Objective: Single-nucleotide polymorphisms (SNPs) in the ataxia telangiectasiaemutated gene ATM have been linked with pneumonitis after radiotherapy for lung cancer but have not been evaluated in terms of pulmonary function impairment. Here we investigated potential associations between SNPs in ATM and changes in diffusing capacity of the lung for carbon monoxide (DLCO) in patients with nonesmall-cell lung cancer (NSCLC) after radiotherapy. Methods: From November 1998 through June 2009, 448 consecutive patients with inoperable primary NSCLC underwent definitive (≥60 Gy) radiotherapy, with or without chemotherapy. After excluding patients with a history of thoracic surgery, ra-diation, or lung cancer; without DNA samples available for analysis; or without pulmonary function testing within the 12 months before and the 12 months after radiotherapy, 100 patients were identified who are the subjects of this study. We genotyped two SNPs of ATM previously found to be associated with radiation-induced pneumonitis (rs189037 and rs228590) and evaluated potential correlations between these SNPs and impairment (decreases) in DLCO by using logistic regression analysis. Results: Univariate and multivariate analyses showed that the AA genotype of ATM rs189037 was associated with decreased DLCO after definitive radiotherapy than the GG/AG genotypes [univariate coefficient, -0.122; 95％ confidence interval (CI),-0.236 to -0.008; P = 0.037; and multivariate coefficient, -0.102; 95％ CI, -0.198 to -0.005; P = 0.038]. No such correlations were found for rs228590 (univariate coefficient, -0.096; 95％ CI, -0.208 to 0.017; P = 0.096). Conclusions: The AA genotype of ATM rs189037 was associated with higher risk of lung injury than were the GG/AG genotypes in patients with NSCLC treated with radiotherapy. This finding should be validated prospectively with other patient populations.

Objective: The DNA repair capacity (DRC) of tumor cells is an important contributor to resistance to radiation and platinum-based drugs. Because DRC may be affected by tumor cell metabolism, we measured DRC in lymphocytes from patients with non-small-cell lung cancer (NSCLC) and compared the findings with the maximum standardized uptake value (SUVmax) on 18 F-fluorodeoxyglucose positron emission tomography (FDG PET) after (chemo)radiation therapy. Methods: This study included 151 patients with stage IA-IV NSCLC who had FDG PET at a single institution and donated blood samples before chemotherapy. We assessed the correlation of DRC, measured in peripheral T lymphocytes by a host-cell reac-tivation assay with SUVmax and their associations with overall survival (OS) time by hazards ratios calculated with a Cox pro-portional hazards regression model. Results: SUVmax of the primary tumor at diagnosis was inversely associated with lymphocyte DRC (r＝－0.175, P＝0.032), particularly among patients with advanced disease (r ＝ －0.218, P ＝ 0.015). However, △SUVmax of primary tumor was not significantly associated with DRC (r＝0.005, P＝0.968). SUVmax of regional lymph nodes at diagnosis (r＝－0.307, P＝0.0008) and after (chemo)radiation treatment (r＝－0.329, P＝0.034) and SUVmax of the primary tumor after (chemo)radiation treatment (r＝－0.253, P＝0.045) were also inversely associated with OS time. Conclusion: DRC was inversely associated with primary tumor SUVmax before treatment but not with △SUVmax after (chemo)radiation.

Objective: Single-nucleotide polymorphisms (SNPs) in the ataxia telangiectasiaemutated gene ATM have been linked with pneumonitis after radiotherapy for lung cancer but have not been evaluated in terms of pulmonary function impairment. Here we investigated potential associations between SNPs in ATM and changes in diffusing capacity of the lung for carbon monoxide (DLCO) in patients with nonesmall-cell lung cancer (NSCLC) after radiotherapy. Methods: From November 1998 through June 2009, 448 consecutive patients with inoperable primary NSCLC underwent definitive (≥60 Gy) radiotherapy, with or without chemotherapy. After excluding patients with a history of thoracic surgery, ra-diation, or lung cancer; without DNA samples available for analysis; or without pulmonary function testing within the 12 months before and the 12 months after radiotherapy, 100 patients were identified who are the subjects of this study. We genotyped two SNPs of ATM previously found to be associated with radiation-induced pneumonitis (rs189037 and rs228590) and evaluated potential correlations between these SNPs and impairment (decreases) in DLCO by using logistic regression analysis. Results: Univariate and multivariate analyses showed that the AA genotype of ATM rs189037 was associated with decreased DLCO after definitive radiotherapy than the GG/AG genotypes [univariate coefficient, -0.122; 95％ confidence interval (CI),-0.236 to -0.008; P = 0.037; and multivariate coefficient, -0.102; 95％ CI, -0.198 to -0.005; P = 0.038]. No such correlations were found for rs228590 (univariate coefficient, -0.096; 95％ CI, -0.208 to 0.017; P = 0.096). Conclusions: The AA genotype of ATM rs189037 was associated with higher risk of lung injury than were the GG/AG genotypes in patients with NSCLC treated with radiotherapy. This finding should be validated prospectively with other patient populations.

Objective: The DNA repair capacity (DRC) of tumor cells is an important contributor to resistance to radiation and platinum-based drugs. Because DRC may be affected by tumor cell metabolism, we measured DRC in lymphocytes from patients with non-small-cell lung cancer (NSCLC) and compared the findings with the maximum standardized uptake value (SUVmax) on 18 F-fluorodeoxyglucose positron emission tomography (FDG PET) after (chemo)radiation therapy. Methods: This study included 151 patients with stage IA-IV NSCLC who had FDG PET at a single institution and donated blood samples before chemotherapy. We assessed the correlation of DRC, measured in peripheral T lymphocytes by a host-cell reac-tivation assay with SUVmax and their associations with overall survival (OS) time by hazards ratios calculated with a Cox pro-portional hazards regression model. Results: SUVmax of the primary tumor at diagnosis was inversely associated with lymphocyte DRC (r＝－0.175, P＝0.032), particularly among patients with advanced disease (r ＝ －0.218, P ＝ 0.015). However, △SUVmax of primary tumor was not significantly associated with DRC (r＝0.005, P＝0.968). SUVmax of regional lymph nodes at diagnosis (r＝－0.307, P＝0.0008) and after (chemo)radiation treatment (r＝－0.329, P＝0.034) and SUVmax of the primary tumor after (chemo)radiation treatment (r＝－0.253, P＝0.045) were also inversely associated with OS time. Conclusion: DRC was inversely associated with primary tumor SUVmax before treatment but not with △SUVmax after (chemo)radiation.

Purpose:To analyze the dependence of a cu te esophagitis (AE) on the dose and volume of irradiated esophagus during concur rent chemoradiation therapy of NSCLC.Methods:39 NSCLC patients previously treated with concurrent ch emoradiation therapy were studied , a subset of 62 patients who were recruited e arlier in a randomized phase Ⅲ study designed to evaluate the effect of amifost ine. The radiotherapy regimen was 1.2 Gy/fraction, Bid to a total dose of 69.6 G y. In this study 19 and 20 patients were in the control arm and amifostine arm, respectively. The AE score, evaluated by the RTOG acute morbidity criteria, was collected for each treatment week and one month following radiotherapy. DVH of t he esophagus was computed. A multivariate random-effect logistic model was used to investigate the correlation between the incidence of AE and various dose-vo lume factors among these 39 patients. The variables analyzed included total tumo r dose (TD), the mean and maximum dose to esophagus, the volume of esophagus tre ated above certain dose, and the dose of the esophagus treated to certain volume .Results:Among the 39 patients studied, two patients of the amif ostine arm (11%) and six patients of the non-amifostine arm (30%) experienced g rade Ⅲ AE. Grade Ⅲ AE was first seen at week 4th after a cumulative tumor dose to 36 Gy. However after week 4, it did not increase significantly with dose. Th e cumulative TD and patient sensitivity were found to have the strongest and sta tistically significant influence on the risk of AE in all dose and volume factor s.Conclusions:The risk of severe (grade Ⅲ) AE was associated wit h the cumulative dose to tumor and intrinsic patient sensitivity. Due to the tim e course of the development of AE, the daily dose rate or the cumulative dose by the 4th week of the treatment may be more predicative for the risk of AE rather than the total dose from the entire treatment course. Current clinical practice in using the total dose to assess the normal-tissue toxicity may need to be ad justed to account for the onset time of the acute end-point.