TY  - JOUR
AB  - Purpose: The value of stereotactic body radiation therapy (SBRT) in patients with oligometastatic head-and-neck squamous cell carcinoma (HNSCC) remains unclear, as existing evidence is primarily derived from retrospective single-center analyses with small patient cohorts. This study aimed to evaluate the outcomes of pulmonary SBRT in patients with oligometastatic HNSCC and to identify factors associated with survival. Methods and Materials: This trinational multicenter cohort study, including 16 centers from Germany, Austria, and Switzerland, retrospectively analyzed patients with oligometastatic HNSCC undergoing SBRT for pulmonary metastases between 2010 and 2023. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival and incidence of local failures. Results: A total of 178 patients with 284 irradiated lung metastases were analyzed. The most common primary HNSCC subsites were oropharyngeal (n = 71), laryngeal (n = 37), and hypopharyngeal (n = 31). Lung metastases were treated with a median biologically effective dose (BEDα/β =10 Gy) of 105 Gy (IQR, 84-113) at the planning target volume periphery. After a median follow-up of 40 months (95% CI, 34-46), the median OS and progression-free survival were 33 months (95% CI, 26-40) and 9 months (95% CI, 7-11), respectively. The 1-year cumulative incidence of local failures was 5.5% (95% CI, 3.2-8.8). One patient (0.6%) developed acute grade 3 dysphagia, and among 146 patients assessed for chronic toxicities, 2 (1.4%) experienced grade 3 events, with no grade 4-5 toxicities. On multivariable analysis, older (>65 years) patients (hazard ratio [HR], 1.59; 95% CI, 1.02-2.49; P = .040) and females (HR, 1.76; 95% CI, 1.04-2.99; P = .035) exhibited worse OS, whereas longer time between HNSCC diagnosis and first SBRT was associated with longer OS (HR, 0.99; 95% CI, 0.99-1.00; P = .045). Conclusion: SBRT for pulmonary metastases achieves excellent local control with minimal toxicity in patients with oligometastatic HNSCC. Prospective trials are needed to determine the optimal timing for integrating SBRT with systemic treatment.
AU  - Nägler, F.*
AU  - Vorbach, S.*
AU  - Mohamed, A.A.*
AU  - Thaqi, S.*
AU  - Adebahr, S.*
AU  - Ehret, F.*
AU  - Kraft, J.*
AU  - Fabian, A.*
AU  - Weissmann, T.*
AU  - Kaufmann, J.*
AU  - Drabke, S.*
AU  - Looman, E.L.*
AU  - Waltenberger, M.*
AU  - Kraus, K.M.
AU  - Grohmann, M.*
AU  - Dehl, K.*
AU  - Rogers, S.*
AU  - Gawish, A.*
AU  - Becker, J.N.*
AU  - Klement, R.J.*
AU  - Partl, R.*
AU  - Trommer, M.*
AU  - Grosu, A.L.*
AU  - Rimner, A.*
AU  - Gkika, E.*
AU  - Riesterer, O.*
AU  - Putz, F.*
AU  - Ganswindt, U.*
AU  - Moustakis, C.*
AU  - Nicolay, N.H.*
AU  - Brunner, T.B.*
AU  - Blanck, O.*
AU  - Wittig-Sauerwein, A.*
AU  - Balermpas, P.*
AU  - Rühle, A.*
C1  - 73377
C2  - 57030
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 140-149
TI  - Pulmonary stereotactic body radiation therapy of oligometastatic head-and-neck squamous cell carcinoma: A multicenter retrospective study.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 122
IS  - 1
PB  - Elsevier Science Inc
PY  - 2025
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - BACKGROUND: Minibeam and microbeam radiation therapy promise improved treatment outcomes through reduced normal tissue toxicity at better tumor control rates. The lack of suitable compact radiation sources limits the clinical application of minibeams to superficial tumors and renders it impossible for microbeams. We developed and constructed the first prototype of a compact line-focus X-ray tube (LFXT) with technology potentially suitable for clinical translation of minibeams and microbeams. METHODS: We give an overview of the commissioning process preceding the first operation, present optical and radiological focal spot characterization methods, and dosimetric measurements. Additionally, we report on first preclinical in vitro cell and in vivo mouse brain irradiations conducted with the LFXT prototype. RESULTS: The LFXT was high-voltage conditioned up to 300 kV. The focal spot characterization resulted in a strongly eccentric electron distribution with a width of 72.3 μm. Dosimetry showed sharp microbeam dose profiles with steep lateral penumbras and a peak-to-valley dose ratio above 10 throughout a 70 mm thick PMMA phantom. An open-field dose rate of 4.3 Gy/s was measured at an acceleration voltage of 150 kV and a beam current of 17.4 mA at 150 mm distance from the focal spot. In vitro and in vivo experiments demonstrated the feasibility of the LFXT for minibeam and microbeam applications with field sizes of 1.5 - 2 cm. The mice displayed no observable side effects throughout the follow-up period after whole-brain 260 μm-minibeam irradiation. CONCLUSION: We successfully constructed and commissioned the first proof-of-concept LFXT prototype. Dosimetric characterizations of the achieved microbeam field showed the superiority of the LFXT compared to conventional X-ray tubes in terms of beam quality. In future developments, the remaining limitations of the prototype will be addressed, paving the way for improved minibeam and first ever microbeam radiation therapy in a clinical setting.
AU  - Petrich, C.
AU  - Winter, J.
AU  - Dimroth, A.*
AU  - Stolz, J.
AU  - Beiser, T.*
AU  - Dehn, M.*
AU  - Frignani, J.*
AU  - Combs, S.E.
AU  - Schilling, F.*
AU  - Natour, G.*
AU  - Aulenbacher, K.*
AU  - Raulefs, S.
AU  - Schmid, T.E.
AU  - Wilkens, J.J.*
AU  - Bartzsch, S.
C1  - 75853
C2  - 58145
TI  - Commissioning, characterization and first high dose rate irradiations at a compact X-ray tube for microbeam and minibeam radiation therapy.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
PY  - 2025
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - PURPOSE: Combining immune checkpoint inhibitors (ICIs) with radiation therapy (RT) has led to significant advancements in cancer treatment. However, evidence from clinical and experimental studies suggests that this combination may increase hematopoietic and lymphatic toxicity. This study aims to investigate the effects of the concurrent application of ICIs (anti-PD-1 and anti-CTLA-4) on radiation-induced hematopoietic and lymphatic injuries under standardized and controlled experimental conditions. MATERIALS AND METHODS: We utilized various experimental models in C57BL/6 and BALB/c mice to evaluate the impact of ICIs combined with RT on the hematopoietic system. These models involved different RT doses, regimens, and target sites in both healthy and tumor-bearing mice. RESULTS: Our findings showed that the concurrent use of ICIs did not meaningfully affect post-RT pancytopenia kinetics or the regeneration of specific blood cell lineages over time. Consistently, combining RT with ICIs did not significantly enhance DNA damage in immune cells within the bloodstream. This outcome was comparable across different RT doses, regimens, and target sites and was reproducible in both tumor-bearing and non-tumor-bearing mice. Additionally, there were no significant increases in late side effects, including reductions in bone marrow cell counts or megakaryocyte numbers, after combined radioimmunotherapy. CONCLUSION: These findings suggest that combining ICIs with RT does not exacerbate hematological toxicity. This information is valuable for interpreting adverse events in clinical trials involving radioimmunotherapy and for predicting potential hematological side effects in cancer patients receiving these treatments.
AU  - Timnik, V.R.*
AU  - Zoeschg, A.*
AU  - Diederich, S.*
AU  - Nefzger, S.M.*
AU  - Huang, Z.*
AU  - Schmid, N.A.*
AU  - Giller, M.*
AU  - Steiger, K.*
AU  - Combs, S.E.
AU  - Kroemer, G.*
AU  - Schmid, T.E.
AU  - Fischer, J.C.*
C1  - 74154
C2  - 57346
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 523-535
TI  - Experimental investigation of hematological toxicity after radiation therapy combined with immune checkpoint inhibitors.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 123
IS  - 2
PB  - Elsevier Science Inc
PY  - 2025
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - BACKGROUND: Scintillation dosimetry has promising qualities for ultra-high dose rate (UHDR) radiotherapy (RT), but no system has shown compatibility with mean dose rates (DR‾) above 100 Gy/s and doses per pulse (Dp) exceeding 1.5 Gy typical of UHDR (FLASH)-RT. The aim of this study was to characterize a novel scintillation dosimetry system with the potential of accommodating UHDRs. METHODS AND MATERIALS: We undertook a thorough dosimetric characterization of the system on an UHDR electron beamline. The system's response as a function of dose, DR‾, Dp, and the pulse dose rate (DRp) was investigated, as was the system's dose sensitivity (signal per unit dose) as a function of dose history. The capabilities of the system for time-resolved dosimetric readout were also evaluated. RESULTS: Within a tolerance of ±3%, the system exhibited dose linearity and was independent of DR‾ and Dp within the tested ranges of 1.8-1341 Gy/s and 0.005-7.68 Gy, respectively. A 6% reduction in the signal per unit dose was observed as DRp was increased from 8.9e4 to 1.8e6 Gy/s. The dose delivered per integration window of the continuously sampling photodetector had to remain between 0.028 and 11.56 Gy to preserve a stable signal response per unit dose. The system accurately measured Dp of individual pulses delivered at up to 120 Hz. The day-to-day variation of the signal per unit dose in a reference setup varied by up to ±13% but remained consistent (<±2%) within each treatment day and showed no signal loss as a function of dose history. CONCLUSIONS: With daily calibrations and DRp-specific correction factors, the system reliably provides real-time, millisecond-resolved dosimetric measurements of pulsed conventional and UHDR beams from typical electron linacs, marking an important advancement in UHDR dosimetry and offering diverse applications to FLASH-RT and related fields.
AU  - Baikalov, A.
AU  - Tho, D.*
AU  - Liu, K.*
AU  - Bartzsch, S.
AU  - Beddar, S.*
AU  - Schüler, E.*
C1  - 72588
C2  - 56636
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 1372-1383
TI  - Characterization of a time-resolved, real-time scintillation dosimetry system for ultra-high dose rate radiation therapy applications.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 121
IS  - 5
PB  - Elsevier Science Inc
PY  - 2024
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - IMPORTANCE: The identification of internal mammary lymph node metastases and the assessment of associated risk factors are crucial for adjuvant regional lymph node irradiation in breast cancer patients. The current study aims to investigate if tumor contact with internal mammary perforator vessels is associated with gross internal mammary lymph node involvement. METHODS: We included 297 patients with primary breast cancer and gross internal mammary (IMN+) and/or axillary metastases (AXN+) as well as 230 patients without lymph node metastasis. Based on pre-treatment dynamic contrast-enhanced magnetic resonance imaging (DE-MRI), we assessed contact of the tumor to the internal mammary perforating vessels (IMPV). RESULTS: 59 patients had ipsilateral IMN+ (iIMN+), 10 patients contralateral IMN+ (cIMN+) and 228 patients had ipsilateral axillary metastases without IMN. 230 patients had node negative breast cancer. In patients with ipsilateral IMN+, 100% of tumors had contact with ipsilateral IMPV with 94.9% (n=56) classified as major contact. In iIMN- patients on the other hand, major IMPV contact was observed in only 25.3% (n=116) and 36.2% (n=166) had no IMPV contact at all. Receiver operating characteristic (ROC) analysis revealed that "major IMPV contact" was more accurate in predicting ipsilateral IMN+ (AUC 0.85) compared to a multivariate model combining grade of differentiation, tumor site, size and molecular subtype (AUC 0.65). Strikingly, among patients with contralateral IMN+ (cIMN+), 100% of tumors had contact to a crossing contralateral IMPV, whereas in contralateral IMN- (cIMN-) patients, IMPVs to the contralateral side were observed in only 53.4% (iIMN+) and 24.8% (iIMN-), respectively. CONCLUSION: Tumor contact with the IMPV is highly associated with risk of gross IMN involvement. Further studies are warranted to investigate whether this identified risk factor is also associated with microscopic IMN involvement and whether it can assist in the selection of breast cancer patients for IMNI.
AU  - Behzadi, S.T.*
AU  - Moser, R.*
AU  - Kiesl, S.*
AU  - Nano, J.*
AU  - Peeken, J.C.*
AU  - Fischer, J.C.*
AU  - Fallenberg, E.M.*
AU  - Huber, T.*
AU  - Haller, B.*
AU  - Klein, E.*
AU  - Kiechle, M.*
AU  - Combs, S.E.
AU  - Borm, K.J.*
C1  - 70168
C2  - 55441
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 1455-1463
TI  - Tumor contact with internal mammary perforator vessels as risk factor for gross internal mammary lymph node involvement in breast cancer patients.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 119
IS  - 5
PB  - Elsevier Science Inc
PY  - 2024
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - BACKGROUND: Childhood cancer survivors are at high risk of long-term iatrogenic events, in particular those treated with radiotherapy. The prediction of risk of such events is mainly based on the knowledge of the radiation dose received to healthy organs and tissues during treatment of childhood cancer diagnosed decades ago. PURPOSE: We aimed to set up a standardised organ dose table in order to help former patients and clinician in charge of long term follow-up clinics. MATERIAL AND METHODS: We performed whole body dosimetric reconstruction for 2646 patients from 12 European Countries treated between 1941 and 2006 (median: 1976). Most planning were 2D or 3D, 46% of patients were treated using Cobalt 60 and 41% using linear accelerator, the median prescribed dose being 27.2 Gy (IQ1-IQ3: 17.6-40.0 Gy), A patient specific voxel-based anthropomorphic phantom with more than 200 anatomical structures or sub-structures delineated as a surrogate of each subject's anatomy was used. The radiation therapy was simulated with a treatment planning system (TPS) based on available treatment information. The radiation dose received by any organ of the body was estimated by extending the TPS dose calculation to the whole-body, by type and localisation of childhood cancer. RESULTS: The integral dose and normal-tissue doses to most of the 23 considered organs increased between the 1950's and the 1970's and decreased or plateaued thereafter. Whatever the organ considered, the type of childhood cancer explained most of the variability in organ dose. The country of treatment explained only a small part of the variability. CONCLUSION: The detailed dose estimates provide very useful information for former patients or clinicians who have only limited knowledge about radiation therapy protocols or techniques, but who know the type and site of childhood cancer, gender, age and year of treatment. This will allow better prediction of the long-term risk of iatrogenic events and better referral to long-term follow-up clinics.
AU  - Diallo, I.*
AU  - Allodji, R.S.*
AU  - Veres, C.*
AU  - Bolle, S.*
AU  - Llanas, D.*
AU  - Ezzouhri, S.*
AU  - Zrafi, W.*
AU  - Debiche, G.*
AU  - Souchard, V.*
AU  - Fauchery, R.*
AU  - Haddy, N.*
AU  - Journy, N.*
AU  - Demoor-Goldschmidt, C.*
AU  - Winter, D.L.*
AU  - Hjorth, L.*
AU  - Wiebe, T.*
AU  - Haupt, R.*
AU  - Robert, C.*
AU  - Kremer, L.*
AU  - Bardi, E.*
AU  - Sacerdote, C.*
AU  - Terenziani, M.*
AU  - Kuehni, C.E.*
AU  - Schindera, C.*
AU  - Skinner, R.*
AU  - Winther, J.F.*
AU  - Lähteenmäki, P.*
AU  - Byrn, J.*
AU  - Jakab, Z.*
AU  - Cardis, E.*
AU  - Pasqual, E.*
AU  - Tapio, S.
AU  - Baatout, S.*
AU  - Atkinson, M.*
AU  - Benotmane, M.A.*
AU  - Sugden, E.*
AU  - Zaletel, L.Z.*
AU  - Ronckers, C.*
AU  - Reulen, R.C.*
AU  - Hawkins, M.M.*
AU  - de Vathaire, F.*
C1  - 70425
C2  - 55615
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 439-453
TI  - Radiation doses received by major organs at risk in children and young adolescents treated for cancer with external beam radiation therapy: A large-scale study from 12 European countries.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 120
IS  - 2
PB  - Elsevier Science Inc
PY  - 2024
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Buchner, J.A.*
AU  - Kofler, F.
AU  - Mayinger, M.C.*
AU  - Brunner, T.B.*
AU  - Wittig, A.*
AU  - Menze, B.*
AU  - Zimmer, C.*
AU  - Meyer, B.*
AU  - Guckenberger, M.*
AU  - Andratschke, N.*
AU  - ElShafie, R.*
AU  - Rogers, S.*
AU  - Schulze, K.*
AU  - Blanck, O.*
AU  - Zamboglou, C.*
AU  - Grosu, A.*
AU  - Combs, S.E.
AU  - Bernhardt, D.*
AU  - Wiestler, B.*
AU  - Peeken, J.C.
C1  - 69118
C2  - 55103
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - E704-E705
TI  - What MRI Sequences are Necessary for Automated Neural Network-Based Metastasis Segmentation An Ablation Study.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 117
IS  - 2
PB  - Elsevier Science Inc
PY  - 2023
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - PURPOSE: Preoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT) which combines simultaneous radio-chemotherapy with additional courses of chemotherapy (CTx) has emerged as an effective approach. TNT achieves a pathological complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-PD-1 immunotherapy (IT) can induce clinical complete responses in patients with specific genetic alterations. Overall, there is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to IT remain poorly understood. MATERIALS AND METHODS: We developed a novel orthotopic mouse model of rectal cancer which is based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT, and validated rectal tumor growth and response rates to therapy using small animal magnetic resonance imaging and endoscopic follow-up. RESULTS: Rectal tumor formation was successfully induced in all mice following two organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, longterm survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiological tumor staging and histopathological examination. CONCLUSIONS: Our novel mouse model combines orthotopic tumor growth via non-invasive and precise rectal organoid injection and small animal RT. This model holds significant promise for investigating the impact of tumor cell-intrinsic aspects, genetic alterations of the host, or exogenous factors (e.g., nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving CTx, IT or novel targeted therapies.
AU  - Felchle, H.*
AU  - Brunner, V.*
AU  - Groll, T.*
AU  - Walther, C.N.*
AU  - Nefzger, S.M.*
AU  - Zaurito, A.E.*
AU  - Silva, M.G.*
AU  - Gissibl, J.*
AU  - Topping, G.J.*
AU  - Rotgerink, L.L.*
AU  - Saur, D.*
AU  - Steiger, K.*
AU  - Combs, S.E.
AU  - Tschurtschenthaler, M.*
AU  - Fischer, J.C.*
C1  - 68702
C2  - 54911
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 1094-1104
TI  - Novel tumor organoid-based mouse model to study image-guided radiation therapy of rectal cancer after non-invasive and precise endoscopic implantation.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 118
IS  - 4
PB  - Elsevier Science Inc
PY  - 2023
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - PURPOSE: This study provides the first experimental application of multiscale three-dimensional (3D) X-ray Phase Contrast Imaging Computed Tomography (XPCI-CT) virtual histology for the inspection and quantitative assessment of the late stage effects of radio-induced lesions on lungs in a small animal model. METHODS AND MATERIALS: Healthy male Fischer rats were irradiated with X-ray standard broad beams and Microbeam Radiation Therapy (MRT), a high dose rate (14 kGy/s), FLASH spatially-fractionated X-ray therapy to avoid the beamlets smearing due to cardiosynchronous movements of the organs during the irradiation. After organ dissection, ex-vivo XPCI-CT was applied to all the samples and the results were quantitatively analysed and correlated to histologic data. RESULTS: XPCI-CT enables the 3D visualization of lung tissues with unprecedented contrast and sensitivity allowing alveoli, vessels and bronchi hierarchical visualization. XPCI-CT discriminates in 3D radio-induced lesions such as fibrotic scars, Ca/Fe deposits and, in addition, allows a full-organ accurate quantification of the fibrotic tissue within the irradiated organs. The radiation-induced fibrotic tissue content is less than 10% of the analyzed volume for all the MRT treated organs while it reaches the 34% in the case of irradiations with 50 Gy using a broad beam. CONCLUSIONS: XPCI-CT is an effective imaging technique able to provide detailed 3D information for the assessment of lung pathology and treatment efficacy in a small animal model.
AU  - Romano, M.*
AU  - Bravin, D.A.*
AU  - Wright, D.M.D.*
AU  - Jacques, L.*
AU  - Miettinen, D.A.*
AU  - Hlushchuk, D.R.*
AU  - Dinkel, J.*
AU  - Bartzsch, S.
AU  - Laissue, J.A.*
AU  - Djonov, V.*
AU  - Coan, D.P.*
C1  - 63454
C2  - 51539
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 818-830
TI  - X-ray Phase Contrast 3D virtual histology: Evaluation of lung alterations after micro-beam irradiation.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 112
IS  - 3
PB  - Elsevier Science Inc
PY  - 2022
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - BACKGROUND AND PURPOSE: Acute coronary events (ACEs) are considered the most important side effect of radiotherapy (RT) for breast cancer but underlying mechanisms still have to be identified. Process oriented models mathematically describe the development of disease and provide a link between mechanisms and subsequent risk. Here, this link is exploited to learn about the underlying mechanisms from the observed age-time patterns of ACE risk. MATERIALS AND METHODS: A process oriented model of atherosclerosis and subsequent ACEs was applied to a contemporary breast cancer cohort of 810 patients with measurements of coronary artery calcification. Patients with prior ischemic heart disease were excluded. The process oriented model describes disease development as a series of different stages. Different variants of the model were fitted to the data. In each variant, one stage was assumed to be accelerated in relation to mean heart dose. RESULTS: During a mean follow up of 9.1 years, 25 ACEs occurred. The model reproduced the prevalence and associated risk of coronary calcifications. Mean heart dose significantly improved the fit only when implemented as affecting a late stage of atherosclerosis on already existing, complicated lesions (achieving p = 0.007). This can be understood by atherosclerosis being a slowly progressing disease. Therefore, an increase of ACEs few years after RT requires advanced atherosclerosis at the time of RT. CONCLUSION: Risk of ACE increases within few years in patients with advanced atherosclerosis at RT. Therefore, patients should be assessed for cardiovascular risk, and also elderly patients need to be considered for heart sparing techniques.
AU  - Simonetto, C.
AU  - Kaiser, J.C.
AU  - van den Bogaard, V.A.B.*
AU  - Langendijk, J.A.*
AU  - Crijns, A.P.G.*
C1  - 65666
C2  - 52877
SP  - 409-415
TI  - Breast cancer radiotherapy and the risk of acute coronary events - insights from a process oriented model.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 114
IS  - 3
PY  - 2022
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - INTRODUCTION: Prostate specific membrane antigen positron-emission tomography (PSMA-PET) is increasingly used to guide salvage radiotherapy (sRT) in prostate cancer (PCa) patients with biochemical recurrence/persistence after prostatectomy. This work examines (i) metastasis-free survival (MFS) following PSMA-PET guided sRT and (ii) the metastatic patterns on PSMA-PET images after sRT. METHODS: This retrospective, multicenter (9 centers, 5 countries) study included patients referred for PSMA-PET due to recurrent/persistent disease after prostatectomy. Patients with distant metastases (DM) on PSMA-PET prior to sRT were excluded. Cox-regression was performed to assess the impact of clinical parameters on MFS. The distribution of PSMA-PET detected DM following sRT and their respective risk factors were analysed. RESULTS: All (n=815) patients received intensity-modulated RT to the prostatic fossa. In case of PET-positive pelvic lymph nodes (PLN-PET, n=275, 34%), pelvic lymphatics had been irradiated. Androgen deprivation therapy had been given in 251 (31%) patients. The median follow-up after sRT was 36 months. The 2-/4-year MFS following sRT were 93%/81%. In multivariate analysis the presence of PLN-PET was a strong predictor for MFS (HR=2.39, p<0.001). Following sRT, DM were detected by PSMA-PET in 128/198 (65%) patients and two metastatic patterns were observed: 43% had DM in sub diaphragmatic paraaortic LNs (abdominal-lymphatic) whereas 45% in bones, 9% in supra diaphragmatic LNs and 6% in visceral organs (distant). Two distinct signatures with risk factors for each pattern were identified. CONCLUSION: MFS in our study is lower compared to previous studies, obviously due to the higher detection rate of DM in PSMA-PET after sRT. Thus, it remains unclear whether MFS is a surrogate endpoint for overall survival in PSMA PET-staged patients in the post sRT setting. PLN-PET may be proposed as a new surrogate parameter predictive of MFS. Analysis of recurrence patterns in PET after sRT revealed risk factor signatures for two metastatic patterns (abdominal-lymphatic and distant), which may allow individualized sRT concepts in the future.
AU  - Zamboglou, C.*
AU  - Strouthos, I.*
AU  - Sahlmann, J.*
AU  - Farolfi, A.*
AU  - Serani, F.*
AU  - Medici, F.*
AU  - Cavallini, L.*
AU  - Morganti, A.G.*
AU  - Trapp, C.*
AU  - Koerber, S.A.*
AU  - Peeken, J.C.
AU  - Vogel, M.M.
AU  - Schiller, K.
AU  - Combs, S.E.
AU  - Eiber, M.*
AU  - Vrachimis, A.*
AU  - Ferentinos, K.*
AU  - Spohn, S.K.B.*
AU  - Kirste, S.*
AU  - Gratzke, C.*
AU  - Ruf, J.*
AU  - Grosu, A.L.*
AU  - Ceci, F.*
AU  - Fendler, W.P.*
AU  - Miksch, J.*
AU  - Kroeze, S.*
AU  - Guckenberger, M.*
AU  - Lanzafame, H.*
AU  - Fanti, S.*
AU  - Hruby, G.*
AU  - Wiegel, T.*
AU  - Emmett, L.*
AU  - Schmidt-Hegemann, N.S.*
AU  - Henkenberens, C.*
C1  - 65467
C2  - 52696
SP  - 1015-1024
TI  - Metastasis-free survival and patterns of distant metastatic disease after PSMA-PET-guided salvage radiotherapy in recurrent or persistent prostate cancer after prostatectomy.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 113
IS  - 5
PY  - 2022
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Purpose: Proton minibeam radiation therapy, a spatial fractionation concept, widens the therapeutic window. By reducing normal tissue toxicities, it allows a temporally fractionated regime with high daily doses. However, an array shift between daily fractions can affect the tissue-sparing effect by decreasing the total peak-to-valley dose ratio. Therefore, combining temporal fractions with spatial fractionation raises questions about the impact of daily applied dose modulations, reirradiation accuracies, and total dose modulations. Methods and Materials: Healthy mouse ear pinnae were irradiated with 4 daily fractions of 30 Gy mean dose, applying proton pencil minibeams (pMB) of Gaussian σ = 222 μm in 3 different schemes: a 16 pMB array with a center-to-center distance of 1.8 mm irradiated the same position in all sessions (FS1) or was shifted by 0.9 mm to never hit the previously irradiated tissue in each session (FS2), or a 64 pMB array with a center-to-center distance of 0.9 mm irradiated the same position in all sessions (FS3), resulting in the same total dose distribution as FS2. Reirradiation positioning and its accuracy were obtained from image guidance using the unique vessel structure of ears. Acute toxicities (swelling, erythema, and desquamation) were evaluated for 153 days after the first fraction. Late toxicities (fibrous tissue, inflammation) were analyzed on day 153. Results: Reirradiation of highly dose-modulated arrays at a positioning accuracy of 110 ± 52 μm induced the least severe acute and late toxicities. A shift of the same array in FS2 led to significantly inducted acute toxicities, a higher otitis score, and a slight increase in fibrous tissue. FS3 led to the strongest increase in acute and late toxicities. Conclusions: The highest normal-tissue sparing is achieved after accurate reirradiation of a highly dose modulated pMB array, although high positioning accuracies are challenging in a clinical environment. Nevertheless, the same integral dose applied in highly dose-modulated fractions is superior to low daily dose-modulated fractions.
AU  - Sammer, M.*
AU  - Dombrowsky, A.
AU  - Schauer, J.*
AU  - Oleksenko, K.
AU  - Bicher, S.
AU  - Schwarz, B.*
AU  - Rudigkeit, S.*
AU  - Matejka, N.*
AU  - Reindl, J.*
AU  - Bartzsch, S.
AU  - Blutke, A.
AU  - Feuchtinger, A.
AU  - Combs, S.E.
AU  - Dollinger, G.*
AU  - Schmid, T.E.
C1  - 60069
C2  - 48976
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 76-83
TI  - Normal tissue response of combined temporal and spatial fractionation in proton minibeam radiation therapy.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 109
IS  - 1
PB  - Elsevier Science Inc
PY  - 2021
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Purpose: Radiation therapy is an important treatment component for patients with lung cancer. However, the survival time gained with clinical radiation therapy techniques is relatively short. Data from preclinical experiments suggest that synchrotron microbeam radiation therapy could be much better suited to control malignant brain tumors than current clinical concepts of radiation therapy. Even at peak doses of several hundred gray, the extent of functional deficits is low. Methods and Materials: We have developed the first mouse model to study the effects of microbeam irradiation in lung tissue. Results: Up to peak doses of 400 Gy, no acute adverse effects were seen. Conclusion: This model is well suited to explore the potential of microbeam radiation therapy in the treatment of lung cancer and the response of normal lung tissue and organs at risk.
AU  - Schültke, E.*
AU  - Bayat, S.*
AU  - Bartzsch, S.
AU  - Bräuer-Krisch, E.*
AU  - Djonov, V.*
AU  - Fiedler, S.*
AU  - Fernandez-Palomo, C.*
AU  - Jaekel, F.*
AU  - Pellicioli, P.*
AU  - Trappetti, V.*
AU  - Hildebrandt, G.*
C1  - 61251
C2  - 49787
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 521-525
TI  - A mouse model for microbeam radiation therapy of the lung.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 110
IS  - 2
PB  - Elsevier Science Inc
PY  - 2021
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Purpose: Microbeam radiation therapy is a preclinical concept in radiation oncology. It spares normal tissue more effectively than conventional radiation therapy at equal tumor control. The radiation field consists of peak regions with doses of several hundred gray, whereas doses between the peaks (valleys) are below the tissue tolerance level. Widths and distances of the beams are in the submillimeter range for microbeam radiation therapy. A similar alternative concept with beam widths and distances in the millimeter range is presented by minibeam radiation therapy. Although both methods were developed at large synchrotron facilities, compact alternative sources have been proposed recently. Methods and Materials: A small-animal irradiator was fitted with a special 3-layered collimator that is used for preclinical research and produces microbeams of flexible width of up to 100 μm. Film dosimetry provided measurements of the dose distributions and was compared with Monte Carlo dose predictions. Moreover, the micronucleus assay in Chinese hamster CHO-K1 cells was used as a biological dosimeter. The focal spot size and beam emission angle of the x-ray tube were modified to optimize peak dose rate, peak-to-valley dose ratio (PVDR), beam shape, and field homogeneity. An equivalent collimator with slit widths of up to 500 μm produced minibeams and allowed for comparison of microbeam and minibeam field characteristics. Results: The setup achieved peak entrance dose rates of 8 Gy/min and PVDRs >30 for microbeams. Agreement between Monte Carlo simulations and film dosimetry is generally better for larger beam widths; qualitative measurements validated Monte Carlo predicted results. A smaller focal spot enhances PVDRs and reduces beam penumbras but substantially reduces the dose rate. A reduction of the beam emission angle improves the PVDR, beam penumbras, and dose rate without impairing field homogeneity. Minibeams showed similar field characteristics compared with microbeams at the same ratio of beam width and distance but had better agreement with simulations. Conclusion: The developed setup is already in use for in vitro experiments and soon for in vivo irradiations. Deviations between Monte Carlo simulations and film dosimetry are attributed to scattering at the collimator surface and manufacturing inaccuracies and are a matter of ongoing research.
AU  - Treibel, F.
AU  - Nguyen, M.
AU  - Ahmed, M.
AU  - Dombrowsky, A.
AU  - Wilkens, J.J.*
AU  - Combs, S.E.
AU  - Schmid, T.E.
AU  - Bartzsch, S.
C1  - 60527
C2  - 49333
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 626-636
TI  - Establishment of microbeam radiation therapy at a small animal irradiator.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 109
IS  - 2
PB  - Elsevier Science Inc
PY  - 2020
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Purpose: The aim of this study was to localize locoregional lymph node metastases using positron emission tomography with fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) data sets in a large cohort of patients and to evaluate the existing Radiation Therapy Oncology Group (RTOG) clinical target volume (CTV) and the European Society for Radiation Therapy & Oncology (ESTRO) CTV contouring guidelines.Methods and Materials: A total of 235 patients with 580 FDG/PET-CT positive locoregional lymph node metastases were included in our analysis. The patients were divided into 4 groups according to their course of disease (primary vs recurrent breast cancer) and the presence or absence of distant metastasis at the time of the FDG-PET/ CT staging (distant metastasis vs no distant metastasis). All imaging data were imported into the planning system, and each lymph node was manually contoured. A patient with " standard anatomy" was chosen as a template, and all contoured structures were registered rigidly and nonrigidly to this patient. A comprehensive 3-dimensional atlas was created, including all identified lymph node metastases. The incidences of lymph node metastases were analyzed and are presented with color coding in the atlas. Lymph node levels (axillary, internal mammary, supraclavicular) were contoured according to RTOG and ESTRO guidelines and evaluated.Results: The mean volume of the lymph nodes was 1.7 +/- 2.6 cm(3) with an average diameter of 1.3 +/- 0.7 cm. Most lymph nodes were in level I (n = 316; 54.5%) followed by the supraclavicular region (n = 80; 13.8%), level II (n Z 57; 9.8%), level III (n = 58; 10.0%), and the internal mammary region (n = 55; 9.5%). The covered lymph node volume was 69.8% +/- 35.5% (69.1% +/- 36.3%) for primary breast cancer and 57.6% +/- 38.9% (51.1% +/- 39.1%) for recurrent breast cancer using the RTOG (ESTRO) guidelines. The internal mammary region and supraclavicular region were affected more often in recurrent breast cancer compared with primary breast cancer. The occurrence of lymph node metastases outside the RTOG and ESTRO margins in patients with and without distant metastases was similar. The largest geometric deviations between RTOG/ESTRO CTV contours and lymph node occurrence were measured in the supraclavicular region, the internal mammary region, and level II.Conclusions: The provided lymph node atlas illustrates where lymph node metastases occur in different clinical situations and presents areas at high risk (ie " hot spots" of lymph node metastases). (C) 2018 Elsevier Inc. All rights reserved.
AU  - Borm, K.J.*
AU  - Voppichler, J.*
AU  - Düsberg, M.*
AU  - Oechsner, M.*
AU  - Vag, T.*
AU  - Weber, W.*
AU  - Combs, S.E.
AU  - Duma, M.N.
C1  - 54789
C2  - 45855
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 574-582
TI  - FDG/PET-CT-based lymph node atlas in breast cancer patients.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 103
IS  - 3
PB  - Elsevier Science Inc
PY  - 2019
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Duma, M.N.
C1  - 55360
C2  - 46119
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 779-780
TI  - In Reply to Byun et al.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 103
IS  - 3
PB  - Elsevier Science Inc
PY  - 2019
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Purpose: Type I interferon (IFN-I) and interleukin (IL)-22 modulate regeneration of the thymus and intestinal epithelial cells (IECs) after cytotoxic stress such as irradiation. Radiation-induced damage to thymic tissues and IECs is a crucial aspect during the pathogenesis of inadequate immune reconstitution and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative total body irradiation (TBI), respectively. IL-22 and IFN-I reduce the severity of acute GVHD after allo-HSCT with myeloablative TBI. However, the role of biologically related type III interferon (IFN-III), also known as interferon lambda (IFN-lambda) or IL-28, in this context is unclear. We therefore studied the role of the IFN-III pathway in thymic regeneration and GVHD after TBI and allo-HSCT.Methods and Materials: Cohoused wild-type (WT) and IFN-III receptor-deficient (IL-28 receptor alpha subunit-deficient/IL-28Ra(-/-)) mice were analyzed in models of TBI-induced thymus damage and a model of GVHD after allo-HSCT with myeloablative TBI. PASylated IFN-III (PASylated IL-28A, XL-protein GmbH) was generated to prolong the plasma half-life of IFN-III. Pharmacologic activity and the effects of PASylated IL-28A on radiation-induced thymus damage and the course of GVHD after allo-HSCT with myeloablative TBI were tested.Results: The course and severity of GVHD after myeloablative TBI and allo-HSCT in IL-28Ra(-/-) mice was comparable to those in WT mice. Activation of the IFN-III pathway by PASylated IL-28A did not significantly modulate GVHD after allo-HSCT with TBI. Furthermore, IL28Ra(-/-) mice and WT mice showed similar thymus regeneration after radiation, which could also not be significantly modulated by IFN-III receptor engagement using PASylated IL-28A.Conclusions: We analyzed the role of IFN-III signaling during radiation-mediated acute tissue injury. Despite molecular and biologic homologies with IFN-I and IL-22, IFN-III signaling did not improve thymus regeneration after radiation or the course of GVHD after myeloablative TBI and allo-HSCT. (C) 2018 Elsevier Inc. All rights reserved.
AU  - Fischer, J.C.*
AU  - Lin, C.C.*
AU  - Heidegger, S.*
AU  - Wintges, A.*
AU  - Schlapschy, M.*
AU  - Beudert, M.*
AU  - Combs, S.E.
AU  - Bassermann, F.*
AU  - Skerra, A.*
AU  - Haas, T.*
AU  - Poeck, H.*
C1  - 55461
C2  - 46167
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 970-976
TI  - Regeneration after radiation- and immune-mediated tissue injury is not enhanced by type III interferon signaling.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 103
IS  - 4
PB  - Elsevier Science Inc
PY  - 2019
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Purpose Experimental neuroimaging provides a wide range of methods for the visualization of brain anatomic morphology down to subcellular detail. Still, each technique-specific detection mechanism presents compromises among the achievable field-of-view size, spatial resolution, and nervous tissue sensitivity, leading to partial sample coverage, unresolved morphologic structures, or sparse labeling of neuronal populations and often also to obligatory sample dissection or other sample invasive manipulations. X-ray phase-contrast imaging computed tomography (PCI-CT) is an experimental imaging method that simultaneously provides micrometric spatial resolution, high soft-tissue sensitivity, and ex vivo full organ rodent brain coverage without any need for sample dissection, staining or labeling, or contrast agent injection. In the present study, we explored the benefits and limitations of PCI-CT use for in vitro imaging of normal and cancerous brain neuromorphology after in vivo treatment with synchrotron-generated x-ray microbeam radiation therapy (MRT), a spatially fractionated experimental high-dose radiosurgery. The goals were visualization of the MRT effects on nervous tissue and a qualitative comparison of the results to the histologic and high-field magnetic resonance imaging findings. Methods and Materials MRT was administered in vivo to the brain of both healthy and cancer-bearing rats. At 45 days after treatment, the brain was dissected out and imaged ex vivo using propagation-based PCI-CT. Results PCI-CT visualizes the brain anatomy and microvasculature in 3 dimensions and distinguishes cancerous tissue morphology, necrosis, and intratumor accumulation of iron and calcium deposits. Moreover, PCI-CT detects the effects of MRT throughout the treatment target areas (eg, the formation of micrometer-thick radiation-induced tissue ablation). The observed neurostructures were confirmed by histologic and immunohistochemistry examination and related to the micro-magnetic resonance imaging data. Conclusions PCI-CT enabled a unique 3D neuroimaging approach for ex vivo studies on small animal models in that it concurrently delivers high-resolution insight of local brain tissue morphology in both normal and cancerous micro-milieu, localizes radiosurgical damage, and highlights the deep microvasculature. This method could assist experimental small animal neurology studies in the postmortem evaluation of neuropathology or treatment effects.  
AU  - Barbone, G.E.*
AU  - Bravin, A.*
AU  - Romanelli, P.*
AU  - Mittone, A.*
AU  - Bucci, D.*
AU  - Gaaß, T.*
AU  - Le Duc, G.*
AU  - Auweter, S.*
AU  - Reiser, M.*
AU  - Kraiger, M.
AU  - Hrabě de Angelis, M.
AU  - Battaglia, G.*
AU  - Coan, P.*
C1  - 53392
C2  - 44552
CY  - Po Box 211, 1000 Ae Amsterdam, Netherlands
SP  - 965-984
TI  - Micro-imaging of brain cancer radiotherapy using phase-contrast computed tomography.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 101
IS  - 4
PB  - Elsevier Science Bv
PY  - 2018
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Purpose: To assess the differences in unintended regional nodal irradiation between free breathing (FB) and deep-inspiration breath-hold (DIBH) during tangential field irradiation. Methods and Materials: We randomly chose 32 patients from our database who underwent both DIBH and FB treatment planning. Contouring of the axillary lymph node levels (LI, LII, and LIII) was performed retrospectively according to the Radiation Therapy Oncology Group contouring atlas. We assessed the center of mass of each level and the planning target volume, as well as the dose distribution (Dmean, Dmedian, Dmax, Dmin, V30, and V40) in the lymph node levels I-III. Subsequently center of mass movement and dose changes due to deep inspiration treatment planning were calculated. Results: All lymph node levels showed significant (P<.001) movement in anterior and cranial directions due to DIBH. The overall median movement (range) in the x (lateral), y (anterior-posterior), and z (cranio-caudal) directions was 0.1 cm (0.0-1.1 cm), 0.9 cm (0.1-2.0 cm), and 1.2 cm (0.0-2.6 cm), respectively. Movement of the planning target volume showed significant correlation (r=0.72, r=0.63, r=0.63; P<.05) with levels I-III. The average Dmean during FB/DIBH was as follows: LI 33.9 Gy/30.8 Gy (P<.001), LII 23.7 Gy/24.1 Gy (P=.74), and LIII 14.0 Gy/15.6 Gy (P=.14). V30 was as follows: LI 63.8%/56.5% (P<.001), LII 44.6%/45.5% (P=.76), and LIII 24.2%/27.8% (P<.05). V40 was as follows: LI 58.9%/51.0% (P<.001), LII 39.3%/40.1% (P=.79), and LIII 20.4%/23.9% (P<.05). Conclusions: Deep-inspiration breath-hold results in a significant dose reduction in level I. Only minor changes in dose distribution were recorded for levels II and III. Thus, DIBH seems to have an impact on unintended regional nodal irradiation as compared with FB.
AU  - Borm, K.J.*
AU  - Oechsner, M.*
AU  - Combs, S.E.
AU  - Duma, M.N.
C1  - 52222
C2  - 43846
CY  - New York
SP  - 263-269
TI  - Deep-inspiration breath-hold radiation therapy in breast cancer: A word of caution on the dose to the axillary lymph node levels.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 100
IS  - 1
PB  - Elsevier Science Inc
PY  - 2018
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Corradini, S.*
AU  - Simonetto, C.
AU  - Eidemüller, M.
AU  - Gaasch, A.*
AU  - Pazos, M.*
AU  - Schönecker, S.*
AU  - Reitz, D.*
AU  - Braun, M.*
AU  - Harbeck, N.*
AU  - Ganswindt, U.*
AU  - Niyazi, M.*
AU  - Belka, C.*
C1  - 54806
C2  - 45881
CY  - 360 Park Ave South, New York, Ny 10010-1710 Usa
SP  - E598-E599
TI  - Does deep inspiration breath hold prolong life? Individual risk estimates of ischemic heart disease after breast cancer radiation therapy.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 102
IS  - 3
PB  - Elsevier Science Inc
PY  - 2018
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Mayinger, M.C.*
AU  - Reibelt, A.*
AU  - Borm, K.*
AU  - Ettl, J.*
AU  - Kiechle, M.*
AU  - Wilkens, J.*
AU  - Combs, S.E.
AU  - Oechsner, M.*
AU  - Duma, M.N.
C1  - 54805
C2  - 45883
CY  - 360 Park Ave South, New York, Ny 10010-1710 Usa
SP  - E239-E239
TI  - Neuroanatomical differences in the brains of cerebral metastasized breast cancer patients: Meningeal carcinomatosa patients vs. brain oligometastatic patients vs. multiple metastastic brain patients.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 102
IS  - 3
PB  - Elsevier Science Inc
PY  - 2018
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Purpose: The aim was to reduce radiation exposure of the lung in experimental models to increase overall survival of mice to study late radiation-induced heart disease. Methods and Materials: A new irradiation plan was established on the Small Animal Radiation Research Platform machine for local heart irradiation of mice with single doses of 8 and 16 Gy. Lung damage was analyzed 20, 30, 40, and 50 weeks after irradiation by computed tomography scans and histology and compared with a sham-irradiated, age-matched, control group. Results: The use of an 8 × 6-mm2collimator enabled local heart irradiation whereby only 18% of the lung received any irradiation. The V10 and V16 of the lung were 14% and 7%, respectively. After a mean heart dose of 8 and 16 Gy, mice survived for at least 50 weeks after irradiation. Computed tomography images demonstrated increased cell densities in the irradiated lung volume 50 weeks after irradiation. Concomitantly, histologic examination revealed fibrotic and inflammatory changes in the irradiated lung volume. In the heart, amyloid depositions and left ventricle hypertrophy were observed. Conclusions: High-precision heart irradiation with 8 and 16 Gy using an 8 × 6-mm2beam induced cardiac amyloidosis and hypertrophy, which did not lead to myocardial dysfunction despite the presence of radiation pneumopathy in the small V16 of the exposed lung. By using the improved irradiation plan (V16: 7%), long-term survival of the mice after heart irradiation can be achieved that allows clinically relevant experimental investigation of late radiation-induced heart disease effects.
AU  - Sievert, W.*
AU  - Stangl, S.*
AU  - Steiger, K.
AU  - Multhoff, G.*
C1  - 53443
C2  - 44794
SP  - 671-679
TI  - Improved overall survival of mice by reducing lung side effects after high-precision heart irradiation using a small animal radiation research platform.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 101
IS  - 3
PY  - 2018
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Voppichler, J.*
AU  - Borm, K.*
AU  - Duesberg, M.*
AU  - Oechsner, M.*
AU  - Combs, S.E.
AU  - Duma, M.N.
C1  - 54804
C2  - 45874
CY  - 360 Park Ave South, New York, Ny 10010-1710 Usa
SP  - E569-E569
TI  - Analysis of patterns of lymph node metastases in primary and recurrent breast cancer by evaluation of FDG / PET-CT image datasets.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 102
IS  - 3
PB  - Elsevier Science Inc
PY  - 2018
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Kessel, K.A.
AU  - Vogel, M.M.
AU  - Kessel, C.*
AU  - Bier, H.*
AU  - Biedermann, T.*
AU  - Friess, H.*
AU  - Herschbach, P.*
AU  - von Eisenhart-Rothe, R.*
AU  - Meyer, B.*
AU  - Kiechle, M.*
AU  - Keller, U.*
AU  - Peschel, C.*
AU  - Combs, S.E.
C1  - 52289
C2  - 43840
CY  - New York
SP  - E402-E402
TI  - mHealth in oncology: A Patient survey evaluating the acceptance of app-assisted cancer treatment.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 99
IS  - 2
PB  - Elsevier Science Inc
PY  - 2017
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - PURPOSE: Proton minibeam radiation therapy is a novel approach to minimize normal tissue damage in the entrance channel by spatial fractionation while keeping tumor control through a homogeneous tumor dose using beam widening with an increasing track length. In the present study, the dose distributions for homogeneous broad beam and minibeam irradiation sessions were simulated. Also, in an animal study, acute normal tissue side effects of proton minibeam irradiation were compared with homogeneous irradiation in a tumor-free mouse ear model to account for the complex effects on the immune system and vasculature in an in vivo normal tissue model. METHODS AND MATERIALS: At the ion microprobe SNAKE, 20-MeV protons were administered to the central part (7.2 × 7.2 mm(2)) of the ear of BALB/c mice, using either a homogeneous field with a dose of 60 Gy or 16 minibeams with a nominal 6000 Gy (4 × 4 minibeams, size 0.18 × 0.18 mm(2), with a distance of 1.8 mm). The same average dose was used over the irradiated area. RESULTS: No ear swelling or other skin reactions were observed at any point after minibeam irradiation. In contrast, significant ear swelling (up to fourfold), erythema, and desquamation developed in homogeneously irradiated ears 3 to 4 weeks after irradiation. Hair loss and the disappearance of sebaceous glands were only detected in the homogeneously irradiated fields. CONCLUSIONS: These results show that proton minibeam radiation therapy results in reduced adverse effects compared with conventional homogeneous broad-beam irradiation and, therefore, might have the potential to decrease the incidence of side effects resulting from clinical proton and/or heavy ion therapy.
AU  - Girst, S.*
AU  - Greubel, C.*
AU  - Reindl, J.*
AU  - Siebenwirth, C.*
AU  - Zlobinskaya, O.*
AU  - Walsh, D.W.*
AU  - Ilicic, K.*
AU  - Aichler, M.
AU  - Walch, A.K.
AU  - Wilkens, J.J.*
AU  - Multhoff, G.*
AU  - Dollinger, G.*
AU  - Schmid, T.E.*
C1  - 47571
C2  - 37893
CY  - New York
SP  - 234-241
TI  - Proton minibeam radiation therapy reduces side effects in an in vivo mouse ear model.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 95
IS  - 1
PB  - Elsevier Science Inc
PY  - 2016
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Oechsner, M.*
AU  - Chizzali, B.*
AU  - Devecka, M.*
AU  - Wilkens, J.J.
AU  - Combs, S.E.
AU  - Duma, M.N.
C1  - 50544
C2  - 42366
CY  - New York
SP  - E665-E665
TI  - Interobserver comparison on patient positioning using 4 different computed tomography datasets for image registration with cone beam computed tomography in lung stereotactic body radiation therapy.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 96
IS  - 2
PB  - Elsevier Science Inc
PY  - 2016
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - PURPOSE: Tumor cells, in contrast to normal cells, frequently overexpress heat shock protein 70 (Hsp70) in the cytosol, present it on their cell surface, and actively release it. Therefore, soluble Hsp70 (sHsp70) was investigated as a potential tumor biomarker for monitoring the outcome of radiation therapy. METHODS AND MATERIALS: Plasma from mice bearing membrane Hsp70 (mHsp70)-positive FaDu human squamous cell carcinoma of the head and neck and spontaneous pancreatic ductal adenocarcinoma (PDAC) was investigated. A cohort of mice with FaDu tumors (0.32 cm(3)) was irradiated with 30 Gy, and plasma was collected 24 hours after irradiation, after the tumors had shrunk to 50% of their starting volume and after complete remission. sHsp70 levels in the plasma were quantified by enzyme-linked immunosorbent assay. RESULTS: sHsp70 levels were significantly higher in the blood of tumor-bearing mice than that of control animals. A correlation between increasing sHsp70 plasma levels and tumor volume in the range of 0.01 cm(3) to 0.66 cm(3) was observed. Radiation-induced regression of the tumors was associated with significantly decreased sHsp70 levels, which returned to the level of control animals after complete remission. CONCLUSION: We propose sHsp70 as an innovative biomarker for detecting tumors and for monitoring the clinical outcome of radiation therapy in cancer patients.
AU  - Bayer, C.*
AU  - Liebhardt, M.E.*
AU  - Schmid, T.E.*
AU  - Trajkovic-Arsic, M.*
AU  - Hube, K.*
AU  - Specht, H.M.*
AU  - Schilling, D.
AU  - Gehrmann, M.*
AU  - Stangl, S.*
AU  - Siveke, J.T.*
AU  - Wilkens, J.J.*
AU  - Multhoff, G.
C1  - 30743
C2  - 33809
CY  - New York
SP  - 694-700
TI  - Validation of heat shock protein 70 as a tumor-specific biomarker for monitoring the outcome of radiation therapy in tumor mouse models.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 88
IS  - 3
PB  - Elsevier Science Inc
PY  - 2014
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - PURPOSE: Previous studies have shown that the plasminogen activator inhibitor type-1 (PAI-1) and vascular endothelial growth factor (VEGF) are regulated by hypoxia and irradiation and are involved in neoangiogenesis. The aim of this study was to determine in vivo whether changes in PAI-1 and VEGF during fractionated irradiation could predict for radiation resistance. METHODS AND MATERIALS: Six xenografted tumor lines from human squamous cell carcinomas (HSCC) of the head and neck were irradiated with 0, 3, 5, 10, and 15 daily fractions of 2 Gy. The PAI-1 and VEGF antigen levels in tumor lysates were determined by enzyme-linked immunosorbent assay kits. The amounts of PAI-1 and VEGF were compared with the dose to cure 50% of tumors (TCD(50)). Colocalization of PAI-1, pimonidazole (hypoxia), CD31 (endothelium), and Hoechst 33342 (perfusion) was examined by immunofluorescence. RESULTS: Human PAI-1 and VEGF (hVEGF) expression levels were induced by fractionated irradiation in UT-SCC-15, UT-SCC-14, and UT-SCC-5 tumors, and mouse VEGF (msVEGF) was induced only in UT-SCC-5 tumors. High hVEGF levels were significantly associated with radiation sensitivity after 5 fractions (P=.021), and high msVEGF levels were significantly associated with radiation resistance after 10 fractions (P=.007). PAI-1 staining was observed in the extracellular matrix, the cytoplasm of fibroblast-like stroma cells, and individual tumor cells at all doses of irradiation. Colocalization studies showed PAI-1 staining close to microvessels. CONCLUSIONS: These results indicate that the concentration of tumor-specific and host-specific VEGF during fractionated irradiation could provide considerably divergent information for the outcome of radiation therapy.
AU  - Bayer, C.*
AU  - Kielow, A.*
AU  - Schilling, D.
AU  - Maftei, C.A.*
AU  - Zips, D.*
AU  - Yaromina, A.*
AU  - Baumann, M.*
AU  - Molls, M.*
AU  - Multhoff, G.
C1  - 8211
C2  - 30044
SP  - e409-e417
TI  - Monitoring PAI-1 and VEGF levels in 6 human squamous cell carcinoma xenografts during fractionated irradiation.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 84
IS  - 3
PB  - Elsevier
PY  - 2012
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - PURPOSE: It has been shown that plasminogen activator inhibitor type-1 (PAI-1) and vascular endothelial growth factor (VEGF) are involved in neo-angiogenesis. The aim of this study was to investigate the irradiation-induced regulation of PAI-1 and VEGF in squamous cell carcinomas of the head and neck (SCCHN) cell lines of varying radiation sensitivity. METHODS AND MATERIALS: Six cell lines derived from SCCHN were investigated in vitro. The colorimetric AlamarBlue assay was used to detect metabolic activity of cell lines during irradiation as a surrogate marker for radiation sensitivity. PAI-1 and VEGF secretion levels were measured by enzyme-linked immunosorbent assay 24, 48, and 72 h after irradiation with 0, 2, 6, and 10 Gy. The direct radioprotective effect of exogenous PAI-1 was measured using the clonogenic assay. For regulation studies, transforming growth factor-beta1 (TGF-beta1), hypoxia-inducible factor-1alpha (HIF-1alpha), hypoxia-inducible factor-2alpha (HIF-2alpha), or both HIF-1alpha and HIF-2alpha were downregulated using siRNA. RESULTS: Although baseline levels varied greatly, irradiation led to a comparable dose-dependent increase in PAI-1 and VEGF secretion in all six cell lines. Addition of exogenous stable PAI-1 to the low PAI-1-expressing cell lines, XF354 and FaDu, did not lead to a radioprotective effect. Downregulation of TGF-beta1 significantly decreased VEGF secretion in radiation-sensitive XF354 cells, and downregulation of HIF-1alpha and HIF-2alpha reduced PAI-1 and VEGF secretion in radiation-resistant SAS cells. CONCLUSIONS: Irradiation dose-dependently increased PAI-1 and VEGF secretion in all SCCHN cell lines tested regardless of their basal levels and radiation sensitivity. In addition, TGF-beta1 and HIF-1alpha could be partly responsible for VEGF and PAI-1 upregulation after irradiation.
AU  - Artman, T.*
AU  - Schilling, D.
AU  - Gnann, J.*
AU  - Molls, M.*
AU  - Multhoff, G.
AU  - Bayer, C.*
C1  - 430
C2  - 27190
SP  - 574-582
TI  - Irradiation-induced regulation of plasminogen activator inhibitor type-1 and vascular endothelial growth factor in six human squamous cell carcinoma lines of the head and neck.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 76
IS  - 2
PB  - Elsevier
PY  - 2010
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Müller, I.
AU  - Geinitz, H.*
AU  - Braselmann, H.
AU  - Baumgartner, A.
AU  - Fasan, A.*
AU  - Molls, M.*
AU  - Meineke, V.*
AU  - Zitzelsberger, H.
C1  - 1312
C2  - 23387
SP  - 1214-1220
TI  - Time-Course of Radiation-Induced Chromosomal Aberrations in Tumor Patients after Radiotherapy.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 63
PY  - 2005
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Purpose: To study the influence of tumor fibroblasts on radiosensitivity and stem cell fraction of tumor cells in squamous cell carcinoma megacolonies by determining colony cure and clonogen survival, Methods and Materials: Murine squamous cell carcinoma cells (AT478c) grown as flat but multilayered megacolonies were co-cultured with pre-irradiated tumor fibroblasts derived from the same carcinoma, and irradiated with 1, 2, 4, or 8 fractions. Recurrent clones and their growth pattern in situ were recorded. From megacolony cure data and clonogen survival data, the clonogen number and the parameters of cellular radiosensitivity were calculated, Results: The curability of the co-cultured megacolonies, as determined by TCD50 values, was significantly increased compared to the megacolonies without fibroblasts (p < 0.01). Both the megacolony cure and clonogen survival data suggested a decrease of the clonogen fraction in the so-cultured megacolonies, Conclusion: The presence of tumor fibroblasts increases megacolony radiosensitivity. This is due to a decrease in the fraction of clonogens in the tumor megacolony, apparently caused by a downregulation of the stem cell fraction of the tumor cells.
AU  - Kummermehr, J.C.
AU  - Malinen, E.*
AU  - Freykowski, S.
AU  - Sund, M.
AU  - Trott, K.-R.*
C1  - 22024
C2  - 20590
SP  - 229-237
TI  - The influence of autologous tumor fibroblasts on the radiosensitivity of squamous cell carcinoma megacolonies.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 50
IS  - 1
PB  - Elsevier Science
PY  - 2001
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Kummermehr, J.
AU  - Trott, K.R.
AU  - Beck-Bornholdt, H.P.
C1  - 40341
C2  - 38978
SP  - 154-155
TI  - Should tumors be clamped in radiobiological fractionation experiments? [3].
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 25
IS  - 1
PY  - 1993
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Noninvasive methods have been used to study the long-term cardiovascular and pulmonary functional changes at rest and after exercise in adult rats following local heart irradiation with single x-ray doses of 15, 17.5 or 20 Gy, and in non-irradiated control animals. Rats that had undergone a chronic exercise program were compared with untrained cohorts. The earliest dysfunction detected was an increased respiratory rate (f) at 10 weeks after irradiation in the highest dose group. In contrast, both telemetric heart-rate (HR) and rhythm and indirect systolic blood pressure measurements performed at rest only revealed changes starting at 43 weeks after irradiation with 20 Gy, up to which point the rats showed no clinical signs of heart failure. However, the number of minutes required for the recovery of the HR to pre-exercise levels following the implementation of a standardized exercise challenge was elevated in untrained rats compared with their trained cohorts at 18 weeks after irradiation with 20 Gy. Increases in recovery times were required in the two lowest dose groups, starting at 26 weeks after irradiation. It was concluded that the reserve capacity of the cardiopulmonary system masks functional decrements at rest for many months following local heart irradiation, necessitating the use of techniques which reveal reductions in reserve capacities. Further, the influence of local irradiation to the heart and lungs deserves closer scrutiny due to mutual interactions.
AU  - Geist, B.J.
AU  - Lauk, S.
AU  - Bornhausen, M.
AU  - Trott, K.R.
C1  - 42345
C2  - 40134
SP  - 1107-1113
TI  - Physiologic consequences of local heart irradiation in rats.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 18
IS  - 5
PY  - 1990
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Breiter, N.
AU  - Trott, K.-R.
AU  - Sassy, T.
C1  - 17175
C2  - 10281
TI  - Effect of X-irradiation on the stomach of the rat.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
PY  - 1988
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Spontaneously hypertensive Wistar rats were given single doses of X rays to their heart. Irradiation decreased the blood pressure before any myocardial radiation damage was apparent. Male rats, which were more hypertensive than female rats, had a shorter survival time after local heart irradiation than female rats. Antihypertensive treatment with hydralazine did not increase the survival time. It is considered that myocardial hypertrophy is the cause of the increased susceptibility of spontaneously hypertensive rats to local heart irradiation.
AU  - Lauk, S.
AU  - Trott, K.R.
C1  - 41758
C2  - 38212
SP  - 109-114
TI  - Radiation induced heart disease in hypertensive rats.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 14
IS  - 1
PY  - 1988
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - After local irradiation of the rat heart with X ray doses of over 10 Gy (single doses), animals developed symptoms of radiation-induced heart disease, which at higher doses would lead to fatal cardiac failure. The LD 50 at 1 year was between 15 Gy and 20 Gy. The pericardium and epicardium responded to irradiation with exudative pericarditis after 4 months. Focal myocardial damage was secondary to progressive capillary damage.
AU  - Lauk, S.
AU  - Kiszel, Z.
AU  - Buschmann, J.
AU  - Trott, K.R.
C1  - 41381
C2  - 38223
SP  - 801-808
TI  - Radiation-induced heart disease in rats.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 11
IS  - 4
PY  - 1985
SN  - 0360-3016
ER  - 

TY  - JOUR
AU  - Trott, K.-R.
C1  - 17788
C2  - 10699
SP  - 907-913
TI  - Chronic Damage after Radiation Therapy: Challenge to Radiation Biology.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 10
PY  - 1984
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Modifications of cell proliferation and survival induced by 2-DG and X-irradiation alone or in combination were studied under both aerobic and hypoxic conditions and for cells both in exponential and plateau phase. The degree of inhibition of cell proliferation was found to be dependent on absorbed dose of X rays and on the 2-DG/Glucose Molar ratio in the medium. At an equimolar ratio (2-DG/Glucose = 1) in nutrient medium the growth of euoxic EATC was inhibited by 80% relative to the control (without 2-DG). This inhibition was fully reversible up to 48 hours of the culture inoculation if 2-DG was removed from the medium, demonstrating the importance of glucose and glycolysis for tumor growth. The inhibitory effects of 2-DG on the viability of cultured cells when applied alone or in combination with radiation was found to be more pronounced in hypoxic cells than in euoxic cells. The combined effect of both noxae (2-DG and X-irradiation) on the growth inhibition of euoxic EATC in cultures was slightly more than additive, while they were clearly synergistic on the growth inhibition of solid tumors in vivo. As tumors are known to have a fraction of hypoxic cells, it seems likely that synergistic action of 2-DG results from the stronger effect of 2-DG on these cells. The reason for the stronger effect may be a result of inhibition of their glycolytic energy supply limiting repair processes. Our results suggest that 12-DG could be used to advantage as an adjuvant in radiotherapy of human tumors.
AU  - Purohit, S.C.
AU  - Pohlit, W.
C1  - 42502
C2  - 36113
SP  - 495-499
TI  - Experimental evaluation of the glucose antimetabolite, 2-deoxy-D-glucose (2-DG) as a possible adjuvant to radiotherapy of tumors: I. Kinetics of growth and survival of Ehrlich ascites tumor cells (EATC) in vitro and of growth of solid tumors after 2-DG and X-irradiation.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 8
IS  - 3-4
PY  - 1982
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Human and hamster malanoma cells were irradiated is vitro with single and fractionated daces of γ-rays. Except for a tendency to high extrapolation numbers, survival curves did not show particular radioresistance. D2-D1 was between 220 and 300 rad. Regrowth delay after split dose irradiation to the hypoxic Hardiog-Passey malanoma in vivo yielded a D2-D, of 700 rad. While the tumor control dose for 50% (TCD-50) was within normal range (4,400 rad) Harding-Passey malanom as regressed very slowly after irradiation and often took months to clear away.
AU  - Trott, K.R.*
AU  - Lieven, H.V.*
AU  - Kummermehr, J.C.
AU  - Skopal, D.*
AU  - Lukacs, S.*
AU  - Braun-Falco, O.*
C1  - 41080
C2  - 38544
SP  - 9-13
TI  - The radiosensitivity of malignant melanomas part I: Experimental studies.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 7
IS  - 1
PY  - 1981
SN  - 0360-3016
ER  - 

TY  - JOUR
AB  - Forty-four lymph node or skin metastases of malignant melanomas received definite radiotherapy. Twenty were locally controlled for 2 or more years. Local control rate increased with dose. TCD-50 was about 1800 ret. The effectiveness of radiotherapy was more dependent on overall treatment time than on fraction size or number of fractions. Radiotherapy is suggested to decrease the high rate of locoregional failure of surgery of nodular melanomas in the foot and face.
AU  - Trott, K.R.*
AU  - Lieven, H.V.*
AU  - Kummermehr, J.C.
AU  - Skopal, D.*
AU  - Lukacs, S.*
AU  - Braun-Falco, O.*
AU  - Kellerer, A.M.*
C1  - 41732
C2  - 38561
SP  - 15-20
TI  - The radiosensitivity of malignant melanomas part II: Clinical studies.
JO  - Int. J. Radiat. Oncol. Biol. Phys.
VL  - 7
IS  - 1
PY  - 1981
SN  - 0360-3016
ER  -