Radiation-induced Late Effects Research Articles

75 Inflammation and post-tx sickness syndrome as an explanation for late effects

The changing epidemiology of head and neck cancer, with an increase in HPV-positive oropharyngeal cancers and the refinement of a multidisciplinary approach, has led to an increase in the prevalence of long-term survivors after treatment. Consequently, a higher proportion of patients are suffering from late effects of the treatments, temporally defined as effects occurring or persisting more than 3 months after the end of the treatments. These late toxicities consist both of locoregional problems and systemic syndromes, with an impact on patients’ quality of life.There is still limited knowledge about the precise causes of these late toxicities, and at the same level, we lack predictive factors able to identify patients at higher risk of late effects. Treatment combinations with surgery followed by (chemo)radiation or with chemotherapy added to radiation with a radiosensitizing effect increase the probability of suffering from the late consequences of the same therapies. Pain, swallowing difficulties, trismus, osteonecrosis, dental disorders, mucositis, xerostomia or sticky saliva, hoarseness, lymphedema, and fibrosis are the most reported symptoms and signs, while fatigue, anxiety, depression, and cognitive impairment are the counterparts at the systemic level.There is growing evidence for the role of inflammation in the progression of cancer and treatment-related side effects. However, for head and neck cancer patients, there are still a lot of unanswered questions related to the role of inflammation as being both related to cancer disease and to the consequences of the intensive treatments carried out for this disease. In particular, it is well known that pro-inflammatory cytokines have been shown to be activated by malignant tumors and cancer treatment, and that their level during treatment is linked to higher acute toxicities. Also, the level of pro-inflammatory cytokines such as interleukin (IL)-1 beta (IL-1β), IL-6, IL-8, and tumor necrosis factor (TNF) has been correlated to higher mucositis, dysphagia, and pain due to the acute toxic effect of chemoradiation. However, researchers have not yet proven the association between the level of proinflammatory cytokines in the acute phase of the treatment and the development of late toxicities. Even the role of the same pro-inflammatory mediators in the follow-up period has a conflicting correlation with the late toxicities reported by the patients. Chronic inflammation may cause fibrosis, one of the key pathological features of radiation-induced late effects such as dysphagia and transforming growth factor beta (TGF-β) and TNF are involved in the formation of fibrosis in irradiated tissue. There is even more debate about the cause of systemic symptoms after cancer treatment. Head and neck cancer patients may develop the post-treatment sickness syndrome, consisting of chronic fatigue, mood alteration, cognitive impairment, and sleep problems, among the most frequently reported symptoms. The neuro-behavioral sickness model recapitulates all these symptoms as being related to the stress induced by the treatment, causing alterations in mood, cognition, nutritional intake, and the neurovegetative system. One of the hypotheses is that activation of peripheral pro-inflammatory cytokine networks transmits signals to the brain, which promote sickness behavior. The tissue damage induced by the oncological treatments would result in a self-perpetuating activation of biological processes, leading to a persistent inflammation condition that results in worsening systemic late effects over time. However, this theory needs to be carefully validated with prospective studies exploring patient-reported outcomes and their correlation with inflammatory mediators. According to this model, if inflammation recapitulates the locoregional and systemic late toxicities induced by the treatments, research should lead efforts to find ways to counteract it. From one side, it is possible to define de-escalating treatments that could offer the same level of cancer control with a reduced burden of acute and late toxicities. This is particularly awaited in HPV-positive cancer patients, who are usually younger patients, obtaining higher survival rates and thus a higher impact of toxicities on quality of life. On the other hand, it is important to define specific protocols to reduce the impact of inflammation in the long-term. In this regard, the role of physical exercise has been clearly underestimated, and recent research has shown benefits for the survival and quality of life of head and neck cancer patients. Also, even with less scientific evidence, nutrition could offer a less inflamed systemic status that could help minimize the late effects of cancer treatment. It is clear that research in this field is in its infancy, and we need to put more efforts into defining the translational correlates of late toxicities and exploring new ways to counteract the post-treatment sickness syndrome.

PO-2205 Histopathological examination of proton radiation-induced late effects in mice legs

PO-2205 Histopathological examination of proton radiation-induced late effects in mice legs

All eyes on the EuroNet-PHL-C1 trial for paediatric classical Hodgkin lymphoma.

Combined-modality therapy has been the paradigm in the treatment of paediatric classical Hodgkin lymphoma for 15–20 years, leading to event-free survival rates of around 90% and overall survival rates of around 95%. 1 Mauz-Korholz C Metzger ML Kelly KM et al. Pediatric Hodgkin lymphoma. J Clin Oncol. 2015; 33: 2975-2985 Crossref PubMed Scopus (86) Google Scholar In the past two decades, however, the strategy has silently shifted towards a response-based approach with shrinking radiation fields and clearly characterised patients in whom radiotherapy could safely be either completely or partially omitted to minimise the radiation-induced late effects of therapy. 2 Ehrhardt MJ Flerlage JE Armenian SH Castellino SM Hodgson DC Hudson MM Integration of pediatric hodgkin lymphoma treatment and late effects guidelines: seeing the forest beyond the trees. JNCCN. 2021; 19: 755-764 PubMed Google Scholar Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trialOur results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. Full-Text PDF Open Access

Comparative Effectiveness of Proton Therapy versus Photon Radiotherapy in Adolescents and Young Adults for Classical Hodgkin Lymphoma.

PurposeEarly stage (stages I-II) classical Hodgkin lymphoma (cHL) is a highly curable disease typically diagnosed in adolescents and young adults (AYAs). Proton therapy can also reduce the late toxicity burden in this population, but data on its comparative efficacy with photon radiotherapy in this population are sparse. We assessed outcomes in AYAs with cHL in a multi-institution retrospective review.Materials and MethodsWe identified 94 patients aged 15 to 40 years with stages I and II cHL treated with radiotherapy as part of their initial treatment between 2008 and 2017. We used Kaplan-Meier analyses and log-rank testing to evaluate survival differences between groups of patients.ResultsA total of 91 patients were included in the analysis. The 2-year progression-free survival (PFS) rate was 89%. Of the 12 patients who experienced progression after radiotherapy, 4 occurred out-of-field, 2 occurred in-field, and 6 experienced both in- and out-of-field progression. There was no significant difference in 2-year PFS among AYA patients by radiotherapy dose received (≥ 30 Gy, 91%; < 30 Gy, 86%; P = .82). Likewise, there was no difference in 2-year PFS among patients who received either proton or photon radiotherapy (proton, 94%; photon, 83%; P = .07).ConclusionOur cohort of AYA patients had comparable outcomes regardless of radiotherapy dose or modality used. For patients with significant risk of radiation-induced late effects, proton therapy is a reasonable treatment modality.

Abstract 680: A DNA repair biomarker signature to predict radiotherapy side-effects in breast and prostate cancers

Abstract Introduction: About 50% of patients with solid tumors receive radiotherapy (RT) which induces cancer cells death through radiation-induced DNA damage. Five to 10% of these patients experience severe toxicity that can heavily impact their quality of life. The identification of predictive biomarkers to discriminate patients at high risk of developing radiotoxicity is needed to move towards a personalized treatment and to improve the management of these patients. Purpose: The aim of this clinical proof-of-concept was to identify blood radiotoxicity biomarkers based on a comprehensive analysis of several DNA repair activities. We relied on the hypothesis that DNA damage, DNA repair and inflammation are functionally associated and mutually supportive, and related to the appearance of side effects. Methods: 200 patients with either prostate or breast cancer who underwent RT were enrolled at the Lucien Neuwirth Cancer institute. Late radio-induced adverse events were recorded 6 months after the beginning of the treatment. Three blood samples per patient were collected before and early during the treatment course to monitor the ability of enzymes contained in lymphocytes to repair series of DNA lesions immobilized on biochip (Glyco-SPOT assay). We analyzed the association between the Base Excision Repair (BER), the primary pathway responsible for DNA repair during inflammation, and the appearance of severe late radiation-induced effects (3 in the female and 4 in the male cohort). Results: Late severe (Grade ≥3) and late moderate (Grade ≥2) radiation-induced events were recorded. Cutaneous, and gastro-intestinal and genitourinary adverse events, were considered respectively in breast cancer and prostate cancer patients. We observed some significantly lower BER activities in breast cancer patients who developed severe late events compared to those who did not. By contrast, it was the opposite in prostate cancer patients. In both cohort we defined a combination of biomarkers that predicted the appearance of severe late adverse events with 100% sensitivity and 100% negative predictive value using the blood sample taken after the first dose of RT. Conclusion: The risk of late radiotoxicity could be accurately predicted on the basis of combination of BER-related biomarkers. Interestingly, the biomarkers differed in breast and prostate cancer patients suggesting that beyond inflammation, hormone pathway regulation impacted the BER response to ionizing radiation, and the relationship with long-term severe side effects. These results require confirmation on a larger cohort. Citation Format: Giovanna Muggiolu, Libert Libert, Elisabeth Daguenet, Thierry Maillet, Claire Rodriguez-Lafrasse, Sylvie Sauvaigo, Nicolas Magné. A DNA repair biomarker signature to predict radiotherapy side-effects in breast and prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 680.

Atlas construction and spatial normalisation to facilitate radiation-induced late effects research in childhood cancer

Reducing radiation-induced side effects is one of the most important challenges in paediatric cancer treatment. Recently, there has been growing interest in using spatial normalisation to enable voxel-based analysis of radiation-induced toxicities in a variety of patient groups. The need to consider three-dimensional distribution of doses, rather than dose-volume histograms, is desirable but not yet explored in paediatric populations. In this paper, we investigate the feasibility of atlas construction and spatial normalisation in paediatric radiotherapy. We used planning computed tomography (CT) scans from twenty paediatric patients historically treated with craniospinal irradiation to generate a template CT that is suitable for spatial normalisation. This childhood cancer population representative template was constructed using groupwise image registration. An independent set of 53 subjects from a variety of childhood malignancies was then used to assess the quality of the propagation of new subjects to this common reference space using deformable image registration (i.e. spatial normalisation). The method was evaluated in terms of overall image similarity metrics, contour similarity and preservation of dose-volume properties. After spatial normalisation, we report a dice similarity coefficient of 0.95 ± 0.05, 0.85 ± 0.04, 0.96 ± 0.01, 0.91 ± 0.03, 0.83 ± 0.06 and 0.65 ± 0.16 for brain and spinal canal, ocular globes, lungs, liver, kidneys and bladder. We then demonstrated the potential advantages of an atlas-based approach to study the risk of second malignant neoplasms after radiotherapy. Our findings indicate satisfactory mapping between a heterogeneous group of patients and the template CT. The poorest performance was for organs in the abdominal and pelvic region, likely due to respiratory and physiological motion and to the highly deformable nature of abdominal organs. More specialised algorithms should be explored in the future to improve mapping in these regions. This study is the first step toward voxel-based analysis in radiation-induced toxicities following paediatric radiotherapy.

Total body irradiation causes a chronic decrease in antioxidant levels

Ionizing radiation exposure may not only cause acute radiation syndrome, but also an increased risk of late effects. It has been hypothesized that induction of chronic oxidative stress mediates the late effects of ionizing radiation. However, only a few reports have analyzed changes in long-term antioxidant capacity after irradiation in vivo. Our previous study demonstrated changes in whole-blood antioxidant capacity and red blood cell (RBC) glutathione levels within 50 days after total body irradiation (TBI). In this study, seven-week-old, male, C57BL/6J mice exposed to total body irradiation by X-ray and changes in whole-blood antioxidant capacity and RBC glutathione levels at ≥ 100 days after TBI were investigated. Whole-blood antioxidant capacity was chronically decreased in the 5-Gy group. The RBC reduced glutathione (GSH) level and the GSH/oxidative glutathione (GSSG) ratio were chronically decreased after ≥ 1 Gy of TBI. Interestingly, the complete blood counts (CBC) changed less with 1-Gy exposure, suggesting that GSH and the GSH/GSSG ratio were more sensitive radiation exposure markers than whole-blood antioxidant capacity and CBC counts. It has been reported that GSH depletion is one of the triggers leading to cataracts, hypertension, and atherosclerosis, and these diseases are also known as radiation-induced late effects. The present findings further suggest that chronic antioxidant reduction may contribute to the pathogenesis of late radiation effects.

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.

Late Side Effects in Normal Mouse Brain Tissue After Proton Irradiation

Radiation-induced late side effects such as cognitive decline and normal tissue complications can severely affect quality of life and outcome in long-term survivors of brain tumors. Proton therapy offers a favorable depth-dose deposition with the potential to spare tumor-surrounding normal tissue, thus potentially reducing such side effects. In this study, we describe a preclinical model to reveal underlying biological mechanisms caused by precise high-dose proton irradiation of a brain subvolume. We studied the dose- and time-dependent radiation response of mouse brain tissue, using a high-precision image-guided proton irradiation setup for small animals established at the University Proton Therapy Dresden (UPTD). The right hippocampal area of ten C57BL/6 and ten C3H/He mice was irradiated. Both strains contained four groups (nirradiated = 3, ncontrol = 1) treated with increasing doses (0 Gy, 45 Gy, 65 Gy or 85 Gy and 0 Gy, 40 Gy, 60 Gy or 80 Gy, respectively). Follow-up examinations were performed for up to six months, including longitudinal monitoring of general health status and regular contrast-enhanced magnetic resonance imaging (MRI) of mouse brains. These findings were related to comprehensive histological analysis. In all mice of the highest dose group, first symptoms of blood-brain barrier (BBB) damage appeared one week after irradiation, while a dose-dependent delay in onset was observed for lower doses. MRI contrast agent leakage occurred in the irradiated brain areas and was progressive in the higher dose groups. Mouse health status and survival corresponded to the extent of contrast agent leakage. Histological analysis revealed tissue changes such as vessel abnormalities, gliosis, and granule cell dispersion, which also partly affected the non-irradiated contralateral hippocampus in the higher dose groups. All observed effects depended strongly on the prescribed radiation dose and the outcome, i.e. survival, image changes, and tissue alterations, were very consistent within an experimental dose cohort. The derived dose–response model will determine endpoint-specific dose levels for future experiments and may support generating clinical hypotheses on brain toxicity after proton therapy.

The risk of late effects following pediatric and adult radiotherapy regimens in Hodgkin lymphoma.

Adolescent young adults (AYA) with Hodgkin lymphoma (HL) are treated according to either pediatric or adult protocols, however, the best strategy has yet to be established. We describe the AYA patients referred for radiotherapy and quantify the risk of radiation-induced late effects and the corresponding life years lost (LYL) following pediatric and adult regimens. Patients ≤24years irradiated for HL were included. For each patient, organs at risk (OARs) were contoured and dosimetric parameters were extracted. Estimated excess hazard ratios of radiation-induced late effects were calculated from dose-response models and LYL attributable to various late effects were estimated. In total, 77patients were analyzed (pediatric regimen: 15; adult regimen: 62). Age, clinical stage, and the number of patients enrolled in protocols were significantly different between the groups. Pediatric patients had more advanced disease, which resulted in larger target volumes and higher doses to most OARs, despite alower prescribed dose compared to adult regimens. LYL estimates were all higher with the pediatric regimens. Total LYL with pediatric and adult treatment regimens were 3.2years and 2.3years, respectively. Due to the clinical stage variation and heterogeneity in disease location, adirect comparison of the estimated risks of late effects was only exploratory. Pediatric regimens selected patients with more advanced disease to radiotherapy resulting in larger target volumes and higher doses to the OARs. Target volume rather than prescribed dose impacted OAR exposure. Consequently, the estimated risk of radiation-induced late effects and corresponding LYL was increased when compared to adult regimens.

GCT-09. HEALTH AND SOCIAL ISSUES IN THE LONG-TERM GERM-CELL TUMOR SURVIVORS

Germ cell tumor (GCT) is a rare juvenile CNS tumor that is more frequent in eastern Asia. Most survivors require continuous medical care for hormone replacement, maintenance of shunting devices, and late radiation-induced effects. In the present study, we retrospectively analyzed medical records of long-term GCT survivors, and make the health and social issues clear. Ninety-two GCT patients were treated in our institute from 1982 to 2018, and 81 patients, of which medical records are available, are included. The median follow-up period is 12.2 years, and 47 patients (58.1%) are followed for more than ten years. The overall survival rate is gradually decreasing more than ten years follow-up, such as 10-, 15- and 25-years survival are 92.3, 87.7, and 73.3%, respectively. In the long-term follow-up, eight subsequent malignancy and seven cerebrovascular events are recorded. These events occurred 20 years or more after the treatments, and six CNS malignancies were observed in survivors irradiated with 50Gy or more. As social issues, forty-two of 50 adult survivors had been employed after the treatments, but only thirty-four (70.8%) are still working. Of note, only nine (18.8% of adults) survivors got married. All four married women require any hormone replacement, while only one of 4 men requires the replacement. Long-term follow-up of GCT survivors revealed subsequent malignancy and social problems. A recent attempt to decrease the dose of irradiation might overcome some issues. As a conclusion, GCT survivors require a supporting program for not only health but also social issues.

RONC-02. MEASURING THE EFFECT OF CLINICALLY-RELEVANT RADIOTHERAPY PROTOCOLS ON THE JUVENILE MOUSE BRAIN

Treatment for medulloblastoma involves craniospinal irradiation which is associated with devastating late effects. Clinical trials that simply reduce radiotherapy dosage have resulted in inferior survival rates, whereas new chemo/radiotherapy combinations that improve survival have been identified using preclinical models. However, the potential late effects of novel treatments are currently understudied and the assessment of radiation-induced late effects in mice remains challenging. Here, we aimed to measure the effect of multifractionated radiotherapy on the juvenile mouse brain as a baseline measure for future studies. NOD/Rag1-/- mice received either 8Gy whole-brain radiotherapy (WBRT) using an X-RAD SmART preclinical platform, 18Gy fractionated WBRT (9x2Gy doses), single, or multiple sham treatments beginning at postnatal day (P)16. Mice were aged to adulthood (>P63), then high resolution anatomical brain scans were obtained on a Bruker 9.4T MRI to measure the effects of WBRT on whole brain and specific regional area volumes. A single 8Gy dose (n=10) markedly reduced brain volume by 8.5% compared to single-sham controls (n=11, p<0.0001), whereas fractionated 18Gy treatment (n=7) did not cause significant differences in brain volume compared to multi-sham controls (n=4, p>0.99). Current analyses are focused on measuring treatment effects on specific areas of the brain, as well as other anatomical differences using a range of MRI techniques. These results will serve as a valuable tool to measure potential treatment-associated effects caused by novel chemo/radiotherapy combinations on the developing brain. This will enable future studies to assess the potential safety of novel treatment to inform clinical decision making.

Study of Indicators for Early and Rapid Diagnosis of Radiation Injury Is the Most Important in Patients With Cancer During Radiotherapy.

Objective:To establish a complete technical solution for the radiation biological dose estimation, to enable prediction of individuals’ response to radiotherapy (RT), and to control treatment dose for reduced irradiation injury and promote repair; and to evaluate the risk of radiation-induced late effects for patients undergoing external photon beam RT and provide the reliable dose–response relationships.Methods:Select 49 tumor patients using 60Co and linear accelerator for radiation therapy; initial radiation dose was 250 cGy. Chromosome aberration and blood count were analyzed before radiation therapy and 2 hours after the first day of RT.Results:Two hours after the first day of RT, peripheral blood cell count of lymphocytes of patients with cancer was significantly decreased (P < .01). The frequency of chromosome aberration was higher (P < .01).Conclusion:High-dose radiation of the radiation therapy makes significant injuries to peripheral blood lymphocytes.

Impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer: Evidences from a cohort study and a trial sequential meta-analysis.

The relationship between the ataxia-telangiectasia mutated (ATM) rs1801516 gene polymorphism and risk of radiation-induced late skin side effects remains a highly debated issue. In the present study, we assessed the role of ATM rs1801516 as risk factor for radiation-induced fibrosis and telangiectasia, using the LENT-SOMA scoring scale in 285 breast cancer patients who received radiotherapy after breast conserving surgery. A systematic review with meta-analysis and trial sequential analysis (TSA) was then conducted to assess reliability of the accumulated evidence in breast cancer patients. In our cohort study, no association was found between ATM rs1801516 and grade ≥ 2 telangiectasia (GA+AA vs GG, HRadjusted: 0.699; 95%CI: 0.273–1.792, P = 0.459) or grade ≥ 2 fibrosis (GA+AA vs GG, HRadjusted: 1.175; 95%CI: 0.641–2.154, P = 0.604). Twelve independent cohorts of breast cancer patients were identified through the systematic review, of which 11 and 9 cohorts focused respectively on the association with radiation-induced fibrosis and radiation-induced telangiectasia. Pooled analyses of 10 (n = 2928 patients) and 12 (n = 2783) cohorts revealed, respectively, no association of ATM rs1801516 with radiation-induced telangiectasia (OR: 1.14; 95%CI: 0.88–1.48, P = 0.316) and a significant correlation with radiation-induced fibrosis (OR: 1.23; 95%CI: 1.00–1.51, P = 0.049), which however did not remain significant after TSA adjustment (TSA-adjusted 95%CI: 0.85–1.78). These results do not support an impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer, nevertheless further large studies are still required for conclusive evidences.

Outils pour la prédiction de la réponse tumorale et des tissus sains en oncologie radiothérapie

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the target volume. Tumor sensitivity to radiotherapy may be particularly inconstant depending on location, histology, somatic genetic parameters and the capacity of the immune system to infiltrate the tumor. In addition, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many radiation treatments. In a same population treated in one center with the same technique, it appears that individual radiosensitivity clearly exists, namely in terms of late side effects that are in principle non-reversible. This review details the different radiobiological approaches that have been developed to better predict the tumor response but also the radiation-induced late effects.

Radiotherapy of prostate cancer in renal transplant recipients: single-center experience.

This study analyzed the long-term outcomes of localized prostate cancer in renal transplant recipients after radiotherapy treatment - mainly brachytherapy. We retrospectively analyzed clinical data of renal transplant recipients between 2003 and 2016 at a single tertiary center, and identified four patients with high serum PSA level during regular follow-up, 1-108 months after primary renal transplantation. The mean age of patients with detected high serum PSA level with 9.25µg/l median was 59.05 years. All four patients had functioning grafts. To prove prostate cancer, they underwent trans-rectal prostate biopsy, with no complications. Histological evaluation identified prostate adenocarcinoma (Gleason 6-7, stage T1-2cN0M0) in three patients. The biopsy in the fourth patient was negative and he therefore had trans-urethral prostate resection. Histological evaluation of resected prostate tissue revealed prostate adenocarcinoma (Gleason 7, 4+3). All patients began treatment with androgen deprivation therapy. Three patients were indicated for permanent prostate brachytherapy (BT) with iodine-125 (125I) seeds and the trans-urethral resection patient was referred for external beam radiotherapy (EBRT). After a mean follow-up of 49 months (range, 30-73), all patients, irrespective of type of radiotherapy, were in complete clinical and biochemical remission, with undetectable PSA levels. The kidney grafts remained functional, with a mean creatinine level of 99 µmol/l (range 64-123) and a glomerular filtration rate of 1.17 ml/s/1.73 m2 (range, 0.89-1.59). Radiation-induced late adverse effects were reported in two BT patients; one had clinically significant urine incontinency and the other suffered urethral stricture. Localized prostate tumor was identified in all reported patients, and all received radiotherapy plus androgen deprivation. All patients were disease-free at the time of the last follow-up. Therefore, combined BT and twelve months androgen deprivation appears both safe and effective for patients with prostate cancer after kidney transplantation.

Abstract 3593: Noncoding RNAs in early detection of radiation-induced late pulmonary effects

Abstract Normal tissue toxicity is an undesired outcome in patients receiving radiation therapy, manifested as acute radiation syndromes (ARS) and as late effects in survivors. The purpose of the study is to develop biomarkers for assessing the extent of lung inflammation and early detection of delayed and late radiation toxicities such as pneumonitis and pulmonary fibrosis. Circulating miRNAs offer great promise as diagnostic predictive biomarkers due to their high abundance, high stability and sensitivity. A longitudinal analysis of evolutionarily conserved noncoding RNAs was done using NanoString platform in serum samples from leukemia patients and pneumonitis-prone BALB/c mice exposed to clinically relevant doses of whole-body, organ-targeted/protected irradiation to compare the treatment-induced alterations. The associated immune response was evaluated by cytokine multiplexing and gene expression analysis and imaging with micro-CT. Bleomycin and targeted miRNA knockout mice models were used to evaluate functional significance of the identified biomarkers. Quantification of time-dependent alterations in serum and plasma miRNAs from rodents samples collected after thoracic, gut versus whole-body exposure have identified a panel of five miRNAs that are capable of providing an early readout of delayed lung toxicities. The specificity of the candidate miRNAs as potential early indicators of lung injury was confirmed in a bleomycin model of acute lung injury where an overlapping miRNA signature was observed in serum. Among these conserved miRNAs, serum miR-21 and miR-29a were found significantly elevated in two weeks in lung irradiated animals with concomitant increase in proinflammatory cytokines. The significance of the markers was further validated in serum miRNA profile of leukemia patients who exhibited pneumonitis symptoms post radiation therapy. The functional role of miR-21 in promoting radiation-induced inflammation was evident from compromised response of genes associated with inflammation in irradiated miR-21-/- mice. Our study has identified a panel of evolutionarily and functionally conserved sensitive miRNA biomarkers that facilitate rapid and early detection of late pulmonary toxicities in leukemia and lung cancer patients who receive therapeutic radiation. Analysis of circulating biomarkers will potentially assist in making therapeutic and follow-up decision based on individual's own physiologic response and developing strategies for timely mitigation and treatment. Citation Format: Marshleen Yadav, Feifei Song, Zahida Qamri, Arnab Chakravarti, Naduparambil K. Jacob. Noncoding RNAs in early detection of radiation-induced late pulmonary effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3593.

Cancer Incidence in C3H Mice Protected from Lethal Total-Body Radiation after Amifostine.

Amifostine is a potent antioxidant that protects against ionizing radiation effects. In this study, we evaluated the effect of Amifostine administered before total-body irradiation (TBI), at a drug dose that protects against TBI lethality, for potential protection against radiation-induced late effects such as a shortened lifespan and cancer. Three groups of mice were studied: 0 Gy control; 10.8 Gy TBI with Amifostine pretreatment; and 5.4 Gy TBI alone. Animals were monitored for their entire lifespan. The median survival times for mice receiving 0, 5.4 or 10.8 Gy TBI were 706, 460 and 491 days, respectively. Median survival of both irradiated groups was significantly shorter compared to nonirradiated mice ( P < 0.0001). Cancer incidence (hematopoietic and solid tumors) was similar between the irradiated groups and was significantly greater than for the 0 Gy controls. The ratio of hematopoietic-to-solid tumors differed among the groups, with the 5.4 Gy group having a higher incidence of hematopoietic neoplasms compared to the 10.8 Gy/Amifostine group (1.8-fold). Solid tumor incidence was greater in the 10.8 Gy/Amifostine group (1.6-fold). There are few mouse lifespan studies for agents that protect against radiation-induced lethality. Mice treated with 10.8 Gy/Amifostine yielded a lower incidence of hematopoietic neoplasms and higher incidence of solid neoplasms. In conclusion, mice protected from lethal TBI have a shortened lifespan, due in large part to cancer induction after exposure compared to nonexposed controls. Amifostine treatment did protect against radiation-induced hematopoietic tumors, while protection against solid neoplasms was significant but incomplete.

Late normal tissue response in the rat spinal cord after carbon ion irradiation

BackgroundThe present work summarizes the research activities on radiation-induced late effects in the rat spinal cord carried out within the “clinical research group ion beam therapy” funded by the German Research Foundation (DFG, KFO 214).Methods and materialsDose–response curves for the endpoint radiation-induced myelopathy were determined at 6 different positions (LET 16–99 keV/μm) within a 6 cm spread-out Bragg peak using either 1, 2 or 6 fractions of carbon ions. Based on the tolerance dose TD50 of carbon ions and photons, the relative biological effectiveness (RBE) was determined and compared with predictions of the local effect model (LEM I and IV). Within a longitudinal magnetic resonance imaging (MRI)-based study the temporal development of radiation-induced changes in the spinal cord was characterized. To test the protective potential of the ACE (angiotensin converting enzyme)-inhibitor ramipril™, an additional dose–response experiment was performed.ResultsThe RBE-values increased with LET and the increase was found to be larger for smaller fractional doses. Benchmarking the RBE-values as predicted by LEM I and LEM IV with the measured data revealed that LEM IV is more accurate in the high-LET, while LEM I is more accurate in the low-LET region. Characterization of the temporal development of radiation-induced changes with MRI demonstrated a shorter latency time for carbon ions, reflected on the histological level by an increased vessel perforation after carbon ion as compared to photon irradiations. For the ACE-inhibitor ramipril™, a mitigative rather than protective effect was found.ConclusionsThis comprehensive study established a large and consistent RBE data base for late effects in the rat spinal cord after carbon ion irradiation which will be further extended in ongoing studies. Using MRI, an extensive characterization of the temporal development of radiation-induced alterations was obtained. The reduced latency time for carbon ions is expected to originate from a dynamic interaction of various complex pathological processes. A dominant observation after carbon ion irradiation was an increase in vessel perforation preferentially in the white matter. To enable a targeted pharmacological intervention more details of the molecular pathways, responsible for the development of radiation-induced myelopathy are required.

IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects.

There is an ongoing and significant need for radiation countermeasures to reduce morbidities and mortalities associated with exposure of the heart and lungs from a radiological or nuclear incidents. Radiation-induced late effects occur months to years after exposure, stemming from significant tissue damage and remodeling, resulting in fibrosis and loss of function. TGF-β is reported to play a role in both pulmonary and cardiac fibrosis. We investigated the ability of a small molecule TGF-β receptor 1 inhibitor, IPW-5371, to mitigate the effects of thoracic irradiation in C57L/J mice, a murine model that most closely resembles that observed in humans in the induction of fibrosis and dose response. To simulate a radiological event, radiation was administered in two doses: 5 Gy total-body irradiation (eliciting a whole-body response) and immediately after that, a thoracic "top-up" of 6.5 Gy irradiation, for a total dose of 11.5 Gy to the thorax. IPW-5371 was administered once daily, orally, starting 24 h postirradiation for 6 or 20 weeks at a dose of 10 mg/kg or 30 mg/kg. Animals were monitored for a period of 180 days for survival, and cardiopulmonary injury was assessed by echocardiography, breathing rate and arterial oxygen saturation. Exposure of the thorax (11.5 Gy) induced both pulmonary and cardiac injury, resulting in a reduced life span with median survival of 135 days. IPW-5371 treatment for 6 weeks, at both 10 mg/kg and 30 mg/kg, delayed disease onset and mortality, with median survival of 165 days. Twenty weeks of IPW-5371 treatment at 30 mg/kg preserved arterial O2 saturation and cardiac contractile reserve and resulted in significant decreases in breathing frequency and cardiac and pulmonary fibrosis. This led to dramatic improvement in survival compared to the irradiated, vehicle-treated group (P < 0.001), and was statistically insignificant from the nonirradiated group. We observed that IPW-5371 treatment resulted in decreased pSmad3 tissue levels, confirming the effect of IPW-5371 on TGF-β signaling. These results demonstrate that IPW-5371 represents a potentially promising radiation countermeasure for the treatment of radiation-induced late effects.