We have analyzed the Ha-ras, Ki-ras and N-ras gene for point mutations at codons 12, 13 and 61 via restriction fragment length polymorphism/polymerase chain reaction analysis and subsequent direct sequencing in non-cultured fresh-frozen tissues of 16 superficial spreading melanomas (SSM), 13 nodular malignant melanomas (NMM), 2 lentigo malignant melanomas (LMM), 1 dysplastic nevus, 1 congenital nevus and 5 normal nevi from 38 patients. Mutations were found in 4 melanoma samples, all belonging to the nodular malignant type. Three of them were mutated in N-ras and one in the Ha-ras gene. Mutation in N-ras was also detected in the congenital nevus. All mutations were exclusively located at the first two base pairs of codon 61. No Ki-ras mutation was detected in any lesion. No mutation could be found in SSM and LMM in addition to dysplastic and normal nevi. The frequency of ras mutation in NMM was 31%, whereas in SSM it was 0%. Our study suggests (a) an association between ras mutations (mainly N-ras) and the NMM as a subgroup of human melanoma; (b) that activation of Ki-ras is not involved in the pathogenesis of melanoma. The role of UV radiation in point mutations of ras genes in human melanoma is discussed.

Administration of N-acetylcysteine may be effective in diseases caused by oxidative-antioxidative imbalance. We aimed to determine the effect administration for 4 months of N-acetylcysteine (1200 mg daily) on sulfur mustard-induced bronchiolitis obliterans in patients with normal pulmonary function test. In a double-blind clinical trial, 144 patients with bronchiolitis obliterans due to sulfur mustard and bronchiolitis obliterans syndrome class 0, randomly entered to group 1 (n = 72, N-acetylcysteine) and group 2 (n = 72, placebo). The changes in dyspnoea, wake-up dyspnoea, cough and sputum were measured after 4 months using a 'delta value' (i.e. symptom score after 4 months -symptom score before the trial). Spirometric findings were measured at the beginning of the trial, 2 months later and 4 months later. Dyspnoea (delta value: -0.78 (0.61), P < 0.001), wake-up dyspnoea (delta value: -0.57 (0.64), P < 0.001), and cough (delta value: -0.86 (0.63), P < 0.001) improved after 4 months of N-acetylcysteine administration compared to the control group. N-acetylcysteine reduced sputum from 76.9% (n = 40) of cases before the trial to 9.6% (n = 5) of cases after the trial. Spirometric components were significantly improved in N-acetylcysteine group compared to the placebo group: FEV1 (P < 0.0001), FVC (P = 0.014) and FEV1/FVC (P = 0.003). A 4-month trial with 1200 mg oral N-acetylcysteine per day can be used for treating bronchitis, but is also effective in treating bronchiolitis. It also prevents sulfur mustard-induced oxidative stress, and can be used in the treatment of sulfur mustard-induced pulmonary disease.

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In this study we analysed snap-frozen surgical resections of 16 superficial spreading melanomas, 13 nodular malignant melanomas, 2 lentigo maligna melanomas, 1 dysplastic nevus, 1 congenital nevus and 5 normal nevi from 38 patients for point mutations in the human p53 gene at exons 5-8 by polymerase chain reaction/single-strand conformation polymorphism as well as for loss of heterozygosity of p53 by restriction-fragment-length polymorphism/polymerase chain reaction in order to determine whether p53 aberrations are associated with melanoma subtypes. In addition, we analysed six melanoma cell lines for point mutations in p53. Our results revealed the absence of point mutations and loss of heterozygosity in all fresh resected lesions. However, a TAC (Tyr) to TGC (Cys) transition at codon 163 in exon 5 was found in one cell line.

The GEMOX/bevacizumab regimen demonstrated an excellent median overall survival but did not meet our objective of a 14 month median survival. Toxicity was significant. We do not recommend further evaluation of this regimen.