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International audience; In BRAF wild type advanced melanoma, immune checkpoint blockers such as anti-PD1 (anti-programmed cell death 1) are usually continued beyond progression for a hypothetical rare further response. Chemotherapy as a second-line option is considered ineffective by many practitioners based on historical data. Continuing anti-PD1 beyond progression has a high health-economic impact and is not recommended by the FDA. This study aimed to describe the efficacy and survival of advanced melanoma patients who received second-line (or more) chemotherapy after immunotherapy failure. This was a retrospective single center study conducted in a French University Hospital during an 11-month period. All advanced melanoma patients treated with chemotherapy after immunotherapy failure were included. Eighteen patients were analyzed. Therapeutic response to chemotherapy was evaluable in 16 patients: partial response was achieved in 3/16 (19%), stable disease in 1/16 (6%) and progressive disease in 12/16 (75%). Median overall survival from chemotherapy start was 12 months. Median progression-free survival was 5.4 months. The 6-month overall survival rate was 81% and the 6-month progression-free survival rate was 40%. Although the disease control rate with chemotherapy was low (25%), survival data in our study are far superior to those previously published. This could be linked to a high proportion of patients treated with anti-PD1 just prior to chemotherapy, which may suggest a potential synergy between immunotherapy and chemotherapy.

Edouard CHASSEUIL and Mélanie SAINT-JEAN contributed equally and should be considered as first authors.; International audience; Nivolumab response rate is 40% in metastatic melanoma. Few studies have evaluated pre-treatment biomarkers predictive of response. The aim of this study was to identify potential peripheral blood biomarkers associated with survival in patients with advanced melanoma treated with nivolumab. All advanced melanoma cases treated with anti-programmed cell death protein 1 (anti-PD1) over a 3-year period in the Dermato-Oncology Department, Nantes, France were identified. For each case, 9 potential blood biomarkers were identified. Bivariate and multivariate analyses, adjusted for the American Joint Committee on Cancer (AJCC) classification stage, Eastern Cooperative Oncology Group (ECOG) performance status, lactate dehydrogenase (LDH) level and failure to respond to first-line therapy, were used to test the association between biomarkers and overall survival (primary outcome) or progression-free survival (secondary outcome). Increased monocyte count, leukocyte/lymphocyte ratio and neutrophil/lymphocyte ratio were significantly associated with decreased overall survival after bivariate and multivariate analyses. Increased monocyte count was also significantly associated with decreased progression-free survival. These blood variables are easily measured and could help to predict patient response before the introduction of anti-PD1 therapy.

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.

International audience; The prevalence of acne in the adult population is increasing, particularly in women. Spironolactone regulates sebaceous gland activity by blocking androgen receptor. To evaluate retrospectively the efficacy of spironolactone in women with acne. Data from 70 women of at least 20 years, treated for their acne between 2010 and 2015 with low-dose spironolactone (≤150 mg/day), were analysed. Remission was defined by the number of retentional lesions inferior or equal to five and inflammatory lesions inferior or equal to two on the face. Variables influencing the response were studied using the Cox model. The mean age was 31.3 years; 39 (56%) women had prior courses of isotretinoin and 53 (76%) had an oral contraception prior to treatment. Remission data from a median treatment period of six months (95% CI: 4-9) were obtained from 47 (71%) women. Markers for a positive response to spironolactone were a high number of inflammatory lesions at inclusion (OR: 1.08; 95% CI: 1.03-1.13; p = 0.001) and relapse with previous isotretinoin (OR: 2.46; 95% CI: 1.09-5.54; p = 0.03). The marker for a negative response was an association with oral contraceptives containing first or second-generation progestin (OR: 2.77; 95% CI: 1.35-5.71; p = 0.005). This retrospective data analysis confirms that the use of low doses of spironolactone is a valuable alternative in women with acne in whom oral isotretinoin has failed. Moreover, the analysis shows that first and second-generation oral contraceptives decrease the efficacy of spironolactone, confirming the interest of using two third or fourth-generation oral contraceptives.

International audience; BACKGROUND:Fixed tissues are the standard samples used in routine practice for molecular testing. But sometimes tissues are lacking or difficult to obtain. In these cases, circulating tumor DNA released from tumor cells can be used as an alternative source of tumor DNA.CASE PRESENTATION:We present the case of a 63-year-old Caucasian woman with a metastatic melanoma and a very poor performance status. A plasma sample was tested and the BRAF p.V600E mutation was detected. Based on this result, a treatment combining a BRAF inhibitor and a MEK inhibitor was immediately started. This patient achieved a complete response. In addition, by repeating the plasma test, we could obtain a precise kinetic of release of mutated BRAF DNA in plasma.CONCLUSIONS:We report here for the first time the efficient treatment of a metastatic melanoma patient on the basis of circulating tumor DNA analysis. This urgent treatment provided a dramatic response in a patient with a very poor initial condition. The kinetic data most likely reflect treatment efficacy.

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.

e23537 Background: R0 surgery in reference centers is the cornerstone for sarcomas treatment with better local control and survival and is mandatory for ESMO-EURACAN and NCCN guidelines. The medical community is out on this issue for cutaneous sarcomas, if they have to follow suit. This retrospective descriptive study focused on margin status and local relapse-free survival (LRFS) and overall survival (OS) of patients (pts) with cutaneous sarcomas. Methods: Between 01/01/10 and 30/12/17, surgery was performed on 2044 pts with cutaneous sarcomas from 20 centers. Data were collected from the NETSARC national network database ( http://netsarc.sarcomabcb.org ). Diagnosis of cutaneous sarcoma was reviewed and histologically confirmed by a local expert pathologist of RRePS (“Network for expert pathology diagnosis in sarcoma”). Dermatofibrosarcoma, Kaposi sarcoma and rare subtypes (< 20 cases in the database) were excluded. Univariate analyses were conducted using log rank test or Cox test. Multivariate analyses were conducted using Cox test. Age and tumor size were analyzed as continuous values. Two-sided significant p level was set at < 0.05. Results: Mean age was 66 years. Primary tumor was localized in lower limb, trunk wall, head and neck and upper limb for 30%, 26%, 26% and 18% pts respectively. Main subtypes were leiomyosarcoma, undifferentiated sarcoma, and myxofibrosarcoma for 29%, 29%, and 14% pts respectively. Angiosarcoma was the subtype of 9% of the patients (n = 193). Mean size was 45 mm. FNCLCC grade was 1, 2, and 3 for 14%, 29.5%, and 24% tumors respectively. Before surgery, imaging and biopsy were performed for 21% and 51% pts respectively. Surgery was carried out in a NETSARC center for 26% of the pts. Margin status after initial surgery was R0, R1, and R2 for 35% (n = 724), 34% (n = 696), and 12% pts (n = 246) respectively. Re-excision was performed for 34% (703/2044 pts), leading to a subsequent R0 margin for 74% of them (523/703 pts, equivalent to 26% of the overall population). Local relapse occurred for 21% of pts after a median time of 10 months. Metastatic relapse occurred for 13% of pts after a median time of 11 months. One hundred and ninety-three pts (9%) died. Median follow-up was 12 months. In multivariate analyses, statistically significant favorable prognostic factors for LRFS were: young age, small tumor size and non-angiosarcoma subtype. Significant prognostic factors associated with longer OS were: young age, small tumor size, non-angiosarcoma subtype, FNCLCC grade (1 vs 2 and 1 vs 3) and initial R0 surgery. Conclusions: Cutaneous sarcomas share same favorable clinical prognostic factors than non-cutaneous sarcomas. Quality of surgery remains the mainstay for OS.

International audience; PURPOSE:The dermatological toxicity of cancer treatments is frequent and sometimes debilitating. Its reference classification, the NCI-CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events), is sometimes difficult to use and does not include yet the newest toxicities. Our objective was to create a guide, TOXICAN, based on the CTCAE, which is easy to use in everyday practice and which facilitates the recognition and grading of these dermatological toxicities.METHODS:This guide was developed by a working group ("GESTIM") comprising oncodermatologists, allergists, pathologists, and researchers from Nantes University Hospital. It was based on the dermatological toxicities found in the CTCAE and adapted to daily practice. These toxicities were grouped into categories and associated with photographs of typical cases to aid recognition. A simplified grading scale derived from the CTCAE was also created. This booklet was validated by means of user evaluation, and then the Delphi consensus method.RESULTS:We selected 32 dermatological toxicities, including 12 created by our group, sorted into 7 categories: skin rash, dry skin/pruritus, hyperkeratotic papules, palmoplantar changes, hair and nail changes, mucosal changes, and others. Our simplified grading scale only differed from the CTCAE for one item, urticaria. Three items were modified after evaluation by the user group and 11 after application of the Delphi method.CONCLUSION:The objective of our practical guide is to facilitate the use of the CTCAE for recognizing and grading dermatological toxicity of cancer treatments in order to provide optimal guidance for therapeutic adaptations. Its impact on clinical practice remains to be evaluated.

International audience; no abstract

Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen. Nine women and 1 man were treated for unresectable stage IIIC (n=4) or IV (n=6) melanoma. All but 1 patient with unresectable stage III melanoma (1st line) had received at least 2 previous treatments, including anti-CTLA-4 antibody for 4. The number of TILs infused ranged from 0.23 × 109 to 22.9 × 109. Regarding safety, no serious adverse effect was reported. Therapeutic responses included a complete remission, a partial remission, 2 stabilizations, and 6 progressions. Among these 4 patients with clinical benefit, 1 is still alive with 9 years of follow-up and 1 died from another cause after 8 years of follow-up. Notably, patients treated with high percentages of CD4 + CD25 + CD127lowFoxp3+ T cells among their TILs had significantly shorter OS. The therapeutic effect of combining TILs with new immunotherapies needs further investigation.

International audience; Background Acne is an inflammatory disease of the pilosebaceous follicle, affecting 41–54% of adult women, with a particular form that involves the mandible.Methods We characterized infundibulum morphology in two groups of adult women using reflectance confocal microscopy. First, we investigated acne visually “healthy zones” on the forehead in 15 adult women with diffuse acne and compared with acne-free controls. We then compared healthy forehead and affected mandibular zone in 15 acne patients with mandibular involvement. Exposed results had a P < 0.05.Results Seven hundred and ninety-one follicles were observed on apparently healthy skin of 15 adult women with acne, with a larger diameter, thicker (68%), and hyper keratinized (65%) follicle border, and more keratin plugs (44%) than in controls. In the second group of 15 adult women with mandibular acne, we compared 569 follicles in the mandibular zone and 475 on forehead. In the mandibular area, follicles were significantly larger, thicker (76%), more hyper keratinized (72%), with more keratin plugs (47%) and increased inflammation (23%) compared with the forehead area. In the mandibular area, 0.2% of follicles showed isolated inflammation without hyper keratinization, and 15.3% had both thickened borders with an onion-like appearance and keratin plugs associated with inflammation.Conclusions Hyper keratinization was higher in healthy skin of adult women with acne compared with controls, confirming that microcomedo is crucial in the development of acne lesions. We also demonstrate that the repartition of comedones and microcomedones is inhomogeneous with a great number in the mandibular area where acne lesions are located.

International audience; Propionibacterium acnes, a major member of normal skin microbiota, is subdivided into 6 phylotypes: IA1, IA2, IB, IC, II and III. This study investigated P. acnes subgroups on the face and back in patients with severe acne and in healthy controls. In 71.4% of patients with severe acne, P. acnes phylotypes were identical on the face and back, whereas this was the case in only 45.5% of healthy controls. The healthy group carried phylotypes IA1 (39.1%) and II (43.4%), whereas the acne group carried a high predominance of IA1 (84.4%), especially on the back (95.6%). In addition, the single-locus sequence typing (SLST) method revealed A1 to be the predominant type on the back of patients with acne, compared with a wide diversity in the healthy group. We report here that severity of acne on the back is associated with loss of diversity of P. acnes phylotype, with a major predominance of phylotype IA1. The change in balance of cutaneous P. acnes subgroups might be an inducing factor in the activation of P. acnes, which could trigger inflammation.

International audience; no abstract

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.

To date, facial acne flare-ups in adult women during the luteal phase of the menstrual cycle have been poorly investigated. To clinically characterize premenstrual acne flare-up in adult women and investigate the effect of a dermocosmetic treatment. This single-centre study included 32 young adult women with declared premenstrual acne flares and was composed of two phases: (1) an observational phase (two menstrual cycles) and (2) an interventional phase (one menstrual cycle) in a controlled, randomised, double-blind, intra-individual (half-face) setting in which a dermocosmetic (containing lipohydroxyacid, nicotinamide, and piroctone-olamine) and placebo were compared. Initially, during the first part of the study, we observed that premenstrual acne flare-ups in adult women were characterized by a significant increase in the number of papules (20.2 vs. 13.7; p = 0.0008) and to a lesser extent, closed comedones (25.6 vs. 22.7; p = 0.04). Secondly, during the interventional phase, the half-face treated with the dermocosmetic formulation showed a significantly lower number of inflammatory lesions (7.6 vs 9.4; p = 0.01) during the luteal phase compared to the half-face treated with the placebo. Tolerance of the dermocosmetic formulation was rated as good or excellent. Our data indicate a significant increase in the number of papules during premenstrual acne flare-ups in adult women and the use of a dermocosmetic may be of benefit in partially reducing this premenstrual inflammatory flare-up.

International audience; Data on BRAF, NRAS and KIT mutations are scarce in patients with vulvo-vaginal melanomas and are associated with important therapeutic issues. We investigated their prevalence in a cohort of patients with female lower genital tract melanomas between 2003 and 2017. Of the 22 patients, 5 (22.7 %) harbored a BRAF mutation which was much higher than the rate of 5% reported in the literature. One patient, who was tested negative on the primary melanoma, had a NRAS mutation in a cutaneous metastasis. Our data provides a rationale for prospective and repeated mutations testing in female lower genital tract melanomas.

Immune checkpoint inhibitors might be therapeutic options for unresectable or metastatic melanomas of the vulva and vagina but data available in the literature in these melanomas are very limited 1 2 3 4. The aim of this retrospective study was to investigate the effect of anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and anti-programmed death 1 (PD-1) antibodies in patients treated in our Skin Cancer Department for unresectable or metastatic vulvar or vaginal melanoma since 2013. This article is protected by copyright. All rights reserved.

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.

Summary Backround Propranolol is now widely used to treat severe infantile haemangiomas (IHs). Very few cases of propranolol-resistant IH (PRIH) are mentioned in the literature. Objectives To describe the characteristics of PRIHs. Methods A national, multicentre, retrospective, observational study was conducted from February 2011 to December 2011. All patients with PRIH evaluated by the members of the Groupe de Recherche Clinique en Dermatologie Pediatrique from 1 January 2007 to 1 December 2011 were eligible. Results Among 1130 patients treated with propranolol for infantile haemangioma, 10 (0·9%) had PRIHs. Haemangioma propranolol resistance was observed at all ages during early childhood and at any proliferation stage. Conclusions PRIH is a rare phenomenon that raises questions and merits further investigation.

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.

International audience; Vismodegib is an effective treatment for advanced basal cell carcinoma (BCC), but primary resistance to vismodegib remains to be elucidated. Alternative approaches are warranted to help selecting patients most likely to be responsive to treatment. The identification of immunohistochemical markers may support this perspective, as well as better understanding of resistance mechanisms. To determine the level of expression of CD56, PDGF-R, CD117, MMP9, TIMP3, and CXCR4 in advanced BCC, and explore whether expression levels are associated with non-response to vismodegib. A cross-sectional study was conducted. Immunohistochemical markers were selected based on their roles in tumour proliferation and/or migration in skin tumours. Tissue samples included pretreatment advanced BCC samples from patients treated with vismodegib, with an available response after six months of treatment. Regression optimised models were used to build hypotheses regarding a possible association between expression levels and non-response to vismodegib, which was then tested by logistic regression. Twenty-three patients were included. The percentage of samples expressing markers ranged from 43.5% (CD117) to 91.3% (CXCR4). CD56 expression was significantly associated with an increased risk of non-response to vismodegib (OR = 5.5; CI 95%: 3.4-29.8; p = 0.0488); a similar association was suggested for CXCR4 (p = 0.066), but not identified for other markers. These results provide a better understanding of the expression of immunohistochemical markers in advanced BCC. Further detailed analysis of CD56 expression may provide insights into guiding further investigation of the correlation between this marker and non-response to vismodegib.

Acne is a chronic inflammatory disease associated with scar development in many patients. To check whether early inflammatory events in the epidermis via keratinocytes influence the development of scars in acne patients. We investigated several immunological markers involved in epidermal innate immunity in both clinically normal skin and inflammatory early papules in acne patients prone to scars or not. In normal skin of acne patients prone to scars vs not prone to scars, TLR-4, IL-2, IL-10, TIMP-2 and JUN were significantly overexpressed and the MMP-9 protein level was decreased. Similar results were obtained in early inflammatory papules (no more than three days), except for TLR-4. These results suggest for the first time a link between the early events of inflammation with levels of activation of innate immunity in normal epidermis of acne patients and the development of scars. These markers could be a target for drugs in the field of scar prevention.

International audience; Purpose Whereas vismodegib is effective in the treatment of locally advanced/metastatic basal cell carcinoma, dysgeusia and weight loss are common side effects of such treatment. The main objective of this study was to monitor the nutritional status of vismodegib-treated patients. Secondary objective was to assess the incidence of dysgeusia and the benefit of early nutritional management. Methods This prospective study included all patients who started vismodegib between October 2011 and May 2013 at Nantes University Hospital. Prior to July 2012, patients treated with vismodegib had not received any specific nutritional management (Historical cohort). Body weight and presence of dysgeusia were recorded monthly. Patients treated after July 2012 (Nutrition cohort) were evaluated by a physician of the Nutrition Support Unit and received dietary counseling at vismodegib initiation. A standardized nutritional management protocol was initiated in case of significant weight loss. Results Forty-five patients (21 and 24 in the Nutrition and Historical cohort, respectively) were enrolled. In the Nutrition cohort, five patients (24 %) were undernourished at vismodegib initiation, and the 6-month cumulative incidence of dysgeusia was 71 %. Eight patients (38 %) and 13 patients (54 %) had a weight loss greater than 5 % in the Nutrition and Historical cohort, respectively (p = 0.3727). Conclusion The results of this pilot study suggest the benefit of early nutritional screening. The potential benefit of nutritional support in this setting warrants further investigation.

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 pustulose aseptique des plis est une affection rattachee aux dermatoses neutrophiliques. Elle se caracterise par des pustules des plis d’apparition brutale, l’existence d’une maladie auto-immune associee et l’efficacite de la corticotherapie generale. Nous rapportons un nouveau cas de pustulose aseptique des plis associee a une erythroblastopenie auto-immune, association qui n’a ete decrite qu’une seule fois dans la litterature a notre connaissance. Observation Une femme de 24 ans consultait pour une dermatose evoluant depuis plusieurs mois. Il existait une atteinte crouteuse des plis inguinaux et du cuir chevelu avec des bordures pustuleuses, ainsi que des lesions eczematiformes du tronc. S’y associait une anemie macrocytaire aregenerative en lien avec une erythroblastopenie medullaire. En l’absence d’autre cause prouvee, cette erythroblastopenie etait rapportee a une cause auto-immune. Le prelevement bacteriologique d’une pustule intacte etait sterile. Il existait des anticorps anti-nucleaires circulants a specificite anti-SSA. La biopsie cutanee montrait des pustules intraepidermiques et un infiltrat inflammatoire du derme. L’immunofluorescence directe etait negative. L’evolution etait favorable sous corticotherapie generale. Discussion Trente-six cas de pustulose aseptique des plis ont ete rapportes dans la litterature. Cette affection touche presque exclusivement des femmes jeunes atteintes d’une maladie auto-immune (lupus erythemateux dissemine dans la plupart des cas). Elle se caracterise cliniquement par des pustules aseptiques des grands et petits plis, du cuir chevelu et de la region perineale, associees a des lesions eczematiformes a distance. Des criteres diagnostiques ont ete recemment proposes. Le traitement repose sur la corticotherapie generale.

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.

Acne fulminans is a rare and severe form of acne characterized by the development of painful and inflammatory nodules on the face, chest, and back. Systemic signs are associated with the onset, including fever, chills, and musculoskeletal pain. Erythema nodosum, liver or spleen enlargement, myositis, or aseptic bone involvement have been reported more rarely. Its etiology remains unknown. It is assumed that a strong activation of the cutaneous innate immunity induced by Propionibacterium acnes antigens could be involved. Another hypothesis is that it could be a dysregulation of some receptors expressed by sebaceous glands and keratinocytes, in particular, the androgen receptors. Moreover, these abnormalities could be genetically determined.

International audience; Since the approval of vorinostat for the treatment of refractory cutaneous epidermotropic T-cell lymphoma (CTCL) in 2006, very little data about this treatment have been published. The aim of this retrospective study was to assess the efficacy and safety of vorinostat in patients with CTCL treated between 2007 and 2013 in our department. Fifteen patients (median age 64 years) were included: 9 with Sézary syndrome and 6 with mycosis fungoides. They were all in progression and the median number of systemic treatments previously administered was 3 (range 1-7). With vorinostat treatment, the best response was partial remission in 5 patients (33%) and stabilization in 4 patients (27%). Six patients experienced disease progression. The mean time to response and response duration were 70 (range 31-140) and 300 days (range 157-663) , respectively. The most frequent adverse events were asthenia, weight loss, nausea and anaemia. Vorinostat could be a therapeutic alternative for CTCL after treatment failure.

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.

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.

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.

Background Ulcerated infantile hemangiomas (IH) are a therapeutic challenge. Propranolol, a nonselective beta-blocker, was recently introduced as a novel treatment for IH. Objective To evaluate our experience of propranolol in the management of ulcerated IH. Methods A national, multicenter, retrospective, observational study was conducted. Data were collected from the medical charts of patients treated from 2008 to 2009 and supplemented by information obtained from parents during targeted telephone interviews. Results Thirty-three infants with propranolol-treated ulcerated IH were included. The average time to complete ulceration healing was 4.3 weeks in 30 of 33 patients and was significantly faster for head-and-neck locations ( P = .0354). The mean time to complete pain control was 14.5 days. Parents rated treatment as very effective for 27 of 31 patients and very well tolerated for 29 of 31 cases. Limitations This was a retrospective uncontrolled study. Conclusion Propranolol appears to be an effective and well-tolerated treatment for ulcerated IH.

Lapatinib is a dual tyrosine kinase inhibitor indicated in breast cancer [1] targeting the Human Epidermal Growth Factor Receptor-1 (HER1), also called EGFR and HER2. Lapatinib-induced skin toxicity is common, usually mild and is often similar to that reported with EGFR inhibitors (EGFRI). We report the first case of cutaneous vasculitis observed with lapatinib.A 57-year old patient was followed up for 2 years for a right breast adenocarcinoma with liver metastases at the initial diagnosis. She was [...]

9017 Background: Determination of the BRAF mutation status is a requirement for treatment selection of metastatic melanoma patients. However, the inter and intra-tumor genetic heterogeneity for BRAF status has been described supporting the need for testing multiple sites for the same patient. Circulating DNA is considered a promising non-invasive tool for cancer monitoring. The objective of our work was to determine the potential of plasma DNA to detect BRAF mutations, particularly in patients presenting discordant BRAF status from different tumor sites. Methods: Plasma DNA was extracted using the iPrep PureLink Virus Kit on an iPrep purification system (Invitrogen). BRAF mutations were detected using the Therascreen BRAF RGQ kit (Qiagen). Results: Ninety-nine patients were included, and plasma was collected at baseline. Nine stage III melanoma patients presenting a mutant BRAF (6 V600E, 2 V600K and 1 V600D) were tested and for 4 of them we detected the corresponding mutation (including the V600D and both...

9042 Background: Melanoma brain metastases are frequent and severe. We studied their characteristics in a retrospective cohort of patients treated with vemurafenib, a BRAF inhibitor indicated in V600-mutant metastatic melanoma. Methods: We included in this study all patients receiving vemurafenib in our department between November 2010 and November 2013 without melanoma brain metastases at initiation of treatment. Brain scans were performed after 2 months, and then every 3 months or in case of neurologic symptoms. RMI could be performed to confirm scan result. Our primary endpoint was the brain metastases incidence. Secondary endpoints were associated risk factors, onset modalities and clinical evolution. Results: In our cohort of 86 patients, incidence of brain metastases was 20% after a median follow-up of 9 months (1 to 26 months). They appeared after a mean of 5.3 months of vemurafenib exposure (1 to 15 months). The only identified risk factor was a high number of metastases before treatment (p=0.045)...

9069 Background: Mutant BRAF DNA can be detected in plasma of melanoma patients bearing a mutation in their tumor. Detection of these genetic alterations in circulating DNA has potential clinical a...

e20022 Background: The purpose of this study was to evaluate the feasibility, safety and efficacy of adding intra-tumoral injections of TG1042 (Adenovirus 5 expressing Interferon-γ) to adoptive T cell therapy in patients with advanced stage melanoma. Methods: This was a monocentric phase I/II study. The main inclusion criteria were: stage IIIc/IV melanoma, age 18 to 75, at least one injectable metastasis. Tumor infiltrating lymphocytes (TILs) produced from a surgical biopsy of a lesion were infused on days 1 and 29 followed by IL2 injections (6M UI daily) for 10 days. TG1042 was injected at the dose of 5x1010 viral particles per lesion (in up to 6 lesions) every 2 weeks from day -15 to month 2 and then every month up to month 11 or progression. Primary objective was the safety of the procedure; secondary objectives included response according to RECIST and translational research. Results: Eighteen patients have been included. The TILs production was successful in 16 of them. Minor erythema at the TG1042 injection site as well as minor to moderate flu-like symptoms linked to IL2 injections were the most frequent adverse events observed. No grade 3 or 4 treatment related adverse events was recorded. Among the 13 patients evaluable for tumor response 4 patients (31%) had an overall objective response (2 complete, 2 partial), 1patient had a stable disease and 8 progressed. When considering only the injected lesions 6 (46%) had an objective response (3 complete, 3 partial), 3 had a stable disease and 4 progressed. Distant responses in non-injected lesions were observed for 2 patients. Translational research on cutaneous biopsies before and after injections (3 months) showed an increase of CD8 T lymphocytes, IFN-γ and STAT 1 expression in 3 patients. Conclusions: This study demonstrates that co-delivery of TILs and intra lesional TG1042 is feasible and safe. Stimulation of innate immunity by adenovirus expressing interferon-γ could contribute to reverse the immunotolerant profile of the tumour environment. These results support to further explore combined immunotherapies in the treatment of melanoma. Clinical trial information: NCT01082887.