National Center for Radiation Research in Oncology

Dresden, Germany

National Center for Radiation Research in Oncology

Dresden, Germany
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Wink K.C.J.,Maastricht University | van Baardwijk A.,Maastricht University | Troost E.G.C.,Maastricht University | Troost E.G.C.,Helmholtz Center Dresden | And 6 more authors.
Cancer Treatment Reviews | Year: 2017

Stereotactic body radiotherapy (SBRT) is an alternative to surgery for patients with early stage non-small cell lung cancer (NSCLC) who are inoperable due to comorbid disease or who refuse surgery. SBRT results in an excellent local control rate of more than 90%, which is comparable to surgery, while short and long-term overall toxicity is low. Surgically treated patients are often more extensively staged pre-operatively, e.g. with endobronchial ultrasound and/or mediastinoscopy, and typically undergo intra-operative lymph node dissection or sampling. Occult nodal metastases (ONM), detected by lymph node dissection, have been shown to increase the incidence of regional recurrence (RR) after surgery, which is associated with poor outcome. In patients undergoing SBRT, however, definite pathological nodal staging is lacking and so other ways to identify patients at high risk for ONM and RR are desirable. The aim of this systematic review is to summarize the incidence of, and risk factors for, RR after SBRT and compare these to those after surgery. The available evidence shows the incidence of RR after SBRT or surgery to be comparable, despite more elaborate pre- and intra-operative lymph node evaluation in surgical patients. However, the fact that this finding is based on mostly retrospective studies in which the majority of patients treated with SBRT were inoperable, needs to be taken into consideration. For now, there is no evidence that inoperable clinical stage I patients with no indication of pathological lymph nodes on PET/CT will benefit from more invasive lymph node staging prior to SBRT. © 2017 Elsevier Ltd

Kriegs M.,University of Hamburg | Gurtner K.,National Center for Radiation Research in Oncology | Can Y.,University of Hamburg | Brammer I.,University of Hamburg | And 14 more authors.
Radiotherapy and Oncology | Year: 2015

Purpose How EGF receptor (EGFR) inhibition induces cellular radiosensitization and with that increase in tumor control is still a matter of discussion. Since EGFR predominantly regulates cell cycle and proliferation, we studied whether a G1-arrest caused by EGFR inhibition may contribute to these effects. Materials and methods We analyzed human non-small cell lung cancer (NSCLC) cell lines either wild type (wt) or mutated in p53 (A549, H460, vs. H1299, H3122) and HCT116 cells (p21 wt and negative). EGFR was inhibited by BIBX1382BS, erlotinib or cetuximab; p21 was knocked down by siRNA. Functional endpoints analyzed were cell signaling, proliferation, G1-arrest, cell survival as well as tumor control using an A549 tumor model. Results When combined with IR, EGFR inhibition enhances the radiation-induced permanent G1 arrest, though solely in cells with intact p53/p21 signaling. This increase in G1-arrest was always associated with enhanced cellular radiosensitivity. Strikingly, this effect was abrogated when cells were re-stimulated, suggesting the initiation of dormancy. In line with this, only a small non-significant increase in tumor control was observed for A549 tumors treated with fractionated RT and EGFR inhibition. Conclusion For NSCLC cells increase in radiosensitivity by EGFR inhibition results from enhanced G1-arrest. However, this effect does not lead to improved tumor control because cells can be released from this arrest by re-stimulation. © 2015 Elsevier Ireland Ltd. All rights reserved.

Wink K.C.J.,Maastricht University | Belderbos J.S.A.,Netherlands Cancer Institute | Dieleman E.M.T.,Amsterdam Medical Center | Rossi M.,Netherlands Cancer Institute | And 7 more authors.
Radiotherapy and Oncology | Year: 2016

Background and purpose The aim was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome. Material and methods A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients). All received cCRT in one of three participating radiation oncology departments in the Netherlands between January 2008 and January 2013. Primary endpoint was locoregional recurrence free survival (LRFS), secondary endpoints were overall survival (OS), progression-free survival (PFS) and distant metastasis free survival (DMFS). Results No significant differences in LRFS or OS were found. Metformin use was associated with an improved DMFS (74% versus 53% at 2 years; p = 0.01) and PFS (58% versus 37% at 2 years and a median PFS of 41 months versus 15 months; p = 0.01). In a multivariate cox-regression analysis, the use of metformin was a statistically significant independent variable for DMFS and PFS (p = 0.02 and 0.03). Conclusions Metformin use during cCRT is associated with an improved DMFS and PFS for locally advanced NSCLC patients, suggesting that metformin may be a valuable treatment addition in these patients. Evidently, our results merit to be verified in a prospective trial. © 2015 Elsevier Ireland Ltd. All rights reserved.

Garbe Y.,National Center for Radiation Research in Oncology | Maletzki C.,University of Rostock | Linnebacher M.,University of Rostock
PLoS ONE | Year: 2011

Background: Microsatellite instability (MSI) resulting from inactivation of the DNA mismatch repair system (MMR) characterizes a highly immunological subtype of colorectal carcinomas. Those tumors express multiple frameshift-mutated proteins which present a unique pool of tumor-specific antigens. The DNA MMR protein MSH3 is frequently mutated in MSI+ colorectal tumors, thus making it an attractive candidate for T cell-based immunotherapies. Methodology/Principal Findings: FSP-specific CD8+ T cells were generated from a healthy donor using reverse immunology. Those T cells specifically recognized T2 cells sensitized with the respective peptides. Specific recognition and killing of MSI+ colorectal carcinoma cells harbouring the mutated reading frame was observed. The results obtained with T cell bulk cultures could be reproduced with T cell clones obtained from the same cultures. Blocking experiments (using antibodies and cold target inhibition) confirmed peptide as well as HLA-A0201-specificity. Conclusions: We identified two novel HLA-A0201-restricted cytotoxic T cell epitopes derived from a (-1) frameshift mutation of a coding A(8) tract within the MSH3 gene. These were 386-FLLALWECSL (FSP18) and 387-LLALWECSL (FSP19) as well as 403-IVSRTLLLV (FSP23) and 402-LIVSRTLLLV (FSP31), respectively. These results suggest that MSH3(-1) represents another promising MSI+-induced target antigen. By identifying two distinct epitopes within MSH3(-1), the sustained immunogenicity of the frameshift mutated sequence was confirmed. Our data therefore encourage further exploitation of MSH3 as a piece for peptide-based vaccines either for therapeutic or -even more important- preventive purposes. © 2011 Garbe et al.

Lebeda O.,Nuclear Physics Institute of Czech Republic | Lozza V.,TU Dresden | Petzoldt J.,TU Dresden | Petzoldt J.,National Center for Radiation Research in Oncology | And 3 more authors.
Nuclear Physics A | Year: 2014

Cross-sections for the proton-induced reactions on natural neodymium in energy regions 5-10 MeV and 30-35 MeV were measured using the cyclotron U-120M at the Nuclear Physics Institute at Rˇezˇ near Prague. This measurement completes the investigation previously done in the 10-30 MeV energy range. Results revealed practical production thresholds and secondary maxima and minima in the excitation functions. It allowed for more appropriate calculation of thick target yields and production rates of many longer-lived radionuclides potentially disturbing the search for neutrinoless double beta decay. Measured cross-sections are consistent with our previously published data. © 2014 Elsevier B.V.

Wijsman R.,Radboud University Nijmegen | Dankers F.,Radboud University Nijmegen | Troost E.G.C.,Helmholtz Center Dresden | Troost E.G.C.,TU Dresden | And 7 more authors.
Radiotherapy and Oncology | Year: 2015

Background and purpose The majority of normal-tissue complication probability (NTCP) models for acute esophageal toxicity (AET) in advanced stage non-small cell lung cancer (AS-NSCLC) patients treated with (chemo-)radiotherapy are based on three-dimensional conformal radiotherapy (3D-CRT). Due to distinct dosimetric characteristics of intensity-modulated radiation therapy (IMRT), 3D-CRT based models need revision. We established a multivariable NTCP model for AET in 149 AS-NSCLC patients undergoing IMRT. Materials and methods An established model selection procedure was used to develop an NTCP model for Grade ≥2 AET (53 patients) including clinical and esophageal dose-volume histogram parameters. Results The NTCP model predicted an increased risk of Grade ≥2 AET in case of: concurrent chemoradiotherapy (CCR) [adjusted odds ratio (OR) 14.08, 95% confidence interval (CI) 4.70-42.19; p < 0.001], increasing mean esophageal dose [Dmean; OR 1.12 per Gy increase, 95% CI 1.06-1.19; p < 0.001], female patients (OR 3.33, 95% CI 1.36-8.17; p = 0.008), and ≥cT3 (OR 2.7, 95% CI 1.12-6.50; p = 0.026). The AUC was 0.82 and the model showed good calibration. Conclusions A multivariable NTCP model including CCR, Dmean, clinical tumor stage and gender predicts Grade ≥2 AET after IMRT for AS-NSCLC. Prior to clinical introduction, the model needs validation in an independent patient cohort. © 2015 Elsevier Ireland Ltd. All rights reserved.

Yaromina A.,TU Dresden | Meyer S.,Johannes Gutenberg University Mainz | Fabian C.,Johannes Gutenberg University Mainz | Zaleska K.,TU Dresden | And 6 more authors.
Strahlentherapie und Onkologie | Year: 2012

Background. High pretreatment tumor lactate content is associated with poor outcome after fractionated irradiation in human squamous cell carcinoma (hSCC) xenografts. Therefore, decreasing lactate content might be a promising approach for increasing tumor radiosensitivity. As the basis for such experiments, the effects of the biochemical inhibitors pyruvate dehydrogenase kinase dichloroacetate (DCA), lactate dehydrogenase oxamate, and monocarboxylic acid transporter- 1 α-cyano-4-hydroxycinnamate (CHC) on tumor micromilieu and growth were investigated. Materials and methods. Oxygen consumption (OCR) and extracellular acidification rates (ECAR) were measured in FaDu and UT-SCC-5 hSCC in response to DCA in vitro. Mice bearing FaDu, UT-SCC-5, and WiDr colorectal adenocarcinoma received either DCA in drinking water or DCA injected twice a day, or CHC injected daily. WiDr was also treated daily with oxamate. FaDu and UT-SCC-5 were either excised 8 days after treatment for histology or tumor growth was monitored. WiDr tumors were excised at 8 mm. Effect of inhibitors on ATP, lactate, hypoxia, and Ki67 labeling index (LI) was evaluated.Results. DCA increased OCR and decreased ECAR in vitro. None of the treatments with inhibitors significantly changed lactate content, hypoxia levels, and Ki67 LI in the three tumor lines in vivo. ATP concentration significantly decreased after only daily twice injections of DCA in FaDu accompanied by a significant increase in necrotic fraction. Tumor growth was not affected by any of the treatments.Conclusion. Overall, tumor micromilieu and tumor growth could not be changed by glycolysis modifiers in the three tumor cell lines in vivo. Further studies are necessary to explore the impact of metabolic targets on radiation response. © Springer-Verlag 2012.

Zips D.,National Center for Radiation Research in Oncology | Boke S.,National Center for Radiation Research in Oncology | Kroeber T.,National Center for Radiation Research in Oncology | Meinzer A.,National Center for Radiation Research in Oncology | And 5 more authors.
Strahlentherapie und Onkologie | Year: 2011

Background and Purpose: Previous experiments showed that the fraction of radiobiologically hypoxic tumor cells (rHF) in un-treated tumors did not accurately predict local tumor control after fractionated irradiation. Thus, the prognostic value of rHF determined during fractionated irradiation was investigated. Materials and Methods: Six human squamous cell carcinoma lines were transplanted into nude mice and then irradiated with 15 fractions over 3 weeks. Thereafter, single dose irradiation under normal and clamped blood flow was given. Local tumor con-trol rates were used to calculate the rHF and the TCD 50, i.e., the radiation dose necessary to control 50% of the tumors, after single dose irradiation. These values were compared with the in parallel determined TCD 50 after 30 fractions in 6 weeks. Results: The rHF after 15 fractions varied between 28% and 100%. No correlation was found with the TCD 50 after 30 fractions in 6 weeks. Single dose top-up TCD 50 under ambient and clamp conditions after 15 fractions significantly correlated with TCD 50 after 30 fractions in 6 weeks. Conclusion: rHF after 15 fractions is not a prognostic parameter for the outcome after fractionated irradiation. In contrast, the radiobiological parameters number of tumor stem cells, intrinsic radiosensitivity, and number of radiobiologically hypoxic tumor cells appear promising to predict outcome after fractionated irradiation.

Lozza V.,TU Dresden | Petzoldt J.,TU Dresden | Petzoldt J.,National Center for Radiation Research in Oncology
Astroparticle Physics | Year: 2015

130Te is one of the candidates for the search for neutrinoless double beta decay. It is currently planned to be used in two experiments: CUORE and SNO+. In the CUORE experiment TeO2 crystals cooled at cryogenic temperatures will be used. In the SNO+ experiment natTe will be deployed up to 0.3% loading in the liquid scintillator volume. A possible background for the signal searched for, are the high Q-value, long-lived isotopes, produced by cosmogenic neutron and proton spallation reaction on the target material. A total of 18 isotopes with Q-value larger than 2 MeV and T1/2 > 20 days have been identified as potential backgrounds. In addition low Q-value, high rate isotopes can be problematic due to pile-up effects, specially in liquid scintillator based detectors. Production rates have been calculated using the ACTIVIA program, the TENDL library, and the cosmogenic neutron and proton flux parametrization at sea level from Armstrong and Gehrels for both long and short lived isotopes. The obtained values for the cross sections are compared with the existing experimental data and calculations. Good agreement has been generally found. The results have been applied to the SNO+ experiment for one year of exposure at sea level. Two possible cases have been considered: a two years of cooling down period deep underground, or a first purification on surface and 6 months of cooling down deep underground. Deep underground activation at the SNOLAB location has been considered. © 2014 Elsevier B.V. All rights reserved.

PubMed | TU Munich and National Center for Radiation Research in Oncology
Type: Journal Article | Journal: Medical physics | Year: 2016

Laser-acceleration of particles may offer a cost- and spaceefficient alternative for future radiation therapy with particles. Laser-driven particle beams are pulsed with very short bunch times, and a high number of particles is delivered within one laser shot which cannot be portioned or modulated during irradiation. The goal of this study was to examine whether good treatment plans can be produced for laser-driven proton beams and to investigate the feasibility of a laser-driven treatment unit.An exponentially decaying proton spectrum was tracked through a gantry and energy selection beam line design to produce multiple proton spectra with different energy widths centered on various nominal energies. These spectra were fed into a treatment planning system to calculate spot scanning proton plans using different lateral widths of the beam and different numbers of protons contained in the initial spectrum. The clinical feasibility of the resulting plans was analyzed in terms of dosimetric quality and the required number of laser shots as an estimation of the overall treatment time.We were able to produce treatment plans with plan qualities of clinical relevance for a maximum initial proton number per laser shot of 6*10With the simulated beam line and the assumed shape of the proton spectrum it was impossible to produce clinically acceptable treatment plans that can be delivered in a reasonable time. The situation can be improved by a method or a device in the beam line which can modulate the number of protons from shot to shot. Supported by DFG Cluster of Excellence: Munich-Centre for Advanced Photonics.

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