Moderate Doses Of Radiation Research Articles

Intensity-modulated radiotherapy reduces gastrointestinal toxicity in pelvic radiation therapy with moderate dose.

This retrospective study was performed to evaluate and compare gastrointestinal (GI) toxicities caused by conventional radiotherapy (cRT) and intensity modulated radiotherapy (IMRT) in 136 cancer patients treated with pelvic radiotherapy (RT) with moderate radiation dose in a single institution. A matched-pair analysis of the two groups was performed; each group included 68 patients. Conventional RT was delivered using the four-field box technique and IMRT was delivered with helical tomotherapy. The median daily dose was 1.8 Gy and the median total dose was 50.4 Gy (range 25.2–56 Gy). Primary end point was GI toxicity during and after RT. Secondary end point was factors that affect toxicity. Patients treated with IMRT had lower incidence of grade ≥ 2 acute GI toxicity compared to the patients treated with cRT (p = 0.003). The difference remained significant in multivariate analysis (p = 0.01). The incidence of chronic GI toxicity was not statistically different between the two groups, but the cRT group had higher incidence of grade 3 chronic GI toxicity. Based on our results, IMRT can reduce GI toxicity compared to cRT in the treatment of pelvic radiotherapy even with moderate radiation dose and this will enhance patients’ quality of life and treatment compliance.

Influence of longitudinal radiation exposure from microcomputed tomography scanning on skeletal muscle function and metabolic activity in female CD-1 mice.

Microcomputed tomography (μ CT) is an imaging technology to assess bone microarchitecture, a determinant of bone strength. When measured in vivo, μ CT exposes the skeletal site of interest to a dose of radiation, in addition to nearby skeletal muscles as well. Therefore, the aim of this study was to determine the effects of repeated radiation exposure from in vivo μ CT on muscle health – specifically, muscle morphometrics, contractile function, and enzyme activity. This study exposed the right hind limb of female mice to either a low (26 cGy) or moderate (46 cGy) dose, at 2, 4, and 6 months of age, while the left hind limb of the same animal was exposed to a single dose at 6 months to serve as a nonirradiated control. Muscle weight, cross‐sectional area, isometric contractile function, and representative maximal enzyme activities of amino acid, fatty acid, glucose, and oxidative metabolism in extensor digitorum longus (EDL) and soleus were assessed. Low‐dose radiation had no effect. In contrast, moderate‐dose radiation resulted in a 5% increase in time‐to‐peak tension and 16% increase in half‐relaxation time of isometric twitches in EDL, although these changes were not seen when normalized to force. Moderate‐dose radiation also resulted in an ~33% decrease in citrate synthase activity in soleus but not EDL, with no changes to the other enzymes measured. Thus, three low doses of radiation over 6 months had no effect on contractile function or metabolic enzyme activity in soleus and EDL of female mice. In contrast, three moderate doses of radiation over 6 months induced some effects on metabolic enzyme activity in soleus but not EDL. Future studies that wish to investigate muscle tissue that is adjacent to scanned bone should take radiation exposure dose into consideration.

Incidence and Predictors of Pericardial Effusion After Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

Findings from Radiation Therapy Oncology Group (RTOG) 0617 suggested that collateral radiation to the heart may contribute to early death in patients receiving chemoradiation therapy for non-small cell lung cancer (NSCLC); however, reports of cardiac toxicity after thoracic radiation therapy (RT) remain limited. Because pericardial disease is the most common cardiac complication of thoracic RT, we investigated the incidence of and risk factors for pericardial effusion (PCE) in patients enrolled in a phase 2 prospective randomized study of intensity modulated RT versus proton therapy for locally advanced NSCLC. From July 2009 through April 2014, 201 patients were prospectively treated with proton beam therapy or intensity modulated RT to 60 to 74Gy with concurrent chemotherapy. The primary endpoint (grade ≥2 PCE) was diagnosed on review of follow-up images. Clinical characteristics and cardiac dose-volume parameters associated with PCE were identified via Cox proportional hazards modeling and recursive partitioning analysis of null Martingale residuals. Reproducibility was evaluated in a separate retrospective cohort of 301 patients. The cumulative incidence rates of PCE among patients in the trial were 31.4% at 1year and 45.4% at 2years, with a median time to PCE of 8.9months. Several cardiac dose-volume parameters (eg, V20 [volume receiving ≥20Gy] to V65 [volume receiving ≥65Gy]) predicted PCE, but heart volume receiving ≥35Gy (HV35) was the most strongly associated, with a cutoff volume of 10%.On multivariate analysis, HV35>10% independently predicted PCE (hazard ratio [HR], 2.14; P=.002), a finding that maintained reproducibility in the retrospective validation cohort. Other factors associated with PCE included receipt of adjuvant chemotherapy (HR, 2.82; P<.001) and prior cardiac disease (HR, 1.68; P=.020). PCE was common after RT for NSCLC, occurring in nearly half of patients even after moderate radiation doses to the heart. Adjuvant chemotherapy may increase the risk of PCE, and HV35>10% may identify patients at risk of development of this cardiac toxicity.

Basics of Radiation Biology When Treating Hyperproliferative Benign Diseases.

For decades, low- and moderate-dose radiation therapy (RT) has been shown to exert a beneficial therapeutic effect in a multitude of non-malignant conditions including painful degenerative muscoloskeletal and hyperproliferative disorders. Dupuytren and Ledderhose diseases are benign fibroproliferative diseases of the hand/foot with fibrotic nodules and fascial cords, which determine debilitating contractures and deformities of fingers/toes, while keloids are exuberant scar formations following burn damage, surgery, and trauma. Although RT has become an established and effective option in the management of these diseases, experimental studies to illustrate cellular composites and factors involved remain to be elucidated. More recent findings, however, indicate the involvement of radiation-sensitive targets like mitotic fibroblasts/myofibroblasts as well as inflammatory cells. Radiation-related molecular mechanisms affecting these target cells include the production of free radicals to hamper proliferative activity and interference with growth factors and cytokines. Moreover, an impairment of activated immune cells involved in both myofibroblast proliferative and inflammatory processes may further contribute to the clinical effects. We here aim at briefly describing mechanisms contributing to a modulation of proliferative and inflammatory processes and to summarize current concepts of treating hyperproliferative diseases by low and moderate doses of ionizing radiation.

28Si total body irradiation injures bone marrow hematopoietic stem cells via induction of cellular apoptosis

Long-term space mission exposes astronauts to a radiation environment with potential health hazards. High-energy charged particles (HZE), including 28Si nuclei in space, have deleterious effects on cells due to their characteristics with high linear energy transfer and dense ionization. The influence of 28Si ions contributes more than 10% to the radiation dose equivalent in the space environment. Understanding the biological effects of 28Si irradiation is important to assess the potential health hazards of long-term space missions. The hematopoietic system is highly sensitive to radiation injury and bone marrow (BM) suppression is the primary life‐threatening injuries after exposure to a moderate dose of radiation. Therefore, in the present study we investigated the acute effects of low doses of 28Si irradiation on the hematopoietic system in a mouse model. Specifically, 6-month-old C57BL/6J mice were exposed to 0.3, 0.6 and 0.9Gy 28Si (600MeV) total body irradiation (TBI). The effects of 28Si TBI on BM hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were examined four weeks after the exposure. The results showed that exposure to 28Si TBI dramatically reduced the frequencies and numbers of HSCs in irradiated mice, compared to non-irradiated controls, in a radiation dose-dependent manner. In contrast, no significant changes were observed in BM HPCs regardless of radiation doses. Furthermore, irradiated HSCs exhibited a significant impairment in clonogenic ability. These acute effects of 28Si irradiation on HSCs may be attributable to radiation-induced apoptosis of HSCs, because HSCs, but not HPCs, from irradiated mice exhibited a significant increase in apoptosis in a radiation dose-dependent manner. However, exposure to low doses of 28Si did not result in an increased production of reactive oxygen species and DNA damage in HSCs and HPCs. These findings indicate that exposure to 28Si irradiation leads to acute HSC damage.

In-Utero Low-Dose Irradiation Leads to Persistent Alterations in the Mouse Heart Proteome.

Prenatal exposure to stress such as increased level of reactive oxygen species or antiviral therapy are known factors leading to adult heart defects. The risks following a radiation exposure during fetal period are unknown, as are the mechanisms of any potential cardiac damage. The aim of this study was to gather evidence for possible damage by investigating long-term changes in the mouse heart proteome after prenatal exposure to low and moderate radiation doses. Pregnant C57Bl/6J mice received on embryonic day 11 (E11) a single total body dose of ionizing radiation that ranged from 0.02 Gy to 1.0 Gy. The offspring were sacrificed at the age of 6 months or 2 years. Quantitative proteomic analysis of heart tissue was performed using Isotope Coded Protein Label technology and tandem mass spectrometry. The proteomics data were analyzed by bioinformatics and key changes were validated by immunoblotting. Persistent changes were observed in the expression of proteins representing mitochondrial respiratory complexes, redox and heat shock response, and the cytoskeleton, even at the low dose of 0.1 Gy. The level of total and active form of the kinase MAP4K4 that is essential for the embryonic development of mouse heart was persistently decreased at the radiation dose of 1.0 Gy. This study provides the first insight into the molecular mechanisms of cardiac impairment induced by ionizing radiation exposure during the prenatal period.

CROSS and beyond: a clinical perspective on the results of the randomized ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study.

Despite extensive research efforts oesophageal cancer remains a malignancy with a poor prognosis. Improvement of treatment is urgently needed. Although multimodality treatment for resectable oesophageal cancer has established it place in standard practice, there are still many differences worldwide in the preferred treatment. The Dutch ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial has contributed significantly to the current use of neoadjuvant chemoradiation. This study compared neoadjuvant chemoradiotherapy (CRT) using a moderate radiation dose weekly combined with carboplatin and paclitaxel followed by surgery versus surgery alone. Median overall survival in the CRT group is 49.4 months compared to 24.0 months in the surgery alone group, resulting in an overall survival benefit of 13% in favor of the CRT group (HR, 0.81; 95% CI: 0.70-0.93; P=0.002). Recently the results after long-term follow-up (median 60 months) have been published and confirm the benefit of neoadjuvant CRT to surgery alone. Perioperative mortality rates are low and did not increase by adding CRT (4%) and the CROSS scheme has a favorable toxicity profile. Recurrence patterns in patients treated according to the CROSS protocol report significantly reduced loco regional recurrence in the CRT group (34% to 14%; P<0.001) and less peritoneal carcinomatosis (14% to 4%; P<0.001). With the contemporary focus of research on tumor tailored therapy, the effective and safe CROSS protocol serves as a backbone in many ongoing trials.

Abstract P3-12-13: Radiation enhancement with cysteine coated platinum nanoparticles

Abstract Background: Radiation is the current choice treatment for non-operable metastatic breast-brain cancer. When cancer lesions are located in sensitive areas like the brain or have excessive amounts of metastatic sites, radiation usually proves to be a more viable option than excision. Ionizing (X-ray and gamma) radiation is non-selective and affects all the tissue it penetrates. In order to concentrate the dose on tumors, high energy radiation from multiple directions is typically used, reaching the highest dose where the radiation crosses. This type of multiple angle treatment minimizes the dose to normal tissue by increasing overall normal tissue irradiation. The objective is to achieve sufficient radiation in the tumor tissue to cause the DNA strands to break and to disrupt the reproduction and maintenance of cancer cells while keeping the damage to normal tissue in a reasonable range for tissue preservation. Metal nanoparticles have shown promising results for reinforcing the radiation dose effect. High atomic number (Z) elements absorb a greater amount of radiation because the higher density raises the probability of interaction. The metal nanoparticles interact with the energy of the ionizing radiation by either scattering or absorbing, or accumulating the energy, thus increasing the number of DNA strand breaks in the nucleus of cells. Methods: Four breast cancer cell lines (BT-474, MDA-231, BT-549 and MCF-7) were incubated with 1-2 nm platinum nanoparticles (0-1000 μg/mL) produced with a cysteine coating. 24 hours later cells were exposed to 2 Gy radiation with a C-arm (Toshiba Infinix VF-i/SP) using 125 KVP to deliver a spectrum of KeV low energy X-rays. After 24 hours the cells were washed and analyzed using a bioluminescence assay to assess cell proliferation based on ATP production. Results: Of the four cell lines tested the BT-474 and BT-549 demonstrated limited reduction in cell proliferation at up to the highest treatment concentration 1000 μg/mL with no radiation exposure. As a result of the limited toxicity of the platinum nanoparticles the effect from increased radiation can be more readily observe when 2 Gy radiation is added resulting a in platinum nanoparticle dose dependent decrease in proliferation in the BT-474 cell line. Nanoparticle Toxicity Concentration of Platinum Nanoparticles (μ/mL) 02505007501000MDA-2311.000±0.0050.995±0.0120.974±0.0130.979±0.0140.777±0.014BT-5491.000±0.0131.003±0.0091.003±0.0170.969±0.0170.894±0.009MCF-71.000±0.0140.960±0.0150.927±0.0220.851±0.0220.769±0.032BT-4741.000±0.0240.961±0.0290.957±0.0330.965±0.0630.985±0.065Table 1: Indexed values for cell proliferation for the BT-474 cell Radiation Toxicity Concentration of Platinum Nanoparticles (μ/mL) 02505007501000*0 Gy1.000±0.0240.961±0.0290.957±0.0330.965±0.0630.985±0.0652 Gy1.027±0.0380.966±0.0230.908±0.0340.870±0.0310.799±0.037Table 2: Indexed values for cell proliferation for the BT-474 cell line 0 and 2 Gy radiation doses, 6 averages. * Student T-TEST P&amp;lt;0.05 Conclusions: At moderate doses of low energy radiation, a reduction in cell proliferation can be detected. This data supports follow-up experiments to add a targeting protein to facilitate uptake by cancer cells based on cell receptor expression. Experiments are current being done to utilize the HER2+ cell receptor upregulation to increase internalization of the particles to achieve a greater effect. Citation Format: Wagner S, Yue Y, Cui X, Zhang G, Bingchen H, Li D, Medina-Kauwe L. Radiation enhancement with cysteine coated platinum nanoparticles. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-13.

Dose optimization: a major challenge for acceptability of nuclear medicine

In real life, the perception of a risk depends not only on its reality and severity, but also on subjective external factors. The fear of potential health risks of ionizing radiation is very present in collective unconscious of our society, most probably because of their military use, which preceded their civil and medical use. This, as well as the principle of the risk/benefit balance optimization inherent to any good medical practice, makes this topic of major importance for the diffusion of nuclear medicine. The therapeutic field uses high doses were the risk is always present, but with a large expected benefit. In contrast, imaging field is in the range of very low doses where the risk is still unknown. But for both applications, major improvements have been and still can be done, and this supposes for each nuclear physician or physicist to be aware and well trained in the field. Potential health risks of ionizing radiation were identified soon after the discovery of x-rays in 1895. In the field of Nuclear Medicine, functional and molecular imaging as well as therapy demonstrated their benefits in terms of medical usefulness. Medical diagnostic exposure is nowadays the first cause of radiation exposure, raising some concerns regarding potential side effects, which are to be weighed against the specific risk of the disease(s) that are taken in charge, mainly in elderly patients. However, optimization continuously aims to decrease these side effects for the same or extended benefit [1]. Injuries to highly exposed tissues, such as encountered in therapeutic applications of Nuclear Medicine, are classified as deterministic effects because they will always occur once a particular threshold dose has been exceeded. Tissue reactions are caused by cell death and increase in severity as radiation dose increases. Deterministic effects can impair the tissue integrity, and compromise the function of non-target organs. A threshold dose is needed for damage to become clinically observable, and the extent of damage depends upon the absorbed dose, dose rate, and radiation quality. Thus, the severity of the effect increases with increasing absorbed dose. Apart from the case of accidental irradiation with early clinical reaction, these deterministic effects are usually delayed, occurring years or sometimes decades later and include tissue reactions such as cataracts, cardiovascular disorders, and necrosis. The risk of stochastic effects increases with dose, in theory with no threshold. In addition to hereditary effects, which originate in germline mutations, cancer is classified as a stochastic effect since it originates in somatic mutations. Even if the reality of this risk is still uncertain in the domain of very low doses such as used in the field of imaging, this has led to the adoption of international rules in the field. Cancer risk increases after exposure to moderate and high doses of radiation (more than 0.1–0.2 Gy); however, whether cancer risk is increased below this level is unclear and is the object of extensive research. Currently, one in three women and one in two men will develop cancer in his or her lifetime. Since this is so much higher than any estimated effect of medical radiation, and since medical exposure is in the same range than natural exposure, the potential increase in cancer due to radiation is extremely difficult to detect. In addition, no prospective Dominique Le Guludec and Jocelyne Aigueperse contributed equally to the literature search and manuscript writing.

Mouse models of radiation-induced glioblastoma.

Glioblastomas (GBM) are lethal brain tumors that can be triggered by exposure to ionizing radiation (IR), even at low doses from CT scans [1]. High doses of IR are also used to treat GBM, but the irradiated tumors inevitably recur. This raises the possibility that genomic changes induced by radiation may contribute not only to glioma initiation, but also to tumor recurrence. Thus, there is a compelling need for experimental model systems that recapitulate the process of radiation-induced gliomagenesis. Such models could not only help predict GBM-development risks from radiation exposure, but also help identify genetic alterations defining radiation-induced GBM, thereby facilitating the development of rational therapies for treating these recalcitrant tumors. Our study published in the journal Oncogene employed a systematic approach to develop sensitive mouse models that can be used to study radiation-induced gliomagenesis [2]. Ink4a, Ink4b and Arf are key tumor suppressor genes that are deleted in a majority of GBMs [3]. We utilized transgenic mice with brain-restricted deletions of these tumor suppressors, individually and in combination, and examined their susceptibility to IR-induced GBM development. The most deleterious lesion inflicted by IR is the DNA double-strand break (DSB). We have shown previously that accelerated ions (particle radiation) induce complex DSBs that are refractory to repair unlike the simple breaks induced by X-rays (electromagnetic radiation) which are repaired to completion [4]. Therefore, we intra-cranially irradiated these transgenic mice with either X-rays or accelerated Fe ions to understand the process of radiation-induced gliomagenesis, and how this may be influenced by DNA damage complexity. We found that these mice did not develop gliomas spontaneously, but were prone to GBM development after exposure to a single, moderate dose of radiation. Remarkably, we found that Fe ions were at least four-fold more effective than X-rays in inducing these tumors, thereby confirming that complex DSBs triggered by accelerated ions are more harmful than simpler breaks induced by X-rays. This finding has important implications as the use of particle radiation (such as protons and carbon ions) for cancer therapy is steadily increasing. Our work indicates that particle radiation could indeed turn out to be more effective than X-rays for tumor control, but this also raises the specter of increased likelihood of secondary cancers triggered by such radiation. Interestingly, while wild type mice did not develop gliomas upon radiation exposure, loss of Ink4a and Arf was sufficient to render these mice susceptible to IR-induced gliomas; additional loss of Ink4b significantly increased tumor incidence. These observations indicate that Ink4a, Ink4b and Arf act as key barriers to radiation-induced gliomagenesis, and confirms previous results from our laboratory and others implicating Ink4b as an important “backup” tumor suppressor for Ink4a [5]. One of the most interesting findings of our study came from multimodal analyses of the IR-induced tumors and neurosphere cultures derived thereof. We found amplification of the receptor tyrosine kinase Met to be the most prominent oncogenic alteration in these tumors. Met amplification was critical for transformation as well as for the maintenance of a cancer stem cell phenotype via upregulation of the re-programming transcription factor Sox2. Recent studies of other cancers show that MET amplification enables cancer cells to evolve and survive under therapeutic pressure, and that MET amplification confers radioresistance to cancer cells [6]. In light of these studies and our results, we speculate that radiotherapy of GBM could engender clones of MET-amplified cancer cells that drive tumor recurrence. If so, recurrent glioblastomas may be particularly vulnerable to radiosensitization strategies involving the use of MET inhibitors. We are currently validating additional transgenic models with brain-targeted deletions of other GBM-relevant tumor suppressor genes like p53 and Pten. The use of distinct yet complementary mouse models could prove to be very useful for analyzing the mechanistic underpinnings of radiation-induced gliomagenesis. For example, by crossing these mice with DNA repair-deficient mouse models, we hope to understand how specific DSB repair pathways act as barriers to gliomagenesis. In the future, this study could also have “far”-reaching implications for astronauts 100 million miles away on the surface of Mars. These models (along with models of other cancers) are being used in NASA-funded studies to understand cancer risks for Mars-bound astronauts from space radiation which consists of accelerated ions such as the Fe ions used in this study [7]. In sum, validation of these sensitive yet simple mouse models sets the stage for in-depth mechanistic studies of radiation-induced gliomagenesis which could lead to effective approaches for treating radiogenic cancers.

Autologous bone marrow stromal cell transplantation as a treatment for acute radiation enteritis induced by a moderate dose of radiation in dogs

Radiation enteritis is one of the most common complications of cancer radiotherapy, and the development of new and effective measures for its prevention and treatment is of great importance. Adult bone marrow stromal stem cells (ABMSCs) are capable of self-renewal and exhibit low immunogenicity. In this study, we investigated ABMSC transplantation as a treatment for acute radiation enteritis. We developed a dog model of acute radiation enteritis using abdominal intensity-modulated radiation therapy in a single X-ray dose of 14 Gy. ABMSCs were cultured in vitro, identified via immunofluorescence and flow cytometry, and double labeled with CM-Dil and superparamagnetic iron oxide (SPIO) before transplantation, which took place 48 hours after abdominal irradiation in a single fraction. The dog model of acute radiation enteritis was transplanted with cultured ABMSCs labeled with CM-Dil and SPIO into the mesenteric artery through the femoral artery. Compared with untreated control groups, dogs treated with ABMSCs exhibited substantially longer survival time and improved relief of clinical symptoms. ABMSC transplantation induced the regeneration of the intestinal epithelium and the recovery of intestinal function. Furthermore, ABMSC transplantation resulted in elevated serum levels of the anti-inflammatory cytokine interleukin-11 (IL10) and intestinal radioprotective factors, such as keratinocyte growth factor, basic fibroblast growth factor-2, and platelet-derived growth factor-B while reducing the serum level of the inflammatory cytokine IL17. ABMSCs induced the regeneration of the intestinal epithelium and regulated the secretion of serum cytokines and the expression of radioprotective proteins and thus could be beneficial in the development of novel and effective mitigators of and protectors against acute radiation enteritis.

Long-Term Effects of Exposure to Ionizing Irradiation on Periodontal Health Status - The Tinea capitis Cohort Study.

Studies among long-term survivors of childhood cancer who had received high-dose irradiation therapy of 4–60 Gy, demonstrated acute and chronic dental effects, including periodontal diseases. However, the possible effects of low to moderate doses of radiation on dental health are sparse. The aim of this study is to investigate the association between childhood exposure to low–moderate doses of ionizing radiation and periodontal health following 50 years since exposure. The study population included 253 irradiated subjects (treated for Tinea capitis in the 1950s) and, 162 non-irradiated subjects. The estimated dose to the teeth was 0.2–0.4 Gy. Dental examination was performed according to the community periodontal index (CPI). Socioeconomic and health behavior variables were obtained through a personal questionnaire. Periodontal disease was operationally defined as “deep periodontal pockets.” A multivariate logistic regression model was used for the association of irradiation status and other independent variables with periodontal status. The results showed that among the irradiated subjects, 23%, (95% CI 18–28%) demonstrated complete edentulousness or insufficient teeth for CPI scoring as compared to 13% (95% CI 8–19%) among the non-irradiated subjects (p = 0.01). Periodontal disease was detected among 54% of the irradiated subjects as compared to 40% of the non-irradiated (p = 0.008). Controlling for education and smoking, the ORs for the association between radiation and periodontal disease were 1.61 (95% CI 1.01–2.57) and 1.95 (95% CI 1.1–3.5) for ever never and per 1 Gy absorbed in the salivary gland, respectively. In line with other studies, a protective effect for periodontal diseases among those with high education and an increased risk for ever smokers were observed. In conclusion, childhood exposure to low-moderate doses of ionizing radiation might be associated with later outcomes of dental health. The results add valuable data on the long-term health effects of exposure to ionizing radiation and support the implementation of the ALARA principle in childhood exposure to diagnostic procedure involving radiation.

Defining the role of proton therapy in the optimal management of paediatric patients in Australia and New Zealand.

Optimal management of paediatric patients with tumours may include radiation therapy. Proton therapy, in theory, should achieve superior outcomes. For children referred overseas, multiple factors are taken into consideration. The purpose of this article is to provide context to current decision making. The MEDLINE, EMBASE and PubMed databases were searched for relevant literature. The delivery of proton therapy is in evolution. Tissue homogeneity, movement and anatomical changes all present a greater challenge for proton therapy compared with photon therapy. Many dosimetry studies are relying on historical data for cost-benefit analyses that do not accurately reflect contemporary photon therapy. The low dose regions generally do not create significant toxicity, whereas moderate dose regions can be reduced by different techniques such as stereotactic radiotherapy and brachytherapy. Neuro-cognitive and neuro-endocrine toxicities are associated with the greatest health cost, so the greatest gain is for tumours within or abutting the central nervous system. Proton therapy does not eliminate the risk of second malignancy. The benefits of proton therapy must be weighed against not just the estimated impact of low and moderate radiation doses on the developing child but the disruptions to the child, and family life. Relative contraindications to proton therapy include when the relevant late toxicities relate to the high radiation dose region, when the tumour volumes encompass whole body sections and when the target is imprecise. Children with base of skull tumours or an inherited risk of cancer (e.g. those with p53 or Rb1 genes) should be considered for proton therapy.

Mesenchymal stromal cells enhance the engraftment of hematopoietic stem cells in an autologous mouse transplantation model.

IntroductionStudies have proposed that mesenchymal stem cells (MSCs) improve the hematopoietic engraftment in allogeneic or xenogeneic transplants and this is probably due to the MSCs’ immunosuppressive properties. Our study aimed to discern, for the first time, whether MSC infusion could facilitate the engraftment of hematopoietic stem cells (HSCs) in autologous transplantations models, where no immune rejection of donor HSCs is expected.MethodsRecipient mice (CD45.2) mice, conditioned with moderate doses of radiation (5-7 Gy), were transplanted with low numbers of HSCs (CD45.1/CD45.2) either as a sole population or co-infused with increasing numbers of adipose-derived-MSCs (Ad-MSCs). The influence of Ad-MSC infusion on the short-term and long-term engraftment of donor HSCs was investigated. Additionally, homing assays and studies related with the administration route and with the Ad-MSC/HSC interaction were conducted.ResultsOur data show that the co-infusion of Ad-MSCs with low numbers of purified HSCs significantly improves the short-term and long-term hematopoietic reconstitution of recipients conditioned with moderate irradiation doses. This effect was Ad-MSC dose-dependent and associated with an increased homing of transplanted HSCs in recipients’ bone marrow. In vivo and in vitro experiments also indicate that the Ad-MSC effects observed in this autologous transplant model are not due to paracrine effects but rather are related to Ad-MSC and HSC interactions, allowing us to propose that Ad-MSCs may act as HSC carriers, facilitating the migration and homing of the HSCs to recipient bone marrow niches.ConclusionOur results demonstrate that Ad-MSCs facilitate the engraftment of purified HSCs in an autologous mouse transplantation model, opening new perspectives in the application of Ad-MSCs in autologous transplants, including HSC gene therapy.

Risk of a Second Kidney Carcinoma Following Childhood Cancer: Role of Chemotherapy and Radiation Dose to Kidneys

Kidney carcinoma is a rare second malignancy following childhood cancer. We sought to quantify risk and assess risk factors for kidney carcinoma following treatment for childhood cancer. We evaluated a cohort of 4,350 patients who were 5-year cancer survivors and had been treated for cancer as children in France and the United Kingdom. Patients were treated between 1943 and 1985, and were followed for an average of 27 years. Radiation dose to the kidneys during treatment was estimated with dedicated software, regardless of the site of childhood cancer. Kidney carcinoma developed in 13 patients. The cumulative incidence of kidney carcinoma was 0.62% (95% CI 0.27%-1.45%) at 40 years after diagnosis, which was 13.3-fold higher (95% CI 7.1-22.3) than in the general population. The absolute excess risk strongly increased with longer duration of followup (p<0.0001). Compared to the general population, the incidence of kidney carcinoma was 5.7-fold higher (95% CI 1.4-14.7) if radiotherapy was not performed or less than 1 Gy had been absorbed by the kidney but 66.3-fold higher (95%CI23.8-142.5) if the radiation dose to the kidneys was 10 to 19 Gy and 14.5-fold higher (95% CI 0.8-63.9) for larger radiation doses to the kidney. Treatment with chemotherapy increased the risk of kidney carcinoma (RR 5.1, 95% CI1.1-22.7) but we were unable to identify a specific drug or drug category responsible for this effect. Moderate radiation dose to the kidneys during childhood cancer treatment increases the risk of a second kidney carcinoma. This incidence will befurther increased when childhood cancer survivors reach old age.

Global quantification of γH2AX as a triage tool for the rapid estimation of received dose in the event of accidental radiation exposure

The phosphorylation of the H2AX histone to form γH2AX foci has been shown to be an accurate biomarker of ionizing radiation exposure. It is well established that there is a one-to-one correlation between the number of γH2AX foci and radiation-induced double strand breaks in cellular DNA, which can be translated to the received dose. However, manual counting of foci is time-consuming, and cannot accommodate high throughput analysis required to obtain rapid results for medical triage purposes in the case of large-scale accidental exposure. Furthermore, the accuracy of γH2AX measurements could potentially be compromised by delays between the time of exposure and analysis of results, as well as inter-cellular and inter-individual variability of this biological response. To evaluate more rapid approaches of quantifying γH2AX for use in an emergency situation, and to determine the impact of inter-individual variability, we compared two methods of global γH2AX fluorescence quantification (low magnification immunofluorescence microscopy and flow cytometry) to the well-established γH2AX foci scoring method in human primary fibroblasts. All three approaches were well correlated, indicating that global γH2AX fluorescence measurements are suitable for dose estimation. For rapid triage in an emergency situation, we propose the use of flow cytometry, as it is more highly correlated with foci scoring and because of the speed and ease of the method. Dose response curves (0.25–6Gy) using flow cytometry measurements showed that inter-individual variability in global γH2AX fluorescence is statistically insignificant at 4h post-irradiation. Based on these data, we propose calibration curves that can be applied to populations exposed to moderate radiation doses to estimate individual received doses, independent of individual radiosensitivity, at this specific time point post-irradiation using human fibroblasts and lymphocytes. Furthermore, we define three triage categories that could facilitate immediate and follow-up care in the case of a radiological accident.

Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques

Purpose: The threat of radiation exposure requires a mechanistic understanding of radiation-induced immune injury and recovery. The study objective was to evaluate responses to ionizing radiation in ovariectomized (surgically post-menopausal) female cynomolgus macaques.Materials and methods: Animals received a single total-body irradiation (TBI) exposure at doses of 0, 2 or 5 Gy with scheduled necropsies at 5 days, 8 weeks and 24 weeks post-exposure. Blood and lymphoid tissues were evaluated for morphologic, cellular, and molecular responses.Results: Irradiated animals developed symptoms of acute hematopoietic syndrome, and reductions in thymus weight, thymopoiesis, and bone marrow cellularity. Acute, transient increases in plasma monocyte chemoattractant protein 1 (MCP‐1) were observed in 5 Gy animals along with dose-dependent alterations in messenger ribonucleic acid (mRNA) signatures in thymus, spleen, and lymph node. Expression of T cell markers was lower in thymus and spleen, while expression of macrophage marker CD68 (cluster of differentiation 68) was relatively elevated in lymphoid tissues from irradiated animals.Conclusions: Ovariectomized female macaques exposed to moderate doses of radiation experienced increased morbidity, including acute, dose-dependent alterations in systemic and tissue-specific biomarkers, and increased macrophage/T cell ratios. The effects on mortality exceeded expectations based on previous studies in males, warranting further investigation.

Volumetric modulated arc therapy vs. c-IMRT for the treatment of upper thoracic esophageal cancer.

ObjectiveTo compare plans using volumetric-modulated arc therapy (VMAT) with conventional sliding window intensity-modulated radiation therapy (c-IMRT) to treat upper thoracic esophageal cancer (EC).MethodsCT datasets of 11 patients with upper thoracic EC were identified. Four plans were generated for each patient: c-IMRT with 5 fields (5F) and VMAT with a single arc (1A), two arcs (2A), or three arcs (3A). The prescribed doses were 64 Gy/32 F for the primary tumor (PTV64). The dose-volume histogram data, the number of monitoring units (MUs) and the treatment time (TT) for the different plans were compared.ResultsAll of the plans generated similar dose distributions for PTVs and organs at risk (OARs), except that the 2A- and 3A-VMAT plans yielded a significantly higher conformity index (CI) than the c-IMRT plan. The CI of the PTV64 was improved by increasing the number of arcs in the VMAT plans. The maximum spinal cord dose and the planning risk volume of the spinal cord dose for the two techniques were similar. The 2A- and 3A-VMAT plans yielded lower mean lung doses and heart V50 values than the c-IMRT. The V20 and V30 for the lungs in all of the VMAT plans were lower than those in the c-IMRT plan, at the expense of increasing V5, V10 and V13. The VMAT plan resulted in significant reductions in MUs and TT.ConclusionThe 2A-VMAT plan appeared to spare the lungs from moderate-dose irradiation most effectively of all plans, at the expense of increasing the low-dose irradiation volume, and also significantly reduced the number of required MUs and the TT. The CI of the PTVs and the OARs was improved by increasing the arc-number from 1 to 2; however, no significant improvement was observed using the 3A-VMAT, except for an increase in the TT.

The cognitive defects of neonatally irradiated mice are accompanied by changed synaptic plasticity, adult neurogenesis and neuroinflammation.

Background/purpose of the studyEpidemiological evidence suggests that low doses of ionising radiation (≤1.0 Gy) produce persistent alterations in cognition if the exposure occurs at a young age. The mechanisms underlying such alterations are unknown. We investigated the long-term effects of low doses of total body gamma radiation on neonatally exposed NMRI mice on the molecular and cellular level to elucidate neurodegeneration.ResultsSignificant alterations in spontaneous behaviour were observed at 2 and 4 months following a single 0.5 or 1.0 Gy exposure. Alterations in the brain proteome, transcriptome, and several miRNAs were analysed 6–7 months post-irradiation in the hippocampus, dentate gyrus (DG) and cortex. Signalling pathways related to synaptic actin remodelling such as the Rac1-Cofilin pathway were altered in the cortex and hippocampus. Further, synaptic proteins MAP-2 and PSD-95 were increased in the DG and hippocampus (1.0 Gy). The expression of synaptic plasticity genes Arc, c-Fos and CREB was persistently reduced at 1.0 Gy in the hippocampus and cortex. These changes were coupled to epigenetic modulation via increased levels of microRNAs (miR-132/miR-212, miR-134). Astrogliosis, activation of insulin-growth factor/insulin signalling and increased level of microglial cytokine TNFα indicated radiation-induced neuroinflammation. In addition, adult neurogenesis within the DG was persistently negatively affected after irradiation, particularly at 1.0 Gy.ConclusionThese data suggest that neurocognitive disorders may be induced in adults when exposed at a young age to low and moderate cranial doses of radiation. This raises concerns about radiation safety standards and regulatory practices.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-57) contains supplementary material, which is available to authorized users.

Shifting paradigm in the management of anal canal carcinoma.

Anal canal is the lower most part of the gastrointestinal tract harbouring 4 % of all gastrointestinal cancer. Most common treatment for anal canal carcinoma includes chemoradiotherapy. We reviewed the recent landmark trials to find a road map in the management of anal canal carcinoma. Concurrent chemoradiotherapy appears to be the most effective treatment schedule. Induction, as well as maintenance chemotherapy, has no definite role. Moderate dose radiation 50.4-54 Gy with concurrent mitomycin C (MMC) and 5-fluorouracil (5-FU) remains the standard. Split course is detrimental. Intensity-modulated radiotherapy and targeted drugs are investigated. Combined modality therapy is the standard for anal canal carcinoma.