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Reliable data on the effects of chronic prenatal exposure to low dose (LD) of ionizing radiation in humans are missing. There are concerns about adverse long-term effects that may persist throughout postnatal life of the offspring. Due to their slow cell cycle kinetics and life-long residence time in the organism, mesenchymal stem cells (MSCs) are more susceptible to low level genotoxic stress caused by extrinsic multiple LD events. The aim of this study was to investigate the effect of chronic, prenatal LD gamma irradiation to the biology of MSCs later in life. C3H mice were exposed in utero to chronic prenatal irradiation of 10 mGy/day over a period of 3 weeks. Two years later, MSCs were isolated from the bone marrow and analyzed in vitro for their radiosensitivity, for cellular senescence and for DNA double-strand break recognition after a second acute gamma-irradiation. In addition to these cellular assays, changes in protein expression were measured using HPLC–MS/MS and dysregulated molecular signaling pathways identified using bioinformatics. We observed radiation-induced proteomic changes in MSCs from the offspring of in utero irradiated mice (leading to ~ 9.4% of all detected proteins being either up- or downregulated) as compared to non-irradiated controls. The proteomic changes map to regulation pathways involved in the extracellular matrix, the response to oxidative stress, and the Wnt signaling pathway. In addition, chronic prenatal LD irradiation lead to an increased rate of in vitro radiation-induced senescence later in life and to an increased number of residual DNA double-strand breaks after 4 Gy irradiation, indicating a remarkable interaction of in vivo radiation in combination with a second acute dose of in vitro radiation. This study provides the first insight into a molecular mechanism of persistent MSC damage response by ionizing radiation exposure during prenatal time and will help to predict therapeutic safety and efficacy with respect to a clinical application of stem cells. Supplementary Information The online version contains supplementary material available at 10.1007/s00411-021-00925-7.

The MSc Radiation Biology course is a highly interdisciplinary degree program placing radiation biology at the interface between biology, medicine, and physics, as well as their associated technologies. The goal was to establish an internationally acknowledged program with diverse and heterogeneous student cohorts, who benefit from each other academically as well as culturally. We have completed a Five-Year evaluation of the program to assess our qualification profile and the further direction we want to take.We evaluated the student cohort's data from the last 5 years regarding gender, age, and nationality as well as the highest degree before applying and career path after graduation.Data shows a great diversity regarding nationalty as well as undergraduate background. Cohort sizes could be increased and future prospects mainly aimed to a PhD. Measures after regular quality meetings and students' feedback led to improving the curriculum and workload, teacher's training, and changes to examination regulations.After 5 years, statistics show that our expectations have been met exceedingly. All graduates had excellent career opportunities reflecting the necessity of this MSc and its topics. We are continuously working on improving the program and adapting the curriculum to the requirements in radiation sciences. The future vision includes an expansion of the program as well as undergraduate education opportunities in this field.

Strahlentherapie und Onkologie 196(8), 679 - 682 (2020). doi:10.1007/s00066-020-01635-7, Published by Springer Medizin, Heidelberg

In the event of a mass casualty radiological or nuclear scenario, it is important to distinguish between the unexposed (worried well), low-dose exposed individuals and those developing the hematological acute radiation syndrome (HARS) within the first three days postirradiation. In previous baboon studies, we identified altered gene expression changes after irradiation, which were predictive for the later developing HARS severity. Similar changes in the expression of four of these genes were observed using an in vitro human whole blood model. However, these studies have provided only limited information on the time frame of the changes after exposure in relationship to the development of HARS. In this study we analyzed the time-dependent changes in mRNA expression after in vitro irradiation of whole blood. Changes in the expression of informative mRNAs (FDXR, DBB2, POU2AF1 and WNT3) were determined in the blood of eight healthy donors (6 males, 2 females) after irradiation at 0 (control), 0.5, 2 and 4 Gy using qRT-PCR. FDXR expression was significantly upregulated (P < 0.001) 4 h after ≥0.5 Gy irradiation, with an 18-40-fold peak attained 4-12 h postirradiation which remained elevated (4-9-fold) at 72 h. DDB2 expression was upregulated after 4 h (fold change, 5-8, P < 0.001 at ≥ 0.5 Gy) and remained upregulated (3-4-fold) until 72 h (P < 0.001). The earliest time points showing a significant downregulation of POU2AF1 and WNT3 were 4 h (fold change = 0.4, P = 0.001, at 4 Gy) and 8 h (fold change = 0.3-0.5, P < 0.001, 2-4 Gy), respectively. These results indicate that the diagnostic window for detecting HARS-predictive changes in gene expression may be opened as early as 2 h for most (75%) and at 4 h postirradiation for all individuals examined. Depending on the RNA species studied this may continue for at least three days postirradiation.

The success of any research programme is dependent on a continuing influx of new expertise, and continuing education to ensure the newest technologies and methods are exploited. In the past decade, a strategic approach has been used to build up the research expertise in the area of radiation protection and risk estimation. The High Level Expert Group (HLEG, www.hleg.de) in their 2009 report on European low-dose research asserted that education and training were key components in the development and maintenance of expertise for research into the risks from low-levels of ionising radiation. Following their recommendations, a Euratom-funded Network of Excellence (DoReMi, www.doremi-noe.net) was setup to develop a platform of European research institutions to coordinate the research programme and develop expertise in the area. We present here the activities initiated by DoReMi and currently continued by CONCERT (www.concert-h2020.eu) in support of education and training in the scientific areas underpinning radiation protection research.

A review is presented to the program of education and training setup within the DoReMi Network of Excellence. DoReMi was funded by Euratom under the EU 7th Framework Programme to coordinate the EU research into risks from low-dose ionizing radiation. It was seen to be necessary to form a network of expert institutions in order to tackle the scientific questions with the resources available. From the start, importance was given to the need to stimulate and support education and training to build up the capability of the research community. DoReMi dedicated a workpackage to education and training that put in place a number of activities that have been successful in attracting new students into the area and introducing research scientists to new topic areas and technologies. The program of education and training in DoReMi provided a significant contribution to the low-dose radiation research community and has been further developed and extended in the following Euratom-funded project OPERRA and the European Joint Programme CONCERT.

Reliable data on the effects of chronic prenatal exposure to low dose (LD) of ionizing radiation in humans are missing. There are concerns about adverse long-term effects that may persist throughout postnatal life of the offspring. Due to their slow cell cycle kinetics and life-long residence time in the organism, mesenchymal stem cells (MSCs) are more susceptible to low level genotoxic stress caused by extrinsic multiple LD events. The aim of this study was to investigate the effect of chronic, prenatal LD gamma irradiation to the biology of MSCs later in life. C3H mice were exposed in utero to chronic prenatal irradiation of 10 mGy/day over a period of 3 weeks. Two years later, MSCs were isolated from the bone marrow and analyzed in vitro for their radiosensitivity, for cellular senescence and for DNA double-strand break recognition after a second acute gamma-irradiation. In addition to these cellular assays, changes in protein expression were measured using HPLC–MS/MS and dysregulated molecular signaling pathways identified using bioinformatics. We observed radiation-induced proteomic changes in MSCs from the offspring of in utero irradiated mice (leading to ~ 9.4% of all detected proteins being either up- or downregulated) as compared to non-irradiated controls. The proteomic changes map to regulation pathways involved in the extracellular matrix, the response to oxidative stress, and the Wnt signaling pathway. In addition, chronic prenatal LD irradiation lead to an increased rate of in vitro radiation-induced senescence later in life and to an increased number of residual DNA double-strand breaks after 4 Gy irradiation, indicating a remarkable interaction of in vivo radiation in combination with a second acute dose of in vitro radiation. This study provides the first insight into a molecular mechanism of persistent MSC damage response by ionizing radiation exposure during prenatal time and will help to predict therapeutic safety and efficacy with respect to a clinical application of stem cells.

In absolute terms: second cancer risks from radiotherapy of first cancers in adults are small compared to the benefits from radiotherapy but this is not so for radiotherapy of childhood cancers. Moreover, the radiation dose dependence of cancer induction differs between organs and tissues. The organ-specific dose dependence of second cancer risks may indicate the existence of different radiobiological mechanisms. As an inevitable consequence of the age dependence of organ sensitivity to second cancer induction, the organ/tissue weighting factors which have been proposed by ICRP for calculating effective dose (the dose unit Sv) and for risk estimation in the general population should not be used in medical radiation exposures. In adult cancer radiotherapy, the most common unwanted effect is local tumour recurrence whereas both, severe late normal tissue damage and radiation-induced second cancers are rare, around 1% of locally controlled cancer patients. In childhood cancers, local failures are rare (

Oliver Scott is best known for his research into the role of tumour hypoxia in radiation oncology. Yet no less important were Oliver’s activities in the development of concepts and methods for performing translational research on the effect of ionising radiation on tumour in experimental animals, stressing the importance of using strictly inbred animals for transplantation of tumours which had arisen in exactly the identical mouse strain. Otherwise residual immunity would lead to uncontrollable bias in the results of cure experiments, invalidating conclusions. These pioneering views are no less valid in today’s cancer research.

Background and purpose Radiotherapy of thoracic tumors increases the risk to develop cardiac diseases at later time-points. We compared time kinetics of radiation-induced changes of surface markers related to proliferation, progenitor cell development and inflammation in lung and heart microvascular endothelial cells (ECs). Material and methods Mice received local thorax irradiation with a single dose of 0, 2 or 8Gy. Following magnetic bead separation and biotin-streptavidin competition, cell surface markers of isolated ECs from the lung and heart were analyzed 5, 10, 15 and 20weeks after irradiation by flow cytometry. Results Irradiation with 8Gy resulted in a temporary and differential up-regulation of proliferation markers (HCAM, Integrin β-3, Endoglin, VE-cadherin, VEGFR-2) on ECs. Mucosialin a progenitor marker increased in lung ECs 15–20weeks and inflammatory markers (PECAM-1, ICAM-1, ICAM-2, VCAM-1) started to increase 10weeks after thorax irradiation with 8Gy. Interestingly, ICAM-1 and VCAM-1 remained up-regulated 20weeks after irradiation in heart and lung ECs. Conclusions The persistently elevated expression density of ICAM-1 and VCAM-1 on ECs may suggest that an irradiation at 8Gy induces late inflammatory responses in heart and lung ECs.

Fewer than ten years after the discovery of Roentgen rays, in 1903, the first radiation-induced cancer was diagnosed in a Roentgen technologist.

Background and purposeThe aim of the present study was to evaluate if it is feasible for experienced radiation oncologists to visually sort out patients with a large dose to the heart. This would facilitate large retrospective data evaluations. And in case of an insufficient visual assessment, to define which structures should be contoured and which structures can be skipped as their dose can be derived from other easily contoured structures for future clinical trials.Material and methodsPlanning CTs of left-sided breast cancer patients treated with 3D-conformal radiotherapy by tangential fields were visually divided into two groups: with an estimated high dose (HiD) and with an estimated low dose (LoD) to the heart. For 46 patients (22 HiD and 24 LoD), the heart, the left ventricle, the left anterior descending artery (LAD), the right coronary artery, and the ramus circumflexus were contoured. A helper structure (HS) around the LAD was generated in order to consider if contouring uncertainties of the LAD could be acceptable. We analyzed the mean dose (Dmean), the maximum dose, the V10, V20, V30, V40, and the length of the LAD that received 20 and 40 Gy.ResultsThe two groups had a significant different Dmean of the heart (p

The authors of this report met at the Head Quarter of the International Atomic Energy Agency (IAEA) in Vienna, Austria, on 2-4 July 2012, for intensive discussions of an abundance of original publications on new epidemiological studies on cardiovascular effects after low-dose exposure and radiotherapy and radiobiological experiments as well as several comprehensive reviews that were published since the previous meeting by experts sponsored by the IAEA in June 2006. The data necessitated a re-evaluation of the situation with special emphasis on the consequences current experimental and clinical data may have for clinical oncology/radiotherapy and radiobiological research. The authors jointly arrived at the conclusions and recommendations presented here.

In previous studies we determined a gene expression signature in baboons for predicting the severity of hematological acute radiation syndrome. We subsequently validated a set of eight of these genes in leukemia patients undergoing total-body irradiation. In the current study, we addressed the effect of intra-individual variability on the basal level of expression of those eight radiation-responsive genes identified previously, by examining baseline levels in 200 unexposed healthy human donors (122 males and 88 females with an average age of 46 years) using real-time PCR. In addition to the eight candidate genes ( DAGLA, WNT3, CD177, PLA2G16, WLS, POU2AF1, STAT4 and PRF1), we examined two more genes ( FDXR and DDB2) widely used in ex vivo whole blood experiments. Although significant sex- (seven genes) and age-dependent (two genes) differences in expression were found, the fold changes ranged only between 1.1-1.6. These were well within the twofold differences in gene expression generally considered to represent control values. Age and sex contributed less than 20-30% to the complete inter-individual variance, which is calculated as the fold change between the lowest (reference) and the highest Ct value minimum-maximum fold change (min-max FC). Min-max FCs ranging between 10-17 were observed for most genes; however, for three genes, min-max FCs of complete inter-individual variance were found to be 37.1 ( WNT3), 51.4 ( WLS) and 1,627.8 ( CD177). In addition, to determine whether discrimination between healthy and diseased baboons might be altered by replacing the published gene expression data of the 18 healthy baboons with that of the 200 healthy humans, we employed logistic regression analysis and calculated the area under the receiver operating characteristic (ROC) curve. The additional inter-individual variance of the human data set had either no impact or marginal impact on the ROC area, since up to 32-fold change gene expression differences between healthy and diseased baboons were observed.

Low-dose radiotherapy (RT) has often been used effectively for the treatment of a variety of benign diseases, particularly those with acute inflammatory features. Here we report findings on radiation treatment of acute inflammation using a murine carrageenin air pouch model.Air pouches raised on the dorsal surface of mice were injected with lambda carrageenin and were irradiated 6 h later with doses ranging from 0-5 Gy. Treatment success was evaluated at various times thereafter by volume of exudate and number of inflammatory cells, and levels of inflammation-related cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and transforming growth factor beta-1 (TGFbeta-1), and expression of inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX-2) and inducible heat shock protein 70 (HSP70) as determined by enzyme-linked immunosorbent assay (ELISA) and Western blotting, respectively.Crude inflammatory parameters such as the amount of exudates and number of inflammatory cells remained largely unaffected by radiation or were even a slightly and transiently increased. However, the expression of iNOS was attenuated by radiation concomitant with an increase in the levels of HO-1 and HSP70. Cytokine levels varied with the radiation dose and the time point.Ionizing radiation, even at low doses, functionally modulates inflammatory cells. Our findings indicate possible mechanisms as to how low-dose radiation may exert anti-inflammatory effects and provide the first evidence that heat shock proteins may be involved in this response.

Die gute Prognose einiger Tumorerkrankungen im jungen Erwachsenenalter fordert haufig die Beratung der Patienten mit Kinderwunsch nach Therapieende hinsichtlich der genetischen Konsequenzen der Strahlenbehandlung. Es wird uber die Ergebnisse der uber einen Zeitraum von 20 Jahren wiederholten Untersuchungen von 61 Kindern berichtet, von denen sich ein Elternteil wegen einer Tumorerkrankung einer alleinigen Strahlentherapie (nur in drei Fallen mit zusatzlicher Chemotherapie) unterziehen musste. Dabei wurden Gonadendosen von 0,01–2,0 Gy verabfolgt. Die haufigsten Tumorerkrankungen der 47 Eltern waren Lymphogranulomatose (n = 25), Seminome (n = 7), Schilddrusenkarzinome (n = 3) und Melanome (n = 3). Die untersuchten Kinder zeigten eine Neigung zur Fruhgeburtlichkeit (52,5% Geburten vor dem errechneten Geburtstermin) bei regelrechtem Geburtsgewicht und regelrechter Geburtslange. Obwohl das Skelettalter zu den drei Untersuchungszeitpunkten gegenuber dem chronologischen Alter zuruckblieb, erfolgte die korperliche Entwicklung innerhalb der Standardwerte eines deutschen Normalkollektivs. Alle Kinder wiesen einen unauffalligen Karyotyp auf, besuchten altersgerecht Bildungseinrichtungen und zeigten im Beobachtungszeitraum keinen Hinweis auf eine maligne Tumorerkrankung. Insgesamt fallt eine leicht erhohte Haufigkeit von Normabweichungen bei insgesamt vier schwereren Malformationen auf, ohne dass ein direkter Zusammenhang zur durchgefuhrten Strahlenbehandlung bewiesen werden kann. In einem Fall deckte die Untersuchung eine familiare Translokation 5;17 auf, die vom nicht bestrahlten Elternteil auf das untersuchte Kind vererbt wurde. Die Problematik des Fertilitatserhalts sowie der durch die Therapie ausgelosten erblich bedingten Entwicklungsstorungen und Erkrankungen der Nachkommen sollte beim Aufklarungsgesprach aktiv vom Radioonkologen bei Patienten entsprechenden Lebensalters angesprochen werden, da wichtige Entscheidungen wie Kryokonservierung von Sperma, Ovaropexie und Messung der Gonadendosis wahrend der Bestrahlungsserie nur zu diesem Zeitpunkt sinnvoll getroffen werden konnen. Die durch eine alleinige Strahlentherapie eines Elternteils zu erwartende Erhohung der Malformationsrate liegt bei < 0,1% bei einer Gonadenbelastung von 1 Gy. Allerdings muss bei multimodalen Konzepten der bisher schlecht quantifizierbare Einfluss einer Chemotherapie berucksichtigt werden.

Radiotherapy plays an important role in the management of prostate cancer. Epidemiological data indicate a small but significant risk of radiation-induced leukemia after radiotherapy which might be related to the high mean bone marrow dose associated with radiotherapy of prostate cancer. The purpose of the study was to investigate the relation between the mean bone marrow dose and unstable chromosome aberrations in peripheral blood lymphocytes in patients undergoing conformal radiotherapy for prostate cancer as a possible indicator of risk. Endometrial cancer patients were also included for comparison.Nine patients, six with prostate cancer (60-73 years old) and three with endometrial cancer (61-81 years old) treated with radiotherapy were included in the study. The non-bony spaces inside the pelvic bones were outlined on every CT slice using the treatment planning system and mean doses to the bone marrow calculated. Blood samples of the patients were obtained at different times before, during and at the end of treatment. Lymphocytes were cultured in the usual way and metaphases scored for dicentric aberrations.46 samples from nine patients were obtained. The mean number of metaphases analyzed per sample was 180 with a range from 52 to 435. The mean bone marrow doses for prostate cancer patients ranged from 2.8 to 4.2 Gy and for endometrial cancer patients from 12.8 to 14.8 Gy. The aberration yield increased with the planning target volume and the mean bone marrow dose.The yield of dicentric aberrations for prostate cancer patients correlated closely with the mean bone marrow dose albeit the induction of dicentrics occurred in mature T lymphocytes most of which were probably in transit through the irradiated volumes. Therefore, the observed relationship between dicentrics and mean bone marrow doses are indirect.

As radical radiotherapy treatments become more effective, more and more cancer patients are becoming cured of their disease and surviving for decades. Damage to exposed healthy tissues that becomes manifest in the medium-to-long-term is becoming a more significant factor in the choice of individual treatment plans and treatment modality. However, currently there are no reliable objective methods for predicting in an individual patient the occurrence of normal tissue complications, or second cancers caused by radiation. This is especially needed as new competing techniques and modalities become available, such as IMRT, protons, carbon ions, etc., all advancing the ability to focus the radiation dose on the target while sparing normal tissue. ALLEGRO is a Euratom-funded project that is currently investigating the current state of knowledge, and attempting to define the priority research areas. Preliminary considerations of the problems to be solved and research priorities are presented.

BackgroundComparative analysis of the cellular biology of the microvasculature in different tissues requires the availability of viable primary endothelial cells (ECs). This study describes a novel method to isolate primary ECs from healthy organs, repair blastemas and tumors as examples of non-proliferating and proliferating benign and malignant tissues and their functional characterization.Methodology/principal findingsSingle cell suspensions from hearts, lungs, repair blastemas and tumors were incubated consecutively with an anti-CD31 antibody and magnetic micro-beads, coupled to a derivative of biotin and streptavidin, respectively. Following magnetic bead separation, CD31-positive ECs were released by biotin-streptavidin competition. In the absence of micro-beads, ECs became adherent to plastic surfaces. ECs from proliferating repair blastemas and tumors were larger and exhibited higher expression densities of CD31, CD105 and CD102 compared to those from non-proliferating normal tissues such as heart and lung. The expression density of CD34 was particularly high in tumor-derived ECs, and that of CD54 and CD144 in ECs of repair blastemas. Functionally, ECs of non-proliferating and proliferating tissues differed in their capacity to form tubes in matrigel and to align under flow conditions.Conclusions/significanceThis method provides a powerful tool to generate high yields of viable, primary ECs of different origins. The results suggest that an altered expression of adhesion molecules on ECs in proliferating tissues contribute to loss of EC function that might cause a chaotic tumor vasculature.

Local tumour control by radiotherapy requires the complete sterilization of all tumour 'stem' cells in the tumour volume. Neither bystander effect nor radiation-induced genomic instability is able to contribute substantially to the probability of local tumour control of the primary cancer by radiotherapy. However, the progeny of these surviving tumour 'stem' cells are likely to suffer from radiation-induced genomic instability, which results in the persistent appearance of non-stem cells, i.e. a reduced probability of self-maintenance. This results in a slower growth rate of the recurrent tumour, a reduced stem-cell fraction and, as a consequence, an increased radiosensitivity of the recurrent tumour. In some recurrent tumours, particularly those that develop very late and grow very slowly, radiosensitivity may be further increased by increased intrinsic radiosensitivity, which could be related to the as yet poorly defined phenotype of 'small colony formation'.

Purpose : To explore the radiobiological evidence for a dependence of normal tissue complication probability on irradiated normal tissue volume. Materials and methods : Data from experimental studies on the volume effect in different organs, using different criteria of structural or functional organ damage and in different animals, were evaluated to investigate the volume effects for structural radiation damage as opposed to functional radiation damage, and the importance of organ anatomy and dose distribution within the organ on the development of chronic radiation damage in the respective organ. Results : There is little or no volume effect for structural radiation damage, however, some very pronounced volume effects have been reported for functional damage. Volume, as such, is not the relevant criterion, since critical, radiosensitive structures are not homogeneously distributed within organs. Conclusion : Volume effects in patients and experimental animals are more related to organ anatomy and organ physiology than to cellular radiobiology.

The discussion of the potential risk of second cancer induction by curative radiotherapy of the first cancer is a recent phenomenon. This is surprising, as during the follow-up of treated patients doctors, carefully searching for local recurrence of the treated primary or for distant metastasis, often inadvertently come across another malignancy which clearly is a new, an independent second cancer. Again and again, doctors and patients probably wondered whether the second cancer was the direct result of the treatment of the first cancer and in particular, whether radiation being a well known carcinogenic agent had caused the second cancer. In hindsight, it is difficult to understand why there has been so little research into this most serious potential complication of radiotherapy while radiobiologists and radiotherapists kept concentrating on investigating the pathogenesis and the risks of much less severe normal tissue effects and on how to avoid them. This situation has dramatically changed in the recent years. A large number of clinical/epidemiological studies provided indisputable evidence that patients who have been cured from their cancer by radiotherapy have an increased risk of developing the second cancer. During the last few months, three major reviews discussed different aspects of this problem [1–3]. All stress that treatment-related second cancers are the direct consequence of treatment success. Without cure from the first cancer there is no second cancer. Moreover, in most clinical situations (with the possible exceptions of lymphoma and childhood cancers), more patients die from the failure of curing the first cancer than from the treatment-induced second cancers. Yet, all reviews agree that the problem of treatment-induced second cancers is severe, and is likely to become even more severe in the future. A broad discussion among cancer therapists is required with the aim of developing criteria for quantifying the various factors which define second cancer risk and of developing criteria for reducing second cancer risk by the modification of treatment protocols without compromising the chances of cure of the first cancer. The three reviews differ in their approach and in their aims. The review by Suit et al. of 2007 [1] is the earliest of those critical reviews, and has been written by a team of eminent American radiobiologists of different backgrounds. They discussed the clinical problem of radiotherapy-induced second cancers within the context of experimental and epidemiological studies of radiation carcinogenesis in general. They put second cancer risk after radical radiotherapy into the context of radiobiological studies on cell transformation in vitro, radiation-induced cancers in experimental animals from mice to monkeys, the Japanese A-bomb survivors, radiation workers, patients treated for benign diseases and those treated with radiotherapy for cancer. Estimating relative risk values in comparison with the general population and with patients treated with non-radiation modalities, they demonstrated that some (but not all) cured cancer patients have a higher risk of developing cancer than the general population. They concluded that ‘‘radiation can induce malignant transformation of mammalian tissue and that the relationship between radiation dose and risk of cancer is clearly complex and not amenable to a simple definition applicable to all mammalian species, all members of a species, or even to all organs in one inbred strain of a species. Due to quite large and undefined heterogeneity in the patient populations studied, no precise quantification of the risk of radiation-induced secondary cancer is available at present. However, the clear implication of this review ... is that the basic concept for planning radiation treatment should be that the risk of radiation-induced secondary cancer would be reduced by any dose decrement to uninvolved normal tissues, at least down to 0.05 Gy. The factorial decrease in risk would be greatest for the reduction in dose levels below 2 Gy”. By pooling data from 14 published radiotherapy series, Suit et al. (2007) explored the evidence for a dose dependence of second cancer risk. While there was a significant increase of risk with dose up to >25 Gy for the stomach and the pancreas, the dose–risk relationship was flat for bladder and rectum between

Radiotherapy with total doses of < or =6 Gy has been given as very effective and low risk treatment of painful degenerative joint diseases and other inflammatory processes. Recent radiobiological experiments in vitro and in vivo identified mechanisms which may be related to these anti-inflammatory radiation effects, in particular functional modulation of the adhesion of white blood cells to activated endothelial cells and modulation of the induction of nitric oxide synthase in activated macrophages.

The objective of this report is to present a summary of progress of the Marshall Islands Nationwide Thyroid Study. As well known, the US atomic weapons testing program in the Pacific was conducted primarily between 1946 and 1958 in the Marshall Islands. The nuclear tests resulted in radioactive contamination of a number of atolls and resulted in exposure of Marshallese to undefined levels before our study. Little information has been paid to health consequences among residents of the nearly twenty inhibited atolls except for some information about nodular thyroid disease which was reported on by an US group. In a cooperative agreement with the Government of the Marshall Islands, between 1993 and 1997 we studied the prevalence of both thyroid nodules and thyroid cancer among 4766 Marshallese potentially exposed to radioiodines from bomb test fallout. That group represents more than 65% of the population at risk. We diagnosed 45 thyroid cancers and 1398 benign thyroid nodules. In addition, 23 study participants had been operated on prior to our study for thyroid cancer. Presently, we are developing a database of information to estimate radiation doses and planning a statistical analysis to determine if a dose-response relationship exists. These data will be important for the health promotion of exposed people all over the world including Hiroshima, Nagasaki, Semipalatinsk, Chernobyl and other locations. A timely completion is important for purpose of assisting Marshallese as well as to add the global understanding of radiation induced thyroid cancer.

Recent experimental data relating to the mechanisms of accelerated repopulation during daily fractionated irradiation are reviewed. There is evidence indicating that acceleration of repopulation is an active response towards the progressively accumulating radiation damage which is characteristic for squamous cell carcinomas and their tissue of origin, i.e. normal squamous epithelium. Whereas little is known about the mechanisms in tumours, various aspects of the trigger and the biological mechanisms have recently been elucidated in normal squamous epithelium. It is reasonable to expect that some of them might also operate in squamous cell carcinomas. Acceleration is due to the loss of asymmetry of stem cell divisions. This may be associated with changes in the keratinocyte differentiation pattern leading to a functionally defective, parakeratotic and hyperproliferative epithelium. This occurs at a certain level of tissue injury. Although related to the time of incipient erythema, the trigger is not the inflammatory response itself or the functional insufficiency of the irradiated epithelium. Rather, the trigger is directly related to the progressive hypoplasia which causes changes in intercellular communication. There is also evidence that acceleration is modulated by signalling processes between the effector keratinocytes and various mesenchymal cells in the irradiated tissue.

In V79 Chinese hamster cells, radiation-induced genomic instability results in a persistently increased frequency of micronuclei, dicentric chromosomes and apoptosis and in decreased colony-forming ability. These manifestations of radiation-induced genomic instability may be attributed to an increased rate of chromosome breakage events many generations after irradiation. This chromosomal instability does not seem to be a property which has been inflicted on individual chromosomes at the time of irradiation. Rather, it appears to be secondary to an increased level of non-specific clastogenic factors in the progeny of most if not all irradiated cells. This conclusion is drawn from the observations presented here, that all the chromosomes in surviving V79 cells are involved in the formation of dicentric chromosome aberrations 1 or 2 weeks after irradiation with about equal probability if corrections are made for chromosome length.

Substantial clinical evidence shows the efficacy of low-dose radiotherapy in the treatment of a wide variety of benign conditions. However, experimental investigations into these empirically clinical observations remain scarce. We investigated in vivo low-dose radiation effects on chronic granulomatous tissue by using the air pouch model in mice.Chronic granulomatous air pouches were induced in mice and dosed according to 4 protocols: group I: sham control; group II: 2 Gy on day 2; group III: 2 Gy on day 6; group IV: 5 daily doses of 0.5 Gy from day 2 to 6. On day 7 after granuloma induction the granuloma wet and dry weight was estimated, the vascular content was assessed by the formation of vascular casts incorporating carmine, the inducible nitric oxide synthase (iNOS)- and heme oxygenase 1 (HO-1)-expression in tissue homogenates was assessed by Western blot analysis, and the immunohistochemical localization of iNOS was carried out in cryostat sections of the granulomatous tissue.We did not observe any significant reduction in granulomatous tissue wet weight or dry weight following the different radiation treatments, which indicates that anti-proliferative effects in response to the low radiation doses used, are probably not involved in the effects of anti-inflammatory radiotherapy. A single dose of 2 Gy on day 2, as well as fractionated treatment with 5 x 0.5 Gy lead to an increase in vascularity. iNOS-expression in the homogenized granulomatous tissue was decreased, being most pronounced after single-dose irradiation with 2 Gy on day 2, early on in the acute phase of inflammation. In contrast, the HO-1-expression was increased in all irradiated groups.Low doses of radiation interfere with the NO- and the HO-1 pathway. Since NO contributes to several aspects of inflammation such as oedema formation and inflammatory pain, we put forward the hypothesis, that the inhibitory effect of low doses of ionizing radiation on the NO pathway is one radiobiological mechanism underlying the clinically observed efficacy of anti-inflammatory radiotherapy and might result in the reduction of swelling as well as relief of pain. Furthermore, the suppression of iNOS activity could be due to the increase in the stress protein HO-1 by low dose radiotherapy.

Die strahlenbiologischen Mechanismen, die bei der Planung neuer Strategien der Radiochemotherapie therapeutisch ausgenutzt werden konnen, werden dargestellt. Die Analyse pathogenetischer Mechanismen der Tumorheilung sowie akuter und chronischer Strahlenfolgen und die Analyse von experimentell dokumentierten Mechanismen der Interaktion von Chemotherapie und Radiotherapie sind die Voraussetzung, therapeutisch nutzbare Mechanismen zur Verbesserung der Radiochemotherapie zu identifizieren. Wahrend fur die Wirkung auf den Tumor ausschlieslich die unabhangige, additive Wirkung von Chemotherapeutikum und Strahlen verlaslich nutzbar ist, mus in der Pathogenese von Nebenwirkungen neben zellularen Mechanismen mit Interaktionen komplexer geweblicher Mechanismen gerechnet werden. Keine der derzeit in randomisierten Studien angewandten Therapieschemata genugt den aufgestellten Forderungen an ein wissenschaftlich fundiertes Therapieprotokoll. Fur Plattenepithelkarzinome ist am aussichtsreichsten ein Protokoll, das eine simultane oder interdigitierende Radiochemotherapie beinhaltet, die beide Modalitaten in wirksamer Dosierung (das heist ohne Reduktion der Strahlendosis oder Verlangerung der Behandlungsdauer) einsetzt, ohne das es zu einer Verstarkung akuter Nebenwirkungen kommt.

Recent radiobiological modeling of experimental and clinical data suggests a low α/s ratio for prostate cancer. If this assumption holds true, it represents a unique opportunity for exploiting a therapeutic window with hypo-fractionated radiotherapy schedules, especially in case α/s for prostate cancer is lower than that for rectal complications. This chapter will—after general considerations on fractionation and the α/s ratio—summarize the current scientific status on the assumed α/s for prostate cancer and relevant normal tissue complications and discuss the potential and the caveats of hypo-fractionation for prostate cancer.

Fractionated X-ray irradiation simulating routine radiotherapy (RT) can increase mouse epidermal cell proliferation resulting in a hyperplasic epidermis which is, in some ways, similar to that of human proliferative skin disorders. Dendritic epidermal T cells (DETC), CD4+, and CD8+ cells were studied at various times during daily X-ray irradiation of mouse skin up to 6 weeks. The number of DETC increased during the first week while epidermal cell density decreased but they gradually disappeared during the following weeks when the irradiated epidermis became hyperplastic. CD4+ or CD8+ cells are rare in normal interfollicular epidermis. CD4+ cells are mainly located in the deeper dermis and often around hair follicles in normal skin. Their numbers decreased during the first week, but increased during the third week when hyperplasia developed. The number of CD8+ cells is small in both normal and irradiated skin although they increased in the late stage of continued irradiation. The negative correlation of CD3+ cells and positive correlation of CD4+ cells with epidermal cell density support the speculation that one of the functions of CD3+ γδ cells is downregulation of responses mediated by conventional CD4+ αβ T cells and suggest that the latter cells play a role in the development of radiation-induced hyperplasia in mouse epidermis. Radiat. Oncol. Invest. 4:261–267, 1996. © 1997 Wiley-Liss, Inc.

The clinical importance of radiation-induced heart disease, in particular in post-operative radiotherapy of breast cancer patients, has been recognised only recently. There is general agreement, that a co-ordinated research effort would be needed to explore all the potential strategies of how to reduce the late risk of radiation-induced heart disease in radiotherapy. This approach would be based, on one hand, on a comprehensive understanding of the radiobiological mechanisms of radiation-induced heart disease after radiotherapy which would require large-scale long-term animal experiments with high precision local heart irradiation. On the other hand - in close co-operation with mechanistic in vivo research studies - clinical studies in patients need to determine the influence of dose distribution in the heart on the risk of radiation-induced heart disease. The aim of these clinical studies would be to identify the critical structures within the organ which need to be spared and their radiation sensitivity as well as a potential volume and dose effect. The results of the mechanistic studies might also provide concepts of how to modify the gradual progression of radiation damage in the heart by drugs or biological molecules. The results of the studies in patients would need to also incorporate detailed dosimetric and imaging studies in order to develop early indicators of impending radiation-induced heart disease which would be a pre-condition to develop sound criteria for treatment plan optimisation.

INTRODUCTIONIt has been recognized since the 1960s that the heart may bedamaged by substantial doses of radiation [>30 Gray (Gy)],such as used to occur during mantle radiotherapy for Hodg-kin lymphoma. During the last few years, however, evidencethat radiation-related heart disease (RRHD) can occur fol-lowing doses below 20 Gy has emerged from several inde-pendent sources. Those sources include studies of breastcancer patients who received mean cardiac doses of 3 to 17Gy when given radiotherapy following surgery and studiesof survivors of the atomic bombings of Japan who receiveddoses of up to 4 Gy.At doses above 30 Gy, an increased risk of RRHD can be-comes apparent within a year or two of exposure, and the riskincreases with higher radiotherapy dose, younger age at irra-diation, and the presence of conventional risk factors. Atlower doses, the typical latency period is much longer andis often more than a decade. The nature and magnitude ofthe risk following lower doses is not well characterized,and it is not yet clear whether there is a threshold dose belowwhich there is no risk.The evidence regarding RRHD comes from several differ-ent disciplines. The present review brings together informa-tion from pathology, radiobiology, cardiology, radiationoncology, and epidemiology; it summarizes current knowl-edge, identifies gaps in that knowledge, and outlines somepotential strategies for filling them.CURRENT KNOWLEDGEPathologyThe pathological expressions of RRHD documented fol-lowing therapeutic irradiation can be broadly reduced tofour conditions: pericarditis, pericardial fibrosis, diffusemyocardial fibrosis, and coronary artery disease (CAD)(1, 2). Radiation may also cause valvular disease, althoughtheevidence for this isnotasstrong.None of these conditionsis specific to radiation.Radiation-related pericarditis is characterized by an exu-date of a variable amount of protein-rich fluid within thepericardial sac (pericardial effusion). Rapid accumulationof this fluid can, in rare cases, cause potentially fatal cardiactamponade. Almost invariably, fibrin accumulates on the

Eine Reihe experimenteller Untersuchungen und randomisierter klinischer Studien zeigen eine Abnahme der lokalen Tumorkontrolle mit zunehmender Gesamtbehandlungszeit einer fraktionierten Strahlentherapie. Die wahrscheinlichste Ursache dises Zeitfaktors ist die Proliferation klonogener Tumorzellen wahrend der Therapie. Durch eine gezielte Hemmung der Proliferation klonogener Zellen wahrend einer Strahlenbehandlung konnten daher moglicherweise wesentliche Fortschritte in der Radioonkologie erreicht werden.

The present work summarises the history and current status of research into the importance of cancer stem cells for radiobiological research and for clinical radiation oncology. An effort is made to differentiate clonogenicity from stemness of cancer cells.In radiooncology, cancer stem cells have been an important research field for five decades. Quantitative transplantation assays with evaluation of the take dose 50% (TD50) remain the gold standard to verify the stemness of the selected cells. New technologies allow sorting of tumour cells according to their surface marker expression and thereby selecting subpopulations that are enriched in cancer stem cells (e.g., CD133, CD44, CD29). While development of surface-marker-based assays is a highly important step in cancer-stem-cell research, to date there are still problems to be solved, e.g., the specifity of markers, adequate animal models, and optimised in vitro assays. Of special concern for radiobiology is that clonogenic in vitro assays do not necessarily measure stemness of cancer cells. This hampers investigations into the important question of whether cancer stem cells are more radioresistant than non-stem cells. The most extensive of the limited data on this topic relate to glioma stem cells identified by the surface marker CD133. These do not provide firm evidence for difference of radiosensitivity between stem and non stem cells. In spite of many problems to be solved, the combination of stem cell markers with radiobiological assays bears considerable promise for advancing translational research in radiation oncology.