RESUMO
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare yet severe adverse drug-induced reaction with up to 10% mortality rate. Recent clinical trials reported an association between DRESS and telaprevir (TVR), an NS3/4A protease inhibitor of chronic hepatitis C (CHC) virus genotype 1. Its diagnosis is challenging given the variable pattern of cutaneous eruption and the myriad internal organ involvement. We present two patients who are middle-aged, obese, and white with CHC cirrhosis. They both developed a progressive diffuse, painful pruritic maculopapular rash at weeks 8 and 10 of CHC therapy with TVR, Peg-Interferon alfa-2a, and Ribavirin. They had no exposures to other medications that can cause this syndrome. Physical exam and labs and skin biopsy supported a "Definite" clinical diagnosis of DRESS, per RegiSCAR criteria. Thus Telaprevir-based triple therapy was discontinued and both patients experienced rapid resolution of the systemic symptoms with gradual improvement of eosinophilia and the skin eruption. These two cases illustrate the paramount importance of having a high index of suspicion for TVR-induced DRESS, critical for early diagnosis. Immediate discontinuation of TVR is essential in prevention of a potentially life-threatening complication. Risk factors for development of DRESS in patients receiving TVR remain to be elucidated.
RESUMO
PURPOSE: Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the O(6)-methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16/CDKN2A genes. Epigenetic alterations affect genetic events: Loss of MGMT via hypermethylation reportedly predisposes to guanine-to-adenine or cytosine-to-thymine (G:C-->A:T) transition mutations in KRAS and P53, and silencing of hMLH1 leads to high levels of microsatellite instability (MSI-H)/mutator phenotype, suggesting that epigenetic-genetic subtypes exist. EXPERIMENTAL DESIGN: We evaluated the relationships of aberrant methylation of APC, MGMT, hMLH1, P16, N33, and five MINTs to mutations in APC, KRAS, BRAF, and P53 in 208 colorectal carcinomas. RESULTS: We found that APC hypermethylation was age related (P = 0.04), in contrast to the other genes, and did not cluster with CpG island methylator phenotype (CIMP) markers. Hypermethylation of APC concurrently with either MGMT or hMLH1 was strongly associated with occurrence of G-to-A transitions in APC [odds ratio (OR), 26.8; P < 0.0002 from multivariable logic regression model], but C-to-T transitions had no associations. There was no relationship of hypermethylation of any gene, including MGMT, with G-to-A or C-to-T transitions in KRAS or P53, although APC hypermethylation was associated with P53 mutation (P < 0.0002). CIMP with MSI-H due to hMLH1 hypermethylation, or CIMP with loss of MGMT expression in non-MSI-H tumors, was associated with BRAF mutation (OR, 4.5; P < 0.0002). CIMP was also associated with BRAF V600E T-to-A transversion (OR, 48.5; P < 0.0002). CONCLUSIONS: Our findings suggest that the heterogeneous epigenetic dysregulation of promoter methylation in various genes is interrelated with the occurrence of mutations, as manifested in epigenetic-genetic subgroups of tumors.
Assuntos
Neoplasias Colorretais/genética , Ilhas de CpG/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Epigênese Genética , Genes APC , Proteínas Supressoras de Tumor/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais/metabolismo , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Genes p53 , Genes ras , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Proteínas Supressoras de Tumor/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
A 39-year-old woman presenting with microscopic hematuria was found to have an extensively calcified mass in the upper pole of the right kidney. Gross and histologic examination of the nephrectomy specimen revealed a 9.3-cm renal tumor composed of solid trabecular sheets of polygonal epithelial cells with clear cytoplasm and distinct cell borders characteristic of a chromophobe renal cell carcinoma. Electron microscopy showed the presence of numerous intracytoplasmic microvesicles, thereby confirming the diagnosis. However, the unique additional feature of this tumor included the presence of dense calcification and ossification throughout the tumor. To our knowledge, we report the first case of chromophobe renal cell carcinoma with the concomitant presence of extensive calcification and ossification. A literature review on chromophobe renal cell carcinoma with either calcification or ossification is performed.
