S Neubauer

Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Bavaria, Germany

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Publications (30)68.99 Total impact

  • A Weise · T Liehr · B Fritz · K Schubert · S Neubauer

    No preview · Article · Jan 2009 · Medizinische Genetik
  • Luitpold Distel · Ulrike Keller · Susann Neubauer
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    ABSTRACT: Fluorescence in situ hybridization (FISH) using whole-chromosome painting (wcp) probes has been shown to be a reliable technique for studying chromosomal changes. The three-color FISH method presented here is a simple and rapid assay that can be used for the detection of individual radiosensitivity. The individual chromosomal sensitivity is estimated after in vitro irradiation of only a limited amount of peripheral blood. By performing the three-color FISH approach, one is able to detect and quantify radiosensitivity on the one hand by quantifying the mis- and unrepaired break events, and on the other hand by scoring the frequency of translocations and complex aberrations. The three-color FISH method is described in detail, and results are provided that show the reliability of this approach.
    No preview · Chapter · Dec 2008

  • No preview · Chapter · Jan 2008
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    ABSTRACT: A molecular cytogenetic study was performed on 48 infertile patients who were identified as carriers of balanced translocations (40 cases), inversions (6 cases) or insertions (2 cases) by means of banding cytogenetics. Cases with a Robertsonian translocation or pericentric inversion 2 or 9 were not included. In summary, 100 break-events occurred in these patients, and 90 different chromosomal regions were involved. Thus, this study confirmed the presence of abnormal karyotypes in a subgroup of patients seeking infertility treatment. Breaks were demonstrated to appear preferentially in GTG-light bands in these patients. Furthermore, the observed breakpoints were associated with genomic regions prone to instability due to the presence of segmental duplications. Nonetheless, further detailed molecular analysis will be necessary in the future to characterize the mechanisms and genetic basis for this phenomenon.
    No preview · Article · Jul 2007 · International Journal of Molecular Medicine
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    ABSTRACT: Radiosensitivity of normal tissue is a crucial factor of radiotherapy (RT)-related side effects. Here, we report the analysis of spontaneous and in vitro irradiation-induced chromosomal aberrations in 256,679 metaphases from 222 different individuals using three-color fluorescence in situ hybridization as a measure of radiosensitivity. Samples were categorized into the following 6 groups: (1) healthy individuals, (2) cancer patients prior to radiotherapy, (3) RT-treated cancer patients, (4) individuals heterozygous or (5) homozygous for a mutation in the ataxia telangiectasia mutated (ATM) gene or in the Nijmegen breakage syndrome (NBS1) gene and (6) hypersensitive patients (outliers). A normal distribution of the number of chromosomal aberrations, measured as breaks per metaphase (B/m), was adopted for all examined groups. The mean value of the control group was 0.40B/m (SD+/-0.07). This value was lower compared to the mean breakage rate from 175 non-exposed (0.50+/-0.12B/m) and pre-exposed (0.50+/-0.16B/m) cancer patients. Nineteen of the metaphase spreads from the analyzed cancer patients had a high number of chromosomal aberrations (1.04+/-0.29B/m) and were designated as a separate hypersensitive subgroup (outliers). The aberration frequency of this group was comparable to those of ATM or NBS1 heterozygotes (0.86+/-0.26B/m). The highest incidence of aberrations was observed in ATM and NBS1 homozygous patients (2.23+/-1.03B/m). The frequency of break events in the analyzed groups resulted in a normal distribution with varying means and broadnesses defining a characteristic sensitivity pattern for each group. In the RT-relevant group of cancer patients, those patients who have cancer, about one-third of the normally distributed samples were determined to be sensitive as defined by the number of induced aberrations higher than the 99% confidence interval of the normal individual's Gaussian distribution. About 5% of these samples were outside of the 99% confidence interval for the RT-relevant group's normal distribution. These outliers with higher chromosomal breakage rates suggest a unique class of hypersensitive individuals that are susceptible to chromosomal damage and may be directly associated with an increased risk to suffer from radiotherapy-related complications.
    No preview · Article · Jan 2007 · Radiotherapy and Oncology
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    ABSTRACT: In large-scale pediatric chemo- and radiotherapy trials a proportion of patients as high as 10-15% is usually reported as having severe treatment related toxicity occasionally resulting in toxic death. Little is known on the underlying predisposition of the individual child. Several hereditary disorders including immunodeficiency (ID) syndromes or repair disorders, Ataxia Telangiectasia (AT), and Nijmegen breakage syndrome (NBS) were associated with an elevated risk for severe treatment related toxicity. This report involves the case of a 7-year-old boy with medulloblastoma who suffered from remarkably severe side effects during and after postoperative radio- and chemotherapy. Several months following craniospinal radiation with a total dose of 36 Gy, late normal tissue side effects were observed within the treated volume. Eighteen months after initiation of treatment the patient died due to protracted cardiopulmonary failure. To quantify the intrinsic radiation sensitivity, lymphoblastoid cells were used to examine chromosomal aberrations by fluorescence in situ hybridization detecting between two to ninefold higher chromosomal breakage rates in comparison to cells of average cancer patients. Skin fibroblasts showed in the clonogenic survival assays a twofold increased sensitivity. Western blotting demonstrated a typical lack of Nbs1. PCR-SSCP analysis followed by direct sequencing of positive samples revealed a homozygous truncating mutation of the NBS1 gene (657del5). This case highlights that severe treatment related complications in pediatric cancer patients may be the result of increased intrinsic radio- and chemosensitivity due to NBS, AT, and other ID syndromes. It is suggested to exclude such conditions in all patients with anthropometric parameters below the 3rd centile and other signs suggestive for repair disorders or ID syndromes.
    No preview · Article · Jul 2003 · Medical and Pediatric Oncology
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    ABSTRACT: Reliable determination of intrinsic radiosensitivity in individual patients is a serious need in radiation oncology. Chromosomal aberrations are sensitive indicators of a previous exposure to ionizing irradiation. Former molecular cytogenetic studies showed that such aberrations as an equivalent of intrinsic radiosensitivity can be detected by fluorescence in-situ hybridization (FISH) techniques using whole chromosome painting (wcp) probes. However, only one up to three randomly chosen wcp probes have been applied for such approaches until now. As a random distribution of chromosomal rearrangements along the chromosomes is up to now still controversial, the power of the 24-color FISH approach should be elucidated in the present study. Lymphocytes derived from lymphoblastoid cell lines of one patient with Nijmegen breakage syndrome (NBS homozygote) and of two NBS heterozygotes and peripheral blood lymphocytes of two controls were analyzed. Samples of each patient/control were irradiated in vitro with 0.0 Gy, 0.7 Gy or 2.0 Gy prior to cultivation. Chromosomal aberrations were analyzed in detail and quantified by means of 24-color FISH as an expression of the individual intrinsic radiosensitivity. 24-color FISH analyses were done in a total of 1,674 metaphases. After in-vitro irradiation, 21% (0.7 Gy) or 57% (2.0 Gy) of the controls' cells, 15% (0.7 Gy) or 53% (2.0 Gy) of the heterozygotes' cells and 54% (0.7 Gy) or 79% (2.0 Gy) of the homozygote's cells contained aberrations. The highest average rates of breaks per mitosis [B/M] (0.7 Gy: 1.80 B/M, 2.0 Gy: 4.03 B/M) and complex chromosomal rearrangements [CCR] (0.7 Gy: 0.20 CCR/M, 2.0 Gy: 0.47 CCR/M) were observed in the NBS patient. Moreover, the proportion of different aberration types after irradiation showed a distinct increase in the rate of CCR combined with a decrease in dicentrics in the NBS homozygote. To come to a more complete picture of radiation-induced aberrations and to detect and quantify genetically determined intrinsic radiosensitivity, a 24-color FISH approach using all human chromosome painting probes has been successfully applied on cytogenetic preparation lymphocytes. The controls and NBS heterozygotes were clearly distinguished from the NBS homozygote subject.
    No preview · Article · May 2002 · Strahlentherapie und Onkologie
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    ABSTRACT: A three-color chromosome painting technique was used to examine the spontaneous and radiation-induced chromosomal damage in peripheral lymphocytes and lymphoblastoid cells from 11 patients with ataxia telangiectasia (AT) and from 14 individuals heterozygous for an AT allele. In addition, cells from two homozygous and six obligate heterozygous carriers of mutations in the Nijmegen breakage syndrome gene (NBS) were investigated. The data were compared to those for chromosome damage in 10 unaffected control individuals and 48 cancer patients who had not yet received therapeutic treatment. Based on the well-documented radiation sensitivity of AT and NBS patients, it was of particular interest to determine whether the FISH painting technique used in these studies allowed the reliable detection of an increased sensitivity to in vitro irradiation of cells from heterozygous carriers. Peripheral blood lymphocytes and lymphoblastoid cells from both the homozygous AT and NBS patients showed the highest cytogenetic response, whereas the cells from control individuals had a low number of chromosomal aberrations. The response of cells from heterozygous carriers was intermediate and could be clearly differentiated from those of the other groups in double-coded studies. AT and NBS heterozygosity could be distinguished from other genotypes by the total number of breakpoints per cell and also by the number of the long-lived stable aberrations in both AT and NBS. Only AT heterozygosity could be distinguished by the fraction of unstable chromosome changes. The slightly but not significantly increased radiosensitivity that was found in cancer patients was apparently due to a higher trend toward rearrangements compared to the controls. Thus the three-color painting technique presented here proved to be well suited as a supplement to conventional cytogenetic techniques for the detection of heterozygous carriers of these diseases, and may be superior method.
    No preview · Article · Apr 2002 · Radiation Research
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    ABSTRACT: The suitability of a three-color fluorescence in situ suppression hybridization technique was examined for monitoring five different groups of individuals: 30 occupied in radiology, 26 occupied in nuclear medicine or radiation physics, 32 patients with breast cancer, 26 occupied with military waste disposal, all presumably exposed to low doses of radiation or chemical mutagens and a non-exposed control group (N=29). The average frequency of breaks constituting the various aberrations did not significantly differ between the groups of medical radiation appliers and the control group. However, breast tumor patients and military waste disposers, as groups, showed a higher aberration rate than did healthy controls. Stable rearrangements mainly characterized the groups of controls, tumor patients, and radiation appliers, while a higher proportion of unstable aberrations was found in the chemically exposed individuals. Individuals with an increased frequency of aberrations could be detected within each examined group, which clearly determined the average values of the whole group. With respect to interchromosomal distribution of the breakpoints constituting the found aberrations and the involvement of the labeled chromosomes in rearrangements, the observed values were very close to the expected ones in the controls. A rather similar trend of deviations from expectation was observed in all other groups. Chromosome 4 was slightly over-affected, while chromosome 2 was slightly underrepresented in all analyzed groups (except tumor patients). Rearrangements of the labeled chromosomes with the unlabeled ones exceeded expectation. In conclusion, chromosome painting if included in further attempts of human population monitoring will broaden the basis of argumentation with respect to health risks introduced by mutagen exposure.
    No preview · Article · May 2001 · Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
  • R. Arutyunyan · S. Neubauer · P. Martus · T. Dörk · M. Stumm · E. Gebhart
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    ABSTRACT: A three-color chromosome in situ suppression (CISS) hybridization technique (chromosome painting) was applied to analyze spontaneous and induced (by in vitro irradiation) chromosomal aberrations in peripheral lymphocytes and lymphoblastoid cell lines of homozygote and heterozygote individuals with ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS). The painting technique employing for hybridization DNA libraries of the chromosomes 1, 2, and 4 allows the additional detection of chromosomal rearrangements which are not or at least not easily detectable by the classical cytogenetic methods. In all investigated groups the observed intercellular distribution of chromosomal aberrations and breaks was compared with Poisson distribution and geometric distribution. In the lymphocytes of homozygous patients with AT a very high level of chromosomal aberrations and breaks was induced by the irradiation of cultures at a dose of 2.0 Gy, as compared with AT heterozygotes irradiated with the same dose. The observed distributions of chromosomal aberrations in cells fitted Poisson distribution in the absolute majority of variants, while geometric distribution fitted much lesser number of variants. In AT heterozygous individuals levels of chromosomal aberrations induced by in vitro irradiation at a dose of 2.0 Gy were lower than in AT homozygotes, and their observed distributions were mainly described by geometric distribution and only in a few cases by Poisson distribution. In one NBS homozygous patient the comparatively low level of aberrations per cell upon irradiation at a dose of 2.0 Gy was described by geometric distribution, while under identical experimental conditions, in the group of NBS heterozygous individuals the low levels of chromosomal aberrations per cell were described both by Poisson and geometric distribution. The low levels of spontaneous and radiation-induced chromosomal aberrations in all investigated groups fitted both distributions. The distributions of breaks in the absolute majority of irradiated variants fitted neither Poisson nor geometric distribution reguiring further comparison with other distributions or combination of distributions. The problems of description of observed distributions by the theoretical ones are discussed taking into account specific experimental conditions or nonspecific parameters. Comparative analysis of intercellular distributions could be regarded as an informative cytogenetic approach to the research of radiosensitivity in the patients with chromosomal instability.
    No preview · Article · Mar 2001 · Eksperimentalʹnai͡a onkologii͡a
  • M Stumm · S Neubauer · S Keindorff · R D Wegner · P Wieacker · R Sauer
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    ABSTRACT: The application of fluorescence in situ hybridization (FISH) using whole-chromosome paints (WCPs) is proving to be a very powerful technique for revealing chromosomal instability that, for the most part, has gone undetected by conventional cytogenetic analysis. We have analyzed the frequency of translocations in lymphocytes and lymphoblastoid cell lines from ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) homozygotes and heterozygotes using a three-color chromosome-painting technique (WCP 1, 2, 4). With this assay we were able to detect an increased frequency of spontaneous translocations in AT homozygotes (median, 18.47 +/- 10.82 translocations per 1,000 metaphase cells; 10 patients) and AT heterozygotes (median, 7.87 +/- 3.15 translocations per 1,000 cells; 7 patients), in comparison to controls (median, 2.26 +/- 1.75 translocations per 1,000 cells; 10 controls). Analysis of NBS homozygotes (median, 19.05 +/- 11.27 translocations per 1,000 cells; 5 patients) and NBS heterozygotes (median, 6.93 +/- 3.04 translocations per 1,000 cells; 6 patients) also showed an increased frequency of translocations in these patients compared to controls. The presence of such hitherto undetected chromosomal aberrations corroborate previous findings of spontaneous chromosomal instability in AT and NBS patients, as manifested by an increased rate of open breaks and rearrangements involving chromosomes 7 and 14. Moreover, we show that the degree of genomic instability in AT and NBS patients is even higher than previously established and that some AT and NBS heterozygotes evidence spontaneous chromosomal instability as well. These increased levels of nonspecific translocations could be an important risk factor for the development of malignancies in homozygotes and heterozygotes for ATM or NBS1 gene mutations.
    No preview · Article · Feb 2001 · Cytogenetics and cell genetics
  • S Neubauer · T Liehr
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    ABSTRACT: Interphase cytogenetics using formalin-fixed/paraffin-embedded tissue is now a well-established technique, which renders it possible to obtain "cytogenetic information" from interphase nuclei of solid tumors (1,2, for ovarian cancer, e.g., 3-8). It is the only tool to investigate specific numerical chromosomal aberrations (3-7), amplification.
    No preview · Article · Jan 2001 · Methods in molecular medicine
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    ABSTRACT: The majority of antigen receptor diversity in mammals is generated by V(D)J recombination. During this process DNA double strand breaks are introduced at recombination signals by lymphoid specific RAG1/2 proteins generating blunt ended signal ends and hairpinned coding ends. Rejoining of all DNA ends requires ubiquitously expressed DNA repair proteins, such as Ku70/86 and DNA ligase IV/XRCC4. In addition, the formation of coding joints depends on the function of the scid gene encoding the catalytic subunit of DNA-dependent protein kinase, DNA-PK(CS), that is somehow required for processing of coding end hairpins. Recently, it was shown that purified RAG1/2 proteins can cleave DNA hairpins in vitro, but the same activity was also described for a protein complex of the DNA repair proteins Nbs1/Mre11/Rad50. This leaves the possibility that either protein complex might be involved in coding end processing in V(D)J recombination. We have therefore analyzed V(D)J recombination in cells from patients with Nijmegen breakage syndrome, carrying a mutation in the nbs1 gene. We find that V(D)J recombination frequencies and the quality of signal and coding joining are comparable to wild-type controls, as analyzed by a cellular V(D)J recombination assay. In addition, we did not detect significant differences in CDR3 sequences of endogenous Ig lambdaL and kappaL chain gene loci cloned from peripheral blood lymphocytes of an NBS patient and of healthy individuals. These findings suggest that the Nbs1/Mre11/Rad50 complex is not involved in coding end processing of V(D)J recombination.
    No preview · Article · Nov 2000 · Molecular Immunology
  • L. V. Distel · S. Neubauer · G. G. Grabenbauer · R. Sauer

    No preview · Article · Dec 1999 · International Journal of Radiation OncologyBiologyPhysics
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    ABSTRACT: Spitz nevi are benign melanocytic neoplasias which have distinct pathological features that make the pathological differential diagnosis from malignant melanomas extremely difficult. The Spitz nevi may be misdiagnosed as malignant melanoma and vice versa. Therefore, interphase fluorescence in situ hybridization (I-FISH) was used for a possible discrimination between Spitz nevi and malignant melanomas on the basis of numerical aberrations of the chromosome complement in interphase nuclei of thin sections. Previous studies had shown changes in malignant melanomas which were not found at the same level in normal tissue or benign tumors. Thin sections of archival paraffin material from 42 Spitz nevi with different histological type and grade of anomaly were subjected to FISH-analyses using commercially available biotinylated and/or digoxigenated alphoid DNA probes of chromosomes 1, 6, 7, 9, 17 and 18, which were applied in combinations in a two- or three-color-FISH. Unaffected epithelial areas from the same sections served as. The obtained data were compared with those collected previously from thin sections of malignant melanomas prepared in the same way. Due to the sometimes limited nevus area investigated, the number of evaluable nuclei was lower than expected from previous experiences with malignant melanomas. Therefore, only 20 nevi could be reliably evaluated. The comparison of the group of Spitz nevi with the group of controls did not show any significant difference regarding chromosomes 1, 6, 7, 9 and 17 (Wilcoxon test). The method used to detect chromosomal loss or gain in the individual Spitz nevi demonstrated only two nevi (one of the spindle cell type with a low to middle grade of anomaly, the other of the epitheloid cell type with a middle grade of anomaly) with a gain of chromosome 7 and chromosome 17, respectively. So, with respect to the histological type and grade of anomaly, no numerical aberrations could be detected in Spitz nevi. The comparison of the group of Spitz nevi with subgroups of malignant melanomas (metastatic, non-metastatic, melanomas with a thickness <1.5 mm and melanomas with a thickness >2. 0 mm) and with the whole group of malignant melanomas showed significant differences concerning chromosome 9 (Mann-Whitney U test), signal indices, which were higher in the melanomas than in the Spitz nevi. Regarding chromosomes 6, 7 and 17 no significant differences could be shown, although a trend of gain in melanomas and of loss in Spitz nevi was observed of these chromosomes.
    No preview · Article · Jun 1999 · International Journal of Oncology
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    ABSTRACT: To estimate the frequency of single-strand breaks on a single cell level the so-called comet-assay (single cell gel electrophoresis) is a well-established technique. We present a modified protocol suitable for testing primary tumors, a kind of tissue very uneasy to be analysed in former single cell gel electrophoresis assays. Tumor cells of 12 studied cases showed a typical dose-rate effect on in vitro irradiation with different X-ray doses, as observed in peripheral blood leukocytes. Interestingly, the repair capability of primary tumor cells was lower than that of peripheral blood leukocytes of the same patients.
    No preview · Article · Nov 1998 · Genetic Analysis Biomolecular Engineering
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    ABSTRACT: A three-colour chromosome in situ suppression (CISS) hybridization technique (chromosome painting) was used to analyse X-ray-induced chromosome aberrations in peripheral lymphocytes of 83 cancer patients who were assigned to (N = 34) or had just undergone radiation therapy (N = 49). The imperical intercellular distribution of chromosomal aberrations was compared with Poisson distribution and geometric distribution. The impact of complex aberrations on this disributions allowed to discern patients with a high radiation sensitivity from those with an average clinical reaction to therapeutic irradiation. In the group of non-exposed patients, the low mean level of aberrations fitted both distributions in the majority of cases. In contrast, in the group of previously irradiated patients, the geometric distribution in most cases fitted more variants. After an in vitro irradiation of the lymphocytes both groups showed a great interindividual variation between the patients concerning the means and the fit to the distributions, despite similar mean values. The distribution of break points generating the observed spectrum of aberrations, except their variants with low level of mean, did even less fit either of the examined distributions. The use of parameters not only concerning the average number of aberrations or breaks but also their intercellular patterns improved the separation of the previously exposed from the non-exposed, as well as average-reacting patients from radiosensitive patients. The data presented have also documented the high power of the chromosome painting technique in detecting and analysing long-term clastogenic effects as well as complex rearrangements. Examination of these patterns by use of goodnessof-fit tests is expected to offer additional information for discriminating radiosensitive cancer patients.
    No preview · Article · Sep 1998 · Eksperimentalʹnai͡a onkologii͡a

  • No preview · Article · Jan 1998 · Work
  • Jürgen Dunst · Neubauer S · Gebhart E

    No preview · Article · Aug 1997 · European Journal of Cancer
  • Susann Neubauer · Jürgen Dunst · Erich Gebhart
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    ABSTRACT: Lymphocytes of a small fraction of cancer patients responded to in vitro irradiation with an extreme chromosomal reaction. A large portion of the observed chromosome aberrations were complex chromosomal rearrangements (CCR). The present study is an attempt to define the impact of CCR on the predictive detection of an intrinsic clinical radiosensitivity in cancer patients in more detail. A three-colour 'FISH-painting' technique (chromosome in situ suppression (CISS) hybridization) was used for the detection of chromosomal rearrangements, induced by in vitro irradiation, in 81 samples of peripheral blood lymphocytes from 66 cancer patients. Thirty-three of those were assigned for radiation therapy, the others having just undergone radiation therapy. Seven healthy individuals served as controls. CCRs are a very rare event in non-irradiated cells. Lymphocytes of patients who had just undergone therapeutic irradiation, however, not only exhibited high basic frequencies of CCR but also responded to in vitro irradiation with a more drastic increase of CCR than did the lymphocytes of non-exposed patients. A high inter-individual variability of the reaction to in vitro irradiation could be generally stated. The lymphocytes of patients with clinical signs of an outstanding radiosensitivity responded with an unusually high frequency of CCR. The total number of CCRs detected by CISS was found to be dependent on the interval from a previous radiation therapy and was slightly influenced by previous cytostatic therapy. Irrespective of these influences, patients with clinically defined radiation hypersensitivity were those with the highest radiosensitivity also in cytogenetic terms (including CCR). The successful use of FISH-painting for the detection of CCR, in addition to the general breakage frequency, highlights its suitability in the identification of individual hypersensitivity to ionizing radiation. The time-consuming cytogenetic examination can be considerably reduced by its use.
    No preview · Article · Jun 1997 · Radiotherapy and Oncology

Publication Stats

489 Citations
68.99 Total Impact Points


  • 1992-2007
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • • Occupational Social and Environmental Medicine and Policlinic
      • • Department of Radiation Therapy
      Erlangen, Bavaria, Germany
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
  • 2001
    • Yerevan State University
      Ayrivan, Yerevan, Armenia
  • 1995-1998
    • Martin Luther University Halle-Wittenberg
      Halle-on-the-Saale, Saxony-Anhalt, Germany