Vicente Oliver

Infliximab in the management of severe pemphigus vulgaris

1 Niemann S, Richter E, Rusch-Gerdes S. Differentiation among members of the Mycobacterium tuberculosis complex by molecular and biochemical features: evidence for two pyrazinamide-susceptible subtypes of M. bovis. J Clin Microbiol 2000; 38:152–7. 2 Blaas SH, Bohm S, Martin G et al. Pericarditis as primary manifestation of Mycobacterium bovis ssp. caprae infection. Diagn Microbiol Infect Dis 2003; 47:431–3. 3 Kubica T, Rusch-Gerdes S, Niemann S. Mycobacterium bovis subsp. caprae caused one-third of human M. bovis-associated tuberculosis cases reported in Germany between 1999 and 2001. J Clin Microbiol 2001; 41:3070–7. 4 Aranaz A, Cousins D, Mateos A et al. Elevation of Mycobacterium tuberculosis subsp. caprae Aranaz et al. 1999 to species rank as Mycobacterium caprae comb. nov., sp. nov. International J Syst Evol Microbiol 2003; 53:1785–9. 5 Tappeiner G, Wolff K. Tuberculosis and other mycobacterial infections. In: Dermatology in General Medicine (Austen, KF, ed.), 4th edn. New York: McGraw-Hill, 1993: 2370–91. 6 Hruza GJ, Snow SN. Cutaneous Mycobacterium bovis infection of 40 years’ duration. Arch Dermatol 1990; 126:123–4. 7 Wilkins EG, Griffiths RJ, Roberts C. Bovine tuberculosis of the skin. J Infect 1986; 12:280–1. 8 Betti R, Tolomio E, Vergani R et al. [Squamous epithelial carcinoma as a complication of lupus vulgaris]. Hautarzt 2002, 53:118–20.

Detection of Epstein-Barr virus and human herpesvirus 7 and 8 genomes in primary cutaneous T- and B-cell lymphomas

Background Several studies have investigated the possible involvement of viral agents, particularly herpesviruses, in primary cutaneous lymphoma (PCL).  Objectives Our aim was to screen for the presence of human herpesvirus 7 (HHV‐7) and 8 (HHV‐8) genomes in samples of PCL, and to determine if their presence was independent of Epstein–Barr virus (EBV).  Methods Screening was performed using polymerase chain reaction assay in 64 skin samples from historical lesional tissues with PCL.  Results Only nine cases showed positivity for HHV‐7: four of 29 mycosis fungoides (MF), two of four CD30‐positive large‐cell cutaneous T‐cell lymphoma (CTCL), two of 12 follicle centre cutaneous B‐cell lymphoma (CBCL) and one of nine marginal zone CBCL. Fifteen cases tested positive for EBV: seven of 29 MF, two of four pleomorphic small/medium sized CTCL, three of three angiocentric CTCL, one of 12 follicle centre CBCL and two of nine marginal zone CBCL. All cases were uniformly negative for HHV‐8. No simultaneous positivity was found for EBV and HHV‐7. Controls tested negative for all viruses.  Conclusions The findings indicate that EBV, HHV‐7 and HHV‐8 seem not to be involved in the pathogenesis of PCL.

Efficacy of Etanercept in Psoriatic Patients Previously Treated with Infliximab

Background: There are few data to enable us to ascertain whether switching to another systemic agent is useful in patients with psoriasis who have not responded favorably to a first systemic treatment. Objective: To evaluate the efficacy and safety of etanercept in patients with moderate-to-severe plaque psoriasis previously treated with infliximab. Methods: We analyzed data from patients with moderate-to-severe psoriasis and a poor primary or secondary response to infliximab, and who were later treated with etanercept. Results: Data were collected from 8 patients who were first treated with infliximab. At 54 weeks of therapy, 25% had a psoriasis area and severity index (PASI) of 75. At 24 weeks of therapy with etanercept, 75% had a PASI of 75. Consecutive administration of both therapies did not increase the number of adverse events. Limitations:The data should be regarded with caution due to the scant number of patients. Conclusions: Switching from infliximab to etanercept can be useful and safe in nonresponders.

Dabska tumor developing within a preexisting vascular malformation

Malignant endovascular papillary angioendothelioma, first described by Dabska in 1969, is a rare vascular tumor that primarily affects children and is characterized by papillary proliferations of endothelial cells into vessel lumens. We report a case of this rare neoplasm in a boy with angiomatosis who developed Kasabach-Merritt syndrome. The tumor evolved as an ulcerated lesion superficially within a previous vascular malformation on his buttock. A review of the literature is presented.

Primary cutaneous melanoma in hidden sites is associated with thicker tumours - a study of 829 patients.

The aim of this study was to determine if primary cutaneous melanomas in hidden anatomical sites were associated with thicker tumours. Retrospective medical data of 829 patients with melanomas diagnosed at our centre between January 1976 and July 1998 were recorded from our database. Three groups were defined according to the anatomical site of the primary melanoma: (1) visible areas (group 1: 493 patients); (2) visible areas only to the patients or to their partners in privacy (group 2: 281 patients); and (3) hidden areas (group 3: 55 patients). Univariate analysis indicated that patients with melanoma in hidden regions presented significantly thicker tumours (median for group 3: 2.25 versus 1.17 for group 1 and 1.42 for group 2). This group were also more commonly males (group 3: 58% men versus group 1: 38% and group 2: 51%), in a more advanced stage (metastatic disease at diagnosis in 16% of patients in group 3 versus 6% in groups 1 and 2) and at a more advanced age (median group 3: 66 years versus group 1: 59 years and group 2: 51 years), than patients in the other two groups. The association between tumour thickness and body site remained statistically significant after a multivariate analysis. As a delay in diagnosis may be responsible for the thicker size of melanoma in the hidden areas, preventive programmes should stress the importance of not forgetting these locations in self-examination and screening. Special attention should be given to educating elderly men.

Influence of loss of function MC1R variants in genetic susceptibility of familial melanoma in Spain.

We explored the presence of germline alterations in CDK4 exon 2, CDKN2A and MC1R in a hospital-based study of 89 melanoma cases from 89 families with at least two members affected by cutaneous melanoma. A total of 30% of the melanoma kindreds studied were carriers of CDKN2A variants, and three of these variants were known predominant alleles that have been identified earlier in Mediterranean populations (p.G101W, p.V59G and c.358delG). We observed a higher frequency of nonsynonymous MC1R variants in these Spanish melanoma kindreds (72%) with respect to the general population (60%). We observed a higher frequency of nonsynonymous MC1R variants in this Spanish melanoma kindred (72%) respect to general population (60%). A new classification of MC1R variants based on their functional effects over melanocortin-1 receptor, including the dominant-negative effect of some of them in heterozygotes, suggested an association of loss of function MC1R variants and multiple primary melanoma cases from melanoma kindred (odds ratio: 6.07, 95% confidence interval: 1.35–27.20). This study proposes the relevance of loss of function MC1R variants in the risk of melanoma in multiple primary melanoma cases with family history from areas with low melanoma incidence rate.

Nódulos subcutáneos dolorosos abdominales como forma de presentación de una calcifilaxia en la insuficiencia renal crónica

Resumen .—Una mujer de 86 anos en tratamiento con hemodialisis por insuficiencia renal terminal obstructiva presentaba unos nodulos subcutaneos abdominales dolorosos con histologia tipica de calcifilaxia. La paciente desarrollo necrosis cutanea 3 meses mas tarde. Estas lesiones parecen ser un estadio clinico de calcifilaxia cuyo reconocimiento podria permitir un diagnostico y tratamiento precoz que, posiblemente, mejorara el pronostico.

Treatment of Livedoid Vasculopathy with Short-cycle Intravenous Immunoglobulins

Sir, Livedoid vasculopathy manifests in the form of painful, recurrent ulcers on the lower limbs. The condition is mainly found in young and middle-aged women (1). Histologically, the disorder is characterized by the presence of hyaline thrombi in the cutaneous microcirculation. The underlying pathogenesis is not known, although local or systemic alterations in coagulation control appear to be involved, leading to fibrin thrombus formation in the blood vessels of the superficial dermis. Although sometimes considered synonymous, it is advisable to avoid the terms livedoid vasculitis and segmental hyalinizing vasculitis, as there is no histological evidence of vasculitis (2). The term atrophie blanche should also be avoided, as it is merely descriptive – referring to the formation of whitish scars with telangiectatic margins, although without considering the aetiology or physiology of the lesions. The term livedoid vasculopathy should be reserved for the primary idiopathic presentations of the disease. No controlled comparative studies have been made of the different treatment modalities used. We report here a case of livedoid vasculopathy treated with intravenous immunoglobulins (IVIg).

Molecular genetic analysis of HLA-DR and -DQ alleles in Spanish patients with melanoma.

Controversial data have been reported about HLA alleles and susceptibility to melanoma. The relationship between distribution of HLA alleles in patients with melanoma and susceptibility to tumour was analysed, to study the possible correlation between HLA class II DQA1, DQB1 and DRBI genes and melanoma in a Spanish population. Genomic DNA from 82 patients with melanoma and 367 random healthy donors, from the same geographic area, were typed by PCR-SSP (sequence specific primers). The patients were also divided into different groups according to the age and presence of cancer relatives, and compared with the controls. None of these HLA class II alleles showed significant positive or negative associations with either the overall population of patients with melanoma or the considered subgroups. Moreover, values for relative risk of DQB1*0301, DQB1*0302, DQB1*0303, DQB*05, DQA1*0401, DQA1*0101/0104 and DRB*08, which have been reported to be increased or decreased in patients with melanoma, were very low and of no statistical significance. Our results indicate that HLA class II alleles may not contribute to a strong susceptibility to melanoma in the Spanish population, although further studies on larger series are needed to corroborate this. Key words:

BRAF, NRAS and MC1R status in a prospective series of primary cutaneous melanoma.

DEAR EDITOR, Nonacral cutaneous melanomas have been suggested to develop through chronic sun exposure or modest intermittent sun exposures on a genetic host background of melanocytic instability, which is expressed as a phenotype with multiple common melanocytic naevi. In general, melanomas located at the areas of skin with chronic sun damage (CSD) differ from those without any histological evidence of CSD (nonCSD). Melanomas on non-CSD sites carry mainly BRAF mutations along with loss of CDKN2A and PTEN. Although NRAS mutations occur mainly in melanomas on CSD, mutations in the gene even occur in about 20% of melanomas on non-CSD sites. This study was designed to investigate the factors associated with BRAF and NRAS mutations in a homogeneous series of melanomas located on areas of skin without histological CSD. In a multi-institutional series of non-CSD melanomas we investigated distribution of BRAF and NRAS mutations, and their association with clinical–pathological factors and MC1R variants. Patients prospectively enrolled between January 2009 and June 2012 at five centres from the Region of Valencia, with a histologically proven diagnosis of primary invasive cutaneous melanoma localized on areas with intermittent sunexposure, and without a degree of solar elastosis in the range of CSD, were selected. The trunk and the extremities were predefined as intermittently exposed areas. However, an individual patient was excluded based on information provided by the patient about being chronically exposed as in the case of an outdoor worker. The patients included in the study gave their written informed consent and the study was approved by the ethics boards of all participating centres. Detailed methodology can be found in Supplementary Supporting Data S1 (see Supporting Information). Clinical and phenotypic data were collected at the first visit to the clinic by the patients (Table 1). MC1R genotypes were generated by direct sequencing of germline DNA. Statistical analysis was performed to determine associations between mutations and different clinical and phenotypic parameters using Pearson’s chi square and/or Fisher’s exact test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models. All analyses were carried out using the statistical package SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL, U.S.A.). All P-values were two sided and P-values < 0 05 were considered statistically significant. Of 230 (125 men and 105 women; median age 55 5 years) Caucasian patients with primary invasive cutaneous melanoma investigated for NRAS and BRAF mutations, MC1R genotype data was available for 191 patients. Results showed that mutations in BRAF were present in 75 (32 6%) and NRAS in 17 (7 4%) melanomas (Table 1 and Table S1; see Supporting Information). The difference in age at diagnosis based on mutational status was statistically significant (Table 1). The NRAS mutations were abundant in patients over 60 years (52 9%) and almost absent in patients 40 years or younger. In contrast, a relatively high percentage (22 7%) of the patients with BRAF mutations were ≤ 40 years old at the time of diagnosis (Table 1). NRAS mutations were more frequent in melanoma on extremities (68 8%) than on other sites (P = 0 02) (Table 1). BRAF mutations were common in nodular melanoma (NM) [29/49 (59 2%); P = 0 001] (Table 1). Tumours with BRAF mutations were thicker (mean 3 2 mm) than tumours with NRAS mutations (mean 2 6 mm) and without either mutation (1 6 mm) (P < 0 001; Table 1). BRAFmutated tumours were more frequently ulcerated (P = 0 001) and showed a tendency to have microscopic satellites (P = 0 09) (Table 1). Tumours with BRAF or NRAS mutations showed predominance of epithelioid cell type (P = 0 03) (Table 1). Mild or moderate (non-CSD) solar elastosis was more frequent in tumours without mutations than in tumours with NRAS and BRAF mutations (P = 0 04) (Table 1). The presence of preexisting naevus or the number of common and atypical melanocytic naevi was not significantly different (Table 1). We found no statistically significant association between BRAF and NRAS mutations and MC1R variants (P = 0 43) (Table 1 and Table S2; see Supporting Information). Similar results were observed when only red hair colour variants were considered (data not shown). The skin phototype also did not show any association with the mutational status (P = 0 96) (Table 1). Multivariate analysis showed that Breslow thickness > 2 mm, predominance of epithelioid cells in the tumour as well as the absence of solar elastosis were independently associated to BRAF mutations (Table 2). The association of NRAS mutations with tumour location on the lower extremities (OR 5 2; 95% CI 1 5–18 0) and Breslow thickness > 2 mm (OR 6 0; 95% CI 1 8–20 0) was also statistically significant in multivariate analysis (Table 2). Thus, in this study on a prospective series of 230 consecutive primary cutaneous invasive melanomas we show that melanomas at non-CSD sites with BRAF and NRAS mutations tend to be associated with aggressive tumour characteristics. The