Philippe Saiag

Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

PURPOSE To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma. PATIENTS AND METHODS Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms. CONCLUSION ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.

Flow cytometric analysis of conjunctival epithelium in Ocular rosacea and keratoconjunctivitis sicca

PURPOSE To investigate by flow cytometry and impression cytology (IC) specimens the inflammatory status of the conjunctival epithelium and goblet cell density in two series of patients with rosacea and dry eye syndrome compared with a population of healthy subjects. DESIGN Nonrandomized, prospective, comparative case series. PARTICIPANTS Twenty-six eyes of 13 patients with rosacea, 26 eyes of 13 patients with dry eye syndrome, and 24 eyes of 12 control subjects were included in this study. METHODS IC specimens were collected after clinical examination of the ocular surface and analyzed by flow cytometry, using antibodies directed to human lymphocyte antigen-DR (HLA-DR), intercellular adhesion molecule-1 (ICAM-1) (CD 54), and the peptidic core of the conjunctival mucin (M1/MUC5AC). The percentage of positive cells was calculated and levels of fluorescence expression quantified and compared with those obtained in a series of 12 healthy subjects. MAIN OUTCOME MEASURES Tear break-up time (TBUT), Schirmer test, fluorescein and lissamin green stainings, and IC were realized in this study. RESULTS A significant increase of HLA-DR and ICAM-1 expressions by epithelial cells was consistently found in the two pathologic groups compared with levels calculated in normal eyes. The two markers were well correlated with each other and inversely with TBUT and Schirmer test. The percentage of goblet cells was significantly decreased in rosacea patients and in dry eye patients compared with the normal group with a significant negative correlation with both HLA DR and ICAM-1 markers. CONCLUSIONS Ocular rosacea and keratoconjunctivitis sicca were associated with severe ocular surface changes, such as an overexpression of inflammatory markers and a significant decrease in the number of goblet cells.

Drug-induced toxic epidermal necrolysis (Lyell syndrome) in patients infected with the human immunodeficiency virus

BACKGROUND Although patients infected with the human immunodeficiency virus (HIV) are predisposed to cutaneous adverse drug reactions, only a few cases of toxic epidermal necrolysis (TEN) have been reported in this setting. OBJECTIVE Our purpose was to examine the features of TEN in HIV-infected patients. METHODS We performed a retrospective analysis of all HIV-infected patients in a series of 80 consecutive cases of TEN during a 6-year period. RESULTS Fourteen patients were HIV infected. They had typical TEN, with epidermal detachment involving 20.6% +/- 8.0% of the skin surface. Suspected drugs were sulfadiazine, trimethoprim-sulfamethoxazole, sulfadoxine, clindamycin, phenobarbital, and chlormezanone. Patients with the acquired immunodeficiency syndrome (AIDS) exhibit a dramatically increased risk of TEN. During our study period 15 cases of AIDS-associated TEN occurred in the greater Paris area, whereas 0.04 case would have been expected if the incidence of TEN were the same in these patients as in the general population. CONCLUSION HIV-infected patients, especially those with AIDS, may develop TEN that shares many similarities with the disease in immunocompetent patients.

Long-term efficacy on Kaposi's sarcoma of highly active antiretroviral therapy in a cohort of Hiv-positive patients

ObjectiveTo assess the efficacy of highly active antiretroviral treatment (HAART) on AIDS–Kaposis sarcoma (KS). DesignProspective cohort of patients followed for 24 months. SettingFour referral hospitals of the West Paris metropolitan area. Patients/interventionThirty-nine AIDS–KS patients, 42 ± 9 years old, who began HAART (HIV-protease inhibitor and two nucleoside analogues) between March and December 1996, were enrolled. One was lost to follow-up at month 12. Main outcome measuresKS response, using criteria of the AIDS clinical trials group (ACTG), CD4 cell counts, and plasma HIV-RNA, assessed every 6 months. ACTG TIS staging of KS. ResultsEighteen patients had T1 KS and 21 T0 KS. One patient died from KS at month 6. KS improved progressively, with complete and partial response rates of 46% and 28% at month 24, respectively. Only six patients were still receiving systemic KS therapy at month 24. Complete response was observed in 10 of the 19 patients without systemic KS therapy at inclusion. Patients with complete response at month 24 had higher CD4 cell counts than others (465 ± 343 versus 185 ± 167 × 106/l;P  < 0.01), but the proportion of patients with HIV-1 RNA < 500 copies/ml was not significantly different. An increase in CD4 cell counts from inclusion to month 12 of > 150 × 106/l [odds ratio (OR), 13.4; 95% confidence interval (CI), 2–82] and T0 KS at inclusion: [OR, 7; 95% CI, 1.1–42] were predictive of complete response at month 24. ConclusionsHAART appears to have prolonged efficacy on AIDS–KS, even without specific KS therapy, and this effect appears to be linked to the restoration of immune function.

Ultrasonography or palpation for detection of melanoma nodal invasion: a meta-analysis

Because treatment of distant melanoma metastases is not very effective, nodal spread should be diagnosed early so that therapeutic lymphadenectomy can be started as early as possible. Physical examination alone often does not detect nodal metastases and palpable nodes cannot be clasified unambiguously. Whether lymph-node ultrasonography-an inexpensive procedure-improves detection of nodal invasion during the initial staging and follow-up of patients with melanoma is controversial. We used meta-analysis techniques for diagnostic tests to assess the merit of ultrasonography and palpation in detection of nodal invasion in patients with melanoma. Five databases were screened until December, 2003. 12 studies, including 6642 patients and 18?610 paired palpation and ultrasound examinations, were eligible. The main limitations were variations in the definition of false negatives, and verification bias. Ultrasonography had a higher discriminatory power (odds ratio 1755; 95% CI 726-4238) than did palpation (21 [4-111]; p=0.0001). Furthermore, positive-likelihood ratios were 41.9 (95% CI 29-75) for ultrasonography and 4.55 (2-18) for palpation; negative-likelihood ratios were 0.024 (0.01-0.03) and 0.22 (0.06-0.31), respectively. Our results showed clearly that ultrasonography detects lymph-node invasion more accurately than palpation, and should therefore probably be used routinely in patients with melanoma.

Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in Caucasian populations, accounting for 20% of all cutaneous malignancies. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cSCC diagnosis and management, based on a critical review of the literature, existing guidelines and the experts experience. The diagnosis of cSCC is primarily based on clinical features. A biopsy or excision and histologic confirmation should be performed in all clinically suspicious lesions in order to facilitate the prognostic classification and correct management of cSCC. The first line treatment of cutaneous SCC is complete surgical excision with histopathological control of excision margins. The EDF-EADO-EORTC consensus group recommends a standardised minimal margin of 5 mm even for low-risk tumours. For tumours, with histological thickness of >6 mm or in tumours with high risk pathological features, e.g. high histological grade, subcutaneous invasion, perineural invasion, recurrent tumours and/or tumours at high risk locations an extended margin of 10 mm is recommended. As lymph node involvement by cSCC increases the risk of recurrence and mortality, a lymph node ultrasound is highly recommended, particularly in tumours with high-risk characteristics. In the case of clinical suspicion or positive findings upon imaging, a histologic confirmation should be sought either by fine needle aspiration or by open lymph node biopsy. In large infiltrating tumours with signs of involvement of underlying structures, additional imaging tests, such as CT or MRI imaging may be required to accurately assess the extent of the tumour and the presence of metastatic spread. Current staging systems for cSCC are not optimal, as they have been developed for head and neck tumours and lack extensive validation or adequate prognostic discrimination in certain stages with heterogeneous outcome measures. Sentinel lymph node biopsy has been used in patients with cSCC, but there is no conclusive evidence of its prognostic or therapeutic value. In the case of lymph node involvement by cSCC, the preferred treatment is a regional lymph node dissection. Radiation therapy represents a fair alternative to surgery in the non-surgical treatment of small cSCCs in low risk areas. It generally should be discussed either as a primary treatment for inoperable cSCC or in the adjuvant setting. Stage IV cSCC can be responsive to various chemotherapeutic agents; however, there is no standard regimen. EGFR inhibitors such as cetuximab or erlotinib, should be discussed as second line treatments after mono- or polychemotherapy failure and disease progression or within the framework of clinical trials. There is no standardised follow-up schedule for patients with cSCC. A close follow-up plan is recommended based on risk assessment of locoregional recurrences, metastatic spread or development of new lesions.

Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma

The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the ‘combination test’ enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.

Diagnosis and treatment of Merkel Cell Carcinoma. European consensus-based interdisciplinary guideline

Merkel cell carcinoma (MCC) is a rare tumour of the skin of neuro-endocrine origin probably developing from neuronal mechanoreceptors. A collaborative group of multidisciplinary experts form the European Dermatology Forum (EDF), The European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on MCC diagnosis and management, based on a critical review of the literature, existing guidelines and experts experience. Clinical features of the cutaneous/subcutaneous nodules hardly contribute to the diagnosis of MCC. The diagnosis is made by histopathology, and an incisional or excisional biopsy is mandatory. Immunohistochemical staining contributes to clarification of the diagnosis. Initial work-up comprises ultrasound of the loco-regional lymph nodes and total body scanning examinations. The primary tumour should be excised with 1-2cm margins. In patients without clinical evidence of regional lymph node involvement, sentinel node biopsy is recommended, if possible, and will be taken into account in a new version of the AJCC classification. In patients with regional lymph node involvement radical lymphadenectomy is recommended. Adjuvant radiotherapy might be considered in patients with multiple affected lymph nodes of extracapsular extension. In unresectable metastatic MCC mono- or poly-chemotherapy achieve high remission rates. However, responses are usually short lived. Treatment within clinical trials is regarded as a standard of care in disseminated MCC.

Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease characterized by malignant proliferation of a contingent blastic plasmacytoid dendritic cell. This rare entity is recognized mostly by cutaneous spreading, or not having a leukaemic component. The prognosis is very poor.

Variants of the MATP/SLC45A2 gene are protective for melanoma in the French population.

In this study, we investigated whether variants in three key pigmentation genes—MC1R, MATP/SLC45A2, and OCA2—were involved in melanoma predisposition. A cohort comprising 1,019 melanoma patients (MelanCohort) and 1,466 Caucasian controls without skin cancers were studied. A total of 10 polymorphisms, including five functional MC1R alleles (p.Asp84Glu, p.Arg142His, p.Arg151Cys, p.Arg160Trp, and p.Asp294His), two nonsynonymous SLC45A2 variants (p.Phe374Leu and p.Glu272Lys), and three intronic OCA2 variants previously shown to be strongly associated with eye color (rs7495174 T>C, rs4778241 G>T, and rs4778138 T>C) were genotyped. As expected, MC1R variants were closely associated with melanoma risk (P value <2.20.10−16; odds ratio [OR]=2.29 [95% confidence interval, CI=1.85–2.82 and OR=3.3 [95% CI=2.00–5.45], for the presence of one or two variants, respectively). Interestingly, the SLC45A2 variant p.Phe374Leu was significantly and strongly protective for melanoma (P‐value=2.12.10−15; OR=0.35 [95% CI=0.26–0.46] and OR=0.32 [95% CI=0.24–0.43], considering the genotypes Phe/Leu and Leu/Leu, respectively). MC1R and SLC45A2 variants had additive effects on melanoma risk, and after adjusting for pigmentation characteristics, the risk was persistent, even though both genes had a strong impact on pigmentation. Future studies may show whether genetic information could provide a useful complement to physical examination in predicting melanoma risk. Hum Mutat 0,1–7, 2008.