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The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

The aim of this study was to determine the effects of ionizing radiation on gene expression by using for a first time a qPCR platform specifically established for the detection of 94 DNA repair genes but also to test the robustness of these results by using three analytical methods (global pattern recognition, ΔΔCq/Normfinder and ΔΔCq/Genorm). Study was focused on these genes because DNA repair is known primarily to determine the radiation response. Six strains of normal human fibroblasts were exposed to 2 Gy, and changes in gene expression were analyzed 24 h thereafter. A significant change in gene expression was found for only few genes, but the genes detected were mostly different for the three analytical methods used. For GPR, a significant change was found for four genes, in contrast to the eight or nine genes when applying ΔΔCq/Genorm or ΔΔCq/Normfinder, respectively. When using all three methods, a significant change in expression was only seen for GADD45A and PCNA. These data demonstrate that (1) the genes identified to show an altered expression upon irradiation strongly depend on the analytical method applied, and that (2) overall GADD45A and PCNA appear to play a central role in this response, while no significant change is induced for any of the other DNA repair genes tested.

Despite considerable progress in (I) our understanding of the aetiopathology of head and neck cancer and (II) the precise delivery of radiotherapy, long-term survival rates for many patients with head and neck cancer remain disappointingly low. Over the past years, gold nanoparticles (NP) have emerged as promising radiation dose enhancers. In a recent study published in Nanoscale, Popovtzer et al. have used gold NP coated with an antibody against the epidermal growth factor receptor (EGFR) in an attempt to enhance radiation-induced tumour cell killing in a head and neck cancer xenograft model. They report a significant impact of the combined treatment with radiation and gold NP on tumour growth and suggest an involvement of apoptosis, inhibition of angiogenesis and diminished tissue repair. In this perspective, we illustrate the underlying radiobiophysical concepts and discuss some of the challenges associated with this and related nanoparticle-radiotherapy studies from a physics, chemistry, biology and therapy angle. We conclude that strong interdisciplinary collaborations spanning all these areas are crucially important to proceed towards effective cancer treatment with gold NP "from bench to bedside".

Background and purpose: Reported associations between risk of radiation-induced normal tissue injury and single nucleotide polymorphisms (SNPs) in TGFB1, encoding the pro-fibrotic cytokine transforming growth factor-beta 1 (TGF-beta 1), remain controversial. To overcome publication bias, the international Radiogenomics Consortium collected and analysed individual patient level data from both published and unpublished studies. Materials and methods: TGFB1 SNP rs1800469 c.-1347T>C (previously known as C-509T) genotype, treatment-related data, and clinically-assessed fibrosis (measured at least 2 years after therapy) were available in 2782 participants from 11 cohorts. All received adjuvant breast radiotherapy. Associations between late fibrosis or overall toxicity, reported by STAT (Standardised Total Average Toxicity) score, and rs1800469 genotype were assessed. Results: No statistically significant associations between either fibrosis or overall toxicity and rs1800469 genotype were observed with univariate or multivariate regression analysis. The multivariate odds ratio (OR), obtained from meta-analysis, for an increase in late fibrosis grade with each additional rare allele of rs1800469 was 0.98 (95% Confidence Interval (CI) 0.85-1.11). This CI is sufficiently narrow to rule out any clinically relevant effect on toxicity risk in carriers vs. non-carriers with a high probability. Conclusion: This meta-analysis has not confirmed previous reports. of association between fibrosis or overall toxicity and rs1800469 genotype in breast cancer patients. It has demonstrated successful collaboration within the Radiogenomics Consortium. (C) 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 105 (2012) 289-295

A key event in the progression of glomerular disease is podocyte loss that leads to focal and segmental glomerulosclerosis (FSGS). Because adult podocytes are postmitotic cells, podocyte replacement by bone marrow–derived progenitors could prevent podocytopenia and FSGS. This study uses double immunofluorescence for Wilms' tumor-1 and enhanced green fluorescent protein (eGFP) to examine whether an eGFP-positive bone marrow transplant can replace podocytes under normal circumstances and in 3 different rat models of FSGS: puromycin aminoglycoside nephropathy, subtotal nephrectomy, and uninephrectomy. Bone marrow engraftment was successful, with more than 70% eGFP-positive cells and virtually normal histologic findings. No bone marrow transplant–derived podocytes were found in four control rats after transplantation, in nine rats at up to 10 weeks after puromycin aminoglycoside nephropathy induction, in three rats 23 days after subtotal nephrectomy, and in six rats up to 21 days after uninephrectomy. A total of 2200 glomeruli with 14,474 podocytes were evaluated in all groups. Thus, podocyte replacement by bone marrow–derived cells does not contribute to podocyte turnover in rats, even in models of podocyte damage. This is in contrast to previous studies in mice, in which bone marrow–derived podocytes were found. Further studies will address this discrepancy, which could be explained by species differences or by predominant podocyte regeneration from a parietal epithelial cell niche.

Purpose To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with fibrosis and also individual radiosensitivity. Methods and materials Retrospective analysis with 69 breast cancer patients treated with breast-conserving radiotherapy; total dose delivered was restricted to vary between 54 and 55Gy. Fibrosis was evaluated according to LENT/SOMA score. DNA was extracted from blood samples; cellular radiosensitivity was measured using the G0 assay and polymorphisms by PCR–RFLP and MALDI-TOF, respectively. Results Twenty-five percent of all patients developed fibrosis of grade 2 or 3. This proportion tends to be higher in patients being polymorphic in TGFB1 or XRCC1 when compared to patients with wildtype genotype, whereas for ATM , GSTP1 , SOD2 and XPD the polymorphic genotype appears to be associated with a lower risk of fibrosis. However, none of these associations are significant. In contrast, when a risk score is calculated based on all risk alleles, there was significant association with an increased risk of fibrosis (per risk allele odds ratio (ORs)=2.09, 95% confidence interval (CI): 1.32–3.55, p =0.0005). All six polymorphisms were found to have no significant effect on cellular radiosensitivity. Conclusions It is most likely that risk for radiation-induced fibrosis can be assessed by a combination of risk alleles. This finding needs to be replicated in further studies.

Purpose Comparing the chromosomal radiosensitivity of prostate cancer patients with that of healthy donors. Materials and methods The study was performed on 81 prostate cancer patients characterised by a clinical stage of predominantly pT2c or pT3a and a median age of 67years. As healthy donors 60 male monozygotic twin pairs were recruited with a median age of 28years. Chromosomal radiosensitivity was measured using both G0- and G2-assay. Results No difference between healthy donors and prostate cancer patients was detected concerning G0-radiosensitivity, since medians were similar (Hodges–Lehmann estimate: −0.05, 95% CI: −0.18–0.08, p =0.4167). However, a pronounced difference was determined for G2-radiosensitivity with prostate cancer patients showing a significantly higher sensitivity compared to healthy donors (Hodges–Lehmann estimate: −0.41, 95% CI: −0.53 to −0.30, p =1.75 −9 ). Using the 90% quantile of G2-radiosensitivity in healthy donors as a threshold for discrimination the fraction of prostate cancer patients with elevated radiosensitivity increased to 49%. Conclusion G2-, but not G0-radiosensitivity is a promising marker for predisposition of prostate cancer.

To study the effect of treatment time prolongation following initial dose acceleration on the response of subcutaneously growing R1H tumor. Continuous standard fractionation (30 fractions/40 days) was compared to initially accelerated treatment (30 fractions/21 days) followed by five to two fractions per week yielding total treatment times from 40 to 72 days. Local tumor control was assessed as endpoint. Radiation dose to control 50% of the tumors (TCD50%) decreased statistically significant from 83.5 Gy (95% confidence interval [CI]: 78.6 .. 88.4) for standard fractionation to 74.1 Gy (95% CI: 72.7 .. 75.5) determined for all accelerated treatment arms (p = 0.003). Prolongation of treatment time after initial acceleration from 40 to 72 days led to a small but statistically not significant increase in TCD50% from 72.0 Gy (95% CI: 71.0 .. 72.9) to 76.2 Gy (95% CI: 69.9 .. 82.4) corresponding to a repopulated dose of 0.9 Gy per week. This time factor is considerably smaller than for conventional radiation treatment as determined in previous experiments. The results indicate that initially accelerated irradiation not only improves local tumor control but also minimizes the negative effect of treatment time prolongation. This might be due to changes in tumor cell repopulation kinetics.

HBOC-201 is an ultra purified bovine hemoglobin solution. It has already been used in clinical phase II/III trials for emergency treatments. Animal experiments have shown that HBOC-201 is highly effective in tissue oxygenation. The study was performed in order to assess the potential of low dose HBOC-201 to improve tumor oxygenation.30 rats with a subcutaneously growing rhabdomyosarcoma R1H tumor were randomly assigned either to be ventilated with carbogen (n = 10), or to receive an IV injection of 0.3 g/kg HBOC-201 (n = 10) or a combination of 0.3 g/kg HBOC-201 and carbogen breathing (n = 10). Under general anesthesia the effects of the respective treatment on the tissue oxygen tension (tpO2) of the tumor were determined using a flexible stationary probe at baseline (b) and 15 and 60 min after application of the respective medication.HBOC-201 alone failed to improve tumor tpO2 (b: 1.3 +/- 1.2mmHg; 15min: 1.4 +/- 1 mmHg; 60min: 1 +/- 1 mmHg). In combination with carbogen the mean tpO2 of the tumor raised in comparison to baseline values (b: 3.1 +/- 4.6 mmHg; mmHg; 15min: 8.5 +/- 11*mmHg; 60min: 4.8 +/- 5mmHg; *p0.05 vs. b), but this effect was less pronounced than the increase in tpO2 by carbogen alone (b: 3.4 +/- 3.4mmHg; 15min: 9 +/- 10* mmHg; 60 min: 13 +/- 19* mmHg; *p0.05 vs. b).The application of low dose hemoglobin solution HBOC-201 does not result in improvement of tissue oxygenation in the rat rhabdomyosarcoma R1H.

To determine the sensitivity and specificity of 18F-fluorodeoxyglucose-positron-emission tomography (FDG-PET) in the diagnosis of R1H tumours after fractionated radiotherapy, and the dependency of sensitivity and specificity on time after therapy. In addition, the time benefit of FDG-PET concerning early recognition of recurrences after fractionated radiotherapy was assessed.Subcutaneously growing rat rhabdomyosarcoma R1H tumours were irradiated by applying total doses of 80 or 85 Gy after reaching a start volume of 0.8 cm3. Twenty animals were treated. Tumour volume was determined twice a week. FDG-PET was performed weekly before, during and for 6 months after therapy using a conventional full-ring whole-body PET scanner. In total, 600 PET results were evaluated qualitatively using a six-scale score. PET results and actual tumour volumes were compared. The sensitivity and specificity of tumour detection by PET was calculated for different times after the onset of therapy. The optimal score for tumour detection and the influence of time after therapy on the quality of PET (time benefit) was evaluated using receiver-operating characteristics.After irradiation, 8/20 tumours (40%) were locally controlled, while 12/20 recurred. In this tumour model, evidence of relapse is assured when a volume of 0.1 cm3 is reached. Sensitivity of tumour diagnosis by PET increases with time, i.e. with the volume of recurrent tumours after the onset of therapy, mounting to0.95 after 100 days. Specificities of 0.95-1.0 were determined after therapy, showing no increase with time. Tumour diagnosis by PET is highly accurate when performed 80 days after the start of treatment. On average, tumours were recognized by PET on 31, 62, 74 and 81 days (median) before approaching volumes of 0.2, 0.5, 0.8 or 1.0 cm3, respectively.An experimental system was implemented that allows reproducible detection of recurrent R1H tumours after radiotherapy using FDG-PET. The usefulness of PET as a diagnostic test for R1H tumours is very good and a reliable resolution for PET is demonstrated for volumes1 cm3. The results indicate that FDG-PET enables early recognition of recurrences after fractionated radiotherapy.

Whole brain radiation therapy (WBRT) is reported to improve local control after resection of brain metastases. Improvement of survival was only observed in patients with controlled extracranial disease. The optimum radiation schedule has yet to be defined. The authors’ experience with a postoperative approach including WBRT and a radiation boost to the metastatic site is presented. Criteria for inclusion into this retrospective analysis were solitary brain metastasis, Karnofsky performance status ≥ 70%, and controlled extracranial disease. Two therapies were compared for local control and survival: surgery followed by 40 Gy WBRT (group A) versus surgery followed by 40 Gy WBRT and a 10 Gy boost (group B). Statistical analysis was performed using the Kaplan-Meier method and log-rank test. 33 patients were included (17 group A, 16 group B). The results suggested better local control (p = 0.0087) and survival (p = 0.0023) for group B. 17/17 patients (100%) of group A and 13/16 patients (81%) of group B showed progression of brain metastasis, 8/17 and 3/16 patients in the area of metastatic surgery. Median time to progression was 7 (1–22) months in group A and 12 (3–42) months in group B. The number of cancer-related deaths amounted to 17/17 (100%) in group A after a median interval of 9 (3–26) months, and to 9/16 (56%) in group B after 14 (4–46) months. After resection of solitary brain metastasis, a radiation boost in addition to WBRT seems to improve local control and survival when compared to postoperative WBRT alone. The results should be confirmed in a larger prospective trial.

The aim of this study was to determine the impact of functional single nucleotide polymorphism (SNP) pathways involved in the ROS pathway, DNA repair, or TGFB1 signaling on acute or late normal toxicity as well as individual radiosensitivity. Patients receiving breast-conserving surgery and radiotherapy were examined either for erythema (n = 83), fibrosis (n = 123), or individual radiosensitivity (n = 123). The 17 SNPs analyzed are involved in the ROS pathway (GSTP1, SOD2, NQO1, NOS3, XDH), DNA repair (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) or TGFB signaling (SKIL, EP300, APC, AXIN1, TGFB1). Associations with biological and clinical endpoints were studied for single SNPs but especially for combinations of SNPs assuming that a SNP is either beneficial or deleterious and needs to be weighted. With one exception, no significant association was seen between a single SNP and the three endpoints studied. No significant associations were also observed when applying a multi-SNP model assuming that each SNP was deleterious. In contrast, significant associations were obtained when SNPs were suggested to be either beneficial or deleterious. These associations increased, when each SNP was weighted individually. Detailed analysis revealed that both erythema and individual radiosensitivity especially depend on SNPs affecting DNA repair and TGFB1 signaling, while SNPs in ROS pathway were of minor importance. Functional pathways of SNPs may be used to form a risk score allowing to predict acute and late radiation-induced toxicity but also to unravel the underlying biological mechanisms.

Das Ziel der vorliegenden Arbeit ist es, die wissenschaftliche Qualitat der Beitrage in “Strahlentherapie und Onkologie” zu verbessern und damit auch den Impact Factor anzuheben. Material und Methoden: In allen 164 Beitragen der Rubriken “Aktuelles Forum”, “Originalarbeiten” und “Kurzmitteilungen” der Jahrgange 1999 und 2000 wurden Anzahl und Alter der Zitate untersucht. Ergebnis: Im Median gab es in den Jahren 1999 und 2000 pro Artikel 26 Zitate (Range: 0–264). Das mediane Alter im Untersuchungszeitraum betragt 4 Jahre. Schlussfolgerung: Arbeiten anderer Autoren sollten gebuhrend und nachvollziehbar zitiert werden. Eigenzitate aus den letzten 2 Jahren beeinflussen den Impact Factor einer Zeitschrift.

Gaps are a common feature of clinical radiotherapy. Only little information is available about the influence of the position of a gap on tumor response.In a rodent tumor model (rhabdomyosarcoma R1H of the rat) three split-course schedules were carried out by inserting a 2-week gap either after the 1st, the 3rd, or the 5th week into a standard schedule of 30 fractions in 6 weeks. For comparison a standard and an accelerated treatment were carried out.The position of the gap was found to have a significant influence on the tumor response (p = 0.018).

In clinical practice a concomitant boost is usually given as a second daily dose to a reduced field. The question arises which part of treatment should be accelerated to achieve optimal tumor control. An experiment was performed on tumor bearing rats to determine the optimal timing of treatment acceleration for this experimental tumor system.Rhabdomyosarcoma R1H of the rat were treated applying 30 fractions in an overall treatment time of 40-42 days, up to total doses ranging from 67.5 to 97.5 Gy were administered. For control a standard treatment was given as continuous treatment applying one fraction per day. A boost of five additional fractions was given as a second fraction during 5 days. Three experimental arms received a boost either in the 1st, 4th, or in the last week of treatment. Treatment outcome was assessed using tumor control as endpoint.All experimental arms proved more effective than the standard treatment. Treatment was most effective when the boost was administered in the 1st week of treatment. A TCD37% of 87.1 Gy (95% CI: 82.8 ... 92.7 Gy), 96.5 Gy (89.9 ... 107.1), and 107.3 Gy (97.2 ... 131.0) was determined, when the boost was given in the 1st, 4th, or last week of treatment, respectively. The observed difference between the experimental arms was statistically significant (p = 0.004).Initially accelerated treatment schedules were found to be more effective for tumor control in an experimental tumor system.

Das Ziel der vorliegenden Arbeit ist es, die wissenschaftliche Qualitat der Beitrage in “Strahlentherapie und Onkologie” zu verbessern und damit auch den Impact Factor anzuheben.

Purpose To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position −509), XPD (codon 751), and XRCC1 (codon 399) with the risk of severe erythema after breast conserving radiotherapy. Methods and materials Retrospective analysis of 83 breast cancer patients treated with breast conserving radiotherapy. A total dose of 50.4 Gy was administered, applying 1.8 Gy/fraction within 42 days. Erythema was evaluated according to the Radiation Therapy Oncology Group (RTOG) score. DNA was extracted from blood samples and polymorphisms were determined using either the Polymerase Chain Reaction based Restriction-Fragment-Length-Polymorphism (PCR-RFL) technique or Matrix-Assisted-Laser-Desorption/Ionization –Time-Of-Flight-Mass-Spectrometry (MALDI-TOF). Relative excess heterozygosity (REH) was investigated to check compatibility of genotype frequencies with Hardy-Weinberg equilibrium (HWE). In addition, p-values from the standard exact HWE lack of fit test were calculated using 100,000 permutations. HWE analyses were performed using R. Results Fifty-six percent (46/83) of all patients developed erythema of grade 2 or 3, with this risk being higher for patients with large breast volume (odds ratio, OR = 2.55, 95% confidence interval, CI: 1.03–6.31, p = 0.041). No significant association between SNPs and risk of erythema was found when all patients were considered. However, in patients with small breast volume the TGFB1 SNP was associated with erythema (p = 0.028), whereas the SNP in XPD showed an association in patients with large breast volume (p = 0.046). A risk score based on all risk alleles was neither significant in all patients nor in patients with small or large breast volume. Risk alleles of most SNPs were different compared to a previously identified risk profile for fibrosis. Conclusions The genetic risk profile for erythema appears to be different for patients with small and larger breast volume. This risk profile seems to be specific for erythema as compared to a risk profile for fibrosis.

Purpose To study whether the promoter polymorphism (C-509T) affects transforming growth factor β1 gene ( TGFB1 ) expression, protein secretion, and/or cellular radiosensitivity for both human lymphocytes and fibroblasts. Methods and Materials Experiments were performed with lymphocytes taken either from 124 breast cancer patients or 59 pairs of normal monozygotic twins. We used 15 normal human primary fibroblast strains as controls. The C-509T genotype was determined by polymerase chain reaction-restriction fragment length polymorphism or TaqMan single nucleotide polymorphism (SNP) genotyping assay. The cellular radiosensitivity of lymphocytes was measured by G0/1 assay and that of fibroblasts by colony assay. The amount of extracellular TGFB1 protein was determined by enzyme-linked immunosorbent assay, and TGFB1 expression was assessed via microarray analysis or reverse transcription-polymerase chain reaction. Results The C-509T genotype was found not to be associated with cellular radiosensitivity, neither for lymphocytes (breast cancer patients, P =.811; healthy donors, P =.181) nor for fibroblasts ( P =.589). Both TGFB1 expression and TGFB1 protein secretion showed considerable variation, which, however, did not depend on the C-509T genotype (protein secretion: P =.879; gene expression: lymphocytes, P =.134, fibroblasts, P =.605). There was also no general correlation between TGFB1 expression and cellular radiosensitivity (lymphocytes, P =.632; fibroblasts, P =.573). Conclusion Our data indicate that any association between the SNP C-509T of TGFB1 and risk of normal tissue toxicity cannot be ascribed to a functional consequence of this SNP, either on the level of gene expression, protein secretion, or cellular radiosensitivity.

Stress induced by social conflict in rainbow trout is known to result in physiological and haematological alterations as well as immune suppression. Based on these findings we sought to determine whether structure and function of the phagocytes in subordinate fish respond to the stressful situation. Phagocytes are essentially involved in the immune defence of teleosts. Histological and ultrastructural studies of haemopoietic pronephros tissue have shown that under stress, potential phagocytes (histiocytes, reticulum cells, endothelial cells, and neutrophils) become activated. They show marked hypertrophy, increased pseudopod formation and enhanced autophagocytosis. Erythrophagocytosis is particularly conspicuous suggesting some impairment of the red blood cell vitality. In vivo and in vitro tests using yeast cells also indicate an average increase in the phagocytosis rate in the subordinate fish. However, a considerable percentage of the phagocytes show signs of degeneration. They disintegrate, thereby forming necrotic tissue areas.

To correlate the potential time benefit of (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) in terms of early detection of recurrences of subcutaneously growing R1H tumors with therapy-specific parameters of recurrent tumor.Twelve, eleven, and seven recurrences were followed after fractionated radiotherapy, surgery, and chemotherapy for 6 months, respectively, and (18)FDG-PET was performed weekly using a conventional full-ring whole-body PET scanner. By comparing PET results and actual tumor volume, the time benefit of (18)FDG-PET in detection of recurrent tumors of 0.1, 0.2, and 0.5 cm(3) was determined for the different treatment strategies.A significant time benefit of (18)FDG-PET of 26.9 days and 67 days was solely determined for recurrences after radiotherapy of 0.2 cm(3) and 0.5 cm(3), respectively. The potential time benefit showed a strong correlation with growth delay, which was increased after radiotherapy due to a pronounced tumor-bed effect.The potential time benefit of (18)FDG-PET is strongly determined by the growth kinetics of the recurrence. A tumor-bed effect, which is a phenomenon solely seen after radiotherapy, favors early detection by (18)FDG-PET. The experimental data, clinical experience and theoretical consideration all indicate a noticeable benefit of (18)FDG-PET especially after radiotherapeutic treatment.

Tumor hypoxia is regarded as one important underlying feature of radioresistance. The authors report on an experimental approach to improve tumor response to radiation by combining fractionated irradiation with HBOC-201, an ultrapurified polymerized hemoglobin solution, which is currently used in clinical phase II/III trials as alternative oxygen carrier and proved to be highly effective in tissue oxygenation (tpO(2)).Subcutaneously growing rhabdomyosarcoma R1H tumors of the rat were treated with either 40 Gy (2 Gy/fraction, 20 fractions in 2 weeks, ambient) followed by graded top-up doses (clamped) alone, or in combination with HBOC-201, or with HBOC-201 plus carbogen (95% O(2) + 5% CO(2)). Local tumor control (TCD50%) and growth delay were used as endpoints. In addition, the effect of HBOC-201 alone or in combination with carbogen on the tpO(2) of tumor and muscle was determined using a flexible stationary probe (Licox, GMS).TCD50% values of 119 Gy (95% confidence interval 103;135), 111 Gy (84;138), and 102 Gy (83;120) were determined for tumors irradiated alone, in combination with HBOC-201, and with HBOC-201 plus carbogen, respectively. Although the dose-response curves showed a slight shift to lower doses when HBOC-201 or HBOC-201 plus carbogen was added, the differences in TCD50% were not statistically significant. No effect was seen on the growth delay of recurrent tumors. HBOC-201 alone did not effect tumor or muscle tpO(2). In combination with carbogen the mean tpO(2) of muscle raised from 23.9 mmHg to 59.3 mmHg (p0.05), but this effect was less pronounced than the increase in tpO(2) by carbogen alone.Low-dose application of HBOC-201 does not improve the response of the rhabdomyosarcoma R1H of the rat to fractionated irradiation.

The aim was to investigate the influence of pulmonary metastases of the rhabdomyosarcoma R1H on the radiation response of the lung of the WAG/Rij rat.Three groups of animals were investigated: metastases-free animals treated with fractionated irradiation of the lungs; metastases-bearing animals receiving no irradiation; and metastases-bearing animals treated with fractionated irradiation initiated 14, 21 or 28 days after induction of pulmonary metastases of the R1H-tumour by i.v. injection of viable tumour cells. Metastases were thus treated at various well-defined sizes. Total doses of 20-60Gy were applied in fractions of 2 Gy within 11 days. Complication rate and survival time were used as endpoints.About 2 months after onset of irradiation treatment, animals had to be sacrificed because of severe respiratory distress either caused by irradiation-induced lung damage (median 57 days, range 36-77 days), or because of development of lung metastases (65, 20-160 days). A decrease of the ED(50) (dose required to induce lethal lung damage in 50% of irradiated animals) was determined for metastases-bearing animals. This effect increased with metastatic volume.The results suggest that the presence of tumours in the lung decreased the lung tolerance to radiation. This effect can hardly be explained by a reduction in functional lung volume by metastatic volume.

Background and purpose : Macroscopic subcutaneously growing R1H-tumours have been shown to respond almost independently of the dose per fraction when treated under ambient conditions. In addition decelerated repopulation during fractionated irradiation has been shown for this experimental tumour. The aim of the present study was to investigate whether this is also the case for pulmonary micrometastases which are assumed to be fully oxygenated or whether differences in the oxygenation status of the tumour possibly alters its response to fractionation. The influence of the dose per fraction and overall treatment time on the response of micrometastases to fractionated irradiation was studied. Materials and methods : Pulmonary metastases were induced by i.v. injection of viable tumour cells. Treatment was started 14 days later, when metastases reached an average size of four cells. Total doses of 16 to 28 Gy were administered within an overall treatment time of 11 or 25 days, using doses per fraction of 1, 2, or 4 Gy. Tumour response was quantified by metastatic control (MCD 37% ). Results : Fractionation had a significant influence on local control ( P =0.009). After application of 1, 2, or 4 Gy and an overall treatment time of 11 days the MCD 37% was 25.4 (95% C.I.: 21.5–32.0) Gy, 20.7 (17.0–24.0) Gy, and 18.5 (14.9–21.6) Gy, respectively. When overall treatment time was prolonged to 25 days the MCD 37% increased to 25.5 (21.3–33.5) Gy when fractions of 2 Gy where applied, but this difference was not significant ( P =0.13). The doubling time of 12.8 days determined for the metastatic clonogenic tumour cells during fractionated irradiation was significantly longer than the 4.1 days observed for untreated metastases ( P =0.006). Conclusions : The results show a strong influence of fractionation on treatment outcome and a decelerated repopulation during fractionated irradiation treatment for well oxygenated pulmonary metastases of the R1H-tumour.

Background and purpose : The combination of radiotherapy with nicotinamide and carbogen is a promising method to improve treatment outcome. The aim of the present study was to investigate its effect on rat lungs, the R1H-tumour and its pulmonary metastases. Materials and methods : Subcutaneous tumours and artificially induced pulmonary metastases of the rhabdomyosarcoma R1H of the rat were treated either with fractionated irradiation alone or in combination with nicotinamide and carbogen. Local metastatic control, net growth delay and lethal lung damage were used as endpoints. Results : Radiosensitivity of the lungs of WAG/Rij rats increased by a factor of 1.13, while no positive effect of the combined treatment either on subcutaneous R1H-tumours or on pulmonary metastases could be detected. This resulted in a therapeutic loss of 18% ( P = 0.003). Conclusion : The results indicate that deleterious effects of the combination of radiotherapy with nicotinamide and carbogen cannot be excluded under all circumstances.

The aim of the study was to determine the radiosensitivity and the growth kinetics of pulmonary micrometastases of the R1H tumour of the rat. Lung metastases were induced by intravenous injection of viable tumour cells. At different time intervals (3–32 days) after injection, lungs were locally irradiated with 200 kVp X-rays, using 1.5 Gy/fraction. Total doses of 6–33 Gy were administered within 11 days. Endpoints used were survival time, local control rate, and number of metastases in the lungs at autopsy. The data were evaluated using the multi-target model. Beginning in the fifth week after tumour cell inoculation the animals started to exhibit a pronounced dyspnoea and were sacrificed. Sections revealed an extensive metastatic infiltration of the lungs. With increasing total dose a prolongation of survival time as well as an increase in cure rate was observed. The number of metastases found in the lungs decreased with increasing total dose. It is concluded that metastatic growth does not start earlier than 3 days after tumour cell inoculation and accelerates continuously. The doubling time of the tumour cells in the micrometastases decreases continuously and from 5.2 to 1.2 days between day 3 and 40, whereas larger metastases containing more than 10 6 cells show gompertzian growth kinetics. The cell doubling time in this stage of metastatic growth is longer than 5 days. During the first 4 weeks of metastatic growth the radiosensitivity of metastatic R1H cells in the lungs is the same as in vitro.

The breathing frequency is a common parameter to assess the radiation response of the lungs of laboratory rodents. Rats of the strain WAG/Rij which were bred in Hamburg show different breathing patterns which consist of short regular and long irregular breaths. Depending on the breathing pattern, the breathing frequency of untreated animals varies by a factor of three. Although this phenomenon might be strain-specific, it seems noteworthy because it might influence the results obtained after irradiation significantly, especially if breathing frequency is automatically converted into a numerical value.