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Targeted therapies have developed rapidly over the last few years in the field of oncology thanks to a better understanding of carcinogenesis. They target pathways involved in signal transduction (EGFR, HER2, HER3, HER4, FLT3, RAS, RAF, MEK, KIT, RET, mTOR, SRC, EPH, SCF), tumor angiogenesis (VEGFR, TIE2), and tumor microenvironment (PDGFR, FGFR). They rarely cause the systemic adverse reactions generally associated with chemotherapy, but frequently cause disabling and specific skin toxicity. The impact on patient quality of life can be important both in terms of symptoms caused and of potentially aesthetic consequences. Inappropriate management can increase the risk of dose reduction or discontinuation of the cancer treatment. In this review, we will discuss skin toxicity associated with the main drug classes-EGFR, BRAF, MEK, mTOR, c-KIT, CTLA4, and SMO inhibitors, and anti-angiogenic agents. Targeted therapy-induced skin toxicities will be detailed in terms of symptoms, frequency, evolution, complications, and topical and oral treatments in order to improve their diagnosis and management. [ABSTRACT FROM AUTHOR]

Simple Summary: 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 well-described in the literature. The objective of our retrospective multicenter study was to evaluate the efficacy and safety of ICI rechallenge in patients with advanced melanoma who had achieved disease control with ICI in a real-life setting. Our study, which included 85 patients, predominantly rechallenged with anti-PD1 antibodies, confirms the efficacy of ICI rechallenge, with a best overall response rate of 54% and a disease control rate of 75%. Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1–2 AEs and 10 grade 3–4 AEs. Therefore, ICI rechallenge should be considered as a compelling therapeutic option. 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. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study was to assess the effi-cacy 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 intrave-nously. 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 ri-tuximab. This therapy is a safe and effective treatment and could represent an excellent alternative treatment to radiotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Immunotherapy is becoming one of today's most important systemic treatments in oncology after demonstrating its efficacy and acceptable tolerance in many types of cancer.[1] However, with increasing patient exposition, new side effects appear, including cutaneous ones. This granulomatous reaction, as triggers, could induce widespread reactions in other black tattoos, called a "rush phenomenon".[5] The granulomatous reactions related to immunotherapy, whether cutaneous or systemic, correspond to a real entity that is still poorly understood. 5 Sepehri M, Hutton Carlsen K, Serup J. Papulo-nodular reactions in black tattoos as markers of sarcoidosis: study of 92 tattoo reactions from a hospital material. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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%) harboured 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 provide a rationale for prospective and repeated mutations testing in female lower genital tract melanomas. [ABSTRACT FROM AUTHOR]

Background Immune checkpoint blockade therapy ( ICBT) for the treatment of melanoma has led to an important improvement of overall survival in advanced stage patients. However, secondary cutaneous maculopapular eruptions ( CMPEs) are frequent and remain poorly characterized. Methods We performed a retrospective analysis of melanoma patients from our institution who developed CMPEs during ICBT. Clinical information was retrieved, and histopathological and immunohistochemical characterization was performed by two pathologists. For comparison, a group of biopsies from CMPE caused by anti-v-raf murine sarcoma viral oncogene homolog B1 ( BRAF) therapy was analyzed. Results Eleven patients met the inclusion criteria. On clinical grounds, CMPE developed mainly on early onset of immunotherapy and were of low grade. Typical lesions included erythematous papules and macules affecting the trunk and/or extremities with associated pruritus. The histopathological patterns consisted of a superficial perivascular lymphocytic dermatitis ( SPLD) with eosinophils followed by a granulomatous dermatitis. Other patterns included lichenoid, spongiotic, and a case of Grover's disease. The inflammatory infiltrate consisted of T lymphocytes ( CD3+) with a predominance of CD4+ over CD8+ cells; isolated Foxp3+ cells were invariably present, and PD-1 was not expressed. Biopsies from CMPE caused by anti- BRAF therapy showed an SPLD and a similar lymphocytic immunophenotype. Conclusions Our study showed the clinical features of a group of melanoma patients with CMPE for ICBT and emphasized the wide spectrum of histological findings as well as their immunohistochemical profile. Differential diagnosis can be difficult with CMPE provoked by other therapies as was seen in our comparison group of anti- BRAF-induced eruptions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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<.01) and S100 protein concentration ( P<.01). Finally, seven patients presented discordant BRAF status in different tumor sites. In all these patients, the test performed on ct DNA was positive, suggesting that ct DNA analysis might be less sensitive to tumor heterogeneity. Altogether, these results suggest that plasmatic mutant BRAF DNA is a prognostic factor of OS, correlated with tumor burden. In addition, it represents an interesting alternative source of DNA to detect BRAF mutations before treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

Background: 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. Objective: The authors report results of a pilot study conducted in inoperable CSCC patients treated with cetuximab alone or combined with chemotherapy or radiotherapy. Material and methods: This study was conducted in 20 CSCC patients. RECIST criteria were used to evaluate clinical and radiological responses. Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses a study that examines whether a single BRAF wild-type test is sufficient to exclude the melanoma patients form Vemurafenib therapy. The study determines the BRAF mutation status of all samples from consecutive inpatients with melanoma. It also suggests that the absence of BRAFV600 mutation in one melanoma tumor sample is not a definitive result.

The article presents case study of a 74-year-old man, who presented with the history of hypertension and was on treatment with lercanidipine, candesartan, and hydrochlorothiazide. Topics discussed include presence of primary melanoma on back and tumour necrosis; vemurafenib therapy; and anti-inflammatory drugs.

The article presents the case study of a 72-year-old woman with a 6-month history of skin eruption in the intertriginous areas of the skin. The medical history of the woman includes chronic lymphocytic leukemia (CLL) that is in remission and was treated with rituximab and fludarabine cyclophosphamide. The article discusses the case of a syringotropic mycosis fungoides with chronic lymphocytic leukemia (CLL).