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.

Prognostic factors of paraneoplastic pemphigus.

OBJECTIVE: To identify the prognostic factors of overall survival in a series of patients with paraneoplastic pemphigus (PNP). DESIGN: Multicenter retrospective cohort study. SETTING: Twenty-seven dermatology departments in France. PATIENTS: A total of 53 patients (31 men and 22 women; median age, 59 years; age range, 30-88 years) were diagnosed as having PNP between 1992 and 2010. MAIN OUTCOME MEASURES: Overall Kaplan-Meier survival rates were estimated, and features associated with survival were assessed using univariate (log-rank test) and multivariate (Cox regression) analyses. RESULTS: The study included 53 patients with PNP. Thirty-six patients (68%) died during the study. The 1-, 3-, and 5-year overall survival rates were 49%, 41%, and 38%, respectively. The main causes of death were infections (n=21) and evolution of neoplasia (n=6). In univariate analysis, the main detrimental prognostic factors identified were erythema multiforme­like skin lesions (P=.05) and histologic keratinocyte necrosis (P=.03). None of the 5 patients with Castleman disease died during the study. After adjustment for age and sex in multivariate analysis, erythema multiforme­like skin lesions remained predictive of fatal outcome, with a 2-fold increase in death rate (hazard ratio [HR], 2.3; 95% CI, 1.05-5.03; P=.04). The prognosis of patients with PNP was even poorer when erythema multiforme­like skin lesions were associated with severe skin or mucosal involvement at presentation (HR of death, 3.0; 95% CI, 1.01-8.92; P=.049). CONCLUSION: Patients with PNP with erythema multiforme­like skin lesions and histologic keratinocyte necrosis, especially when associated with extensive lesions at presentation, are likely to have a more severe and rapid fatal outcome and should be managed very carefully.

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.

A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study.

Superpotent topical corticosteroids (CS) have been demonstrated to improve bullous pemphigoid (BP) patients' survival. We assessed whether a mild regimen using lower doses of topical CS and a shorter duration could improve the outcome of BP patients even more. Three-hundred and twelve BP patients were included in a multicenter randomized controlled trial and stratified depending on the extent of BP as moderate (n=134) or extensive (n=178). Patients were randomly assigned to the standard regimen (clobetasol propionate cream, 40 g per day initially, with CS tapering over 12 months) or the mild regimen (10-30 g per day), with CS tapering over 4 months. A noninferior rate of BP control was obtained with the mild regimen 156/159 (98%) as compared with the standard regimen 150/150 (100%; P=0.005). Event-free survival, that is, the combined outcome of deaths and life-threatening adverse events did not differ between the two treatment groups (P=0.77). However, upon adjusting through the Cox model for age and Karnofsky score, a strong beneficial effect of the mild regimen was observed in patients with moderate BP, with an almost twofold decrease in the risk of death or life-threatening adverse events relative to the standard regimen (hazard ratio=0.54; 95% confidence interval, 0.30-0.97; P=0.039). This mild regimen allows a 70% reduction of the cumulative doses of CS and improves BP patients' outcome.

The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma.

Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.

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.

Primary cutaneous cribriform carcinoma: a rare apocrine tumour.

BACKGROUND: Primary cutaneous cribriform carcinoma (PCCC) is a rare apocrine tumour occurring in middle-aged people. This neoplasm is often located on the limbs. The histopathological diagnosis is difficult, mainly because this tumour is exceptional. We, in this study, report a patient with PCCC. CASE REPORT: The patient was a 37-year-old man who presented with a nodule of the left knee. RESULTS: Histopathologic findings showed an asymmetrical deep dermal tumour with a cribriform pattern. The aggregations of neoplastic cells were interconnected and varied in size and shape. The cells were arranged in solid nests or tubular structures. In the lumina of tubules, some papillary protrusion of basophilic cells was seen. The ductal elements were lined by cuboidal or cylindric cells with images of decapitation secretion. The nuclei of the neoplastic cells were pleomorphic. A wide excision was performed with sentinel inguinal node biopsy. After a 2-year follow-up, neither persistence at the local site nor metastasis was observed. CONCLUSIONS: Clinical and pathological features of PCCC are reviewed. Differential diagnoses, including cutaneous metastasis of adenocarcinoma, adenoid basal cell carcinoma and adenoid cystic carcinoma, are discussed.

[Multicentric reticulohistiocytosis: report of a case with systemic disease]. / Réticulohistiocytose multicentrique: a propos d'un cas avec atteinte systémique.

Multicentric reticulohistiocytosis (RHM) is a rare non Langherhans cell histiocytosis with skin and joint involvment. Nearly all organs can be involved. Association with cancer occurs in about 25% of cases. Association with auto-immune diseases has also been recorded. Microscopic examination shows a histiocytic nodular infiltrate made of giant cells with ground-glass appearance and PAS positive cytoplasm. Immunostaining shows cell positivity for CD68 and negativity for CD1a and S100 protein. No Birbeck granules are found at ultrastructural examination.

Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome.

Among hereditary inflammatory disorders, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome (CINCA), and familial cold urticaria have recently been shown to be caused by dominantly inherited mutations in the CIAS1 gene. Reports suggest that these 3 diseases result from distinct missense mutations, with very few overlapping symptoms. We describe a French family presenting an intrafamilial overlapping clinical phenotype of CINCA and Muckle-Wells syndrome, caused by a mutation in CIAS1 gene. Clinical and genetic observations suggest that Muckle-Wells syndrome, CINCA, and familial cold urticaria are various phenotypic expressions of the same disease.

Cutaneous malignant melanoma and neurofibromatosis type 1.

Neurofibromatosis 1 (NF1) is a genetically transmitted disease occurring approximately once in 3000 live births and resulting from mutations of the NF1 gene that encodes a protein named neurofibromin, a negative regulator of the ras-dependent pathway. An excess of neoplasia especially tumours of neuroectodermal origin is classically observed. The occurrence of malignant melanoma in patients with NF1 has already been described in scattered clinical reports but little is known as to the characteristics of melanoma arising in NF1 patients. A multicentric retrospective study was conducted on a panel of French referring centres for a period of 13 years to identify patients with both melanoma and NF1. Patients with mucosal or ocular melanoma were excluded. The diagnosis of malignant melanoma was based on specific histology whereas NF1 was identified according to the criteria proposed by the NIH Consensus Conference. All patient fulfilling criteria for both melanoma and NF1 were investigated using a common procedure recording clinical and histological data along with prognostic factors for the two diseases. Eleven patients were identified with both diseases. The clinical pattern of NF1 was quite similar to the classical form of the disease, but some unusual features were present as regards to the melanoma: a sex-ratio of 10 women for one man and an average age lower than expected (median age=33 years) for melanoma occurrence. Among prognostic factors, median thickness was high compared to large series of melanoma in the literature (3.20 versus 1.5 mm). Another neoplasia occurred in three patients. An increase in melanoma incidence in patients with NF1 remains hypothetical but our small series of malignant melanoma arising in NF1 patients displays a large female preponderance, a higher thickness than expected and a frequent association with a second neoplasia. The peculiar female proneness for cancer whatever its localization and the risk of multiple neoplasias have already been reported in NF1 patients and could be true for malignant melanoma as well.

Injection by various routes of melanoma antigen-associated macrophages: biodistribution and clinical effects.

Patients' autologous macrophages (AM) were used as antigen-presenting cells (APC) in a vaccination protocol against malignant melanoma. AM were administered by various routes, including intralymphatic, since these cells did not express CCR7, a molecule required for APC migration to lymph nodes. Seven HLA-A2 patients with metastatic melanoma-two classified as M1 and five as M3-were included in the study. AM were produced from leukapheresis-separated mononuclear cells by 7-day culture with granulocyte-macrophage colony-stimulating factor. After separation by elutriation, AM were frozen in aliquots and subsequently thawed at monthly intervals, exposed to MAGE-3(271-279) peptide and injected subcutaneously into lymph nodes or into one peripheral lymph vessel. Intradermal tests were performed before and after treatment to determine peptide reactivity. No acute toxicity was observed following injection. One M1 patient had a 7-mm induration intradermal reaction response and was stabilized for 64 weeks. The M3 patients did not show any immunological or clinical response. In 11 patients, the biodistribution of 111In-labeled AM was investigated. There was no clear evidence that AM injected intradermally or subcutaneously left the site of injection. After injection into a lymph vessel of the foot region, scintigraphs showed five to ten popliteal and inguinocrural lymph nodes. This appeared to be the most efficient way to administer rapidly and safely large amounts of peptide-loaded APC into lymph nodes.

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.