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

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

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

OBJECTIVE Severe dermatophytosis is described in immunocompromised patients with defective cellular immunity. We report here a large series and a literature review of severe dermatophytosis in solid-organ transplant (SOT) recipients. METHOD The data main source was a national French retrospective study of severe dermatophytosis in SOT recipients between 2010 and 2016. Inclusion criteria were the presence of dermatophytes in skin culture and 1 severity criteria: dermal invasion by dermatophytes (invasive dermatophytosis) or involvement of at least two body sites or >10% of body surface area (extensive dermatophytosis). RESULTS A total of 12 patients were included (8 men, median age of 56 years [range: 33-71]). Of the 12 patients, 10 underwent kidney transplantation. The median time from transplantation to severe dermatophytosis diagnosis was 16 months [range: 2-94]. Clinical signs of superficial dermatophytosis were present in 8/12 patients before the emergence of severe dermatophytosis. Nine patients had invasive forms and three extensive ones, and nodules of the lower extremities were found in eight. Trichophyton rubrum was isolated in 11 cases. First-line treatment was terbinafine (7/12), posaconazole (3/12), or topical treatment alone (2/12). Immunosuppressive therapy was reduced in 3 patients because of associated infections. Complete response was obtained for 3/3 and 5/9 patients with extensive or invasive forms, respectively, after a median treatment's duration of 2.5 [range: 1.5-5] months and 7.5 months [range: 4-12]. Unrelated deaths (n = 2) and graft function impairment (n = 3) occurred. CONCLUSION Severe dermatophytosis is a late complication in SOT recipients presenting with lower limb nodules, which might be prevented by prompt treatment of superficial dermatophytosis.

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.

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.

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

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

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

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.

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

International audience; Immunotherapy by adoptive T-cell transfer aims at maximizing tumor antigen-specific T-cell responses. We treated 14 patients at the metastatic stage in a phase II study with Melan-A-specific T-cell clones generated from patient blood. During the period required for T-cell clone generation, the patients were treated by dacarbazine. Every patient received a T-cell clone suspension followed by subcutaneous injections of interleukin 2 and interferon alpha. Patients were monitored until disease progression occurred. We succeeded in obtaining autologous Melan-A-specific cytotoxic T lymphocyte clones, which were highly reactive against tumor cells for all the patients. Of the 14 patients treated, six (43%) experienced an objective response (CR þ PR) with long-term complete remission for two patients (1 CR for 5 years and 1 CR for 28 months). Furthermore, we showed that all the clinical responses were significantly associated with in vivo expansion of the Melan-A-specific T-cell repertoire. This phenomenon appeared to be significantly associated with clinical responses. Thus, over the course of an adoptive cell transfer, monitoring this melanoma-specific T-cell expansion in patient blood appears crucial for predicting the clinical efficiency of such an immunological approach.

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

While treating stage III melanoma patients with autologous therapeutic TIL in an adjuvant setting, we previously reported a significant benefit of treatment on both progression-free survival and overall survival in patients with only one invaded lymph node (early stage III) compared to patients with more than one invaded lymph nodes (advanced stage III). In this context, in order to understand the difference of activity of TIL therapy according to the progression of the illness at stage III, the first objective of the present study was to determine potential differences in the characteristics of TIL populations obtained from an early stage III and a more advanced stage III when tumor burden is more important. The second objective was to determine possible differences in tissue expression level of several molecules involved in interactions between tumor cells and T cells between early and advanced stage III considering that the tumor microenvironment of invaded lymph nodes could become more tolerant with the progression of the disease. A total of 47 samples of melanoma invaded LN from stage IIIb (AJCC 2007) melanoma patients treated with TIL plus IL-2 were included in this study. We confirmed that both PFS and OS were significantly associated to the presence of tumor-reactive T-cells among TIL injected to the patients and that these tumor reactive T cells were more frequently observed at the early stage III. Moreover, while analyzing the expression of 17 markers on 34/47 tumor specimens using immunohistochemistry, we identified that 3 tissue markers involved in interactions between melanoma cells and T cells have a significant difference of expression between early and advanced stage III: MHC class I, adhesion molecule ICAM-1 and the co-stimulation molecule LFA-3 had a significantly weaker expression in melanoma tissue specimens from advanced stage III. In addition, the expression of the alpha chain of the IL-2 receptor (CD25) and the nuclear transcription factor Foxp3 was significantly increased in the melanoma tissue specimens from advanced stage III. Our results suggest differences in the immunological status of the tumor microenvironment between early and advanced stage III, which could explain the difference in clinical response to TIL infusion in an adjuvant setting between early and advanced stage III.