Clinical Cooperation Unit Neurooncology

Bonn, Germany

Clinical Cooperation Unit Neurooncology

Bonn, Germany
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Kebir S.,University of Bonn | Khurshid Z.,University of Bonn | Gaertner F.C.,University of Bonn | Essler M.,University of Bonn | And 8 more authors.
Oncotarget | Year: 2017

Rationale: Timely detection of pseudoprogression (PSP) is crucial for the management of patients with high-grade glioma (HGG) but remains difficult. Textural features of O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography (FET-PET) mirror tumor uptake heterogeneity; some of them may be associated with tumor progression. Methods: Fourteen patients with HGG and suspected of PSP underwent FETPET imaging. A set of 19 conventional and textural FET-PET features were evaluated and subjected to unsupervised consensus clustering. The final diagnosis of true progression vs. PSP was based on follow-up MRI using RANO criteria. Results: Three robust clusters have been identified based on 10 predominantly textural FET-PET features. None of the patients with PSP fell into cluster 2, which was associated with high values for textural FET-PET markers of uptake heterogeneity. Three out of 4 patients with PSP were assigned to cluster 3 that was largely associated with low values of textural FET-PET features. By comparison, tumor-to-normal brain ratio (TNRmax) at the optimal cutoff 2.1 was less predictive of PSP (negative predictive value 57% for detecting true progression, p=0.07 vs. 75% with cluster 3, p=0.04). Principal Conclusions: Clustering based on textural O-(2-[18F]fluoroethyl)-Ltyrosine PET features may provide valuable information in assessing the elusive phenomenon of pseudoprogression.

Schafer N.,Medical Center Bonn | Schafer N.,University of Bonn | Gielen G.H.,Institute of Neuropathology | Kebir S.,Medical Center Bonn | And 18 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2016

Purpose: Dovitinib (TKI258) is an oral multi-tyrosine kinase inhibitor of FGFR, VEGFR, PDGFR β, and c-Kit. Since dovitinib is able to cross the blood–brain barrier and targets brain tumor-relevant pathways, we conducted a phase I trial to demonstrate its safety in recurrent glioblastoma (GBM). Patients and methods: Patients with first or second GBM recurrence started treatment with the maximal tolerated dose (MTD) previously established in systemic cancer patients (500 mg/d, 5 days on/2 days off). A modified 3 + 3 design in three cohorts (500, 400, 300 mg) was used. Results: Twelve patients were enrolled. Seventy-two adverse events (AEs) occurred and 16.7 % of AEs were classified as ≥CTC grade 3 toxicity, mainly including hepatotoxicity and hematotoxicity. Only one out of six patients of the 300-mg cohort showed grade 3 toxicity. The PFS-6 rate was 16.7 %, and it was not associated with detection of the FGFR-TACC gene fusion in the tumor. Conclusion: Dovitinib is safe in patients with recurrent GBM and showed efficacy in only some patients unselected for target expression. The recommended phase II dose of 300 mg would be substantially lower than the recently established MTD in systemic cancer patients. Further personalized trials are recommended. © 2016 Springer-Verlag Berlin Heidelberg

Kebir S.,University of Bonn | Kebir S.,Universities of Cologne and Bonn | Fimmers R.,University of Bonn | Galldiks N.,Universities of Cologne and Bonn | And 25 more authors.
Clinical Cancer Research | Year: 2016

Purpose: Pseudoprogression (PsP) is characterized by therapyassociated but not tumor growth-associated increases of contrastenhancing glioblastoma lesions on MRI. Although typically occurring during the first 3 months after radiochemotherapy, PsP may occur later in the course of the disease and may then be particularly difficult to distinguish from true tumor progression. We explored PET using O-(2-[18 F]fluoroethyl)-L-tyrosine (18 F-FET-PET) to approach the diagnostic dilemma. Experimental Design: Twenty-six patients with glioblastoma that presented with increasing contrast-enhancing lesions later than 3 months after completion of radiochemotherapy underwent 18F-FET-PET. Maximum and mean tumor/brain ratios (TBRmax and TBRmean ) of 18F-FET uptake as well as time-to-peak (TTP) and patterns of the time-activity curves were determined. The final diagnosis of true progression versus late PsP was based on follow-up MRI using RANO criteria. Results: Late PsP occurred in 7 patients with a median time from radiochemotherapy completion of 24 weeks while the remaining patients showed true tumor progression. TBRmax and TBRmean were significantly higher in patients with true progression than in patients with late PsP (TBRmax 2.4 o± 0.1 vs. 1.5 o± 0.2, P= 0.003; TBRmean 2.1 o± 0.1 vs. 1.5 o± 0.2, P = 0.012) whereas TTP was significantly shorter (mean TTP 25 o± 2 vs. 40 o± 2 min, P < 0.001). ROC analysis yielded an optimal cutoff value of 1.9 for TBRmax to differentiate between true progression and late PsP (sensitivity 84%, specificity 86%, accuracy 85%, P = 0.015). Conclusions: O-(2-[18 F]fluoroethyl)-L-tyrosine PET provides valuable information in assessing the elusive phenomenon of late PsP ©2015 American Association for Cancer Research.

Schaub C.,University of Bonn | Greschus S.,MediClin Robert Janker Klinik | Seifert M.,MediClin Robert Janker Klinik | Waha A.,MediClin Robert Janker Klinik | And 17 more authors.
Oncology (Switzerland) | Year: 2013

Objectives: In this study, we analyzed the prognostic value of different MRI progression patterns for survival in patients with recurrent malignant glioma treated with the vascular endothelial growth factor antibody bevacizumab. Patients and Methods: Twenty-six adult patients with recurrent malignant glioma treated with bevacizumab or bevacizumab/irinotecan were retrospectively analyzed for the development of contrast-enhanced (T1-weighted MRI) and T2/FLAIR lesions. According to the progression pattern, patients were divided into 3 subgroups: (1) patients with primarily progressive contrast-enhanced lesions in the first MRI after initiation of therapy ('primary PD group'); (2) patients with stable or regressive enhanced lesions but progressive FLAIR lesions ('FLAIR-only PD group'), and (3) patients with stable or regressive contrast-enhanced T1 and FLAIR lesions ('no PD group'). Results: Overall survival (OS) in the 6 patients in the FLAIR-only PD group was not significantly different from the 11 patients in the no PD group (median 311 vs. 254 days, respectively). In contrast, survival in the FLAIR-only PD group was significantly better (p = 0.025) than in the primary PD group. Conclusion: FLAIR-only progression is not an independent prognostic factor negatively influencing OS in recurrent glioblastoma treated with bevacizumab and should not lead to discontinuation of bevacizumab therapy. © 2013 S. Karger AG, Basel.

Bostrom J.P.,University of Bonn | Seifert M.,University of Bonn | Greschus S.,University of Bonn | Schafer N.,University of Bonn | And 6 more authors.
Strahlentherapie und Onkologie | Year: 2014

Background and purpose. Recently two retrospective cohort studies report efficacy of bevacizumab in patients with recurrent atypical and anaplastic meningioma. Another successful therapeutic option of bevacizumab seems to be treatment of cerebral radiation necrosis. However, the antiangiogenic effects in MRI diffusion and perfusion in meningiomas have not been previously described in detail. The objective of this research was to evaluate the clinical and MR imaging effects of bevacizumab in a malignant meningioma patient harboring additional cerebral radiation necrosis. Case presentation. We report the case of an 80-year-old woman who underwent bevacizumab therapy (5 mg/kg every 2 weeks for 2 months) for treatment of a symptomatic radiation necrosis in malignant meningiomatosis of World Health Organization (WHO) grade III. The patient was closely monitored with MRI including diffusion and perfusion studies. Upon bevacizumab therapy, the clinical situation was well stabilized over a period of 4 months until the patient unfortunately died due to pneumonia/septicemia probably unrelated to bevacizumab therapy. Consecutive MRI demonstrated 4 important aspects: (1) considerable decrease of the contrast medium (CM)-enhanced radiation necrosis, (2) mixed response with respect to the meningiomatosis with stable and predominantly growing tumor lesions, (3) a new diffusion-weighted imaging (DWI) lesion in a CM-enhanced tumor as described in gliomas, which we did not interpret as a response to bevacizumab therapy, and (4) new thrombembolic infarcts, which are a known side-effect of bevacizumab treatment. Conclusion. Bevacizumab is effective in the treatment of radiation necrosis. We could not confirm the potential antitumor effect of bevacizumab in this patient. However, we could describe several new radiographic effects of bevacizumab therapy in malignant meningioma. © 2014 Springer-Verlag.

Till A.,University of California at San Diego | Till A.,The San Diego Center for Systems Biology | Till A.,Life and Brain GmbH | Saito R.,The San Diego Center for Systems Biology | And 15 more authors.
Autophagy | Year: 2015

All eukaryotic cells utilize autophagy for protein and organelle turnover, thus assuring subcellular quality control, homeostasis, and survival. In order to address recent advances in identification of human autophagy associated genes, and to describe autophagy on a system-wide level, we established an autophagy-centered gene interaction network by merging various primary data sets and by retrieving respective interaction data. The resulting network (‘AXAN’) was analyzed with respect to subnetworks, e.g. the prime gene subnetwork (including the core machinery, signaling pathways and autophagy receptors) and the transcription subnetwork. To describe aspects of evolution within this network, we assessed the presence of protein orthologs across 99 eukaryotic model organisms. We visualized evolutionary trends for prime gene categories and evolutionary tracks for selected AXAN genes. This analysis confirms the eukaryotic origin of autophagy core genes while it points to a diverse evolutionary history of autophagy receptors. Next, we used module identification to describe the functional anatomy of the network at the level of pathway modules. In addition to obvious pathways (e.g., lysosomal degradation, insulin signaling) our data unveil the existence of context-related modules such as Rho GTPase signaling. Last, we used a tripartite, image-based RNAi – screen to test candidate genes predicted to play a role in regulation of autophagy. We verified the Rho GTPase, CDC42, as a novel regulator of autophagy-related signaling. This study emphasizes the applicability of system-wide approaches to gain novel insights into a complex biological process and to describe the human autophagy pathway at a hitherto unprecedented level of detail. © 2015 Taylor and Francis Group, LLC.

Schaub C.,University of Bonn | Tichy J.,Senckenberg Institute | Schafer N.,University of Bonn | Franz K.,Goethe University Frankfurt | And 14 more authors.
Journal of Neuro-Oncology | Year: 2016

The value of bevacizumab (BEV) in recurrent glioblastoma is unclear. Imaging parameters and progression-free survival (PFS) are problematic endpoints. Few data exist on clinical factors influencing overall survival (OS) in unselected patients with recurrent glioblastoma exposed to BEV. We retrospectively analyzed 174 patients with recurrent glioblastoma treated with BEV at two German brain tumor centers. We evaluated general patient characteristics, MGMT status, pretreatment, concomitant oncologic treatment and overall survival. Karnofsky performance score, number of prior chemotherapies, number of prior recurrences and combined treatment with irinotecan (IRI) were significantly associated with OS in univariate analysis. We did not find differences in OS related to sex, age, histology, MGMT status, prior surgical treatment or number of prior radiotherapies. Combined treatment with IRI and higher KPS both remained significantly associated with prolonged survival in multivariate analysis, but patients receiving IRI co-treatment had less advanced disease. Grouping into clinically relevant categories revealed an OS of 16.9 months from start of BEV in patients with first recurrence and KPS ≥ 80 % (n = 25). In contrast, in patients with second recurrence and KPS < 80 %, OS was 3.6 months (n = 27). Our observational data support an early use of BEV in patients with good performance status. The benefit of co-treatment with IRI in our cohort seems to be the result of biased patient recruitment. © 2016 Springer Science+Business Media New York

Kebir S.,University of Bonn | Gaertner F.C.,University of Bonn | Mueller M.,University of Bonn | Nelles M.,University of Bonn | And 12 more authors.
Oncology Letters | Year: 2016

Large demyelinating inflammatory central nervous system (CNS) lesions may present with contrast enhancement on magnetic resonance imaging and may mimic CNS tumors such as glioma. In ambiguous cases, new diagnostic tools that may be helpful for distinguishing between demyelinating inflammatory and neoplastic CNS lesions are required. The current study presents the case of a patient with a large contrast‑enhanced frontal brain lesion, who was initially diagnosed with tumefactive multiple sclerosis. Following the progression of the brain lesion, an18F‑fluoroethyl‑L‑tyrosine positron emission tomography (18F‑FET PET) was performed, revealing markedly elevated static18F‑FET uptake parameters along with time activity‑curves consistent with glioma. Subsequently, a biopsy was undertaken, which confirmed the presence of anaplastic oligoastrocytoma. This case illustrates that18F‑FET PET may provide useful diagnostic information in cases where distinction between neoplastic and demyelinating inflammatory CNS lesions is challenging. However, further systematic and prospective analyses are warranted to explore the value of this method in this setting. © 2016, Spandidos Publications. All rights reserved.

Schaub C.,University of Bonn | Schafer N.,University of Bonn | Mack F.,University of Bonn | Stuplich M.,University of Bonn | And 9 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2016

Purpose: The adequate second-line therapy of patients with glioblastoma (GBM) is a matter of ongoing debate. This particularly applies to patients with a non-methylated MGMT promotor who are known to have a poor response to alkylating chemotherapy. In some countries, antiangiogenic therapy with BEV is applied as second-line therapy, and in others nitrosourea therapy is second-line choice. It is an open question whether the delay of BEV to third-line therapy has a negative impact on survival. Methods: A total of 61 adult patients (median age 56.9 years) with MGMT-non-methylated relapsed GBM treated with BEV (n = 45) or nitrosourea (n = 16) as second-line therapy were analyzed retrospectively and compared regarding progression-free survival (PFS) and overall survival (OS). Results: Patients treated with second-line BEV had longer median PFS (107 days, 95 % CI 80.7–133.2 days) than patients with second-line nitrosourea (52 days, 95 % CI 36.3–67.7 days, P = 0.011, logrank test). However, there was no significant difference in overall survival (BEV median 170 days, 95 % CI 87.2–252.8 days; nitrosourea median 256 days, 95 % CI 159.9–352.0 days, P = 0.468). PFS was similar after BEV third-line therapy (median 117 days, 95 % CI 23.6–210.4 days) as compared to second-line BEV therapy (median 107 days, 95 % CI 80.7–133.3 days, P = 0.584). Conclusion: Our findings suggest that early treatment with BEV in patients with MGMT-non-methylated relapsed GBM is associated with a better PFS, but not with superior OS, possibly implicating that the early, i.e., second-line, use of BEV is not mandatory and BEV treatment may safely be delayed to third-line therapy in this subgroup of patients. © 2016 Springer-Verlag Berlin Heidelberg

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