Individual Radiosensitivity as a Risk Factor for the Radiation-Induced Acute Radiodermatitis

Background: Up to 95% of irradiated patients suffer from ionizing radiation (IR) induced early skin reaction, acute radiation dermatitis (ARD). Some experts think that additional skin hydration can reduce acute skin reactions. Individual radiosensitivity (IRS) determined from lymphocytes may help to predict acute radiation toxicity. The purpose of this study is to evaluate the clinical manifestation of ARD in different skincare groups during whole breast radiotherapy depending on IRS and other risk factors. Methods: A total of 108 early-stage breast cancer patients were randomized into best supportive care (BSC) and additional skincare (ASC) groups. IRS was evaluated using a G2 assay modified with caffeine-induced G2 checkpoint arrest. All patients received a 50 Gy dose to the breast planning target volume (PTV). Clinical assessment of ARD symptoms according to the CTCAE grading scale was performed once a week. Results: IRS was successfully determined for 91 out of 108 patients. A total of 10 patients (11%) had normal IRS, 47 patients (52%) were categorized as radiosensitive, and 34 (37%) as highly radiosensitive. There was no significant difference in the manifestation of ARD between patient groups by skincare or IRS. According to logistic regression, patients with bigger breasts were prone to more severe ARD (p = 0.002). Conclusions: The additional skincare did not improve skin condition during RT. A total of 89% of patients had increased radiosensitivity. IRS determined before RT did not show the predictive value for the manifestation of ARD. Logistic regression revealed that breast volume was the most significant risk factor for the manifestation of ARD.

Radiation protection perspective to recurrent medical imaging: what is known and what more is needed?

This review summarises the current knowledge about recurrent radiological imaging and associated cumulative doses to patients. The recent conservative estimates are for around 0.9 million patients globally who cumulate radiation doses above 100 mSv, where evidence exists for cancer risk elevation. Around one in five is estimated to be under the age of 50. Recurrent imaging is used for managing various health conditions and chronic diseases such as malignancies, trauma, end-stage kidney disease, cardiovascular diseases, Crohn’s disease, urolithiasis, cystic pulmonary disease. More studies are needed from different parts of the world to understand the magnitude and appropriateness. The analysis identified areas of future work to improve radiation protection of individuals who are submitted to frequent imaging. These include access to dose saving imaging technologies; improved imaging strategies and appropriateness process; specific optimisation tailored to the clinical condition and patient habitus; wider utilisation of the automatic exposure monitoring systems with an integrated option for individual exposure tracking in standardised patient-specific risk metrics; improved training and communication. The integration of the clinical and exposure history data will support improved knowledge about radiation risks from low doses and individual radiosensitivity. The radiation protection framework will need to respond to the challenge of recurrent imaging and high individual doses. The radiation protection perspective complements the clinical perspective, and the risk to benefit analysis must account holistically for all incidental and long-term benefits and risks for patients, their clinical history and specific needs. This is a step toward the patient-centric health care.

Proof of Concept of a Binary Blood Assay for Predicting Radiosensitivity

Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was performed on 150 blood lymphocytes of patients with several cancer types. Patients were divided into 2 groups, according to the grade of experienced toxicity. The global quantity of pATM molecules was assessed by ELISA on lymphocytes to determine the best threshold value. Then, the binary assay was assessed on a validation cohort of 36 patients with head and neck cancers. The quantity of pATM molecules in each sample of the training cohort was found in agreement with the observed Common Terminology Criteria for Adverse Events (CTCAE) grades with an AUC = 0.71 alone and of 0.77 combined to chemotherapy information. In the validation cohort, the same test was conducted with the following performances: sensitivity = 0.84, specificity = 0.54, AUC = 0.70 and 0.72 combined to chemotherapy. This study provides the basis of an easy to perform assay for clinical use.

Telomere Length Dynamics and Chromosomal Instability for Predicting Individual Radiosensitivity and Risk via Machine Learning

The ability to predict a cancer patient’s response to radiotherapy and risk of developing adverse late health effects would greatly improve personalized treatment regimens and individual outcomes. Telomeres represent a compelling biomarker of individual radiosensitivity and risk, as exposure can result in dysfunctional telomere pathologies that coincidentally overlap with many radiation-induced late effects, ranging from degenerative conditions like fibrosis and cardiovascular disease to proliferative pathologies like cancer. Here, telomere length was longitudinally assessed in a cohort of fifteen prostate cancer patients undergoing Intensity Modulated Radiation Therapy (IMRT) utilizing Telomere Fluorescence in situ Hybridization (Telo-FISH). To evaluate genome instability and enhance predictions for individual patient risk of secondary malignancy, chromosome aberrations were assessed utilizing directional Genomic Hybridization (dGH) for high-resolution inversion detection. We present the first implementation of individual telomere length data in a machine learning model, XGBoost, trained on pre-radiotherapy (baseline) and in vitro exposed (4 Gy γ-rays) telomere length measurements, to predict post radiotherapy telomeric outcomes, which together with chromosomal instability provide insight into individual radiosensitivity and risk for radiation-induced late effects.

EFFECT OF RADIOTHERAPY-INDUCED ALTERATION OF INDIVIDUAL RADIOSENSITIVITY ON DEVELOPMENT OF SIDE EFFECT IN CANCER PATIENTS

Ionizing radiation is commonly used for cancer treatment. Human response to the same dose of ionizing radiation can vary among individuals, therefore individual radiosensitivity (IRS) was proposed to be an important factor for development of radiotherapy (RT) related side effects. Ionizing radiation especially at low doses can modify organism sensitivity causing its sensitization or adaptation to further exposure, thus IRS of cancer patient can change during RT and so effect the development of normal tissue toxicity as well. Therefore, objective of our study was to determine the correlation between IRS of prostate cancer patients during RT and outcome of treatment adverse reactions. This pilot study included six prostate cancer patients without previous exposure to ionizing radiation treated with salvage RT. IRS was assessed using G2 chromosomal radiosensitivity assay with G2-checkpoint abrogation by caffeine three times for each patient: prior RT, after first fraction, and after completing treatment and acute genitourinary (GU) and gastrointestinal (GI) toxicity were reported. It was found that three of selected patients experienced grade 1-2 RT acute GU/GI toxicity. According to IRS tests, before RT two patients were classified as normal, two – as radiosensitive, and two – as highly radiosensitive. After the first fraction there were three individuals classified as nor-mal, one patient remained radiosensitive and two others felt to the highly radiosensitive group. After completion of treatment, the distribution of IRS in selected patients recovered to that observed before the treatment. Despite that pattern of IRS changes during RT varied in every patient, the common tendencies and their correlation with the development of toxicity was observed. It was found that, IRS of patient experienced adverse reaction riced during RT, meanwhile in patients without side effects it decreased. So, it could be concluded that difference in radiation-induced IRS alteration tendency could be reflected in pattern of adverse reaction development. This phenomenon could be associated with attribute of preexposure to initiate individually either an adaptive response increasing resistance to further irradiation or sensitization. Therefore, further investigations of more RT patients employing G2 assay are foreseen to reveal the possible correlation between IRS and adverse clinical outcome of RT.

Evaluation of cytokine expression and circulating immune cell subsets as potential parameters of acute radiation toxicity in prostate cancer patients

One of the challenges of radiation oncology in the era of personalized medicine is identification of biomarkers associated with individual radiosensitivity. The aim of research was to evaluate the possible clinical value of the associations between clinical, physical, and biological factors, and risk for development of acute radiotoxicity in patients with prostate cancer. The study involved forty four patients treated with three-dimensional conformal radiotherapy. The concentrations of IL-1β, IL-2, IL-6, IFN-γ and TGF-β1 were assessed before radiotherapy, after 5th, 15th and 25th radiotherapy fractions, at the end, and 1 month after the end of radiotherapy. Cytokine gene expression was determined in peripheral blood mononuclear cells. The univariate analysis of circulating cytokine levels during radiotherapy showed that increased serum concentrations of IL-6 were significantly associated with higher grade of acute genitourinary toxicity. The multivariate analysis demonstrated that increased level of IL-6 during the radiotherapy was significantly associated with higher grade of acute genitourinary toxicity across treatment. TGF-β expression levels significantly decreased during course of radiotherapy. Research indicates that changes in circulating cytokine levels might be important parameter of radiotoxicity in patients with prostate cancer. These findings suggest that future studies based on multi-parameter examination are necessary for prediction of individual radiosensitivity.

Ex vivo radiosensitivity is increased in non-cancer patients taking valproate

Background Valproate (VPA) is a commonly prescribed antiepileptic drug for patients experiencing epileptic seizures due to brain tumors. VPA increases radiation sensitivity in various tumor cells in vitro due to complex mechanisms. This could make tumors more vulnerable to ionizing radiation or overcome radioresistance. Yet, clinical data on possible improvement of tumor control by adding VPA to tumor therapy is controversial. Potentially radiosensitizing effects of VPA on healthy tissue remain unclear. To determine individual radiosensitivity, we analyzed blood samples of individuals taking VPA. Methods Ex vivo irradiated blood samples of 31 adult individuals with epilepsy were studied using 3-color fluorescence in situ hybridization. Aberrations in chromosomes 1, 2 and 4 were analyzed. Radiosensitivity was determined by the mean breaks per metaphase (B/M) and compared to age-matched (2:1) healthy donors. Results The patient cohort (n = 31; female: 38.7%) showed an increase of their average B/M value compared to healthy individuals (n = 61; female: 56.9%; B/M: 0.480 ± 0.09 vs. 0.415 ± 0.07; p = .001). The portion of radiosensitive (B/M > 0.500) and distinctly radiosensitive individuals (B/M > 0.600) was increased in the VPA group (54.9% vs. 11.3 and 9.7% vs. 0.0%; p < .001). In 3/31 patients, radiosensitivity was determined prior to and after VPA treatment and radiosensitivity was increased by VPA-treatment. Conclusions In our study, we confirmed that patients treated with VPA had an increased radiosensitivity compared to the control group. This could be considered in patients taking VPA prior to the beginning of radiotherapy to avoid toxic side effects of VPA-treatment.

Influence of Individual Radiosensitivity on the Hormesis Phenomenon: Toward a Mechanistic Explanation Based on the Nucleoshuttling of ATM Protein

Hormesis is a low-dose phenomenon that has been reported to occur, to different extents, in animals, plants, and microorganisms. However, a review of the literature shows that only a few reports describe it in humans. Also, the diversity of experimental protocols and cellular models used makes deciphering the mechanisms of hormesis difficult. In humans, hormesis mostly appears in the 20 to 75 mGy dose range and in nontransformed, radioresistant cells. In a previous paper by Devic et al, a biological interpretation of the adaptive response (AR) phenomenon was proposed using our model that is based on the radiation-induced nucleoshuttling of the ATM protein (the RIANS model). Here, we showed that the 20 to 75 mGy dose range corresponds to a maximum amount of ATM monomers diffusing into the nucleus, while no DNA double-strand breaks is produced by radiation. These ATM monomers are suggested to help in recognizing and repairing spontaneous DNA breaks accumulated in cells and contribute to reductions in genomic instability and aging. The RIANS model also permitted the biological interpretation of hypersensitivity to low doses (HRS)—another low-dose phenomenon. Hence, for the first time to our knowledge, hormesis, AR, and HRS can be explained using the same unified molecular model.