A.-B. Duval-Modeste

Phase II Study of Cetuximab As First-Line Single-Drug Therapy in Patients With Unresectable Squamous Cell Carcinoma of the Skin

PURPOSE To evaluate the efficacy and safety of cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), as a first-line monotherapy in patients with unresectable squamous cell carcinoma of the skin (SCCS). PATIENTS AND METHODS Thirty-six patients received cetuximab (initial dose of 400 mg/m(2) followed by subsequent weekly doses of 250 mg/m(2)) for at least 6 weeks with a 48-week follow-up. The primary end point was the disease control rate (DCR) at 6 weeks (according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria). Secondary end points included best response rate, overall survival, progression-free survival (PFS), and toxicity assessment. Association of treatment efficacy with RAS mutations or FcγR genotypes was investigated. RESULTS Median age of the study population was 79 years. DCR at 6 weeks was obtained in 25 of 36 patients (69%; 95% CI, 52% to 84%) of the intention-to-treat population. The best responses were eight partial responses and two complete responses. There were no cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78% of patients and was associated with prolonged PFS. One HRAS mutation was identified. Combined FcγRIIa-131H/H and/or FcγRIIIa-158V/V polymorphisms were not associated with the clinical outcomes. CONCLUSION As a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69% DCR. A randomized phase III trial is warranted to confirm that cetuximab may be considered as a therapeutic option especially in elderly patients. The low frequency of RAS mutations in SCCS makes SCCS tumors attractive for EGFR inhibition.

Prospective study to evaluate the association between systemic sclerosis and occupational exposure and review of the literature.

INTRODUCTION Systemic sclerosis (SSc) has complex pathogenesis and likely multifactorial causes. Environmental exposures have been suggested to play a role in SSc pathogenesis, including occupational exposure to pollutants and chemicals as well as use of drugs leading to modulation of immune response. Thus, this case-control study aimed to assess: the relationship between SSc and occupational exposure; and the risk of SSc related to occupational exposure in male and female patients. METHODS From 2005 to 2008, 100 patients with a definite diagnosis of SSc were included in the study; 3 age, gender, and smoking habits matched controls were selected for each patient. A committee of experts evaluated blindly occupational exposure to crystalline silica, white spirit, organic solvents, ketones, welding fumes, epoxy resins, and pesticides; an occupational exposure score was calculated for all subjects. Our findings were compared with previous data in the literature. RESULTS Increased ORs for SSc were found for: crystalline silica (p<0.0001), white spirit (p<0.0001), aromatic solvents (p=0.0002), chlorinated solvents (p=0.014), trichlorethylene (p=0.044), ketones (p=0.002) and welding fumes (p=0.021). Elevated risk associated with high final cumulative score in SSc was observed for: crystalline silica, white spirit, chlorinated solvents, trichlorethylene, aromatic solvents, any type of solvents, ketones and welding fumes. A marked association between SSc and occupational exposure was further found for: 1) crystalline silica, chlorinated solvents, trichloroethylene, white spirit, ketones and welding fumes in male patients; and 2) white spirit, aromatic solvents, any type of solvent and ketones in female patients. Finally, we did not find an association between SSc and: 1) the use of drugs that have been speculated to play a role in SSc onset (anorexigens, pentazocine, bromocriptine, l-tryptophan); 2) implants - that are prosthesis, silicone implants, and contact lenses; and 3) dyeing hair. In the literature, SSc has been associated with occupational exposure to silica and solvents, while the association between SSc and specific organic solvents and welding fumes has been anecdotally reported. CONCLUSION The following occupational factors have an impact in the development of SSc: crystalline silica, white spirit, aromatic solvents, chlorinated solvents, trichlorethylene, ketones and welding fumes. The risk of SSc appears to be markedly associated with high cumulative exposure. Finally, the association between SSc and occupational exposure may be variable according to gender.

Association of occupational exposure with features of systemic sclerosis

BACKGROUND Occupational exposure is reported as playing a substantial causative role in systemic sclerosis (SSc). OBJECTIVE We sought to compare the characteristics of SSc in patients with and without occupational exposure to crystalline silica/solvents. METHODS In all, 142 patients with SSc were enrolled in this prospective study. An expert committee performed blind evaluation of occupational exposure to crystalline silica/solvents. RESULTS Patients exposed to crystalline silica more often exhibited: diffuse cutaneous SSc (P = .02), digital ulcers (P = .05), interstitial lung disease (P = .0004), myocardial dysfunction (P = .006), and cancer (P = .06). Patients exposed to solvents more frequently developed: diffuse cutaneous SSc (P = .001), digital ulcers (P = .01), interstitial lung disease (P = .02), myocardial dysfunction (P = .04), and cancer (P = .003); in addition, these patients were more frequently anti-Scl 70 positive and anticentromere negative. Under multivariate analysis, significant factors for SSc associated with exposure to silica/solvents were: male gender (odds ratio 19.31, 95% confidence interval 15.34-69.86), cancer (odds ratio 5.97, 95% confidence interval 1.55-23.01), and digital ulcers (odds ratio 2.42, 95% confidence interval 1.05-5.56). LIMITATIONS The cohort originated from a single geographic region. CONCLUSION Occupational exposure to crystalline silica/solvents is correlated with more severe forms of SSc characterized by: diffuse cutaneous involvement, interstitial lung disease, general microangiopathy (digital ulcers and myocardial dysfunction), and association with cancer. Occupational exposure should be systematically checked in all patients with SSc, as exposed patients seem to develop more severe forms of SSc.

Outbreak of Mycobacterium chelonae in France

Tattooing is common worldwide.1 Various infections have been reported, including local infections mainly due to pyogenic bacteria and systemic infections such as hepatitis B and C and HIV.2 3 We report a large outbreak of Mycobacterium chelonae skin infection occurring in France over eight months that was related to contaminated ink. Forty eight patients presented with skin lesions, mainly pustules, occurring from 3 to 35 …

Syndrome d’hypersensibilité médicamenteuse à l’imatinib

BACKGROUND Imatinib (Glivec) is a tyrosine kinase inhibitor used to treat certain cases of leukaemia. We report a case of a drug-induced reaction with eosinophilia and systemic symptoms (DRESS) caused by imatinib. CASE-REPORT A 77-year-old woman with a chronic myeloid leukaemia was treated with imatinib and allopurinol. Nineteen days after the start of treatment, the patient presented fever with a generalized polymorphous rash associated with oral erosions, facial oedema, diffuse lymphadenopathy and blood hypereosinophilia. Histological analysis of skin biopsy specimens suggested a drug-induced reaction. The outcome was favourable two weeks after discontinuation of treatment. Three months later, imatinib was reintroduced because of progression of the patients chronic myeloid leukaemia, and recurrence of the skin rash and fever was observed within 12 hours. DISCUSSION Allopurinol was stopped definitively because of its more frequent imputability. Imatinib was reintroduced after considering the benefit-risk ratio and in full knowledge of the existence of cutaneous reactions to imatinib, despite there being only one recent report of DRESS following treatment with imatinib. According to the causality criteria of Bégaud et al. regarding imatinib, inherent causality of the drug in our patient was initially possible (I2) and appeared likely (I3) after the rechallenge test. This case clearly illustrates that imatinib is a potential cause of DRESS.

Cas cliniqueSyndrome d’hypersensibilité médicamenteuse à l’imatinibImatinib-induced DRESS

BACKGROUND Imatinib (Glivec) is a tyrosine kinase inhibitor used to treat certain cases of leukaemia. We report a case of a drug-induced reaction with eosinophilia and systemic symptoms (DRESS) caused by imatinib. CASE-REPORT A 77-year-old woman with a chronic myeloid leukaemia was treated with imatinib and allopurinol. Nineteen days after the start of treatment, the patient presented fever with a generalized polymorphous rash associated with oral erosions, facial oedema, diffuse lymphadenopathy and blood hypereosinophilia. Histological analysis of skin biopsy specimens suggested a drug-induced reaction. The outcome was favourable two weeks after discontinuation of treatment. Three months later, imatinib was reintroduced because of progression of the patients chronic myeloid leukaemia, and recurrence of the skin rash and fever was observed within 12 hours. DISCUSSION Allopurinol was stopped definitively because of its more frequent imputability. Imatinib was reintroduced after considering the benefit-risk ratio and in full knowledge of the existence of cutaneous reactions to imatinib, despite there being only one recent report of DRESS following treatment with imatinib. According to the causality criteria of Bégaud et al. regarding imatinib, inherent causality of the drug in our patient was initially possible (I2) and appeared likely (I3) after the rechallenge test. This case clearly illustrates that imatinib is a potential cause of DRESS.

Efficacy and Tolerance of Anti–Tumor Necrosis Factor α Agents in Cutaneous Sarcoidosis: A French Study of 46 Cases

Importance Evidence for the long-term efficacy and safety of anti–tumor necrosis factor &agr; agents (anti-TNF) in treating cutaneous sarcoidosis is lacking. Objective To determine the efficacy and safety of anti-TNF in treating cutaneous sarcoidosis in a large observational study. Design, Setting, and Participants STAT (Sarcoidosis Treated with Anti-TNF) is a French retrospective and prospective multicenter observational database that receives data from teaching hospitals and referral centers, as well as several pneumology, dermatology, and internal medicine departments. Included patients had histologically proven sarcoidosis and received anti-TNF between January 2004 and January 2016. We extracted data for patients with skin involvement at anti-TNF initiation. Main Outcomes and Measures Response to treatment was evaluated for skin and visceral involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score (from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded. The overall cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0 or 1) or partial response (ePOST drop ≥2 points from baseline but >1 at last follow-up). Results Among 140 patients in the STAT database, 46 had skin involvement. The most frequent lesions were lupus pernio (n = 21 [46%]) and nodules (n = 20 [43%]). The median cutaneous severity score was 5 and/or 6 at baseline. Twenty-one patients were treated for skin involvement and 25 patients for visceral involvement. Reasons for initiating anti-TNF were failure or adverse effects of previous therapy in 42 patients (93%). Most patients received infliximab (n = 40 [87%]), with systemic steroids in 28 cases (61%) and immunosuppressants in 32 cases (69.5%). The median (range) follow-up was 45 (3-103) months. Of the 46 patients with sarcoidosis and skin involvement who were treated with anti-TNF were included, median (range) age was 50 (14-78) years, and 33 patients (72%) were women. The OCRR was 24% after 3 months, 46% after 6 months, and 79% after 12 months. Steroid sparing was significant. Treatment was discontinued because of adverse events in 11 patients (24%), and 21 infectious events occurred in 14 patients (30%). Infections were more frequent in patients treated for visceral involvement than in those treated for skin involvement (n = 12 of 25 [48%] vs n = 2 of 21 [9.5%], respectively; P = .02). The relapse rate was 44% 18 months after discontinuation of treatment. Relapses during treatment occurred in 35% of cases, mostly during anti-TNF or concomitant treatment tapering. Conclusions and Relevance Anti-TNF agents are effective but suspensive in cutaneous sarcoidosis. The risk of infectious events must be considered.

Successful use of dabrafenib after the occurrence of drug rash with eosinophilia and systemic symptoms (DRESS) induced by vemurafenib

DRESS: drug rash with eosinophilia and systemic symptoms INTRODUCTION Vemurafenib and dabrafenib are 2 BRAF inhibitors that are approved by the US Food and Drug Administration for the treatment of metastatic malignant melanoma with BRAF mutation. These drugs improve overalland progression-free survival. Some severe vemurafenib-induced reactions have been reported, which commonly require treatment withdrawal. We report the case of a patient with metastatic malignant melanoma in whom DRESS developed likely from vemurafenib. Because the patient did not respond tomany previous treatments, dabrafenib, another BRAF inhibitor, was started without reoccurrence of DRESS.