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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; carcinoma ; COMBINATION ; Germany ; FOLLOW-UP ; imaging ; NEW-YORK ; RISK ; SITE ; SURGERY ; NUCLEAR-MEDICINE ; PATIENT ; treatment ; FIELD ; TARGET ; PATTERNS ; DECREASE ; chemotherapy ; RECURRENCE ; PROGNOSTIC-FACTORS ; RESECTION ; BEAM ; INVOLVEMENT ; local control ; FAILURE ; nuclear medicine ; POSTOPERATIVE RADIOTHERAPY ; radiology ; ONCOLOGY ; PATTERN ; PREOPERATIVE RADIOTHERAPY ; ADJUVANT THERAPY ; methods ; NUCLEAR ; USA ; rectal cancer ; EVALUATE ; soft-tissue sarcoma ; MEDICINE ; medical imaging ; in combination ; FIELDS ; LOCAL-CONTROL ; outcome ; REGIMEN ; BEAM RADIATION-THERAPY ; IOERT ; multimodality treatment ; neoadjuvant ; patterns of failure ; RECURRENT COLORECTAL-CANCER ; total mesorectal excision
    Abstract: Purpose: To evaluate local control and patterns of failure in patients treated with intraoperative electron beam radiotherapy (IOERT) after total mesorectal excision (TME), to appraise the effectiveness of intraoperative target definition. Methods and Materials: We analyzed the outcome of 243 patients with rectal cancer treated with IOERT (median dose, 10 Gy) after TME. Eighty-eight patients received neoadjuvant and 122 patients adjuvant external beam radiotherapy (EBRT) (median dose, 41.4 Gy), and in 88% simultaneous chemotherapy was applied. Median follow-up was 59 months. Results: Local failure was observed in 17 patients (7%), resulting in a 5-year local control rate of 92%. Only complete resection and absence of nodal involvement correlated positively with local control. Considering IOERT fields, seven infield recurrences were seen in the presacral space, resulting in a 5-year local control rate of 97%. The remaining local relapses were located as follows: retrovesical/retroprostatic (5), anastomotic site (2), promontorium (1), ileocecal (1), and perineal (1). Conclusion: Intraoperative electron beam radiotherapy as part of a multimodal treatment approach including TME is a highly effective regimen to prevent local failure. The presacral space remains the site of highest risk for local failure, but IOERT can decrease the percentage of relapses in this area. (c) 2007 Elsevier Inc
    Type of Publication: Journal article published
    PubMed ID: 17275208
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; SURVIVAL ; VITRO ; DENSITY ; MICE ; radiation ; MIGRATION ; GROWTH-FACTOR-BETA ; CELL-MIGRATION ; human glioma ; antiangiogenic therapy ; GLIOBLASTOMA ; VESSEL NORMALIZATION
    Abstract: Here we investigate the effects of the novel transforming growth factor-beta receptor I (TGF-beta RI) serine/threonine kinase inhibitor LY2109761 on glioblastoma when combined with the present clinical standard combination regimen radiotherapy and temozolomide (TMZ). Human GBM U87 (methylated MGMT promoter), T98 (unmethylated MGMT promoter), and endothelial cells (HUVECs) were treated with combinations of LY2109761, TMZ, and radiation. We found that LY2109761 reduced clonogenic survival of U87 and T98 cells and further enhanced the radiation-induced anticlonogenicity. In addition, LY2109761 had antimigratory and antiangiogenic effects in Matrigel migration and tube formation assays. In vivo, in human xenograft tumors growing subcutaneously on BALB/c nu/nu mice, LY2109761 delayed tumor growth alone and in combination with fractionated radiation and TMZ. Interestingly, as expected, the methylated U87 model was more sensitive to TMZ than the unmethylated T98 model in all experiments, whereas the opposite was found for LY2109761. Moreover, with respect to tumor angiogenesis, while LY2109761 decreased the glioblastoma proliferation index (Ki-67) and the microvessel density (CD31 count), the relative pericyte coverage (alpha-SMA/CD31 ratio) increased in particular after triple therapy, suggesting a vascular normalization effect induced by LY2109761. This normalization could be attributed in part to a decrease in the Ang-2/Ang-1 messenger RNA ratio. LY2109761 also reduced tumor blood perfusion as quantified by noninvasive dynamic contrast-enhanced magnetic resonance imaging. Together, the data indicate that the addition of a TGF-beta RI kinase inhibitor to the present clinical standard (radiation plus TMZ) has the potential to improve clinical outcome in human glioblastoma, especially in patients with unmethylated MGMT promoter status
    Type of Publication: Journal article published
    PubMed ID: 21677877
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  • 6
    Keywords: CANCER ; IRRADIATION ; radiotherapy ; tumor ; CELL ; Germany ; LUNG ; THERAPY ; TOXICITY ; lung cancer ; LUNG-CANCER ; COHORT ; DISEASE ; HISTORY ; RISK ; radiation ; ASSOCIATION ; CONFORMAL RADIOTHERAPY ; AGE ; smoking ; chemotherapy ; LOCALIZATION ; PREDICTION ; ESCALATION ; ONCOLOGY ; small cell lung cancer ; REGRESSION ; development ; NSCLC ; RADIATION PNEUMONITIS ; MODALITY ; CONCURRENT CHEMOTHERAPY ; Dose-volume constraints
    Abstract: Purpose: To analyze the association of patient- and treatment-related factors with the onset of radiation pneumonitis in a homogeneously treated cohort of patients suffering from small cell Lung cancer (SCLC). Patients and Methods: 242 patients with SCLC staged as limited disease, who had been treated with chemotherapy and three-dimensional conformal radiotherapy, were retrospectively analyzed. Pneumonitis was defined by typical symptoms and radiographic findings and judged clinically relevant, if drug administration and hospitalization were necessary. Patient- (age, gender, smoking history, performance status, tumor Localization, benign lung disease) and treatment-related parameters (V-10-V-40, mean lung dose [MLD]) were analyzed using chi(2)-tests for categorical parameters and Logistic regression for continuous variables. Results: 33 patients (13.6%) developed a clinically relevant pneumonitis, of whom three patients died. ALL cases of pneumonitis developed within 120 days. None of the patient-related parameters correlated significantly with the onset of pneumonitis. Considering treatment-related parameters, a significant correlation of V-30 in regard to total lung and V-40 in regard to ipsilateral, contralateral and total Lung to the risk of pneumonitis was found. So, the estimated risk of a clinically relevant pneumonitis increased from 10% given a V-30 of 13% to 30% given a V-30 of 35%. In contrast, no significant correlation was found for V-10 and V-20 and only a trend for MLD. Conclusion: In this series, high-dose radiation volume parameters, i.e., V-30 and especially V-40, were identified as the most important factors for the development of radiation pneumonitis. Low-dose radiation volume parameters and clinical parameters played an inferior role in predicting the pneumonitis risk
    Type of Publication: Journal article published
    PubMed ID: 20165822
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  • 7
    Keywords: CANCER ; CELLS ; radiotherapy ; SURVIVAL ; INHIBITION ; MORTALITY ; radiation ; T-CELLS ; RESECTION ; PHENOTYPE ; SAFETY ; adenocarcinoma ; microenvironment ; radiosensitivity ; endothelium ; stellate cells ; low dose radiation ; pancreatic cancer immune therapy
    Abstract: Background: The efficiencies of T cell based immunotherapies are affected by insufficient migration and activation of tumor specific effector T cells in the tumor. Accumulating evidence exists on the ability of ionizing radiation to modify the tumor microenvironment and generate inflammation. The aim of this phase I/II clinical trial is to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with pancreatic cancer. Methods/Design: This trial has been designed as an investigator initiated; prospective randomised, 4-armed, controlled Phase I/II trial. Patients who are candidates for resection of pancreatic cancer will be randomized into 4 arms. A total of 40 patients will be enrolled. The patients receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation precisely targeted to their pancreatic carcinoma. Radiation will be delivered by external beam radiotherapy using a 6 MV Linac with IMRT technique 48 h prior to the surgical resection. The primary objective is the determination of an active local external beam radiation dose, leading to tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include local tumor control and recurrence patterns, survival, radiogenic treatment toxicity and postoperative morbidity and mortality, as well as quality of life. Further, frequencies of tumor reactive T cells in blood and bone marrow as well as whole blood cell transcriptomics and plasma-proteomics will be correlated with clinical outcome. An interim analysis will be performed after the enrolment of 20 patients for safety reasons. The evaluation of the primary endpoint will start four weeks after the last patient's enrolment. Discussion: This trial will answer the question whether a low dose radiotherapy localized to the pancreatic tumor only can increase the number of tumor infiltrating T cells and thus potentially enhance the antitumor immune response. The study will also investigate the prognostic and predictive value of radiation-induced T cell activity along with transcriptomic and proteomic data with respect to clinical outcome
    Type of Publication: Journal article published
    PubMed ID: 21489291
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  • 8
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; PATHWAY ; VITRO ; STEM-CELLS ; GROWTH-FACTOR-BETA ; GLIOMA-CELLS ; EPITHELIAL-MESENCHYMAL TRANSITION ; INITIATING CELLS ; CANCER STEM
    Abstract: Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-beta is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-beta receptor (TGFbetaR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFbetaR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem-like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFbetaR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma.
    Type of Publication: Journal article published
    PubMed ID: 22006998
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  • 9
    Keywords: pancreatic cancer ; nuclear medicine ; PANCREATIC-CANCER ; ONCOLOGY ; radiology ; PATIENT ; NUCLEAR-MEDICINE ; BLOOD ; CANCER ; imaging ; Germany ; NUCLEAR ; MEDICINE
    Type of Publication: Meeting abstract published
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  • 10
    Keywords: ONCOLOGY ; GEMCITABINE ; PANCREATIC-CANCER ; radiology ; CANCER PATIENTS ; CANCER-PATIENTS ; PREDICTION ; IMRT ; nuclear medicine ; pancreatic cancer ; CANCER ; BLOOD ; NEW-YORK ; imaging ; PATIENT ; NUCLEAR-MEDICINE ; USA ; MEDICINE ; biomarker ; NUCLEAR ; outcome ; cetuximab
    Type of Publication: Meeting abstract published
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