ABSTRACT
PURPOSE: This study was conducted to investigate the role of four polymorphic variants of DNA methyltransferase genes as risk factors for radiation-induced fibrosis in breast cancer patients. We also assessed their ability to improve prediction accuracy when combined with mitochondrial haplogroup H, which we previously found to be independently associated with a lower hazard of radiation-induced fibrosis. MATERIALS AND METHODS: DNMT1 rs2228611,DNMT3A rs1550117,DNMT3A rs7581217, and DNMT3B rs2424908 were genotyped by real-time polymerase chain reaction in 286 Italian breast cancer patients who received radiotherapy after breast conserving surgery. Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale. The discriminative accuracy of genetic models was assessed by the area under the receiver operating characteristic curves (AUC). RESULTS: Kaplan-Meier curves showed significant differences among DNMT1 rs2228611 genotypes in the cumulative incidence of grade ≥ 2 subcutaneous fibrosis (log-rank test p-value= 0.018). Multivariate Cox regression analysis revealed DNMT1 rs2228611 as an independent protective factor for moderate to severe radiation-induced fibrosis (GG vs. AA; hazard ratio, 0.26; 95% confidence interval [CI], 0.10 to 0.71; p=0.009). Adding DNMT1 rs2228611 to haplogroup H increased the discrimination accuracy (AUC) of the model from 0.595 (95% CI, 0.536 to 0.653) to 0.655 (95% CI, 0.597 to 0.710). CONCLUSION: DNMT1 rs2228611 may represent a determinant of radiation-induced fibrosis in breast cancer patients with promise for clinical usefulness in genetic-based predictive models.
Subject(s)
Breast Neoplasms/complications , Breast Neoplasms/genetics , DNA Modification Methylases , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Skin Diseases/diagnosis , Skin Diseases/etiology , Alleles , Breast Neoplasms/mortality , Breast Neoplasms/radiotherapy , Female , Fibrosis , Genotype , Humans , Kaplan-Meier Estimate , Prognosis , Proportional Hazards Models , ROC Curve , Radiation Tolerance/genetics , Severity of Illness IndexABSTRACT
PURPOSE: The aim of this study was to analyze the application of the failure modes and effects analysis (FMEA) to intracranial stereotactic radiation surgery (SRS) by linear accelerator in order to identify the potential failure modes in the process tree and adopt appropriate safety measures to prevent adverse events (AEs) and near-misses, thus improving the process quality. METHODS AND MATERIALS: A working group was set up to perform FMEA for intracranial SRS in the framework of a quality assurance program. FMEA was performed in 4 consecutive tasks: (1) creation of a visual map of the process; (2) identification of possible failure modes; (3) assignment of a risk probability number (RPN) to each failure mode based on tabulated scores of severity, frequency of occurrence and detectability; and (4) identification of preventive measures to minimize the risk of occurrence. RESULTS: The whole SRS procedure was subdivided into 73 single steps; 116 total possible failure modes were identified and a score of severity, occurrence, and detectability was assigned to each. Based on these scores, RPN was calculated for each failure mode thus obtaining values from 1 to 180. In our analysis, 112/116 (96.6%) RPN values were <60, 2 (1.7%) between 60 and 125 (63, 70), and 2 (1.7%) >125 (135, 180). The 2 highest RPN scores were assigned to the risk of using the wrong collimator's size and incorrect coordinates on the laser target localizer frame. CONCLUSION: Failure modes and effects analysis is a simple and practical proactive tool for systematic analysis of risks in radiation therapy. In our experience of SRS, FMEA led to the adoption of major changes in various steps of the SRS procedure.