ABSTRACT
To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10-3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10-4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.
ABSTRACT
Sleep disturbance often leads to physical and psychological distress and contributes to poor quality of life in terminal cancer patients. Midazolam is administered by continuous intravenous infusion in many Japanese palliative care units for the purpose of nocturnal sedation when patients cannot take oral medications or do not sufficiently respond to oral or per-rectal medication. However, there is insufficient data to assess optimal doses and other parameters for administration. In addition, the possibility of tolerance to midazolam reported in several studies is a further limitation. The present study retrospectively surveyed inpatient hospice experience in 19 patients who were prescribed midazolam in an attempt to induce nocturnal sedation. The midazolam infusion rate used for the longest period each day to maintain appropriate sleep without oversadation and with clear arousal on the following morning was defined as the "maintenance dose". Midazolam maintenance doses of 2 patients were greatly increased during their treatment period. Statistical analysis was then conducted in the other 17 patients using NONMEM software to analyze time-dependent changes in maintenance doses and possible associated factors. However, in the other 17 patients no significant time-dependent changes were observed during midazolam treatment. It would suggest that torerance may not be induced by intermittent administration of midazolam. Midazolam maintenance doses were significantly greater in patients treated with haloperidol.