Heparin treatment mitigates radiation-induced oral mucositis in mice by interplaying with repopulation processes.

PURPOSE: To investigate the mechanistic background of the muco-protective effect of systemic heparin treatment on the development of radiation-induced oral mucositis in mice. MATERIALS AND METHODS: Fractionated irradiation was given to the snouts of male C3H/Neu mice over 2 weeks (10â€¯× 3 Gy), either alone or in combination with daily subcutaneous application of unfractionated or low molecular weight heparin (40 or 200 I.U./mouse, respectively). Over this course of 14 days, groups of mice (n = 3) were sacrificed every second day, their tongues excised and processed for histological analysis. The epithelial radiation response with and without heparin treatment was evaluated in terms of tissue morphology, proliferation and expression of cell contact molecules. RESULTS: Systemic treatment with heparins significantly reduced the cellular effects of irradiation to the oral epithelium. Heparin treated animals showed significantly higher total epithelial cell numbers and thickness throughout the study course. Bromodeoxyuridine (BrdU) incorporation analyses revealed that markedly more epithelial cells retained their proliferative capacity in the beginning of the first treatment week, but the proliferation of the mucosa was not stimulated during the rest of the study course. The expression of the adherens junction protein ß­catenin was slightly elevated in heparin treated animals, on day 2 the increase was statistically significant. The expression of e­cadherin and occludin was mostly unaffected by the concomitant heparin treatment. CONCLUSION: The findings of this study indicate an interplay of additional heparin treatment with the repopulation processes, leading to an earlier onset of this adaptive radiation response in oral mucosa. Importantly, we could demonstrate that the protective potential of heparin did not rely on stimulation of normal tissue proliferation. Since both heparin preparations are already approved for clinical use, they are considered as promising candidates for future clinical studies.

The Principles and Practice of Re-irradiation in Clinical Oncology: An Overview.

Long-term cancer survivors are at risk of the development of recurrence or a new primary cancer that requires a second (or third) radio-oncological treatment. Publications on re-irradiation have been followed and are summarised in this overview. Information from clinical and experimental animal studies suggests that specific normal tissues can tolerate a considerable retreatment radiation dose. However, the risk of normal tissue damage and the impact on the quality of life must be considered. If a second course of radiotherapy needs to be administered, this should be done with maximum care and accuracy. Optimum conformation of the dose to the planning target volume is required. For radiobiological reasons - in order to reduce the risk of late effects - hyperfractionation protocols should be applied for curative treatments. Alternatively, small volume exposure may be considered in a highly conformal, image-guided stereotactic approach.

[Biological mechanisms of radiation effects]. / Biologische Mechanismen der Strahlenwirkung.

BACKGROUND: Exposure to ionizing radiation for diagnostic purposes is inevitable in modern medicine. The therapeutic application of irradiation is highly effective against cancer; however, this implies exposure of normal tissue structures to significant doses of radiation. Diagnostic or therapeutic exposure to ionizing radiation can result in tissue changes and tumor induction in the long term. Knowledge of the biological mechanisms underlying these effects is essential for individualization of the application. OBJECTIVES: This article examines the biological mechanisms at the tissue and molecular level, the clinical manifestation of radiation effects, dose-dependence of the risk and the temporal progression as well as influencing factors. RESULTS AND CONCLUSION: The time course of the reaction of tissues to radiation exposure extends over wide ranges up to many decades. The effects of radiation on tissues are classified into early and late and their pathobiology is significantly different. Various factors (R) influencing the clinical manifestation of radiation effects have been identified related to the exposure pattern. The radiation tolerance of normal tissue structures regarding the induction of functional deficits shows great variation but always has a threshold value, which is usually not exceeded in diagnostic procedures. The risk of a radiation-induced fatal malignancy (total body exposure 5%/Gy) for a medical administration of radiation must be considered as very low in comparison to the natural risks. Informed consent of patients must reflect this in a balanced way.

Radiobiology of tissue reactions.

Tissue effects of radiation exposure are observed in virtually all normal tissues, with interactions when several organs are involved. Early reactions occur in turnover tissues, where proliferative impairment results in hypoplasia; late reactions, based on combined parenchymal, vascular, and connective tissue changes, result in loss of function within the exposed volume; consequential late effects develop through interactions between early and late effects in the same organ; and very late effects are dominated by vascular sequelae. Invariably, involvement of the immune system is observed. Importantly, latent times of late effects are inversely dependent on the biologically equieffective dose. Each tissue component and--importantly--each individual symptom/endpoint displays a specific dose-effect relationship. Equieffective doses are modulated by exposure conditions: in particular, dose-rate reduction--down to chronic levels--and dose fractionation impact on late responding tissues, while overall exposure time predominantly affects early (and consequential late) reactions. Consequences of partial organ exposure are related to tissue architecture. In 'tubular' organs (gastrointestinal tract, but also vasculature), punctual exposure affects function in downstream compartments. In 'parallel' organs, such as liver or lungs, only exposure of a significant (organ-dependent) fraction of the total volume results in clinical consequences. Forthcoming studies must address biomarkers of the individual risk for tissue reactions, and strategies to prevent/mitigate tissue effects after exposure.

Late inflammatory and thrombotic changes in irradiated hearts of C57BL/6 wild-type and atherosclerosis-prone ApoE-deficient mice.

BACKGROUND AND PURPOSE: Radiation-induced heart disease represents a late complication of thoracic radiotherapy. We investigated the inflammatory and thrombotic response after local heart irradiation in wild-type and atherosclerosis-prone mice. MATERIAL AND METHODS: Atherosclerosis-prone ApoE(-/-) and C57BL/6 wild-type mice were sacrificed 20, 40, and 60 weeks after irradiation with 0.2, 2, 8, or 16 Gy. The expression of CD31, vascular cell adhesion molecule-1 (VCAM-1), thrombomodulin (TM), and CD45 were quantified by immunofluorescence staining of heart tissue sections. RESULTS: Microvascular density decreased at 40 weeks after 16 Gy in C57BL/6 but not in ApoE(-/-) mice. CD31 expression declined in C57BL/6 mice at 40 weeks (8 Gy), but increased in ApoE(-/-) mice at 20 (2/8/16 Gy) and 60 weeks (16 Gy). Capillary area decreased in C57BL/6 at 40 weeks (8/16 Gy) but increased in ApoE(-/-) mice at 20 weeks (16 Gy). Endocardial VCAM-1 expression remained unchanged. TM-positive capillaries decreased at 40 weeks (8/16 Gy) in C57BL/6 and at 60 weeks (2/16 Gy) in ApoE(-/-) mice. Leukocyte infiltration transiently rose 40 weeks after 8 Gy (only ApoE(-/-)) and 16 Gy. After receiving a low irradiation dose of 0.2 Gy, no significant changes were observed in any of the mouse models. CONCLUSION: This study demonstrated that local heart irradiation affects microvascular structure and induces inflammatory/thrombotic responses in mice in a dose- and time-dependent manner. Thereby, significant prothrombotic changes were found in both strains, although they were progressive in ApoE(-/-) mice only. Proinflammatory responses, like the increase of adhesion molecules and leukocyte infiltration, were more pronounced and occurred at lower doses in ApoE(-/-) vs. C57BL/6 mice. These findings indicate that metabolic risk factors, such as decreased ApoE lipoproteins, may lead to an enhanced proinflammatory and prothrombotic late response in locally irradiated hearts.

Distant metastasis in patients with cervical cancer after primary radiotherapy with or without chemotherapy and image guided adaptive brachytherapy.

OBJECTIVE: The aim of this study is to investigate patterns of distant relapse after primary radiochemotherapy in cervical cancer patients. METHODS: All patients with cervical cancer treated in curative intent with external beam radiotherapy +/- chemotherapy and image-guided adaptive brachytherapy between January 1998 and June 2009 at the Medical University of Vienna were included in this retrospective analysis. Patients with locoregional recurrences were excluded from this study. Presence, site of and time to distant metastases were recorded. For identifying prognostic factors, uni- and multivariate analyses using Cox regression analysis were performed. Based on the result from the multivariate analysis, patients were stratified into a high and a low risk group. The Kaplan-Meier method was used to estimate distant-metastasis-free-survival in the overall cohort, in the risk groups and for analysing the impact of chemotherapy within the risk groups. RESULTS: A total number of 189 patients were included in this study. After a median follow-up of 54 months, 49 patients developed distant metastases. Overall, distant-metastasis-free-survival 5 years after treatment was 73%. FIGO stage, lymph node status and the extent of tumour regression during treatment were significant predictors for distant metastasis. Distant-metastasis-free-survival 5 years after treatment was 91% and 60% in the low and high risk groups, respectively. The number of the cycles of chemotherapy had a significant impact on the occurrence of distant metastasis in high risk patients, but not in low risk patients. CONCLUSION: Patients with high risk factors have a 40% probability of developing distant metastasis within 5 years. In these patients, decreasing the number of cycles of cisplatin may increase their probability of developing distant metastasis.

Effects of bone marrow or mesenchymal stem cell transplantation on oral mucositis (mouse) induced by fractionated irradiation.

BACKGROUND AND PURPOSE: Oral mucositis is a severe and dose limiting early side effect of radiotherapy for head-and-neck tumors. This study was initiated to determine the effect of bone marrow- and mesenchymal stem cell transplantation on oral mucositis (mouse tongue model) induced by fractionated irradiation. MATERIAL AND METHODS: Daily fractionated irradiation (5 × 3 Gy/week) was given over 1 (days 0-4) or 3 weeks (days 0-4, 7-11, 14-18). Each protocol was terminated (day 7 or 21) by graded test doses (5 dose groups, 10 animals each) in order to generate complete dose-effect curves. The incidence of mucosal ulceration, corresponding to confluent mucositis grade 3 (RTOG/EORTC), was analyzed as the primary, clinically relevant endpoint. Bone marrow or mesenchymal stem cells were transplanted intravenously at various time points within these fractionation protocols. RESULTS: Transplantation of 6 × 10(6), but not of 3 × 10(6) bone marrow stem cells on day - 1, + 4, + 8, + 11 or + 15 significantly increased the ED50 values (dose, at which an ulcer is expected in 50 % of the mice); transplantation on day + 2, in contrast, was ineffective. Mesenchymal stem cell transplantation on day - 1, 2 or + 8 significantly, and on day + 4 marginally increased the ED50 values. CONCLUSION: Transplantation of bone marrow or mesenchymal stem cells has the potential to modulate radiation-induced oral mucositis during fractionated radiotherapy. The effect is dependent on the timing of the transplantation. The mechanisms require further investigation.

Late effects of local irradiation on the expression of inflammatory markers in the Arteria saphena of C57BL/6 wild-type and ApoE-knockout mice.

Combined action of irradiation (IR), shear stress, and high blood pressure is well recognized to induce damage to vasculature, while data on pathological effects of IR in large peripheral vessels with low blood pressure are scarce. The purpose of the present study was hence to investigate time- and dose-dependent effects of local IR on inflammatory and prothrombotic processes in the Arteria (A.) saphena of C57BL/6 wild-type and apolipoprotein E (ApoE)-knockout mice. Single doses of 2, 5, 8, 10, or 16 Gy were locally delivered to the A. saphena of the left leg of the animals. The expression of CD31, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), and thrombomodulin (TM) was quantified by semiautomatic TissueFax fluorescence analysis in frozen arterial sections. Follow-up periods were 3, 6, 9, 12, or 18 months. Protein expression in the arterial wall displayed dose-dependent changes. Proinflammatory reactions were observed for CD31, E-selectin, ICAM, and VCAM already at doses of 2 Gy. Anti-inflammatory changes were detected for MCP-1 and TM. The effects were more pronounced in wild-type versus ApoE(-/-) mice. Changes remain mostly transient up to 16 Gy. Dose- and time-dependent changes in inflammatory and thrombotic mediators in the wall of the A. saphena were found after local IR but did not transform into histopathological consequences.

Validation and practical implementation of a multidisciplinary cancer distress screening questionnaire.

BACKGROUND: In order to identify cancer patients with psychosocial needs during radiotherapy, a routine screening questionnaire is widely recommended in the literature. Several tools focusing mainly on psychological issues have been developed during the past decade. However, problems with their implementation into clinical routine have been repeatedly reported, due to a lack of practicability for clinicians and nurses. This study reports the compilation of a multidisciplinary screening questionnaire and an analysis of the effectiveness of its implementation into clinical routine at the Department of Radiotherapy, Medical University of Vienna. MATERIALS AND METHODS: The screening questionnaire is based on a compilation of several subscales from established and validated assessment tools. It focuses on comprehensive information with high a clinical relevance for all professions. In a pilot study, patients' acceptance was assessed qualitatively. Analysis of missing screening data in consecutively admitted patients reflects the effectiveness of implementation and representativity of the data. A validation analysis of the psychological subscales was performed using external criteria and its internal consistency was tested with Cronbachs' α. RESULTS: Qualitative patient acceptance of the screening questionnaire is good. The overall response rate in the screening procedure was 75 %. Missing patient screening data sets arose randomly-mainly due to organizational problems-and did not result in systematic errors. The psychological subscales identify highly distressed patients with a sensitivity of 89 and 78 %, and an internal consistency of 0.843 and 0.617. CONCLUSION: The multidisciplinary screening questionnaire compiled in this study has a high patient acceptance, provides reliable and representative data and identifies highly distressed patients with excellent sensitivity. Although requiring additional personnel resources, it can be implemented successfully in clinical routine with benefits for both the patient and the professional team.

Late bone and soft tissue sequelae of childhood radiotherapy. Relevance of treatment age and radiation dose in 146 children treated between 1970 and 1997.

PURPOSE: The present retrospective study was initiated to characterize the effect of oncological treatments in children and adolescents on bone and soft tissues, and to assess their dependence on radiation dose and age at exposure. PATIENTS AND METHODS: The study included 146 patients treated between 1970 and 1997. All patients received external beam radiotherapy to the trunk or extremities, but no cranial irradiation. Median age at treatment was 8.8 years. Patients were screened at 18 years (median time interval since treatment 9.2 years, range 0.9-17.7 years) for pathological changes in the skeletal system and soft tissues (scoliosis, kyphosis, bony hypoplasia, soft tissue defects, asymmetries), which were classified as minor/moderate (grade 1) or substantial (grade 2). RESULTS: Pathological findings were recorded in 75/146 patients (51 %). These were scored as minor in 44 (59 %) and substantial in 31 patients (41 %). Most pathological changes occurred in children treated under the age of 6 years. At 6 years and older, only doses > 35 Gy caused an effect, and no substantial changes were seen for treatment ages exceeding 12 years. Significant effects of radiation dose and age at exposure were observed for kyphoscoliosis (with vertebral body dose gradients < 35 Gy), hypoplasia and soft tissue defects and asymmetrical growth. CONCLUSION: Tolerance doses of 20 Gy need to be respected for growing bone, particularly in children treated under the age of 6 years. The late treatment sequelae analysed in the present study are largely avoided with the use of current therapeutic protocols. However, the systematic evaluation, documentation and continuous analysis of adverse events in paediatric oncology remains essential, as does the evaluation of novel radio(chemo)therapeutic approaches.

Time course of late rectal- and urinary bladder side effects after MRI-guided adaptive brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: To analyze the time course of late rectal- and urinary bladder complications after brachytherapy for cervical cancer and to compare the incidence- and prevalence rates thereof. PATIENTS AND METHODS: A total of 225 patients were treated with external-beam radiotherapy (EBRT) and magnetic resonance imaging (MRI)-guided brachytherapy with or without chemotherapy. Late side effects were assessed prospectively using the Late Effects in Normal Tissue--Subjective, Objective, Management and Analytic (LENT/SOMA) scale. The parameters analyzed were time to onset, duration, actuarial incidence- (occurrence of new side effects during a defined time period) and prevalence rates (side effects existing at a defined time point). RESULTS: Median follow-up was 44 months. Side effects (grade 1-4) in rectum and bladder were present in 31 and 49 patients, 14 and 27 months (mean time to onset) after treatment, respectively. All rectal and 76 % of bladder side effects occurred within 3 years after radiotherapy. Mean duration of rectal events was 19 months; 81 % resolved within 3 years of their initial diagnosis. Mean duration of bladder side effects was 20 months; 61 % resolved within 3 years. The 3- and 5-year actuarial complication rates were 16 and 19 % in rectum and 18 and 28 % in bladder, respectively. The corresponding prevalence rates were 9 and 2 % (rectum) and 18 and 21 % (bladder), respectively. CONCLUSION: Late side effects after cervical cancer radiotherapy are partially reversible, but their time course is organ-dependent. The combined presentation of incidence- and prevalence rates provides the most comprehensive information.

Physical and psychosocial support requirements of 1,500 patients starting radiotherapy.

BACKGROUND: The need for psychosocial support in cancer patients is estimated in the literature at 14-50 %. At the Department of Radiation Oncology, Medical University of Vienna, approximately 3,000 patients are seen annually. Due to limited staff resources, highly distressed patients need to be selected for focused support. A multidisciplinary screening questionnaire covering physical, social and psychological problems and needs was successfully implemented in clinical routine. We present the results of a representative sample of 1,500 heterogeneous cancer patients before beginning radiotherapy. PATIENTS AND METHODS: The prevalence rates of physical, social and psychological problems and needs were evaluated. Independent risk factors for critical psychological distress were analyzed in a multivariate logistic regression model, in order to identify vulnerable subgroups for focused psychosocial support. RESULTS: Critical psychological distress was found in 22 % of the overall cohort, of whom only 26 % reported a need for psychological information. Clinically relevant pain was suffered by 31 %. Patients' most frequent complaints were weakness, sleeping difficulties and exhaustion. Consequently, 40 % were impaired in activities and 35 % reported a requirement for support in daily life. A need for further information was expressed by 37 % of patients. Significant risk factors for critical psychological distress included pain, functional status, support requirements and patient-reported symptoms. Differences in tumor type, metastases and sociodemographic variables had no impact on critical psychological distress. CONCLUSION: Approximately one third of all patients beginning radiotherapy have physical, social and psychological problems and should receive focused psychosocial support. Multivariate analysis reveals that patients with impaired "physical integrity" are at a significantly higher risk of experiencing critical psychological distress.

Residual tumour volumes and grey zones after external beam radiotherapy (with or without chemotherapy) in cervical cancer patients. A low-field MRI study.

BACKGROUND: Grey zones, which are defined as tissue with intermediate signal intensity in the area of primary hyperintense tumour extension, can be seen during radiation with or without chemotherapy on the T2-weighted MRI in patients with cervical cancer. The purpose of this study was to systematically measure the tumour volume at the time of diagnosis and the residual tumour volume at the time of brachytherapy without and with consideration of the grey zones and to estimate tumour regression during external beam radiotherapy (EBRT). MATERIAL AND METHODS: T2-weighted MRI datasets of 175 patients with locally advanced cervical cancer (FIGO stage IB-IVA), who underwent combined external beam radiotherapy and brachytherapy with or without concomitant chemotherapy were available for this study. The gross tumour volume at the time of diagnosis (GTV(init)) and at the time of first brachytherapy without (GTV(res)) and with (GTV(res)+ GZ) consideration of grey zones were measured for each patient. A descriptive statistical analysis was performed and tumour regression rates without (R) and with consideration of grey zones (R(GZ)) were calculated. Further, the role of prognostic factors on GTV(init), GTV(res), GTV(res)+ GZ and tumour regression rates was investigated. RESULTS: The median GTV(init), GTV(res), GTV(res)+ GZ in all patients were 44.4 cm(3), 8.2 cm(3), 20.3 cm(3), respectively. The median R was 78.5% and the median R(GZ) was 50.1%. The histology and FIGO staging showed a significant impact on GTV(init), GTV(res) and GTV(res)+ GZ. CONCLUSION: Grey zones represent a substantial proportion of the residual tumour volume at the time of brachytherapy. Differentiation of high signal intensity mass and surrounding intermediate signal intensity grey zones may be reasonable.

Radiation-induced morphological changes in the vagina.

BACKGROUND AND PURPOSE: Treatment-induced chronic vaginal changes after definitive radio(chemo)therapy for locally advanced cervical cancer patients are reported as one of the most distressing consequences of treatment, with major impact on quality of life. Although these vaginal changes are regularly documented during gynecological follow-up examinations, the classic radiation morbidity grading scales are not concise in their reporting. The aim of the study was therefore to identify and qualitatively describe, on the basis of vaginoscopies, morphological changes in the vagina after definitive radio(chemo)therapy and to establish a classification system for their detailed and reproducible documentation. PATIENTS AND METHODS: Vaginoscopy with photodocumentation was performed prospectively in 22 patients with locally advanced cervical cancer after definitive radio(chemo)therapy at 3-24 months after end of treatment. All patients were in complete remission and without severe grade 3/4 morbidity outside the vagina. RESULTS: Five morphological parameters, which occurred consistently after treatment, were identified: mucosal pallor, telangiectasia, fragility of the vaginal wall, ulceration, and adhesions/occlusion. The symptoms in general were observed at different time points in individual patients; their quality was independent of the time of assessment. Based on the morphological findings, a comprehensive descriptive and semiquantitative scoring system was developed, which allows for classification of vaginal changes. A photographic atlas to illustrate the morphology of the alterations is presented. CONCLUSION: Vaginoscopy is an easily applicable, informative, and well-tolerated procedure for the objective assessment of morphological vaginal changes after radio(chemo)therapy and provides comprehensive and detailed information. This allows for precise classification of the severity of individual changes.

Do clinicians and patients agree regarding symptoms? A comparison after definitive radiochemotherapy in 223 uterine cervical cancer patients.

BACKGROUND: In clinical cancer research of morbidity, low associations between clinician-assessed toxicity/morbidity and patient-reported symptoms are consistently described in the literature. While morbidity grading systems are supposed to follow more or less objective criteria, patient reported symptoms inherently are based on a subjective self-evaluation of the impact on quality of life. The aim of this study was to focus on major discrepancies with high clinical relevance and to evaluate its impact with regard to underreporting of morbidity. MATERIAL AND METHODS: Early morbidity assessed by clinicians with CTCAEv.3 and patient reported quality of life (EORTC-QLQ-C30/CX24) were compared regarding 12 overlapping symptoms in 223 patients with uterine cervical cancer 3 months after definitive radio(chemo)therapy in the ongoing EMBRACE study. Mismatches showing discrepancies between both grading systems were classified, if patients reported substantial symptoms (quite a bit/very much) and CTCAE grading was rated G0. RESULTS: In total, 360 substantial symptoms were reported by patients by EORTC-QLQ; 159 (44%) of those were not recognized by CTCAE. Symptoms with the highest occurrence of mismatches overall are urinary frequency, fatigue, and insomnia. Large institutional differences were found, showing two centers with 4 vs. 71% of patients with at least one mismatch. CONCLUSION: Analysis of mismatches indicated a high risk of underestimation of early morbidity. Thus, nearly half of the patient-reported substantial symptoms were not recognized by CTCAE scoring (G0) 3 months after treatment. Prospective assessment of morbidity in clinical studies should, therefore, integrate patient reported symptoms to receive a complete and comprehensive picture.

FISH-based analysis of 10- and 25-kV soft X-ray-induced DNA damage in 184A1 human mammary epithelial cells.

Over the past years, several in vitro studies have been performed on DNA damage induced by soft X-rays, especially in the energy range below 50 keV. Radiation effects originating from such low-energy photons are relevant in the context of medical diagnostics, for example, mammography, or of accidental exposure to scattered radiation. The present study was initiated to investigate the X-ray energy-dependent induction of stable and unstable chromosomal aberrations in the human mammary epithelial cell line 184A1. Three colour fluorescence in situ hybridisation was applied to identify chromosomal damage in chromosomes 1, 8 and 17, induced by 10-kV or 25-kV soft X-rays as well as by 200-kV X-rays as a reference quality. The overall results confirm the X-ray energy dependencies published for human lymphocytes showing increasing chromosomal aberration frequencies and higher aberration complexity with decreasing X-ray energy and increasing dose. Comparing the obtained dose dependencies, ratios of 0.84 ± 0.09 and 1.22 ± 0.18 were revealed for stable translocations induced by 25- and 10-kV X-rays, respectively, using 200-kV X-rays as reference. Moreover, the analysis of the minimum number of breaks required to form the visible chromosomal damage resulted in similar ratios of 0.93 ± 0.07 for 25-kV X-rays and 1.25 ± 0.10 for 10-kV X-rays relative to 200-kV X-rays. In addition, non-DNA-proportional contributions of chromosomes 8 and 17 to the whole DNA damage and deviations from the expected 1:1 ratio of translocations and dicentrics were observed for cell line 184A1.

[Radiation effect in normal tissue - principles of damage and protection]. / Strahlenwirkung am Normalgewebe. Prinzipien der Schüdigung und Protektion.

The curative effectivity of external or internal radiotherapy necessitates exposure of normal tissues with significant radiation doses, and hence must be associated with an accepted rate of side effects. These complications can not a priori be considered as an indication of a too aggressive therapy. Based on the time of first diagnosis, early (acute) and late (chronic) radiation sequelae in normal tissues can be distinguished. Early reactions per definition occur within 90 days after onset of the radiation exposure. They are based on impairment of cell production in turnover tissues, which in face of ongoing cell loss results in hypoplasia and eventually a complete loss of functional cells. The latent time is largely independent of dose and is defined by tissue biology (turn-over time). Usually, complete healing of early reactions is observed. Late radiation effects can occur after symptom-free latent times of months to many years, with an inverse dependence of latency on dose. Late normal tissue changes are progressive and usually irreversible. They are based on a complex interaction of damage to various cell populations (organ parenchyma, connective tissue, capillaries), with a contribution from macrophages. Late effects are sensitive for a reduction in dose rate (recovery effects). A number of biologically based strategies for protection of normal tissues or for amelioration of radiation effects was and still is tested in experimental systems, yet, only a small fraction of these approaches has so far been introduced into clinical studies. One advantage of most of the methods is that they may be effective even if the treatment starts way after the end of radiation exposure. For a clinical exploitation, hence, the availability of early indicators for the progression of subclinical damage in the individual patient would be desirable. Moreover, there is need to further investigate the molecular pathogenesis of normal tissue effects in more detail, in order to optimise biology based preventive strategies, as well as to identify the precise mechanisms of already tested approaches (e.g. stem cells).

Radiation cataractogenesis: a review of recent studies.

The lens of the eye is recognized as one of the most radiosensitive tissues in the human body, and it is known that cataracts can be induced by acute doses of less than 2 Gy of low-LET ionizing radiation and less than 5 Gy of protracted radiation. Although much work has been carried out in this area, the exact mechanisms of radiation cataractogenesis are still not fully understood. In particular, the question of the threshold dose for cataract development is not resolved. Cataracts have been classified as a deterministic effect of radiation exposure with a threshold of approximately 2 Gy. Here we review the combined results of recent mechanistic and human studies regarding induction of cataracts by ionizing radiation. These studies indicate that the threshold for cataract development is certainly less than was previously estimated, of the order of 0.5 Gy, or that radiation cataractogenesis may in fact be more accurately described by a linear, no-threshold model.