[Hypersensitivity to dacarbazine in patients with metastatic malignant melanoma]. / Hypersensibilité à la dacarbazine chez les malades traités pour mélanome métastatique.

BACKGROUND: Dacarbazine (DTIC) is the first-line chemotherapy for metastatic malignant melanoma without cerebral metastasis. Its clinical and hematological safety is usually good. Hypersensitivity in hepatic failure patients is the most serious side effect described. PATIENTS AND METHODS: This was a retrospective study of the prevalence of hypersensitivity in patients treated with DTIC for metastatic melanoma between 11/01/2002 and 10/31/2003. Hypersensitivity was diagnosed in the event of fever, hypereosinophilia (> 500/mm3) with or without liver dysfunction (> twice pre-therapeutic values). Clinical data, DTIC administration modalities, number of courses and clinical and laboratory safety data were recorded. RESULTS: Twenty patients were included, 11 women and 9 men of median age 58.6 years (22-82 years) with multiple metastases in all cases. DTIC was the first-line treatment for 19 patients, being administered for 4 days to 10 patients and for 1 day to the other 10 patients, depending on their overall health status. Five hypersensitivity-like manifestations were observed, all in the 4-day treatment group. In 3 patients, fever and hypereosinophilia were seen without liver dysfunction at D3 of the second course of treatment. In 2 patients, treatment was stopped after the second course because of disease progression. In the third patient, 4 courses were given with recurrence of symptoms, although the latter were controlled during the fifth course with corticosteroids and antihistamines given 15 minutes before the start of treatment. Two patients experienced severe forms of hypersensitivity with fever, hypereosinophilia, liver dysfunction (cytolysis and cholestasis) and delayed medullar aplasia, after the first and second course respectively. In one patient, bone marrow examination showed a block at the promyelocytic stage consistent with a toxic etiology. Treatment with DTIC was stopped, and all signs regressed with symptomatic treatment. DISCUSSION: Hypersensitivity with DTIC seems to be frequent, being observed in 20% of our patients, with early onset (after the first or second course) and absence of dose-dependence. We describe for the first time two cases of medullar aplasia occurring in association with DTIC hypersensitivity. During phase I studies, the hematologic toxicity of DTIC was moderate, rarely affecting red cells, and was observed with higher doses than those used in metastatic malignant melanoma. We suggest that this aplasia forms part of the signs of hypersensitivity because of the bone marrow morphology, the existence of anemia and concomitant resolution with all the others signs of hypersensitivity. CONCLUSION: Laboratory monitoring (NFS, liver enzymes) is thus justified, particularly after the first and second courses of DTIC. In case of fever and hypereosinophilia without liver dysfunction, DTIC may be continued together with symptomatic treatment. In the event of hepatic dysfunction, and of course severe hematological disorders, potentially fatal complications can occur and treatment must be stopped.

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma.

Germline anomalies of the INK4a-ARF and Cdk4 genes were sought in a series of 89 patients suspected of having a genetic predisposition to melanoma. Patients were selected based on the following criteria: (a) familial melanoma (23 cases), (b) multiple primary melanoma (MPM; 18 cases), (c) melanoma and additional unrelated cancers (13 cases), (d) age at diagnosis less than 25 years (21 cases), and (e) nonphoto-induced melanoma (NPIM; 14 cases). Mutations of INK4a-ARF and Cdk4 were characterised by automated sequencing, and germline deletions of INK4a-ARF were also examined by real-time quantitative PCR. Seven germline changes of INK4a-ARF, five of which were novel, were found in seven patients (8%). Four were very likely to be pathogenic mutations and were found in three high-risk melanoma families and in a patient who had a pancreatic carcinoma in addition to melanoma. Three variants of uncertain significance were detected in one MPM patient, one patient <25 years, and one NPIM patient. No germline deletion of INK4a-ARF was found in 71 patients, and no Cdk4 mutation was observed in the 89 patients. This study confirms that INK4a-ARF mutations are infrequent outside stringent familial criteria, and that germline INK4a-ARF deletions are rarely involved in genetic predisposition to melanoma.

[Pretibial epidermolysis bullosa. A rare form of epidermolysis bullosa simplex]. / Epidermolyse bulleuse prétibiale. Une forme inhabituelle d'épidermolyse bulleuse simple.

INTRODUCTION: Pretibial epidermolysis bullosa had been classified as a rare localized form of autosomal dominant dystrophic epidermolysis bullosa. OBSERVATION: We report a sporadic case of a patient suffering from bullous lesions induced by minor trauma on pretibial skin. The lesions healed with atrophic scars. No milia formation was observed. The mapping of dermoepidermal junction by LH 7:2 and GB3 monoclonal antibodies was normal. By electron microscopy, numerous perinuclear vacuoles were observed and the cleavage occurred within the basal keratinocytes. DISCUSSION: This patient had clinical features in accordance with a diagnosis of pretibial epidermolysis bullosa. However, in contrast to previous case reports, the ultrastructural pattern was this of an epidermolysis bullosa of simplex type.

[Double-blind study versus excipient of 0.75% metronidazole gel in the treatment of rosacea]. / Etude en double insu contre excipient du métronidazole gel à 0.75 p. 100 dans le traitement de la rosacée.

INTRODUCTION: The proven value of tetracyclines and metronidazole administered orally in the treatment of the chronic and recurrent disease that is rosacea is tempered by the important undesirable effects observed in long-term therapy. The purpose of this study was to test the effectiveness of an 0.75 p. 100 metronidazole gel in the treatment of rosacea. PATIENTS AND METHODS: The study involved two groups of patients: one received the metronidazole gel and the other the vehicle of the gel used as placebo. The multicentre randomized trial was conducted in the double-blind fashion by 18 private dermatologists working in the Paris region. Fifty one patients who, since more than 3 months, had been presenting with rosacea, defined as at least 4 papulopustules associated with erythema and/or telangiectasia, entered the trial. Topical treatments and systemic treatments which had shown some activity against rosacea had been interrupted for 15 days or 2 months respectively. The product (or the placebo) was applied a.m. and p.m. on the whole dry face. The patients were seen on days 0, 21 and 42. The evaluation was purely clinical, and the principal criterion of judgement was a change in the number of papulopustules between days 0 and 42. RESULTS: The metronidazole gel reduced the number of papulopustules between day 0 and day 42, and this reduction was significantly greater than that observed with the excipient alone. The active product began to be effective during the third week and remained so during the next three weeks. Both the metronidazole gel and its excipient seemed to be poorly tolerated, with frequent complaints of dry skin, but in 5 women of the metronidazole group this dryness was alleviated by application of moisturizers. CONCLUSION: This study has demonstrated that the 0.75 p. 100 metronidazole gel is effective in the treatment of the papulopustular component of rosacea.

[A double-blind placebo-controlled study of a 2 percent foaming lotion of ketoconazole in a single application in the treatment of pityriasis versicolor]. / Etude en double insu contre excipient du kétoconazole lotion moussante à 2 p. 100 en application unique dans le traitement du pityriasis versicolor.

A double-blind, placebo-controlled therapeutic trial of ketoconazole presented as a foam and applied only once was carried out on 61 patients by a group of 15 private dermatologists practising in the Paris region. All patients had tinea versicolor clinically diagnosed, then confirmed by a positive patch test, as assessed by a single mycologist. The main criterion of therapeutic effectiveness was negativation of the patch test 30 days after a single topical application of the ketoconazole foam. On day 30, the test was negative in 22 of the 28 patients in the ketoconazole group and in 5 of the 29 patients in the placebo (i.e. excipient) group (p less than 10(-5). Clinical and mycological cure was observed in only 11 of the 28 patients treated with the active substance, but among the 11 patients who still showed skin lesions despite a negative mycological examination 10 had achromic lesions which could be regarded as residual. This clearly indicates that the only criterion that can be used in a therapeutic trial on tinea versicolor is the mycological result. The active substance and the excipient were well tolerated; two patients in the ketoconazole group reported tingling of the skin at the site of application. We conclude that a single application of ketoconazole foam in effective and well tolerated in tinea versicolor. The single application technique unquestionably has advantages over repeated applications and should result in better patient's compliance and greater effectiveness in the long term.