Antituberculosis drug-induced hepatitis is one of the most prevalent drug-induced liver injuries. Isoniazid is the major drug incriminated in this hepatotoxicity. Isoniazid is mainly metabolized to hepatotoxic intermediates by N-acetyltransferase (NAT). However, the association of polymorphic NAT acetylator status and antituberculosis drug-induced hepatitis is debatable. To determine whether acetylator status is a risk factor for antituberculosis druginduced hepatitis, we genotyped NAT2 in 224 incident tuberculosis patients who received antituberculosis treatment. Antituberculosis drug-induced hepatitis was diagnosed based on a positive isoniazid rechallenge test and exclusion of viral hepatitis. Acetylator status was determined by genotyping NAT2 in patients using a polymerase chain reaction with restriction fragment length polymorphism. Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. Thirty-three patients (14.7%) were diagnosed with antituberculosis drug-induced hepatitis. Slow acetylators had a higher risk of hepatotoxicity than rapid acetylators (26.4% vs. 11.1%, P ‫؍‬ .013). Among patients with hepatotoxicity, slow acetylators had significantly higher serum aminotransferase levels than rapid acetylators. Logistic regression showed that slow-acetylator status (odds ratio [OR], 3.66; 95% CI, 1.58-8.49; P ‫؍‬ .003) and age (OR, 1.09; 95% CI, 1.04-1.14; P < .001) were the only 2 independent risk factors for antituberculosis drug-induced hepatitis. In conclusion, slow-acetylator status of NAT2 is a significant susceptibility risk factor for antituberculosis drug-induced hepatitis. Additionally, slow acetylators are prone to develop more severe hepatotoxicity than rapid acetylators. Regular monitoring of serum aminotransferase levels is mandatory in patients receiving antituberculosis treatment, especially in slow acetylators. (HEPATOLOGY 2002;35:883-889.)

This study examined the effects of p53 gene status on DNA damage-induced cell death and chemosensitivity to various chemotherapeutic agents in non-small cell lung cancer (NSCLC) cells. A mutant p53 gene was introduced into cells carrying the wild-type p53 gene and also vice versa to introduce the wild-type p53 gene into cells carrying the mutant p53 gene. Chemosensitivity and DNA damage-induced apoptosis in these cells were then examined. This study included five cell lines, NCI-H1437, NCI-H727, NCI-H441 and NCI-H1299 which carry a mutant p53 gene and NCI-H460 which carries a wild-type p53 gene. Mutant p53-carrying cells were transfected with the wild-type p53 gene, while mutant p53 genes were introduced into NCI-H460 cells. These p53 genes were individually mutated at amino acid residues 143, 175, 248 and 273. The representative cell line NCI-H1437 cells transfected with wild-type p53 gene (H1437/wtp53) showed a dramatic increase in susceptibility to three anticancer agents (7-fold to cisplatin, 21-fold to etoposide, and 20-fold to camptothecin) compared to untransfected or neotransfected H1437 cells. An increase in chemosensitivity was also observed in wild-type p53 transfectants of H727, H441, H1299 cells. The results of chemosensitivity were consistent with the observations on apoptotic cell death. H1437/wtp53 cells, but not H1437 parental cells, exhibited a characteristic feature of apoptotic cell death that generated oligonucleosomal-sized DNA fragments. In contrast, loss of chemosensitivity and lack of p53-mediated DNA degradation in response to anticancer agents were observed in H460 cells transfected with mutant p53. These observations suggest that the increase in chemosensitivity was attributable to wild-type p53 mediation of the process of apoptosis. In addition, our results also suggest that p53 gene status modulates the extent of chemosensitivity and the induction of apoptosis by different anticancer agents in NSCLC cells.

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Background: This study aimed to analyze pathologic characteristics, treatment, prognosis, and tumor epidermal growth factor receptor/anaplastic large-cell lymphoma kinase (EGFR/ALK) mutation proportion of non–small cell lung cancer (NSCLC) patients aged <40 years at diagnosis. Methods: We retrospectively reviewed data of NSCLC patients diagnosed at Taipei Veterans General Hospital between June 2007 and December 2014, aged <90 years at the time of the diagnosis. Results: We found 5051 cases of NSCLC, including 168 patients who were <40 years (younger group) and 4883 patients aged 40 to 89 years (older group). We found that the younger group had a significantly higher proportion of the EGFR mutation (22.6% vs 16.2%, p = 0.026) and the ALK mutation (4.2% vs 0.5%, p < 0.001) than the older group. Although the younger group included more stage IV patients (60.1% vs 49.6%, p = 0.002), it had a better overall survival (OS) rate (1 year: 73.7% vs 66.2%, p = 0.043; 5 years: 44.4% vs 33.7%, p = 0.004) (median survival time: 55 vs 26 months, p = 0.002). About the histologic subtype of NSCLC, the younger group presented less frequent cases of squamous cell carcinoma (4.2% vs 16.1%, p < 0.001), whereas the adenocarcinoma subtype was similarly frequent in the two groups (76.8% vs 76.5%, p = 0.924). Conclusion: The OS rate in younger NSCLC patients was higher than that in the older NSCLC patients, despite the higher rate of stage IV NSCLC patients in the younger group. This survival benefit is most likely due to the higher proportion of the EGFR and ALK mutations and the corresponding tyrosine kinase inhibitor treatment.