RESUMO
Xeroderma pigmentosum variant (XP-V) is a rare genetic disease, characterized by some sunlight sensitivity and predisposition to cutaneous malignancies. We described clinical and genetic features of the largest collection ever published of 23 XPV patients (ages between 21 and 86) from 20 unrelated families. Primary fibroblasts from patients showed normal nucleotide excision repair but UV-hypersensitivity in the presence of caffeine, a signature of the XP-V syndrome. 87% of patients developed skin tumors with a median age of 21 for the first occurrence. The median numbers of basal-cell carcinoma was 13 per patient, six for squamous-cell carcinoma, and five for melanoma. XP-V is due to defects in the translesion-synthesis DNA polymerase Polη coded by the POLH gene. DNA sequencing of POLH revealed 29 mutations, where 12 have not been previously identified, leading to truncated polymerases in 69% of patients. Four missense mutations are correlated with the protein stability by structural modeling of the Polη polymerase domain. There is a clear relationship between the types of missense mutations and clinical severity. For truncating mutations, which lead to an absence of or to inactive proteins, the life-cumulated UV exposure is probably the best predictor of cancer incidence, reinforcing the necessity to protect XP-Vs from sun exposure.
Assuntos
DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Neoplasias Cutâneas/genética , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cafeína , Carcinoma Basocelular/epidemiologia , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Células Cultivadas , Reparo do DNA , Feminino , Fibroblastos/metabolismo , Variação Genética , Genótipo , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Modelos Moleculares , Mutação de Sentido Incorreto , Fenótipo , Estabilidade Proteica , Estudos Retrospectivos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Raios Ultravioleta , Xeroderma Pigmentoso/complicações , Adulto JovemRESUMO
OBJECTIVE: To study the efficacy of bagged larvae on wound debridement compared with conventional treatment. DESIGN: Randomized, multicenter, controlled, prospective phase 3 trial with blinded assessment of outcome measures by a single observer. SETTING: Two hospital referral centers in Caen and Lyon, France. PATIENTS: Random sampling of 119 patients with a nonhealing, sloughy wound 40 cm(2) or smaller, less than 2 cm deep, and an ankle brachial index of 0.8 or higher. INTERVENTION: During a 2-week hospital stay, patients received either maggot debridement therapy (MDT) or conventional treatment. At discharge, conventional dressings were applied and a follow-up visit occurred at day 30. MAIN OUTCOME MEASURE: Percentage of slough in wounds at day 15. RESULTS: There was a significant difference between groups at day 8 (54.5% in the MDT group and 66.5% in the control group) (P = .04). The mean percentage of slough at day 15 was 55.4% in the MDT group and 53.8% in the control group (P = .78). CONCLUSIONS: Although MDT shows no significant benefit at day 15 compared with conventional treatment, debridement by MDT is significantly faster and occurs during the first week of treatment. Because there is no benefit in continuing the treatment after 1 week, another type of dressing should be used after 2 or 3 applications of MDT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01211236.