Dependence of Induced Biological Damage on the Energy Distribution and Intensity of Clinical Intra-Operative Radiotherapy Electron Beams.

The survival fraction of epithelial HaCaT cells was analysed to assess the biological damage caused by intraoperative radiotherapy electron beams with varying energy spectra and intensities. These conditions were achieved by irradiating the cells at different depths in water using nominal 6 MeV electron beams while consistently delivering a dose of 5 Gy to the cell layer. Furthermore, a Monte Carlo simulation of the entire irradiation procedure was performed to evaluate the molecular damage in terms of molecular dissociations induced by the radiation. A significant agreement was found between the molecular damage predicted by the simulation and the damage derived from the analysis of the survival fraction. In both cases, a linear relationship was evident, indicating a clear tendency for increased damage as the averaged incident electron energy and intensity decreased for a constant absorbed dose, lowering the dose rate. This trend suggests that the radiation may have a more pronounced impact on surrounding healthy tissues than initially anticipated. However, it is crucial to conduct additional experiments with different target geometries to confirm this tendency and quantify the extent of this effect.

Conventional 3D conformal radiotherapy and volumetric modulated arc therapy for cervical cancer: Comparison of clinical results with special consideration of the influence of patient- and treatment-related parameters.

PURPOSE: Intensity-modulated radiotherapy (IMRT) for cervical cancer yields favorable results in terms of oncological outcomes, acute toxicity, and late toxicity. Limited data are available on clinical results with volumetric modulated arc therapy (VMAT). This study's purpose is to compare outcome and toxicity with VMAT to conventional 3D conformal radiotherapy (3DCRT), giving special consideration to the influence of patient- and treatment-related parameters on side effects. MATERIALS AND METHODS: Patients with cervical cancer stage I-IVA underwent radiotherapy alone or chemoradiotherapy using 3DCRT (n = 75) or VMAT (n = 30). Survival endpoints were overall survival, progression-free survival, and locoregional control. The National Cancer Institute Common Terminology Criteria for Adverse Events and the Late Effects of Normal Tissues criteria were used for toxicity assessment. Toxicity and patient- and treatment-related parameters were included in a multivariable model. RESULTS: There were no differences in survival rates between treatment groups. VMAT significantly reduced late small bowel toxicity (OR = 0.10, p = 0.03). Additionally, VMAT was associated with an increased risk of acute urinary toxicity (OR = 2.94, p = 0.01). A low body mass index (BMI; OR = 2.46, p = 0.03) and overall acute toxicity ≥grade 2 (OR = 4.17, p < 0.01) were associated with increased overall late toxicity. CONCLUSION: We demonstrated significant reduction of late small bowel toxicity with VMAT treatment, an improvement in long-term morbidity is conceivable. VMAT-treated patients experienced acute urinary toxicity more frequently. Further analysis of patient- and treatment-related parameters indicates that the close monitoring of patients with low BMI and of patients who experienced relevant acute toxicity during follow-up care could improve late toxicity profiles.

Issues in Interpreting Epidemiologic Studies of Populations Exposed to Low-Dose, High-Energy Photon Radiation.

This article addresses issues relevant to interpreting findings from 26 epidemiologic studies of persons exposed to low-dose radiation. We review the extensive data from both epidemiologic studies of persons exposed at moderate or high doses and from radiobiology that together have firmly established radiation as carcinogenic. We then discuss the use of the linear relative risk model that has been used to describe data from both low- and moderate- or high-dose studies. We consider the effects of dose measurement errors; these can reduce statistical power and lead to underestimation of risks but are very unlikely to bring about a spurious dose response. We estimate statistical power for the low-dose studies under the assumption that true risks of radiation-related cancers are those expected from studies of Japanese atomic bomb survivors. Finally, we discuss the interpretation of confidence intervals and statistical tests and the applicability of the Bradford Hill principles for a causal relationship.

Association between acute histopathological changes of rectal walls and late radiation proctitis following radiotherapy for prostate cancer.

PURPOSE: The impact of acute histopathological changes (HC) of the rectum on development of late clinical proctitis (LCP) after external radiotherapy (RT) for prostate cancer is poorly explored and was the primary end point of this prospective study. METHODS: In 70 patients, 15 HC of early rectal biopsies after RT were identified, whereby RT was conventional 2D RT in 41 cases and conformational 3D RT in 29. Associations of HC in anterior and posterior rectal walls (ARW, PRW) with LCP, acute endoscopic (AEP) and acute clinical proctitis (ACP) were statistically evaluated considering as explicative variables the patient general characteristics and the HC. RESULTS: The mean patients' follow-up was 123.5 months (24-209). The median prostatic dose was 72 Gy (2 Gy/fraction). For the 41 and 29 patients the ARW and PRW doses were 64 and 49 Gy vs. 63 and 50 Gy, respectively. The incidence of LCP ≥ grade 2 at 10 years was 12.9%. The univariate (p = 0.02) and Kaplan-Meyer methods (p = 0.007) showed that the gland (or crypts) loss in the ARW was significantly associated with LCP. AEP and ACP occurred in 14.3 and 55.7% of cases. At multivariate level AEP significantly correlated with hemorrhoids (p = 0.014) and neutrophilia in ARW (p = 0.042). CONCLUSIONS: Early after RT, substantial gland loss in ARW is predictive of LCP. To reduce this complication with conventional fractionation, we suggest keeping the mean dose to ARW ≤48-52 Gy.

Evaluation of the efficacy of lipotransfer to manage radiation-induced fibrosis and volume defects in head and neck oncology.

BACKGROUND: Multimodality treatment for head and neck cancer leads to substantial functional and esthetic impairment mainly manifested as radiation-induced skin fibrosis (RIF) in combination with volumetric defects and reduction in neck mobility. This study assessed the impact of lipotransfer as part of secondary surgical procedure(s) in patients treated for head and neck malignancies. METHODS: Retrospective analysis was performed between 2005 and 2016. All patients with a history of head and neck malignancy, multimodal treatment including at least surgery or radiotherapy, and at least 2-year disease-free survival were included. Thirty-eight patients (22 men, 16 women) matched the inclusion criteria. RESULTS: Thirty seven (97%) reported esthetic and functional improvements in their RIF and volumetric defect at follow-up of 32 months. Major improvement in esthetic and functional outcome was reported by 24 (63%) patients and surgeons and minor by 13 patients and surgeons (34%) without causing any complications. Lipotransfer was also found to significantly improve patient's psychological health postoperatively as showed by significant improvements in Derriford Appearance Scale (DAS24), Short Form Health Survey (SF-36), and University of Washington Quality of Life Questionnaire (UW-QOL V4) scores (P < .001). CONCLUSIONS: Lipotransfer is effective for volume restoration and treating scar and RIF from head and neck defects.

Temporomandibular disorder in head and neck cancer patients undergoing radiotherapy: Clinical findings and patient-reported symptoms.

BACKGROUND: The aim of this study was to investigate how common temporomandibular disorder (TMD) symptoms are among head and neck cancer (HNC) patients before and after oncological treatment. METHODS: Eighty-nine patients with HNC receiving radiotherapy were enrolled in the study. Patients were examined before radiotherapy and at 6 and 12 months after radiotherapy to evaluate the function and tenderness of the temporomandibular jaw and the muscles of mastication as well as the patient-reported symptoms. RESULTS: At 6 months after radiotherapy, there was a large increase in the number of patients reporting problems with opening their mouth, fatigue, stiffness, and pain of the jaw. Sixty-eight percent of the patients had symptoms of TMD before oncological treatment and 94% and 81% had symptoms at the 6- and 12-month follow-up, respectively. CONCLUSION: The signs and symptoms of TMD escalate after radiotherapy, with symptoms peaking at 6 months after radiotherapy. Most commonly, patients suffer from restricted mouth opening, stiffness, fatigue, and pain of the jaw.

Radiation-induced undifferentiated pleomorphic sarcoma of the breast: a rare but serious complication following breast-conserving therapy. A case report and literature review.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) of the breast is an extremely rare, but aggressive subtype of sarcoma that can develop in radiotherapy (RT)-treated breast cancer patients. Due to the low incidence, there are many uncertainties regarding the adequate management of these tumors. We present a rare case of radiation-induced UPS in a 63-year-old woman who had undergone breast conserving therapy for invasive ductal carcinoma of the left breast, six years prior to presentation. CASE PRESENTATION: A 63-year-old woman presented with a rapidly growing left breast mass. She had been diagnosed with invasive ductal carcinoma of the left breast for which she underwent a left upper outer quadrantectomy and ipsilateral axillary dissection followed by RT, six years previously. During her routine oncologic follow-up, the mammography revealed a dense, nodular opacity with microcalcifications. The breast ultrasound (US) confirmed the presence of the nodule. US-guided fine needle aspiration biopsy was performed and the diagnosis of UPS was made, the reason for which the patient underwent wide local excision of the left breast. CONCLUSION: The diagnosis of RT-induced UPS is challenging and often missed due to the low incidence, long latency period, unspecific imaging findings, and difficulties in clinical and histological detection of these lesions. These tumors should be considered in differential diagnoses of rapidly-growing breast masses in previously RT-treated breast cancer patients, as they can mimic the local recurrence of the primary tumor. Since the prevalence of breast-conserving surgery followed by RT has been increasing, the careful monitoring of at risk patients is of utmost importance, as UPSs are highly aggressive tumors associated with very poor outcomes.

Essential considerations for accurate evaluation of photoneutron contamination in Radiotherapy.

Nowadays, high-energy X-rays produced by medical linear accelerators (LINACs) are widely used in many Radiation Therapy (RT) centers. High-energy photons (> 8 MeV) produce undesired neutrons in the LINAC head which raise concerns about unwanted neutron dose to the patients and RT personnel. Regarding the significance of radiation protection in RT, it is important to evaluate photoneutron contamination inside the RT room. Unfortunately, neutron dosimeters used for this purpose have limitations that can under the best conditions cause to > 10% uncertainty. In addition to this uncertainty, the present Monte Carlo (MC) study introduces another uncertainty in measurements (nearly up to 20%) when neutron ambient dose equivalent (Hn*(10)) is measured at the patient table or inside the maze and the change in neutron energy is ignored. This type of uncertainty can even reach 35% if Hn*(10) is measured by dosimeters covered by a layer of 10B as converter. So, in these cases, neglecting the change in neutron energy can threaten the credibility of measured data and one should attend to this energy change in order to reduce measurement uncertainty to the possible minimum. This study also discusses the change in neutron spectra and Hn*(10) at the patient table caused by removing a typical RT room from MC simulations. Under such conditions, neutron mean energy (En) overestimated by 0.2-0.4 MeV at the patient table. Neutron fluence (φn) at the isocenter (IC) was underestimated by 23-54% for different field sizes that caused Hn*(10) to be miscalculated up to 24%. This finding informs researchers that for accurate evaluation of Hn*(10) at the patient table, simulating the RT room is an effective parameter in MC studies.

Radiation-induced nasopharyngeal ulcers after intensity modulated radiotherapy in primary nasopharyngeal carcinoma patients: A dose-volume-outcome analysis.

OBJECTIVE: This is a retrospective dose-volume-outcome analysis of radiation-induced nasopharyngeal ulcers after intensity modulated radiotherapy in primary nasopharyngeal carcinoma (NPC) patients, with the aim to determine how the radiation doses to nasopharynx influence the occurence of radiation-induced nasopharyngeal ulcer (RINU) and predict the most serious complication of radiotherapy for NPC. METHODS: Data from 6023 consecutive and nonselected histologically proven primary NPC patients treated with definitive IMRT were collected and 25 patients were diagnosed with nasopharyngeal ulcer and met the diagnosis criteria of RINU. Predictive dosimetric factors were identified by using univariate and multivariate analysis. RESULTS: Paired samples t-tests showed all dosimetric factors were significantly correlated with the development of RINU, and these factors were associated with each other closely. (P < 0.001) Multivariate analysis revealed D3cc (dose to 3 mL of the nasopharynx) was an independent predictor for RINU (P = 0.01); the area under the ROC curve for D3cc was 0.87 (P < 0.001), and the cutoff point 73.67 Gy may be the dose tolerance of the nasopharynx. The primary tumor location, distribution of high dose regions and the location of RINU were consistent. CONCLUSIONS: The study indicates that radiation-induced nasopharyngeal ulcer is consistent with primary tumor location and 'hottest spots' regions and we suggest a D3cc limit of 73.67 Gy for the nasopharynx. Physicians should be cautious of such 'hot spots' in the nasopharynxduring IMRT treatment plan optimization, review and approval to avoid the most serious complication of radiotherapy for NPC.

A REVIEW ON THE RADIATION THERAPY TECHNOLOGIST RECEIVED DOSE FROM INDUCED ACTIVATION IN HIGH-ENERGY MEDICAL LINEAR ACCELERATORS.

Despite all advantages for using high-energy photons for radiotherapy, high-energy photon beams (≥10 MV) induce photonuclear and neutron capture interactions, which result in producing radionuclide byproducts inside the Linac head and bunker, exposing radiation therapy technologists (RTTs) and patients to excessive dose. By the use of higher photon energy, greater number of monitor unit, greater field size and adding treatment accessories, induced dose rate become greater in the isocenter mainly due to activation of high-Z materials inside the Linac head. Activated radionuclides disintegrate with γ, ß+ and ß- rays with half-lives between 2 min up to more than 5 years. Several researches estimated additional exposure to an RTT depend on treatment strategies, beam energy, and delay time before entrance to the treatment room between 0.1 and 4.9 mSv/y and proposed at least 2 min delay before entrance to the treatment room after treatments with high-energy photon beams.

Corneal complications after orbital radiotherapy for primary epithelial malignancies of the lacrimal gland.

PURPOSE: To review the long-term corneal complications after high-dose external beam orbital radiotherapy given to patients for lacrimal gland carcinomas. The impact of prophylactic measures to improve long-term ocular surface health is also assessed. DESIGN: Retrospective case series. PARTICIPANTS: Patients under the care of Moorfields Eye Hospital and receiving external beam radiotherapy for primary epithelial lacrimal gland carcinoma between 1975 and 2014. METHODS: Retrospective review of ophthalmic case notes at Moorfields Eye Hospital, and oncology and general physician records. MAIN OUTCOME MEASURES: The occurrence of corneal perforation, and time to perforation. RESULTS: Sixty-seven patients were included in this study, of whom nine (13%) developed corneal perforation at a median time of 10.4 months after radiotherapy (mean 35; range 3.2 months to 14.5 years); the majority (7/9; 78%) perforated within 36 months of radiotherapy. The mean follow-up interval of the whole cohort was 8.2 years (median 4.6; range, 2 months to 30.7 years). CONCLUSIONS: Although most patients with globe-sparing treatment of lacrimal gland carcinoma did not suffer corneal perforation, they usually require long-term therapy to maintain the ocular surface. The high-dose external beam radiotherapy needed for lacrimal gland carcinoma can produce significant ocular surface morbidity, and the 13% incidence of corneal perforation was greatest in the first 3 years after irradiation.

Total Skin Electron Beam Therapy as Part of Multimodal Treatment Strategies for Primary Cutaneous T-Cell Lymphoma.

Total-skin electron beam therapy (TSEBT) is one of most effective treatments that has been used for cutaneous T-cell lymphoma. Low-dose TSEBT regimens (10-12 Gy) appear to be an effective alternative to conventional-dose TSEBT (30-36 Gy), yielding short-term remission of cutaneous manifestations with minimal toxicity. TSEBT can be administered to patients any time after a diagnosis of mycosis fungoides (MF). Patients requiring rapid relief from cutaneous lesions or symptoms may particularly benefit from TSEBT as an initial therapy. Radiotherapy (RT) dose, boost radiation delivery, maintenance treatment, and radiation tolerability may enhance remission rates and improve relapse-free survival following TSEBT. In addition, salvage local RT or TSEBT may be safely applied with high effectiveness. In this review, we focus on the use of TSEBT in patients with several forms of primary cutaneous T-cell lymphoma, and highlight the potential of low-dose TSEBT as part of a promising therapeutic approach.

Bone texture analysis using CT-simulation scans to individuate risk parameters for radiation-induced insufficiency fractures.

This study deals with the role of texture analysis as a predictive factor of radiation-induced insufficiency fractures in patients undergoing pelvic radiation. INTRODUCTION: This study aims to assess the texture analysis (TA) of computed tomography (CT) simulation scans as a predictive factor of insufficiency fractures (IFs) in patients with pelvic malignancies undergoing radiation therapy (RT). METHODS: We performed an analysis of patients undergoing pelvic RT from January 2010 to December 2014, 24 of whom had developed pelvic bone IFs. We analyzed CT-simulation images using ImageJ macro software and selected two regions of interest (ROIs), which are L5 body and the femoral head. TA parameters included mean (m), standard deviation (SD), skewness (sk), kurtosis (k), entropy (e), and uniformity (u). The IFs patients were compared (1:2 ratio) with controlled patients who had not developed IFs and matched for sex, age, menopausal status, type of tumor, use of chemotherapy, and RT dose. A reliability test of intra- and inter-reader ROI TA reproducibility with the intra-class correlation coefficient (ICC) was performed. Univariate and multivariate analyses (logistic regression) were applied for TA parameters observed both in the IFs and the controlled groups. RESULTS: Inter- and intra-reader ROI TA was highly reproducible (ICC > 0.90). Significant TA parameters on paired t test included L5 m (p = 0.001), SD (p = 0.002), k (p = 0.006), e (p = 0.004), and u (p = 0.015) and femoral head m (p < 0.001) and SD (p = 0.001), whereas on logistic regression analysis, L5 e (p = 0.003) and u (p = 0.010) and femoral head m (p = 0.027), SD (p = 0.015), and sex (p = 0.044). CONCLUSIONS: In our experience, bone CT TA could be correlated to the risk of radiation-induced IFs. Studies on a large patient series and methodological refinements are warranted.

[Local failures of nasopharynx carcinoma: Anatomoclinical aspects and therapeutic results]. / Aspects anatomocliniques et thérapeutiques des récidives locales des carcinomes du nasopharynx.

PURPOSE: Retrospective analysis of clinical aspects and therapeutic results of nasopharynx cancer local failures. PATIENTS AND METHODS: Forty patients with local failure with or without nodal involvement of nasopharyngeal carcinoma were treated between 1993 and 2013. Reirradiation of nasopharynx was delivered at the dose of 60Gy. Platinum-based chemotherapy was indicated in case of locally advanced disease and/or associated nodal failure. RESULTS: The mean age at diagnosis of primitive tumour was 41.9 years (26-67 years). The mean time of relapse occurrence was 31.7 months (6-104 months). Sixty five percent of failures were confined to the nasopharynx. Nodal failure was seen in 14 cases. Twenty-eight patients had chemotherapy. Twenty-five patients had reirradiation of nasopharynx. Mean follow-up was 98 months (12-191 months). Fourteen patients were still alive and in complete remission. Five-year survival was 40.7%. Xerostomia was the most frequent late toxicity. No haemorrhage was seen. CONCLUSION: Reirradiation is the mainstay treatment of nasopharyngeal local failure. Late toxicity seems to decrease with novel techniques of reirradiation.

Risks of second malignancies after breast cancer treatment: Long-term results.

PURPOSE: To estimate the long-term risk of second malignancies after breast cancer treatment in a large homogeneous cohort from a single institution. PATIENTS AND METHODS: All patients in this study were treated for non-metastatic breast cancer at the Curie institute, Paris, between 1981 and 2000. We calculated the cumulative incidence of second malignancies and the risk of developing each type of second malignancies over a period of 10 to 15 years. The observed crude incidence rates in the entire patient population were then compared to the expected incidence in the general population of French women, as provided by age-standardized data. A standardized incidence ratio (SIR) was calculated for all second malignancies. We also calculated second malignancies standardized incidence ratios for patients who underwent adjuvant therapy for breast cancer. RESULTS: The study cohort included a total of 17,745 women. The median follow-up since diagnosis was 13.4 years (range: 2-29 years). The 15-year cumulative incidence of second malignancies was 1.807 per 100,000 (CI 1.729-1.884). A total of 2370 second malignancies were observed during follow-up, 2010 in the radiotherapy arm and 360 in the no radiotherapy arm (relative risk [RR] 1.15 [1.03-1.28], P=0.0134). Crude incidence rates were significantly higher in our cohort than in the general population for contralateral breast cancer (SIR 2.96 [confidence interval (CI) 2.82-3.12], P<0.0001), sarcomas (SIR 8.48 [CI 6.41-11.22], P<0.0001), leukaemia (SIR 2.37 [CI 1.85-3.04], P<0.0001), lung cancer (SIR 1.39 [CI 1.13-1.72], P<0.0022) and gynaecological cancer (SIR 1.31 [CI 1.15-1.50], P=0.0001). Among patients treated for breast cancer, those who received radiotherapy was associated with an excess risk of sarcoma as compared to those have not had (RR 5.59 [CI 1.35-23.17], P<0.001). CONCLUSIONS: Women treated for breast cancer had a significantly increased risk of several kinds of second malignancies compared to the general population.

DOSE AND GAMMA-RAY SPECTRA FROM NEUTRON-INDUCED RADIOACTIVITY IN MEDICAL LINEAR ACCELERATORS FOLLOWING HIGH-ENERGY TOTAL BODY IRRADIATION.

Production of radioisotopes in medical linear accelerators (linacs) is of concern when the beam energy exceeds the threshold for the photonuclear interaction. Staff and patients may receive a radiation dose as a result of the induced radioactivity in the linac. Gamma-ray spectroscopy was used to identify the isotopes produced following the delivery of 18 MV photon beams from a Varian 21EX and an Elekta Synergy. The prominent radioisotopes produced include 187W, 63Zn, 56Mn, 24Na and 28Al in both linac models. The dose rate was measured at the beam exit window (12.6 µSv in the first 10 min) following 18 MV total body irradiation (TBI) beams. For a throughput of 24 TBI patients per year, staff members are estimated to receive an annual dose of up to 750 µSv at the patient location. This can be further reduced to 65 µSv by closing the jaws before re-entering the treatment bunker.

Effect of high energy X-ray irradiation on the nano-mechanical properties of human enamel and dentine.

Radiotherapy for malignancies in the head and neck can cause common complications that can result in tooth damage that are also known as radiation caries. The aim of this study was to examine damage to the surface topography and calculate changes in friction behavior and the nano-mechanical properties (elastic modulus, nanohardness and friction coefficient) of enamel and dentine from extracted human third molars caused by exposure to radiation. Enamel and dentine samples from 50 human third molars were randomly assigned to four test groups or a control group. The test groups were exposed to high energy X-rays at 2 Gy/day, 5 days/week for 5 days (10 Gy group), 15 days (30 Gy group), 25 days (50 Gy group), 35 days (70 Gy group); the control group was not exposed. The nanohardness, elastic modulus, and friction coefficient were analyzed using a Hysitron Triboindenter. The nano-mechanical properties of both enamel and dentine showed significant dose-response relationships. The nanohardness and elastic modulus were most variable between 30-50 Gy, while the friction coefficient was most variable between 0-10 Gy for dentine and 30-50 Gy for enamel. After exposure to X-rays, the fracture resistance of the teeth clearly decreased (rapidly increasing friction coefficient with increasing doses under the same load), and they were more fragile. These nano-mechanical changes in dental hard tissue may increase the susceptibility to caries. Radiotherapy caused nano-mechanical changes in dentine and enamel that were dose related. The key doses were 30-50 Gy and the key time points occurred during the 15th-25th days of treatment, which is when application of measures to prevent radiation caries should be considered.

Effect of high energy X-ray irradiation on the nano-mechanical properties of human enamel and dentine

Abstract Radiotherapy for malignancies in the head and neck can cause common complications that can result in tooth damage that are also known as radiation caries. The aim of this study was to examine damage to the surface topography and calculate changes in friction behavior and the nano-mechanical properties (elastic modulus, nanohardness and friction coefficient) of enamel and dentine from extracted human third molars caused by exposure to radiation. Enamel and dentine samples from 50 human third molars were randomly assigned to four test groups or a control group. The test groups were exposed to high energy X-rays at 2 Gy/day, 5 days/week for 5 days (10 Gy group), 15 days (30 Gy group), 25 days (50 Gy group), 35 days (70 Gy group); the control group was not exposed. The nanohardness, elastic modulus, and friction coefficient were analyzed using a Hysitron Triboindenter. The nano-mechanical properties of both enamel and dentine showed significant dose-response relationships. The nanohardness and elastic modulus were most variable between 30-50 Gy, while the friction coefficient was most variable between 0-10 Gy for dentine and 30-50 Gy for enamel. After exposure to X-rays, the fracture resistance of the teeth clearly decreased (rapidly increasing friction coefficient with increasing doses under the same load), and they were more fragile. These nano-mechanical changes in dental hard tissue may increase the susceptibility to caries. Radiotherapy caused nano-mechanical changes in dentine and enamel that were dose related. The key doses were 30-50 Gy and the key time points occurred during the 15th-25th days of treatment, which is when application of measures to prevent radiation caries should be considered.

Low-dose radiation affects cardiac physiology: gene networks and molecular signaling in cardiomyocytes.

There are 160,000 cancer patients worldwide treated with particle radiotherapy (RT). With the advent of proton, and high (H) charge (Z) and energy (E) HZE ionizing particle RT, the cardiovascular diseases risk estimates are uncertain. In addition, future deep space exploratory-type missions will expose humans to unknown but low doses of particle irradiation (IR). We examined molecular responses using transcriptome profiling in left ventricular murine cardiomyocytes isolated from mice that were exposed to 90 cGy, 1 GeV proton ((1)H) and 15 cGy, 1 GeV/nucleon iron ((56)Fe) over 28 days after exposure. Unsupervised clustering analysis of gene expression segregated samples according to the IR response and time after exposure, with (56)Fe-IR showing the greatest level of gene modulation. (1)H-IR showed little differential transcript modulation. Network analysis categorized the major differentially expressed genes into cell cycle, oxidative responses, and transcriptional regulation functional groups. Transcriptional networks identified key nodes regulating expression. Validation of the signal transduction network by protein analysis and gel shift assay showed that particle IR clearly regulates a long-lived signaling mechanism for ERK1/2, p38 MAPK signaling and identified NFATc4, GATA4, STAT3, and NF-κB as regulators of the response at specific time points. These data suggest that the molecular responses and gene expression to (56)Fe-IR in cardiomyocytes are unique and long-lasting. Our study may have significant implications for the efforts of National Aeronautics and Space Administration to develop heart disease risk estimates for astronauts and for patients receiving conventional and particle RT via identification of specific HZE-IR molecular markers.