associe a une photographie pour en faciliter la reconnaissance, a la liste des molecules imputables et a une echelle de gravite derivee de la CTCAE mais simplifiee. Ce travail a ete realise au sein du service par un groupe compose de dermato-oncologues, dermato-allergologues et de l’equipe de recherche clinique. Ce groupe a revu toutes les toxicites severes ou inhabituelles induites par les traitements anticancereux, rencontrees dans le service depuis 6 mois. Resultats A partir de 32 observations et de notre experience, nous avons identifie 27 items classes en 7 categories : eruptions cutanees/toxidermies, xerose/prurit, papules hyperkeratosiques, atteintes palmoplantaires, atteintes des phaneres, atteintes muqueuses, autres. Un grade de severite allant de 1 (minime) a 5 (deces) etait defini pour chaque item. Discussion En pratique clinique quotidienne, la description et la cotation de la severite des lesions cutanees induites par les traitements anticancereux peuvent differer entre 2 evaluateurs et meme chez un seul d’un moment a l’autre. Une harmonisation est donc utile pour optimiser la prise en charge puisque la conduite a tenir vis-a-vis du traitement peut varier en fonction du type de toxicite et de sa severite. Avec la creation de ce livret, nous presentons un outil pratique unique et novateur, axe a la fois sur la semiologie et les grades de severite des lesions cutanees. Conclusion Nous avons cree un outil afin de faciliter au quotidien la reconnaissance et la gradation de la severite des toxicites cutanees des traitements anticancereux. L’impact de cet outil sur l’attitude therapeutique reste a valider.

A 77-year-old patient treated with ipilimumab (anti-CTLA-4 antibody) for metastatic melanoma developed autoimmune pancytopenia (anemia, thrombocytopenia, and neutropenia) 8 days after the fourth infusion. This pancytopenia was resistant to high-dose oral corticosteroids (1 mg/kg) and to hematopoietic growth factors. It resolved after intravenous immunoglobulins injection. To date, only 1 case of autoimmune pancytopenia has been reported after this treatment. According to the case that we report, it seems essential to control the leukocyte count before any injection of ipilimumab.

The relationship between BRAF mutations and the patient clinical profile is still under question. The objective of the present study was to correlate the BRAF mutation status in primary and metastatic melanomas with the clinicopathological profile, disease-free (DFS) and overall survival (OS). A total of 367 melanoma samples from 278 patients were screened for their BRAF status using a combination of allele-specific amplification and DNA sequencing. Two or three tissue samples from the same patient were available for 74 patients. The clinicopathological characteristics were tested for their association with the BRAF mutation using the Fisher's or Pearson's χ2 test. Log-rank tests and Cox models were used for survival analyses. BRAF mutation was found in 152 samples (41.4%). Ten of the 74 patients with several tissue samples (13.5%) had discordant BRAF mutation results. BRAF-mutated patients were significantly younger at the time of primary melanoma and first diagnosis of metastasis than BRAF wild-type patients but with no difference in DFS and OS. According to our results, a primary melanoma with BRAF mutation is not associated with a more aggressive illness.

Esthetic or functional repercussions in localized scleroderma may be considerable. Numerous treatments have been proposed with limited effectiveness. The purpose of this study was to evaluate the efficacy of high-dose zinc gluconate in the treatment of morphea. We are reporting a retrospective study of 17 patients with histologically confirmed localized scleroderma active for more than one year and whose treatment with a high potency dermocorticosteroid was a failure. The patients received 60 to 90 mg of zinc metal daily. The clinical evaluation was performed by the physician and the patient. An efficacy of 53% was obtained (5 partial remissions and 4 complete remissions) with a mean dose of 83.3 mg/day of zinc metal. Two patients (11.8%) had epigastralgia; no discontinuation of zinc gluconate for poor tolerability was noted.We conclude that high-dose zinc gluconate can therefore be a valuable alternative treatment for localized scleroderma, with good tolerability, although placebo-controlled studies are necessary to confirm our results.

There are several approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are one of the major biologic response modifiers used in CTCL, producing good response rates but few complete responses. Bexarotene has been demonstrated to act on malignant T-cells by inducing their apoptosis, but nothing is known about its role on keratinocytes and Langerhans cells. Immunohistochemical analysis using CD1a, HLA-DR, ICAM-1 (activation markers), CD95 and CD40 (apoptosis markers) was conducted on frozen sections of bexarotene-exposed cutaneous explants and skin biopsy specimens from patients treated with bexarotene. None of the studied markers was significantly modulated both on cutaneous explants and on skin biopsy specimens after treatment with bexarotene, compared to controls. Langerhans cells and keratinocytes do not appear to play a central role in the therapeutic control of CTCL by bexarotene therapy. The main bexarotene's target thus remains T-cells by inducing their apoptosis, a mechanism that is different from the other retinoids used in CTCL.

Background: Hidradenitis suppurativa (Verneuil’s disease) is a chronic suppurative dermatosis involving apocrine glands with a severe impact on the quality of life, which is enhanced by the fact that the drugs usually prescribed are poorly effective. Objective: We discuss a new therapeutic approach based on zinc salts. Methods: We performed a pilot study on 22 patients, mainly from grade I or II in Hurley’s classification. All included patients had previously been prescribed a treatment (antibiotic, isotretinoin, surgery or anti-androgens), which was inefficient. They were then treated with 90 mg of zinc gluconate per day (15 mg zinc per Rubozinc® capsule). Results: We observed a clinical response in all patients, with 8 complete remissions (CR) and 14 partial remissions (PR). When CR was obtained, the treatment was progressively decreased (average of 3.5 capsules/day); 4/22 patients experienced side-effects, mainly gastro-intestinal. Conclusion: Zinc salts could provide a new therapeutic alternative for the treatment of hidradenitis suppurativa.

Introduction Si les nouveaux traitements ont revolutionne la prise en charge du melanome metastatique, leur place a un stade plus precoce (stade IIIb) implique de considerer le rapport benefice/risque. Dans ce contexte, mieux definir les patients pour lesquels un traitement adjuvant pourrait etre indique, est un objectif important, auquel nous avons essaye de repondre, en etudiant le niveau d’expression de molecules impliquees dans l’activation du lymphocyte T au sein du tissu tumoral ganglionnaire. Materiel et methodes Cette etude retrospective monocentrique a inclus, de janvier 2013 a janvier 2015, tous les patients atteints de melanome stade IIIb AJCC ganglionnaire et traites par curage. Les marqueurs suivants ont ete etudies par une technique d’immunohistochimie : CD4, CD8, B7-1, B7-2, CTLA4, Foxp3, Melan-A, tyrosinase, gp100, pan-MAGEs, BTLA, IDO-1, LAG-3, PD-1, PD-L1, PD-L2 et TIM-3. En parallele, les donnees cliniques du patient, les dates de recidive et de deces etaient recueillies. La survie a ete etudiee par Log-rank test et l’analyse multivariee realisee selon le modele de Cox. Resultats Cinquante-quatre patients ont ete inclus. Le type du melanome primitif etait : 23 SSM, 10 nodulaires, 7 acrolentigineux, 1 Dubreuilh, 1 muqueux, 2 sans primitif retrouve et 10 autres. Le Breslow moyen etait de 4,85 ± 1,6 mm. Les mutations BRAF et NRAS etaient presentes respectivement dans 41 % et 31 % des cas. Le nombre de ganglions envahis au curage etait de 1 dans 42 % des cas et > 1 dans 58 %. Vingt-huit patients (52 %) ont rechute apres un delai moyen de 7,4 mois et 13 patients (24 %) sont decedes. L’expression de CD8, gp100, tyrosinase ou PD-1 au niveau du ganglion envahi, etait associee a une meilleure survie globale (p Discussion Cette etude nous a permis d’etablir un profil de patients atteints de melanome metastatique stade IIIb a risque plus eleve de rechute avec une diminution de la survie globale. Chez ces patients, l’expression de CTLA4, B7-2 et IDO est forte associee a une faible expression de gp 100, de tyrosinase ainsi que des lymphocytes CD8+ PD1+. Le lien entre expression d’IDO ou de CTLA4 et un mauvais pronostic a deja ete rapporte chez des patients atteints de melanome mais sur cellules circulantes et non pour B7-2 a notre connaissance. Conclusion Ces resultats preliminaires confortent l’importance d’identifier des biomarqueurs, permettant de selectionner des sous-groupes de patients de moins bon pronostic justifiant de traitements adjuvants.

Introduction Le sarcome a cellules claires (SCC) est une entite rare qui touche preferentiellement les tissus mous profonds des membres inferieurs Le diagnostic est pose sur des arguments histologiques, immuno-histochimiques et de biologie moleculaire. Cependant, beaucoup de SCC restent diagnostiques comme metastases de melanome, d’autant plus que les caracteristiques moleculaires ne sont qu’en partie connues. Observation Nous rapportons ici le cas d’une patiente de 64 ans adressee pour une tumefaction pre-tibiale droite de 30 × 20 mm. La biopsie concluait a une metastase de melanome avec une proliferation dermique de cellules tumorales en nappes ou en travees sans pigment intracytoplasmique, exprimant fortement PS100, HMB 45 et Melan A. Le bilan d’extension etant negatif, une exerese de la lesion etait pratiquee. L’analyse anatomopathologique trouvait des cellules epithelioides de taille moyenne a cytoplasme eosinophile avec de volumineux noyaux, sans cellules geantes multinucleees. L’immuno-histochimie etait identique mais devant un aspect morphologique atypique, le diagnostic differentiel de SCC etait evoque, motivant une recherche specifique en biologie moleculaire. On trouvait ainsi un rearrangement du gene EWS en FISH, qui est specifique du SCC. Le transcrit de fusion EWS/ATF1 n’a pas ete mis en evidence mais il pourrait s’agir d’un transcrit rare comme EWSR1/CREB1. En parallele, on trouvait egalement une mutation BRAF V600E. La patiente est actuellement consideree en remission complete et suivie tous les 2 mois. Discussion Le SCC est decrit comme etant une tumeur des parties molles avec une translocation t(12;22) et un rearrangement du gene ESWR avec transcrit de fusion le plus souvent EWS/ATF1 qui, lorsqu’il est present, est pathognomonique. Concernant l’association avec la mutation du gene BRAF , celle-ci a ete decrite dans 5 cas seulement dans la litterature sur 3 publications differentes. Une etude retrospective de 52 patients atteints de SCC de 1979 a 2005 a montre que seuls 3 % (2 cas) avaient la mutation. Notre cas illustre donc qu’une mutation du gene BRAF dans le SCC est exceptionnelle mais possible et ne doit donc pas etre consideree comme un argument de diagnostic d’une metastase de melanome. L’etude du gene EWS doit toujours etre faite en cas de doute diagnostique. Conclusion La presence de cette mutation BRAF chez notre patiente presentant un SCC ouvre la possibilite d’un traitement par inhibiteur de BRAF en cas de recidive non extirpable.

Introduction Peu de donnees existent concernant la recherche translationnelle sur les melanomes des patients greffes. Nous avons etudie chez les patients transplantes de rein au CHU de Nantes les caracteristiques cliniques, mutationnelles et l’immunite innee des melanomes survenus apres greffe. Patients et methodes Il s’agissait d’une etude monocentrique retrospective incluant les patients transplantes de rein ayant developpe un melanome post-greffe, de 1970 a aout 2013. Ils ont ete identifies a partir de la consultation dermatologique dediee au suivi des patients transplantes et de la base Divat, « donnees informatisees et validees en transplantation » de l’institut de transplantation uro-nephrologie. Les caracteristiques cliniques, histologiques, le statut mutationnel et l’expression des marqueurs IDO, PD-1, PD-L1, CD8, foxP3 en immuno-histochimie (IHC) ont ete recueillies. Resultats Nous avons recense 20 melanomes parmi 4663 greffes renaux : 13 hommes et 7 femmes. L’âge moyen a la transplantation etait 47,7 ans, et 60,46 ans lors du diagnostic de melanome. La duree moyenne de suivi etait 16,1 ans. On notait 5 deces (22,7 %) lies au melanome, en moyenne 2,48 ans apres le diagnostic. L’indice de Breslow (Br) moyen/median etait de 3,08 mm/1,56 mm. On notait 9 SSM, 3 nodulaires, 2 muqueux, 4 melanomes de Dubreuilh, 1 inclassable. Trois melanomes sur 8 survenaient sur naevus preexistant. Quatre melanomes se localisaient sur le tronc, 8 sur le visage, 4 au membre superieur ; 2 au membre inferieur et 2 etaient muqueux. Six melanomes etaient depistes en consultation dediee (Br moyen 1,28 mm) et 9 en consultation de ville (Br moyen 3,11 mm). Il y avait 4 (40 %) cas avec mutation BRAF et 6 non mutes BRAF ; 3 avec mutation NRAS et 10 non mutes NRAS, aucun cas mute c-kit. On ne trouvait pas d’expression de PD-1, PD-L1, foxp3 ; CD8 etait faiblement exprime dans 6 blocs sur 17, IDO etait exprime dans tous les blocs testes. Discussion 20 melanomes ont ete recenses sur un seul centre. Par rapport a la litterature, le delai de survenue de melanome est plus important, pouvant etre explique en partie par une duree de suivi plus longue (16,1 ans). On trouve moins de SSM et plus de melanomes de Dubreuilh que dans la population immunocompetente, avec davantage de localisations cephaliques et moins sur le tronc, faisant poser la question d’exposition UV chronique comme facteur de risque dans cette population. La consultation dermatologique dediee permet de suivre de facon reguliere les patients, limitant les perdus de vue, et permettrait de diagnostiquer les melanomes a un stade plus precoce. La proportion de cas mutes BRAF concorde avec celle des sujets immunocompetents, permettant d’envisager une therapie ciblee en cas de melanome metastatique. Il est a noter l’absence d’expression de PD-L1 ce qui pourrait diminuer l’efficacite des anti-PD-1 par rapport a la population generale.

Introduction Les anti-PD-1 font parties des immunotherapies utilisees dans le traitement du melanome metastatique. Leurs effets secondaires cutanes sont frequents (environ 30 %, rash maculopapuleux et prurit majoritairement). Nous rapportons le cas original d’un patient traite par nivolumab, ayant presente a la deuxieme perfusion un erytheme polymorphe majeur. Observation Un homme de 67 ans etait suivi pour un melanome de stade IV de primitif lingual BRAF sauvage avec cibles ganglionnaires et cutanees. Il avait pour principal antecedent un syndrome metabolique. Suite a une progression sous ipilimumab n’ayant induit aucun effet secondaire, il avait ete decide un traitement par nivolumab (anti-PD-1) a la dose de 3 mg/kg tous les 15 jours. Vingt-quatre heures apres la deuxieme perfusion, le patient presentait une eruption erythemato-papuleuse avec cocardes et une atteinte des muqueuses sans atteinte oculaire ni fievre. Il n’etait pas trouve d’autre prise medicamenteuse recente. Les PCR virales (HHV6, parvovirus B19, CMV, EBV et HSV 1–2) etaient negatives ainsi que la serologie mycoplasme. Le bilan biologique montrait un syndrome inflammatoire modere (CRP a 22,8 mg/L ; N Discussion Les anti-PD-1 sont des traitements tres prometteurs qui ont fait leurs preuves dans le melanome metastatique. Des reactions d’hypersensibilite ont deja ete rapportees sous forme de rashs cutanes mais a notre connaissance, les toxidermies bulleuses n’ont jamais ete decrites. La question soulevee par ce cas est celle de la reintroduction du traitement, avec d’un cote le risque d’une toxidermie plus severe (syndrome de Stevens-Johnson, voire de Lyell) et de l’autre le controle de la maladie metastatique. Conclusion Nous rapportons le premier cas original d’un erytheme polymorphe majeur sous anti-PD-1. Notre observation montre qu’un tableau d’erytheme polymorphe justifie d’un arret definitif de l’anti-PD-1.

Background: Vemurafenib is a BRAF inhibitor indicated for the treatment of metastatic melanoma. We report the two first cases of severe and prolonged radiotherapy-induced visceral toxicity in patients treated concomitantly with vemurafenib: a brain radionecrosis and an anorectitis. It raises the question of both the risks of this association and its benefit in melanoma. Observations: The first patient, a female aged 32, treated with vemurafenib for three months, presented a steroid-dependent radionecrosis after brain stereotactic radiosurgery. Symptoms persisted until her death six months later. The second patient, a male aged 64 and treated with vemurafenib for nineteen days, presented a radiation-induced anorectitis complicated by diarrhoea, anorexia and weight loss following the concomitant radiation of a primary rectal tumour. A colostomy was needed after ten months in order to improve local status and general health. Conclusions: In our patients, the radiotherapy-induced toxicity under vemurafenib was unusual in its intensity and duration, suggesting a radiosensitization phenomenon. This hypothesis is reinforced by the publication of six cases of severe radiodermatitis under vemurafenib and by in vitro data. The combination of vemurafenib and radiotherapy should thus lead to discussion of a transient cessation of vemurafenib, given the severity of the adverse events experienced. Meanwhile, further studies are needed to determine the potential benefit of this combined treatment in metastatic melanoma.

International audience; Background: Publications reporting photodynamic therapy (PDT) in mycosis fungoides (MF) are rare, involve small samples, and are difficult to compare because of a lack of technical standardization. Objective: We sought to assess PDT effectiveness and tolerability in early-stage MF using a strict reproducible procedure. Methods: This was a prospective study conducted in Nantes University Hospital, France, including patients older than 18 years with histologically proven MF (stage IA or IB). Methyl-aminolevulinic acid-PDT sessions were repeated monthly for 6 months. Clinical and histologic responses were assessed 1 month after the last session. Patient satisfaction was assessed by telephone survey. Results: Twelve patients (with 29 lesions) were treated with PDT. An objective response in target lesions was obtained in 75% of patients. Response rates were similar between plaques and patches but higher in sun-protected compared with sun-exposed areas (trend without reaching significance). During PDT, new lesions appeared in 5 of 12 patients in untreated areas. Most patients were highly satisfied and preferred PDT to the topical chemotherapy previously used. Limitations: PDT procedure criteria selection was partially arbitrary. Conclusions: In early-stage MF, PDT is effective and appreciated (especially when compared with conventional topical chemotherapy). Unilesional and paucilesional forms and lesions in sun-protected areas are to be preferred.

Introduction Les melanomes de la muqueuse genitale feminine sont rares et ont un pronostic encore plus sombre que les cutanes. L’anti-CTLA4 ipilimumab et les anti-PD1 pourraient etre des options therapeutiques mais il y a tres peu d’element dans la litterature quant a leur efficacite dans cette indication. Patientes et methodes Etude retrospective de toutes les patientes vues dans notre unite et traitees par anti-CTLA4 ou anti-PD1 pour un melanome vulvovaginal inextirpable ou metastatique. Resultats Cinq patientes ont ete traitees par ipilimumab (Yervoy ® ), dans 4 cas pour des metastases muqueuses et ganglionnaires loco-regionales (stade IIIc inextirpable) et dans le dernier cas pour des metastases hepatiques. Aucune n’avait de mutation pour B-RAF. Chez 4 patientes, aucune reponse tumorale n’a ete obtenue ; ces patientes sont decedees avec un delai median de survie de 9,6 mois. Chez la cinquieme patiente, qui recevait l’ipilimumab en 1 re ligne a un stade IIIc inextirpable, une reponse partielle profonde (−82 %) a ete obtenue 3 mois apres la 4 e perfusion d’ipilimumab. Cette reponse s’est maintenue 12 mois puis, en raison d’une reprise evolutive, le nivolumab a ete debute. Cette patiente est toujours en cours de suivi avec un recul de 28 mois apres ipilimumab. Cinq patientes ont ete traitees par anti-PD1, nivolumab, 4 pour des metastases muqueuses et ganglionnaires et la 5 e pour un melanome vulvaire primitif inextirpable. Aucune n’avait de mutation pour B-RAF. Une stabilite a ete obtenue pour 2 patientes ; ces patientes sont encore en cours de nivolumab (21 et 26 cures). Les 3 autres patientes ont progresse sous nivolumab. Apres un suivi median de 10 mois apres le debut du nivolumab, 4 des 5 patientes sont toujours en vie. Discussion L’ipilimumab a permis d’obtenir une reponse profonde et durable chez 1 patiente/5 (20 %). Seules deux etudes rapportant l’efficacite de l’ipilimumab dans les melanomes metastatiques primitivement muqueux ont ete publiees. La premiere rapporte l’utilisation de l’ipilimumab dans 71 melanomes muqueux metastatiques (dont 22 % vaginaux) avec un taux global d’efficacite de 12 % mais le taux de reponse des melanomes vaginaux n’est pas precise. La seconde rapporte l’utilisation de l’ipilimumab dans 33 melanomes muqueux dont 8 vulvovaginaux. Seules une 1 reponse complete et 1 reponse partielle ont ete obtenues. D’apres nos resultats, les taux de reponse obtenus avec l’anti-PD1 semblent plus decevants par rapport a ceux des melanomes cutanes dans la litterature. Meme si notre faible nombre de patients limite la valeur de ces resultats, ces donnees sont tres importantes car il n’y a actuellement dans la litterature aucune information sur l’utilisation de l’anti-PD1 dans les melanomes vulvovaginaux. Conclusion Notre etude confirme que l’ipilimumab est une option therapeutique dans les melanomes vulvovaginaux metastatiques. Le taux de reponse est faible mais ces reponses sont parfois durables.

Cutaneous squamous cell carcinomas (CSCC) are very common. Localized CSCC are cured by surgery and/or radiotherapy and have a better prognosis than locally inoperable advanced CSCC. Cetuximab has recently been proposed to treat locally advanced CSCC when surgery or radiotherapy cannot be offered.The authors report results of a pilot study conducted in inoperable CSCC patients treated with cetuximab alone or combined with chemotherapy or radiotherapy.This study was conducted in 20 CSCC patients. RECIST criteria were used to evaluate clinical and radiological responses.Five patients received cetuximab associated with radiotherapy (CR), nine with carboplatin (CC) and six as monotherapy (CM) over 1-month cycle treatment. Response to treatment was evaluated every two cycles. After 2 months of treatment, the authors observed nine partial responses, six stabilizations and four progressions. Disease control rate was of 78% (100% for CR, 87.5% for CC and 50% for CM) with a 47% response rate (80% for CR, 37.5% for CC and 33% for CM).The authors confirm the potential interest of cetuximab to treat unresectable advanced CSCC alone or combined with CC and CM. These results justify discussing a further randomized study combining radiotherapy and cetuximab.

The term phaeohyphomycosis refers to a rare group of fungal infections characterized by the presence of dark-walled hyphae or yeast-like cells in affected tissues. Herein, we report on the clinical and epidemiological characteristics of six cases of phaeohyphomycosis due to Alternaria spp. that occurred in our hospital over a 30-month period (from January 2008 to June 2010). Interestingly, whereas histopathological examinations were positive and fungal cultures yielded molds in all cases, mycological identification using conventional phenotypic methods was never possible despite prolonged incubation of the isolates. Identification of Alternaria infectoria species complex was obtained for each isolate by amplification and sequencing of the internal transcribed spacer of the ribosomal DNA (ITS rDNA). All patients had favourable outcomes following the introduction of azole-based antifungal therapy. This case series describes the clinical course of these six patients and highlights the utility of molecular identification to help in the identification of the etiologic agent when classical mycological methods have failed.

Background: Apparent skin lesions can impair quality of life (QoL). Objective: To assess QoL improvement brought by a medical corrective make-up lesson and its daily use in practice using the Dermatology Life Quality Index (DLQI). Methods: Patients with facial disorders participating during 2 years in our lessons conducted by a trained nurse were included in an open prospective study. Results: 86 patients aged 4–79 years were included. They suffered from acne (25), rosacea (10), scars (14) and various dermatoses (19). 63 patients (73%) sent back the questionnaire. One-month DLQI improvement was significant (p < 0.001) in acne (p = 0.006) as well as rosacea (p = 0.036), with a trend for scars (p = 0.057). QoL significantly improved, independently of a low (p < 0.001) or high (p = 0.006) initial DLQI. Since the lesson, 95% of patients re-made up with 97% of good tolerance. Conclusion: This is the first study examining at-home make-up completion and showing the beneficial effect of a medical corrective make-up lesson on the QoL of patients with various facial dermatoses in France.

The aim of this retrospective study was to assess the efficacy and tolerance of intravenous rituximab in multifocal primary cutaneous follicle centre lymphomas (PCFCL). Eleven patients with a multifocal PCFCL were treated with rituximab (MabThera(®)) administrated intravenously. After four infusions, an objective response was observed in 90% of patients, and one month after all the infusions (median of 6 infusions) all the patients had an objective response and complete remission was obtained in 7 of 11 patients (64%). Follow-up ranged from 9 to 65 months (median: 30 months). Local disease recurrence was observed in five patients. The median progression-free survival time after the end of treatment was 23.6 months. This study is the largest series of patients with multifocal primary PCFCL treated with intravenous rituximab. This therapy is a safe and effective treatment and could represent an excellent alternative treatment to radiotherapy.

Regulatory T cells have already been associated with poor prognosis in various types of cancer. It was previously reported, in ovarian carcinoma, that quantification of Foxp3 identified a subgroup of patients characterized by a significantly worse prognosis in terms of overall survival (OS) and progression-free survival (PFS), suggesting that high expression levels of Foxp3 might represent a surrogate marker for an immunosuppressive microenvironment contributing to tumor immune escape. The main objective of the present study was to precise the prognostic value of Foxp3 regarding PFS and OS in stage III (AJCC) melanoma patients. Total RNA was isolated from 102 metastatic melanoma lymph nodes and from eight tumor-free lymph nodes. Real-time PCR for Foxp3 was performed and correlated with patients' outcome. Quantification of Foxp3 identified a patient subgroup (90th percentile), which is characterized by a significantly worse prognosis in terms of PFS (P = 0.000271) but not in terms of OS (P = 0.11). In conclusion, quantification of Foxp3 expression using qPCR appears as an independent prognostic factor for PFS in stage III melanoma patients (AJCC). High Foxp3 expression might thus enable the identification of patients most at risk of relapse.

Melanoma is one of the fastest growing cancers worldwide. We need to have tools to identify patients with high risk of melanoma. We carried out a case-control study and tested three methods to develop an individual score of melanoma risk, usable in routine practice. All cases included newly diagnosed invasive cutaneous melanoma of stage I or II (6th American Joint Committee on Cancer) seen in 2007 at the Skin Cancer Unit of Nantes Hospital, France. Controls included 1500 consecutive patients consulting their general practitioners. A self-administrated questionnaire was used for assessment of melanoma risk factors. Three methods of scoring were used and compared: one with common relative risks reported in the literature, one with odds ratios estimated by logistic regression, and a combinatorial analysis. The method based on combinatorial analysis permitted one to obtain a simple rule to define individuals at risk: the association of the rule 'presence of at least three risk factors or presence of more than 20 naevi on the arms' for the patients aged under 60 years and 'presence of at least three risk factors or presence of freckles' for the patients aged 60 years and above (sensitivity: 63.2% and specificity: 68.8%). The tool we propose is easy to use every day in routine health care to select patients with high risk of melanoma. It can be assessed without any computer or calculator and is based on the self-assessment of the melanoma risk factors by the patient and thus is not medical time consuming.

Introduction La maladie de Verneuil est une maladie inflammatoire chronique associee a un deficit de l’immunite innee cutanee, qui se manifeste par des nodules douloureux pouvant s’abceder, des fistules et des cicatrices, typiquement dans les regions axillaires, inguinales et ano-perineales. A ce jour, il n’existe pas d’etude sur le deficit en vitamine D dans la maladie de Verneuil, or la vitamine D joue un role dans la regulation genique et stimule l’immunite innee cutanee via l’augmentation d’expression des toll-like receptors et des peptides anti-microbiens. L’objectif principal est d’evaluer si les patients sont plus deficitaires en vitamine D que les sujets sains. L’objectif secondaire est d’evaluer si la supplementation en vitamine D des patients permet une amelioration des lesions inflammatoires. Materiel et methodes Les patients inclus etaient suivis dans le service de dermatologie du centre hospitalier de Nantes pour une maladie de Verneuil, non traites ou sous gluconate de zinc, ayant donne leur consentement. Premier temps : nous avons compare leurs dosages de 25(OH)vitamine D a ceux realises a la meme periode chez des donneurs sains de l’etablissement francais du sang de Nantes (realises entre debut janvier et fin mars), avec un appariement de 1 pour 1 sur le sexe, l’âge, l’indice de masse corporelle, le tabagisme. Deuxieme temps : dans le cadre d’une etude pilote sur 6 mois, si deficit en 25(OH) vitamine (dosage Observations Le critere de jugement a 6 mois etait la diminution du nombre de nodules, avec un succes obtenu pour chaque patient si diminution d’au moins 20 %. Resultats Premier temps : les 22 patients inclus (100 %) etaient deficitaires en vitamine D, dont 36 % carences (dosages Discussion Notre etude montre que la maladie de Verneuil est associee a un deficit en vitamine D. Elle suggere que la vitamine D permet une amelioration significative des nodules inflammatoires, probablement en stimulant l’immunite innee cutanee via l’augmentation d’expression des toll-like receptors et des peptides anti-microbiens, et en regulant la proliferation keratinocytaire. Conclusion Cette etude est la premiere a montrer que la maladie de Verneuil est associee a un deficit majeur en vitamine D correle a la severite de la maladie. Ces resultats necessitent une confirmation par une etude randomisee.

Introduction La toxicite cutanee du vemurafenib est frequente, mais rarement severe. Nous rapportons la 1re serie de patients ayant presente une toxicite cutanee severe (grades 3–4) necessitant une adaptation therapeutique. Materiel et methodes Il s’agit d’une etude retrospective ouverte incluant tous les patients traites en 42 mois dans notre service par vemurafenib pour un melanome metastatique mute BRAFV600. Analyse des caracteristiques cliniques et du devenir des toxicites cutanees severes. Observations Quatorze patients sur les 126 traites par vemurafenib ont presente une toxicite cutanee severe (11 %) apres 9 jours en moyenne (2 a 19 jours). Resultats Cette toxicite regressait en moyenne en 24 jours (6 a 75 jours). Il s’agissait de onze rash maculopapuleux diffus, debutant par une atteinte photodistribuee chez 4 patients, d’un rash maculopapuleux du tronc et du visage, d’un DRESS syndrome pustuleux et d’un syndrome de Stevens Johnson (SJS). Six avaient des lesions cutanees associees : hyperkeratose palmoplantaire (3), photosensibilite (2), keratoacanthomes (1), papillomes multiples (1). Onze avaient des signes systemiques : 4 syndromes pseudo-grippaux, 4 alterations de l’etat general, 3 arthralgies. Dix avaient des anomalies biologiques : 7 insuffisances renales grade 1, 5 cytolyses hepatiques grades 1 a 3, 4 lymphopenies grades 1 a 2, et 3 hypereosinophilies grades 1 a 3. Cette toxicite cutanee induisait un arret du vemurafenib chez 5 patients d’emblee et chez 6 autres apres recidive des symptomes quelques heures apres reintroduction du vemurafenib a 75 % (n = 4) ou 100 % (n = 2) de la dose normale. Trois patients n’avaient pas de rechute a la reprise du traitement a 50 et 75 % de la dose. Cinq patients etaient traites par dabrafenib apres leur reaction cutanee severe au vemurafenib. Un seul a du l’arreter pour recidive de son rash maculopapuleux diffus des la reprise du traitement. Discussion Onze pour cent de nos patients traites par vemurafenib ont presente une toxicite cutanee severe (grades 3–4) necessitant soit un arret, soit une diminution de dose. Seuls 5 % des patients presentent des toxicites cutanees de grades 3–4 dans le cadre des protocoles therapeutiques, par rapport a notre etude se deroulant en pratique quotidienne. Deux de nos patients avaient un tableau de toxidermie classique : un DRESS syndrome traite par prednisone 1 mg/kg/j et un SJS spontanement resolutif. Parmi les 12 autres, seuls 25 % ont pu poursuivre le vemurafenib apres une reduction de la dose. Chez 4/5 patients le dabrafenib a ete une alternative n’induisant pas de toxidermie cutanee. Conclusion Notre etude montre pour la 1re fois que les toxicites cutanees severes au vemurafenib sont plus frequentes (11 %) que dans les protocoles. La reprise du vemurafenib etait possible chez un quart des patients a dose reduite. Nous montrons surtout pour la premiere fois que le dabrafenib est une alternative interessante pour ces patients. Cela amene a soulever l’hypothese de metabolites differents des 2 molecules au niveau de la peau.

Introduction L’urticaire solaire (US) est une forme rare d’urticaire physique declenchee par l’exposition solaire. Nous presentons ici un cas de semiologie trompeuse chez une patiente dont le T-shirt, porte le jour de la consultation, permettait d’evoquer une US avant sa confirmation par des phototests. Observations Une patiente de 30 ans, sans antecedents d’atopie, s’est presentee pour une eruption intermittente erythemateuse et prurigineuse evoluant depuis 3 ans et atteignant uniquement le tronc en ete et parfois le visage en hiver, sans symptomes systemiques associes. Le jour de sa consultation, la patiente portait un T-shirt sans manches, rouge raye de blanc. L’eruption etait erythemateuse, prurigineuse, legerement papuleuse, uniquement situee au niveau des bandes blanches, sans aucune atteinte des zones photo-exposees. Le diagnostic d’US etait suspecte devant le declenchement rapide apres 1/4 h d’exposition solaire et surtout leur disparition apres mise a l’ombre ( Les phototests ont confirme le diagnostic d’US et determine son spectre : la lumiere visible. Un double traitement anti-histaminique H1 a double dose a permis une nette amelioration cutanee. Une induction de tolerance solaire au printemps par expositions repetees de plus en plus longues sous antihistaminique a ete proposee a la patiente. Discussion L’US est une photodermatose dont l’agent photosensibilisant n’est pas encore connu, survenant habituellement chez des femmes entre 20 et 40 ans. Elle est caracterisee par des plaques urticariennes prurigineuses siegeant au niveau des zones exposees habituellement couvertes avec possibilite d’association a des signes systemiques. L’evolution est chronique avec des poussees estivales. La tolerance acquise l’ete sur les zones exposees (visage et dos des mains) est frequente et peut etre deroutante pour le diagnostic d’une photodermatose. L’atteinte paradoxale des zones couvertes comme le tronc peut etre expliquee par les rayons qui traversent les vetements legers et clairs, comme l’illustre bien notre observation. Les phototests confirment le diagnostic. Le spectre d’action interesse le plus souvent les UVA, le visible et moins frequemment les UVB. Les traitements proposes restent symptomatiques et n’ont qu’un effet suspensif. La photoprotection vestimentaire et les antihistaminique H1 associees a l’acquisition d’une tolerance a la lumiere par des expositions repetees sont les traitements de base. D’autres therapeutiques (immunoglobulines IV, omalizumab, αMSH) peuvent etre proposees dans les formes refractaires impactant la qualite de vie des patients. Conclusion En consultation dermatologique, tout detail meme banal peut constituer une aide majeure au diagnostic.

Psoriasis is thought to be associated with an increased risk of lymphoma. We report here the first case of an aggressive primary cutaneous pleomorphic T-cell lymphoma in a patient with psoriasis. The 36-year-old patient, who had previously been treated successively with methotrexate, ciclosporin and etanercept, presented with rapidly growing nodules on the leg. A biopsy confirmed a stage IVa primary cutaneous pleomorphic T-cell lymphoma. Despite treatment with pegylated liposomal doxorubicin, the disease progressed and the patient died 5 months later. This case of pleomorphic T-cell lymphoma was remarkable in both its extremely rapid onset and the aggressive nature of the disease. The onset of this disease in a patient with psoriasis who had been previously treated with immunosuppressive drugs and a tumour necrosis factor (TNF)-α blocker is of major interest. Only eight cases of cutaneous lymphomas associated with treatment with TNF-α blockers have been published previously. Most of these eight cases related to anti-TNFα antibodies; only two were linked to etanercept.

Primary cutaneous diffuse large B-cell lymphoma leg type (PCDLBCL-LT) is a rare type of lymphoma, of poor prognosis, which affects elderly people. Rituximab is an anti-CD20 monoclonal antibody and has demonstrated its efficiency in the treatment of nodal lymphomas. Rituximab with polychemotherapy has been reported in PCDLBCL-LT with a good response but many adverse effects. We evaluated the risk-benefit ratio of treatment with single-agent rituximab in a retrospective study on 8 patients with PCDLBCL-LT treated with rituximab. The main evaluation clinical endpoint was the rate of objective responses to the treatment. The secondary endpoints were the adverse effects, disease-free survival and overall survival. After 4 courses of single-agent rituximab, 75% of objective responses were achieved. 100% of patients relapsed (median disease-free survival: 5.25 months, median follow-up: 17.7 months). The tolerance was excellent with one adverse event (Grade I). Rituximab monotherapy induces a rate of objective responses which is less than rituximab with polychemotherapy, with no lasting therapeutic response. The tolerance of rituximab monotherapy is higher than rituximab with polychemotherapy. The risk-benefit ratio is a bit lower but rituximab is well tolerated and may be useful for short term palliative treatment.

Cutaneous T-cell lymphoma (CTCL) are a heterogeneous group of lymphoproliferative disorders, characterized by the infiltration of the epidermis by mature and activated malignant CD4+ T-lymphocytes. Retinoids such as retinoic acid and synthetic analogues have long been used alone or in combination with other therapies for CTCL. Bexarotene, the first synthetic highly selective RXR retinoid, was approved for the treatment of all stages of CTCL in patients refractory to at least one systemic therapy. Recently, six cases in which the initiation of bexarotene therapy for CTCL was associated with the progression of internal disease despite improvement of cutaneous signs and symptoms were reported. Moreover, it has been established that retinoids promote the generation of CD4+ Foxp3+ regulatory T cells, raising the question of an induction of regulatory T-cells by bexarotene. The aim of this work was to determine if bexarotene induces an increase of functional regulatory T cells which could play a role in the development of secondary extra-cutaneous lymphomas. Regulatory T cells were studied both in cutaneous biopsy specimens using an immunohistochemical analysis of CD4, CD25 and Foxp3 and in blood where proportion and functionality of circulating CD4+CD25(high) T-cells were determined. The study was performed in 10 patients [five patients with Sézary syndrome (SS) and five mycosis fungoïdes (MF)], treated for 6 months with bexarotene. Four healthy donors were used as controls for phenotypic and functional analysis on PBL. We found that the frequency of CD4+CD25(high) Treg cells was not significantly different before starting bexarotene and after 6 months of treatment in CTCL patients. However, we observed that the frequency of CD4+CD25(high) Treg cells before the beginning of the treatment was significantly increased compared to healthy donors. In addition, functional assays demonstrated that Foxp3 expressing CD4+CD25(high) T-cells were capable of suppressing autologous CD4 + CD25- T-cell proliferation. In the present work, we detected the presence of functional circulating CD4+CD25(high) Foxp3+ regulatory T-cells in CTCL patients, with an increased frequency compared to healthy donors. The treatment with bexarotene does not seem to affect the regulatory T-cell compartment.

There are several approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are one of the major biologic response modifiers used in CTCL, producing good response rates but few complete responses. Bexarotene has been demonstrated to act on malignant T-cells by inducing their apoptosis, but nothing is known about its role on keratinocytes and Langerhans cells. Immunohistochemical analysis using CD1a, HLA-DR, ICAM-1 (activation markers), CD95 and CD40 (apoptosis markers) was conducted on frozen sections of bexarotene-exposed cutaneous explants and skin biopsy specimens from patients treated with bexarotene. None of the studied markers was significantly modulated both on cutaneous explants and on skin biopsy specimens after treatment with bexarotene, compared to controls. Langerhans cells and keratinocytes do not appear to play a central role in the therapeutic control of CTCL by bexarotene therapy. The main bexarotene's target thus remains T-cells by inducing their apoptosis, a mechanism that is different from the other retinoids used in CTCL.