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    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; IONIZING-RADIATION ; IRRADIATION ; proliferation ; radiotherapy ; SURVIVAL ; tumor ; AGENTS ; CELL ; CELL-PROLIFERATION ; COMBINATION ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; PROSTATE ; THERAPY ; tumor growth ; VITRO ; DENSITY ; DRUG ; TUMORS ; MICE ; radiation ; PATIENT ; MECHANISM ; INDEX ; TYROSINE KINASE INHIBITOR ; DESIGN ; UP-REGULATION ; prostate cancer ; PROSTATE-CANCER ; DAMAGE ; MUSCLE ; MIGRATION ; experimental design ; CELL-MIGRATION ; TUMOR ANGIOGENESIS ; VEGF ; signaling ; AGENT ; ONCOLOGY ; RE ; antiangiogenesis ; SU5416 ; TUMOR-GROWTH ; THERAPIES ; INCREASE ; cell proliferation ; cell migration ; USA ; vascular endothelial growth factor ; cancer research ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; SMOOTH-MUSCLE-CELLS ; ENDOTHELIAL GROWTH ; MUSCLE-CELLS ; tumor therapy ; radiation dose ; FRACTIONATED-IRRADIATION ; SU6668
    Abstract: Purpose: Investigations on the combination of radiotherapy with vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) antiangiogenic agents, which has the potential to improve the clinical outcome in cancer patients. Experimental Design: Here, we analyze the combined VEGF (SU5416) and PDGF (SU6668) receptor tyrosine kinase inhibition with irradiation in human endothelium (HUVEC), prostate cancer (PC3), and glioblastoma (U87) in vitro and in vivo. Results: Combined inhibition of VEGF and PDGF signaling resulted in enhanced apoptosis, reduced cell proliferation, and clonogenic survival as well as reduced endothelial cell migration and tube formation compared with single pathway inhibition. These effects were further enhanced by additional irradiation. Likewise, in PC3 and U87 tumors growing s.c. on BALB/c nu/nu mice, dual inhibition of VEGF and PDGF signaling significantly increased tumor growth delay versus each monotherapy. Interestingly, radiation at similar to 20% of the dose necessary to induce local tumor control exerts similar tumor growth-inhibitory effects as the antiangiogenic drugs given at their maximum effective dose. Addition of radiotherapy to both mono- as well as dual-antiangiogenic treatment markedly increased tumor growth delay. With respect to tumor angiogenesis, radiation further decreased microvessel density (CD31 count) and tumor cell proliferation (Ki-67 index) in all drug-treated groups. Of note, the slowly growing PC3 tumor responded better to the antiangiogenic drug treatments than the faster-growing U87 tumor. In addition to the beneficial effect of abrogating VEGF survival signaling when combined with radiation, we identified here a novel mechanism for the tumor escape from radiation damage. We found that radiation induced up-regulation of all four isoforms of PDGF (A-D) in endothelial cells supporting adjacent smooth muscle cells resulting in a prosurvival effect of radiation. The addition of SU6668 attenuated this undesirable paracrine radiation effect, which may rationalize the combined application of radiation with PDGF signaling inhibition to increase antitumor effects. Conclusion: A relative low radiation dose markedly enhances local antitumor effects of combined VEGF and PDGF signaling inhibition, suggesting a promising combination regimen for local tumor treatment with radiotherapy remaining an essential element
    Type of Publication: Journal article published
    PubMed ID: 18381963
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  • 3
    Abstract: PURPOSE: We analyzed our experience with intraoperative electron radiotherapy (IOERT) followed by moderate doses of external beam radiotherapy (EBRT) after organ-sparing surgery in patients with primary or recurrent aggressive fibromatosis. METHODS AND MATERIALS: Indication for IOERT and postoperative EBRT as an individual treatment approach to avoid mutilating surgical procedures was seen when complete surgical removal seemed to be unlikely or impossible. A total of 31 lesions in 30 patients were treated by surgery and IOERT with a median dose of 12 Gy. Median age was 31 years (range, 13-59 years). Resection status was close margin in six lesions, microscopically positive in 13, and macroscopically positive in 12. Median tumor size was 9 cm. In all, 25 patients received additional EBRT, with a median dose of 45 Gy (range, 36-54 Gy). RESULTS: After a median follow-up of 32 months (range, 3-139 months), no disease-related deaths occurred. A total of five local recurrences were seen, resulting in actuarial 3-year local control rates of 82% overall and 91% inside the IOERT areas. Trends to improved local control were seen for older age (〉31 years) and negative margins, but none of these factors reached significance. Perioperative complications were found in six patients, in particular as wound healing disturbances in five patients and venous thrombosis in one patient. Late toxicity was seen in five patients. CONCLUSION: Introduction of IOERT into a multimodal treatment approach in patients with aggressive fibromatosis is feasible with low toxicity and yielded good local control rates even in patients with microscopical or gross residual disease. Copyright 2010 Elsevier Inc. All rights reserved.
    Type of Publication: Journal article published
    PubMed ID: 19647952
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  • 4
    Abstract: Despite great efforts in the field of preclinical and clinical research, pancreatic cancer is still one of the most devastating cancer diagnoses and nearly always results in death. With neoadjuvant chemoradiotherapy higher R0 resection rates can be achieved in pancreatic cancer and may even lead to a secondary resection in primarily inoperable tumors. Patients who experience a disease progression due to aggressive tumor biology can be spared the unnecessary morbidity of resection by neoadjuvant therapy. Even in the adjuvant situation the rates of local relapse can be significantly reduced by combined chemoradiotherapy. Through progress in radiation techniques the toxicity of combined chemoradiotherapy could be lowered. If symptoms of the metastasized disease are caused by localized solitary or more widespread tumor manifestation, chemoradiotherapy should be considered for a rapid symptom relief. The adjunct of various biologicals to chemoradiotherapy is a promising new way to improve the prognosis of pancreatic cancer. Results from initial trials to clarify this concept are expected soon. Despite all progress in radiation techniques and in systemic therapy of pancreatic cancer, psychooncological care and good nutrition is of especially high importance in the care of this group of patients.
    Type of Publication: Journal article published
    PubMed ID: 19156394
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  • 5
    Keywords: radiotherapy ; TUMORS ; RADIATION-THERAPY ; chemotherapy ; SQUAMOUS-CELL CARCINOMA ; INTENSITY-MODULATED RADIOTHERAPY ; CISPLATIN ; IMRT ; reirradiation ; NASOPHARYNGEAL CARCINOMA ; ONCOLOGY-GROUP ; head and neck cancer ; XEROSTOMIA ; Recurrent head and neck cancer ; late toxicity ; UNRESECTABLE HEAD
    Abstract: Background In this retrospective investigation we analyzed outcome and toxicity after intensity-modulated reirradiation of recurrent head and neck cancer. Results Median overall survival was 17 months, and the 1- and 2-year overall survival rates were 63% and 34%. The 1- and 2-year local control rates were 57% and 53%. Distant spread occurred in 34%, and reirradiation induced considerable late toxicity in 21% of the patients. Thirty-two percent showed increased xerostomia after reirradiation. The risk for xerostomia was significantly higher for cumulative mean doses of greater-than-or-equal 45 Gy to parotid glands. Considering median cumulative maximum doses of 53 Gy to the spinal cord and 63 Gy to the brainstem, no late toxicities were observed. Conclusions Reirradiation with intensity-modulated radiotherapy in recurrent head and neck cancer is feasible with acceptable toxicity and yields encouraging rates of local control and overall survival.
    Type of Publication: Journal article published
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  • 6
    Keywords: CANCER ; EXPRESSION ; IRRADIATION ; tumor ; carcinoma ; THERAPY ; MORTALITY ; TUMORS ; T-CELLS ; FREQUENCY ; BONE-MARROW ; MIGRATION ; inflammation ; PANCREATIC-CANCER ; low dose radiation ; colorectal liver metastasis ; ERADICATION ; tumor specific T cells
    Abstract: BACKGROUND: Insufficient migration and activation of tumor specific effector T cells in the tumor is one of the main reasons for inadequate host anti-tumor immune response. External radiation seems to induce inflammation and activate the immune response. This phase I/II clinical trial aims to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with colorectal liver metastases. METHODS: This is an investigator-initiated, prospective randomised, 4-armed, controlled Phase I /II trial. Patients undergoing elective hepatic resection due to colorectal cancer liver metastasis will be enrolled in the study. Patients will receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation targeted to their liver metastases. Radiation will be applied by external beam radiotherapy using a 6 MV linear accelerator (Linac) with intensity modulated radiotherapy (IMRT) technique two days prior to surgical resection. All patients admitted to the Department of General-, Visceral-, and Transplantion Surgery, University of Heidelberg for elective hepatic resection are consecutively screened for eligibility into this trial, and written informed consent is obtained before inclusion. The primary objective is to assess the effect of active local external beam radiation dose on tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include radiogenic treatment toxicity, postoperative morbidity and mortality, local tumor control and recurrence patterns, survival and quality of life. Furthermore, frequencies of systemic tumor reactive T cells in blood and bone marrow will be correlated with clinical outcome. DISCUSSION: This is a randomized controlled patient blinded trial to assess the safety and efficiency of low dose radiotherapy on metastases infiltrating T cells and thus potentially enhance the antitumor immune response. Trial registration: ClinicalTrials.gov - NCT01191632.
    Type of Publication: Journal article published
    PubMed ID: 21961577
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  • 7
    Keywords: radiotherapy ; COMBINATION ; STEREOTACTIC RADIOSURGERY ; adenocarcinoma ; GEMCITABINE ; CURATIVE RESECTION ; PHASE-III TRIAL ; BEAM IRRADIATION ; CHEMORADIOTHERAPY ; EXTERNAL-BEAM
    Abstract: ABSTRACT: BACKGROUND: To evaluate the use of intraoperative radiation therapy (IORT) in the multimodality treatment of patients with isolated local recurrences of pancreatic cancer. METHODS: We retrospectively analyzed 36 patients with isolated local recurrences of pancreatic cancer who have been treated with a combination of surgery, IORT and EBRT. Median time from initial treatment to recurrence was 20 months. All patients were surgically explored. In 18 patients a gross total resection was achieved, whereas the other half received only debulking or no resection at all. All patients received IORT with a median dose of 15 Gy. Additional EBRT was applied to 31 patients with a median dose of 45 Gy, combined with concurrent, mainly gemcitabine-based chemotherapy. RESULTS: Median follow-up in surviving patients was 23 months. Local progression was found in 6 patients after a median time of 17 months, resulting in estimated 1- and 2-year local control rates of 91% and 67%, respectively. Distant failure was observed in 23 patients, mainly in liver or peritoneal space. The median estimated progression-free survival was 9 months with 1- and 2-year rates of 40% and 26%, respectively. We found an encouraging estimated median overall survival of 19 months, transferring into 1- and 2-year rates of 66% and 45%. Notably 6 of 36 patients (17%) lived for more than 3 years. Severe postoperative complications were found in 3 and chemoradiation-related grade III toxicity in 6 patients. No severe IORT related toxicity was observed. CONCLUSION: Combination of surgery, IORT and EBRT in patients with isolated local recurrences of pancreatic cancer resulted in encouraging local control and overall survival in our cohort with acceptable toxicity. Our approach seems to be superior to palliative chemotherapy or chemoradiation alone and should be further investigated in a prospective setting specifically addressing isolated local recurrences of pancreatic cancer.
    Type of Publication: Journal article published
    PubMed ID: 22809267
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  • 8
    Keywords: LUNG ; PATHWAYS ; MICE ; CANCER-THERAPY ; FACTOR-BETA-1 ; GLIOBLASTOMA ; TRANSFORMING-GROWTH-FACTOR ; KINASE INHIBITOR LY2109761 ; NORMAL TISSUE-INJURY ; THORACIC IRRADIATION
    Abstract: PURPOSE: Radiotherapy is used for the treatment of lung cancer, but at the same time induces acute pneumonitis and subsequent pulmonary fibrosis, where TGF-beta signaling is considered to play an important role. EXPERIMENTAL DESIGN: We irradiated thoraces of C57BL/6 mice (single dose, 20 Gy) and administered them a novel small-molecule TGF-beta receptor I serine/threonine kinase inhibitor (LY2109761) orally for 4 weeks before, during, or after radiation. Noninvasive lung imaging including volume computed tomography (VCT) and MRI was conducted 6, 16, and 20 weeks after irradiation and was correlated to histologic findings. Expression profiling analysis and protein analysis was conducted in human primary fibroblasts. RESULTS: Radiation alone induced acute pulmonary inflammation and lung fibrosis after 16 weeks associated with reduced life span. VCT, MRI, and histology showed that LY2109761 markedly reduced inflammation and pulmonary fibrosis resulting in prolonged survival. Mechanistically, we found that LY2109761 reduced p-SMAD2 and p-SMAD1 expression, and transcriptomics revealed that LY2109761 suppressed expression of genes involved in canonical and noncanonical TGF-beta signaling and downstream signaling of bone morphogenetic proteins (BMP). LY2109761 also suppressed radiation-induced inflammatory [e.g., interleukin (IL)-6, IL-7R, IL-8] and proangiogenic genes (e.g., ID1) indicating that LY2109761 achieves its antifibrotic effect by suppressing radiation-induced proinflammatory, proangiogenic, and profibrotic signals. CONCLUSION: Small-molecule inhibitors of the TGF-beta receptor I kinase may offer a promising approach to treat or attenuate radiation-induced lung toxicity or other diseases associated with fibrosis.
    Type of Publication: Journal article published
    PubMed ID: 22547771
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  • 9
    Keywords: ANGIOGENESIS ; BONE-MARROW ; microenvironment ; inflammation ; INFILTRATION ; PANCREATIC-CANCER ; TUMORIGENESIS ; DESTRUCTION ; TUMOR-ASSOCIATED MACROPHAGES ; endothelium
    Abstract: Inefficient T cell migration is a major limitation of cancer immunotherapy. Targeted activation of the tumor microenvironment may overcome this barrier. We demonstrate that neoadjuvant local low-dose gamma irradiation (LDI) causes normalization of aberrant vasculature and efficient recruitment of tumor-specific T cells in human pancreatic carcinomas and T-cell-mediated tumor rejection and prolonged survival in otherwise immune refractory spontaneous and xenotransplant mouse tumor models. LDI (local or pre-adoptive-transfer) programs the differentiation of iNOS(+) M1 macrophages that orchestrate CTL recruitment into and killing within solid tumors through iNOS by inducing endothelial activation and the expression of TH1 chemokines and by suppressing the production of angiogenic, immunosuppressive, and tumor growth factors.
    Type of Publication: Journal article published
    PubMed ID: 24209604
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  • 10
    Keywords: CANCER ; IRRADIATION ; radiotherapy ; SURVIVAL ; Germany ; LUNG ; THERAPY ; TOXICITY ; lung cancer ; LUNG-CANCER ; SURGERY ; radiation ; PATIENT ; CYCLE ; treatment ; antibodies ; antibody ; STAGE ; TRIAL ; RADIATION-THERAPY ; RATES ; metastases ; chemotherapy ; RESECTION ; CARCINOMAS ; OVEREXPRESSION ; IMRT ; FEASIBILITY ; PHASE-II ; NECK-CANCER ; SUBSET ; CONCURRENT ; ADVANCED HEAD ; INFUSION ; PHASE ; REMISSION ; prospective ; NSCLC ; C225 ; FACTOR RECEPTOR BLOCKADE ; stage III ; surgical resection
    Abstract: Background: Even today, treatment of Stage III NSCLC still poses a serious challenge. So far, surgical resection is the treatment of choice. Patients whose tumour is not resectable or who are unfit to undergo surgery are usually referred to a combined radio-chemotherapy. However, combined radio-chemotherapeutic treatment is also associated with sometimes marked side effects but has been shown to be more efficient than radiation therapy alone. Nevertheless, there is a significant subset of patients whose overall condition does not permit administration of chemotherapy in a combined-modality treatment. It could be demonstrated though, that NSCLCs often exhibit over-expression of EGF-receptors hence providing an excellent target for the monoclonal EGFR-antagonist cetuximab (Erbitux(R)) which has already been shown to be effective in colorectal as well as head-and-neck tumours with comparatively mild side-effects. Methods/design: The NEAR trial is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combination's efficacy and rate of development of distant metastases with an accrual of 30 patients. Patients receive weekly infusions of cetuximab (Erbitux(R)) plus loco-regional radiation therapy as intensity-modulated radiation therapy. After conclusion of radiation treatment patients continue to receive weekly cetuximab for 13 more cycles. Discussion: The primary objective of the NEAR trial is to evaluate toxicities and feasibility of the combined treatment with cetuximab (Erbitux(R)) and IMRT loco-regional irradiation. Secondary objectives are remission rates, 3-year-survival and local/systemic progression-free survival
    Type of Publication: Journal article published
    PubMed ID: 16681848
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