J. Chevrant-Breton

A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (ΨKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents

Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. Methods: These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk. Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

Delays in diagnosis and melanoma prognosis (I): The role of patients

A prospective survey was conducted to assess the role of patients in the melanoma prognosis. Consecutive patients with primary melanoma were interviewed and examined using a comprehensive questionnaire including a psychological instrument. Main outcome measures were the delay before medical intervention and the tumor thickness. Of 590 melanomas, 70.8% were detected by patients and this proportion was higher in females. Relatives were involved in the detection of half of the cases. Median delays before the patient realized he had a suspicious lesion, before this lesion was seen by a doctor, and before the melanoma was removed were 4 months, 2 months, and 1 week, respectively. Delays up to several years were observed in some cases. The rate of self‐detection tended to be lower, the delays before seeking medical advice to be longer, and the tumor thickness to be higher in old people, in males, in lower‐educated individuals, in those living out of towns, and in people with a low awareness about melanocytic tumors than in other cases. Conversely, individuals with a high number of atypical nevi, those who were aware to be at risk, and those who regularly visited a dermatologist tended to detect their melanoma more rapidly. No specific psychological traits were associated with a late reaction, although negligence and anxiety tended to prolong the delays. Knowledge about melanoma was poor in many patients, especially in males, and wrong beliefs were widespread. This study provides the targets of future education programs. Int. J. Cancer 89:271–279, 2000.

Delays in diagnosis and melanoma prognosis (II): The role of doctors

A prospective survey was conducted to assess physician responsibility in melanoma prognosis. Consecutive patients with primary melanoma were interviewed and examined using a standardized questionnaire. Main outcome measures were medical components of the delay before tumor resection and tumor thickness. Of 590 melanomas, 29.1% were coincidentally detected by physicians and their tumor depth was lower than in melanomas detected by patients (p < 0.001). Physician sensitivity for melanoma diagnosis was evaluated at 86%. Median time intervals to propose resection and to perform removal of melanoma were short: 0 (mean 103) and 7 (mean 68) days, respectively. Melanomas were managed in an inappropriate way in 14.2% of cases. Location on acral areas and absence of pigmentation were associated with longer medical delays and more frequent inappropriate medical attitudes. Melanomas located on hardly visible areas were less frequently detected by physicians than those on visible areas. Medical delays were shorter, doctors attitude was more frequently appropriate, and melanoma thickness was lower (p < 0.001) when the patient visited a dermatologist (54.7%) than when he or she visited a general practitioner (33.4%). Our study shows that doctor responsibility accounts for only a small part of the total delay before melanoma removal. However, systematic total examination and better training of doctors, especially about unusual forms of melanoma, could still improve melanoma detection. Int. J. Cancer 89:280–285, 2000.

Low Blood Concentration of Hydroxychloroquine in Patients With Refractory Cutaneous Lupus Erythematosus: A French Multicenter Prospective Study

OBJECTIVE To study the relation between blood concentration of hydroxychloroquine and the clinical efficacy of hydroxychloroquine sulfate in a series of patients with cutaneous lupus erythematosus (CLE). DESIGN Prospective multicenter study. A staff dermatologist blinded to blood hydroxychloroquine concentrations performed a standardized review of medical records and assessment of hydroxychloroquine efficacy in the following 3 categories: complete remission, partial remission (clearing of >50% of skin lesions), or treatment failure. Whole-blood samples were collected for measurement of blood hydroxychloroquine concentration. SETTING Fourteen French university hospitals. PATIENTS Three hundred consecutive patients with subacute or chronic CLE who had been treated with hydroxychloroquine for at least 3 months. MAIN OUTCOME MEASURES The statistical significance of correlation between blood hydroxychloroquine concentration and efficacy of hydroxychloroquine and the statistical associations in univariate and multivariate analyses of complete remission with several variables. RESULTS The study included 300 patients with discoid lupus erythematosus (n = 160), subacute CLE (n = 86), lupus erythematosus tumidus (n = 52), chilblain lupus (n = 26), and lupus panniculitis (n = 16); 38 of these patients had 2 or more associated forms. Median blood hydroxychloroquine concentration was significantly higher in patients with complete remission (910 [range, <50 to 3057] ng/mL) compared with partial remission (692 [<50 to 2843] ng/mL) and treatment failure (569 [<50 to 2242] ng/mL) (P = .007). In the multivariate analysis, complete remission was associated with higher blood hydroxychloroquine concentrations (P = .005) and the absence of discoid lesions (P = .004). Thirty patients (10.0%) had very low blood hydroxychloroquine concentrations (<200 ng/mL) and may be considered nonadherent to the treatment regimen. CONCLUSION Monitoring hydroxychloroquine blood concentrations might improve the management of refractory CLE.

The kinetics of the visible growth of a primary melanoma reflects the tumor aggressiveness and is an independent prognostic marker: a prospective study.

Primary melanoma (MM) could be a good model to test an intuitive concept: a cancer that is growing fast in its early phase is likely to have a high aggressiveness. Since MMs are visible tumors, many patients can provide information to indirectly assess the kinetics of their lesion. A prospective study was designed to assess if the kinetics of the visible growth of a primary MM, as described by the patient, could be a noninvasive prognostic marker. The ratio of MM thickness to delay between MM appearance and MM removal was used as a surrogate value for the kinetics of the MM growth. To assess the delay between MM appearance and removal, 362 patients with self‐detected invasive MM fulfilled a detailed questionnaire, which provided 2 types of estimations of this delay and thus 2 melanoma kinetics indexes (MKI and MKI*). After a median follow‐up of 4 years, univariate and multivariate analyses assessed whether relapse‐free survival was linked to MKI or MKI*. MKI was significantly predictive of relapse‐free survival (HR = 1.84 [1.51–2.25]) and relapse at 1 year (RR = 2.93 [1.84–4.69]), independently from Breslow thickness. MKI was retained in multivariate prognostic models, just after thickness and before other usual markers. MKI* was also a significant independent risk marker, although less predictive. In this model, the initial growth kinetics of a cancer reflects its aggressiveness and a high index predicts a short‐term relapse. The “subjective” data obtained from patients about their MM history, although usually neglected, can thus provide a better prognostic marker than many “objective” tests.

Pyoderma gangrenosum treated with high-dose intravenous immunoglobulins: Two cases and review of the literature.

Pyoderma gangrenosum (PG) is a neutrophilic skin disease commonly treated with immunosuppressants. High-dose intravenous immunoglobulins are used to treat a range of inflammatory diseases, but we found only five reports of the use of high-dose intravenous immunoglobulins in the treatment of PG. We report on two patients with PG for whom immunosuppressants could not be prescribed and who were treated with high-dose intravenous immunoglobulins.Case 1 was a 58-year-old man who presented with a 6-year history of PG. He was initially treated with prednisone. The 20 mg/day dosage of prednisone could not be reduced and treatment had to be discontinued after 1 year because of serious adverse effects. Minocycline treatment led to improvement but had to be discontinued after 6 years because of facial skin hyperpigmentation. Case 2 was a 66-year-old man who presented with a 3-year history of PG. Different therapeutic procedures for PG (prednisone, topical tacrolimus or betamethasone) had failed. High-dose intravenous immunoglobulins were administered monthly at a dose of 2 g/kg for 6 months. The treatment induced stabilisation of the disease and made it possible to reduce corticosteroid use in both patients.These cases show that high-dose intravenous immunoglobulins represent a therapeutic alternative for PG, but the efficacy of this treatment should be confirmed in further studies.

A Randomized, Investigator-Masked, Double-Blind, Placebo-Controlled Trial on Thalidomide in Severe Cutaneous Sarcoidosis

BACKGROUND Thalidomide use in cutaneous sarcoidosis is based on data from small case series or case reports. The objective of this study was to evaluate the efficacy and safety of thalidomide in severe cutaneous sarcoidosis. METHODS This study consisted of a randomized, double-bind, parallel, placebo-controlled, investigator-masked, multicenter trial lasting 3 months and an open-label study from month 3 to month 6. Adults with a clinical and histologic diagnosis of cutaneous sarcoidosis were included in nine hospital centers in France. Patients were randomized 1:1 to oral thalidomide (100 mg once daily) or to a matching oral placebo for 3 months. In the course of an open-label follow-up from month 3 to month 6, all patients received thalidomide, 100 mg to 200 mg daily. The proportions of patients with a partial or complete cutaneous response at month 3, based on at least a 50% improvement in three target lesions scored for area and infiltration, were compared across randomization groups. RESULTS The intent-to-treat population included 39 patients. None of them had a complete cutaneous response. Four out of 20 patients in the thalidomide group (20%) vs four out of 19 patients in the placebo group (21%) had a partial cutaneous response at month 3 (difference in proportion of -1% [95% CI, -26% to +24%] for thalidomide vs placebo, P = 1.0). Eight patients with side effects were recorded in the thalidomide group vs three in the placebo group. We observed a large number of adverse event-related discontinuations in patients taking thalidomide in the first 3 months (four patients with thalidomide, zero with placebo) and in the 3 following months (five patients). CONCLUSIONS At a dose of 100 mg daily for 3 months, our results do not encourage thalidomide use in cutaneous sarcoidosis. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT0030552; URL: www.clinicaltrials.gov.

Syndrome d’hypersensibilité médicamenteuse (DRESS) au ranélate de strontium

INTRODUCTION Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe form of adverse drug reaction. Strontium ranelate has recently been authorised for postmenopausal osteoporosis. We report a case of strontium ranelate-induced DRESS complicated by linear Ig A dermatosis due to vancomycin. CASE REPORT A 77-year-old woman with osteoporosis had been treated by strontium ranelate for 4 weeks when she developed a febrile generalized skin rash. Blood tests showed eosinophilia (12.74 × 10(9)/L) and liver damage. A diagnosis of DRESS was made, leading to discontinuation of strontium ranelate and prescription of systemic corticosteroids. Two days later, methicillin-resistant Staphylococcus aureus bacteraemia occurred and treatment with vancomycin was started. The liver dysfunction resolved. After two weeks of antibiotherapy, bullous lesions were noted on the thighs. Skin biopsy results suggested a diagnosis of linear IgA bullous dermatosis. Vancomycin was stopped. Two weeks later, the eruption resolved. The eosinophil count gradually returned to normal after four months of corticosteroid therapy. DISCUSSION More than 15 cases of DRESS syndrome have been reported in Europe, including 2 deaths related to ranelate strontium, prompting European health authorities to publish a warning concerning the risk of strontium ranelate-induced DRESS. A particular feature of our patient was complication with linear IgA bullous dermatosis caused by vancomycin. In conclusion, it is essential to be aware of the risk of severe cutaneous reaction to strontium ranelate, a new drug used to treat osteoporosis.

Positive photobiological investigation in reticular erythematous mucinosis syndrome

Background: Reticular erythematous mucinosis (REM) syndrome is a rare disorder. Its clinical course is cyclic with remissions and exacerbations. In this disease, photosensitivity has previously been noticed but rarely demonstrated. We report three new cases with positive photobiological investigation.