TY - JOUR AB - BACKGROUND AND PURPOSE: This study investigates the use of Vision Transformers (ViTs) to predict Freedom from Local Failure (FFLF) in patients with brain metastases using pre-operative MRI scans. The goal is to develop a model that enhances risk stratification and informs personalized treatment strategies. MATERIALS AND METHODS: Within the AURORA retrospective trial, patients (n = 352) who received surgical resection followed by post-operative stereotactic radiotherapy (SRT) were collected from seven hospitals. We trained our ViT for the direct image-to-risk task on T1-CE and FLAIR sequences and combined clinical features along the way. We employed segmentation-guided image modifications, model adaptations, and specialized patient sampling strategies during training. The model was evaluated with five-fold cross-validation and ensemble learning across all validation runs. An external, international test cohort (n = 99) within the dataset was used to assess the generalization capabilities of the model, and saliency maps were generated for explainability analysis. RESULTS: We achieved a competent C-Index score of 0.7982 on the test cohort, surpassing all clinical, CNN-based, and hybrid baselines. Kaplan-Meier analysis showed significant FFLF risk stratification. Saliency maps focusing on the BM core confirmed that model explanations aligned with expert observations. CONCLUSIO: Our ViT-based model offers a potential for personalized treatment strategies and follow-up regimens in patients with brain metastases. It provides an alternative to radiomics as a robust, automated tool for clinical workflows, capable of improving patient outcomes through effective risk assessment and stratification. AU - Erdur, A.C.* AU - Scholz, D.* AU - Nguyen, Q.M.* AU - Buchner, J.A.* AU - Mayinger, M.* AU - Christ, S.M.* AU - Brunner, T.B.* AU - Wittig, A.* AU - Zimmer, C.* AU - Meyer, B.* AU - Guckenberger, M.* AU - Andratschke, N.* AU - El Shafie, R.A.* AU - Debus, J.U.* AU - Rogers, S.* AU - Riesterer, O.* AU - Schulze, K.* AU - Feldmann, H.J.* AU - Blanck, O.* AU - Zamboglou, C.* AU - Bilger-Z, A.* AU - Grosu, A.L.* AU - Wolff, R.* AU - Eitz, K.A. AU - Combs, S.E. AU - Bernhardt, D.* AU - Wiestler, B.* AU - Rueckert, D.* AU - Peeken, J.C. C1 - 75086 C2 - 57795 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Improving risk assessment of local failure in brain metastases patients using vision transformers - A multicentric development and validation study. JO - Radiother. Oncol. VL - 210 PB - Elsevier Ireland Ltd PY - 2025 SN - 0167-8140 ER - TY - JOUR AU - Erdur, A.C.* AU - Peeken, J.C. C1 - 75917 C2 - 58186 SP - 111233 TI - Response to commentary on "Improving risk assessment of local failure in brain metastases patients using vision transformers - A multicentric development and validation study" by Zhang et al. JO - Radiother. Oncol. PY - 2025 SN - 0167-8140 ER - TY - JOUR AB - Current risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity, and digital pathology (DP) combined with artificial intelligence (AI) tools (DP-AI) may offer a solution to this challenge. The aim of this work is to summarize the role of DP-AI for PCa patients treated with radiotherapy (RT), and to point out future areas of research. We conducted (1) a systematic review on the evidence of DP-AI for patients treated with RT and (2) a survey of experts using a modified Delphi method, addressing the current role of DP-AI in clinical and research practice to identify relevant fields of future development. Eleven studies investigated DP-AI in PCa RT, with most using the multimodal AI (MMAI) classifier and four ongoing studies are currently prospectively testing the DP-AI performance. DP-AI showed strong prognostic and predictive performance for endpoints like distant metastasis free survival and overall survival, outperforming traditional risk models and assisting treatment decisions such as androgen deprivation therapy (ADT) duration. Fifty-one and 35 experts responded to round 1 and round 2 of the survey respectively. Questions with ≥75 % agreement were considered relevant and included in the qualitative analysis. Survey results confirmed growing adoption of DP scanners, although regional differences in re-imbursement mechanisms and availability persist, with experts endorsing DP-AI's potential across localized, postoperative, and metastatic settings, though further prospective validation is needed. DP-AI tools show strong prognostic and predictive potential in various PCa by guiding patient stratification and optimising ADT duration in primary RT. Prospective studies and validation in cohorts using modern diagnostic and treatment methods are needed before broad clinical adoption. AU - Zamboglou, C.* AU - Doncker, W.* AU - Christoforou, A.T.* AU - Arcangeli, S.* AU - Berlin, A.* AU - Blanchard, P.* AU - Bauman, G.* AU - Campi, R.* AU - Castro, E.* AU - Choudhury, A.* AU - Pra, A.D.* AU - Draulans, C.* AU - Desai, N.* AU - Ferentinos, K.* AU - Francolini, G.* AU - Gillessen, S.* AU - Grosu, A.L.* AU - Rivas, J.G.* AU - Hoelscher, T.* AU - Hruby, G.* AU - Jereczek-Fossa, B.A.* AU - Kamran, S.* AU - Kasivisvanathan, V.* AU - Kishan, A.U.* AU - Kounnis, V.* AU - Loblaw, A.* AU - Martin, J.* AU - Mastroleo, F.* AU - Merseburger, A.S.* AU - Miszczyk, M.* AU - Mohamad, O.* AU - Ost, P.* AU - Papatsoris, A.* AU - Peeken, J.C. AU - Sanguedolce, F.* AU - Sargos, P.* AU - Schmidt-Hegemann, N.* AU - Seibert, T.M.* AU - Shelan, M.* AU - Siva, S.* AU - Soeterik, T.F.W.* AU - Spratt, D.E.* AU - Stenzl, A.* AU - Strouthos, I.* AU - Sutera, P.* AU - Supiot, S.* AU - Tilki, D.* AU - Tran, P.T.* AU - Tree, A.C.* AU - Tward, J.* AU - Ürün, Y.* AU - Vapiwala, N.* AU - Waddle, M.R.* AU - Wegener, E.* AU - Zilli, T.* AU - Murthy, V.* AU - Thieme, A.H.* AU - Spohn, S.* C1 - 75127 C2 - 57826 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - oDigital pathology biomarkers for guiding radiotherapy-based treatment concepts in prostate cancer - a systematic review and expert consensus. JO - Radiother. Oncol. VL - 210 PB - Elsevier Ireland Ltd PY - 2025 SN - 0167-8140 ER - TY - JOUR AB - BACKGROUND AND PURPOSE: Due to the high intrinsic radioresistance of pancreatic ductal adenocarcinoma (PDAC), radiotherapy (RT) is only beneficial in 30% of patients. Therefore, this study aimed to identify targets to improve the efficacy of RT in PDAC. MATERIALS AND METHODS: Alamar Blue proliferation and colony formation assay (CFA) were used to determine the radioresponse of a cohort of 38 murine PDAC cell lines. A gene set enrichment analysis was performed to reveal differentially expressed pathways. CFA, cell cycle distribution, γH2AX FACS analysis, and Caspase 3/7 SYTOX assay were used to examine the effect of a combination treatment using KIRA8 as an IRE1α-inhibitor and Ceapin-A7 as an inhibitor against ATF6. RESULTS: The unfolded protein response (UPR) was identified as a pathway highly expressed in radioresistant cell lines. Using the IRE1α-inhibitor KIRA8 or the ATF6-inhibitor Ceapin-A7 in combination with radiation, a radiosensitizing effect was observed in radioresistant cell lines, but no substantial alteration of the radioresponse in radiosensitive cell lines. Mechanistically, increased apoptosis by KIRA8 in combination with radiation and a cell cycle arrest in the G1 phase after ATF6 inhibition and radiation have been observed in radioresistant cell lines. CONCLUSION: So, our data show evidence that the UPR is involved in radioresistance of PDAC. Increased apoptosis and a G1 cell cycle arrest seem to be responsible for the radiosensitizing effect of UPR inhibition. These findings are supportive for developing novel combination treatment concepts in PDAC to overcome radioresistance. AU - Kern, J.* AU - Schilling, D. AU - Schneeweis, C.* AU - Schmid, R.M.* AU - Schneider, G.* AU - Combs, S.E. AU - Dobiasch, S. C1 - 69041 C2 - 53823 TI - Identification of the unfolded protein response pathway as target for radiosensitization in pancreatic cancer. JO - Radiother. Oncol. VL - 191 PY - 2024 SN - 0167-8140 ER - TY - JOUR AB - BACKGROUND: Volume of interest (VOI) segmentation is a crucial step for Radiomics analyses and radiotherapy (RT) treatment planning. Because it can be time-consuming and subject to inter-observer variability, we developed and tested a Deep Learning-based automatic segmentation (DLBAS) algorithm to reproducibly predict the primary gross tumor as VOI for Radiomics analyses in extremity soft tissue sarcomas (STS). METHODS: A DLBAS algorithm was trained on a cohort of 157 patients and externally tested on an independent cohort of 87 patients using contrast-enhanced MRI. Manual tumor delineations by a radiation oncologist served as ground truths (GTs). A benchmark study with 20 cases from the test cohort compared the DLBAS predictions against manual VOI segmentations of two residents (ERs) and clinical delineations of two radiation oncologists (ROs). The ROs rated DLBAS predictions regarding their direct applicability. RESULTS: The DLBAS achieved a median dice similarity coefficient (DSC) of 0.88 against the GTs in the entire test cohort (interquartile range (IQR): 0.11) and a median DSC of 0.89 (IQR 0.07) and 0.82 (IQR 0.10) in comparison to ERs and ROs, respectively. Radiomics feature stability was high with a median intraclass correlation coefficient of 0.97, 0.95 and 0.94 for GTs, ERs, and ROs, respectively. DLBAS predictions were deemed clinically suitable by the two ROs in 35% and 20% of cases, respectively. CONCLUSION: The results demonstrate that the DLBAS algorithm provides reproducible VOI predictions for radiomics feature extraction. Variability remains regarding direct clinical applicability of predictions for RT treatment planning. AU - Peeken, J.C. AU - Etzel, L.* AU - Tomov, T.* AU - Münch, S.* AU - Schüttrumpf, L.* AU - Shaktour, J.H.* AU - Kiechle, J.* AU - Knebel, C.* AU - Schaub, S.K.* AU - Mayr, N.A.* AU - Woodruff, H.C.* AU - Lambin, P.* AU - Gersing, A.S.* AU - Bernhardt, D.* AU - Nyflot, M.J.* AU - Menze, B.* AU - Combs, S.E. AU - Navarro, F.* C1 - 70758 C2 - 55882 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Development and benchmarking of a Deep Learning-based MRI-guided gross tumor segmentation algorithm for Radiomics analyses in extremity soft tissue sarcomas. JO - Radiother. Oncol. VL - 197 PB - Elsevier Ireland Ltd PY - 2024 SN - 0167-8140 ER - TY - JOUR AB - Background: Many automatic approaches to brain tumor segmentation employ multiple magnetic resonance imaging (MRI) sequences. The goal of this project was to compare different combinations of input sequences to determine which MRI sequences are needed for effective automated brain metastasis (BM) segmentation. Methods: We analyzed preoperative imaging (T1-weighted sequence ± contrast-enhancement (T1/T1-CE), T2-weighted sequence (T2), and T2 fluid-attenuated inversion recovery (T2-FLAIR) sequence) from 339 patients with BMs from seven centers. A baseline 3D U-Net with all four sequences and six U-Nets with plausible sequence combinations (T1-CE, T1, T2-FLAIR, T1-CE + T2-FLAIR, T1-CE + T1 + T2-FLAIR, T1-CE + T1) were trained on 239 patients from two centers and subsequently tested on an external cohort of 100 patients from five centers. Results: The model based on T1-CE alone achieved the best segmentation performance for BM segmentation with a median Dice similarity coefficient (DSC) of 0.96. Models trained without T1-CE performed worse (T1-only: DSC = 0.70 and T2-FLAIR-only: DSC = 0.73). For edema segmentation, models that included both T1-CE and T2-FLAIR performed best (DSC = 0.93), while the remaining four models without simultaneous inclusion of these both sequences reached a median DSC of 0.81–0.89. Conclusions: A T1-CE-only protocol suffices for the segmentation of BMs. The combination of T1-CE and T2-FLAIR is important for edema segmentation. Missing either T1-CE or T2-FLAIR decreases performance. These findings may improve imaging routines by omitting unnecessary sequences, thus allowing for faster procedures in daily clinical practice while enabling optimal neural network-based target definitions. AU - Buchner, J.A.* AU - Peeken, J.C. AU - Etzel, L.* AU - Ezhov, I.* AU - Mayinger, M.* AU - Christ, S.M.* AU - Brunner, T.B.* AU - Wittig, A.* AU - Menze, B.H.* AU - Zimmer, C.* AU - Meyer, B.* AU - Guckenberger, M.* AU - Andratschke, N.* AU - El Shafie, R.A.* AU - Debus, J.* AU - Rogers, S.* AU - Riesterer, O.* AU - Schulze, K.* AU - Feldmann, H.J.* AU - Blanck, O.* AU - Zamboglou, C.* AU - Ferentinos, K.* AU - Bilger, A.* AU - Grosu, A.L.* AU - Wolff, R.* AU - Kirschke, J.S.* AU - Eitz, K.A. AU - Combs, S.E. AU - Bernhardt, D.* AU - Rueckert, D.* AU - Piraud, M. AU - Wiestler, B.* AU - Kofler, F. C1 - 68247 C2 - 54729 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Identifying core MRI sequences for reliable automatic brain metastasis segmentation. JO - Radiother. Oncol. VL - 188 PB - Elsevier Ireland Ltd PY - 2023 SN - 0167-8140 ER - TY - JOUR AB - PURPOSE: To assess the robustness of prognostic biomarkers and molecular tumour subtypes developed for patients with head and neck squamous cell carcinoma (HNSCC) on cell-line derived HNSCC xenograft models, and to develop a novel biomarker signature by combining xenograft and patient datasets. MATERIALS AND METHODS: Mice bearing xenografts (n=59) of ten HNSCC cell lines and a retrospective, multicentre patient cohort (n=242) of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) were included. All patients received postoperative radiochemotherapy (PORT-C). Gene expression analysis was conducted using GeneChip Human Transcriptome Arrays. Xenografts were stratified based on their molecular subtypes and previously established gene classifiers. The dose to control 50% of tumours (TCD50) was compared between these groups. Using differential gene expression analyses combining xenograft and patient data, a gene signature was developed to define risk groups for the primary endpoint loco-regional control (LRC). RESULTS: Tumours of mesenchymal subtype were characterized by a higher TCD50 (xenografts, p<0.001) and lower LRC (patients, p<0.001) compared to the other subtypes. Similar to previously published patient data, hypoxia- and radioresistance-related gene signatures were associated with high TCD50 values. A 2-gene signature (FN1, SERPINE1) was developed that was prognostic for TCD50 (xenografts, p<0.001) and for patient outcome in independent validation (LRC: p=0.007). CONCLUSION: Genetic prognosticators of outcome for patients after PORT-C and subcutaneous xenografts after primary clinically relevant irradiation show similarity. The identified robust 2-gene signature may help to guide patient stratification, after prospective validation. Thus, xenografts remain a valuable resource for translational research towards the development of individualized radiotherapy. AU - Linge, A.* AU - Patil, S.* AU - Grosser, M.* AU - Lohaus, F.* AU - Gurtner, K.* AU - Kemper, M.* AU - Gudziol, V.* AU - Haim, D.* AU - Nowak, A.* AU - Tinhofer, I.* AU - Zips, D.* AU - Guberina, M.* AU - Stuschke, M.* AU - Balermpas, P.* AU - Rödel, C.* AU - Schäfer, H.* AU - Grosu, A.L.* AU - Abdollahi, A.* AU - Debus, J.* AU - Ganswindt, U.* AU - Belka, C. AU - Pigorsch, S.* AU - Combs, S.E. AU - Boeke, S.* AU - Gani, C.* AU - Jöhrens, K.* AU - Baretton, G.B.* AU - Löck, S.* AU - Baumann, M.* AU - Krause, M.* C1 - 69066 C2 - 53841 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - The value of subcutaneous xenografts for individualised radiotherapy in HNSCC: robust gene signature correlates with radiotherapy outcome in patients and xenografts. JO - Radiother. Oncol. VL - 191 PB - Elsevier Ireland Ltd PY - 2023 SN - 0167-8140 ER - TY - JOUR AB - BACKGROUND/PURPOSE: The present study aimed to assess whether SRT to the prostatic fossa should be initiated in a timely manner after detecting biochemical recurrence (BR) in patients with prostate cancer, when no correlate was identified with prostate-specific membrane antigen positron emission tomography (PSMA-PET). MATERIALS AND METHODS: This retrospective, multicenter analysis included 1222 patients referred for PSMA-PET after a radical prostatectomy due to BR. Exclusion criteria were: pathological lymph node metastases, prostate-specific antigen (PSA) persistence, distant or lymph node metastases, nodal irradiation, and androgen deprivation therapy (ADT). This led to a cohort of 341 patients. Biochemical progression-free survival (BPFS) was the primary study endpoint. RESULTS: The median follow-up was 28.0 months. The 3-year BPFS was 71.6% in PET-negative cases and 80.8% in locally PET-positive cases. This difference was significant in univariate (p = 0.019), but not multivariate analyses (p = 0.366, HR: 1.46, 95%CI: 0.64-3.32). The 3-year BPFS in PET-negative cases was significantly influenced by age (p = 0.005), initial pT3/4 (p < 0.001), pathology scores (ISUP) ≥ 3 (p = 0.026), and doses to fossa > 70 Gy (p = 0.027) in univariate analyses. In multivariate analyses, only age (HR: 1.096, 95%CI: 1.023-1.175, p = 0.009) and PSA-doubling time (HR: 0.339, 95%CI: 0.139-0.826, p = 0.017) remained significant. CONCLUSION: To our best knowledge, this study provided the largest SRT analysis in patients without ADT that were lymph node-negative on PSMA-PET. A multivariate analysis showed no significant difference in BPFS between locally PET-positive and PET-negative cases. These results supported the current EAU recommendation to initiate SRT in a timely manner after detecting BR in PET negative patients. AU - Scharl, S.* AU - Zamboglou, C.* AU - Strouthos, I.* AU - Farolfi, A.* AU - Serani, F.* AU - Lanzafame, H.* AU - Giuseppe Morganti, A.* AU - Trapp, C.* AU - Koerber, S.A.* AU - Debus, J.* AU - Peeken, J.C. AU - Vogel, M.M. AU - Vrachimis, A.* AU - Spohn, S.K.B.* AU - Ruf, J.* AU - Grosu, A.L.* AU - Ceci, F.* AU - Fendler, W.P.* AU - Bartenstein, P.* AU - Kroeze, S.G.C.* AU - Guckenberger, M.* AU - Krafcsik, M.* AU - Klopscheck, C.* AU - Fanti, S.* AU - Hruby, G.* AU - Emmett, L.* AU - Belka, C.* AU - Stief, C.* AU - Schmidt-Hegemann, N.S.* AU - Henkenberens, C.* AU - Mayer, B.* AU - Miksch, J.* AU - Shelan, M.* AU - Aebersold, D.M.* AU - Thamm, R.* AU - Wiegel, T.* C1 - 67769 C2 - 54247 TI - Salvage radiotherapy is effective in patients with PSMA-PET-negative biochemical recurrence- results of a retrospective study. JO - Radiother. Oncol. VL - 184 PY - 2023 SN - 0167-8140 ER - TY - JOUR AB - BACKGROUND: Stereotactic radiotherapy is a standard treatment option for patients with brain metastases. The planning target volume is based on gross tumor volume (GTV) segmentation. The aim of this work is to develop and validate a neural network for automatic GTV segmentation to accelerate clinical daily routine practice and minimize interobserver variability. METHODS: We analyzed MRIs (T1-weighted sequence ± contrast-enhancement, T2-weighted sequence, and FLAIR sequence) from 348 patients with at least one brain metastasis from different cancer primaries treated in six centers. To generate reference segmentations, all GTVs and the FLAIR hyperintense edematous regions were segmented manually. A 3D-U-Net was trained on a cohort of 260 patients from two centers to segment the GTV and the surrounding FLAIR hyperintense region. During training varying degrees of data augmentation were applied. Model validation was performed using an independent international multicenter test cohort (n=88) including four centers. RESULTS: Our proposed U-Net reached a mean overall Dice similarity coefficient (DSC) of 0.92 ± 0.08 and a mean individual metastasis-wise DSC of 0.89 ± 0.11 in the external test cohort for GTV segmentation. Data augmentation improved the segmentation performance significantly. Detection of brain metastases was effective with a mean F1-Score of 0.93 ± 0.16. The model performance was stable independent of the center (p = 0.3). There was no correlation between metastasis volume and DSC (Pearson correlation coefficient 0.07). CONCLUSION: Reliable automated segmentation of brain metastases with neural networks is possible and may support radiotherapy planning by providing more objective GTV definitions. AU - Buchner, J.A.* AU - Kofler, F. AU - Etzel, L.* AU - Mayinger, M.* AU - Christ, S.M.* AU - Brunner, T.B.* AU - Wittig, A.* AU - Menze, B.* AU - Zimmer, C.* AU - Meyer, B.* AU - Guckenberger, M.* AU - Andratschke, N.* AU - El Shafie, R.A.* AU - Debus, J.* AU - Rogers, S.* AU - Riesterer, O.* AU - Schulze, K.* AU - Feldmann, H.J.* AU - Blanck, O.* AU - Zamboglou, C.* AU - Ferentinos, K.* AU - Wolff, R.* AU - Eitz, K.A. AU - Combs, S.E. AU - Bernhardt, D.* AU - Wiestler, B.* AU - Peeken, J.C. C1 - 66853 C2 - 53324 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Development and external validation of an MRI-based neural network for brain metastasis segmentation in the AURORA multicenter study. JO - Radiother. Oncol. VL - 178 PB - Elsevier Ireland Ltd PY - 2022 SN - 0167-8140 ER - TY - JOUR AB - BACKGROUND: Management of high-grade gliomas (HGGs) close to motor areas is challenging due to the risk of treatment-related morbidity. Thus, for resection, functional mapping of the corticospinal tract (CST) with navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI)-based fiber tracking (nTMS-DTI-FT) is increasingly used. This study investigated the application of nTMS-DTI-FT in adjuvant radiation therapy (RT) planning of HGGs for CST avoidance. METHODS: The preoperative nTMS-DTI-FT based CST of 35 patients harboring HGGs were incorporated into the RT planning system and merged with planning imaging. The CST was delineated as PRV-FTTMS. Intensity-modulated RT (IMRT) plans were optimized to preserve PRV-FTTMS. Segments within the planning target volume (PTV) were not spared (overlap). RESULTS: With plan optimization, mean dose (Dmean) of PRV-FTTMS can be reduced by 17.1% on average (range 0.1 - 37.9%), thus from 25.5 Gy to 21.2 Gy (p<0.001 For PRV-FTTMS segments beyond the PTV dose, reduction is possible by 26.8% (range 0.1 - 43.9%, Dmean 17.4 Gy vs. 12.5 Gy, p<0.001 Considering only portions within the 50% isodose level, Dmean is decreased by 46.7% from 38.6 Gy to 20.5 Gy (range 19.1 - 62.8%, p<0.001. PTV coverage was not affected: V95% and V90% were 96.4 ± 3.1% and 98.0 ± 3.9% vs. 96.1 ± 3.5% (p=0.34) and 98.3 ± 2.9% (p=0.58). Dose constraints for organs at risk (OARs) were all met. CONCLUSION: This study demonstrates that nTMS-DTI-FT can be utilized in the RT planning of HGGs for CST sparing. However, the degree of dose reduction depends on the overlap with the PTV. The functional benefit needs to be investigated in future prospective clinical trials. AU - Diehl, C. AU - Rosenkranz, E.* AU - Mißlbeck, M.* AU - Schwendner, M.J.* AU - Sollmann, N.* AU - Ille, S.* AU - Meyer, B.* AU - Combs, S.E. AU - Bernhardt, D. AU - Krieg, S.M.* C1 - 64887 C2 - 52582 SP - 189-197 TI - nTMS-derived DTI-based motor fiber tracking in radiotherapy treatment planning of high-grade gliomas for avoidance of motor structures. JO - Radiother. Oncol. VL - 171 PY - 2022 SN - 0167-8140 ER - TY - JOUR AB - PURPOSE: To develop prognostic biomarker signatures for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated by primary radiochemotherapy (RCTx) based on previously published molecular analyses of the retrospective biomarker study of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG). MATERIAL AND METHODS: In previous studies on the retrospective DKTK-ROG HNSCC cohort treated with primary RCTx, the following clinical parameters and biomarkers were evaluated and found to be significantly associated with loco-regional tumour control (LRC) or overall survival (OS): tumour volume, p16 status, expression of cancer stem cell markers CD44 and SLC3A2, expressions of hypoxia-associated gene signatures, tumour mutational burden (TMB), single nucleotide polymorphisms (SNPs) in the ERCC2 gene (rs1799793, rs13181) and ERCC5 gene (rs17655) as well as the expression of CXCR4, SDF-1 and CD8. These biomarkers were combined in multivariable modelling using Cox-regression with backward variable selection. RESULTS: A baseline signature containing the widely accepted parameters tumour volume, p16 status, cancer stem cell marker expression (CD44) and hypoxia-associated gene expression has been defined, representing the main hypothesis of the study. Furthermore, the baseline signature was extended by additional prognostic biomarkers and a data-driven signature without any pre-hypothesis was generated for both endpoints. In these signatures, the SNPs rs1799793 and rs17655 as well as CXCR4, SDF-1 and SLC3A2 expression were additionally included. The signatures showed significant patient stratifications for LRC and OS. CONCLUSION: Three biomarker signatures were defined for patients with locally advanced HNSCC treated with primary RCTx for the endpoints LRC and OS. These signatures will be validated in the prospective HNprädBio study of the DKTK-ROG that recently completed recruitment, before potential application in an interventional trial. AU - Löck, S.* AU - Linge, A.* AU - Lohaus, F.* AU - Ebert, N.* AU - Gudziol, V.* AU - Nowak, A.* AU - Tinhofer, I.* AU - Kalinauskaite, G.* AU - Guberina, M.* AU - Stuschke, M.* AU - Balermpas, P.* AU - Von der Grün, J.* AU - Grosu, A.L.* AU - Debus, J.* AU - Ganswindt, U. AU - Belka, C. AU - Peeken, J.C. AU - Combs, S.E. AU - De-Colle, C.* AU - Zips, D.* AU - Baretton, G.B.* AU - Krause, M.* AU - Baumann, M.* C1 - 64346 C2 - 52196 SP - 8-14 TI - Biomarker signatures for primary radiochemotherapy of locally advanced HNSCC - hypothesis generation on a multicentre cohort of the DKTK-ROG. JO - Radiother. Oncol. VL - 169 PY - 2022 SN - 0167-8140 ER - TY - JOUR AB - PURPOSE: To assess the relation of the previously reported classification of molecular subtypes to the outcome of patients with HNSCC treated with postoperative radio(chemo)therapy (PORT-C), and to assess the association of these subtypes with gene expressions reflecting known mechanisms of radioresistance. MATERIAL AND METHODS: Gene expression analyses were performed using the GeneChip Human Transcriptome Array 2.0 on a multicentre retrospective patient cohort (N=128) of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG) with locally advanced HNSCC treated with PORT-C. Tumours were assigned to four molecular subtypes, and correlation analyses between subtypes and clinical risk factors were performed. In addition, the classifications of eight genes or gene signatures related to mechanisms of radioresistance, which have previously shown an association with outcome of patients with HNSCC, were compared between the molecular subtypes. The endpoints loco-regional control (LRC) and overall survival (OS) were evaluated by log-rank tests and Cox regression. RESULTS: Tumours were classified into the four subtypes basal (19.5%), mesenchymal (18.8%), atypical (15.6%) and classical (14.1%). The remaining tumours could not be classified (32.0%). Tumours of the mesenchymal subtype showed a lower LRC compared to the other subtypes (p=0.012). These tumours were associated with increased epithelial-mesenchymal transition (EMT) and overexpression of a gene signature enriched in DNA repair genes. The majority of the eight considered gene classifiers were significantly associated to LRC or OS in the whole cohort. CONCLUSION: Molecular subtypes, previously identified on HNSCC patients treated with primary radio(chemo)therapy or surgery, were related to LRC for patients treated with PORT-C, where mesenchymal tumour presented with worse prognosis. After prospective validation, subtype-based patient stratification, potentially in combination with other molecular classifiers, may be considered in future interventional studies in the context of personalised radiotherapy and may guide the development of combined treatment approaches. AU - Patil, S.* AU - Tawk, B.* AU - Grosser, M.* AU - Lohaus, F.* AU - Gudziol, V.* AU - Kemper, M.* AU - Nowak, A.* AU - Haim, D.* AU - Tinhofer, I.* AU - Budach, V.* AU - Guberina, M.* AU - Stuschke, M.* AU - Balermpas, P.* AU - Rödel, C.* AU - Schäfer, H.* AU - Grosu, A.L.* AU - Abdollahi, A.* AU - Debus, J.* AU - Ganswindt, U.* AU - Belka, C. AU - Pigorsch, S.* AU - Combs, S.E. AU - Boeke, S.* AU - Zips, D.* AU - Baretton, G.B.* AU - Baumann, M.* AU - Krause, M.* AU - Löck, S.* AU - Linge, A.* C1 - 63997 C2 - 52040 SP - 300-307 TI - Analyses of molecular subtypes and their association to mechanisms ofradioresistance in patients with HPV-negative HNSCC treated bypostoperative radiochemotherapy. JO - Radiother. Oncol. VL - 167 PY - 2022 SN - 0167-8140 ER - TY - JOUR AB - PURPOSE: The aim of this study was to develop and validate a novel gene signature from full-transcriptome data using machine-learning approaches to predict loco-regional control (LRC) of patients with human papilloma virus (HPV)-negative locally advanced head and neck squamous cell carcinoma (HNSCC), who received postoperative radio(chemo)therapy (PORT-C). MATERIALS AND METHODS: Gene expression analysis was performed using Affymetrix GeneChip Human Transcriptome Array 2.0 on a multicentre retrospective training cohort of 128 patients and an independent validation cohort of 114 patients from the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG). Genes were filtered based on differential gene expression analyses and Cox regression. The identified gene signature was combined with clinical parameters and with previously identified genes related to stem cells and hypoxia. Technical validation was performed using nanoString technology. RESULTS: We identified a 6-gene signature consisting of four individual genes CAV1, GPX8, IGLV3-25, TGFBI, and one metagene combining the highly correlated genes INHBA and SERPINE1. This signature was prognostic for LRC on the training data (ci=0.84) and in validation (ci=0.63) with a significant patient stratification into two risk groups (p=0.005). Combining the 6-gene signature with the clinical parameters T stage and tumour localisation as well as the stem-cell marker CD44 and the 15-gene hypoxia-associated signature improved the validation performance (ci=0.69, p=0.001). CONCLUSION: We have developed and validated a novel prognostic 6-gene signature for LRC of HNSCC patients with HPV-negative tumours treated by PORT-C. After successful prospective validation the signature can be part of clinical trials on the individualization of radiotherapy. AU - Patil, S.* AU - Linge, A.* AU - Grosser, M.* AU - Lohaus, F.* AU - Gudziol, V.* AU - Kemper, M.* AU - Nowak, A.* AU - Haim, D.* AU - Tinhofer, I.* AU - Budach, V.* AU - Guberina, M.* AU - Stuschke, M.* AU - Balermpas, P.* AU - Rödel, C.* AU - Schäfer, H.* AU - Grosu, A.L.* AU - Abdollahi, A.* AU - Debus, J.* AU - Ganswindt, U.* AU - Belka, C. AU - Pigorsch, S.* AU - Combs, S.E. AU - Boeke, S.* AU - Zips, D.* AU - Baretton, G.B.* AU - Baumann, M.* AU - Krause, M.* AU - Löck, S.* C1 - 64787 C2 - 52483 SP - 91-100 TI - Development and validation of a 6-gene signature for the prognosis of loco-regional control in patients with HPV-negative locally advanced HNSCC treated by postoperative radio(chemo)therapy. JO - Radiother. Oncol. VL - 171 PY - 2022 SN - 0167-8140 ER - TY - JOUR AB - Background and purpose: For skull base tumors, target definition is the key to safe high-dose treatments because surrounding normal tissues are very sensitive to radiation. In the present work we established a joint ESTRO ACROP guideline for the target volume definition of skull base tumors. Material and methods: A comprehensive literature search was conducted in PubMed using various combinations of the following medical subjects headings (MeSH) and free-text words: “radiation therapy” or “stereotactic radiosurgery” or “proton therapy” or “particle beam therapy” and “skull base neoplasms” “pituitary neoplasms”, “meningioma”, “craniopharyngioma”, “chordoma”, “chondrosarcoma”, “acoustic neuroma/vestibular schwannoma”, “organs at risk”, “gross tumor volume”, “clinical tumor volume”, “planning tumor volume”, “target volume”, “target delineation”, “dose constraints”. The ACROP committee identified sixteen European experts in close interaction with the ESTRO clinical committee who analyzed and discussed the body of evidence concerning target delineation. Results: All experts agree that magnetic resonance (MR) images with high three-dimensional spatial accuracy and tissue-contrast definition, both T2-weighted and volumetric T1-weighted sequences, are required to improve target delineation. In detail, several key issues were identified and discussed: i) radiation techniques and immobilization, ii) imaging techniques and target delineation, and iii) technical aspects of radiation treatments including planning techniques and dose-fractionation schedules. Specific target delineation issues with regard to different skull base tumors, including pituitary adenomas, meningiomas, craniopharyngiomas, acoustic neuromas, chordomas and chondrosarcomas are presented. Conclusions: This ESTRO ACROP guideline achieved detailed recommendations on target volume definition for skull base tumors, as well as comprehensive advice about imaging modalities and radiation techniques. AU - Combs, S.E. AU - Baumert, B.G.* AU - Bendszus, M.* AU - Bozzao, A.* AU - Brada, M.* AU - Fariselli, L.* AU - Fiorentino, A.* AU - Ganswindt, U.* AU - Grosu, A.-L.* AU - Lagerwaard, F.L.* AU - Niyazi, M.* AU - Nyholm, T.* AU - Paddick, I.* AU - Weber, D.C.* AU - Belka, C.* AU - Minniti, G.* C1 - 60902 C2 - 49737 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 80-94 TI - ESTRO ACROP guideline for target volume delineation of skull base tumors. JO - Radiother. Oncol. VL - 156 PB - Elsevier Ireland Ltd PY - 2021 SN - 0167-8140 ER - TY - JOUR AB - PURPOSE: Radioresistance in pancreatic cancer patients remains a critical obstacle to overcome. Understanding the molecular mechanisms underlying radioresistance may achieve better response to radiotherapy and thereby improving the poor treatment outcome. The aim of the present study was to elucidate the mechanisms leading to radioresistance by detailed characterization of isogenic radioresistant and radiosensitive cell lines. METHODS: The human pancreatic cancer cell lines, Panc-1 and MIA PaCa-2 were repeatedly exposed to radiation to generate radioresistant (RR) isogenic cell lines. The surviving cells were expanded, and their radiosensitivity was measured using colony formation assay. Tumor growth delay after irradiation was determined in a mouse pancreatic cancer xenograft model. Gene and protein expression were analyzed using RNA sequencing and Western blot, respectively. Cell cycle distribution and apoptosis (Caspase 3/7) were measured by FACS analysis. Reactive oxygen species generation and DNA damage were analyzed by detection of CM-H2DCFDA and γH2AX staining, respectively. Transwell chamber assays were used to investigate cell migration and invasion. RESULTS: The acquired radioresistance of RR cell lines was demonstrated in vitro and validated in vivo. Ingenuity pathway analysis of RNA sequencing data predicted activation of cell viability in both RR cell lines. RR cancer cell lines demonstrated greater DNA repair efficiency and lower basal and radiation-induced reactive oxygen species levels. Migration and invasion were differentially affected in RR cell lines. CONCLUSIONS: Our data indicate that repeated exposure to irradiation increases the expression of genes involved in cell viability and thereby leads to radioresistance. Mechanistically, increased DNA repair capacity and reduced oxidative stress might contribute to the radioresistant phenotype. AU - Nguyen, L. AU - Dobiasch, S. AU - Schneider, G.* AU - Schmid, R.M.* AU - Azimzadeh, O. AU - Kanev, K.* AU - Buschmann, D.* AU - Pfaffl, M.W.* AU - Bartzsch, S. AU - Schmid, T.E. AU - Schilling, D. AU - Combs, S.E. C1 - 61783 C2 - 50457 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 265-276 TI - Impact of DNA repair and reactive oxygen species levels on radioresistance in pancreatic cancer. JO - Radiother. Oncol. VL - 159 PB - Elsevier Ireland Ltd PY - 2021 SN - 0167-8140 ER - TY - JOUR AB - PURPOSE: In high-grade soft-tissue sarcomas (STS) the standard of care encompasses multimodal therapy regimens. While there is a growing body of evidence for prognostic pretreatment radiomic models, we hypothesized that temporal changes in radiomic features following neoadjuvant treatment ("delta-radiomics") may be able to predict the pathological complete response (pCR). METHODS: MRI scans (T1-weighted with fat-saturation and contrast-enhancement (T1FSGd) and T2-weighted with fat-saturation (T2FS)) of patients with STS of the extremities and trunk treated with neoadjuvant therapy were gathered from two independent institutions (training: 103, external testing: 53 patients). pCR was defined as < 5% viable cells. After segmentation and preprocessing, 105 radiomic features were extracted. Delta-radiomic features were calculated by subtraction of features derived from MRI scans obtained before and after neoadjuvant therapy. After feature reduction, machine learning modeling was performed in 100 iterations of 3-fold nested cross-validation. Delta-radiomic models were compared with single timepoint models in the testing cohort. RESULTS: The combined delta-radiomic models achieved the best area under the receiver operating characteristic curve (AUC) of 0.75. Pre-therapeutic tumor volume was the best conventional predictor (AUC 0.70). The T2FS-based delta-radiomic model had the most balanced classification performance with a balanced accuracy of 0.69. Delta-radiomic models achieved better reproducibility than single timepoint radiomic models, RECIST or the peri-therapeutic volume change. Delta-radiomic models were significantly associated with survival in multivariate Cox regression. CONCLUSION: This exploratory analysis demonstrated that MRI-based delta-radiomics improves prediction of pCR over tumor volume and RECIST. Delta-radiomics may one day function as a biomarker for personalized treatment adaptations. AU - Peeken, J.C. AU - Asadpour, R.* AU - Specht, K.* AU - Chen, E.Y.* AU - Klymenko, O.* AU - Akinkuoroye, V.* AU - Hippe, D.S.* AU - Spraker, M.B.* AU - Schaub, S.K.* AU - Dapper, H.* AU - Knebel, C.* AU - Mayr, N.A.* AU - Gersing, A.S.* AU - Woodruff, H.C.* AU - Lambin, P.* AU - Nyflot, M.J.* AU - Combs, S.E. C1 - 63066 C2 - 51257 SP - 73-82 TI - MRI-based delta-radiomics predicts pathologic complete response in high-grade soft-tissue sarcoma patients treated with neoadjuvant therapy. JO - Radiother. Oncol. VL - 164 PY - 2021 SN - 0167-8140 ER - TY - JOUR AB - Objective: The purpose of this study was to estimate the dose distribution from randomized trials (MA.20, EORTC 22922-10925 (EORTC), AMAROS and the Z0011 trial) on lymph node (LN) irradiation on a large LN atlas.Methods: 580 F-18-FDG-PET/CT positive LN metastases of 235 patients were transferred rigidly and non-rigidly to three "template CTs" (standard, obese and slender patient). Further, the LN clinical target volumes (CTVs) were contoured according to the ESTRO-guidelines. Treatment plans were designed (each for the left and right side) for all patients based on the study protocols of the MA.20, EORTC, AMAROS and Z0011 trial. Subsequently, the dose distribution in the ESTRO-CTVs and in the 580 LNs were assessed.Results: Our results reveal variable dose coverage (26.8 +/- 17.3 Gy-53.0 +/- 1.8 Gy) in the targeted LN areas (ESTRO-CTV and LN) in dependence of the treatment planning design and the patients' body shape. None of the treatment plan designs provided full dose coverage to the lymphatic drainage system. High tangent irradiation resulted in a similar dose distribution in L I and II compared to the AMAROS field design.Conclusion: Inclusion of the entire lymphatic system may not be necessary for all patients to reproduce the oncologic benefit shown in the randomized LN-irradiation trials. Inclusion of axillary level II and extension of the supraclavicular CTV can be considered in selected high-risk patients, based on dose recalculation of the MA.20 trial. Further, our results amplify earlier assumptions that irradiation may have accounted for the good results after SLND alone in the Z0011 trial. AU - Borm, K.J.* AU - Oechsner, M.* AU - Düsberg, M.* AU - Buschner, G.* AU - Weber, W.* AU - Combs, S.E. AU - Duma, M.N.* C1 - 56943 C2 - 47342 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 195-201 TI - Irradiation of regional lymph node areas in breast cancer - Dose evaluation according to the Z0011, AMAROS, EORTC 10981-22023 and MA-20 field design. JO - Radiother. Oncol. VL - 142 PB - Elsevier Ireland Ltd PY - 2020 SN - 0167-8140 ER - TY - JOUR AU - Akhgar, J.* AU - Peeken, J.C. AU - Pigorsch, S.U.* AU - Combs, S.E. C1 - 56317 C2 - 46979 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S879-S880 TI - Response prediction of palliative radiotherapy to painful spinal bone metastases. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Bartzsch, S. C1 - 56310 C2 - 46986 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S176-S177 TI - Compact microbeam sources and microbeam treatment planning. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Bierbaumer, D.* AU - Muench, S.* AU - Haller, B.* AU - Habermehl, D.* AU - Pfluger, P.T. AU - Stemmer, K. AU - Combs, S.E.* C1 - 56302 C2 - 46975 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S794-S795 TI - Impact of diabetes on outcome and toxicity of neoadjuvant (chemo)radiation for rectal cancer. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Bierbaumer, D.* AU - Muench, S.* AU - Haller, B.* AU - Habermehl, D.* AU - Pfluger, P.T. AU - Stemmer, K. AU - Combs, S.E.* C1 - 56304 C2 - 46973 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S780-S780 TI - Impact of diabetes on outcome and toxicity of chemoradiation for esophageal squamous cell carcinoma. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AB - Purpose: Non-resectable cholangiocarcinoma (CCC) is a significant therapeutic challenge because of bad prognosis. This study analyzed the outcome after SBRT for intra-and extrahepatic CCC.Material and methods: Sixty-four patients with 82 CCC lesions from a retrospective multicenter database were analyzed. Available parameters were analyzed for local control (LC), overall survival (OS) and toxicity.Results: Median follow-up time for patients alive was 35 months (range 7-91 months). Median overall survival (OS) time was 15 months; 2-year and 3-year OS rates were 32% and 21%. Median prescribed biological effective radiation dose (BED, alpha/beta = 10) was 67.2 Gy(10) (range, 36-115 Gy(10); SD: 20 Gy(10)) in median 8 fractions (range, 3-17; 95% CI: 3-12), median BEDmax was 91 Gy(10). BED was the only prognostic factor for LC and OS. Patients receiving BEDmax >91 Gy(10) had a median OS of 24 months vs. 13 months for those receiving lower doses (p = 0.008). LC rates at 12 and 24 months were 91% and 80% for BEDmax > 91 Gy(10) vs. 66% and 39% for lower doses (p = 0.009). Of note, tumor size and PTV were neither predictive nor prognostic for LC and OS. Treatment tolerance was good with 17% of grade 1 gastroduodenitis, 11% of grade 2-3 cholangitis and 4.7% of grade 3 gastrointestinal bleeding.Conclusion: This is the largest reported series on SBRT in cholangiocarcinoma. Overall survival and local control were significantly improved after higher doses (BED) and tolerance was excellent. (C) 2018 Elsevier B.V. All rights reserved. AU - Brunner, T.B.* AU - Blanck, O.* AU - Lewitzki, V.* AU - Abbasi-Senger, N.* AU - Momm, F.* AU - Riesterer, O.* AU - Duma, M.N. AU - Wachter, S.* AU - Baus, W.* AU - Gerum, S.* AU - Guckenberger, M.* AU - Gkika, E.* C1 - 55043 C2 - 46055 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 42-47 TI - Stereotactic body radiotherapy dose and its impact on local control and overall survival of patients for locally advanced intrahepatic and extrahepatic cholangiocarcinoma. JO - Radiother. Oncol. VL - 132 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Dapper, H.* AU - Schiller, K.* AU - Muench, S.* AU - Peeken, J.C.* AU - Borm, K.* AU - Weber, W.* AU - Combs, S.E. C1 - 56313 C2 - 46989 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S193-S194 TI - A PET-based patterns of failure analysis in the context of contouring guidelines in anal cancer. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AB - Background: Navigated transcranial magnetic stimulation (nTMS) is applied in neurosurgical routine to detect motor-eloquent brain areas for safe resection of high-grade gliomas (HGGs). However, in radiation therapy (RT) planning, the primary motor cortex is not respected yet in target volume delineation. This study evaluates the implementation of nTMS motor mapping in RT planning in patients harboring motoreloquent HGGs with the aim of reducing dose applications to the motor cortex.Methods: nTMS motor maps of 30 patients diagnosed with motor-eloquent HGGs were fused with RT planning imaging and volumetric modulated RT plans were optimized using nTMS motor maps as an organ at risk (OAR). Doses to nTMS motor maps were evaluated using dose-volume histogram (DVH) parameters.Results: Mean dose (Dmean) to the nTMS motor maps was 42.3 Gy (3.7-61.1 Gy) and was significantly reduced by 14.3% to 37.0 Gy (3.6-55.8 Gy, p < 0.05) when constraining the dose to nTMS motor areas to 45 Gy. Areas within the planning target volume (PTV) were not spared (overlap). Yet, the dose to PTV was not compromised. Even with an additional dose escalation (70 Gy) to the tumor area, nTMS motor maps can be spared by 4.6 +/- 3.5 Gy (12.8%, p < 0.05).Conclusions: nTMS motor maps can be easily implemented in standard RT planning and applied for target contouring in RT of HGGs. Doses to motor-eloquent areas can be significantly reduced when considering nTMS motor maps without affecting treatment doses to the PTV. Thus, nTMS could be used as a valuable tool in RT planning. AU - Diehl, C.D.* AU - Schwendner, M.J.* AU - Sollmann, N.* AU - Oechsner, M.* AU - Meyer, B.* AU - Combs, S.E. AU - Krieg, S.M.* C1 - 56176 C2 - 46879 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 30-37 TI - Application of presurgical navigated transcranial magnetic stimulation motor mapping for adjuvant radiotherapy planning in patients with high-grade gliomas. JO - Radiother. Oncol. VL - 138 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Gerhardt, A.S.* AU - Duma, M.N. AU - Duesberg, M.* AU - Wilkens, J.J.* AU - Combs, S.E. AU - Oechsner, M.* C1 - 56314 C2 - 46991 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S1210-S1211 TI - Influence of rotational setup errors on dose in target and organs at risk in cranial radiotherapy. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Hirmer, E. AU - Kell, R. AU - Winkler, S. AU - Winkler, K. AU - Mutschelknaus, L. AU - Mörtl, S. AU - Atkinson, M.J. AU - Combs, S.E. AU - Schmid, T.E. AU - Anastasov, N. C1 - 56308 C2 - 46984 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S603-S604 TI - The interaction between miR-221 overexpression and radiosensitivity in mamma carcinoma cell lines. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Hombrink, G. AU - Wilkens, J.J.* AU - Combs, S.E. AU - Bartzsch, S. C1 - 56315 C2 - 46990 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S47-S48 TI - Microcavities in the lung affect the dose distribution in microbeam radiation therapy. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Kessel, K.A. AU - Fischer, H.* AU - Voglhuber, T.* AU - Diehl, C.* AU - Straube, C.* AU - Weber, W.* AU - Combs, S.E. C1 - 56312 C2 - 46988 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S690-S691 TI - Influence of PET-imaging during treatment planning on outcome in meningioma patients. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Klapproth, A.* AU - Li, W.B. AU - Stangl, S.* AU - Diederichs, C.* AU - Shevtsov, M.* AU - Ntziachristos, V. AU - Multhoff, G.* C1 - 56305 C2 - 46972 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S1147-S1148 TI - MC simulations on the dose enhancement effect of antibody conjugated AuNPs in targeted radiotherapy. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AB - Purpose: To provide personalized estimates of doses to contralateral breast (CB) from breast-cancer radiotherapy.Methods: Whole-breast irradiations using 3D conformal, intensity-modulated and hybrid techniques with 50.4 Gy prescribed dose were planned for 128 breast-cancer patients. From their CT images, 17 anatomic measures were assessed and tested by model fitting as predictors for CB dose-volume characteristics.Results: Multi-field intensity-modulated radiotherapy (IMRT) yielded mean CB doses of 0.8-7.1 Gy, with no correlation to the studied anatomic parameters. Tangential whole-breast irradiation led to much lower mean CB doses, 0.2-1.6 Gy. About 60% of this inter-patient variability was explained by individual variations in a single anatomic measure, the minimum breast distance (MBD), defined as the CB distance from the tangent to the treated breast. Per 1 cm increase in MBD, the mean CB dose decreased by 10-15%. As an alternative to MBD, dose estimates could be based on the breast-to-breast distance, which is highly correlated with MBD.Conclusion: The results enable personalized assessment of CB doses from tangential whole-breast irradiation, based only on parameters assessable from CT data. This may help support clinical decision-making processes as well as analyse retrospective studies on CB risks. (C) 2018 Elsevier B.V. All rights reserved. AU - Kundrat, P. AU - Remmele, J.* AU - Rennau, H.* AU - Sebb, S.* AU - Simonetto, C. AU - Eidemüller, M. AU - Wolf, U.* AU - Hildebrandt, G.* C1 - 54382 C2 - 45558 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 186-191 TI - Minimum breast distance largely explains individual variability in doses to contralateral breast from breast-cancer radiotherapy. JO - Radiother. Oncol. VL - 131 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Linge, A.* AU - Tawk, B.* AU - Loeck, S.* AU - Grosser, M.* AU - Lohaus, F.* AU - Gudziol, V.* AU - Nowak, A.* AU - Tinhofer, I.* AU - Budach, V.* AU - Stuschke, M.* AU - Balermpas, P.* AU - Roedel, C.* AU - Schaefer, H.M.* AU - Grosu, A.* AU - Debus, J.* AU - Ganswindt, U. AU - Belka, C. AU - Pigorsch, S.* AU - Combs, S.E. AU - Moennich, D.* AU - Zips, D.* AU - Baretton, G.B.* AU - Abdollahi, A.* AU - Krause, M.* AU - Baumann, M.* C1 - 56307 C2 - 46983 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S196-S196 TI - TCGA molecular subclassification is prognostic for LRC of HNSCC after postoperative RCTx. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Oechsner, M.* AU - Duesberg, M.* AU - Borm, K.* AU - Wilkens, J.J.* AU - Combs, S.E. AU - Duma, M.N. C1 - 56318 C2 - 46978 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S715-S715 TI - Gated treatment of left-sided breast cancer: Evaluation of lung movement, irradiated volume and mass. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AB - Purpose: In soft tissue sarcoma (STS) patients systemic progression and survival remain comparably low despite low local recurrence rates. In this work, we investigated whether quantitative imaging features (“radiomics”) of radiotherapy planning CT-scans carry a prognostic value for pre-therapeutic risk assessment. Methods: CT-scans, tumor grade, and clinical information were collected from three independent retrospective cohorts of 83 (TUM), 87 (UW) and 51 (McGill) STS patients, respectively. After manual segmentation and preprocessing, 1358 radiomic features were extracted. Feature reduction and machine learning modeling for the prediction of grading, overall survival (OS), distant (DPFS) and local (LPFS) progression free survival were performed followed by external validation. Results: Radiomic models were able to differentiate grade 3 from non-grade 3 STS (area under the receiver operator characteristic curve (AUC): 0.64). The Radiomic models were able to predict OS (C-index: 0.73), DPFS (C-index: 0.68) and LPFS (C-index: 0.77) in the validation cohort. A combined clinical-radiomics model showed the best prediction for OS (C-index: 0.76). The radiomic scores were significantly associated in univariate and multivariate cox regression and allowed for significant risk stratification for all three endpoints. Conclusion: This is the first report demonstrating a prognostic potential and tumor grading differentiation by CT-based radiomics. AU - Peeken, J.C. AU - Bernhofer, M.* AU - Spraker, M.B.* AU - Pfeiffer, D.* AU - Devecka, M.* AU - Thamer, A.* AU - Shouman, M.A.* AU - Ott, A.* AU - Nüsslin, F.* AU - Mayr, N.A.* AU - Rost, B.* AU - Nyflot, M.J.* AU - Combs, S.E. C1 - 55827 C2 - 46605 SP - 187-196 TI - CT-based radiomic features predict tumor grading and have prognostic value in patients with soft tissue sarcomas treated with neoadjuvant radiation therapy. JO - Radiother. Oncol. VL - 135 PY - 2019 SN - 0167-8140 ER - TY - JOUR AB - Purpose: Glioblastoma is routinely treated by concomitant radiochemotherapy. Current target definition guidelines use anatomic MRI (magnetic resonance imaging) scans, taking into account contrast enhancement and the rather unspecific hyperintensity on the fluid-attenuated inversion recovery (FLAIR) sequence.Methods and materials: We applied deep learning based free water correction of diffusion tensor imaging (DTI) scans to estimate the infiltrative gross tumor volume (iGTV) inside of the FLAIR hyperintense region. We analyzed the resulting iGTVs and their impact on target volume definition in a retrospective cohort of 33 GBM patients.Results: iGTVs were significantly smaller compared to standard pre-and post-operative gross tumor volume (GTV) definitions. Two novel infiltrative tumor GTVs (nGTV(PRE-OP) and nGTV(POST-OP)) defined as the conjunction volume of the standard GTV and the iGTV showed only a moderate increase in size compared to standard GTV definitions. On postoperative scans, the iGTV was predominantly covered by the two clinical target volume (CTV) concepts CTVEORTC and CTVROTG1. A novel infiltrative tumor CTV (nCTV) [nGTV(POST-OP) + 2 cm margin] was significantly smaller compared to CTVROTG1 but larger than CTVEORTC. The overlap volume and conformity index demonstrated a distinct spatial configuration of the nCTV. Tumor recurrences overlapped with the iGTV in all but one patients and were completely covered by the nCTV in all patients. After reducing the margin to 1 cm recurrences coverage was at least in-field in all patients.Conclusion: To conclude, free water corrected DTI scans may help to define infiltrative tumor areas of GBM that could ultimately be used to individualize RT treatment planning in terms of dose sparing or dose escalation. AU - Peeken, J.C. AU - Molina-Romero, M.* AU - Diehl, C.* AU - Menze, B.H.* AU - Straube, C.* AU - Meyer, B.* AU - Zimmer, C.* AU - Wiestler, B.* AU - Combs, S.E. C1 - 56574 C2 - 47161 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 166-172 TI - Deep learning derived tumor infiltration maps for personalized target definition in Glioblastoma radiotherapy. JO - Radiother. Oncol. VL - 138 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Porth, A.* AU - Hunger, A. AU - Setzkorn, T. AU - Mehrabi, N.* AU - Burger, K.* AU - Combs, S.E. AU - Schmid, T.E. C1 - 56316 C2 - 46980 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S1198-S1198 TI - Analysis of Chromosomal Aberrations by FISH in FaDu tumor cells after in vivo X-ray MRT irradiation. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AB - Background and purpose: High-precision radiotherapy is an effective treatment modality for tumors. Intensity-modulated radiotherapy techniques permit close shaping of high doses to tumors, however healthy organs outside the target volume are repeatedly exposed to low-dose radiation (LDR). The inherent vulnerability of hippocampal neurogenesis is likely the determining factor in radiation-induced neurocognitive dysfunctions. Using preclinical in-vivo models with daily LDR we attempted to precisely define the pathophysiology of radiation-induced neurotoxicity.Material and methods: Genetically defined mouse strains with varying DNA repair capacities were exposed to fractionated LDR (5 x /10 x /15 x /20 x 0.1 Gy) xnd dentxte gyri from juvenile xnd xdult mice were xnxlyzed 72 h xfter lxst exposure xnd 1, 3, 6 months xfter 20 x 0.1 Gy. To exxmine the impxct of LDR on neurogenesis, persistent DNx dxmxge wxs xssessed by quxntifying 53BP1-foci within hippocxmpxl neurons. Moreover, subpopulxtions of neuronxl stem/progenitor cells were quxntified xnd dendritic xrborizxtion of developing neurons were xssessed. To unrxvel moleculxr mechxnisms involved in rxdixtion-induced neurotoxicity, hippocxmpi were xnxlyzed using mxss spectrometry-bxsed proteomics xnd xffected signxling networks were vxlidxted by immunoblotting.Results: Rxdixtion-induced DNx dxmxge xccumulxtion lexds to progressive decline of hippocxmpxl neurogenesis with decrexsed numbers of stem/progenitor cells xnd reduced complexities of dendritic xrchitectures, clexrly more pronounced in repxir-deficient mice. Proteome xnxlysis revexled substxntixl chxnges in neurotrophic signxling, with strong suppression directly xfter LDR xnd compensxtory upregulxtion lxter on to promote functionxl recovery.Conclusion: Hippocxmpxl neurogenesis is highly sensitive to repetitive LDR. Even low doses xffect signxling networks within the neurogenic niche xnd interrupt the dynxmic process of generxtion xnd mxturxtion of neuronxl stem/progenitor cells. (C) 2019 Elsevier B.V. All rights reserved. AU - Schmal, Z.* AU - Isermann, A.* AU - Hladik, D. AU - von Toerne, C. AU - Tapio, S. AU - Rübe, C.E.* C1 - 56000 C2 - 46742 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 45-54 TI - DNA damage accumulation during fractionated low-dose radiation compromises hippocampal neurogenesis. JO - Radiother. Oncol. VL - 137 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Schmid, T. AU - Hellmundt, F. AU - Lemmer, S. AU - Ilicic, K. AU - Melzner, M.* AU - Bartzsch, S. AU - Wilkens, J.J.* AU - Combs, S.E. C1 - 56311 C2 - 46987 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S600-S601 TI - Biological interaction of a static magnetic field (SMF) with ionizing irradiation. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AB - Purpose: Aim of the current comparative modelling study was to estimate the individual radiation-induced risk for death of ischaemic heart disease (IHD) under free breathing (FB) and deep inspiration breath-hold (DIBH) in a real-world population.Materials and methods: Eighty-nine patients with left-sided early breast cancer were enrolled in the prospective SAVE-HEART study. For each patient three-dimensional conformal treatment plans were created in FB and DIBH and corresponding radiation-induced risks of IHD mortality were estimated based on expected survival, individual IHD risk factors and the relative radiation-induced risk.Results: With the use of DIBH, mean heart doses were reduced by 35% (interquartile range: 23-46%) as compared to FB. Mean expected years of life lost (YLL) due to radiation-induced IHD mortality were 0.11 years in FB, and 0.07 years in DIBH. YLL were remarkably independent of age at treatment in patients with a favourable tumour prognosis. DIBH led to more pronounced reductions in YLL in patients with high baseline risk (0.08 years for upper vs 0.02 years for lower quartile), with favourable tumour prognosis (0.05 years for patients without vs 0.02 years for those with lymph-node involvement), and in patients with high mean heart doses in FB (0.09 years for doses >3 Gy vs 0.02 years for doses <1.5 Gy).Conclusion: Ideally, the DIBH technique should be offered to all patients with left-sided breast cancer. However, highest benefits are expected for patients with a favourable tumour prognosis, high mean heart dose or high baseline IHD risk, independent of their age. (C) 2018 The Authors. Published by Elsevier B.V. AU - Simonetto, C. AU - Eidemüller, M. AU - Gaasch, A.* AU - Pazos, M.* AU - Schönecker, S.* AU - Reitz, D.* AU - Kääb, S.* AU - Braun, M.* AU - Harbeck, N.* AU - Niyazi, M.* AU - Belka, C.* AU - Corradini, S.* C1 - 54112 C2 - 45354 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 202-207 TI - Does deep inspiration breath-hold prolong life? Individual risk estimates of ischaemic heart disease after breast cancer radiotherapy. JO - Radiother. Oncol. VL - 131 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Starke, S.* AU - Leger, S.* AU - Zwanenburg, A.* AU - Pilz, K.* AU - Lohaus, F.* AU - Linge, A.* AU - Zoephel, K.* AU - Kotzerke, J.* AU - Schreiber, A.* AU - Tinhofer, I.* AU - Budach, V.* AU - Stuschke, M.* AU - Balermpas, P.* AU - Roedel, C.* AU - Ganswindt, U. AU - Belka, C. AU - Pigorsch, S.* AU - Combs, S.E. AU - Moennich, D.* AU - Zips, D.* AU - Krause, M.* AU - Baumann, M.* AU - Richter, C.* AU - Troost, E.G.C.* AU - Loeck, S.* C1 - 56309 C2 - 46985 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S254-S255 TI - Deep-learning based estimation of loco-regional control for patients with locally advanced HNSCC. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Treibel, F. AU - Wilkens, J.J.* AU - Bartzsch, S. AU - Combs, S.E. C1 - 56303 C2 - 46974 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S56-S57 TI - An optimized compact microbeam source for preclinical studies. JO - Radiother. Oncol. VL - 133 PB - Elsevier Ireland Ltd PY - 2019 SN - 0167-8140 ER - TY - JOUR AU - Brunner, T.* AU - Blanck, O.* AU - Abbasi-Senger, N.* AU - Momm, F.* AU - Andratschke, N.* AU - Habermehl, D. AU - Wachter, S.* AU - Baus, W.* AU - Gerum, S.* AU - Guckenberger, M.* AU - Gkika, E.* C1 - 54074 C2 - 45286 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S85-S86 TI - Dose of stereotactic radiotherapy, local control and overall survival in cholangiocarcinoma. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AB - Purpose: To evaluate outcome in patients with base of skull meningiomas treated with modern high precision radiation therapy (RT) techniques.Patients and methods: 927 patients from three centers were treated with either radiosurgery or fractionated high-precision RT for meningiomas. Treatment planning was based on CT and MRI following institutional guidelines. For radiosurgery, a median dose of 13 Gy was applied, for fractionated treatments, a median dose of 54 Gy in 1.8 Gy single fractions was prescribed. Follow-up included a clinical examination as well as contrast-enhanced imaging. All patients were followed up prospectively after radiotherapy in the three departments within a strict follow-up regimen. The median follow-up time was 81 months (range 1-348 months).Results: Median local control was 79 months (range 1-348 months). Local control (LC) was 98% at 1 year, 94% at 3 years, 92% at 5 years and 86% at 10 years. There was no difference between radiosurgery and fractionated RT. We analyzed the influence of higher doses on LC and could show that dose did not impact LC. Moreover, there was no difference between 54 Gy and 57.6 Gy in the fractionated group. Side effects were below 5% in both groups without any severe treatment-related complications.Discussion: Based on the pooled data analysis this manuscript provides a large series of meningiomas of the skull base treated with modern high precision RT demonstrating excellent local control and low rates of side effects. Such data support the recommendation of RT for skull base meningiomas in the interdisciplinary tumor board discussions. The strong role of RT must influence treatment recommendations keeping in mind the individual risk-benefit profile of treatment alternatives. (C) 2018 Elsevier B.V. All rights reserved. AU - Combs, S.E. AU - Farzin, M.* AU - Boehmer, J.* AU - Oehlke, O.* AU - Molls, M.M.* AU - Debus, J.* AU - Grosu, A.-L.* C1 - 53344 C2 - 44834 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 274-279 TI - Clinical outcome after high-precision radiotherapy for skull base meningiomas: Pooled data from three large German centers for radiation oncology. JO - Radiother. Oncol. VL - 127 IS - 2 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Dapper, H.* AU - Oechsner, M.* AU - Münch, S.* AU - Combs, S.E. AU - Habermehl, D. C1 - 54365 C2 - 45498 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S802-S803 TI - DVH- and NTCP-based dosimetric comparison of different cranial margins for VMAT of rectal cancer. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AB - Introduction: Preclinical and clinical data suggest that the chemokine pathway governed by SDF-1 and CXCR4 contributes to a resistant phenotype. This retrospective biomarker study aims to explore the specific prognostic value of SDF-1 and CXCR4 expression in locally advanced head and neck squamous cell carcinomas (HNSCC) treated with primary radiochemotherapy (RT-CT). Material and methods: Biopsies from 141 HNSCC tumours of the oral cavity, oropharynx and hypopharynx were evaluated for SDF-1 and CXCR4 expression by immunofluorescence. SDF-1 and CXCR4 expression was correlated with clinico-pathological characteristics and outcome after RT-CT. Results: Patients with tumours exhibiting overexpression of intracellular SDF-1 and CXCR4 have a higher risk for loco-regional relapse and a worse overall survival after RT-CT (multivariate analysis, hazard ratio 2.33, CI [1.18-4.62], p = 0.02 and hazard ratio 2.02, CI [1.13-3.59], p = 0.02, respectively). Similar results were observed when only the subgroup of HPV DNA negative patients were analysed (hazard ratio 2.23 and 2.16, p = 0.02 and p = 0.01, respectively). Conclusions: Our data support the importance of SDF-1 and CXCR4 expression for loco-regional control and overall survival in HNSCC after primary radiochemotherapy. Prospective multivariate validation and further studies into CXCR4 inhibition to overcome radiation resistance are warranted. (C) 2017 Elsevier B.V. All rights reserved. AU - De-Colle, C.* AU - Menegakis, A.* AU - Mönnich, D.* AU - Welz, S.* AU - Boeke, S.* AU - Sipos, B.* AU - Fend, F.* AU - Mauz, P.S.* AU - Tinhofer, I.* AU - Budach, V.* AU - Abu Jawad, J.* AU - Stuschke, M.* AU - Balermpas, P.* AU - Rödel, C.* AU - Grosu, A.-L.* AU - Abdollahi, A.* AU - Debus, J.* AU - Belka, C.* AU - Ganswindt, U.* AU - Pigorsch, S.U. AU - Combs, S.E. AU - Lohaus, F.* AU - Linge, A.* AU - Krause, M.* AU - Baumann, M.* AU - Zips, D.* C1 - 52190 C2 - 43808 CY - Clare SP - 125-131 TI - SDF-1/CXCR4 expression is an independent negative prognostic biomarker in patients with head and neck cancer after primary radiochemotherapy. JO - Radiother. Oncol. VL - 126 IS - 1 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Forster, C.* AU - Schilling, D. AU - Wank, M. AU - Schmid, T.E. AU - Combs, S.E. C1 - 54366 C2 - 45499 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S1281-S1282 TI - Effects of the proteasome inhibitor bortezomib on radiosensitivity of glioblastoma cells. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Gora, T.* AU - Burkhardt, R. AU - Umkehrer, S.* AU - Herzen, J.* AU - Schilling, D. AU - Feuchtinger, A. AU - Walch, A.K. AU - Schmid, T.E. AU - Multhoff, G. AU - Noel, P.B.* AU - Rummeny, E.J.* AU - Pfeiffer, F.* AU - Combs, S.E. AU - Wilkens, J.J.* C1 - 54075 C2 - 45287 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - E581-E582 TI - Detection of radiation induced lung fibrosis using x-ray dark-field imaging in a murine model. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Hofmeister, A.* AU - Duma, M.N. AU - Wiegandt, M.* AU - Combs, S.E. AU - Wilkens, J.J. AU - Oechsner, M.* C1 - 54362 C2 - 45495 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S758-S759 TI - Reduction of lung dose during stereotactic radiation of lung tumors using respiratory gating. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Kessel, K.A. AU - Salfelder, M.E.* AU - Thiel, U.* AU - Habl, G.* AU - Burdach, S.* AU - Kampfer, S.* AU - Combs, S.E. C1 - 54071 C2 - 45284 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S610-S611 TI - Tomotherapy of pediatric sarcomas: Outcome and toxicity rates. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Kessel, K.A. AU - Kessel, C.* AU - Vogel, M.M.E.* AU - Bier, H.* AU - Biedermann, T.* AU - Friess, H.* AU - Herschbach, P.* AU - von Eisenhart-Rothe, R.* AU - Meyer, B.* AU - Kiechle, M.* AU - Keller, U.* AU - Peschel, C.* AU - Schmid, R.* AU - Schwaiger, M.* AU - Combs, S.E. C1 - 54076 C2 - 45288 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S50-S50 TI - Cancer Clinical Trials - survey evaluating patient participation and attitude in an Oncology Center. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Kessel, K.A. AU - Bihoi, G.A.* AU - Oechsner, M.* AU - Duma, M.N.* AU - Combs, S.E. C1 - 54077 C2 - 45290 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S636-S637 TI - Influence of dose applied to cochlea during RT of vestibular schwannoma and its effect on hearing. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Klymenko, O. AU - Baumeister, P. AU - Zitzelsberger, H. AU - Unger, K. AU - Hess J. AU - Schoetz, U.* AU - Belka, C. AU - Lauber, K. C1 - 54363 C2 - 45496 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S1266-S1267 TI - HNSCC derived cell lines and subclones differ in genomic copy number changes and radiation response. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AB - OBJECTIVE: To compare six HPV detection methods in pre-treatment FFPE tumour samples from patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who received postoperative (N = 175) or primary (N = 90) radiochemotherapy. MATERIALS AND METHODS: HPV analyses included detection of (i) HPV16 E6/E7 RNA, (ii) HPV16 DNA (PCR-based arrays, A-PCR), (iii) HPV DNA (GP5+/GP6+ qPCR, (GP-PCR)), (iv) p16 (immunohistochemistry, p16 IHC), (v) combining p16 IHC and the A-PCR result and (vi) combining p16 IHC and the GP-PCR result. Differences between HPV positive and negative subgroups were evaluated for the primary endpoint loco-regional control (LRC) using Cox regression. RESULTS: Correlation between the HPV detection methods was high (chi-squared test, p < 0.001). While p16 IHC analysis resulted in several false positive classifications, A-PCR, GP-PCR and the combination of p16 IHC and A-PCR or GP-PCR led to results comparable to RNA analysis. In both cohorts, Cox regression analyses revealed significantly prolonged LRC for patients with HPV positive tumours irrespective of the detection method. CONCLUSIONS: The most stringent classification was obtained by detection of HPV16 RNA, or combining p16 IHC with A-PCR or GP-PCR. This approach revealed the lowest rate of recurrence in patients with tumours classified as HPV positive and therefore appears most suited for patient stratification in HPV-based clinical studies. AU - Linge, A.* AU - Schoetz, U. AU - Loeck, S.* AU - Lohaus, F.* AU - von Neubeck, C.* AU - Gudziol, V.* AU - Nowak, A.* AU - Tinhofer, I.* AU - Budach, V.* AU - Sak, A.* AU - Stuschke, M.* AU - Balermpas, P.* AU - Roedel, C.* AU - Bunea, H.* AU - Grosu, A.* AU - Abdollahi, A.* AU - Debus, J.* AU - Ganswindt, U.* AU - Lauber, K. AU - Pigorsch, S.* AU - Combs, S.E.* AU - Moennich, D.* AU - Zips, D.* AU - Baretton, G.B.* AU - Buchholz, F.* AU - Krause, M.* AU - Belka, C. AU - Baumann, M.* C1 - 53646 C2 - 44820 SP - 27-35 TI - Comparison of detection methods for HPV status as a prognostic marker for loco-regional control after radiochemotherapy in patients with HNSCC. JO - Radiother. Oncol. VL - 127 IS - 1 PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Martin, F.* AU - Wank, M. AU - Laemmer, F.* AU - Schlegel, J.* AU - Schilling, D.* AU - Schmid, T.E. AU - Combs, S.E. C1 - 54364 C2 - 45497 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S1283-S1283 TI - Downregulation of ALDH1A1 reduces radioresistance and migration of glioblastoma cells. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Mueller, B.S.* AU - Ryang, Y.M.* AU - Ringel, F.* AU - Oechsner, M.* AU - Specht, H.M.* AU - Meyer, B.* AU - Combs, S.E. AU - Wilkens, J.J.* C1 - 54368 C2 - 45500 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S1052-S1053 TI - Dosimetric impact of stabilizing spinal implants in proton therapy: Titanium vs. carbon systems. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Schilling, D. AU - Herold, B.* AU - Combs, S.E. AU - Schmid, T.E. C1 - 54367 C2 - 45491 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S1271-S1271 TI - Selenium does not affect radiosensitivity of human breast cancer cell lines. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Schmidt, A.A.* AU - Kessel, K.A.* AU - Duma, M.N.* AU - Combs, S.E. C1 - 54072 C2 - 45282 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S659-S660 TI - 15 years of cerebral stereotactic radiotherapy at the Klinikum rechts der Isar, Munich. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AU - Schoetz, U.* AU - Orth, M.* AU - Selmansberger, M. AU - Schuster, J.* AU - Stegen, B.* AU - Hess J. AU - Unger, K. AU - Zitzelsberger, H. AU - Belka, C. AU - Engenhart-Cabillic, R.* AU - Lauber, K. C1 - 54069 C2 - 45283 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - S251-S251 TI - Prognostic biomarkers and targets for personalization of radiotherapy of HNSCC: CD44v6. JO - Radiother. Oncol. VL - 127 PB - Elsevier Ireland Ltd PY - 2018 SN - 0167-8140 ER - TY - JOUR AB - PURPOSE: To retrospectively assess the feasibility and safety of a sequential proton boost following conventional chemoradiation in high-grade glioma (HGG). METHOD AND MATERIALS: Sixty-six consecutive patients with HGG were treated with 50.0 Gy photons (50.0-50.4 Gy) in 2.0 Gy (1.8-2.0 Gy) fractions, followed by a proton boost with 10 Gy equivalent (Gy(RBE)) in 2.0 Gy(RBE) fractions. Patients were matched one to one with 66 patients with HGG undergoing conventional radiation therapy (RT) with 60.0 Gy photons (59.4-60.0 Gy) in 2.0 Gy fractions (1.8-2.0 Gy). Matching criteria were age, WHO grade, Karnofsky's performance status, PTV size, temozolomide therapy (each p > 0.1). The study assessed progression-free survival (PFS), overall survival (OS), acute treatment-related toxicity (CTCAE v.4.03) and pseudoprogression (RANO criteria). RESULTS: Median PFS and OS were similar in both treatment groups (bimodality RT, PFS: 8.8 months [2-32 months], OS 19.1 months [4-41 months]; photon-only RT, PFS: 7.2 months [2-39 months], 20.9 months [3-53 months]; p = 0.430 and p = 0.125). The median PTV of the proton boost was significantly smaller than the photon plan PTVs (each p < 0.001). Acute toxicity was mild. Toxicity ≥grade 2 was observed in 6 patients (9%) receiving bimodality RT and 9 patients (14%) receiving photon-only RT. Two types of severe adverse events (CTCAE grade 3) occurred solely in the photon-only group: severe increase in intracranial pressure (5%); and generalized seizures (3%). Pseudoprogression was rare, occurring on average 6 weeks after radiotherapy, and was balanced in both treatment groups (n = 4 each; 8%). CONCLUSION: Delivering a proton boost to significantly smaller target volumes when compared to photon-only plans, yielded comparable progression and survival rates at lower CTCAE grade 3 acute toxicity rates. Pseudoprogression occurred rarely and evenly distributed in both treatment groups. Thus, bimodality RT was at least equivalent regarding outcome and potentially superior with respect to toxicity in patients with HGG. SUMMARY: Treating patients with HGG with 50.0 Gy photons in 2.0 Gy fractions, followed by a proton boost with 10 Gy(RBE) in 2.0 Gy(RBE) fractions, is safe and feasible. Severe radiation-induced acute toxicity and pseudoprogression were rare in both treatment groups. Therefore, in this clinical setting, combined proton radiotherapy might be beneficial in terms of further risk reduction for treatment-related side effects. Interestingly, treatment volume reduction using a proton boost led to comparable survival and progression rates with decreased severe treatment-related toxicity compared to conventional photon radiotherapy. AU - Adeberg, S.* AU - Bernhardt, D.* AU - Harrabi, S.B.* AU - Uhl, M.* AU - Paul, A.* AU - Bougatf, N.* AU - Verma, V.* AU - Unterberg, A.* AU - Wick, W.* AU - Haberer, T.* AU - Combs, S.E. AU - Herfarth, K.* AU - Debus, J.* AU - Rieken, S.* C1 - 52170 C2 - 43802 CY - Clare SP - 266-272 TI - Sequential proton boost after standard chemoradiation for high-grade glioma. JO - Radiother. Oncol. VL - 125 IS - 2 PB - Elsevier Ireland Ltd PY - 2017 SN - 0167-8140 ER - TY - CONF AB - An overview is given on bottom-up stochastic modeling of radiation-induced effects on sub- cellular and cellular scales with the PARTRAC suite of Monte Carlo codes. PARTRAC simulations start from modeling particle tracks by following individual interactions of the primary as well as all secondary particles with the traversed medium, typically liquid wa- ter as a surrogate for biological material. Dedicated modules then convert these energy deposits to reactive species and follow their diffusion and mutual reactions. Multi-scale models of DNA and chromatin structures in human cell nuclei are implemented, represent- ing DNA double-helix, nucleosomes, chromatin fiber, domains and chromosome territories. By overlapping with the simulated tracks, these target structures are used in assessing ini- tial radiation-induced DNA and chromatin damage both via direct energy depositions and indirectly through attacks of reactive species. DNA fragmentation patterns can be analyzed. In a subsequent module, cellular repair of DNA double-strand breaks by non-homologous end-joining is simulated. Followed is the enzymatic processing as well as spatial mobil- ity of individual broken chromatin ends; correct rejoining, misrejoining, and formation of chromosome aberrations are scored. The chapter is focused on the underlying principles of radiation action in biological systems on subcellular scales and their stochastic mod- eling with PARTRAC. The pieces of experimental information represented in this tool are highlighted, together with numerous independent benchmarking tests against observed data and trends. Future developments are discussed, directed towards extending PARTRAC scope and predictive power, but also towards applications in medical physics and radiation protection.   AU - Friedland, W. AU - Kundrát, P. C1 - 53479 C2 - 44587 SP - 147-180 TI - Stochastic multi-scale modelling of biological effects induced by ionizing radiation. JO - Radiother. Oncol. PY - 2017 SN - 0167-8140 ER - TY - JOUR AB - Background and purpose: Our aim was to evaluate the feasibility and potential advantages of dose guided patient positioning based on dose recalculation on scatter corrected cone beam computed tomography (CBCT) image data. Material and methods: A scatter correction approach has been employed to enable dose calculations on CBCT images. A recently proposed tool for interactive multicriterial dose-guided patient positioning which uses interpolation between pre-calculated sample doses has been utilized. The workflow was retrospectively evaluated for two head and neck patients with a total of 39 CBCTs. Dose-volume histogram (DVH) parameters were compared to rigid image registration based isocenter corrections (clinical scenario). Results: The accuracy of the dose interpolation was found sufficient, facilitating the implementation of dose guided patient positioning. Compared to the clinical scenario, the mean dose to the parotid glands could be improved for 2 out of 5 fractions for the first patient while other parameters were preserved. For the second patient, the mean coverage over all fractions of the high dose PTV could be improved by 4%. For this patient, coverage improvements had to be traded against organ at risk (OAR) doses within their' clinical tolerance limits. Conclusions: Dose guided patient positioning using in-room CBCT data is feasible and offers increased control over target coverage and doses to OARs. AU - Hofmaier, J.* AU - Haehnle, J.* AU - Kurz, C.* AU - Landry, G.* AU - Maihoefer, C. AU - Schüttrumpf, L. AU - Süss, P.* AU - Teichert, K.* AU - Söhn, M.* AU - Spahr, N.* AU - Brachmann, C.* AU - Weiler, F.* AU - Thieke, C.* AU - Küfer, K.H.* AU - Belka, C. AU - Parodi, K.* AU - Kamp, F.* C1 - 52123 C2 - 43730 CY - Clare SP - 464-469 TI - Multi-criterial patient positioning based on dose recalculation on scatter-corrected CBCT images. JO - Radiother. Oncol. VL - 125 IS - 3 PB - Elsevier Ireland Ltd PY - 2017 SN - 0167-8140 ER - TY - JOUR AB - Objective To investigate the impact of the tumour volume, HPV status, cancer stem cell (CSC) marker expression and hypoxia gene signatures, as potential markers of radiobiological mechanisms of radioresistance, in a contemporary cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received primary radiochemotherapy (RCTx). Materials and Methods For 158 patients with locally advanced HNSCC of the oral cavity, oropharynx or hypopharynx who were treated at six DKTK partner sites, the impact of tumour volume, HPV DNA, p16 overexpression, p53 expression, CSC marker expression and hypoxia-associated gene signatures on outcome of primary RCTx was retrospectively analyzed. The primary endpoint of this study was loco-regional control (LRC). Results Univariate Cox regression revealed a significant impact of tumour volume, p16 overexpression, and SLC3A2 and CD44 protein expression on LRC. The tumour hypoxia classification showed a significant impact only for small tumours. In multivariate analyses an independent correlation of tumour volume, SLC3A2 expression, and the 15-gene hypoxia signature with LRC was identified (CD44 protein n/a because of no event in the CD44-negative group). Logistic modelling showed that inclusion of CD44 protein expression and p16 overexpression significantly improved the performance to predict LRC at 2 years compared to the model with tumour volume alone. Conclusions Tumour volume, HPV status, CSC marker expression and hypoxia gene signatures are potential prognostic biomarkers for patients with locally advanced HNSCC, who were treated by primary RCTx. The study also supports that the individual tumour volumes should generally be included in biomarker studies and that panels of biomarkers are superior to individual parameters. AU - Linge, A.* AU - Lohaus, F.* AU - Löck, S.* AU - Nowak, A.* AU - Gudziol, V.* AU - Valentini, C.* AU - von Neubeck, C.* AU - Jütz, M.* AU - Tinhofer, I.* AU - Budach, V.* AU - Sak, A.* AU - Stuschke, M.* AU - Balermpas, P.* AU - Rödel, C.* AU - Grosu, A.-L.* AU - Abdollahi, A.* AU - Debus, J.* AU - Ganswindt, U. AU - Belka, C. AU - Pigorsch, S.* AU - Combs, S.E. AU - Mönnich, D.* AU - Zips, D.* AU - Buchholz, F.* AU - Aust, D.E.* AU - Baretton, G.B.* AU - Thames, H.D.* AU - Dubrovska, A.* AU - Alsner, J.* AU - Overgaard, J.* AU - Krause, M.* AU - Baumann, M.* C1 - 50219 C2 - 42075 CY - Clare SP - 364-373 TI - HPV status, cancer stem cell marker expression, hypoxia gene signatures and tumour volume identify good prognosis subgroups in patients with HNSCC after primary radiochemotherapy: A multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). JO - Radiother. Oncol. VL - 121 IS - 3 PB - Elsevier Ireland Ltd PY - 2016 SN - 0167-8140 ER - TY - JOUR AB - BACKGROUND AND PURPOSE: Target delineation in glioblastoma (GBM) varies substantially between different institutions and several consensus statements are available. This guideline aims to develop a joint European consensus on the delineation of the clinical target volume in patients with a glioblastoma (GBM). MATERIAL AND METHODS: A literature search was conducted in PubMed that evaluated adults with GBM. Both MeSH terms and text words were used and the following search strategy was applied: ("Glioblastoma/radiotherapy" [MeSH] OR "glioblastoma" OR "malignant glioma" OR high-grade glioma) AND ((delineation) OR (target volume) OR (CTV) OR (PTV) OR (margin) OR (recurrence pattern) OR (contouring) OR (organs at risk)). In parallel, abstracts from ESTRO and ASTRO 2010-2015 were analysed and separately reviewed. The ACROP committee identified 14 European experts in close interaction with the ESTRO clinical committee who discussed and analysed the body of evidence concerning GBM target delineation. RESULTS: Several key issues were identified and are discussed including (i) pre-treatment steps and immobilization, (ii) target delineation and the use of standard and novel imaging techniques, and (iii) technical aspects of treatment including planning techniques, and fractionation. Based on the EORTC recommendation focusing on the resection cavity and residual enhancing regions on T1-sequences with the addition of a 20mm margin, special situations are presented with corresponding potential adaptations depending on the specific clinical situation. CONCLUSIONS: Currently, based on the EORTC consensus, a single clinical target volume definition based on postoperative T1/T2 FLAIR abnormalities is recommended, using isotropic margins without the need to cone down. A PTV margin based on the individual mask system and IGRT procedures available is advised, usually of the order of 3-5mm. AU - Niyazi, M.* AU - Brada, M.* AU - Chalmers, A.J.* AU - Combs, S.E. AU - Erridge, S.C.* AU - Fiorentino, A.* AU - Grosu, A.-L.* AU - Lagerwaard, F.J.* AU - Minniti, G.* AU - Mirimanoff, R.-O.* AU - Ricardi, U.* AU - Short, S.C.* AU - Weber, D.C.* AU - Belka, C.* C1 - 50317 C2 - 42094 SP - 35-42 TI - ESTRO-ACROP guideline "target delineation of glioblastomas". JO - Radiother. Oncol. VL - 118 IS - 1 PY - 2016 SN - 0167-8140 ER - TY - JOUR AB - BACKGROUND: Breast cancer is the most common cancer in women worldwide and surgery, radiotherapy (RT) and chemotherapy (ChT) are frequently used to treat this cancer. Adjuvant RT has been shown to cause long-term changes in lymphocyte counts in the peripheral blood. Herein, the time course of changes in lymphocyte subpopulations upon RT was studied in patients with and without adjuvant ChT in order to explore its potential clinical impact. MATERIALS AND METHODS: Total lymphocyte counts and the composition of lymphocyte subpopulations before RT (t0), after 30Gy (t1), at the end of RT (t2), and 6weeks (t3), 6months (t4), and 1year (t5) after RT were studied by flow cytometry. RESULTS: Absolute lymphocyte counts were significantly lower in all breast cancer patients (n=40) before and also 1year after RT compared to healthy controls. The percentage of CD3(+)/CD4(+) helper T cells and FoxP3(+) regulatory T cells increased significantly in patients without adjuvant ChT. Different NK cell subpopulations dropped during RT in patients with and without ChT, but recovered to initial levels 6months after RT (t4). During RT (t0-t2) the percentage of CD19(+) B cells significantly dropped in patients without ChT, but gradually increased in patients with adjuvant ChT. Both patient groups reached initial levels 6months after RT (t4). CONCLUSION: Different lymphocyte subpopulations respond differently to RT with and without adjuvant ChT. CD4(+) T cells increase during RT, whereas NK cells and B cells decrease in patients without ChT, but recover within 6months after RT. Treg cells gradually increase in patients without ChT from t0 to t5, but not in patients with adjuvant ChT. AU - Sage, E.K.* AU - Schmid, T.E. AU - Sedelmayr, M.* AU - Gehrmann, M.* AU - Geinitz, H.* AU - Duma, M.N. AU - Combs, S.E. AU - Multhoff, G. C1 - 47894 C2 - 39699 CY - Clare SP - 176-180 TI - Comparative analysis of the effects of radiotherapy versus radiotherapy after adjuvant chemotherapy on the composition of lymphocyte subpopulations in breast cancer patients. JO - Radiother. Oncol. VL - 118 IS - 1 PB - Elsevier Ireland Ltd PY - 2016 SN - 0167-8140 ER - TY - JOUR AB - BACKGROUND AND PURPOSE: Blocking of the autophagy-signaling has the potential to improve cancer therapy. In the present study, the role of autophagy for radioresistance of human tumor cells was tested under clinically relevant hypoxia (1% O2). MATERIALS AND METHODS: Non-small cell lung cancer cell lines A549 and H460, head and neck squamous cell carcinoma FaDu, colon carcinoma cell line HCT116 and mouse-embryo-fibroblasts were analyzed under normoxic (21% O2) and hypoxic (0.01% and 1% O2) conditions with respect to clonogenic cell survival and hypoxia-induced autophagy. Immunofluorescence and electron microscopy were used to monitor the autophagy process and Western blotting of LC3, AMPK, and BNIP3 was applied to analyze autophagy signaling. RESULTS: Clinically relevant hypoxia stimulated autophagy in tumor cells as indicated by enhanced LC3-I to LC3-II conversion. Furthermore, hypoxia stimulated autophagy was approved by Immunofluorescence staining and electron-microscopy analysis of autophagosome vacuoles. Preconditioning of tumor cells to moderate-hypoxia increased their radioresistance that was significantly reversed following pretreatment with autophagy inhibitor, chloroquine. Using siRNA against AMPK as well as AMPK deficient cells, autophagy stimulation by 1% O2 was shown to be AMPK-independent. However, a correlation between the expression of BNIP3 and autophagy-stimulation was observed under this condition. CONCLUSION: Under clinically relevant hypoxia (1% O2) the stimulation of autophagy mediates resistance of hypoxic tumor cells to ionizing radiation, which is independent of AMPK signaling. AU - Chaachouay, H. AU - Fehrenbacher, B.* AU - Toulany, M.* AU - Schaller, M.* AU - Multhoff, G. AU - Rodemann, H.P.* C1 - 46735 C2 - 37758 SP - 409-416 TI - AMPK-independent autophagy promotes radioresistance of human tumor cells under clinical relevant hypoxia in vitro. JO - Radiother. Oncol. VL - 116 IS - 3 PY - 2015 SN - 0167-8140 ER - TY - JOUR AB - PURPOSE: To evaluate long-term clinical outcome and determine prognostic factors for local-control, hearing preservation and cranial nerve toxicity in 449 patients treated for 451 vestibular schwannomas (VS) with radiosurgery (n=169; 38%) or fractionated stereotactic radiotherapy (FSRT; n=291; 62%). METHODS AND MATERIALS: 245 patients were male (55%), and 204 were female (45%). Median age was 60years (range 17-88years). Median tumor diameter was 15mm. For FSRT, a median dose of 57.6Gy in median single doses of 1.8Gy was applied. For SRS, median dose was 13Gy. The median follow-up time was 67months. RESULTS: Local control was 97% at 36months, 95% at 60months, and 94% at 120months with no difference between FSRT and SRS (p=0.39). "Useful hearing" was present 46%. After RT, "useful hearing" was preserved in 85% of the patients. Loss of useful hearing was observed in the FSRT group in 14%, and in the SRS group in 16% of the patients. For patients treated with SRS ⩽13Gy, useful hearing deterioration was 13%. For trigeminal and facial nerve toxicity, there was no difference between FSRT and SRS. CONCLUSION: Supported by this large multicentric series, both SRS and FSRT can be recommended for the treatment of VS. SRS application is limited by tumor size, and is associated with a steep dose-response-curve. When chosen diligently based on tumor volume, pre-treatment characteristics and volume-dependent dose-prescription in SRS (⩽13Gy), both treatments may be considered equally effective. AU - Combs, S.E.* AU - Engelhard, C.* AU - Kopp, C.* AU - Wiedenmann, N. AU - Schramm, O. AU - Prokic, V.* AU - Debus, J. AU - Molls, M.* AU - Grosu, A.-L.* C1 - 43449 C2 - 36635 CY - Clare SP - 378-383 TI - Long-term outcome after highly advanced single-dose or fractionated radiotherapy in patients with vestibular schwannomas - pooled results from 3 large German centers. JO - Radiother. Oncol. VL - 114 IS - 3 PB - Elsevier Ireland Ltd PY - 2015 SN - 0167-8140 ER - TY - JOUR AB - 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. AU - Sievert, W. AU - Trott, K.-R.* AU - Azimzadeh, O. AU - Tapio, S. AU - Zitzelsberger, H. AU - Multhoff, G. C1 - 46470 C2 - 37622 CY - Clare SP - 376-381 TI - Late proliferating and inflammatory effects on murine microvascular heart and lung endothelial cells after irradiation. JO - Radiother. Oncol. VL - 117 IS - 2 PB - Elsevier Ireland Ltd PY - 2015 SN - 0167-8140 ER - TY - JOUR AB - BACKGROUND AND PURPOSE: Radiotherapy of thoracic and chest-wall tumours increases the long-term risk of radiation-induced heart disease. The aim of this study was to investigate the long-term effect of local heart irradiation on cardiac mitochondria. METHODS: C57BL/6 and atherosclerosis-prone ApoE(-/-) mice received local heart irradiation with a single X-ray dose of 2 Gy. To investigate the low-dose effect, C57BL/6 mice also received a single heart dose of 0.2 Gy. Functional and proteomic alterations of cardiac mitochondria were evaluated after 40 weeks, compared to age-matched controls. RESULTS: The respiratory capacity of irradiated C57BL/6 cardiac mitochondria was significantly reduced at 40 weeks. In parallel, protein carbonylation was increased, suggesting enhanced oxidative stress. Considerable alterations were found in the levels of proteins of mitochondria-associated cytoskeleton, respiratory chain, ion transport and lipid metabolism. Radiation induced similar but less pronounced effects in the mitochondrial proteome of ApoE(-/-) mice. In ApoE(-/-), no significant change was observed in mitochondrial respiration or protein carbonylation. The dose of 0.2 Gy had no significant effects on cardiac mitochondria. CONCLUSION: This study suggests that ionising radiation causes non-transient alterations in cardiac mitochondria, resulting in oxidative stress that may ultimately lead to malfunctioning of the heart muscle. AU - Barjaktarovic, Z. AU - Shyla, A. AU - Azimzadeh, O. AU - Schulz, S. AU - Haagen, J.* AU - Dörr, W.* AU - Sarioglu, H. AU - Atkinson, M.J. AU - Zischka, H. AU - Tapio, S. C1 - 26035 C2 - 32033 SP - 404-410 TI - Ionising radiation induces persistent alterations in the cardiac mitochondrial function of C57BL/6 mice 40 weeks after local heart exposure. JO - Radiother. Oncol. VL - 106 IS - 3 PB - Elsevier Ireland PY - 2013 SN - 0167-8140 ER - TY - JOUR AB - PURPOSE: Hyperthermia (HT) treatment of cancer patients was revived over the last years and has been proven to be beneficiary for many cancer entities when applied temperature controlled in multimodal treatments. We examined whether a combination of ionizing irradiation (X-ray) and HT (41.5°C; 1h) can induce the release of heat shock protein (HSP) 70 by tumor cells and thereby lead to the activation of dendritic cells and macrophages. MATERIAL AND METHODS: Extracellular HSP70 was detected in supernatants (SN) of treated colorectal tumor cells by ELISA. Maturation of dendritic cells (DC) after contact with the SN was measured by flow-cytometry. Phagocytosis assays were conducted to get hints about the immune stimulating potential of the tumor cells after the respective treatments. RESULTS: An increased surface expression of HSP70 was observed after X-ray or X-ray plus HT while the amount of extracellular HSP70 was only increased when HT was given additionally. A high up-regulation of the co-stimulation molecule CD80 and the chemokine receptor CCR7 on DC was measured after contact with SN of X-ray plus HT treated cells. This was dependent on extracellular HSP70. Combined treatments further led to significantly increased phagocytosis rates of macrophages and DC and increased pro-inflammatory cytokine (IL-8 and IL-12) secretion. CONCLUSION: X-ray combined with HT induces HSP70 dependent activation of immune cells and might generate a tumor microenvironment beneficial for cure. AU - Schildkopf, P.* AU - Frey, B.* AU - Ott, O.J.* AU - Rubner, Y.* AU - Multhoff, G. AU - Sauer, R.* AU - Fietkau, R.* AU - Gaipl, U.S.* C1 - 6582 C2 - 28936 SP - 109-115 TI - Radiation combined with hyperthermia induces HSP70-dependent maturation of dendritic cells and release of pro-inflammatory cytokines by dendritic cells and macrophages. JO - Radiother. Oncol. VL - 101 IS - 1 PB - Elsevier PY - 2011 SN - 0167-8140 ER - TY - JOUR AB - The major stress-inducible heat shock protein 70 (Hsp70) is frequently overexpressed in highly aggressive tumors, and elevated intracellular Hsp70 levels mediate protection against apoptosis. Following therapeutic intervention, such as ionizing irradiation, translocation of cytosolic Hsp70 to the plasma membrane is selectively increased in tumor cells and therefore, membrane Hsp70 might serve as a therapy-inducible, tumor-specific target structure. MATERIALS AND METHODS: Based on the IgG1 mouse monoclonal antibody (mAb) cmHsp70.1, we produced the Hsp70-specific recombinant Fab fragment (Hsp70 Fab), as an imaging tool for the detection of membrane Hsp70 positive tumor cells in vitro and in vivo. RESULTS: The binding characteristics of Hsp70 Fab towards mouse colon (CT26) and pancreatic (1048) carcinoma cells at 4°C were comparable to that of cmHsp70.1 mAb, as determined by flow cytometry. Following a temperature shift to 37°C, Hsp70 Fab rapidly translocates into subcellular vesicles of mouse tumor cells. Furthermore, in tumor-bearing mice Cy5.5-conjugated Hsp70 Fab, but not unrelated IN-1 control Fab fragment (IN-1 ctrl Fab), gradually accumulates in CT26 tumors between 12 and 55h after i.v injection.CONCLUSIONS: In summary, the Hsp70 Fab provides an innovative, low immunogenic tool for imaging of membrane Hsp70 positive tumors, in vivo. AU - Stangl, S. AU - Themelis, G. AU - Friedrich, L.* AU - Ntziachristos, V. AU - Sarantopoulos, A. AU - Molls, M. AU - Skerra, A.* AU - Multhoff, G. C1 - 6025 C2 - 28593 SP - 313-316 TI - Detection of irradiation-induced, membrane heat shock protein 70 (Hsp70) in mouse tumors using Hsp70 Fab fragment. JO - Radiother. Oncol. VL - 99 PB - Elsevier PY - 2011 SN - 0167-8140 ER - TY - JOUR AU - Ballarini, F.* AU - Friedland, W. AU - Jacob, P. AU - Ottolenghi, A. AU - Paretzke, H.G. AU - Scannicchio, D.* AU - Valota, A. C1 - 4476 C2 - 23317 SP - S170-S172 TI - Role of DNA organisation and environmental scavenging capacity in the evolution of radiobiological damage: Models and simulations. JO - Radiother. Oncol. VL - 73 PY - 2005 SN - 0167-8140 ER - TY - JOUR AB - An experimental model in the rabbit is presented which is suitable for analysis of clinically relevant, early side-effects of combined upper abdominal IORT and ERT. Fractionated ERT alone given through an upper abdominal a.-p. field including the entire stomach caused gastric ulcerations within < or = 58 days. Latent times decreased with increasing dose and the ED50 for occurrence of ulcers was 39 +/- 3.3 Gy. Single doses of IORT of 20-40 Gy alone administered through a 2-cm diameter field localized on the coeliac axis and carefully excluding any intestinal mucosa caused neither gastric ulcerations nor other clinical symptoms. When ERT with 40 Gy was preceded by IORT with 20-40 Gy or by sham IORT, 13 out of 15 animals developed ulcers after latent times which in a life-table analysis were shown to be significantly shorter than after ERT alone. However, a statistically significant IORT dose-dependence of latent time or incidence of ulcers could not be demonstrated in the present experiment. The most significant histological changes were observed in the areas of gastric ulcers. Already during ERT, the mucosal epithelium was depleted and regenerative activity was evident in spite of ongoing fractionated irradiation. However, profound irregularities in glandular structure and distribution, as well as number of proliferating epithelial cells were still present in healed ulcers at 80 days. In summary, IORT to the coeliac artery did precipitate the development of gastric ulcers induced by subsequent ERT. On the one hand, the data indicate that the surgical procedure of IORT did contribute to this effect. On the other hand, IORT to the coeliac artery could cause transient, functional alterations in blood supply to the depending organs, i.e. the stomach, and could thus precipitate the development of radiation-induced ulcers. AU - Schultz-Hector, S. AU - Brechenmacher, P.* AU - Dörr, W. AU - Grab, J.* AU - Kallfass, E. AU - Krimmel, K.* AU - Kummermehr, J. AU - Sund, M. AU - Wilkowski, R.* AU - Willich, N.* AU - Zaspel, J.* AU - Krämling, H.-J.* C1 - 24202 C2 - 31470 SP - 205-214 TI - Complications of combined intraoperative radiation (IORT) and external radiation (ERT) of the upper abdomen: An experimental model. JO - Radiother. Oncol. VL - 38 IS - 3 PB - Elsevier PY - 1996 SN - 0167-8140 ER - TY - JOUR AU - Kummermehr, J. AU - Trott, K.R. C1 - 40013 C2 - 38064 SP - 91-92 TI - Chronic radiation damage in the rat rectum: An analysis of tiie influences of fractionation, time and volume [1]. JO - Radiother. Oncol. VL - 33 IS - 1 PY - 1994 SN - 0167-8140 ER - TY - JOUR AB - The effect of dose fractionation on the radiation response of mouse tongue epithelium was quantified in fractionation protocols involving 1, 3, 4, 5 and 10 fractions, separated by at least 4 h. Fractionated irradiation was given either to the whole snout by 300 kV X-rays or locally to the tongue using 25 kV X-rays. Each protocol was terminated by a final local top-up dose (25 kV X-rays) of 5 Gy. The frequency of complete local denudation within the test area was used as the quantal end point. The kinetics of repair of sublethal damage was studied by snout irradiation with four equally spaced fractions, delivered at intervals of 35, 60, 90, 480 or 540 min, again followed by a local top-up dose of 5 Gy. The linear-quadratic model gave a satisfactory fit to the data with the exception of the four fraction/30-h data, suggesting cell cycle effects in this schedule. Analysis of the results with different two-step methods and with direct analysis yielded similar results. The alpha/beta ratio was determined to be approximately 11 GY (direct analysis: 11.6 Gy with 95% confidence limits of 8.1 and 16.4 Gy) and T1/2 was found to be 46 min (35-69 min). Both these values are in the range described for other acutely responding rodent tissues. AU - Dörr, W. AU - Breitner, A. AU - Kummermehr, J. C1 - 20193 C2 - 13371 SP - 36-45 TI - Capacity and Kinetics of SLD Repair in Mouse Tongue Epithelium. JO - Radiother. Oncol. VL - 27 IS - 1 PY - 1993 SN - 0167-8140 ER - TY - JOUR AB - Both bleomycin (BLM) and local X-irradiation (25 kV) induce denudation in the tongue epithelium of the C3H-Neuherberg mouse in a dose-dependent manner. In the present study the effect of BLm alone and of combined single doses of drug and radiation were studied using the incidence of epithelial denudation as the end-point. In 'time-line' experiments, 8 mg/kg BLM were given before or after graded doses of X-rays. BLM treatment required a reduction of the radiation dose (ED50) from 15 Gy to 5-7 Gy, independent of sequence or time interval. In contrast, the time course of the response was clearly dependent on the treatment interval. Latency decreased when the drug was injected less than 2 h before irradiation with minimum latency observed at 30 min. Isobologram analysis of experiments with varying combinations of X-rays and BLM demonstrated that small drug doses were relatively more effective than larger doses, suggestinng an upward concavity of the BLM dose-effect curve in vivo, i.e. a 'negative shoulder' of the curve in the low dose region. In contrast to the response to X-rays alone, which has a constant latent ime to ulcer of 10 days, the latency in combined treatment was clearly shortened with increasing drug dose and at high doses eventually approximated the epithelial turnover time of 5 days. The data suggest that BLM both as a single agent and in combination with X-rays reduced the probability of abortive divisions and through this effect shortened the latent time to epithelial denudation. AU - Dörr, W. AU - Hirler, E. AU - Hönig, M. C1 - 40287 C2 - 13450 SP - 237-244 TI - Response of mouse tongue epithelium to single doses of bleomycin and radiation. JO - Radiother. Oncol. VL - 27 IS - 3 PY - 1993 SN - 0167-8140 ER - TY - JOUR AB - The effect of dose fractionation on the radiation response of mouse tongue epithelium was quantified in fractionation protocols involving 1, 3, 4, 5 and 10 fractions, separated by at least 4 h. Fractionated irradiation was given either to the whole snout by 300 kV X-rays or locally to the tongue using 25 kV X-rays. Each protocol was terminated by a final local top-up dose (25 kV X-rays) of 5 Gy. The frequency of complete local denudation within the test area was used as the quantal end point. The kinetics of repair of sublethal damage was studied by snout irradiation with four equally spaced fractions, delivered at intervals of 35, 60, 90, 480 or 540 min, again followed by a local top-up dose of 5 Gy. The linear-quadratic model gave a satisfactory fit to the data [40] with the exception of the four fraction/30-h data, suggesting cell cycle effects in this schedule. Analysis of the results with different two-step methods and with direct analysis [37] yielded similar results. The α/β ratio was determined to be ~ 11 Gy (direct analysis: 11.6 Gy with 95% confidence limits of 8.1 and 16.4 Gy) and T( 1/2 ) was found to be 46 min (35-69 min). Both these values are in the range described for other acutely responding rodent tissues. AU - Dörr, W. AU - Breitner, A. AU - Kummermehr, J.C. C1 - 40386 C2 - 0 SP - 36-45 TI - Capacity and kinetics of SLD repair in mouse tongue epithelium. JO - Radiother. Oncol. VL - 27 IS - 1 PY - 1993 SN - 0167-8140 ER - TY - JOUR AB -  Local heart irradiation with single or fractionated doses leads to heart failure after dose-dependent latency times. Clinical symptoms of heart failure are dyspnoea at rest, apathy and subcutaneous oedema. Animals autopsied when they presented with these symptoms, have a congested liver and occasional pleural effusions. The left ventricle is dilated, showing a reduction in wall thickness by 15-17% of control values. Histological examination reveals a focal degeneration and necrosis of about 23% of the total myocardial volume. Loss of alkaline phosphatase activity from myocardial capillaries, which is known to precede myocardial degeneration, involves 77% of the myocardium. These findings at the time of manifest heart failure are constant, independent on whether injury to the heart was inflicted by single-dose or fractionated irradiation or whether heart failure developed within a relatively short time after high total doses or within many months after low total doses. The latent time of heart failure therefore can be considered an appropriate endpoint for comparison of treatment groups. From experiments giving 1, 2, 4 or 10 dose fractions, a low alpha/beta-ratio of 3.7 Gy (95% confidence interval 1.8-5.6 Gy) can be calculated. When the time interval between dose fractions is varied in a split-dose experiment, time intervals of up to 3 h do not increase the survival time significantly. This appears to indicate very slow repair of sublethal damage. On the other hand, it cannot be excluded that pathogenic mechanisms independent of cell death in the renewing cell population contribute to this effect, making an interpretation of the alpha/beta-ratio in terms of cell survival parameters of a defined target cell population difficult. AU - Schultz-Hector, S. AU - Sund, M. AU - Thames, H.D. C1 - 19018 C2 - 12058 SP - 33-40 TI - Fractionation Response and Repair Kinetics of Radiation-induced Heart Failure in the Rat. JO - Radiother. Oncol. VL - 123 IS - 1 PB - Elsevier PY - 1992 SN - 0167-8140 ER - TY - JOUR AB - Accelerated repopulation is a well established response pattern of normal epithelial to fractionated irradiation. It is delayed until the tissue recognises functional injury. It is well regulated to maintain a steady state and continues until integrity of the tissue is restored. We assume that some of these features of the parental normal tissue are preserved and still operate in squamous cell carcinoma, although probably in a less well controlled and organised manner. AU - Trott, K.R.* AU - Kummermehr, J.C. C1 - 33987 C2 - 40220 SP - 159-160 TI - Accelerated repopulation in tumours and normal tissues. JO - Radiother. Oncol. VL - 22 IS - 3 PY - 1991 SN - 0167-8140 ER - TY - JOUR AU - Dörr, W. AU - Kummermehr, J. C1 - 17816 C2 - 10731 SP - 249-259 TI - Accelerated Repopulation of Mouse Tongue Epithelium During Fractionated Irradiations or Following Single Doses. JO - Radiother. Oncol. VL - 17 PY - 1990 SN - 0167-8140 ER - TY - JOUR AB - Mouse tongue mucosa was established as an animal model to study repopulation after large single doses or during continuous irradiation. A top-up irradiation technique was used employing priming doses or fractionated treatment to the whole snout (300 kV X-rays) followed by local test doses (25 kV X-rays) to elicit denudation in a confined field of the inferior tongue surface. Clearcut quantal dose-response curves of ulcer incidence were obtained to all protocols; animal morbidity, i.e. body weight loss was minimal. Repopulation following priming doses of 10 and 13 Gy started with a delay of at least 3 days and then progressed rapidly to nearly restore original tissue tolerance by day 11. During continuous fractionation over 1 to 3 weeks with 5 fractions/week and doses per fraction of 2.5, 3 and 3.5 Gy, repopulation was small in week one but subsequently increased to fully compensate the weekly dose at all dose levels. Additional measurements of cell density during a 4 weeks course of 5 x 3 Gy or 5 x 4 Gy per week showed only moderate depletion to 67% of the control figures. The fact that rapid repopulation is achieved at relatively moderate damage levels should be taken into account when the timing of a treatment split is considered. AU - Dörr, W. AU - Kummermehr, J.C. C1 - 41899 C2 - 36462 SP - 249-259 TI - Accelerated repopulation of mouse tongue epithelium during fractionated irradiations or following single doses. JO - Radiother. Oncol. VL - 17 IS - 3 PY - 1990 SN - 0167-8140 ER - TY - JOUR AU - Guttenberger, R. AU - Kummermehr, J. AU - Chmelevsky, D. C1 - 18121 C2 - 10975 SP - 79-88 TI - Kinetics of Recovery from Sublethal Radiation Damage in four Murine Tumors. JO - Radiother. Oncol. VL - 18 IS - 1 PY - 1990 SN - 0167-8140 ER - TY - JOUR AB - The kinetics of repair of sublethal radiation damage (SLD) was studied in four transplantable C3H mouse tumors, i.e. mammary carcinoma AT17, fibrosarcoma SSK2, and squamous cell carcinomas AT51 and AT478. Tumors were irradiated with 4 fractions of 300 kV X-rays given under local hypoxia at intervals ranging from 0 to 6 h. Radiation response was measured by growth delay, which was directly analyzed using a general curve description based on the extended linear-quadratic model (exponential repair kinetics). In contrast to existing methods all growth delay values were utilized to estimate the α/β ratios and the half-times as well as their confidence limits in a non-linear least squares analysis. The half-times were 42, 44, 54 and 31 min, respectively. It is concluded that repair of SLD is virtually complete after 5 h in these tumors. This is also due to the relatively small proportion of repairable damage in these tumors reflected in their α/β values, which were 38, 30, 54 and 42 Gy, respectively. AU - Guttenberger, R. AU - Kummermehr, J.C. AU - Chmelevsky, D. C1 - 34143 C2 - 36396 SP - 79-88 TI - Kinetics of recovery from sublethal radiation damage in four murine tumors. JO - Radiother. Oncol. VL - 18 IS - 1 PY - 1990 SN - 0167-8140 ER - TY - JOUR AU - Kolb, H.-J. AU - Lösslein, L.K. AU - Beißer, K. AU - Schäffer, E.H. AU - Holler, E. AU - Schwella, N. AU - Hochhäuser, E. AU - Lehmacher, W. AU - Balk, O. AU - Thierfelder, S. C1 - 17765 C2 - 10673 SP - 51-59 TI - Dose Rate and Fractionation of Total Body Irradiation in Dogs Short and Long Term Effects. JO - Radiother. Oncol. VL - Suppl.1 PY - 1990 SN - 0167-8140 ER - TY - JOUR AB - Variations of regimens of total body irradiation (TBI) were investigated in the dog as a preclinical model for bone marrow transplantation. Inactivation of hemopoietic precursor cells (CFU-GM) was studied following irradiation of marrow in vitro, following TBI at sublethal doses in vivo and following autologous transplantation of marrow obtained after sublethal TBI. Inactivation and recovery of CFU-GM as well as restoration of hemopoiesis following autologous transplantation was independent of the dose rate, but nadirs of blood counts were lower following sublethal TBI with the higher dose rate. Acute non-hemopoietic toxicity of TBI depended on the dose, the dose rate and the total treatment time and not on the fractionation regimen. At a total dose of 25 Gy acute mortality was prevented by prophylactic administration of oral, non-absorbable antibiotics. Late mortality was due to degenerative and autoimmune-like disorders with or without infections and to malignant tumors. Evaluation of long-term survival is still preliminary, since surviving dogs of two groups (10 Gy as single dose, 25 Gy as hyperfractionated TBI) have not yet reached the median survival time of their group. So far, long-term survival depended on the total dose (p = 0.05) and, possibly, the fractionation regimen (p = 0.12). The latency period until development of malignant tumors was influenced by the total doses given in the same treatment time (p = 0.05) and by the total treatment time for equal doses (p = 0.04). It was concluded that TBI at a low dose rate may give the best therapeutic ratio of inactivation of hemopoietic precursor cells to acute toxicity. A possible benefit of hyperfractionation on long-term survival due to less toxicity has to be weighed against less effective inactivation of clonogenic hemopoietic precursors and less effective immunosuppression seen in allogeneic transplantation. AU - Kolb1, H.J.* AU - Lösslein, L.K.* AU - Beißer, K.* AU - Schäffer, E.H. AU - Holler., E.* AU - Schwella, N.* AU - Hochhäusser, E. AU - Lehmacher, W.* AU - Balk, O.A. AU - Thierfelder, S.S.* C1 - 42591 C2 - 40196 SP - 51-59 TI - Dose rate and fractionation of total body irradiation in dogs: Short and long term effects. JO - Radiother. Oncol. VL - 18 IS - SUPPL. 1 PY - 1990 SN - 0167-8140 ER - TY - JOUR AU - Frankenberg-Schwager, M. C1 - 17314 C2 - 9942 SP - 307-320 TI - Review of Repair Kinetics for DNA Damage induced in Eukaryotic Cells in Vitro by Ionizing Radiation. JO - Radiother. Oncol. VL - 14 PY - 1989 SN - 0167-8140 ER - TY - JOUR AU - Frankenberg-Schwager, M. C1 - 33651 C2 - 36581 SP - 307-320 TI - Review of repair kinetics for DNA damage induced in eukaryotic cells in vitro by ionizing radiation. JO - Radiother. Oncol. VL - 14 IS - 4 PY - 1989 SN - 0167-8140 ER - TY - JOUR AU - Guttenberger, R. C1 - 42714 C2 - 36425 SP - 329-330 TI - Reply to: Analysis of the effects of fractionated irradiation to the rat heart (by E. van Rongen). JO - Radiother. Oncol. VL - 10 IS - 4 PY - 1987 SN - 0167-8140 ER - TY - JOUR AU - Knowles, J.F. AU - Trott, K.-R. C1 - 17787 C2 - 10698 SP - 59-66 TI - Experimental Irradiation of the Rat Ureter: The Effects of Field Size and the Presence of Contrast Medium on Incidence and Latency of Hydronephrosis. JO - Radiother. Oncol. VL - 10 PY - 1987 SN - 0167-8140 ER - TY - JOUR AB - The presence of actinomycin D during irradiation of HeLa cells leads to radiosensitization under aerobic but not under hypoxic conditions. Depending on the time interval between incubation with the drug and irradiation, pre- or post-treatment with actinomycin D also increases the radiosensitivity of HeLa cells irradiated in air. Pretreatment with actinomycin D does not inhibit recovery from potentially lethal radiation damage. In split-dose experiments, recovery from sublethal radiation damage was not impaired by the drug if present during the entire fractionation interval or if it was given as a short exposure after the first radiation dose. AU - Ziegler, W.H. AU - Birkenfeld, P. AU - Trott, K.R.* C1 - 33114 C2 - 35532 SP - 141-148 TI - The effect of combined treatment of HeLa cells with actinomycin D and radiation upon survival and recovery from radiation damage. JO - Radiother. Oncol. VL - 10 IS - 2 PY - 1987 SN - 0167-8140 ER - TY - JOUR AB - Combined treatment of HeLa cells with cisplatin and irradiation under aerobic conditions leads to no interaction between the two treatment modalities, either when they are given simultaneously or when cisplatin treatment is followed by irradiation. Simultaneous treatment with cisplatin and irradiation under hypoxic conditions leads to radiosensitization of HeLa cells by cisplatin. This sensitization was independent from the surviving fraction with cisplatin only, the dose modifying factor being approximately 1.2. Pretreatment or post-treatment with cisplatin does not influence the recovery from sublethal radiation damage. AU - Ziegler, W.H. AU - Kopp, J.M. C1 - 41589 C2 - 36267 SP - 71-78 TI - The effect of combined treatment of HeLa cells with cisplatin and irradiation upon survival and recovery from radiation damage. JO - Radiother. Oncol. VL - 8 IS - 1 PY - 1987 SN - 0167-8140 ER - TY - JOUR AB - In this experiment, a protracted fractionation regime (18 fractions/170 days, dose/fraction: 6,7,8 Gy) caused late rectal obstruction in rats independently of any clinically detectable acute damage. Rectal obstruction was due to an ulcer which developed secondary to an atrophic mucosa and capillary damage. In agreement with our earlier protracted fractionation schedules, the results were not fitted well by the linear-quadratic model. However, there are indications of relatively low alpha/beta values. Hydronephroses and hydroureters were the only competing risks to rectal obstruction and they occurred independently of it. AU - Breiter, N. AU - Trott, K.R. C1 - 33049 C2 - 38486 SP - 155-163 TI - Chronic radiation damage in the rectum of the rat after protracted fractionated irradiation. JO - Radiother. Oncol. VL - 7 IS - 2 PY - 1986 SN - 0167-8140 ER - TY - JOUR AU - Lauk, S. C1 - 41602 C2 - 36084 SP - 333-335 TI - Strain differences in the radiation response of the rat heart. JO - Radiother. Oncol. VL - 5 IS - 4 PY - 1986 SN - 0167-8140 ER - TY - JOUR AB - The response of two human tumour xenografts to single dose and fractionated X-rays has been tested using regrowth delay as the assay. The tumours were line transplanted cells from a moderately well-differentiated squamous carcinoma of the tonsillar fossa (XJ) and an undifferentiated carcinoma of the floor of the mouth (XR). Comparison of the dose response curves for single doses in air, clamped, or after misonidazole administration, led to estimates of the hypoxic fraction (∼ 15%) and the sensitizer enhancement ratio (≦1.6). When 5 daily fractions were used, the effect of misonidazole (miso) was lost and reoxygenation appeared to be effective in both tumours. Comparison of single doses and 5 fractions in clamped tumours, and in those sensitized by miso, allowed the sparing effect of fraction to be estimated. When analysed by the linear quadratic model the α/β ratios were found to be in the range of 6.4-9.2 Gy and 6.8-16.0 Gy for the two tumours. These values are in good agreement with murine tumours (assayed in vivo or in vitro), with human tumour cells assayed in vitro, and with analyses of fractionated clinical data for skin cancer. AU - Lindenberger, J.* AU - Hermeking, H.* AU - Kummermehr, J.C. AU - Denekamp, J.* C1 - 41368 C2 - 36099 SP - 15-27 TI - Response of human tumour xenografts to fractionated X-irradiation. JO - Radiother. Oncol. VL - 6 IS - 1 PY - 1986 SN - 0167-8140 ER - TY - JOUR AU - Trott, K.-R. AU - Kummermehr, J. C1 - 17786 C2 - 10697 SP - 1-9 TI - What is Known About Tumour Proliferation Rates to Choose Between Accelerated Fractionation of Hyperfractionation? JO - Radiother. Oncol. VL - 3 PY - 1985 SN - 0167-8140 ER - TY - JOUR AB - The data of 946 skin cancer patients treated with single doses or with 4, 8, 17, 40 or 47 fractions of X-rays were analysed using Strandquist's formalism and the linear-quadratic model. The analysis of tumour control in relation to tumour size and fractionation schedule shows a strong correlation between tumour size and tumour control rate. For small tumours, single dose irradiation was as effective as fractionated treatment. For large tumours, a straight line was easily fitted to the TCD50 and TCD90 values plotted logarithmically against time or number of fractions; the exponent for overall treatment time was 0.27 and for number of fractions it was 0.31. With the linear-quadratic model, an α/β ratio of 13.8 Gy was calculated. On the assumption that the number of clonogenic cells in the tumour increases in proportion to tumour volume, Do values between 0.76 and 1.33 Gy were calculated and cellular survival curves were constructed. The estimated clonogenic fraction of tumour cells is about 10-3; no influence of hypoxic clonogenic cells on local tumour control with single doses could be demonstrated. AU - Trott, K.R. AU - Maciejewski, B.S. AU - Preuss-Bayer, G. AU - Skołyszewski, J.F. C1 - 33140 C2 - 35603 SP - 123-129 TI - Dose-response curve and split-dose recovery in human skin cancer. JO - Radiother. Oncol. VL - 2 IS - 2 PY - 1984 SN - 0167-8140 ER -