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Radiosensitivity of rats was studied after double X-irradiation of head first with doses of 5 and 13 Gy, then with 8-21 Gy.
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The likelihood of radiation pneumonitis and factors associated with its development in breast cancer patients treated with conservative surgery and radiation therapy have not been well established. To assess these, we retrospectively reviewed 1624 patients treated between 1968 and 1985. Median follow-up for patients without local or distant failure was 77 months. Patients were treated with either tangential fields alone (n = 508) or tangents with a third field to the supraclavicular (SC) or SC-axillary (AX) region (n = 1116). Lung volume treated in the tangential fields was generally limited by keeping the perpendicular distance (demagnified) at the isocenter from the deep field edges to the posterior chest wall (CLD) to 3 cm or less. Seventeen patients with radiation pneumonitis were identified (1.0%). Radiation pneumonitis was diagnosed when patients presented with cough (15/17, 88%), fever (9/17, 53%), and/or dyspnea (6/17, 35%) and radiographic changes (17/17) following completion of RT. Radiographic infiltrates corresponded to treatment portals in all patients, and in 12 of the 17 patients, returned to baseline within 1-12 months. Five patients had permanent scarring on chest X ray. No patient had late or persistent pulmonary symptoms. The incidence of radiation pneumonitis was correlated with the combined use of chemotherapy (CT) and a third field. Three percent (11/328) of patients treated with a 3-field technique who received chemotherapy developed radiation pneumonitis compared to 0.5% (6 of 1296) for all other patients (p = 0.0001). When patients treated with a 3-field technique received chemotherapy concurrently with radiation therapy, the incidence of radiation pneumonitis was 8.8% (8/92) compared with 1.3% (3/236) for those who received sequential chemotherapy and radiation therapy (p = 0.002). A case:control analysis was performed to determine if the volume of lung irradiated (as determined using central lung distance [CLD]) was related to the risk of developing radiation pneumonitis. Three control patients were matched to each case of radiation pneumonitis based on age, side of lesion, chemotherapy (including sequencing), use of a third field, and year treated. Lung volumes were similar in the radiation pneumonitis cases and controls. We conclude that radiation pneumonitis following conservative surgery and radiation therapy for breast cancer is a rare complication, and that it is more likely to occur in patients treated with both a 3-field technique and chemotherapy (particularly given concurrently with radiation therapy). Over the limited range of volumes treated, lung volume was not associated with an increased risk of radiation pneumonitis.
Radiation-induced lymphomagenesis and leukemogenesis are complex processes involving both genetic and epigenetic changes. Although genetic alterations during radiation-induced lymphoma- and leukemogenesis are fairly well studied, the role of epigenetic changes has been largely overlooked. Rodent models are valuable tools for identifying molecular mechanisms of lymphoma and leukemogenesis. A widely used mouse model of radiation-induced thymic lymphoma is characterized by a lengthy "pre-lymphoma" period. Delineating molecular changes occurring during the pre-lymphoma period is crucial for understanding the mechanisms of radiation-induced leukemia/lymphoma development. In the present study, we investigated the role of radiation-induced DNA methylation changes in the radiation carcinogenesis target organ--thymus, and non-target organ--muscle. This study is the first report on the radiation-induced epigenetic changes in radiation-target murine thymus during the pre-lymphoma period. We have demonstrated that acute and fractionated whole-body irradiation significantly altered DNA methylation pattern in murine thymus leading to a massive loss of global DNA methylation. We have also observed that irradiation led to increased levels of DNA strand breaks 6 h following the initial exposure. The majority of radiation-induced DNA strand breaks were repaired 1 month after exposure. DNA methylation changes, though, were persistent and significant radiation-induced DNA hypomethylation was observed in thymus 1 month after exposure. In sharp contrast to thymus, no significant persistent changes were noted in the non-target muscle tissue. The presence of stable DNA hypomethylation in the radiation-target tissue, even though DNA damage resulting from initial genotoxic radiation insult was repaired, suggests of the importance of epigenetic mechanisms in the development of radiation-related pathologies. The possible role of radiation-induced DNA hypomethylation in radiation-induced genome instability and aberrant gene expression in molecular etiology of thymic lymphomas is discussed.
PURPOSE: To investigate the clinical, histopathological, and radiological features of radiation pneumonitis arising as a complication of selective internal radiation treatment for liver tumors. To correlate the development of radiation pneumonitis with the degree of lung shunting as assessed by 99mTechnetium-labeled macroaggregated albumin (Tc-MAA) scan. METHODS AND MATERIALS: Five out of 80 patients who had inoperable hepatic tumors and underwent treatment with intraarterial 90Yttrium- (90Y)-microspheres, developed progressive restrictive ventilatory dysfunction without an infective or cardiovascular cause. Histopathological evidence of a pneumonitis and the presence of microspheres in the lung tissue suggested a diagnosis of radiation pneumonitis. The clinical course, radiological and histopathological findings, percentage tumor shunting to the lungs (lung shunting, as predicted by gamma camera scanning after intraarterial Tc-MAA), and the estimated radiation dose to the lungs were analyzed. In an attempt to reduce pulmonary shunting of the microspheres, three patients received partial hepatic embolization with inert particles before selective internal radiation therapy. RESULTS: In the five patients who developed radiation pneumonitis, lung shunting percentages (as predicted by Tc-MAA scan) ranged from 13.1 to 45.6% (median 23.7%). The estimated whole lung radiation dose ranged from 10.43 Gy to 36.44 Gy (median 25.04 Gy). Among 75 patients who did not develop radiation pneumonitis, the percentage lung shunting ranged from less than 1% to 15% (median 6%). Nine patients had lung shunting greater than 13% and five of them developed radiation pneumonitis, whereas this developed in none of those in whom shunting was below 13%. The onset of radiation pneumonitis ranged from 1 to 6 months after internal radiation treatment. All five patients exhibited characteristic plain radiographic and computerized tomographic changes comprising extensive consolidation with well-defined lateral margins. Clinical improvement after corticosteroid treatment was seen in two patients. Three patients died from respiratory failure and two from other causes. Partial hepatic arterial embolization reduced the degree of lung shunting to less than 13%, but did not prevent the development of radiation pneumonitis. CONCLUSION: Radiation pneumonitis may become a complication after intraarterial 90Y-microspheres treatment when lung shunting, as assessed by Tc-MAA scan, is high (above 13%). Prescribed activity of 90Y and lung shunting of Tc-MAA should be considered together before giving selective internal radiation (SIR) therapy for hepatic tumors, and preferably avoided if the lung shunting is above 13%.
External beam radiotherapy has historically played a minor role in the primary treatment of hepatocellular carcinoma. Although there is evidence for tumor response to external beam radiotherapy and despite the fact that a radiation dose-response relationship has been established, the limited radiation tolerance of the adjacent normal liver has prohibited wider use of radiation therapy in this disease. Recent technological and conceptual developments in the field of radiation therapy-such as intensity-modulated radiation therapy, image-guided radiation therapy, and stereotactic body radiation therapy-have the potential to improve radiation treatments by conforming the delivered radiation dose distribution tightly to the tumor or target volume outline while sparing normal liver tissue from high-dose radiation. Image guidance allows for a reduction of added (normal tissue) safety margins designed to account for interfraction patient and target setup variability, and stereotactic targeting will further reduce residual target setup uncertainty. Combining improvements in tumor targeting with normal tissue sparing, radiation dose delivery will enable clinically effective and safe radiation delivery for liver tumors such as hepatocellular carcinoma. This article reviews the role of radiotherapy for hepatocellular carcinoma; presents modern radiation therapy modalities and concepts such as intensity-modulated, image-guided, and stereotactic body radiation therapy; and hypothesizes about their future effect on primary treatment alternatives.
Protein kinase Cdelta (PKCdelta) has an important role in radiation-induced apoptosis. The expression and function of PKCdelta in radiation-induced apoptosis were assessed in a radiation-sensitive mouse thymic lymphoma cell line, 3SBH5, and its radioresistant variant, XR223. Rottlerin, a PKCdelta-specific inhibitor, completely abolished radiation-induced apoptosis in 3SBH5. Radiation-induced PKCdelta activation correlated with the degradation of PKCdelta, indicating that PKCdelta activation through degradation is involved in radiation-induced apoptosis in radiosensitive 3SBH5. In radioresistant XR223, radiation-induced PKCdelta activation was lower than that in radiosensitive 3SBH5. Cytosol PKCdelta levels in 3SBH5 decreased markedly after irradiation, while those in XR223 did not. There was no apparent change after irradiation in the membrane fractions of either cell type. In addition, basal cytosol PKCdelta levels in XR223 were higher than those in 3SBH5. These results suggest that the radioresistance in XR223 to radiation-induced apoptosis is due to a difference in the regulation of radiation-induced PKCdelta activation compared to that of 3SBH5. On the other hand, Atm(-/-) mouse thymic lymphoma cells were more radioresistant to radiation-induced apoptosis than wild-type mouse thymic lymphoma cells. Irradiated wild-type cells, but not Atm(-/-) cells, had decreased PKCdelta levels, indicating that the Atm protein is involved in radiation-induced apoptosis through the induction of PKCdelta degradation. The decreased Atm protein levels induced by treatment with Atm small interfering RNA had no effect on radiation-induced apoptosis in 3SBH5 cells. These results suggest that the regulation of radiation-induced PKCdelta activation, which is distinct from the Atm-mediated cascade, determines radiation sensitivity in radiosensitive 3SBH5 cells.
BACKGROUND: The amount of radiation dose applied in the treatment of Hodgkin's disease is associated with the incidence of complications including radiation-induced pneumonitis, lung fibrosis and pericarditis. Therefore, from the beginning of 1986, we have started to apply a radiation therapy approach with reduced doses in order to minimize complications while maintaining effective treatment. PATIENTS AND METHOD: From 1983 through 1992 141 patients suffering from Hodgkin's disease were included in the present study. All of them were treated by radiation of mediastinum. In 126 cases polychemotherapy was applied before radiation. From 1986 we used a reduced radiation dose in cases that were treated by radiation alone (affected nodal regions with 40 Gy instead of 45 Gy and unaffected nodal regions with 36 Gy instead of 40 Gy) as well as after application of chemotherapy (affected nodal regions 36 Gy instead of 40 Gy and unaffected nodal regions with 30 Gy instead of 36 Gy). Ninety-five patients were treated according to the new therapy protocol. Forty-six patients had been treated with the higher dosages and served as the historical control group. Radiation therapy included Co-60, 15-MV and 9-MV photons, and 15-MeV and 9-MeV electrons. Serial thoracic X-ray controls were performed. CT scans, echocardiographic and electrocardiographic investigations were added in selected cases. RESULTS: During the period from 1983 to 1992, we diagnosed radiation-induced pneumonitis in 31% of the patients who underwent radiation therapy of the mediastinum. In addition, 16% demonstrated lung fibrosis and 10% pericarditis. After implementation of the reduced radiation dosages, the incidence of pneumonitis decreased from 35% to 24% (nearly significant in the 5% range), lung fibrosis from 24% to 12% (p < 0.05) and pericarditis from 26% to 2% (p < 0.01). The efficacy of treatment remained unaffected by the new therapy approach as has been demonstrated for cumulative survival data and recurrence-free intervals. CONCLUSIONS: Reduction of radiation dose in patients with Hodgkin's disease who undergo mediastinal radiation leads to a decrease in the incidence of radiation-induced complications (pneumonitis, lung fibrosis, pericarditis) whereas treatment efficacy remains unchanged.
Implementing an effective radiation safety program requires good communication with workers. The process begins with radiation safety. Before workers take a position involving radiation exposures, they should understand the possible health risks and what to do to keep their risks ALARA. The goal is for workers to achieve a balanced perspective on radiation health risks in order to avoid either undue fear or undue complacency about radiation. Workers should have enough understanding of radiation risks to decide to acceptor not accept-or not accept the risk of radiation as a condition of employment. Furthermore, the decision to accept radiation risk for the benefits of employment should be based on informed consent. Workers with a good understanding of radiation health risks will strive to minimize not only their own radiation exposure but also those of their work group. Normally radiation safety training to achieve worker understanding is focused primarily on the technology of radiation. However, understanding is more than a matter of good technical information. What one chooses to understand is also impacted by perceptions of radiation risks.
Understanding essential metalloelement metabolism and its role in tissue maintenance and function, as well as the roles of essential metalloelement-dependent enzymes in responding to injury, offer a new approach to decreasing and/or treating radiation injury. This review presents the roles of some essential metalloelement-dependent enzymes in tissue maintenance and function, and their responses to radiation injury in accounting for radiation protection and recovery effects observed for nontoxic doses of essential metalloelement compounds. Effects of biochemicals including water undergoing bond radiolysis and the effects of free radicals derived from diatomic oxygen account for the acute and chronic aspects of radiation injury. Recognized biochemical roles of essential metalloelement-dependent enzymes and the observed pharmacological effects of small-molecular mass chelates predict the therapeutic usefulness of essential metalloelement complexes in decreasing and/or treatment of radiation injury. Copper chelates have radiation protection and radiation recovery activities and cause rapid recovery of immunocompetency and recovery from radiation-induced histopathology. Mice treated with Cu(II)2(3,5-diisopropylsalicylate)4[Cu (II)2(3,5-DIPS)4] had increased survival and corresponding increases in numbers of myeloid and multipotential progenitor cells early after irradiation and earlier recovery of immune reactivity. Examination of radiation-induced histopathology in spleen, bone marrow, thymus, and small intestine also revealed Cu(II)2(3,5-DIPS)4-mediated rapid recovery of radiation-induced histopathology. Most recently, Fe, Mn, and Zn complexes have also been found to prevent death in lethally irradiated mice. These pharmacological effects of essential metalloelement chelates can be understood as due to facilitation of de novo synthesis of essential metalloelement-dependent enzymes which have roles in preventing the accumulation of pathological concentrations of oxygen radicals or repairing biochemical damage caused by radiation-induced bond homolysis. Essential metalloelement chelates offer a physiological approach to prevention and/or treatment of radiation injury.
Intracoronary beta (beta) radiation decreases the incidence of target lesion revascularization after percutaneous intervention (PCI) for in-stent restenosis (ISR). Cutting balloon (CB) angioplasty may also be superior to other percutaneous techniques for the treatment of ISR. We sought to study the outcomes of patients with ISR who underwent both CB angioplasty and intracoronay beta radiation and compare them to patients with ISR who underwent other PCI techniques without concomitant radiation. We also sought to evaluate the safety and efficacy of pullback intracoronary beta radiation for the treatment of long ISR lesions. Between January 2001 and November 2001, 102 patients (mean age = 55 +/- 13 years) with ISR underwent both CB angioplasty and intracoronay beta radiation. beta radiation was delivered using the Beta Cath (Novoste) 30 mm system, and pullback radiation was performed in 41 patients. A comparison group included a total of 393 patients with ISR who underwent other PCI techniques without concomitant intracoronary radiation therapy. Follow-up was obtained in 99 patients (97%) in the CB angioplasty with intracoronary radiation group and 377 patients (96%) in the comparison group. At follow-up, both target vessel revascularization (TVR) and major adverse cardiovascular events (MACE) occurred significantly less in the CB angioplasty with intracoronary radiation group than in the comparison group (7% vs. 18% for TVR, and 14% vs. 24% for MACE; P < 0.05 for both). In the pullback radiation group, TVR was performed in five patients (12%), and MACE occurred in eight patients (20%). A combination of CB angioplasty and intracoronay beta radiation for ISR seems to yield low rates of subsequent target vessel revascularization and adverse cardiac events. In addition, pullback beta radiation using the Beta Cath (Novoste) 30 mm system is safe and can be used to treat long ISR lesions effectively. Further randomized trials are needed to confirm these findings.
NASA is very interested in improving its ability to monitor and forecast the radiation levels that pose a health risk to space-walking astronauts as they construct the International Space Station and astronauts that will participate in long-term and deep-space missions. Human exploratory missions to the moon and Mars within the next quarter century, will expose crews to transient radiation from solar particle events which include high-energy galactic cosmic rays and high-energy protons. Because the radiation levels in space are high and solar activity is presently unpredictable, adequate shielding is needed to minimize the deleterious health effects of exposure to radiation. Today, numerous models have been developed and used to predict radiation exposure. Such a model is the Space Environment Information Systems (SPENVIS) modeling program, developed by the Belgian Institute for Space Aeronautics. SPENVIS, which has been assessed to be an excellent tool in characterizing the radiation environment for microelectronics and investigating orbital debris, is being evaluated for its usefulness with determining the dose and dose-equivalent for human exposure. Thus far. the calculations for dose-depth relations under varying shielding conditions have been in agreement with calculations done using HZETRN and PDOSE, which are well-known and widely used models for characterizing the environments for human exploratory missions. There is disagreement when assessing the impact of secondary radiation particles since SPENVIS does a crude estimation of the secondary radiation particles when calculating LET versus Flux. SPENVIS was used to model dose-depth relations for the blood-forming organs. Radiation sickness and cancer are life-threatening consequences resulting from radiation exposure. In space. exposure to radiation generally includes all of the critical organs. Biological and toxicological impacts have been included for discussion along with alternative risk mitigation methods--shielding and anti-carcinogens.
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