title: Theoretical versus Ex Vivo Assessment of Radiation Damage Repair: An Investigation in Normal Breast Tissue.
abstract: In vivo validation of models of DNA damage repair will enable their use for optimizing clinical radiotherapy. In this study, a theoretical assessment was made of DNA double-strand break (DSB) induction in normal breast tissue after intraoperative radiation therapy (IORT), which is now an accepted form of adjuvant radiotherapy for selected patients with early breast cancer. DSB rates and relative biological effectiveness (RBE) were calculated as a function of dose, radiation quality and dose rate, each varying based on the applicator size used during IORT. The spectra of primary electrons in breast tissue adjacent to each applicator were calculated using measured X-ray spectra and Monte Carlo methods, and were used to inform a Monte Carlo damage simulation code. In the absence of repair, asymptotic RBE values (relative to (60)Co) were approximately 1.5. Beam-quality changes led to only minor variations in RBE among applicators, though differences in dose rate and overall dose delivery time led to larger variations and a rapid decrease in RBE. An experimental assessment of DSB induction was performed ex vivo using pre- and postirradiation tissue samples from patients receiving breast intraoperative radiation therapy. Relative DSB rates were assessed via γ-H2AX immunohistochemistry using proportional staining. Maximum-likelihood parameter estimation yielded a DSB repair halftime of 25.9 min (95% CI, 21.5-30.4 min), although the resulting model was not statistically distinguishable from one where there was no change in DSB yield among patients. Although the model yielded an in vivo repair halftime of the order of previous estimates for in vitro repair halftimes, we cannot conclude that it is valid in this context. This study highlights some of the uncertainties inherent in population analysis of ex vivo samples, and of the quantitative limitations of immunohistochemistry for assessment of DSB repair.
authors.affiliation: a   Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia; Schools of.|b   Physics.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Ebert
authors.affiliation: b   Physics.
authors.forename: Bipina
authors.initials: B
authors.lastname: Dhal
authors.affiliation: a   Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia; Schools of.
authors.forename: Janelle
authors.initials: J
authors.lastname: Prunster
authors.affiliation: e   St. John of God Subiaco Hospital, Western Australia;
authors.forename: Sally
authors.initials: S
authors.lastname: McLaren
authors.affiliation: c   Surgery and.|e   St. John of God Subiaco Hospital, Western Australia;
authors.forename: Nikolajs
authors.initials: N
authors.lastname: Zeps
authors.affiliation: b   Physics.
authors.forename: Michael
authors.initials: M
authors.lastname: House
authors.affiliation: f   Research Group NuTeC, CMK, Hasselt University, Diepenbeek, Belgium; and.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Reniers
authors.affiliation: g   Maastro Clinic, Maastricht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Verhaegen
authors.affiliation: a   Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia; Schools of.|d   Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia;
authors.forename: Tammy
authors.initials: T
authors.lastname: Corica
authors.affiliation: c   Surgery and.
authors.forename: Christobel
authors.initials: C
authors.lastname: Saunders
authors.affiliation: a   Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia; Schools of.|c   Surgery and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Joseph
mesh_terms: D001940:Breast / Q000378:metabolism* / Q000528:radiation effects*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009010:Monte Carlo Method
chemical_list: C468783:H2AX protein, human; D006657:Histones