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Cemiplimab, a human monoclonal antibody directed against PD-1, has provided more options in the treatment of locally advanced or metastatic cutaneous squamous-cell carcinoma at an unresectable state. Immune checkpoint inhibitors can induce several unfavorable reactions generally referred to as immune-related adverse effects. Cytokine-release syndrome is an immune-related adverse event that is infrequent and not well known. Diagnosis is difficult because of the unspecific symptoms (e.g., fever, hypotension) but it can also be life threatening. The authors report the case of a 62-year-old treated by cemiplimab for a cutaneous squamous-cell carcinoma of the diaper fold with iliac and inguinal lymph node extension. He presented with severe cytokine-release syndrome, concluding with the discontinuation of cemiplimab.

Background: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. Patients and methods: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. Results: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1–2 AEs in 14 patients (16%) and 10 grade 3–4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). Conclusion: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.

Introduction La crise sanitaire COVID-19 a bouleverse l’organisation du systeme de sante francais et international, par la soudainete de cette epidemie et des mesures ayant ete mises en place pour y faire face. L’objectif de cette etude est d’explorer l’influence de la crise sanitaire COVID-19 et particulierement de la reorganisation medicale qui en a resulte durant le 1er confinement sur un eventuel retard au diagnostic dans le melanome cutaneo-muqueux primitif, sur un bassin de population. Materiel et methodes Etude retrospective multicentrique, a partir des donnees de toutes les reunions de concertation pluridisciplinaire (RCP) d’oncodermatologie du departement de Loire-Atlantique. Comparaison, dans un bassin de population, des melanomes nouvellement diagnostiques durant une periode de 6 mois en 2020 (mars a aout) correspondant au 1er confinement en 2020 et les mois qui ont suivi (P20), aux melanomes diagnostiques sur les memes mois de l’annee precedente (mars a aout 2019), avant la crise sanitaire COVID-19: P19. Les donnees recueillies pour chaque cas etaient les suivantes : – pour le patient: âge et sexe ; –pour le melanome: sous-type histologique, indices de Breslow et de Clark, ulceration, stade AJCC, delai de prise en charge defini par le delai entre l’exerese initiale du melanome et le moment ou le patient est recu en RCP pour organisation d’une reprise chirurgicale ou prise en charge complementaire. Resultats Le nombre de melanomes nouvellement diagnostiques etait de 247 en P19 et 209 en P20. Le sex-ratio homme/femme etait de 1,1 en P19 et 1,2 en P20. La figure 1 illustre le nombre de cas par mois pour chacun des 6 mois en 2019 et 2020. Pendant la periode de confinement de 2020 (du 17 mars au 11 mai), 54 cas ont ete diagnostiques et 73 l’annee precedente sur la meme periode. L’indice de Breslow moyen en P19 etait de 1,83 mm et de 1,65 mm en P20 (p = 0,429). Le delai de prise en charge etait statistiquement significativement plus important en 2020 qu’en 2019 (delais de 33,36 jours versus 28,90 jours, p = 0,023). Discussion Sur ce bassin de population etudie, le nombre de melanomes diagnostiques a ete inferieur a celui observe l’annee precedente sur la meme periode et ce en particulier en avril-mai. Par contre, il ne semble pas y avoir de retard au diagnostic, en se basant sur le critere principal a savoir l’epaisseur au diagnostic. Il a ete montre de facon similaire dans une etude italienne une diminution franche du nombre de diagnostics de melanome en per confinement italien, avec decouverte d’un indice de Breslow moyen durant le confinement abaisse. Toutefois, une autre etude menee a Londres a montre des resultats differents avec notamment un taux de detection plus eleve durant le confinement. Il n’y a actuellement pas d’autre etude dans la litterature etudiant l’impact de la crise sanitaire COVID-19 sur le retard au diagnostic des melanomes en France.

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.

Introduction Un depistage cible du melanome est recommande en France. Le SAMScore est un auto-questionnaire valide permettant le reperage des personnes a risque en soins primaires. Il est cependant peu connu et faiblement utilise en pratique quotidienne. L’objectif de l’etude etait d’evaluer le taux de reponse des patients au SAMScore lorsque celui-ci est remis par leur medecin generaliste au decours d’une consultation. Materiel et methodes Etude observationnelle aupres de 14 medecins generalistes inscrits au CDOM du departement, recrutes par mail. Le questionnaire a ete distribue en fin de consultation a tous leurs patients consultant au cabinet pendant 4 journees. Les patients avaient 4 mois pour y repondre et le ramener a leur medecin, qui devaient verifier le score et l’integrer au dossier. Le critere de jugement principal etait le taux de participation au questionnaire. Analyses statistiques descriptives. Resultats Sur les 946 questionnaires distribues, 515 ont ete rendus par les patients. Ce taux de participation de 54,4 % [27,6–68,2 %] variait selon les medecins (p Discussion La force de cette etude est l’utilisation en situation reelle d’un outil valide. La principale limite est un biais de recrutement des medecins participants volontaires. Plus d’un patient sur deux a participe au SAMScore et pres de la moitie etait a risque de melanome. Cette strategie de depistage cible pourrait devenir systematique avec plus de 2/3 des scores integres aux dossiers medicaux. Pour cela, nous devons ameliorer la formation des medecins generalistes et travailler sur une cooperation en reseau avec les dermatologues.

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.

Introduction Le mogamulizumab (Mog), anti-CCR4, fait partie des traitements prometteurs des lymphomes T. Il n’est disponible pour les mycosis fongoides (MF) que dans des essais cliniques. Nous rapportons 2 cas de reaction cutanee induite par le Mog chez des patients traites pour un MF. Observations Un homme de 48 ans et une femme de 64 ans etaient suivis pour un MF evoluant depuis 5 et 9 ans. Devant une absence de reponse aux traitements anterieurs (interferon, bexarotene, UVB), les patients etaient traites par Mog dans le cadre d’un essai therapeutique (NCT01728805). Le patient 1 developpait apres 5 perfusions de Mog des lesions axillaires eczematiformes, prurigineuses. Le traitement etait initialement poursuivi devant la remission partielle du MF. Une evolution des lesions vers une erythrodermie etait constatee en un mois. L’histologie realisee a 2 reprises trouvait un MF non transforme. Le reste du bilan etiologique (PCR virales, FAN) etait negatif. Le Mog etait stoppe et le patient etait traite par corticotherapie systemique avec une amelioration rapide de l’eruption. Ensuite, une reprise du bexarotene associe aux UVB permettait l’obtention d’une remission complete du MF. La patiente 2 developpait une eruption eczematiforme, prurigineuse, du decollete apres 3 mois de Mog. L’histologie cutanee montrait un aspect de toxidermie. Apres une amelioration par dermocorticoides forts, l’eruption recidivait motivant une suspension du Mog jusqu’a resolution. La reprise du Mog etait suivie d’une recidive de l’eruption, motivant un arret definitif du Mog et du methotrexate etait instaure. Discussion L’anti-CCR4 est une molecule tres prometteuse dans les MF en impasse therapeutique mais ses effets secondaires sont encore tres peu connus. Nous rapportons deux cas de toxicite cutanee sous traitement par Mog, survenus de facon retardee (3 mois). Il s’agissait d’une eruption eczematiforme evoluant dans 1 cas vers une erythrodermie et restant localisee dans l’autre cas. Dans les 2 cas, le Mog a permis une remission partielle du MF. Meme si l’aspect histologique est en faveur d’un MF pour le patient 1, l’aspect clinique, la resolution apres l’arret du Mog et la recidive de l’eruption a la reprise du Mog pour la patiente 2 rendent hautement probable une imputabilite du Mog. Les rashs cutanes sous Mog sont rapportes chez 6 patients (16 %) dans l’essai de phase I concernant des lymphomes cutanes. La presentation clinique est variable : erythrodermie (comme pour le patient 1), erytheme diffus exsudatif, photosensibilite. Deux cas de necrose epidermique toxique sont decrits. Enfin, il est constate chez des patients traites par Mog pour un lymphome systemique une correlation entre la severite de la toxicite cutanee et la bonne reponse au traitement. Conclusion La toxicite cutanee du Mog est a connaitre car elle peut etre severe, limitant alors l’utilisation du traitement meme en cas de bonne reponse therapeutique du MF.

Introduction La place de la chimiotherapie (CT) dans la prise en charge du melanome avance reste a definir depuis l’avenement des nouveaux traitements. La dacarbazine a un taux de reponse « historique » d’environ 15 %. Son efficacite apres immunotherapie (IT) n’a jamais ete evaluee. Patients et methodes Il s’agit d’une etude monocentrique, retrospective de tous les patients ayant recu au moins une cure de CT pour un melanome entre le 01/01/2017 et le 15/11/2017 d’apres le fichier de l’unite qui prepare les CT dans notre centre. Resultats Vingt et un patients ont ete identifies. Deux ont ete exclus car traites par CT en 1re ligne (melanomes primitifs choroidiens). Sur les 19 patients analyses (53 % de femmes, âge moyen = 65 ans), 3 avaient une mutation BRAF V600E et 7 une mutation NRAS. Les patients avaient recu en moyenne 2 lignes anterieures [1 ; 5] incluant une therapie ciblee combinee chez tous les patients mutes BRAF. Tous les patients avaient recu au moins une ligne d’IT prealable (2 lignes dans 10 cas) : anti-PD1 (n = 19), anti-CTLA4 (n = 7), association des 2 (n = 2), TVEC-ipilimumab (n = 1). L’IT avait ete arretee pour toxicite (n = 4) ou pour progression (n = 15). Au debut de la CT, 4 patients avaient des metastases cerebrales (2 traites par radiotherapie stereotaxique). La CT recue etait de la dacarbazine seule (n = 11) associee au carboplatine (n = 5) ou a la fotemustine (n = 3). La reponse therapeutique etait evaluable chez 16 patients : 3/16 (19 %) reponses partielles (RP), 2/16 (12 %) stabilites (SD) et 11/16 (69 %) progressions (PD). Les 4 patients avec metastases cerebrales ont progresse sous CT. La survie globale moyenne (SG) apres mise en route de la CT etait de 11 mois. La survie sans progression moyenne (SSP) etait de 7,7 mois. A 6 mois, 81 % des patients etaient vivants et 40 % n’avaient pas progresse. Neuf patients sont decedes apres un delai moyen de 9,6 mois. Discussion Sur les 19 patients atteints de melanome avance et pre-traites par au moins une IT, aucun n’obtenait de remission complete et 19 % une RP sous CT, ce qui est comparable aux donnees historiques des CT. Cependant, la SG, la SSP et la proportion de patients vivants a 6 mois sont tres superieures a celles rapportees avant l’ere des nouveaux traitements, respectivement 6,2 mois, 1,7 mois et 20,7 %. Les hypotheses possibles expliquant cette difference sont une synergie entre CT et IT, une poursuite de l’efficacite de l’IT apres son arret, un biais de selection des patients longs repondeurs. Notre etude a des limites : faible effectif, heterogeneite des traitements anterieurs et du schema recu de CT. Conclusion Nos resultats suggerent que le pronostic des patients traites par CT apres IT pour un melanome avance est meilleur que celui rapporte dans la litterature. Cette option therapeutique reste donc valable apres progression sous IT ± therapie ciblee chez les BRAF mutes. Ces donnees preliminaires restent a confirmer sur une plus large cohorte prospective.

Introduction L’acne severe est une dermatose inflammatoire chronique du follicule pilo sebace, souvent associee au developpement de cicatrices atrophiques ou hypertrophiques aux consequences psychologiques serieuses. Cutibacterium acnes est une bacterie subdivisee en 6 phylotypes (IA1, IA2, IB, IC, II et III) et jouant un role majeur dans la physiopathologie de cette dermatose inflammatoire. Une etude clinique recente sur les populations de C. acnes en contexte d’acne severe a mis en evidence une perte drastique de la diversite de C. acnes, sur le dos par rapport aux individus sains, associee a la predominance du phylotype IA1. Dans la continuite de cette etude, il apparait important d’evaluer l’impact de la diversite de ces phylotypes sur la reponse inflammatoire cutanee, et ainsi comprendre s’il s’agit d’une cause ou une consequence de la maladie. Materiel et methodes Nous avons emis l’hypothese que cette perte de diversite pourrait etre un declencheur de l’immunite innee cutanee. Nous avons compare l’effet modulateur sur l’immunite innee de chacun des phylotypes de C. acnes IA1, II et III pris individuellement, a un melange de plusieurs phylotypes mimant la diversite du microbiote normal (IA1 + II + III). Apres co-culture avec des explants de peau saine, nous avons mesure les reponses inflammatoires dans la peau entre chaque condition par immunohistochimie et Elisa, ciblant un panel de marqueurs de l’immunite innee (MII). Resultats La plupart des MII testes etaient surexprimes dans les explants de peau lorsqu’ils etaient incubes avec le phylotype IA1 seul, en comparaison avec le melange IA1 + II + III (IL-17, p Conclusion La peau et les micro-organismes commensaux communiquent via l’emission de signaux complexes regulant les reponses immunitaires locales pour assurer les fonctions cutanees et prevenir les maladies chroniques. Recemment, il a ete montre que l’acne severe etait associee a une perte de la diversite des phylotypes, avec une forte predominance du phylotype IA1. Nous rapportons ici que cette perte de diversite des phylotypes est un facteur capable d’activer le systeme immunitaire inne cutane. Ces resultats suggerent l’interet d’un traitement base sur l’utilisation de modulateurs topiques du microbiote, a la fois pour maintenir et restaurer la diversite cutanee des phylotypes de C. acnes.

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; Circulating tumor DNA is a promising non-invasive tool for cancer monitoring. The main objective of our work was to investigate the relationship between mutant BRAF DNA in plasma and clinical response. Thirty-eight stage IV patients with a V600 mutated BRAF melanoma were included prior to any treatment. DNA was extracted from plasma and mutant DNA was detected using the amplification-refractory mutation system method. Before the beginning of any treatment, the corresponding BRAF mutation was detected in 29 of the 38 tested plasma samples (76.3% positive per cent agreement). We observed a strong correlation between the presence of circulating mutated DNA and overall survival (OS; P=.02), and with the number of metastatic sites (P=.01). The presence of circulating mutated DNA was also strongly correlated with serum LDH activity (P

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.

High resistance rate of melanoma to chemotherapy results in the development of other therapeutic strategies such as immunotherapy. Discrepancies observed in clinical responses to immunotherapy suggest the presence of immune polymorphisms and tumor escape mechanisms. The objective of this study was to investigate the expression of B7-H3 and B7-H4 which are major stakeholders in immune regulation, and of the death receptors TRAIL-R1 and TRAIL-R2 which play an important role in controlling tumor cell proliferation and apoptosis. The correlation between the expression levels of these proteins and the clinical outcome has also been assessed. The expression level of the proteins was analyzed on 32 invaded LN samples and on 11 matching tumor cell lines. Immunohistochemical staining and double fluorescent immunostaining on lymph node (LN) frozen sections were performed, as well as flow cytometry on tumor cell lines. The 4 proteins were expressed in all LN biopsies within a range from 40.6% for TRAIL-R1 to 87.5% for TRAIL-R2. These 4 proteins were rarely expressed by the tumor cell lines except for TRAIL-R2 which was detected in 10 of the 11 cell lines. The expression of these proteins by tumor cell lines is not correlated with in vivo expression found in immunohistochemistry (IHC). It raises the question of the role of the tissue environment in the expression of the proteins. The expression levels of B7-H4, TRAIL-R1, and TRAIL-R2 using IHC were correlated with overall survival. In vivo, high expression levels of B7-H4, TRAIL-R1 or TRAIL-R2 appear as poor prognostic factors.

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.

Introduction L’angiosarcome est une tumeur vasculaire maligne rare, de mauvais pronostic et avec un taux de recidive local important. Le traitement de reference est l’exerese chirurgicale, qui dans certains cas, est recusee car trop delabrante. Dans ces cas, seules quelques chimiotherapies sont disponibles (paclitaxel, doxorubicine), avec un faible taux de reponse. Nous avions rapporte aux JDP 2016 un cas d’angiosarcome metastatique traite efficacement par propranolol et cyclophosphamide. Nous rapportons ici un deuxieme cas et l’actualisation du cas precedent. Observations Un homme de 49 ans, d’origine caucasienne presentait une volumineuse lesion du nez d’evolution rapidement progressive depuis 5 mois ( Fig. 1 ). L’analyse histologique trouvait un infiltrat lymphocytaire CD4+, CD3+ et CD5+. L’immunomarquage etait positif pour ERG et CD31, affirmant le diagnostic d’angiosarcome. Le traitement chirurgical etait recuse car trop delabrant. Le patient etait traite par une combinaison de cyclophosphamide oral 200 mg par jour, une semaine sur deux, et propranolol 120 mg par jour en deux prises. Le traitement etait bien tolere. Apres 2 mois de traitement, le patient etait en remission complete (RC), confirmee par IRM et par 4 biopsies chirurgicales ( Fig. 2 ). Le traitement etait arrete apres 5 mois de prise. Le patient est actuellement toujours en RC 7 mois apres arret du traitement. Le cas precedemment decrit rapportait un homme de 73 ans traite selon le meme schema, pour un angiosarcome metastatique mediastinal, hepatique et sous-cutane. Apres une remission partielle (RP) de 13 mois sous traitement, il a recidive au niveau ganglionnaire cervical et progresse au niveau hepatique. Du fait d’une alteration importante de l’etat general, le traitement a ete suspendu et une prise en charge palliative a ete proposee. Discussion Les angiosarcomes comme les hemangiomes expriment des recepteurs beta-adrenergiques, suggerant l’interet des betabloquants dans le traitement des angiosarcomes. Huit cas d’angiosarcomes metastatiques/multifocaux, traites par propranolol et chimiotherapie (autre que le cyclophosphamide), ont ete rapportes dans la litterature, permettant 1 RC et 7 RP. Un seul autre cas traite par propranolol et cyclophosphamide a ete publie avec 1 RC de 20 mois. Nous rapportons 2 cas d’angiosarcomes traites par une combinaison de propranolol et cyclophosphamide oral sequentiel, avec actualisation d’un cas decrit l’annee derniere. L’un est en RC avec un recul de 7 mois, l’autre a eu une RP de 13 mois avec echappement recent. Conclusion Ces 2 cas confirment l’interet de cette combinaison en alternative aux chimiotherapies classiques dans les angiosarcomes localement avances ou metastatiques. Actuellement en France, un essai de phase I–II testant la combinaison propranolol et cyclophosphamide metronomique a dose fixe dans les angiosarcomes est en cours, developpe par le Groupe Sarcome.

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.