TY - JOUR AB - INTRODUCTION: Radiotherapy (RT) plays a central role in multidisciplinary treatment approaches in cancer therapy, particularly as an effective primary treatment modality for patients with head and neck cancer (HNC). One of the most common acute complications of RT for HNC patients is radiation-induced oral mucositis (OM), which can lead to severe oropharyngeal pain, swallowing and speech difficulties, and weight loss, thereby eventually causing interruption of RT. Although OM varies with tumor location and treatment methods, it is overall a common occurrence. However, it is unclear in which patients suffer from this severe condition. This study aimed to evaluate the suitability of acid sphingomyelinase (ASM) as a potential biomarker for predicting the risk of OM and to investigate the association with OM severity. METHODS: We investigated two independent patient cohorts from consecutive prospective studies (n=187). ASM protein levels were analyzed using Western blot analysis in unstimulated saliva samples collected from respective patients at least three days before the RT started. Patients were stratified according to OM occurrence and severity. Group comparisons were performed using non-parametric tests, while logistic regression was applied to assess associations between ASM levels and early OM development. Kaplan-Meier and Cox regression analyses evaluated correlations with overall and recurrence-free survival. RESULTS: In the first cohort, 74 out of 109 patients developed OM during RT, and 42 displayed early OM at low radiation dose. Grade 3 OM developed in 50 (67.6%) patients after definitive and 24 (32.4%) after adjuvant RT. Thirty-four patients did not develop OM. A significant increase in ASM levels was detected in the saliva of patients who developed OM early. Respective findings were confirmed in a second cohort (n=78). 44 out of 78 patients developed OM, of which 21 patients displayed early OM. Fifty-three patients did not develop OM. Elevated ASM levels were confirmed in the saliva of patients who developed OM early, an observation that was found particularly in the saliva of HPV-negative patients. HPV-positivity was present in 32 (41,0%) patients. Overall, regression-free survival did not correlate with the incidence of OM or HPV status. CONCLUSION: Although there is currently limited evidence for the potential implementation of salivary biomarkers to assess their association with the severity of OM, the findings here show that determining ASM levels in the saliva of HNC patients before starting RT could be a promising method to predict OM risk. AU - Ordonez, E.B.M.* AU - Sprave, T.* AU - Thomsen, A.R.* AU - Schäfer, H.* AU - Grosu, A.L.* AU - Jendrossek, V.* AU - Henke, M.* AU - Unger, K. AU - Klein, D.* C1 - 75773 C2 - 57972 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Increased acid sphingomyelinase levels in saliva as oral mucositis severity predictors. JO - Front. Oncol. VL - 15 PB - Frontiers Media Sa PY - 2025 SN - 2234-943X ER - TY - JOUR AB - BACKGROUND: Proton Minibeam Radiation Therapy has shown to widen the therapeutic window compared to conventional radiation treatment in pre-clinical studies. The underlying biological mechanisms, however, require more research. PURPOSE: The purpose of this study was to develop and characterize a mechanical collimation setup capable of producing 250µm wide proton minibeams with a center-to-center distance of 1000µm. METHODS: To find the optimal arrangement Monte Carlo simulations were employed using the Geant4 toolkit TOPAS to maximize key parameters such as the peak-to-valley dose ratio (PVDR) and the valley dose rate. The experimental characterization of the optimized setup was carried out with film dosimetry at the University Proton Therapy beamline in Dresden and the proton beamline of the University of Washington Medical Center in Seattle with 150MeV and 50.5MeV, respectively. A microDiamond detector (PTW, Freiburg, Germany) was utilized at both beamlines for online proton minibeam dosimetry. RESULTS: A PVDR of 10 was achieved in Dresden and a PVDR of 14 in Seattle. Dosimetry measurements were carried out with EBT3 films at a depth of 5mm in a polymethylmethacrylate (PMMA) phantom. When comparing film dosimetry with the microDiamond, excellent agreement was observed in the valleys. However, the peak dose showed a discrepancy of approximately 10% in the 150MeV beam and 20% in the 50.5MeV beam between film and microDiamond. DISCUSSION: The characteristics of the minibeams generated with our system compares well with those of other collimated minibeams despite being smaller. The deviations of microDiamond measurements from film readings might be subject to the diamond detector responding differently in the peak and valley regions. Applying previously reported correction factors aligns the dose profile measured by the microDiamond with the profile acquired with EBT3 films in Dresden. CONCLUSION: The novel proton minibeam system can be operated independently of specific beamlines. It can be transported easily and hence used for inter-institutional comparative studies. The quality of the minibeams allows us to perform in vitro and in vivo experiments in the future. The microDiamond was demonstrated to have great potential for online dosimetry for proton minibeams, yet requires more research to explain the observed discrepancies. AU - Ahmed, M. AU - Beyreuther, E.* AU - Gantz, S.* AU - Horst, F.* AU - Meyer, J.* AU - Pawelke, J.* AU - Schmid, T.E. AU - Stolz, J. AU - Wilkens, J.J.* AU - Bartzsch, S. C1 - 72923 C2 - 56793 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Design and dosimetric characterization of a transportable proton minibeam collimation system. JO - Front. Oncol. VL - 14 PB - Frontiers Media Sa PY - 2024 SN - 2234-943X ER - TY - JOUR AB - BACKGROUND: Brain metastases (BM) are a common and challenging issue, with their incidence on the rise due to advancements in systemic therapies and increased patient survival. Most patients present with single BM, some of them without any further extracranial metastasis (i.e., solitary BM). The significance of postoperative intracranial tumor volume in the treatment of singular and solitary BM is still debated. OBJECTIVE: This study aimed to determine the impact of resection and postoperative tumor burden on overall survival (OS) in patients with single BM. METHODS: Patients with surgically treated single BM between 04/2007-01/2020 were retrospectively included. Residual tumor burden (RTB) was determined by manual segmentation of early postoperative brain MRI (72 h). Survival analyses were performed using Kaplan-Meier estimates for univariate analysis and Cox regression proportional hazards model for multivariate analysis, using preoperative Karnofsky performance status scale (KPSS), age, sex, RTB, incomplete resection and singular/solitary BM as covariates. RESULTS: 340 patients were included, median age 64 years (54-71). 119 patients (35%) had solitary BM, 221 (65%) singular BM. Complete resection (RTB=0) was achieved in 73%, median preoperative tumor burden was 11.2 cm3 (5-25), and RTB 0 cm3 (0-0.2). Median OS of patients with singular BM was 13 months (4-33) vs 20 months (5-92) for solitary BM; p=0.062. Multivariate analysis revealed singular BM as independent risk factor for poorer OS: HR 1.840 (1.202-2.817), p=0.005. Complete vs. incomplete resection showed no significant OS difference (13 vs. 13 months, p=0.737). When focusing on solitary BM, complete resection led to a longer OS than incomplete resection (21 vs. 8 months), without statistical significance(p=0.250). Achieving RTB=0 resulted in higher OS for patients with solitary BM compared to singular BM (21 vs. 12 months, p=0.027). Patients who received postoperative radiotherapy (RT) had significantly longer OS compared to those without it (14 vs. 4 months, p<0.001), with favorable OS in those receiving stereotactic radiosurgery (SRS) (15 months (3-42), p<0.001) or hypofractionated stereotactic radiotherapy (HSRT). CONCLUSION: When complete intracranial tumor resection RTB=0 is achieved, patients with solitary BM have a favorable outcome compared to singular BM. Singular BM was confirmed as independent risk factor. There is a strong presumption that complete resection leads to an improved oncological prognosis. Patients with solitary BM tend to benefit with a favorable outcome following complete resection. Hence, surgical resection should be considered as a treatment option for patients presenting with either no or minimal extracranial disease. Furthermore, the highly favorable impact of postoperative RT on OS was demonstrated and confirmed, especially with SRS or HSRT. AU - Baumgart, L.* AU - Anetsberger, A.* AU - Aftahy, A.K.* AU - Wiestler, B.* AU - Bernhardt, D.* AU - Combs, S.E. AU - Meyer, H.S.* AU - Schneider, G.* AU - Meyer, B.* AU - Gempt, J.* C1 - 70360 C2 - 55529 TI - Single brain metastases - prognostic factors and impact of residual tumor burden on overall survival. JO - Front. Oncol. VL - 14 PY - 2024 SN - 2234-943X ER - TY - JOUR AB - Background: A reduced Karnofsky performance score (KPS) often leads to the discontinuation of surgical and adjuvant therapy, owing to a lack of evidence of survival and quality of life benefits. This study aimed to examine the clinical and treatment outcomes of patients with KPS < 70 after neurosurgical resection and identify prognostic factors associated with better survival. Methods: Patients with a preoperative KPS < 70 who underwent surgical resection for newly diagnosed brain metastases (BM) between 2007 and 2020 were retrospectively analyzed. The KPS, age, sex, tumor localization, cumulative tumor volume, number of lesions, extent of resection, prognostic assessment scores, adjuvant radiotherapy and systemic therapy, and presence of disease progression were analyzed. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with better survival. Survival > 3 months was considered favorable and ≤ 3 months as poor. Results: A total of 140 patients were identified. Median overall survival was 5.6 months (range 0-58). There was no difference in the preoperative KPS between the groups of > 3 and ≤ 3 months (50; range, 20–60 vs. 50; range, 10–60, p = 0.077). There was a significant improvement in KPS after surgery in patients with a preoperative KPS of 20% (20 vs 40 ± 20, p = 0.048). In the other groups, no significant changes in KPS were observed. Adjuvant radiotherapy was associated with better survival (44 [84.6%] vs. 32 [36.4%]; hazard ratio [HR], 0.0363; confidence interval [CI], 0.197–0.670, p = 0.00199). Adjuvant chemotherapy and immunotherapy resulted in prolonged survival (24 [46.2%] vs. 12 [13.6%]; HR 0.474, CI 0.263–0.854, p = 0.013]. Systemic disease progression was associated with poor survival (36 [50%] vs. 71 [80.7%]; HR 5.975, CI 2.610–13.677, p < 0.001]. Conclusion: Neurosurgical resection is an appropriate treatment modality for patients with low KPS. Surgery may improve functional status and facilitate further tumor-specific treatment. Combined treatment with adjuvant radiotherapy and systemic therapy was associated with improved survival in this cohort of patients. Systemic tumor progression has been identified as an independent factor for a poor prognosis. There is almost no information regarding surgical and adjuvant treatment in patients with low KPS. Our paper provides novel data on clinical outcome and survival analysis of patients with BM who underwent surgical treatment. AU - Goldberg, M.* AU - Mondragon-Soto, M.G.* AU - Altawalbeh, G.* AU - Baumgart, L.* AU - Gempt, J.* AU - Bernhardt, D.* AU - Combs, S.E. AU - Meyer, B.* AU - Aftahy, A.K.* C1 - 69842 C2 - 55275 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Enhancing outcomes: Neurosurgical resection in brain metastasis patients with poor Karnofsky performance score - a comprehensive survival analysis. JO - Front. Oncol. VL - 13 PB - Frontiers Media Sa PY - 2024 SN - 2234-943X ER - TY - JOUR AB - BACKGROUND: Due to demographic changes and an increased incidence of cancer with age, the number of patients with brain metastases (BMs) constantly increases, especially among the elderly. Novel systemic therapies, such as immunotherapy, have led to improved survival in recent years, but intracranial tumor progression may occur independently of a systemically effective therapy. Despite the growing number of geriatric patients, they are often overlooked in clinical trials, and there is no consensus on the impact of BM resection on survival. OBJECTIVES: The aim of this study was to analyze the impact of resection and residual tumor volume on clinical outcome and overall survival (OS) in elderly patients suffering from BM. METHODS: Patients ≥ 75 years who had surgery for BM between April 2007 and January 2020 were retrospectively included. Residual tumor burden (RTB) was determined by segmentation of early postoperative brain MRI (72 h). Contrast-enhancing tumor subvolumes were segmented manually. "Postoperative tumor volume" refers to the targeted BMs. Impact of preoperative Karnofsky performance status scale (KPSS), age, sex and RTB on OS was analyzed. Survival analyses were performed using Kaplan-Meier estimates for the univariate analysis and the Cox regression proportional hazards model for the multivariate analysis. RESULTS: One hundred and one patients were included. Median age at surgery was 78 years (IQR 76-81). Sixty-two patients (61%) had a single BM; 16 patients (16%) had two BMs; 13 patients (13%) had three BMs; and 10 patients (10%) had more than three BMs. Median preoperative tumor burden was 10.3 cm3 (IQR 5-25 cm3), and postoperative tumor burden was 0 cm3 (IQR 0-1.1 cm3). Complete cytoreduction (RTB = 0) was achieved in 52 patients (52%). Complete resection of the targeted metastases was achieved in 78 patients (78%). Median OS was 7 months (IQR 2-11). In univariate analysis, high preoperative KPSS (HR 0.986, 95% CI 0.973-0.998, p = 0.026) and small postoperative tumor burden (HR 1.025, 95% CI 1.002-1.047, p = 0.029) were significantly associated with prolonged OS. Patients with RTB = 0 survived significantly longer than those with residual tumor did (12 [IQR 5-19] vs. 5 [IQR 3-7] months, p = 0.007). Furthermore, prolongation of survival was significantly associated with surgery in patients with favorable KPSS, with an adjusted HR of 0.986 (p = 0.026). However, there were no significances regarding age. CONCLUSIONS: RTB is a strong predictor for prolonged OS, regardless of age or cancer type. Postoperative MRI should confirm the extent of resection, as intraoperative estimates do not warrant a complete resection. It is crucial to aim for maximal cytoreduction to achieve the best long-term outcomes for these patients, despite the fact the patients are advanced in age. AU - Baumgart, L.* AU - Aftahy, A.K.* AU - Anetsberger, A.* AU - Thunstedt, D.* AU - Wiestler, B.* AU - Bernhardt, D.* AU - Combs, S.E. AU - Meyer, B.* AU - Meyer, H.S.* AU - Gempt, J.* C1 - 67679 C2 - 53986 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Brain metastases in the elderly - Impact of residual tumor volume on overall survival. JO - Front. Oncol. VL - 13 PB - Frontiers Media Sa PY - 2023 SN - 2234-943X ER - TY - JOUR AB - INTRODUCTION: The intrinsic autofluorescence of biological tissues interferes with the detection of fluorophores administered for fluorescence guidance, an emerging auxiliary technique in oncological surgery. Yet, autofluorescence of the human brain and its neoplasia is sparsely examined. This study aims to assess autofluorescence of the brain and its neoplasia on a microscopic level by stimulated Raman histology (SRH) combined with two-photon fluorescence. METHODS: With this experimentally established label-free microscopy technique unprocessed tissue can be imaged and analyzed within minutes and the process is easily incorporated in the surgical workflow. In a prospective observational study, we analyzed 397 SRH and corresponding autofluorescence images of 162 samples from 81 consecutive patients that underwent brain tumor surgery. Small tissue samples were squashed on a slide for imaging. SRH and fluorescence images were acquired with a dual wavelength laser (790 nm and 1020 nm) for excitation. In these images tumor and non-tumor regions were identified by a convolutional neural network that reliably differentiates between tumor, healthy brain tissue and low quality SRH images. The identified areas were used to define regions.of- interests (ROIs) and the mean fluorescence intensity was measured. RESULTS: In healthy brain tissue, we found an increased mean autofluorescence signal in the gray (11.86, SD 2.61, n=29) compared to the white matter (5.99, SD 5.14, n=11, p<0.01) and in the cerebrum (11.83, SD 3.29, n=33) versus the cerebellum (2.82, SD 0.93, n=7, p<0.001), respectively. The signal of carcinoma metastases, meningiomas, gliomas and pituitary adenomas was significantly lower (each p<0.05) compared to the autofluorescence in the cerebrum and dura, and significantly higher (each p<0.05) compared to the cerebellum. Melanoma metastases were found to have a higher fluorescent signal (p<0.01) compared to cerebrum and cerebellum. DISCUSSION: In conclusion we found that autofluorescence in the brain varies depending on the tissue type and localization and differs significantly among various brain tumors. This needs to be considered for interpreting photon signal during fluorescence-guided brain tumor surgery. AU - Fürtjes, G. AU - Reinecke, D.* AU - von Spreckelsen, N.* AU - Meißner, A.K.* AU - Rueß, D.* AU - Timmer, M.* AU - Freudiger, C.* AU - Ion-Margineanu, A.* AU - Khalid, F.* AU - Watrinet, K.* AU - Mawrin, C.* AU - Chmyrov, A. AU - Goldbrunner, R.* AU - Bruns, O.T. AU - Neuschmelting, V.* C1 - 67887 C2 - 54365 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Intraoperative microscopic autofluorescence detection and characterization in brain tumors using stimulated Raman histology and two-photon fluorescence. JO - Front. Oncol. VL - 13 PB - Frontiers Media Sa PY - 2023 SN - 2234-943X ER - TY - JOUR AB - Background and purpose: In breast cancer patients, the increasing de-escalation of axillary surgery and the improving resolution of diagnostic imaging results in a more frequent detection of residual, radiographically suspect lymph nodes (sLN) after surgery. If resection of the remaining suspect lymph nodes is not feasible, a simultaneous boost to the lymph node metastases (LN-SIB) can be applied. However, literature lacks data regarding the outcome and safety of this technique. Materials and methods: We included 48 patients with breast cancer and sLN in this retrospective study. All patients received a LN-SIB. The median dose to the breast or chest wall and the lymph node system was 50.4 Gy in 28 fractions. The median dose of the LN-SIB was 58.8 Gy / 2.1 Gy (56-63 Gy / 2-2.25 Gy). The brachial plexus was contoured in every case and the dose within the plexus PRV (+0.3-0.5mm) was limited to an EQD2 of 59 Gy. All patients received structured radiooncological and gynecological follow-up by clinically experienced physicians. Radiooncological follow-ups were at baseline, 6 weeks, 3 months, 6 months and subsequent annually after irradiation. Results: The median follow-up time was 557 days and ranged from 41 to 3373 days. Overall, 28 patients developed I°, 18 patients II° and 2 patients III° acute toxicity. There were no severe late side effects (≥ III°) observed during the follow-up period. The most frequent chronic side effect was fatigue. One patient (2.1 %) developed pain and mild paresthesia in the ipsilateral arm after radiotherapy. After a follow-up of 557 days (41 to 3373 days), in 8 patients a recurrence was observed (16.7%). In 4 patients the recurrence involved the regional lymph node system. Hence, local control in the lymph node drainage system after a median follow-up of 557 days was 91.6 %. Conclusion: If surgical re-dissection of residual lymph nodes is not feasible or refused by the patient, LN-SIB-irradiation can be considered as a potential treatment option. However, patients need to be informed about a higher risk of regional recurrence compared to surgery and an additional risk of acute and late toxicity compared to adjuvant radiotherapy without regional dose escalation. AU - Klusen, S.T.* AU - Peiler, A.* AU - Schmidt, G.P.* AU - Kiechle, M.E.* AU - Muench, S.* AU - Asadpour, R.* AU - Combs, S.E. AU - Borm, K.J.* C1 - 68154 C2 - 53604 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Simultaneous integrated boost within the lymphatic drainage system in breast cancer: A single center study on toxicity and oncologic outcome. JO - Front. Oncol. VL - 13 PB - Frontiers Media Sa PY - 2023 SN - 2234-943X ER - TY - JOUR AB - INTRODUCTION: Pneumonitis is a relevant side effect after radiotherapy (RT) and immunotherapy with checkpoint inhibitors (ICIs). Since the effect is radiation dose dependent, the risk increases for high fractional doses as applied for stereotactic body radiation therapy (SBRT) and might even be enhanced for the combination of SBRT with ICI therapy. Hence, patient individual pre-treatment prediction of post-treatment pneumonitis (PTP) might be able to support clinical decision making. Dosimetric factors, however, use limited information and, thus, cannot exploit the full potential of pneumonitis prediction. METHODS: We investigated dosiomics and radiomics model based approaches for PTP prediction after thoracic SBRT with and without ICI therapy. To overcome potential influences of different fractionation schemes, we converted physical doses to 2 Gy equivalent doses (EQD2) and compared both results. In total, four single feature models (dosiomics, radiomics, dosimetric, clinical factors) were tested and five combinations of those (dosimetric+clinical factors, dosiomics+radiomics, dosiomics+dosimetric+clinical factors, radiomics+dosimetric+clinical factors, radiomics+dosiomics+dosimetric+clinical factors). After feature extraction, a feature reduction was performed using pearson intercorrelation coefficient and the Boruta algorithm within 1000-fold bootstrapping runs. Four different machine learning models and the combination of those were trained and tested within 100 iterations of 5-fold nested cross validation. RESULTS: Results were analysed using the area under the receiver operating characteristic curve (AUC). We found the combination of dosiomics and radiomics features to outperform all other models with AUCradiomics+dosiomics, D = 0.79 (95% confidence interval 0.78-0.80) and AUCradiomics+dosiomics, EQD2 = 0.77 (0.76-0.78) for physical dose and EQD2, respectively. ICI therapy did not impact the prediction result (AUC ≤ 0.5). Clinical and dosimetric features for the total lung did not improve the prediction outcome. CONCLUSION: Our results suggest that combined dosiomics and radiomics analysis can improve PTP prediction in patients treated with lung SBRT. We conclude that pre-treatment prediction could support clinical decision making on an individual patient basis with or without ICI therapy. AU - Kraus, K.M. AU - Oreshko, M.* AU - Bernhardt, D.* AU - Combs, S.E. AU - Peeken, J.C. C1 - 67635 C2 - 53942 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Dosiomics and radiomics to predict pneumonitis after thoracic stereotactic body radiotherapy and immune checkpoint inhibition. JO - Front. Oncol. VL - 13 PB - Frontiers Media Sa PY - 2023 SN - 2234-943X ER - TY - JOUR AB - Endometrial cancer is the most common gynaecological malignancy in developed countries. Over 382,000 new cases were diagnosed worldwide in 2018, and its incidence and mortality are constantly rising due to longer life expectancy and life style factors including obesity. Two major improvements are needed in the management of patients with endometrial cancer, i.e., the development of non/minimally invasive tools for diagnostics and prognostics, which are currently missing. Diagnostic tools are needed to manage the increasing number of women at risk of developing the disease. Prognostic tools are necessary to stratify patients according to their risk of recurrence pre-preoperatively, to advise and plan the most appropriate treatment and avoid over/under-treatment. Biomarkers derived from proteomics and metabolomics, especially when derived from non/minimally-invasively collected body fluids, can serve to develop such prognostic and diagnostic tools, and the purpose of the present review is to explore the current research in this topic. We first provide a brief description of the technologies, the computational pipelines for data analyses and then we provide a systematic review of all published studies using proteomics and/or metabolomics for diagnostic and prognostic biomarker discovery in endometrial cancer. Finally, conclusions and recommendations for future studies are also given. AU - Romano, A.* AU - Rizner, T.L.* AU - Werner, H.M.J.* AU - Semczuk, A.* AU - Lowy, C.* AU - Schröder, C.* AU - Griesbeck, A.* AU - Adamski, J. AU - Fishman, D.* AU - Tokarz, J. C1 - 67673 C2 - 53980 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Endometrial cancer diagnostic and prognostic algorithms based on proteomics, metabolomics, and clinical data: A systematic review. JO - Front. Oncol. VL - 13 PB - Frontiers Media Sa PY - 2023 SN - 2234-943X ER - TY - JOUR AU - Romano, A.* AU - Semczuk, A.* AU - Tokarz, J. AU - Rizner, T.L.* C1 - 68723 C2 - 54932 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Translational research for better diagnosis and treatment of endometrial cancer. JO - Front. Oncol. VL - 13 PB - Frontiers Media Sa PY - 2023 SN - 2234-943X ER - TY - JOUR AB - Objective: Head and neck cancer (HNC) accounts for almost 890,000 new cases per year. Radiotherapy (RT) is used to treat the majority of these patients. A common side-effect of RT is the onset of oral mucositis, which decreases the quality of life and represents the major dose-limiting factor in RT. To understand the origin of oral mucositis, the biological mechanisms post-ionizing radiation (IR) need to be clarified. Such knowledge is valuable to develop new treatment targets for oral mucositis and markers for the early identification of “at-risk” patients. Methods: Primary keratinocytes from healthy volunteers were biopsied, irradiated in vitro (0 and 6 Gy), and subjected to mass spectrometry-based analyses 96 h after irradiation. Web-based tools were used to predict triggered biological pathways. The results were validated in the OKF6 cell culture model. Immunoblotting and mRNA validation was performed and cytokines present in cell culture media post-IR were quantified. Results: Mass spectrometry-based proteomics identified 5879 proteins in primary keratinocytes and 4597 proteins in OKF6 cells. Amongst them, 212 proteins in primary keratinocytes and 169 proteins in OKF6 cells were differentially abundant 96 h after 6 Gy irradiation compared to sham-irradiated controls. In silico pathway enrichment analysis predicted interferon (IFN) response and DNA strand elongation pathways as mostly affected pathways in both cell systems. Immunoblot validations showed a decrease in minichromosome maintenance (MCM) complex proteins 2-7 and an increase in IFN-associated proteins STAT1 and ISG15. In line with affected IFN signalling, mRNA levels of IFNβ and interleukin 6 (IL-6) increased significantly following irradiation and also levels of secreted IL-1β, IL-6, IP-10, and ISG15 were elevated. Conclusion: This study has investigated biological mechanisms in keratinocytes post-in vitro ionizing radiation. A common radiation signature in keratinocytes was identified. The role of IFN response in keratinocytes along with increased levels of pro-inflammatory cytokines and proteins could hint towards a possible mechanism for oral mucositis. AU - Subedi, P.* AU - Huber, K.* AU - Sterr, C.* AU - Dietz, A.* AU - Strasser, L.* AU - Kaestle, F.* AU - Hauck, S.M. AU - Duchrow, L.* AU - Aldrian, C.* AU - Monroy Ordonez, E.B.* AU - Luka, B.* AU - Thomsen, A.R.* AU - Henke, M.* AU - Gomolka, M.* AU - Rößler, U.* AU - Azimzadeh, O.* AU - Moertl, S.* AU - Hornhardt, S.* C1 - 68437 C2 - 54647 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Towards unravelling biological mechanisms behind radiation-induced oral mucositis via mass spectrometry-based proteomics. JO - Front. Oncol. VL - 13 PB - Frontiers Media Sa PY - 2023 SN - 2234-943X ER - TY - JOUR AB - Background: Brain metastases were considered to be well-defined lesions, but recent research points to infiltrating behavior. Impact of postoperative residual tumor burden (RTB) and extent of resection are still not defined enough. Patients and Methods: Adult patients with surgery of brain metastases between April 2007 and January 2020 were analyzed. Early postoperative MRI (<72 h) was used to segment RTB. Survival analysis was performed and cutoff values for RTB were revealed. Separate (subgroup) analyses regarding postoperative radiotherapy, age, and histopathological entities were performed. Results: A total of 704 patients were included. Complete cytoreduction was achieved in 487/704 (69.2%) patients, median preoperative tumor burden was 12.4 cm3 (IQR 5.2-25.8 cm3), median RTB was 0.14 cm3 (IQR 0.0-2.05 cm3), and median postoperative tumor volume of the targeted BM was 0.0 cm3 (IQR 0.0-0.1 cm3). Median overall survival was 6 months (IQR 2-18). In multivariate analysis, preoperative KPSS (HR 0.981982, 95% CI, 0.9761-0.9873, p < 0.001), age (HR 1.012363; 95% CI, 1.0043-1.0205, p = 0.0026), and preoperative (HR 1.004906; 95% CI, 1.0003-1.0095, p = 0.00362) and postoperative tumor burden (HR 1.017983; 95% CI; 1.0058-1.0303, p = 0.0036) were significant. Maximally selected log rank statistics showed a significant cutoff for RTB of 1.78 cm3 (p = 0.0022) for all and 0.28 cm3 (p = 0.0047) for targeted metastasis and cutoff for the age of 67 years (p < 0.001). (Stereotactic) Radiotherapy had a significant impact on survival (p < 0.001). Conclusions: RTB is a strong predictor for survival. Maximal cytoreduction, as confirmed by postoperative MRI, should be achieved whenever possible, regardless of type of postoperative radiotherapy. AU - Aftahy, A.K.* AU - Barz, M.* AU - Lange, N.* AU - Baumgart, L.* AU - Thunstedt, C.* AU - Eller, M.A.* AU - Wiestler, B.* AU - Bernhardt, D.* AU - Combs, S.E. AU - Jost, P.J.* AU - Delbridge, C.* AU - Liesche-Starnecker, F.* AU - Meyer, B.* AU - Gempt, J.* C1 - 65074 C2 - 52659 TI - The impact of postoperative tumor burden on patients with brain metastases. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Introduction: Exposure of the posterior skull base and the cerebellopontine angle is challenging due to important neurovascular structures. The retrosigmoid approach (RSA) has become the standard method used in surgery. We report our experiences with RSAs regarding technical obstacles, complications, and approach-related outcomes. Materials and Methods: We performed a retrospective chart review at a tertiary neurosurgical center between January 2007 and September 2020. We included all patients undergoing surgery for oncologic lesions through RSAs, concentrating on surgical technique, postoperative outcome, and complications. Results: A total of 449 RSAs were included. The median age at the time of surgery was 58 years; 168 (37.4%) were male and 281 (62.6%) were female. The median approach surface was 7.8 cm2. The median tumor volume was 5.9 cm3. The median Clavien–Dindo grade was 2, the total complication rate was 28.7%, and gross total resection (GTR) was 78.8%. Findings revealed that tumor volume had no significant impact on postoperative complications in general (p = 0.086) but had a significant impact on postoperative hemorrhage (p = 0.037) and hydrocephalus (p = 0.019). Tumor volume was significant for several preoperative symptoms (p < 0.001). The extent of the approach had no significant impact on complications in general (p = 0.120) but was significant regarding postoperative cerebrospinal fluid (CSF) leaks (p = 0.008). Craniotomy size was not significant regarding GTR (p = 0.178); GTR rate just missed significant correlation with tumor volume (p = 0.056). However, in the case of vestibular schwannomas, the size of craniotomy was important for GTR (p = 0.041). Conclusion: Tumor volume has an important impact on preoperative symptoms as well as on postoperative complications. Although the extent of the craniotomy barely missed significance regarding GTR, a correlation can be assumed. Thus, the extent of craniotomy should be taken into presurgical consideration, especially in the case of postoperative CSF leaks. Regarding vestibular schwannomas, craniotomy size plays an important role in achieving satisfactory oncological outcomes. Different approaches should be selected where necessary regarding superior resection rates. AU - Aftahy, A.K.* AU - Jörger, A.K.* AU - Hillebrand, S.* AU - Harder, F.N.* AU - Wiestler, B.* AU - Bernhardt, D.* AU - Combs, S.E. AU - Meyer, B.* AU - Negwer, C.* AU - Gempt, J.* C1 - 65724 C2 - 52469 TI - The bigger the better? Analysis of surgical complications and outcome of the retrosigmoid approach in 449 oncological cases. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Background: Despite the availability of various therapy options and being a widely focused research area, the prognosis of glioblastoma (GBM) still remains very poor due to therapy resistance, genetic heterogeneity and a diffuse infiltration pattern. The recently described non-apoptotic form of cell death ferroptosis may, however, offer novel opportunities for targeted therapies. Hence, the aim of this study was to investigate the potential role of ferroptosis in GBM, including the impact of treatment on the expression of the two ferroptosis-associated players glutathione-peroxidase 4 (GPX4) and acyl-CoA-synthetase long-chain family number 4 (ACSL4). Furthermore, the change in expression of the recently identified ferroptosis suppressor protein 1 (FSP1) and aldehyde dehydrogenase (ALDH) 1A3 was investigated. Methods: Immunohistochemistry was performed on sample pairs of primary and relapse GBM of 24 patients who had received standard adjuvant treatment with radiochemotherapy. To identify cell types generally prone to undergo ferroptosis, co-stainings of ferroptosis susceptibility genes in combination with cell-type specific markers including glial fibrillary acidic protein (GFAP) for tumor cells and astrocytes, as well as the ionized calcium-binding adapter molecule 1 (Iba1) for microglial cells were performed, supplemented by double stains combining GPX4 and ACSL4. Results: While the expression of GPX4 decreased significantly during tumor relapse, ACSL4 showed a significant increase. These results were confirmed by analyses of data sets of the Cancer Genome Atlas. These profound changes indicate an increased susceptibility of relapsed tumors towards oxidative stress and associated ferroptosis, a cell death modality characterized by unrestrained lipid peroxidation. Moreover, ALDH1A3 and FSP1 expression also increased in the relapses with significant results for ALDH1A3, whereas for FSP1, statistical significance was not reached. Results obtained from double staining imply that ferroptosis occurs more likely in GBM tumor cells than in microglial cells. Conclusion: Our study implies that ferroptosis takes place in GBM tumor cells. Moreover, we show that recurrent tumors have a higher vulnerability to ferroptosis. These results affirm that utilizing ferroptosis processes might be a possible novel therapy option, especially in the situation of recurrent GBM. AU - Kram, H.* AU - Prokop, G.* AU - Haller, B.* AU - Gempt, J.* AU - Wu, Y.* AU - Schmidt-Graf, F.* AU - Schlegel, J.* AU - Conrad, M. AU - Liesche-Starnecker, F.* C1 - 64976 C2 - 52596 TI - Glioblastoma relapses show increased markers of vulnerability to ferroptosis. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Purpose: This study aims to characterize the neutron radiation field inside a scanning proton therapy treatment room including the impact of different pediatric patient sizes. Materials and Methods: Working Group 9 of the European Radiation Dosimetry Group (EURADOS) has performed a comprehensive measurement campaign to measure neutron ambient dose equivalent, H*(10), at eight different positions around 1-, 5-, and 10-year-old pediatric anthropomorphic phantoms irradiated with a simulated brain tumor treatment. Several active detector systems were used. Results: The neutron dose mapping within the gantry room showed that H*(10) values significantly decreased with distance and angular deviation with respect to the beam axis. A maximum value of about 19.5 µSv/Gy was measured along the beam axis at 1 m from the isocenter for a 10-year-old pediatric phantom at 270° gantry angle. A minimum value of 0.1 µSv/Gy was measured at a distance of 2.25 m perpendicular to the beam axis for a 1-year-old pediatric phantom at 140° gantry angle. The H*(10) dependence on the size of the pediatric patient was observed. At 270° gantry position, the measured neutron H*(10) values for the 10-year-old pediatric phantom were up to 20% higher than those measured for the 5-year-old and up to 410% higher than for the 1-year-old phantom, respectively. Conclusions: Using active neutron detectors, secondary neutron mapping was performed to characterize the neutron field generated during proton therapy of pediatric patients. It is shown that the neutron ambient dose equivalent H*(10) significantly decreases with distance and angle with respect to the beam axis. It is reported that the total neutron exposure of a person staying at a position perpendicular to the beam axis at a distance greater than 2 m from the isocenter remains well below the dose limit of 1 mSv per year for the general public (recommended by the International Commission on Radiological Protection) during the entire treatment course with a target dose of up to 60 Gy. This comprehensive analysis is key for general neutron shielding issues, for example, the safe operation of anesthetic equipment. However, it also enables the evaluation of whether it is safe for parents to remain near their children during treatment to bring them comfort. Currently, radiation protection protocols prohibit the occupancy of the treatment room during beam delivery. AU - Mares, V. AU - Farah, J.* AU - De Saint-Hubert, M.* AU - Domanski, S.* AU - Domingo, C.* AU - Dommert, M. AU - Kłodowska, M.* AU - Krzempek, K.* AU - Kuć, M.* AU - Martínez-Rovira, I.* AU - Michaś, E.* AU - Mojzeszek, N.* AU - Murawski, Ł.* AU - Ploc, O.* AU - Romero-Expósito, M.* AU - Tisi, M. AU - Trompier, F.* AU - van Hoey, O.* AU - van Ryckeghem, L.* AU - Wielunski, M. AU - Harrison, R.M.* AU - Stolarczyk, L.* AU - Olko, P.* C1 - 65813 C2 - 52542 TI - Neutron radiation dose measurements in a scanning proton therapy room: Can parents remain near their children during treatment? JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Purpose: The Bragg peak located at the end of the ion beam range is one of the main advantages of ion beam therapy compared to X-Ray radiotherapy. However, verifying the exact position of the Bragg peak within the patient online is a major challenge. The goal of this work was to achieve submillimeter proton beam range verification for pulsed proton beams of an energy of up to 220 MeV using ionoacoustics for a clinically relevant dose deposition of typically 2 Gy per fraction by i) using optimal proton beam characteristics for ionoacoustic signal generation and ii) improved signal detection by correlating the signal with simulated filter templates. Methods: A water tank was irradiated with a preclinical 20 MeV proton beam using different pulse durations ranging from 50 ns up to 1 μs in order to maximise the signal-to-noise ratio (SNR) of ionoacoustic signals. The ionoacoustic signals were measured using a piezo-electric ultrasound transducer in the MHz frequency range. The signals were filtered using a cross correlation-based signal processing algorithm utilizing simulated templates, which enhances the SNR of the recorded signals. The range of the protons is evaluated by extracting the time of flight (ToF) of the ionoacoustic signals and compared to simulations from a Monte Carlo dose engine (FLUKA). Results: Optimised SNR of 28.0 ± 10.6 is obtained at a beam current of 4.5 μA and a pulse duration of 130 ns at a total peak dose deposition of 0.5 Gy. Evaluated ranges coincide with Monte Carlo simulations better than 0.1 mm at an absolute range of 4.21 mm. Higher beam energies require longer proton pulse durations for optimised signal generation. Using the correlation-based post-processing filter a SNR of 17.8 ± 5.5 is obtained for 220 MeV protons at a total peak dose deposition of 1.3 Gy. For this clinically relevant dose deposition and proton beam energy, submillimeter range verification was achieved at an absolute range of 303 mm in water. Conclusion: Optimal proton pulse durations ensure an ideal trade-off between maximising the ionoacoustic amplitude and minimising dose deposition. In combination with a correlation-based post-processing evaluation algorithm, a reasonable SNR can be achieved at low dose levels putting clinical applications for online proton or ion beam range verification into reach. AU - Schauer, J.* AU - Wieser, H.P.* AU - Huang, Y. AU - Ruser, H.* AU - Lascaud, J.* AU - Würl, M.* AU - Chmyrov, A. AU - Vidal, M.* AU - Herault, J.* AU - Ntziachristos, V. AU - Assmann, W.* AU - Parodi, K.* AU - Dollinger, G.* C1 - 66761 C2 - 53296 TI - Proton beam range verification by means of ionoacoustic measurements at clinically relevant doses using a correlation-based evaluation. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Background and Purpose: Increased levels of the chaperone protein GRP78 have been implicated in poorer outcomes of cancer therapy. We have therefore explored the functional connection between the expression of GRP78 and the development of radioresistance and metastatic behavior in HNSCC. Material and Methods: The association between gene expression of GRP78 and survival in HNSCC patients was examined using the TCGA database. The influence of ionizing radiation on the GRP78 levels in HNSCC cell lines, their secreted extracellular vesicles (EV) and non-irradiated EV-recipient cells was investigated by Western Blot and FACS. The consequences of chemical inhibition or experimental overexpression of GRP78 on radioresistance and migration of HNSCC cells were analyzed by clonogenic survival and gap closure assays. Results: Elevated levels of GRP78 RNA in HNSCC correlated with poorer overall survival. Radiation increased GRP78 protein expression on the surface of HNSCC cell lines. Experimental overexpression of GRP78 increased both radioresistance and migratory potential. Chemical inhibition of GRP78 impaired cell migration. EVs were identified as a potential source of increased GRP78 content as elevated levels of surface GRP78 were found in EVs released by irradiated cells. These vesicles transferred GRP78 to non-irradiated recipient cells during co-cultivation. Conclusions: We have identified the chaperone protein GRP78 as a potential driver of increased radioresistance and motility in HNSCC. The uptake of GRP78-rich EVs originating from irradiated cells may contribute to a poorer prognosis through bystander effects mediated by the transfer of GRP78 to non-irradiated cells. Therefore, we consider the chaperone protein GRP78 to be an attractive target for improving radiotherapy strategies. AU - Schneider, M. AU - Winkler, K. AU - Kell, R. AU - Pfaffl, M.W.* AU - Atkinson, M.J.* AU - Moertl, S.* C1 - 64633 C2 - 52427 TI - The chaperone protein GRP78 promotes survival and migration of head and neck cancer after direct radiation exposure and extracellular vesicle-transfer. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Background: Treatment of locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) with photon radiation is the standard of care but shows only moderate success. Alterations in response toward DNA DSB repair, apoptosis, and senescence are underlying determinants of radioresistance in the tumor cells. Recently, senescence and the associated secretory phenotype (SASP) came into the focus of research and raised the need to identify the tumor-promoting molecular mechanisms of the SASP. The aim of this project was to unravel more of this process and to understand the impact of the IL1 pathway, which plays a major role in SASP. The studies were performed for photon and 12C-ion irradiation, which strongly vary in their effect on radioresistance. Materials and Methods: A panel of five HPV-negative HNSCC cell lines was treated with photon and 12C-ion irradiation and examined for clonogenic survival, DNA DSB repair, and senescence. SASP and IL1 gene expressions were determined by RNA sequencing and activation of the IL1 pathway by ELISA. A functional impact of IL1A and IL1B was examined by specific siRNA knockdown. Results: Cell killing and residual DSBs were higher after 12C-ion than after photon irradiation. 12C-ion induced more senescence with a significant correlation with cell survival. The impact on radioresistance appears to be less than after photon irradiation. The expression of SASP-related genes and the IL1 pathway are strongly induced by both types of irradiation and correlate with radioresistance and senescence, especially IL1A and IL1B which exhibit excellent associations. Surprisingly, knockdown of IL1A and IL1B revealed that the IL1 pathway is functionally not involved in radioresistance, DSB repair, or induction of senescence. Conclusions: IL1A and IL1B are excellent indicators of cellular radioresistance and senescence in HNSCC cells without functional involvement in these processes. Clearly more research is needed to understand the molecular mechanisms of senescence and SASP and its impact on radioresistance. AU - Tiwari, D.K.* AU - Hannen, R.* AU - Unger, K. AU - Kohl, S.* AU - Hess J. AU - Lauber, K.* AU - Subtil, F.S.B.* AU - Dikomey, E.* AU - Engenhart-Cabillic, R.* AU - Schötz, U.* C1 - 64975 C2 - 52595 TI - IL1 pathway in HPV-negative HNSCC cells is an indicator of radioresistance after photon and carbon ion irradiation without functional involvement. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Out-of-field patient doses in proton therapy are dominated by neutrons. Currently, they are not taken into account by treatment planning systems. There is an increasing need to include out-of-field doses in the dose calculation, especially when treating children, pregnant patients, and patients with implants. In response to this demand, this work presents the first steps towards a tool for the prediction of out-of-field neutron doses in pencil beam scanning proton therapy facilities. As a first step, a general Monte Carlo radiation transport model for simulation of out-of-field neutron doses was set up and successfully verified by comparison of simulated and measured ambient neutron dose equivalent and neutron fluence energy spectra around a solid water phantom irradiated with a variation of different treatment plan parameters. Simulations with the verified model enabled a detailed study of the variation of the neutron ambient dose equivalent with field size, range, modulation width, use of a range shifter, and position inside the treatment room. For future work, it is planned to use this verified model to simulate out-of-field neutron doses inside the phantom and to verify the simulation results by comparison with previous in-phantom measurement campaigns. Eventually, these verified simulations will be used to build a library and a corresponding tool to allow assessment of out-of-field neutron doses at pencil beam scanning proton therapy facilities. AU - van Hoey, O.* AU - Stolarczyk, L.* AU - Lillhök, J.* AU - Eliasson, L.* AU - Mojzeszek, N.* AU - Liszka, M.* AU - Alkhiat, A.* AU - Mares, V. AU - Trompier, F.* AU - Trinkl, S. AU - Martínez-Rovira, I.* AU - Romero-Expósito, M.* AU - Domingo, C.* AU - Ploc, O.* AU - Harrison, R.* AU - Olko, P.* C1 - 66384 C2 - 52789 TI - Simulation and experimental verification of ambient neutron doses in a pencil beam scanning proton therapy room as a function of treatment plan parameters. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Background: Selective uptake of (18)F-fluoro-ethyl-tyrosine (18F-FET) is used in high-grade glioma (HGG) to assess tumor metabolic activity via positron emission tomography (PET). We aim to investigate its value for target volume definition, as a prognosticator, and associations with whole-blood transcriptome liquid biopsy (WBT lbx) for which we recently reported feasibility to mirror tumor characteristics and response to particle irradiation in recurrent HGG (rHGG). Methods: 18F-FET-PET data from n = 43 patients with primary glioblastoma (pGBM) and n = 33 patients with rHGG were assessed. pGBM patients were irradiated with photons and sequential proton/carbon boost, and rHGG patients were treated with carbon re-irradiation (CIR). WBT (Illumina HumanHT-12 Expression BeadChips) lbx was available for n = 9 patients from the rHGG cohort. PET isocontours (40%-70% SUVmax, 10% steps) and MRI-based treatment volumes (MRIvol) were compared using the conformity index (CI) (pGBM, n = 16; rHGG, n = 27). Associations with WBT lbx data were tested on gene expression level and inferred pathways activity scores (PROGENy) and from transcriptome estimated cell fractions (CIBERSORT, xCell). Results: In pGBM, median SUVmax was higher in PET acquired pre-radiotherapy (4.1, range (R) 1.5-7.8; n = 20) vs. during radiotherapy (3.3, R 1.5-5.7, n = 23; p = 0.03) and in non-resected (4.7, R 2.9-7.9; n = 11) vs. resected tumors (3.3, R 1.5-7.8, n = 32; p = 0.01). In rHGG, a trend toward higher SUVmax values in grade IV tumors was observed (p = 0.13). Median MRIvol was 32.34 (R 8.75-108.77) cm3 in pGBM (n = 16) and 20.77 (R 0.63-128.44) cm3 in rHGG patients (n = 27). The highest median CI was observed for 40% (pGBM, 0.31) and 50% (rHGG, 0.43, all tumors) isodose, with 70% (40%) isodose in grade III (IV) rHGG tumors (median CI, 0.38 and 0.49). High SUVmax was linked to shorter survival in pGBM (>3.3, p = 0.001, OR 6.0 [2.1-17.4]) and rHGG (>2.8, p = 0.02, OR 4.1 [1.2-13.9]). SUVmax showed associations with inferred monocyte fractions, hypoxia, and TGFbeta pathway activity and links to immune checkpoint gene expression from WBT lbx. Conclusion: The benefits of 18F-FET-PET imaging on gross tumor volume (GTV) definition for particle radiotherapy warrant further evaluation. SUVmax might assist in prognostic stratification of HGG patients for particle radiotherapy, highlights heterogeneity in rHGG, and is positively associated with unfavorable signatures in peripheral whole-blood transcriptomes. AU - Waltenberger, M.* AU - Furkel, J.* AU - Röhrich, M.* AU - Salome, P.* AU - Tawk, B.* AU - Gahlawat, A.W.* AU - Kudak, A.* AU - Dostal, M.* AU - Wirkner, U.* AU - Schwager, C.* AU - Herold-Mende, C.* AU - Combs, S.E. AU - König, L.* AU - Debus, J.* AU - Haberkorn, U.* AU - Abdollahi, A.* AU - Knoll, M.* C1 - 66343 C2 - 53141 TI - The impact of tumor metabolic activity assessed by 18F-FET amino acid PET imaging in particle radiotherapy of high-grade glioma patients. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Background: The incidence and mortality of bladder cancer (BCa) are increasing, while the existing diagnostic methods have limitations. Therefore, for early detection and response prediction, it is crucial to improve the prognosis and treatment strategies. However, with existing diagnostic methods, detecting BCa in the early stage is challenging. Hence, novel biomarkers are urgently needed to improve early diagnosis and treatment efficiency. Methods: The gene expression profile and gene methylation profile dataset were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs), differentially methylated genes (DMGs), and methylation-regulated differentially expressed genes (MeDEGs) were gradually identified. A cancer genome map was obtained using online gene expression profile interaction analysis, and survival implications were produced using Kaplan-Meier survival analysis. GSEA was employed to predict the marker pathways where DEGs were significantly involved. The study used bisulfite PCR amplification combined with bisulfite amplicon sequencing (BSAS) to screen for methylation analysis of multiple candidate regions of the adenylate cyclase 2 (ADCY2) based on the sequence design of specific gene regions and CpG islands. Results: In this study, DEGs and DMGs with significantly up- or down-regulated expression were selected. The intersection method was used to screen the MeDEGs. The interaction network group in STRING was then visualized using Cytoscape, and the PPI network was constructed to identify the key genes. The key genes were then analyzed using functional enrichment. To compare the relationship between key genes and the prognosis of BCa patients, we further investigated ADCY2 and found that ADCY2 can be a potential clinical biomarker in BCa prognosis and immunotherapy response prediction. In human BCa 5637 and MGH1 cells, we developed and verified the effectiveness of ADCY2 primers using BSAS technology. The findings revealed that the expression of ADCY2 is highly regulated by the methylation of the promoter regions. Conclusion: This study revealed that increased expression of ADCY2 was significantly correlated with increased tumor heterogeneity, predicting worse survival and immunotherapy response in BCa patients. AU - Yang, J.* AU - Xu, J. AU - Gao, Q.* AU - Wu, F.* AU - Han, W. AU - Yu, C.* AU - Shi, Y.* AU - Qiu, Y.* AU - Chen, Y.* AU - Zhou, X.* C1 - 66554 C2 - 53216 TI - Identification of adenylate cyclase 2 methylation in bladder cancer with implications for prognosis and immunosuppressive microenvironment. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - Introduction: Head and neck squamous cell carcinomas (HNSCC) are characterized by strong cellular and molecular heterogeneity and treatment resistance entailing poor survival. Besides cell-intrinsic properties, carcinoma cells receive important cues from non-malignant cells within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a major component of the TME that impact on the molecular make-up of malignant cells and have a decisive function in tumor progression. However, the potential functionality of fibroblasts within tumor-adjacent, macroscopically normal tissue remains poorly explored. Methods: Here, we isolated primary peritumoral fibroblasts (PtFs) from macroscopically normal tissue in vicinity of primary human papillomavirus-negative and -positive oropharyngeal HNSCC and compared their phenotype and functionality with matched CAFs (n = 5 pairs) and with human oral fibroblasts (hOFs). Results: Expression patterns of CD90, CD73, CD105, smooth muscle actin, Vimentin, and S100A4 were comparable in PtFs, CAFs, and hOFs. Cell proliferation and doubling times of CAFs and PtFs were heterogeneous across patients (n =2 PtF>CAF; n = 1 CAF>PtF; n = 2 CAF=PtF) and reflected inferior growth than hOFs. Furthermore, PtFs displayed an reduced heterogeneity in cell size compared to matched CAFs, which were characterized by the presence of single large cells. Overall, conditioned supernatants from CAFs had more frequently growth-promoting effects on a panel of carcinoma cell lines of the upper aerodigestive tract carcinoma cell lines (Cal27, Cal33, FaDu, and Kyse30), whereas significant differences in migration-inducing effects demonstrated a higher potential of PtFs. Except for Kyse30, CAFs were significantly superior to hOFs in promoting proliferation, while PtFs induced stronger migration than hOFs in all carcinoma lines tested. Analysis of soluble factors demonstrated significantly increased VEGF-A production in CAFs (except in pat.8), and significantly increased PDGF-BB production in PtFs of two patients. Tube formation assays confirmed a significantly enhanced angiogenic potential of conditioned supernatants from CAFs compared to hOFs on human umbilical vascular endothelial cells (HUVECs) in vitro. Discussion: Hence, matched CAFs and PtFs present in HNSCC patients are heterogeneous in their proliferation-, migration-, and angiogenesis-promoting capacity. Despite this heterogeneity, CAFs induced stronger carcinoma cell proliferation and HUVEC tube formation overall, whereas PtFs promoted migration of tumor cells more strongly. AU - Zhou, J.* AU - Schwenk-Zieger, S.* AU - Kranz, G.* AU - Walz, C.* AU - Klauschen, F.* AU - Dhawan, S.* AU - Canis, M. AU - Gires, O. AU - Haubner, F.* AU - Baumeister, P. AU - Kohlbauer, V.* C1 - 67068 C2 - 53439 TI - Isolation and characterization of head and neck cancer-derived peritumoral and cancer-associated fibroblasts. JO - Front. Oncol. VL - 12 PY - 2022 SN - 2234-943X ER - TY - JOUR AB - The Cre/loxP system is a powerful tool for the generation of animal models with precise spatial and temporal gene expression. It has proven indispensable in the generation of cancer models with tissue specific expression of oncogenes or the inactivation of tumor suppressor genes. Consequently, Cre-transgenic mice have become an essential prerequisite in basic cancer research. While it is unlikely that pigs will ever replace mice in basic research they are already providing powerful complementary resources for translational studies. But, although conditionally targeted onco-pigs have been generated, no Cre-driver lines exist for any of the major human cancers. To model human pancreatic cancer in pigs, Cre-driver lines were generated by CRISPR/Cas9-mediated insertion of codon-improved Cre (iCre) into the porcine PTF1A gene, thus guaranteeing tissue and cell type specific function which was proven using dual fluorescent reporter pigs. The method used can easily be adapted for the generation of other porcine Cre-driver lines, providing a missing tool for modeling human cancers in large animals. AU - Kalla, D.* AU - Flisikowski, K.* AU - Yang, K. AU - Sangüesa, L.B.* AU - Kurome, M.* AU - Kessler, B.* AU - Zakhartchenko, V.* AU - Wolf, E.* AU - Lickert, H. AU - Saur, D.* AU - Schnieke, A.* AU - Flisikowska, T.* C1 - 63355 C2 - 51486 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - The missing link: Cre pigs for cancer research. JO - Front. Oncol. VL - 11 PB - Frontiers Media Sa PY - 2021 SN - 2234-943X ER - TY - JOUR AB - BackgroundIn case of oligo-recurrent prostate cancer (PC) following prostatectomy, Ga-68-PSMA-PET/CT can be used to detect a specific site of recurrence and to initiate metastasis-directed radiation therapy (MDT). However, large heterogeneities exist concerning doses, treatment fields and radiation techniques, with some studies reporting focal radiotherapy (RT) to PSMA-PET/CT positive lesions only and other studies using elective RT strategies. We aimed to compare oncological outcomes and toxicity between PET/CT-directed RT (PDRT) and PDRT plus elective RT (eRT; i.e. prostate bed, pelvic or paraaortal nodes) in a large retrospective multicenter study.MethodsData of 394 patients with oligo-recurrent Ga-68-PSMA-PET/CT-positive PC treated between 04/2013 and 01/2018 in six different academic institutions were evaluated. Primary endpoint was biochemical-recurrence-free survival (bRFS). bRFS was analyzed using Kaplan-Meier survival curves and log rank testing. Uni- and multivariate analyses were performed to determine influence of treatment parameters.ResultsIn 204 patients (51.8%) RT was directed only to lesions seen on Ga-68-PSMA-PET/CT (PDRT), 190 patients (48.2%) received PDRT plus eRT. PDRT plus eRT was associated with a significantly improved 3-year bRFS compared to PDRT alone (53 vs. 37%; p = 0.001) and remained an independent factor in multivariate analysis (p = 0.006, HR 0.29, 95% CI 0.12-0.68). This effect was more pronounced in the subgroup of patients who were treated with PDRT and elective prostate bed radiotherapy (ePBRT) with a 3-year bRFS of 61% versus 22% (p <0.001). Acute and late toxicity grade >= 3 was 0.8% and 3% after PDRT plus eRT versus no toxicity grade >= 3 after PDRT alone.ConclusionsIn this large cohort of patients with oligo-recurrent prostate cancer, elective irradiation of the pelvic lymphatics and the prostatic bed significantly improved bRFS when added to Ga-68-PSMA-PET/CT-guided focal radiotherapy. These findings need to be evaluated in a randomized controlled trial. AU - Kirste, S.* AU - Kroeze, S.G.C.* AU - Henkenberens, C.* AU - Schmidt-Hegemann, N.-S.* AU - Vogel, M.M. AU - Becker, J.* AU - Zamboglou, C.* AU - Burger, I.* AU - Derlin, T.* AU - Bartenstein, P.* AU - Ruf, J.* AU - la Fougère, C.* AU - Eiber, M.* AU - Christiansen, H.* AU - Combs, S.E. AU - Mueller, A.* AU - Belka, C.* AU - Guckenberger, M.* AU - Grosu, A.* C1 - 62125 C2 - 50657 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Combining 68Ga-PSMA-PET/CT-directed and elective radiation therapy improves outcome in oligorecurrent prostate cancer: A retrospective multicenter study. JO - Front. Oncol. VL - 11 PB - Frontiers Media Sa PY - 2021 SN - 2234-943X ER - TY - JOUR AB - The occurrence and development of cancer are closely related to the immune escape of tumor cells and immune tolerance. Unlike previous surgical, chemotherapy, radiotherapy and targeted therapy, tumor immunotherapy is a therapeutic strategy that uses various means to stimulate and enhance the immune function of the body, and ultimately achieves the goal of controlling tumor cells.With the in-depth understanding of tumor immune escape mechanism and tumor microenvironment, and the in-depth study of tumor immunotherapy, immune checkpoint inhibitors represented by Programmed Death 1/Programmed cell Death-Ligand 1(PD-1/PD-L1) inhibitors are becoming increasingly significant in cancer medication treatment. employ a variety of ways to avoid detection by the immune system, a single strategy is not more effective in overcoming tumor immune evasion and metastasis. Combining different immune agents or other drugs can effectively address situations where immunotherapy is not efficacious, thereby increasing the chances of success and alternative access to alternative immunotherapy. Immune combination therapies for cancer have become a hot topic in cancer treatment today. In this paper, several combination therapeutic modalities of PD1/PD-L1 inhibitors are systematically reviewed. Finally, an analysis and outlook are provided in the context of the recent advances in combination therapy with PD1/PD-L1 inhibitors and the pressing issues in this field. AU - Li, Z.* AU - Sun, G.* AU - Sun, G.* AU - Cheng, Y.* AU - Wu, L.* AU - Wang, Q. AU - Lv, C.* AU - Zhou, Y.* AU - Xia, Y.* AU - Tang, W.* C1 - 63714 C2 - 51747 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Various uses of PD1/PD-L1 inhibitor in oncology: Opportunities and challenges. JO - Front. Oncol. VL - 11 PB - Frontiers Media Sa PY - 2021 SN - 2234-943X ER - TY - JOUR AB - Background: Women living with HIV in sub-Saharan Africa are at increased risk to develop cervical cancer (CC), which is caused by persistent infection with 13 oncogenic human papilloma viruses (HR-HPVs). It is important to accurately identify and target HIV-positive women at highest risk to develop CC for early therapeutic intervention. Methods: A total of 2,134 HIV+ and HIV− women from South-West Tanzania were prospectively screened for cervical cancer and precancerous lesions. Women with cervical cancer (n=236), high- and low-grade squamous intraepithelial lesions (HSIL: n=68, LSIL: n=74), and without lesion (n=426) underwent high-resolution HPV genotyping. Results: Eighty percent of women who were diagnosed with HSIL or LSIL were living with HIV. Any lesion, young age, HIV status, and depleted CD4 T cell counts were independent risk factors for HPV infections, which were predominantly caused by HR-HPV types. While multiple HR-HPV type infections were predominant in HIV+ women with HSIL, single-type infections predominated in HIV+ CC cases (p=0.0006). HPV16, 18, and 45 accounted for 85% (68/80) and 75% (82/110) of HIV+ and HIV− CC cases, respectively. Of note, HPV35, the most frequent HPV type in HSIL-positive women living with HIV, was rarely detected as a single-type infection in HSIL and cancer cases. Conclusion: HPV16, 18, and 45 should receive special attention for molecular diagnostic algorithms during CC prevention programs for HIV+ women from sub-Saharan Africa. HPV35 may have a high potential to induce HSIL in women living with HIV, but less potential to cause cervical cancer in single-type infections. AU - Mcharo, R.* AU - Lennemann, T.* AU - France, J.* AU - Torres, L.* AU - Garí, M. AU - Mbuya, W.* AU - Mwalongo, W.* AU - Mahenge, A.* AU - Bauer, A.J.* AU - Mnkai, J.* AU - Glasmeyer, L.* AU - Judick, M.* AU - Paul, M.* AU - Schroeder, N.* AU - Msomba, B.* AU - Sembo, M.* AU - Chiwerengo, N.* AU - Hoelscher, M.* AU - Geisenberger, O.* AU - Lelle, R.J.* AU - Saathoff, E.* AU - Maboko, L.* AU - Chachage, M.* AU - Kroidl, A.* AU - Geldmacher, C.* C1 - 63844 C2 - 51773 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - HPV type distribution in HIV positive and negative women with or without cervical dysplasia or cancer in East Africa. JO - Front. Oncol. VL - 11 PB - Frontiers Media Sa PY - 2021 SN - 2234-943X ER - TY - JOUR AB - Radiotherapy is an essential component of multi-modality treatment of glioblastoma (GBM). However, treatment failure and recurrence are frequent and give rise to the dismal prognosis of this aggressive type of primary brain tumor. A high level of inherent treatment resistance is considered to be the major underlying reason, stemming from constantly activated DNA damage response (DDR) mechanisms as a consequence of oncogene overexpression, persistent replicative stress, and other so far unknown reasons. The molecular chaperone heat shock protein 90 (HSP90) plays an important role in the establishment and maintenance of treatment resistance, since it crucially assists the folding and stabilization of various DDR regulators. Accordingly, inhibition of HSP90 represents a multi-target strategy to interfere with DDR function and to sensitize cancer cells to radiotherapy. Using NW457, a pochoxime-based HSP90 inhibitor with favorable brain pharmacokinetic profile, we show here that HSP90 inhibition at low concentrations with per se limited cytotoxicity leads to downregulation of various DNA damage response factors on the protein level, distinct transcriptomic alterations, impaired DNA damage repair, and reduced clonogenic survival in response to ionizing irradiation in glioblastoma cells in vitro. In vivo, HSP90 inhibition by NW457 improved the therapeutic outcome of fractionated CBCT-based irradiation in an orthotopic, syngeneic GBM mouse model, both in terms of tumor progression and survival. Nevertheless, in view of the promising in vitro results the in vivo efficacy was not as strong as expected, although apart from the radiosensitizing effects HSP90 inhibition also reduced irradiation-induced GBM cell migration and tumor invasiveness. Hence, our findings identify the combination of HSP90 inhibition and radiotherapy in principle as a promising strategy for GBM treatment whose performance needs to be further optimized by improved inhibitor substances, better formulations and/or administration routes, and fine-tuned treatment sequences. AU - Orth, M.* AU - Albrecht, V.* AU - Seidl, K.* AU - Kinzel, L.* AU - Unger, K. AU - Hess J. AU - Kreutzer, L. AU - Sun, N. AU - Stegen, B.* AU - Nieto, A.* AU - Maas, J.* AU - Winssinger, N.* AU - Friedl, A.A.* AU - Walch, A.K. AU - Belka, C. AU - Zitzelsberger, H. AU - Niyazi, M.* AU - Lauber, K. C1 - 61732 C2 - 50430 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Inhibition of HSP90 as a strategy to radiosensitize glioblastoma: Targeting the DNA damage response and beyond. JO - Front. Oncol. VL - 11 PB - Frontiers Media Sa PY - 2021 SN - 2234-943X ER - TY - JOUR AB - Introduction: Prostate-specific membrane antigen-positron emission tomography-(PSMA-PET) imaging facilitates dose-escalated salvage radiotherapy (DE-SRT) with simultaneous-integrated boost (SIB) for PET-positive lesions in patients with prostate cancer (PC). Therefore, we aimed to compare toxicity rates of DE-SRT with SIB to conventional SRT (C-SRT) without SIB and to report outcome. Materials and Methods: We evaluated 199 patients who were treated with SRT between June 2014 and June 2020. 101 patients received DE-SRT with SIB for PET-positive local recurrence and/or PET-positive lymph nodes. 98 patients were treated with C-SRT to the prostate bed +/− elective pelvic lymphatic pathways without SIB. All patients received PSMA-PET imaging prior to DE-SRT ([68Ga]PSMA-11: 45.5%; [18F]-labeled PSMA: 54.5%). Toxicity rates for early (<6 months) and late (>6 months) gastrointestinal (GI) toxicities rectal bleeding, proctitis, stool incontinence, and genitourinary (GU) toxicities hematuria, cystitis, urine incontinence, urinary obstruction, and erectile dysfunction were assessed. Further, we analyzed the outcome with disease-free survival (DFS) and prostate-specific antigen (PSA) response. Results: The overall toxicity rates for early GI (C-SRT: 2.1%, DE-SRT: 1.0%) and late GI (C-SRT: 1.4%, DE-SRT: 5.3%) toxicities ≥ grade 2 were similar. Early GU (C-SRT: 2.1%, DE-SRT: 3.0%) and late GU (C-SRT: 11.0%, DE-SRT: 14.7%) toxicities ≥ grade 2 were comparable, as well. Early and late toxicity rates did not differ significantly between DE-SRT versus C-SRT in all subcategories (p>0.05). PSA response (PSA ≤0.2 ng/ml) in the overall group of patients with DE-SRT was 75.0% and 86.4% at first and last follow-up, respectively. Conclusion: DE-SRT showed no significantly increased toxicity rates compared with C-SRT and thus is feasible. The outcome of DE-SRT showed good results. Therefore, DE-SRT with a PSMA-PET-based SIB can be considered for the personalized treatment in patients with recurrent PC. AU - Vogel, M.M. AU - Dewes, S.* AU - Sage, E.K.* AU - Devecka, M.* AU - Eitz, K.A. AU - Gschwend, J.E.* AU - Eiber, M.* AU - Combs, S.E. AU - Schiller, K.* C1 - 62809 C2 - 51078 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Feasibility and outcome of PSMA-PET-based dose-escalated salvage radiotherapy versus conventional salvage radiotherapy for patients with recurrent prostate cancer. JO - Front. Oncol. VL - 11 PB - Frontiers Media Sa PY - 2021 SN - 2234-943X ER - TY - JOUR AB - Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fully humanized mice after EBV/B95-8 or EBV/M81 infections the effects of a clinically used PD-1 blocker. Fifteen to 17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with two types of EBV laboratory strains expressing firefly luciferase. Dynamic optical imaging analyses showed systemic EBV infections and this triggered vigorous human CD8+ T cell expansion. Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice. ICI promoted Ki67+CD30+CD20+EBER+PD-L1+ PTLD with central nervous system (CNS) involvement, mirroring EBV+ CNS PTLD in humans. PD-1 blockade was associated with lower frequencies of circulating T cells in blood and with a profound collapse of CD4+ T cells in lymphatic tissues. Mice treated with pembrolizumab showed an escalation of exhausted T cells expressing TIM-3, and LAG-3 in tissues, higher levels of several human cytokines in plasma and high densities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD. AU - Volk, V.* AU - Theobald, S.J.* AU - Danisch, S.* AU - Khailaie, S.* AU - Kalbarczyk, M.* AU - Schneider, A.* AU - Bialek-Waldmann, J.* AU - Krönke, N.* AU - Deng, Y.* AU - Eiz-Vesper, B.* AU - Dragon, A.C.* AU - von Kaisenberg, C.* AU - Lienenklaus, S.* AU - Bleich, A.* AU - Keck, J.* AU - Meyer-Hermann, M.* AU - Klawonn, F.* AU - Hammerschmidt, W. AU - Delecluse, H.J.* AU - Münz, C.* AU - Feuerhake, F.* AU - Stripecke, R.* C1 - 61155 C2 - 50090 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - PD-1 blockade aggravates Epstein–Barr Virus+ post-transplant lymphoproliferative disorder in humanized mice resulting in central nervous system involvement and CD4+ T cell dysregulations. JO - Front. Oncol. VL - 10 PB - Frontiers Media Sa PY - 2021 SN - 2234-943X ER - TY - JOUR AB - Purpose: Frequency of conventional kV-image guidance is sometimes sacrificed to reduce concomitant risk, leaving deviations of unguided fractions unknown. MV-imaging and treatment dose can be collectively optimized on Halcyon, where fractional MVCBCT provides complete anatomic records for course-wide dose reconstruction. By retrospective dose accumulation, this work simulated the impact of imaging frequency on patient treatment dose on the platform of Halcyon. Methods: Four hundred and sixteen MVCBCT image sets from 16 patients of various tumor sites treated with radiotherapy on Halcyon were retrospectively selected. After applying the image-guided couch shifts of the clinical records, deformable image registration was performed using Velocity software, to deform the planning CTs to the corresponding MVCBCTs, generating pseudo CTs representing the actual anatomies on the treatment day. Fractional treatment dose was reconstructed on pseudo CTs for accumulation, representing the actual patient dose (Ddaily). To simulate weekly image guidance, fractional dose was reconstructed and accumulated by incorporating 1 CBCT-guided corrections and 4 laser-guided setups of each week (Dweekly). Limited by partially imaged volumes and different organs-at-risk of various sites, only target dose-volume parameters were evaluated across all patients. Results: GTV_D98%, CTV_D98%, PTV_D90%, PTV_D95%, PGTV_D90%, and PGTV_D95% were evaluated, where Dx% means the minimal dose received by x% volume. Pairwise comparisons were made between plan dose and Ddaily, Ddaily and Dweekly respectively. PGTV_D95% of accumulated Dweekly were significantly lower than those of accumulated Ddaily by up to 32.90% of prescription dose, suggesting that weekly-guidance may result in unacceptable under dose to the target. The broad distribution of fractional differences between Ddaily and Dweekly suggested unreliable patient positioning based on aligning surface markers to laser beams, as a popular approach broadly used on conventional Linac systems. Slight target under-dose was observed on daily reconstructed results compared with planned dose, which provided quantitative data to guide clinical decisions such as the necessity of adaptive radiotherapy. Conclusion: Fractional image guided radiotherapy on Halcyon provides more reliable treatment accuracy than using sacrificed imaging frequency, which also provides complete anatomic records for deformable dose reconstruction supporting more informed clinical decisions. AU - Wang, H.* AU - Huang, Y.* AU - Hu, Q.* AU - Li, C.* AU - Liu, H.* AU - Wang, X.* AU - Li, W.B. AU - Ma, W.* AU - Pu, Y.* AU - Du, Y.* AU - Wu, H.* AU - Zhang, Y.* C1 - 61309 C2 - 49836 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - A simulated dosimetric study of contribution to radiotherapy accuracy by fractional image guidance protocol of Halcyon system. JO - Front. Oncol. VL - 10 PB - Frontiers Media Sa PY - 2021 SN - 2234-943X ER - TY - JOUR AB - The segmentation of high-grade gliomas (HGG) using magnetic resonance imaging (MRI) data is clinically meaningful in neurosurgical practice, but a challenging task. Currently, most segmentation methods are supervised learning with labeled training sets. Although these methods work well in most cases, they typically require time-consuming manual labeling and pre-trained models. In this work, we propose an automatically unsupervised segmentation toolbox based on the clustering algorithm and morphological processing, named AUCseg. With our toolbox, the whole tumor was first extracted by clustering on T2-FLAIR images. Then, based on the mask acquired with whole tumor segmentation, the enhancing tumor was segmented on the post-contrast T1-weighted images (T1-CE) using clustering methods. Finally, the necrotic regions were segmented by morphological processing or clustering on T2-weighted images. Compared with K-means, Mini-batch K-means, and Fuzzy C Means (FCM), the Gaussian Mixture Model (GMM) clustering performs the best in our toolbox. We did a multi-sided evaluation of our toolbox in the BraTS2018 dataset and demonstrated that the whole tumor, tumor core, and enhancing tumor can be automatically segmented using default hyper-parameters with Dice score 0.8209, 0.7087, and 0.7254, respectively. The computing time of our toolbox for each case is around 22 seconds, which is at least 3 times faster than other state-of-the-art unsupervised methods. In addition, our toolbox has an option to perform semi-automatic segmentation via manually setup hyper-parameters, which could improve the segmentation performance. Our toolbox, AUCseg, is publicly available on Github. (https://github.com/Haifengtao/AUCseg). AU - Zhao, B.* AU - Ren, Y.* AU - Yu, Z.* AU - Yu, J.* AU - Peng, T. AU - Zhang, X.Y.* C1 - 62444 C2 - 50876 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - AUCseg: An automatically unsupervised clustering toolbox for 3D-segmentation of high-grade gliomas in multi-parametric MR images. JO - Front. Oncol. VL - 11 PB - Frontiers Media Sa PY - 2021 SN - 2234-943X ER - TY - JOUR AB - Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor in adults. Despite extensive therapy the prognosis for GBM patients remains poor and the extraordinary therapy resistance has been attributed to intertumoral heterogeneity of glioblastoma. Different prognostic relevant GBM tumor subtypes have been identified based on their molecular profile. This approach, however, neglects the heterogeneity within individual tumors, that is, the intratumoral heterogeneity. Here, we detected the regional immunoreactivity by immunohistochemistry and immunofluorescence using nine different markers on resected GBM specimens (IDH wildtype, WHO grade IV). We found repetitive expression profiles, that could be classified into clusters. These clusters could then be assigned to five pathophysiologically relevant groups that reflect the previously described subclasses of GBM, including mesenchymal, classical, and proneural subtype. Our data indicate the presence of tumor differentiations and tumor subclasses that occur within individual tumors, and might therefore contribute to develop adapted, individual-based therapies. AU - Bergmann, N.* AU - Delbridge, C.* AU - Gempt, J.* AU - Feuchtinger, A. AU - Walch, A.K. AU - Schirmer, L.* AU - Bunk, W.* AU - Aschenbrenner, T.* AU - Liesche-Starnecker, F.* AU - Schlegel, J.* C1 - 59115 C2 - 48658 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - The intratumoral heterogeneity reflects the intertumoral subtypes of glioblastoma multiforme: A regional immunohistochemistry analysis. JO - Front. Oncol. VL - 10 PB - Frontiers Media Sa PY - 2020 SN - 2234-943X ER - TY - JOUR AB - Adoptive T cell therapy (ACT) is highly effective in the treatment of hematologic malignancies, but shows limited success in solid tumors. Inactivation of T cells in the tumor milieu is a major hurdle to a wider application of ACT. Cytotoxicity is the most relevant activity for tumor eradication. Here, we document that cytotoxic T cells (CTL) in lactic acidosis exhibited strongly reduced tumor cell killing, which could be compensated partly by increasing the CTL to tumor cell ratio. Lactic acid intervened at multiple steps of the killing process. Lactic acid repressed the number of CTL that performed lytic granule exocytosis (degranulation) in tumor cell co-culture, and, additionally impaired the quality of the response, as judged by the reduced intensity of degranulation and lower secretion of cytotoxins (perforin, granzyme B, granzyme A). CTL in lactic acid switched to a low bioenergetic profile with an inability to metabolize glucose efficiently. They responded to anti-CD3 stimulation poorly with less extracellular acidification rate (ECAR). This might explain their repressed granule exocytosis activity. Using live cell imaging, we show that CTL in lactic acid have reduced motility, resulting in lower field coverage. Many CTL in lactic acidosis did not make contact with tumor cells; however, those which made contact, adhered to the tumor cell much longer than a CTL in normal medium. Reduced motility together with prolonged contact duration hinders serial killing, a defining feature of killing potency, but also locally confines cytotoxic activity, which helps to reduce the risk of collateral organ damage. These activities define lactic acid as a major signaling molecule able to orchestrate the spatial distribution of CTL inside inflamed tissue, such as cancer, as well as moderating their functional response. Lactic acid intervention and strategies to improve T cell metabolic fitness hold promise to improve the clinical efficacy of T cell–based cancer immunotherapy. AU - Fischbeck, A. AU - Ruehland, S.* AU - Ettinger, A. AU - Paetzold, K. AU - Masouris, I. AU - Nößner, E. AU - Mendler, A.N. C1 - 60864 C2 - 49706 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Tumor lactic acidosis: Protecting tumor by inhibiting cytotoxic activity through motility arrest and bioenergetic silencing. JO - Front. Oncol. VL - 10 PB - Frontiers Media Sa PY - 2020 SN - 2234-943X ER - TY - JOUR AB - Background and purpose:To evaluate the feasibility of dose-guided adaptive radiotherapy (ART) based on deformable image registration (DIR) using fractional megavoltage cone-beam CT (MVCBCT) images from Halcyon system that uses identical beams for treatment and imaging and to retrospectively investigate the influence of anatomic changes on target coverage and organ-at-risk (OAR) sparing across various tumor sites. Materials and Methods:Four hundred twenty-two MVCBCT images from 16 patients (three head and neck, seven thoracic, three abdominal, and three pelvic cases) treated in a phase II clinical trial for Halcyon were selected. DIR between the planning CT and daily MVCBCT image was implemented by Velocity software to create pseudo CT. To investigate the accuracy of dose calculation on pseudo CT, three evaluation patients with rescanned CT and adaptive plans were selected. Dose distribution of adaptive plans calculated on pseudo CT was compared with that calculated on the rescanned planning CT on the three evaluation patients. To investigate the impact of inter-fractional anatomic changes on target dose coverage and dose to OARs of the 16 patients, fractional dose was calculated and accumulated incrementally based on deformable registration between planning CT and daily MVCBCT images. Results:Passing rates using 3 mm/3%/10% threshold local gamma analysis were 93.04, 96.00, and 91.68%, respectively, for the three evaluation patients between the reconstructed dose on pseudo CT (MVCBCT) and rescanned CT, where accumulated dose deviations of over 97% voxels were smaller than 0.5 Gy. Planning target volume (PTV) D95% and D90% (the minimum dose received by at least 95/90% of the volume) of the accumulated dose could be as low as 93.8 and 94.5% of the planned dose, respectively. OAR overdose of various degrees were observed in the 16 patients relative to the planned dose. In most cases, OARs' dose volume histogram (DVH) lines of accumulated and planned dose were very close to each other if not overlapping. Among cases with visible deviations, the differences were bilateral without apparent patterns specific to tumor sites or organs. Conclusion:As a confidence building measure, this simulation study suggested the possibility of ART for Halcyon based on DIR between planning CT and MVCBCT. Preliminary clinical data suggested the benefit of patient-specific dose reconstruction and ART to avoid unacceptable target underdosage and OAR overdosage. AU - Huang, Y.* AU - Wang, H.* AU - Li, C.* AU - Hu, Q.* AU - Liu, H.* AU - Deng, J.* AU - Li, W.B. AU - Wang, R.* AU - Wu, H.* AU - Zhang, Y.* C1 - 60170 C2 - 49092 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - A preliminary simulation study of dose-guided adaptive radiotherapy based on Halcyon MV cone beam CT images with retrospective data from a phase II clinical trial. JO - Front. Oncol. VL - 10 PB - Frontiers Media Sa PY - 2020 SN - 2234-943X ER - TY - JOUR AB - Background:Socioeconomic inequalities in colorectal cancer survival have been observed in many countries. To overcome these inequalities, the underlying reasons must be disclosed. Methods:Using data from three population-based clinical cancer registries in Germany, we investigated whether associations between area-based socioeconomic deprivation and survival after colorectal cancer depended on patient-, tumor- or treatment-related factors. Patients with a diagnosis of colorectal cancer in 2000-2015 were assigned to one of five deprivation groups according to the municipality of the place of residence using the German Index of Multiple Deprivation. Cox proportional hazards regression models with various levels of adjustment and stratifications were applied. Results:Among 38,130 patients, overall 5-year survival was 4.8% units lower in the most compared to the least deprived areas. Survival disparities were strongest in younger patients, in rectal cancer patients, in stage I cancer, in the latest period, and with longer follow-up. Disparities persisted after adjustment for stage, utilization of surgery and screening colonoscopy uptake rates. They were mostly still present when restricting to patients receiving treatment according to guidelines. Conclusion:We observed socioeconomic inequalities in colorectal cancer survival in Germany. Further studies accounting for potential differences in non-cancer mortality and exploring treatment patterns in detail are needed. AU - Jansen, L.* AU - Behrens, G.* AU - Finke, I.* AU - Maier, W. AU - Gerken, M.* AU - Pritzkuleit, R.* AU - Holleczek, B.* AU - Brenner, H.* C1 - 59381 C2 - 48778 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Area-based socioeconomic inequalities in colorectal cancer survival in Germany: Investigation based on population-based clinical cancer registration. JO - Front. Oncol. VL - 10 PB - Frontiers Media Sa PY - 2020 SN - 2234-943X ER - TY - JOUR AB - The metabolic reprogramming of cancer tissue has higher metabolic activity than surrounding tissues. At the same time, the local infiltration of immunosuppressive cells is also significantly increased, resulting in a significant decrease in tumor immunity. During the progression of cancer cells, immunosuppressive tumor microenvironment is formed around the tumor due to their metabolic reprogramming. In addition, it is the changes in metabolic patterns that make tumor cells resistant to certain drugs, impeding cancer treatment. This article reviews the mechanisms of immune escape caused by metabolic reprogramming, and aims to provide new ideas for clinical tumor immunotherapy combined with metabolic intervention for tumor treatment. AU - Wu, F.* AU - Cheng, Y.* AU - Wu, L.* AU - Zhang, W.* AU - Zheng, W.* AU - Wang, Q. AU - Cao, H.* AU - Pan, X.* AU - Tang, W.* C1 - 60386 C2 - 49392 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Emerging landscapes of tumor immunity and metabolism. JO - Front. Oncol. VL - 10 PB - Frontiers Media Sa PY - 2020 SN - 2234-943X ER - TY - JOUR AB - Background: Invasive ductal carcinoma (IDC) is a clinically and molecularly distinct disease. Tumor microenvironment (TME) immune phenotypes play crucial roles in predicting clinical outcomes and therapeutic efficacy. Method: In this study, we depict the immune landscape of IDC by using transcriptome profiling and clinical characteristics retrieved from The Cancer Genome Atlas (TCGA) data portal. Immune cell infiltration was evaluated via single-sample gene set enrichment (ssGSEA) analysis and systematically correlated with genomic characteristics and clinicopathological features of IDC patients. Furthermore, an immune signature was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm. A random forest algorithm was applied to identify the most important somatic gene mutations associated with the constructed immune signature. A nomogram that integrated clinicopathological features with the immune signature to predict survival probability was constructed by multivariate Cox regression. Results: The IDC were clustered into low immune infiltration, intermediate immune infiltration, and high immune infiltration by the immune landscape. The high infiltration group had a favorable survival probability compared with that of the low infiltration group. The low-risk score subtype identified by the immune signature was characterized by T cell-mediated immune activation. Additionally, activation of the interferon-α response, interferon-γ response, and TNF-α signaling via the NFκB pathway was observed in the low-risk score subtype, which indicated T cell activation and may be responsible for significantly favorable outcomes in IDC patients. A random forest algorithm identified the most important somatic gene mutations associated with the constructed immune signature. Furthermore, a nomogram that integrated clinicopathological features with the immune signature to predict survival probability was constructed, revealing that the immune signature was an independent prognostic biomarker. Finally, the relationship of VEGFA, PD1, PDL-1, and CTLA-4 expression with the immune infiltration landscape and the immune signature was analyzed to interpret the responses of IDC patients to immunotherapy. Conclusion: Taken together, we performed a comprehensive evaluation of the immune landscape of IDC and constructed an immune signature related to the immune landscape. This analysis of TME immune infiltration landscape has shed light on how IDC respond to immunotherapy and may guide the development of novel drug combination strategies. AU - Bao, X. AU - Shi, R.* AU - Zhang, K.* AU - Xin, S. AU - Li, X.* AU - Zhao, Y.* AU - Wang, Y.* C1 - 57092 C2 - 47537 TI - Immune landscape of invasive ductal carcinoma tumor microenvironment identifies a prognostic and immunotherapeutically relevant gene signature. JO - Front. Oncol. VL - 9 PY - 2019 SN - 2234-943X ER - TY - JOUR AB - We have recently discovered that cancer cells take up extracellular citrate through plasma membrane citrate transporter (pmCiC) and advantageously use citrate for their metabolism. Citrate uptake can be blocked with gluconate and this results in decreased tumor growth and altered metabolic characteristics of tumor tissue. Interestingly, gluconate, considered to be physiologically neutral, is incidentally used in medicine as a cation carrier, but not as a therapeutically active substance. In this review we discuss the results of our recent research with available literature and suggest that gluconate may be useful in the treatment of cancer. AU - Mycielska, M.E.* AU - Mohr, M.T.J.* AU - Schmidt, K.* AU - Drexler, K.* AU - Ruemmele, P.* AU - Haferkamp, S.* AU - Schlitt, H.J.* AU - Gaumann, A.* AU - Adamski, J. AU - Geissler, E.K.* C1 - 56525 C2 - 47076 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Potential use of gluconate in cancer therapy. JO - Front. Oncol. VL - 9 PB - Frontiers Media Sa PY - 2019 SN - 2234-943X ER - TY - JOUR AB - The Epstein-Barr virus (EBV) is a ubiquitous pathogen that imparts a significant burden of disease on the human population. EBV is the primary cause of infectious mononucleosis and is etiologically linked to the development of numerous malignancies. In recent years, evidence has also been amassed that strongly implicate EBV in the development of several autoimmune diseases, including multiple sclerosis. Prophylactic and therapeutic vaccination has been touted as a possible means of preventing EBV infection and controlling EBV-associated diseases. However, despite several decades of research, no licensed EBV vaccine is available. The majority of EBV vaccination studies over the last two decades have focused on the major envelope protein gp350, culminating in a phase II clinical trial that showed soluble gp350 reduced the incidence of IM, although it was unable to protect against EBV infection. Recently, novel vaccine candidates with increased structural complexity and antigenic content have been developed. The ability of next generation vaccines to safeguard against B-cell and epithelial cell infection, as well as to target infected cells during all phases of infection, is likely to decrease the negative impact of EBV infection on the human population. AU - van Zyl, D.G.* AU - Mautner, J. AU - Delecluse, H.-J.* C1 - 55615 C2 - 46428 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Progress in EBV vaccines. JO - Front. Oncol. VL - 9 PB - Frontiers Media Sa PY - 2019 SN - 2234-943X ER - TY - JOUR AB - Purpose: The purpose of this study is to investigate whether machine learning with dosiomic, radiomic, and demographic features allows for xerostomia risk assessment more precise than normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands. Material and methods: A cohort of 153 head-and-neck cancer patients was used to model xerostomia at 0-6 months (early), 6-15 months (late), 15-24 months (long-term), and at any time (a longitudinal model) after radiotherapy. Predictive power of the features was evaluated by the area under the receiver operating characteristic curve (AUC) of univariate logistic regression models. The multivariate NTCP models were tuned and tested with single and nested cross-validation, respectively. We compared predictive performance of seven classification algorithms, six feature selection methods, and ten data cleaning/class balancing techniques using the Friedman test and the Nemenyi post hoc analysis. Results: NTCP models based on the parotid mean dose failed to predict xerostomia (AUCs < 0.60). The most informative predictors were found for late and long-term xerostomia. Late xerostomia correlated with the contralateral dose gradient in the anterior posterior (AUC = 0.72) and the right left (AUC = 0.68) direction, whereas long-term xerostomia was associated with parotid volumes (AUCs > 0.85), dose gradients in the right left (AUCs > 0.78), and the anterior posterior (AUCs > 0.72) direction. Multivariate models of long-term xerostomia were typically based on the parotid volume, the parotid eccentricity, and the dose volume histogram (DVH) spread with the generalization AUCs ranging from 0.74 to 0.88. On average, support vector machines and extra-trees were the top performing classifiers, whereas the algorithms based on logistic regression were the best choice for feature selection. We found no advantage in using data cleaning or class balancing methods. Conclusion: We demonstrated that incorporation of organ- and dose-shape descriptors is beneficial for xerostomia prediction in highly conformal radiotherapy treatments. Due to strong reliance on patient-specific, dose-independent factors, our results underscore the need for development of personalized data-driven risk profiles for NTCP models of xerostomia. The facilitated machine learning pipeline is described in detail and can serve as a valuable reference for future work in radiomic and dosiomic NTCP modeling. AU - Gabryś, H.S.* AU - Buettner, F. AU - Sterzing, F.* AU - Hauswald, H.* AU - Bangert, M.* C1 - 53229 C2 - 44512 CY - Lausanne TI - Design and selection of machine learning methods using radiomics and dosiomics for normal tissue complication probability modeling of xerostomia. JO - Front. Oncol. VL - 8 PB - Frontiers Media Sa PY - 2018 SN - 2234-943X ER - TY - JOUR AU - Kessel, K.A. AU - Lee, A.W.M.* AU - Bentzen, S.M.* AU - Vikram, B.* AU - Nuesslin, F.* AU - Combs, S.E. C1 - 53066 C2 - 44773 CY - Lausanne TI - Editorial: Data based radiation oncology-design of clinical trials. JO - Front. Oncol. VL - 8 PB - Frontiers Media Sa PY - 2018 SN - 2234-943X ER - TY - JOUR AB - Purpose: In radiotherapy (RT) of brain tumors, the primary motor cortex is not regularly considered in target volume delineation, although decline in motor function is possible due to radiation. Noninvasive identification of motor-eloquent brain areas is currently mostly restricted to functional magnetic resonance imaging (fMRI), which has shown to lack precision for this purpose. Navigated transcranial magnetic stimulation (nTMS) is a novel tool to identify motor-eloquent brain areas. This study aims to integrate nTMS motor maps in RT planning and evaluates the influence on dosage modulations in patients harboring brain metastases. Materials and Methods: Preoperative nTMS motor maps of 30 patients diagnosed with motor-eloquent brain metastases were fused with conventional planning imaging and transferred to the RT planning software. RT plans of eleven patients were optimized by contouring nTMS motor maps as organs at risk (OARs). Dose modulation analyses were performed using dose-volume histogram (DVH) parameters. Results: By constraining the dose applied to the nTMS motor maps outside the planning target volume (PTV) to 15 Gy, the mean dose (Dmean) to the nTMS motor maps was significantly reduced by 18.1% from 23.0 Gy (16.9-30.4 Gy) to 18.9 Gy (13.5-28.8 Gy, p < 0.05). The Dmean of the PTV increased by 0.6 ± 0.3 Gy (1.7%). Conclusion: Implementing nTMS motor maps in standard RT planning is feasible in patients suffering from intracranial metastases. A significant reduction of the dose applied to the nTMS motor maps can be achieved without impairing treatment doses to the PTV. Thus, nTMS might provide a valuable tool for safer application of RT in patients harboring motor-eloquent brain metastases. AU - Schwendner, M.J.* AU - Sollmann, N.* AU - Diehl, C.D.* AU - Oechsner, M.* AU - Meyer, B.* AU - Krieg, S.M.* AU - Combs, S.E. C1 - 54540 C2 - 45587 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - The role of navigated transcranial magnetic stimulation motor mapping in adjuvant radiotherapy planning in patients with supratentorial brain metastases. JO - Front. Oncol. VL - 8 IS - OCT PB - Frontiers Media Sa PY - 2018 SN - 2234-943X ER - TY - JOUR AB - Radiation biology is a highly interdisciplinary field at the interface of biology, physics, and medicine. It is characterized by rapid advances in biological and technical knowledge. The potential for using these advances to optimize medical care, radiation protection, and related fields can be exploited only with complementary activities to support the education of young academics. A small number of academic institutions have committed resources into radiation-related courses and curricula; however, few offer a comprehensive interdepartmental research and training program. At the Technical University of Munich (TUM), a full Master of Science (MSc) course in radiation biology has been established. This article describes the TUM MSc radiation biology program, discusses the scope of the field, the teaching goals, and the interdisciplinary curriculum. Detailed information on the full MSc program can be found continuously updated at www.radonc.med.tum.de/masterradiationbiology. AU - Combs, S.E. AU - Kessel, C. AU - Wilkens, J.J. AU - Multhoff, G. AU - Schmid, T.E. AU - Vaupel, P. AU - Trott, K.R.* AU - Berberat, P.* AU - Atkinson, M.J. C1 - 52013 C2 - 43679 TI - Master of Science (MSc) program in radiation biology: An interdepartmental course bridging the gap between radiation-related preclinical and clinical disciplines to prepare next-generation medical scientists. JO - Front. Oncol. VL - 7 IS - SEP PY - 2017 SN - 2234-943X ER - TY - JOUR AB - Background and purpose: The aim of the present study was to evaluate if it is feasible for experienced radiation oncologists to visually sort out patients with a large dose to the heart. This would facilitate large retrospective data evaluations. And in case of an insufficient visual assessment, to define which structures should be contoured and which structures can be skipped as their dose can be derived from other easily contoured structures for future clinical trials. Material and methods: Planning CTs of left-sided breast cancer patients treated with 3D-conformal radiotherapy by tangential fields were visually divided into two groups: with an estimated high dose (HiD) and with an estimated low dose (LoD) to the heart. For 46 patients (22 HiD and 24 LoD), the heart, the left ventricle, the left anterior descending artery (LAD), the right coronary artery, and the ramus circumflexus were contoured. A helper structure (HS) around the LAD was generated in order to consider if contouring uncertainties of the LAD could be acceptable. We analyzed the mean dose (Dmean), the maximum dose, the V10, V20, V30, V40, and the length of the LAD that received 20 and 40 Gy. Results: The two groups had a significant different Dmean of the heart (p < 0.001). The average Dmean to the heart was 4.0 ± 1.3 Gy (HiD) and 2.3 ± 0.8 Gy (LoD). The average Dmean to the LAD was 26.2 ± 7.4 Gy (HiD) and 13.0 ± 7.5Gy (LoD) with a very strong positive correlation between Dmean LAD and Dmean HS in both groups. The Dmean heart is not a good surrogate parameter for the dose to the LAD since it might underestimate clinically significant doses in 1/3 of the patients in LoD group. Conclusion: A visual assessment of the dose to the heart could be reliable if performed by experienced radiation oncologists. However, the Dmean heart is not always a good surrogate parameter for the dose to the LAD or for the Dmean to the left ventricle. Thus, if specific late toxicities are evaluated, we strongly recommend contouring of the specific heart substructures as a heart Dmean is not highly specific. AU - Duma, M.N. AU - Herr, A.C.* AU - Borm, K.J.* AU - Trott, K.R.* AU - Molls, M.* AU - Oechsner, M.* AU - Combs, S.E. C1 - 51442 C2 - 43232 TI - Tangential field radiotherapy for breast cancer-the dose to the heart and heart subvolumes: What structures must be contoured in future clinical trials? JO - Front. Oncol. VL - 7 PY - 2017 SN - 2234-943X ER - TY - JOUR AB - Hyperthermia (HT) is one of the hot topics that have been discussed over decades. However, it never made its way into primetime. The basic biological rationale of heat to enhance the effect of radiation, chemotherapeutic agents, and immunotherapy is evident. Preclinical work has confirmed this effect. HT may trigger changes in perfusion and oxygenation as well as inhibition of DNA repair mechanisms. Moreover, there is evidence for immune stimulation and the induction of systemic immune responses. Despite the increasing number of solid clinical studies, only few centers have included this adjuvant treatment into their repertoire. Over the years, abundant prospective and randomized clinical data have emerged demonstrating a clear benefit of combined HT and radiotherapy for multiple entities such as superficial breast cancer recurrences, cervix carcinoma, or cancers of the head and neck. Regarding less investigated indications, the existing data are promising and more clinical trials are currently recruiting patients. How do we proceed from here? Preclinical evidence is present. Multiple indications benefit from additional HT in the clinical setting. This article summarizes the present evidence and develops ideas for future research. AU - Peeken, J.C.* AU - Vaupel, P.* AU - Combs, S.E. C1 - 51581 C2 - 43305 TI - Integrating hyperthermia into modern radiation oncology: What evidence is necessary? JO - Front. Oncol. VL - 7 PY - 2017 SN - 2234-943X ER - TY - JOUR AB - Background: Locally advanced rectal cancer (LARC) patients are usually treated within a multimodal therapy regime, in which the tumor resection plays the major role. This treatment ideally includes 5-fluorouracile (5FU)-based chemoradiation (CRT) leading to significantly improved local control rates. Local therapy as radiotherapy (RT) is required to be adapted referring to side effects and efficacy. Purpose of this study is the comparison of dosimetric parameters, acute and late toxicity, and quality of life in terms of patient-reported outcome (PRO) in patients treated with VMAT or 3D conformal radiotherapy (3DCRT) for LARC. Methods: Pelvic RT for LARC was performed with a prescription dose of 45 Gy in 1.8 Gy per fraction, 50.4 Gy in 1.8 Gy per fraction, or 50 Gy in 2 Gy per fraction. Chemotherapy included 5FU or 5FU/Oxaliplatin or Capecitabine-based RT. Acute and late toxicity were evaluated via National Institute Common Terminology Criteria for Adverse Events version (CTCAE) v4.03 and the Scoring System Late effects of Normal Tissue. Quality of life was established via EORTC QLQCR29. Results: After a median follow-up of 38 months (VMAT) and 78 months (3DCRT) there was no significant difference in progression-free survival (p = 0,85) but a significant difference in overall survival (p = 0.032). Regarding dose-volume parameters, patients treated with VMAT plans had a lower V20 of the bladder than 3DCRT-treated patients (p = 0.004). VMAT plans can also reduce Dmean of the right (p = 0.002) and left (p < 0.001) femoral head. Acute side effects between the VMAT and 3DCRT patients showed no significant difference. But concerning long-term effects, VMAT-treated patients had a significant lower appearance of high grade anal incontinence (p = 0.032). Quality of life (PRO) showed no significant different between the patients except of hair loss and worrying about weight. Conclusion: VMAT treatment of LARC in preoperative CRT revealed a reduction of dose to organs at risk (OARs) as bladder and femoral heads. However, no changes in acute and long-term toxicity profiles were detectable. For late toxicity and quality of life data longer follow-up times are required. AU - Regnier, A.* AU - Ulbrich, J.* AU - Münch, S.* AU - Oechsner, M.* AU - Wilhelm, D.* AU - Combs, S.E. AU - Habermehl, D. C1 - 52015 C2 - 43678 TI - Comparative analysis of efficacy, toxicity, and patient-reported outcomes in rectal cancer patients undergoing preoperative 3D conformal radiotherapy or VMAT. JO - Front. Oncol. VL - 7 IS - SEP PY - 2017 SN - 2234-943X ER - TY - JOUR AB - Large clinical cancer registries (CCRs) in Germany shall be strengthened by the German Social Code Book V (SGB V) and implemented until the end of 2017. There are currently several large cancer registries that support clinical data for outcome analysis and knowledge acquisition. The various examples of the Munich Cancer Registry outlined in this paper present many-sided possibilities using and analyzing registry data. The main objective of population-based cancer registration within a defined area and the performance of outcomes research is to provide feedback regarding the results to the broad public, the reporting doctors, and the scientific community. These tasks determine principles of operation and data usage by CCRs. Each clinical department delivers its own findings and applied therapy. The compilation of these data in CCRs provides information on patient progress through the regional network of medical care and delivers meaningful information on the course of oncological diseases. Successful implementation of CCRs allows for presenting the statistical outcomes of health-care delivery, improving the quality of care within the region, accelerating the process of implementing innovative therapies, and generating new hypotheses as a stimulus for research activities. AU - Schubert-Fritschle, G.* AU - Combs, S.E. AU - Kirchner, T.* AU - Nüssler, V.* AU - Engel, J.* C1 - 52305 C2 - 43872 TI - Use of multicenter data in a large cancer registry for evaluation of outcome and implementation of novel concepts. JO - Front. Oncol. VL - 7 PY - 2017 SN - 2234-943X ER - TY - JOUR AB - Background: Prospective clinical studies are the most important tool in modern medicine. The standard in good clinical practice in clinical trials has constantly improved leading to more sophisticated protocols. Moreover, translational questions are increasingly addressed in clinical trials. Such trials must follow elaborate rules and regulations. This is accompanied by a significant increase in documentation issues which require substantial manpower. Furthermore, university-based clinical centers are interested in increasing the amount of patients treated within clinical trials, and this number has evolved to be a key quality criterion. The present study was initiated to elucidate the obstacles that limit clinical scientists in screening and recruiting for clinical trials. Methods: A specific questionnaire with 28 questions was developed focusing on all aspects of clinical trial design as well as trial management. This included questions on organizational issues, medical topics as well as potential patients' preferences and physician's goals. The questionnaire was established to collect data anonymously on a web-based platform. The survey was conducted within the Klinikum rechts der Isar, Faculty of Medicine, Technical University of Munich; physicians of all levels (Department Chairs, attending physicians, residents, as well as study nurses, and other study-related staff) were addressed. The answers were analyzed using the Survio analyzing tool (http://www.survio.com/de/). results: We collected 42 complete sets of answers; in total 28 physicians, 11 study nurses, and 3 persons with positions in administration answered our survey. The study centers reported to participate in a range of 3–160 clinical trials with a recruitment rate of 1–80%. Main obstacles were determined: 31/42 (74%) complained about limited human resources and 22/42 (52%) reported to have a lack on technicalresources, too. 30/42 (71%) consented to the answer, that the documentation effort of clinical trials is too large. A possible increase of the patients' study participation rate up to over 20% was deemed to be possible if the described limitations could be overcome. Discussion: The increasing documentation effort in clinical trials has led to a strong increase in the work load of scientific personnel. Recruiting of patients into clinical trials therefore is not only limited by patient issues, but also by the infrastructure of the centers. Especially the lack of study nurses is likely to be a major limitation. Furthermore, technical resources for time efficient and safe documentation within clinical routine as well as in clinical trials are required. By optimization of these factors, a significant increase in the amount of patients treated in clinical trials seems to be possible. AU - Straube, C.* AU - Herschbach, P.* AU - Combs, S.E. C1 - 51846 C2 - 43530 TI - Which obstacles prevent us from recruiting into clinical trials: A survey about the environment for clinical studies at a German University hospital in a comprehensive cancer center. JO - Front. Oncol. VL - 7 IS - AUG PY - 2017 SN - 2234-943X ER - TY - JOUR AB - Nowadays, applications (apps) for smartphones and tablets have become indispensable especially for young generations. The estimated number of mobile devices will exceed 2.16 billion in 2016. Over 2.2 million apps are available in the Google Play store(®), and about 1.8 million apps are available in the Apple App Store(®). Google and Apple distribute nearly 70,000 apps each in the category Health and Fitness, and about 33,000 and 46,000 each in medical apps. It seems like the willingness to use mHealth apps is high and the intention to share data for health research is existing. This leads to one conclusion: the time for app-accompanied clinical trials (smartRCTs) has come. In this perspective article, we would like to point out the stones put in the way while trying to implement apps in clinical research. Further, we try to offer a glimpse of what the future of smartRCT research may hold. AU - Vogel, M.M. AU - Combs, S.E. AU - Kessel, K.A. C1 - 50828 C2 - 42899 TI - mHealth and application technology supporting clinical trials: Today's limitations and future perspective of smartRCTs. JO - Front. Oncol. VL - 7 IS - MAR PY - 2017 SN - 2234-943X ER - TY - JOUR AB - Recently, information availability has become more elaborate and widespread, and treatment decisions are based on a multitude of factors, including imaging, molecular or pathological markers, surgical results, and patient's preference. In this context, the term "Big Data" evolved also in health care. The "hype" is heavily discussed in literature. In interdisciplinary medical specialties, such as radiation oncology, not only heterogeneous and voluminous amount of data must be evaluated but also spread in different styles across various information systems. Exactly this problem is also referred to in many ongoing discussions about Big Data - the "three V's": volume, velocity, and variety. We reviewed 895 articles extracted from the NCBI databases about current developments in electronic clinical data management systems and their further analysis or postprocessing procedures. Few articles show first ideas and ways to immediately make use of collected data, particularly imaging data. Many developments can be noticed in the field of clinical trial or analysis documentation, mobile devices for documentation, and genomics research. Using Big Data to advance medical research is definitely on the rise. Health care is perhaps the most comprehensive, important, and economically viable field of application. AU - Kessel, K.A. AU - Combs, S.E. C1 - 48379 C2 - 39994 TI - Review of developments in electronic, clinical data collection, and documentation systems over the last decade - are we ready for big data in routine health care? JO - Front. Oncol. VL - 6 PY - 2016 SN - 2234-943X ER - TY - JOUR AB - Proton therapy is actively and repeatedly discussed within the framework of particle therapy for the treatment of prostate cancer (PC). The argument in favor of treating the prostate with protons is partly financial: given that small volumes are treated, treatment times are low, resulting in a hypothetical high patient throughput. However, such considerations should not form the basis of medical decision-making. There are also physical and biological arguments which further support the use of particle therapy for PC. The only relevant randomized data currently available is the study by Zietman and colleagues, comparing a high to a low proton boost, resulting in a significant increase in PSA-free survival in the experimental (high dose) arm (1). With modern photon treatments and image-guided radiotherapy (IGRT), equally high doses can be applied with photons and, thus, a randomized trial comparing high-end photons to protons is warranted. For high-linear energy transfer (LET) particles, such as carbon ions, the increase in relative biological effectiveness could potentially convert into an improvement in outcome. Additionally, through the physical differences of protons and carbon ions, the steeper dose gradient with carbon ions and the lack of beam broadening in the carbon beam lead to a superior dose distribution supporting the idea of hypofractionation. Biological and clinical data are emerging, however, has practice-changing evidence already arrived? AU - Schiller, K.C.* AU - Habl, G.* AU - Combs, S.E. C1 - 47854 C2 - 39700 TI - Protons, photons, and the prostate - is there emerging evidence in the ongoing discussion on particle therapy for the treatment of prostate cancer? JO - Front. Oncol. VL - 6 PY - 2016 SN - 2234-943X ER - TY - JOUR AB - BACKGROUND: NOTCH signaling can exert oncogenic or tumor suppressive functions and can contribute to chemotherapy resistance in cancer. In this study, we aimed to clarify the clinicopathological significance and the prognostic and predictive value of NOTCH1 and NOTCH2 expression in gastric cancer (GC). METHODS: NOTCH1 and NOTCH2 expression was determined immunohistochemically in 142 primarily resected GCs using tissue microarrays and in 84 pretherapeutic biopsies from patients treated by neoadjuvant chemotherapy. The results were correlated with survival, response to therapy, and clinico-pathological features. RESULTS: Primarily resected patients with NOTCH1-negative tumors demonstrated worse survival. High NOTCH1 expression was associated with early-stage tumors and with significantly increased survival in this subgroup. Higher NOTCH2 expression was associated with early-stage and intestinal-type tumors and with better survival in the subgroup of intestinal-type tumors. In pretherapeutic biopsies, higher NOTCH1 and NOTCH2 expression was more frequent in non-responding patients, but these differences were statistically not significant. CONCLUSION: Our findings suggested that, in particular, NOTCH1 expression indicated good prognosis in GC. The close relationship of high NOTCH1 and NOTCH2 expression with early tumor stages may indicate a tumor-suppressive role of NOTCH signaling in GC. The role of NOTCH1 and NOTCH2 in neoadjuvantly treated GC is limited. AU - Bauer, L.* AU - Takacs, A.* AU - Slotta-Huspenina, J.* AU - Langer, R.* AU - Becker, K.* AU - Novotny, A.* AU - Ott, K.* AU - Walch, A.K. AU - Hapfelmeier, A.* AU - Keller, G.* C1 - 44807 C2 - 36701 TI - Clinical significance of NOTCH1 and NOTCH2 expression in gastric carcinomas: An immunohistochemical study. JO - Front. Oncol. VL - 5 PY - 2015 SN - 2234-943X ER - TY - JOUR AB - Epstein-Barr virus (EBV)-associated gastric carcinomas (GC) represent a distinct and well-recognized subtype of gastric cancer with a prevalence of around 10% of all GC. In contrast, EBV has not been reported to play a major role in esophageal adenocarcinomas (EAC) and adenocarcinomas of the gastro-esophageal junction (GEJ). We report our experiences on EBV in collections of gastro-esophageal adenocarcinomas from two surgical centers and discuss the current state of research in this field. Tumor samples from 465 primary resected gastro-esophageal adenocarcinomas (118 EAC, 73 GEJ, and 274 GC) were investigated. Presence of EBV was determined by EBV-encoded small RNAs (EBER) in situ hybridization. Results were correlated with pathologic parameters (UICC pTNM category, Her2 status, tumor grading) and survival. EBER positivity was observed in 14 cases. None of the EAC were positive for EBER. In contrast, we observed EBER positivity in 2/73 adenocarcinomas of the GEJ (2.7%) and 12/274 GC (4.4%). These were of intestinal type (seven cases) or unclassifiable (six cases), while only one case was of diffuse type according to the Lauren classification. No association between EBV and pT, pN, or tumor grading was found, neither was there a correlation with clinical outcome. None of the EBER positive cases were Her2 positive. In conclusion, EBV does not seem to play a role in the carcinogenesis of EAC. Moreover, adenocarcinomas of the GEJ show lower rates of EBV positivity compared to GC. Our data only partially correlate with previous reports from the literature. This highlights the need for further research on this distinct entity. Recent reports, however, have identified specific epigenetic and genetic alterations in EBV-associated GC, which might lead to a distinct treatment approach for this specific subtype of GC in the future. AU - Genitsch, V.* AU - Novotny, A.* AU - Seiler, C.A.* AU - Kröll, D.* AU - Walch, A.K. AU - Langer, R.* C1 - 44340 C2 - 36826 TI - Epstein-Barr virus in gastro-esophageal adenocarcinomas - single center experiences in the context of current literature. JO - Front. Oncol. VL - 5 PY - 2015 SN - 2234-943X ER - TY - JOUR AB - While neutron therapy was a highly topical subject in the 70s and 80s, today there are only a few remaining facilities offering fast neutron therapy (FNT). Nevertheless, up to today more than 30,000 patients were treated with neutron therapy. For some indications like salivary gland tumors and malignant melanoma, there is clinical evidence that the addition of FNT leads to superior local control compared to photon treatment alone. FNT was available in Munich from 1985 until 2000 at the Reactor Neutron Therapy (RENT) facility. Patient treatment continued at the new research reactor FRM II in 2007 under improved treatment conditions, and today it can still be offered to selected patients as an individual treatment option. As there is a growing interest in high-linear energy transfer (LET) therapy with new hadron therapy centers emerging around the globe, the clinical data generated by neutron therapy might help to develop biologically driven treatment planning algorithms. Also FNT might experience its resurgence as a combinational partner of modern immunotherapies. AU - Specht, H.M.* AU - Neff, T.* AU - Reuschel, W.* AU - Wagner, F.M.* AU - Kampfer, S.* AU - Wilkens, J.J. AU - Petry, W.* AU - Combs, S.E. C1 - 47507 C2 - 40609 TI - Paving the road for modern particle therapy - what can we learn from the experience gained with fast neutron therapy in Munich? JO - Front. Oncol. VL - 5 PY - 2015 SN - 2234-943X ER - TY - JOUR AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibrotic reaction or desmoplasia and complex involvement of the surrounding tumor microenvironment. Pancreatic stellate cells are a key mediator of the pancreatic matrix and they promote progression and invasion of pancreatic cancer by increasing cell proliferation and offering protection against therapeutic interventions. Our study utilizes human tumor-derived pancreatic stellate cells (HTPSCs) isolated from fine needle aspirates of pancreatic cancer tissue from patients with locally advanced, unresectable pancreatic adenocarcinoma before and after treatment with full-dose gemcitabine plus concurrent hypo-fractionated stereotactic radiosurgery. We show that HTPSCs survive in vivo chemotherapy and radiotherapy treatment and display a more activated phenotype post-therapy. These data support the idea that stellate cells play an essential role in supporting and promoting pancreatic cancer and further research is needed to develop novel treatments targeting the pancreatic tumor microenvironment. AU - Cabrera, M.C.* AU - Tilahun, E.* AU - Nakles, R.* AU - Diaz-Cruz, E.S.* AU - Charabaty, A.* AU - Suy, S.* AU - Jackson, P.* AU - Ley, L.* AU - Slack, R.* AU - Jha, R.* AU - Collins, S.P.* AU - Haddad, N.* AU - Kallakury, B.V.* AU - Schroeder, T. AU - Pishvaian, M.J.* AU - Furth, P.A.* C1 - 31368 C2 - 34491 TI - Human pancreatic cancer-associated stellate cells remain activated after in vivo chemoradiation. JO - Front. Oncol. VL - 4 PY - 2014 SN - 2234-943X ER - TY - JOUR AB - Innate and adaptive immunity plays important roles in the development and progression of cancer and it is becoming apparent that tumors can influence the induction of potentially protective responses in a number of ways. The prevalence of immunoregulatory T cell populations in the circulation and tumors of patients with cancer is increased and the presence of these cells appears to present a major barrier to the induction of tumor immunity. One aspect of tumor-mediated immunoregulation which has received comparatively little attention is that which is directed toward natural killer (NK) cells, although evidence that the phenotype and function of NK cell populations are modified in patients with cancer is accumulating. Although the precise mechanisms underlying these localized and systemic immunoregulatory effects remain unclear, tumor-derived factors appear, in part at least, to be involved. The effects could be manifested by an altered function and/or via an influence on the migratory properties of individual cell subsets. A better insight into endogenous immunoregulatory mechanisms and the capacity of tumors to modify the phenotype and function of innate and adaptive immune cells might assist the development of new immunotherapeutic approaches and improve the management of patients with cancer. This article reviews current knowledge relating to the influence of tumors on protective anti-tumor immunity and considers the potential influence that radiation-induced effects might have on the prevalence, phenotype, and function of innate and adaptive immune cells in patients with cancer. AU - Foulds, G.A.* AU - Radons, J.* AU - Kreuzer, M.* AU - Multhoff, G. AU - Pockley, A.G.* C1 - 22768 C2 - 30931 TI - Influence of tumors on protective anti-tumor immunity and the effects of irradiation. JO - Front. Oncol. VL - 3 PB - Frontiers Media PY - 2013 SN - 2234-943X ER - TY - JOUR AB - Chronic inflammation has emerged as one of the hallmarks of cancer. Inflammation also plays a pivotal role in modulating radiation responsiveness of tumors. As discussed in this review, ionizing radiation (IR) leads to activation of several transcription factors modulating the expression of numerous mediators in tumor cells and cells of the microenvironment promoting cancer development. Novel therapeutic approaches thus aim to interfere with the activity or expression of these factors, either in single-agent or combinatorial treatment or as supplements of the existing therapeutic concepts. Among them, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. A great variety of classical or novel drugs including nutraceuticals such as plant phytochemicals have the capacity to interfere with the inflammatory network in cancer and are considered as putative radiosensitizers. Thus, targeting the inflammatory signaling pathways induced by IR offers the opportunity to improve the clinical outcome of radiation therapy by enhancing radiosensitivity and decreasing putative metabolic effects. Since inflammation and sex steroids also impact tumorigenesis, a therapeutic approach targeting glucocorticoid receptors and radiation-induced production of tumorigenic factors might be effective in sensitizing certain tumors to IR. AU - Multhoff, G. AU - Radons, J.* C1 - 8214 C2 - 30042 TI - Radiation, inflammation, and immune responses in cancer. JO - Front. Oncol. VL - 2 PB - Frontiers Research Foundation PY - 2012 SN - 2234-943X ER - TY - JOUR AB - The immature, chaotic microvasculature of most solid tumors can present a significant impediment to blood-borne delivery, uneven distribution, and compromised penetration of macromolecular anticancer drugs and diagnostic agents from tumor microvessels across the interstitial space to cancer cells. To reach viable tumor cells in relevant concentrations, macromolecular agents are confronted with several barriers to vascular, transvascular, and interstitial transport. Amongst those (1) heterogeneous and poor blood supply, (2) distinctly reduced or even abolished hydrostatic and oncotic pressure gradients across the microvessel wall abrogating the convective transport from the vessel lumen into the interstitial space (impairment of transvascular transport), and (3) impediment of convective transport within the interstitial compartment due to elevated interstitial fluid pressure (IFP) (resulting from hyperpermeable blood vessels coupled with non-functional lymphatics) and a dense structure of the interstitial matrix are the major mechanisms hindering drug delivery. Upon irradiation, changes in these barrier functions are inconclusive so far. Alterations in vascular transport properties following fractionated radiation up to 40 Gy are quite inconsistent in terms of direction, extent, and time course. Total doses above 45 Gy can damage tumor microvessels, additionally impeding vascular delivery. Vascular permeability for macromolecules might be enhanced up to a total dose of 45 Gy. However, this effect is counteracted/abolished by the elevated IFP in solid tumors. When assessing IFP during fractionated radiotherapy in patient tumors, inconsistent alterations have been observed, both in direction and extent. From these data it is concluded that modulations in vascular, transvascular, and interstitial transport by irradiation of solid tumors are rather unclear so far. Translation of experimental data into the clinical setting thus needs to be undertaken with especial care. AU - Multhoff, G. AU - Vaupel, P.* C1 - 11587 C2 - 30702 TI - Radiation-induced changes in microcirculation and interstitial fluid pressure affecting the delivery of macromolecules and nanotherapeutics to tumors. JO - Front. Oncol. VL - 2 PB - Frontiers Research Foundation PY - 2012 SN - 2234-943X ER - TY - JOUR AB - Ionizing irradiation is an important clinical approach to treat solid tumors. Modern radiation technologies aim to selectively kill tumor cells and protect the surrounding normal tissue. The standard paradigm for radiation effects in cellular systems involves damage of the DNA including DNA double-strand breaks, which are considered as most effective in destroying tumor cells. Due to their enhanced physical and radiobiological properties, high-linear energy transfer radiation qualities are of special interest in tumor therapy. Future radiation therapy strategies aim to utilize carbon ions to effectively treat highly aggressive tumors. More recently, evidence is emerging for non-DNA targeted effects of radiation, including mutations, chromosomal aberrations, and changes in gene expression, which can occur in cells that were not directly exposed to radiation. Radiation oncologists are only gradually beginning to appreciate the clinical relevance of radiation-induced bystander effects, genomic instability, and abscopal effects. Since these effects are sensed by the immune system, a combination of immunotherapy and irradiation presents a new therapeutic opportunity in the future. AU - Schmid, T.E. AU - Multhoff, G. C1 - 8347 C2 - 30067 TI - Non-targeted effects of photon and particle irradiation and the interaction with the immune system. JO - Front. Oncol. VL - 2 PB - Frontiers Media SA PY - 2012 SN - 2234-943X ER -