Guillaume Vogin1, Thierry Bastogne2, Larry Bodgi3, Julien Gillet-Daubin4, Aurélien Canet5, Sandrine Pereira6, Nicolas Foray7. 1. Department of Radiation Oncology, Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy, France; Unite Mixte de Recherche 7365, Centre National de la Recherche Scientifique-Université de Lorraine, Ingénierie Moléculaire et Physiopathologie Articulaire, Vandoeuvre-les-Nancy, France; Department of Radiobiology, Cancer Center of Lyon, Unite Mixte de Recherche Inserm 1052, Conseil National de la Recherche Scientifique 5286 Centre Léon Bérard, Lyon, France. Electronic address: g.vogin@nancy.unicancer.fr. 2. Biology, Genetics, and Statistics, Institut national de recherche en informatique et en automatique, Vandoeuvre-lès-Nancy, France; Unite Mixte de Recherche 7039, Conseil National de la Recherche Scientifique-Université de Lorraine, Centre de Recherche en Automatique de Nancy, Vandoeuvre-lès-Nancy, France; Cybernano, Telecom Nancy, Villers-lès-Nancy, France. 3. Research and Development, Neolys Diagnostics, Lyon, France; American University of Beirut Medical Center, Beirut, Lebanon. 4. Research and Development, Neolys Diagnostics, Lyon, France. 5. Department of Radiobiology, Cancer Center of Lyon, Unite Mixte de Recherche Inserm 1052, Conseil National de la Recherche Scientifique 5286 Centre Léon Bérard, Lyon, France; Research and Development, Neolys Diagnostics, Lyon, France; Institut Camille Jordan-Unite Mixte de Recherche 5208, Villeurbanne, France; Dracula Team, Institut national de recherche en informatique et en automatique, Villeurbanne, France. 6. Department of Radiobiology, Cancer Center of Lyon, Unite Mixte de Recherche Inserm 1052, Conseil National de la Recherche Scientifique 5286 Centre Léon Bérard, Lyon, France; Research and Development, Neolys Diagnostics, Lyon, France. 7. Department of Radiobiology, Cancer Center of Lyon, Unite Mixte de Recherche Inserm 1052, Conseil National de la Recherche Scientifique 5286 Centre Léon Bérard, Lyon, France.
Abstract
PURPOSE: The ability to identify, before treatment, those patients who will overreact to radiation therapy would have sound positive clinical implications. By focusing on DNA double-strand breaks recognition and repair proteins after irradiation, we recently demonstrated that the maximal number of phosphorylated ATM (pATM) nuclear foci in the first hour (pATMmax) after ex vivo irradiation correlated with postradiation therapy toxicity severity. We performed additional analyses of our whole collection of fibroblast lines to refine the predictive performance of our assay. METHODS AND MATERIALS: Immunofluorescence experiments were performed on 117 primary skin fibroblast lines irradiated at 2 Gy. The toxicity response was split into 2 binary classes: 0 if the toxicity grade was <2 and 1 otherwise. To assess the relationship between the quantity of pATMmax foci and toxicity grade, we applied a correlation and then a supervised classification analysis. Training data sets from 13 radiosensitive patients randomly drawn using a random undersampling technique were constituted. Receiver operating characteristic analyses were performed using a Monte-Carlo method to estimate the optimal threshold and discriminate the responses for each data set. The discrimination cutoff was estimated as the maximum value of the 104 thresholds computed from each training subset. RESULTS: As expected, we confirmed a quasi-linear dependence between toxicity and pATMmax (Pearson correlation coefficient -0.85; P < 2.2e-16). When taken as a binary predictive assay with the optimal cutoff value of 34.5 pATM foci/cell, our assay showed outstanding predictive performance (sensitivity, specificity, negative predictive value, positive predictive value, and area under the curve: 100%, 92%, 100%, 99%, and 0.987, respectively). CONCLUSIONS: The results of these experiments allowed us to identify pATMmax as a high-performance predictive parameter of patients with postradiation therapy overreactions. Additional studies are in progress to confirm that this radiosensitivity assay reaches the same performance level in any condition to adapt clinical practice.
PURPOSE: The ability to identify, before treatment, those patients who will overreact to radiation therapy would have sound positive clinical implications. By focusing on DNA double-strand breaks recognition and repair proteins after irradiation, we recently demonstrated that the maximal number of phosphorylated ATM (pATM) nuclear foci in the first hour (pATMmax) after ex vivo irradiation correlated with postradiation therapy toxicity severity. We performed additional analyses of our whole collection of fibroblast lines to refine the predictive performance of our assay. METHODS AND MATERIALS: Immunofluorescence experiments were performed on 117 primary skin fibroblast lines irradiated at 2 Gy. The toxicity response was split into 2 binary classes: 0 if the toxicity grade was <2 and 1 otherwise. To assess the relationship between the quantity of pATMmax foci and toxicity grade, we applied a correlation and then a supervised classification analysis. Training data sets from 13 radiosensitive patients randomly drawn using a random undersampling technique were constituted. Receiver operating characteristic analyses were performed using a Monte-Carlo method to estimate the optimal threshold and discriminate the responses for each data set. The discrimination cutoff was estimated as the maximum value of the 104 thresholds computed from each training subset. RESULTS: As expected, we confirmed a quasi-linear dependence between toxicity and pATMmax (Pearson correlation coefficient -0.85; P < 2.2e-16). When taken as a binary predictive assay with the optimal cutoff value of 34.5 pATM foci/cell, our assay showed outstanding predictive performance (sensitivity, specificity, negative predictive value, positive predictive value, and area under the curve: 100%, 92%, 100%, 99%, and 0.987, respectively). CONCLUSIONS: The results of these experiments allowed us to identify pATMmax as a high-performance predictive parameter of patients with postradiation therapy overreactions. Additional studies are in progress to confirm that this radiosensitivity assay reaches the same performance level in any condition to adapt clinical practice.
Authors: K E Applegate; W Rühm; A Wojcik; M Bourguignon; A Brenner; K Hamasaki; T Imai; M Imaizumi; T Imaoka; S Kakinuma; T Kamada; N Nishimura; N Okonogi; K Ozasa; C E Rübe; A Sadakane; R Sakata; Y Shimada; K Yoshida; S Bouffler Journal: Radiat Environ Biophys Date: 2020-03-07 Impact factor: 1.925
Authors: Paul Ramia; Larry Bodgi; Dima Mahmoud; Mohammad A Mohammad; Bassem Youssef; Neil Kopek; Humaid Al-Shamsi; Mona Dagher; Ibrahim Abu-Gheida Journal: Clin Med Insights Oncol Date: 2022-01-30