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Schmid S.,Ludwig Maximilians University of Munich | Landry G.,Ludwig Maximilians University of Munich | Thieke C.,Ludwig Maximilians University of Munich | Verhaegen F.,GROW School for Oncology and Developmental Biology | And 5 more authors.
Physics in Medicine and Biology | Year: 2015

Proton range verification based on prompt gamma imaging is increasingly considered in proton therapy. Tissue heterogeneity normal to the beam direction or near the end of range may considerably degrade the ability of prompt gamma imaging to detect proton range shifts. The goal of this study was to systematically investigate the accuracy and precision of range detection from prompt gamma emission profiles for various fractions for intensity modulated proton therapy of prostate cancer, using a comprehensive clinical dataset of 15 different CT scans for 5 patients. Monte Carlo simulations using Geant4 were performed to generate spot-by-spot dose distributions and prompt gamma emission profiles for prostate treatment plans. The prompt gammas were scored at their point of emission. Three CT scans of the same patient were used to evaluate the impact of inter-fractional changes on proton range. The range shifts deduced from the comparison of prompt gamma emission profiles in the planning CT and subsequent CTs were then correlated to the corresponding range shifts deduced from the dose distributions for individual pencil beams. The distributions of range shift differences between prompt gamma and dose were evaluated in terms of precision (defined as half the 95% inter-percentile range IPR) and accuracy (median). In total about 1700 individual proton pencil beams were investigated. The IPR of the relative range shift differences between the dose profiles and the prompt gamma profiles varied between ±1.4 mm and ±2.9 mm when using the more robust profile shifting analysis. The median was found smaller than 1 mm. Methods to identify and reject unreliable spots for range verification due to range mixing were derived and resulted in an average 10% spot rejection, clearly improving the prompt gamma-dose correlation. This work supports that prompt gamma imaging can offer a reliable indicator of range changes due to anatomical variations and tissue heterogeneity in scanning proton treatment of prostate cancer patients when considering prompt gamma emission profiles. © 2015 Institute of Physics and Engineering in Medicine. Source


Dingemans A.-M.C.,GROW School for Oncology and Developmental Biology | Mellema W.W.,VU University Amsterdam | Groen H.J.M.,University of Groningen | Van Wijk A.,VU University Amsterdam | And 4 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. Experimental Design: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. Results: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). Conclusion: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy. © 2012 American Association for Cancer Research. Source


Hilgendorf I.,Albert Ludwigs University of Freiburg | Eisele S.,Albert Ludwigs University of Freiburg | Remer I.,Albert Ludwigs University of Freiburg | Schmitz J.,Rigel Pharmaceuticals | And 14 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective-: Spleen tyrosine kinase (SYK) has come into focus as a potential therapeutic target in chronic inflammatory diseases, such as rheumatoid arthritis and asthma, as well as in B-cell lymphomas. SYK has also been involved in the signaling of immunoreceptors, cytokine receptors, and integrins. We therefore hypothesized that inhibition of SYK attenuates the inflammatory process underlying atherosclerosis and reduces plaque development. Methods and results-: Low-density lipoprotein receptor-deficient mice consuming a high-cholesterol diet supplemented with 2 doses of the orally available SYK inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 59±6% compared with the respective controls. Lesions of fostamatinib-treated animals contained fewer macrophages but more smooth muscle cells and collagen-characteristics associated with more stable plaques in humans. Mechanistically, fostamatinib attenuated adhesion and migration of inflammatory cells and limited macrophage survival. Furthermore, fostamatinib normalized high-cholesterol diet-induced monocytosis and inflammatory gene expression. Conclusion-: We present the novel finding that the SYK inhibitor fostamatinib attenuates atherogenesis in mice. Our data identify SYK inhibition as a potentially fruitful antiinflammatory therapeutic strategy in atherosclerosis. © 2011 American Heart Association. All rights reserved. Source


Lambregts D.M.J.,MUMC | Beets G.L.,GROW School for Oncology and Developmental Biology | Maas M.,MUMC | Kessels A.G.H.,Maastricht University | And 9 more authors.
Annals of Surgery | Year: 2011

Objective: To prospectively assess the accuracy of gadofosveset-enhanced magnetic resonance imaging (MRI) for nodal staging and restaging in rectal cancer. Background: Accurate preoperative assessment of nodal disease in rectal cancer impacts treatment management. Staging with modern imaging techniques (computed tomography, MRI and endorectal ultrasound) is insufficiently accurate for clinical decision making. This study aims to assess the accuracy of MRI using a novel lymph node magnetic resonance contrast, gadofosveset, for nodal staging and restaging in rectal cancer using a per node comparison with histology as the reference standard. Methods: Sixty-eight patients underwent gadofosveset-enhanced MRI at 1.5T. Twenty-six patients (primary staging group I) were treated with total mesorectal excision (with or without preoperative 5 × 5 Gy) and 42 (restaging group II) underwent a long course of chemoradiation followed by a restaging MRI and resection. Nodes were scored as benign or malignant by 2 radiologists (experienced and junior reader) first on standard MRI, then on gadofosveset-enhanced MRI. For group I the primary staging MRI was compared with histology. In group II the second, restaging MRI was compared with histology. Results:: For the experienced reader, sensitivity, specificity, and area under the ROC-curve (AUC) improved from 76%, 82% and 0.84 on standard MRI to 80%, 97% and 0.96 on gadofosveset-MRI (P < 0.001). For the junior reader results improved from 69%, 85%, and 0.85 on standard MRI to 70%, 95%, and 0.93 on gadofosveset-MRI (P = 0.03). Interobserver agreement was good on both standard MRI (κ 0.73) and gadofosveset-MRI (κ 0.71). Conclusions: This study shows high reproducibility and significantly improved accuracy compared to standard MRI for gadofosveset-enhanced MRI for nodal staging and restaging in rectal cancer. Copyright © 2011 by Lippincott Williams & Wilkins. Source


Delvoux B.,GROW School for Oncology and Developmental Biology | D'Hooghe T.,University Hospital Gasthuisberg | Kyama C.,University Hospital Gasthuisberg | Koskimies P.,Forendo Pharma | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Endometriosis affects 10%of the women before menopause and has important personal, professional, and societal economic burdens. Because current medical treatments are aimed at reducing the symptoms only, novel therapeutic targets should be identified. Endometriosis is estrogen dependent and in some patients the endometriosis tissue is able to produce estrogens in an autocrine/paracrine manner. In a number of patients, this is the consequence of the high local activity of the 17β-hydroxysteroid-dehydrogenases (17β-HSDs), enzymes able to generate active estrogens from precursors with low activity. Objective: The objective of the study was to identify the 17β-HSD(s) responsible for the high local generation of estrogens in endometriosis and test the possibility to inhibit these enzymes for therapeutic purposes. Design: The expression of different 17β-HSDs involved in the estrogen metabolism was assessed by real-time PCR in eutopic and ectopic tissue from endometriosis patients (n = 14). These biopsies had previously confirmed unbalanced local 17β-HSD activity, which caused high estrogen generation. The possibility to block the synthesis of estrogens by one inhibitor specific for type 1 17β-HSD was assessed by HPLC in tissue lysates from endometriosis tissues (n = 27). Results: In all but one of the patients, a high type 1 17β-HSD level is associated with the unbalanced metabolism of estrogens, leading to higher estrogen synthesis in endometriosis than in the endometrium inside the uterus. Inhibition of type 1 17β-HSD restores to various extents, depending on the patient, the correct metabolism. In 19 of 27 patients analyzed (70%), the 17β-HSD type 1 inhibitor decreased the generation of 17β-estradiol by greater than 85%. Conclusions: Inhibition of 17β-HSD type 1 can be a potential future treatment option aimed at restoring the correct metabolic balance of estrogens in endometriosis patients with increased local 17β-HSD type 1 enzyme activity. (J Clin Endocrinol Metab 99: 276-284, 2014). © Copyright 2014 by The Endocrine Society. Source

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