European recommendations for management of immune checkpoint inhibitors-derived dermatologic adverse events. The EADV task force 'Dermatology for cancer patients' position statement.

The introduction of immune checkpoint inhibitors (ICIs) opened a new era in oncologic therapy. The favourable profile of ICIs in terms of efficacy and safety can be overshadowed by the development of immune-related adverse events (irAEs). Dermatologic irAEs (dirAEs) appear in about 40% of patients undergoing immunotherapy and mainly include maculopapular, psoriasiform, lichenoid and eczematous rashes, auto-immune bullous disorders, pigmentary disorders, pruritus, oral mucosal lesions, hair and nail changes, as well as a few rare and potentially life-threatening toxicities. The EADV task force Dermatology for Cancer Patients merged the clinical experience of the so-far published data, incorporated the quantitative and qualitative characteristics of each specific dirAEs, and released dermatology-derived, phenotype-specific treatment recommendations for cutaneous toxicities (including levels of evidence and grades of recommendation). The basic principle of management is that the interventions should be tailored to serve the equilibrium between patients' relief from the symptoms and signs of skin toxicity and the preservation of an unimpeded oncologic treatment.

Dabrafenib and trametinib exposure-efficacy and tolerance in metastatic melanoma patients: a pharmacokinetic-pharmacodynamic real-life study.

PURPOSE: Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600mut metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients. METHODS: BRAFV600mut metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC0-τ and Ctrough) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed. RESULTS: Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib Ctrough within intermediate range was associated with a significantly higher PFS (HR [95% CI] = 0.41 [0.18; 0.91], p = 0.029) and DOR (HR [95% CI] = 0.39 [0.16; 0.94], p = 0.024), and association with DOR remained significant in multivariate analysis (HR [95% CI] = 0.34 [0.12; 0.95], p = 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE. CONCLUSION: In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600mut metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib.

Penoscrotal Paget's disease.

Paget's disease (PD) denotes an initially intra-epidermal adenocarcinoma that can later invade the dermis and metastasise. Among the extramammary forms of PD (EMPD), penoscrotal presentations are rarer than the vulvar and perianal forms. Once diagnosis has been confirmed by histopathological examination, a search for associated neoplasia must be conducted, although penoscrotal EMPD is less frequently associated with underlying neoplasia than mammary PD (MPD). The associated cancer most often involves a neighbouring organ, with prostate cancer being the most common, or in some cases consists of underlying cutaneous adnexal tumours. First-line therapy consists of surgical excision. Alternatives to surgery (imiquimod, CO2 laser vaporisation, dynamic phototherapy) may be considered in certain cases.

Acquired generalized lipodystrophy under immune checkpoint inhibition.

Immune checkpoint inhibitors are now the standard of care in the treatment of several types of cancer. Cutaneous immune-related adverse events (irAEs) are usually of low grade and reversible, while endocrine irAEs are generally irreversible and managed with hormone replacement therapy. We report a 47-year-old patient, treated with the anti-programmed cell death (PD)1 antibody pembrolizumab for a metastatic melanoma, who developed severe lipodystrophy after 10 months of treatment, characterized by the loss of subcutaneous fat tissue, central obesity and insulin resistance with a decreased leptin level. Histological analysis of a cutaneous biopsy revealed subcutaneous fat cell destruction associated with oedema, the presence of lipophages, and a CD3+ lymphocytic infiltrate involving the panniculus. This led to the diagnosis of anti-PD-1-induced acquired generalized lipodystrophy, after ruling out differential diagnoses (i.e. genetic and systemic autoimmune diseases). No corticosteroids were introduced considering the high risk of inducing severe metabolic complications, and pembrolizumab was discontinued as complete response of the melanoma was achieved. However, after 12 months of follow-up, lipodystrophy and its severe metabolic complications are still ongoing. What's already known about this topic? Anti-programmed cell death (PD)1 agents are now a standard of care in the treatment of several cancers, including melanoma. Endocrine and cutaneous immune-related adverse events (irAEs) are among the most frequent irAEs (14-30% and 30-40%, respectively) in patients treated with immune checkpoint inhibitors. What does this study add? Acquired generalized lipodystrophy can occur during anti-PD1 therapy and is associated with severe metabolic complications. With the increase in anti-PD1 prescription in several cancer types, clinicians must be aware of the whole range of irAEs that may occur.

Stage IV cutaneous squamous cell carcinoma: treatment outcomes in a series of 42 patients.

BACKGROUND: The prevalence and incidence of cutaneous squamous cell carcinoma (cSCC) are increasing due to the ageing of the population and sun exposure. Advanced cSCC forms (locally advanced and/or locoregional metastatic and/or distant metastatic) account for approximately 3% of cSCC and can result in death. OBJECTIVE: Analysis of the clinical characteristics and treatment outcomes in stage IV cSCC with unresectable locoregional extension and/or the presence of metastases. METHODS: A retrospective study was conducted at a single-centre university hospital for stage IV cSCC patients followed between 1 January 2008 and 31 December 2015. Descriptive analyses (demographic, anatomo-clinical characteristics, treatment sequences, response to treatment and survival analysis) were performed. RESULTS: The study included 42 patients (median age = 75.5 years) with a diagnosis of stage IV cSCC who were treated with at least one line of chemotherapy and/or cetuximab. At the time of diagnosis, 85.7% of the patients had locoregional extension (19% of locally advanced and 67% of locoregional metastatic) and 14.3% had distant metastatic disease. Regarding treatment, 40% and 36% of patients received no more than 1 and 2 systemic treatment lines, respectively. The 4-year overall survival was 6%, and the median follow-up was 18.6 months. The objective response rate was 55% after the first line of treatment with a median progression-free survival (PFS) of 6.18 months and 12% after the second line with a median PFS of 6.51 months. Grade 3 and 4 adverse events were observed for 33% of patients. CONCLUSION: Our study confirms a very poor prognosis of stage IV cSCC and a poor response to conventional therapies, indicating that the stage IV cSCC patient population remains with unmet medical needs.

[Apparent worsening of psoriasis lesions revealing methotrexate overdosage]. / Aggravation apparente d'un psoriasis révélant un surdosage en méthotrexate.

BACKGROUND: Methotrexate (MTX) is an antimetabolite drug used in the treatment of cancers and autoimmune diseases and frequently in dermatology for cutaneous and/or arthritic psoriasis. Toxicities due to MTX overdosage are mainly cutaneous, hepatic and hematologic. Herein, we report a case of MTX overdosage presenting as an erosive and an inflammatory flare of preexisting psoriatic plaques and with new palmar lesions. PATIENTS AND METHODS: A 51-year-old male with a 6-year history of plaque psoriasis resistant to topical corticosteroids was started for the first time on MTX 20mg weekly. One week later, he presented with fever, general weakness and mucocutaneous ulcerations. Physical examination revealed inflammatory, erythematous and partially erosive annular plaques strictly confined to preexisting psoriatic lesions, along with keratotic psoriatic palmar plaques. Further questioning indicated that the patient was taking MTX 20mg daily. Investigations revealed neutropenia (1040/mm3) and skin histology showed prominent dystrophic keratinocytes and confirmed the diagnosis of methotrexate toxicity. Clinical and biological improvements were observed after cessation of MTX and treatment with folinic acid, IV hydration and urine alkalization. DISCUSSION: Skin lesions due to acute MTX toxicity are rare, but they herald later-onset pancytopenia. Identification of these cutaneous lesions might enable earlier treatment initiation. The predilection of MTX toxicity for preexisting lesions or the de novo appearance of palmoplantar pustules should not lead to the erroneous diagnosis of psoriasis flare.

Psoriasis associated with idiopathic CD4+ T-cell lymphopenia: a regulatory T-cell defect?

Idiopathic CD4(+) lymphocytopenia (ICL) is a rare immunodeficiency syndrome of unknown origin for which the increased risks of opportunistic infections and of malignancies have been well established; however, skin dysimmune diseases, including psoriasis, have been scarcely reported up to now. We report herein the severe course of psoriasis in four patients with ICL, and show evidence for a defect in the skin recruitment of regulatory CD4(+) FoxP3(+) T cells. These data raise the apparent paradigm of the occurrence of a severe immunomediated disease together with a profound T-cell defect, a model that might also apply to other immune deficiencies associated with psoriasis.