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      Modeling of chronic radiation-induced cystitis in mice

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          Abstract

          Purpose

          Radiation cystitis (RC), a severe inflammatory bladder condition, develops as a side effect of pelvic radiation therapy in cancer patients. There are currently no effective therapies to treat RC, in part from the lack of preclinical model systems. In this study, we developed a mouse model for RC and used a Small Animal Radiation Research Platform to simulate the targeted delivery of radiation as used with human patients.

          Methods and materials

          To induce RC, C3H mice received a single radiation dose of 20 Gy delivered through 2 beams. Mice were subjected to weekly micturition measurements to assess changes in urinary frequency. At the end of the study, bladder tissues were processed for histology.

          Results

          Radiation was well-tolerated; no change in weight was observed in the weeks after treatment, and there was no hair loss at the irradiation sites. Starting at 17 weeks after treatment, micturition frequency was significantly higher in irradiated mice versus control animals. Pathological changes include fibrosis, inflammation, urothelial thinning, and necrosis. At a site of severe insult, we observed telangiectasia, absence of uroplakin-3 and E-cadherin relocalization.

          Conclusions

          We developed an RC model that mimics the human pathology and functional changes. Furthermore, radiation exposure attenuates the urothelial integrity long-term, allowing for potential continuous irritability of the bladder wall from exposure to urine. Future studies will focus on the underlying molecular changes associated with this condition and investigate novel treatment strategies.

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          Most cited references28

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          Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

          Summary Background Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. Methods CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b–T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923. Findings Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9–77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0–90·2) in the 74 Gy group, 90·6% (88·5–92·3) in the 60 Gy group, and 85·9% (83·4–88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68–1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99–1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported. Interpretation Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. Funding Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.
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            High-resolution, small animal radiation research platform with x-ray tomographic guidance capabilities.

            To demonstrate the computed tomography, conformal irradiation, and treatment planning capabilities of a small animal radiation research platform (SARRP). The SARRP uses a dual-focal spot, constant voltage X-ray source mounted on a gantry with a source-to-isocenter distance of 35 cm. Gantry rotation is limited to 120 degrees from vertical. X-rays of 80-100 kVp from the smaller 0.4-mm focal spot are used for imaging. Both 0.4-mm and 3.0-mm focal spots operate at 225 kVp for irradiation. Robotic translate/rotate stages are used to position the animal. Cone-beam computed tomography is achieved by rotating the horizontal animal between the stationary X-ray source and a flat-panel detector. The radiation beams range from 0.5 mm in diameter to 60 x 60 mm(2). Dosimetry is measured with radiochromic films. Monte Carlo dose calculations are used for treatment planning. The combination of gantry and robotic stage motions facilitate conformal irradiation. The SARRP spans 3 ft x 4 ft x 6 ft (width x length x height). Depending on the filtration, the isocenter dose outputs at a 1-cm depth in water were 22-375 cGy/min from the smallest to the largest radiation fields. The 20-80% dose falloff spanned 0.16 mm. Cone-beam computed tomography with 0.6 x 0.6 x 0.6 mm(3) voxel resolution was acquired with a dose of <1 cGy. Treatment planning was performed at submillimeter resolution. The capability of the SARRP to deliver highly focal beams to multiple animal model systems provides new research opportunities that more realistically bridge laboratory research and clinical translation.
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              Gastrointestinal radiation injury: symptoms, risk factors and mechanisms.

              Ionising radiation therapy is a common treatment modality for different types of cancer and its use is expected to increase with advances in screening and early detection of cancer. Radiation injury to the gastrointestinal tract is important factor working against better utility of this important therapeutic modality. Cancer survivors can suffer a wide variety of acute and chronic symptoms following radiotherapy, which significantly reduces their quality of life as well as adding an extra burden to the cost of health care. The accurate diagnosis and treatment of intestinal radiation injury often represents a clinical challenge to practicing physicians in both gastroenterology and oncology. Despite the growing recognition of the problem and some advances in understanding the cellular and molecular mechanisms of radiation injury, relatively little is known about the pathophysiology of gastrointestinal radiation injury or any possible susceptibility factors that could aggravate its severity. The aims of this review are to examine the various clinical manifestations of post-radiation gastrointestinal symptoms, to discuss possible patient and treatment factors implicated in normal gastrointestinal tissue radiosensitivity and to outline different mechanisms of intestinal tissue injury.
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                Author and article information

                Contributors
                Journal
                Adv Radiat Oncol
                Adv Radiat Oncol
                Advances in Radiation Oncology
                Elsevier
                2452-1094
                01 August 2016
                Oct-Dec 2016
                01 August 2016
                : 1
                : 4
                : 333-343
                Affiliations
                [a ]Beaumont Health System, Royal Oak, Michigan
                [b ]Oakland University William Beaumont School of Medicine, Auburn Hills, Michigan
                [c ]Lipella Pharmaceuticals, Pittsburgh, Pennsylvania
                Author notes
                []Corresponding author. Beaumont Research Institute, 3811 W. 13 Mile Road, Suite 187, Royal Oak, MI 48073Beaumont Research Institute3811 W. 13 Mile Road, Suite 187Royal OakMI48073 Laura.lamb@ 123456beaumont.edu
                Article
                S2452-1094(16)30035-5
                10.1016/j.adro.2016.07.004
                5312778
                28217761
                2cce3431-3e34-4c1d-ad42-dd9fd32937db
                © 2016 The Authors on behalf of the American Society for Radiation Oncology

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 13 June 2016
                : 18 July 2016
                : 25 July 2016
                Categories
                Scientific Article

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