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After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.

Cancer stem-like cells represent poorly differentiated multipotent tumor-propagating cells that contribute disproportionately to therapeutic resistance and tumor recurrence. Transcriptional mechanisms that control the phenotypic conversion of tumor cells lacking tumor-propagating potential to tumor-propagating stem-like cells remain obscure. Here we show that the reprogramming transcription factors Oct4 and Sox2 induce glioblastoma cells to become stem-like and tumor-propagating via a mechanism involving direct DNA methyl transferase (DNMT) promoter transactivation, resulting in global DNA methylation- and DNMT-dependent downregulation of multiple microRNAs (miRNAs). We show that one such downregulated miRNA, miRNA-148a, inhibits glioblastoma cell stem-like properties and tumor-propagating potential. This study identifies a novel and targetable molecular circuit by which glioma cell stemness and tumor-propagating capacity are regulated.

BACKGROUND: There is a need for more effective therapies in newly diagnosed glioblastoma (GBM) patients with an MGMT-non-methylated tumor. The GLARIUS trial explored the efficacy of bevacizumab (BEV) + Irinotecan (IRI) as compared to standard TMZ in the first-line therapy of MGMT-non-methylated GBM. The primary endpoint progression-free survival after 6 months (PFS-6) has already been reported as being markedly increased in the BEV/IRI arm (Herrlinger et al., ASCO 2013, LBA 2000). The present report focuses on progression-free survival, overall survival (OS) and quality of life (QoL). METHODS: Patients (n = 170) with newly diagnosed, MGMT-non-methylated glioblastoma received local radiotherapy (RT, 30 x 2 Gy) and were randomized (2:1) for experimental therapy with BEV (10 mg/kg q2w) during RT followed by maintenance BEV (10 mg/kg q2w) + IRI (125 mg/m2 q2w) or standard therapy with daily TMZ (75 mg/m2) during RT followed by 6 courses of TMZ (150-200 mg/m2/day for 5 days q4w). For 5 prespecified dimensions of the EORTC-QLQ C30 and BN20 questionnaires (global health status, physical functioning, social functioning, motor dysfunction, communication deficit as prespecified domains), the time to deterioration by at least 10 points was analyzed using Kaplan-Meier statistics. RESULTS: With BEV/IRI, PFS was significantly prolonged from a median of 5.9 months (95%CI 2.7-6.2 months) to 9.7 months (95%CI 8.5-10.6 months, p < 0.0001; hazard ratio 0.57, 95%CI 0.41-0.79). At progression, the crossover rate was 60.4% (TMZ to BEV/(IRI) and 61.9% (BEV/IRI to TMZ). OS did not show any difference between the two arms: median OS was 16.6 months (95%CI 15.4-18.35 months) in the BEV/IRI arm and 17.3 months (95%CI 14.8-20.4 months). In all prespecified dimensions of QoL, the time to deterioration was not significantly different between the treatment arms. CONCLUSION: BEV/IRI therapy was superior to TMZ regarding PFS but OS was not prolonged. BEV/IRI therapy did not alter QoL as compared to TMZ therapy.

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. 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. 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.

Purpose: Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pharmacotherapy remains an unmet medical need. Experimental Design: Screening of a compound library of 160 synthetic and natural toxic substances identified the antihelmintic niclosamide as a previously unrecognized candidate for clinical development. Considering the cellular and interindividual heterogeneity of glioblastoma, a portfolio of short-term expanded primary human glioblastoma cells (pGBM; n = 21), common glioma lines (n = 5), and noncancer human control cells (n = 3) was applied as a discovery platform and for preclinical validation. Pharmacodynamic analysis, study of cell-cycle progression, apoptosis, cell migration, proliferation, and on the frequency of multipotent/self-renewing pGBM cells were conducted in vitro, and orthotopic xenotransplantation was used to confirm anticancer effects in vivo. Results: Niclosamide led to cytostatic, cytotoxic, and antimigratory effects, strongly reduced the frequencies of multipotent/self-renewing cells in vitro, and after exposure significantly diminished the pGBMs' malignant potential in vivo. Mechanism of action analysis revealed that niclosamide simultaneously inhibited intracellular WNT/CTNNB1-, NOTCH-, mTOR-, and NF-κB signaling cascades. Furthermore, combinatorial drug testing established that a heterozygous deletion of the NFKBIA locus in glioblastoma samples could serve as a genomic biomarker for predicting a synergistic activity of niclosamide with temozolomide, the current standard in glioblastoma therapy. Conclusions: Together, our data advocate the use of pGBMs for exploration of compound libraries to reveal unexpected leads, for example, niclosamide that might be suited for further development toward personalized clinical application. Clin Cancer Res; 19(15); 4124–36. ©2013 AACR.

Intravascular diffuse large B-cell lymphoma limited to the CNS (cIVL) is a very rare malignant disorder characterized by a selective accumulation of neoplastic lymphocytes (usually B cells) within the lumen of CNS blood vessels but not in the brain parenchyma. In the past, treatment of cIVL with anthracycline-based regimens was unsatisfactory with very short survival times. In the case of cIVL presented here, high-dose methotrexate-based polychemotherapy according to the Bonn protocol plus rituximab therapy was successful and led to a complete clinical and MRI remission which is ongoing 29 months after diagnosis.

The conceptual development process is the joint effort of designers and future operators to elicit and analyze requirements and to design a system which plausibly meets these requirements. A continuous build-up of a structured product model that explicitly interrelates system design and its metrics to requirements is desirable. However, requirements and system modeling are usually conducted separately using different tools. Moreover, the phases of the development process are often separated in time, personnel, and space. This practice leaves a considerable number of system design decisions untraceable. We address these problems by two propositions: (1) A use case which describes an iterative, concurrent, and continuous refinement process of the requirements and system model, and (2) a framework that allows the creation of an integrated system and requirements model and the gradual application of increasingly rigorous rules on the model. We demonstrate our approach by a simple conceptual aircraft design example and discuss whether our approach is scalable and promotes the reuse of model parts.

Richter syndrome (RS) describes the development of high-grade non-Hodgkin’s lymphoma (NHL) from low-grade NHL. RS isolated to the brain is very rare and has a poor prognosis. We describe the cases of high-grade large B-cell diffuse NHL in a 56-year-old male with chronic lymphocytic leukemia and in a 71-year-old female with previously unknown low-grade NHL, both with initial appearance of neurological symptoms. This report extends the literature of central nervous system RS and particularly highlights the importance of a thorough diagnostic evaluation of patients with low-grade NHL presenting with neurological symptoms.

Activated mitogen-activated protein kinase MAPK cascade leading to ERK1/2 phosphorylation is expressed in the majority of glial neoplasms and negatively correlates with survival time of patients. Here we show that ERK1/2 kinases are constitutively activated in glioma cell lines and stem cell- enriched primary cultures of glioblastoma. Pharmacological targeting of the activated MEK/ERK1/2 module with the MEK inhibitor U0126 attenuates cell cycle progression (11 out of 11 cell lines), impairs single (7 out of 10) and collective cell migration (9 out of 11) and abolishes single cell emigration from monolayers (4 out of 9). Attacking the activated MEK/ ERK1/2 module thus partially blocks the tumorigenic potential of glial cancer cells on different levels and strongly suggests the application of combination molecularly targeted therapies to interfere more efficiently with glial tumor development and progression.

Using a multi-disciplinary optimization (MDO) approach to aircraft design introduces computational and organizational challenges to an aircraft design process1, 2. This paper presents an open source software tool for conceptual aircraft design called Conceptual Design Tool (CDT). CDT is developed as part of the Open Source for Concept Innovation (OSCI) project at Bauhaus Luftfahrt and addresses some organizational challenges introduced by an MDO approach to aircraft design.

The NOA-05 multicenter trial was performed to analyze the efficacy of primary chemotherapy with procarbazine and lomustine (PC) in patients with gliomatosis cerebri (GC) and to define clinical, imaging, and molecular factors influencing outcome.Thirty-five patients with previously untreated GC were treated with up to six 56-day courses of 110mg/m(2) lomustine on day 1 and 60mg/m(2) procarbazine on days 8 to 21. The primary endpoint was the rate of patients without therapy failure (defined as progressive disease, death from any cause, or termination of PC therapy before the end of course 4) at 8 months after the beginning of PC chemotherapy.The failure-free survival rate at 8 months was 50.3%. Median progression-free survival was 14 months. At progression, 12 patients received salvage radiotherapy. Median overall survival was 30 months. Multivariate analysis revealed isocitrate dehydrogenase 1 (IDH1) gene mutation (hazard ratio [HR], 0.11; 95% confidence interval [CI], 0.02-0.58) and initial presentation without a bilateral symmetrical infiltration pattern on magnetic resonance imaging (HR 0.07, 95%CI 0.01-0.54) as independent prognostic factors associated with prolonged survival. IDH1 mutation was significantly associated with MGMT promoter methylation and an oligodendroglial tumor component.PC chemotherapy is effective in GC. With the NOA-05 trial being the first prospective multicenter trial in GC, PC chemotherapy can be regarded as a promising option for the primary therapy of these tumors.

Residual tumor cells remain beyond the margins of every glioblastoma (GBM) resection. Their resistance to postsurgical therapy is considered a major driving force of mortality, but their biology remains largely uncharacterized. In this study, residual tumor cells were derived via experimental biopsy of the resection margin after standard neurosurgery for direct comparison with samples from the routinely resected tumor tissue. In vitro analysis of proliferation, invasion, stem cell qualities, GBM-typical antigens, genotypes, and in vitro drug and irradiation challenge studies revealed these cells as unique entities. Our findings suggest a need for characterization of residual tumor cells to optimize diagnosis and treatment of GBM.

Background: Gliomatosis cerebri (GC) is a diffuse infiltrating glial tumor with involvement of at least 3 cerebral lobes. There are only few data on the efficacy of initial chemotherapy in patients with GC. Patients and Methods: In 3 neurooncological centers, patients with newly diagnosed GC who had received procarbazine (60 mg/m2, days 8–21/56) and CCNU (110 mg/m2, day 1/56) chemotherapy (PC) as initial treatment were analyzed for progression-free survival, overall survival and toxicity. Results: Twelve patients (median age 46 years, range 27–72) were analyzed. The median progression-free survival and the median overall survival were 16 and 37 months. Grade 3 or 4 hematotoxicity was observed in 3 of 12 patients (25%). Conclusions: These data support the efficacy of PC chemotherapy in newly diagnosed GC. Initial PC chemotherapy should be considered as a treatment option and evaluated in larger clinical trials.

Background: Recurrent malignant glioma has a dismal prognosis, and therapeutic options are scarce. After previous potentially encouraging reports on liposomal pegylated doxorubicin (PEG-DOX) in this setting, PEG-DOX was applied to patients with recurrent malignant glioma in an institutional series. Methods: In a retrospective analysis, 49 patients with recurrent high-grade glioma (WHO III, n = 18; WHO IV, n = 31) were treated with PEG-DOX (days 1 and 14/28, 20 mg/m2, n = 26) alone or in combination with temozolomide (days 1–5/28, 200 mg/m2, n = 23). The response rate, progression-free survival and overall survival were evaluated. Results: The rate of progression-free patients at 6 months after initiation of therapy was 27% (WHO III, 33%; WHO IV, 23%). The median overall survival (mOS) after initiation of PEG-DOX (monotherapy and combination therapy) was 8 months (WHO III, 16 months; WHO IV, 7 months). The mOS after initiation of PEG-DOX monotherapy was 8 months, and after initiation of combination therapy, 10 months. Both regimens were well tolerated, with the main side effect being hematologic toxicity (grade 1–2, 8%; grade 3–4, 18%). Conclusion: These data demonstrate the safety and moderate efficacy of PEG-DOX ± temozolomide therapy in recurrent malignant glioma. The potential of this nonalkylating chemotherapy should be further explored.

BACKGROUND: The phase II GLARIUS trial assigned patients with newly diagnosed, O-6-methylguanine-DNA methyltransferase (MGMT) non-methylated glioblastoma to experimental bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ). BEV/IRI prolonged progression-free survival but overall survival (OS) was similar in both arms. To identify subpopulations with a particularly favourable course, we assessed the prognostic potential of magnetic resonance imaging (MRI) markers at baseline and during the first 4 months of treatment. METHODS: MRIs at baseline, 8, and 16 weeks after therapy initiation were analyzed for T1-hyperintense and diffusion-restricted lesions, contrast-enhancing lesions qualifying for tumor progression (25% increase), and progression of Fluid-attenuated inversion recovery (FLAIR) hyperintense lesions. The MRI findings were correlated with survival. RESULTS: None of the baseline parameters was prognostic in the entire cohort or predictive in the BEV/IRI arm. The presence of diffusion-restricted lesions was neither prognostic nor predictive of BEV/IRI benefit at any timepoint. At 8 weeks of follow-up, 49 patients developing a new combined diffusion-restricted and T1-hyperintense lesion had significantly greater OS than 90 patients without such changes (median OS, 17.5 vs. 15.7 months, p = 0.003). This effect was significant in the BEV/IRI arm (median OS, 17.2 vs. 15.7 months, p = 0.026) whereas significance was narrowly missed in the TMZ arm (median, 18.0 vs. 14.8 months, p = 0.071). At 16 weeks, OS in BEV/IRI-treated patients experiencing exclusively progressive FLAIR hyperintensities (17 of 52 evaluable patients; median OS, 17.5 months) was no worse than in BEV/IRI-treated patients with no progression on FLAIR and T1-weighted contrast-enhancing images (median OS, 19.4 months). In contrast, patients with progressive contrast-enhancing lesions had significantly shorter OS (median, 14.3 months, p = 0.0003, logrank test). CONCLUSIONS: The development of combined T1-hyperintense and diffusion-restricted lesions in early follow-up MRIs is associated with improved OS, particularly in BEV/IRI-treated patients. FLAIR-only progression does not appear to be predictive of a worse outcome with BEV/IRI treatment.

BACKGROUND: We evaluated patterns of tumor progression in patients with primary glioblastoma who were assigned to undergo treatment with bevacizumab/irinotecan (BEV/IRI) versus standard temozolomide (TMZ) within the randomized phase II GLARIUS trial. METHODS: In 160 patients (106 BEV/IRI, 54 TMZ), we reviewed magnetic resonance imaging (MRI) scans at baseline and tumor progression. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) images we assessed tumor patterns and invasiveness. Tumor patterns were classified as either multifocal or local at baseline and progression; at progression, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations were calculated using Fisher's exact test. RESULTS: At baseline, 118 of 160 evaluable patients (73.8%) had a locally confined tumor. In the BEV/IRI arm 10% and in the TMZ arm 8% of patients with an initially local tumor growth changed to a multifocal pattern (p = 0.78); distant lesions were found in 24% in the BEV/IRI arm and 19% in the TMZ arm (p = 0.55). 8% of patients in the BEV/IRI arm and 11% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.58). CONCLUSIONS: The tumor progression and invasiveness patterns do not differ between BEV/IRI and TMZ-treated patients in the GLARIUS trial. BEV/IRI did not increase the rate of multifocal, distant or highly invasive tumors at the time of progression.

We report a now 74-year-old patient who was successfully treated with a methotrexate (MTX)-ssbased polychemotherapy protocol (Bonn protocol) for primary central nervous system lymphoma (PCNSL) in 1996. When presenting with an unusually late relapse after 13 years of tumor-free survival the diagnosis was made on the basis of clinical and radiological criteria. In the context of the very limited treatment options for recurrent PCNSL, it is reassuring that the re-application of high dose-MTX-based polychemotherapy, including intraventricular treatment, again succeeded in a sustained complete response with still low neurotoxicity.

BACKGROUND: In the GLARIUS trial, progression-free survival was significantly prolonged and overall survival was similar in both arms. The present report focuses on quality of life (QoL), Karnofsky performance score (KPS) and cognitive functioning during first-line and postprogression therapy. METHODS: Patients (n = 170) with newly diagnosed, MGMT-non-methylated glioblastoma were randomized 2:1 for bevacizumab (BEV)/irinotecan (IRI) therapy or standard temozolomide (TMZ) therapy. Every 3 months, KPS, QoL (EORTC-QLQ C30 and BN20) and cognitive functioning (MMSE) was determined. Analysis included a longitudinal mixed model analysis and a Kaplan-Meier analysis of the time to deterioration (10 points in QoL, points, 3 points in MMSE, 20% in KPS; tumor progression not regarded as an event). RESULTS: In KPS, MMSE and all 5 prespecified dimensions of QoL (global health status, physical functioning, social functioning, motor dysfunction, communication deficit) mixed model analyses and time to first deterioration analyses did not detect differences between the treatment arms. Time to deterioration of nausea/vomiting was shorter with BEV/IRI (p = 0.024). At progression, the crossover rate in the BEV/IRI arm (to TMZ) and in the standard TMZ arm (to BEV/(IRI) was identical with 65%. Time to postprogression deterioration was significantly longer in the standard TMZ arm receiving crossover BEV/(IRI) in the majority of patients regarding 13 of 26 QoL dimensions including prespecified global health status, social functioning, motor dysfunction, communication deficit. Time to postprogression deterioration was similar for MMSE, but for KPS it tended to be prolonged in the standard arm receiving crossover BEV/(IRI) (p = 0.09). CONCLUSION: Except for IRI-induced nausea/vomiting, first-line BEV/IRI therapy was not associated with any detrimental effects on QoL, performance status or cognition as compared to TMZ standard therapy. After progression, patients pretreated with TMZ in the standard arm had a prolonged stabilization of QoL in many dimensions presumably due to a high rate of crossover BEV therapy.

2042^ Background: There is a need for more effective therapies in newly diagnosed glioblastoma (GBM) patients with an MGMT-non-methylated tumor. The GLARIUS trial explored the efficacy of bevacizum...

Primary central system lymphomas (PCNSL) are highly proliferative tumors that require aggressive treatment, e.g. using high-dose methotrexate-based chemotherapy. Early histological diagnosis is crucial for proper management of PCNSL. Histological diagnosis is obtained through stereotactic biopsy which is usually performed upon demonstration of the typical hallmarks of PCNSL on MRI. This includes large, preferentially periventricular, homogenously contrast-enhancing lesions [1]. Although the MRI presentation of PCNSL is relatively uniform regarding the appearance as homogenously contrast-enhancing lesion(s), the MRI presentation of PCNSL may very rarely be atypical [2, 3] and may lead to significant delay in diagnosis and therapy initiation in such patients. We here present a patient with the rare case of a PCNSL without contrastenhancement. An 81-year-old patient presented with a 5-week history of rapidly progressive dementia. On examination, he was disoriented and showed psychomotor slowing and gait difficulty. The Mini Mental state examination (MMSE) revealed 16/30 points. He was HIV negative and all serological and biochemical tests were normal. The CSF examination showed just a slight increase in protein content (556 mg/l), no pleocytosis and no atypical cells. The MRI of the brain taken without prior steroid treatment revealed diffuse white matter changes involving both hemispheres. No pathological contrast-enhancement could be detected (Fig. 1). A diagnosis of gliomatosis cerebri was initially suspected. A biopsy was taken from the right frontal lobe. Histological examination revealed a diffuse large cell lymphoma (non-Hodgkin’s lymphoma of germinal B cell origin; Fig. 2). The present case highlights the fact that, in very rare cases, PCNSL may present as a non-enhancing lesion. Non-enhancing presentation was found in 1% of patients in a large series of immunocompetent patients [1] and is just one form of atypical MRI presentation of PCNSL. Another atypical form is the presentation with a central nonenhancing necrosis; this is found in 6–17% of immunocompetent PCNSL patients [1]. PCNSL without contrast uptake are usually caused by angiotropic large cell lymphoma or intravascular lymphomatosis [4]. In contrast, the present case did not show a particular angiotropic pattern but had the typical pattern of a diffuse large cell lymphoma with some perivascular accentuation (Fig. 2c). Unusual non-enhancing presentation may lead to substantial prolongation of definitive diagnosis and start of therapy. This underlines that PCNSL without contrast-enhancement has to be kept in the differential diagnosis of diffuse white matter disorders. Also, it further supports the importance of histologic verification before the onset of therapy. Since histological diagnosis of PCNSL may be greatly hampered by the use of lympholytic steroids prior to biopsy, it M. L. Lachenmayer and E. Blasius contributed equally.

Alterations of DNA methylation play an important role in gliomas. In a genome-wide screen, we identified a CpG-rich fragment within the 5′ region of the tumor necrosis factor receptor superfamily, member 11A gene (TNFRSF11A) that showed de novo methylation in gliomas. TNFRSF11A, also known as receptor activator of NF-κB (RANK), activates several signaling pathways, such as NF-κB, JNK, ERK, p38α, and Akt/PKB. Using pyrosequencing, we detected RANK/TNFRSF11A promoter methylation in 8 (57.1%) of 14 diffuse astrocytomas, 17 (77.3%) of 22 anaplastic astrocytomas, 101 (84.2%) of 120 glioblastomas, 6 (100%) of 6 glioma cell lines, and 7 (100%) of 7 glioma stem cell-enriched glioblastoma primary cultures but not in four normal white matter tissue samples. Treatment of glioma cell lines with the demethylating agent 5-aza-2′-deoxycytidine significantly reduced the methylation level and resulted in increased RANK/TNFRSF11A mRNA expression. Overexpression of RANK/TNFRSF11A in glioblastoma cell lines leads to a significant reduction in focus formation and elevated apoptotic activity after flow cytometric analysis. Reporter assay studies of transfected glioma cells supported these results by showing the activation of signaling pathways associated with regulation of apoptosis. We conclude that RANK/TNFRSF11A is a novel and frequent target for de novo methylation in gliomas, which affects apoptotic activity and focus formation thereby contributing to the molecular pathogenesis of gliomas.

13018 Background: There is no established standard chemotherapy for recurrent glioblastoma (GBM). In a previous trial (NOA-01), the combination of nimustine and teniposide showed efficacy in previously untreated GBM. After temozolomide has been established as the standard for primary therapy of GBM, nimustin and teniposide is now been used as a second or third line chemotherapy for recurrent GBM. However, there are no data on toxicity and efficacy of this regimen in recurrent GBM. Methods: In two neurooncological centers, all patients with recurrent glioblastoma who had received nimustine (90 mg/m2, day 1/42) and tenoposide (45–60 mg/m2, days 1–3/42) chemotherapy were analyzed retrospectively for progression-free survival, overall survival and toxicity. Results: Thirty-five patients, median age 51 years (range 25–71), all of them pretreated with temozolomide were identified. The rate of progression-free patients at 6 months after initiation of therapy was 29%. The median overall survival after initiation ...

2073 Background: Results from prospective clinical studies may not always be reproduced in clinical practice. Therefore it is important to compare data from clinical trials with data from compassionate use of the same treatment. Here, we present patients with relapsed high-grade glioma treated outside a clinical trial with liposomal pegylated doxorubin (PEG-DOX). Methods: This data was documented prospectively and compared to our earlier published study results. Forty-nine patients with recurrent high-grade glioma (WHO III: n=18; IV: n=31) were treated with PEG-DOX (days 1 and 14/28, 20 mg/m2) alone or in combination therapy with temozolomide (TMZ) (days 1 to 5/28, 200 mg/m2). The clinical response rate, time to progression, progression free survival and overall survival were evaluated. Results: The overall response rate including disease stabilization was 53% (WHO III: 61; IV: 48). PFS-6 was 27% (WHO III: 33%; IV: 23%). The median OS after initiation of PEG-DOX was 35 weeks (WHO III: 68; IV: 31). Comparison of PEG-DOX monotherapy and combination therapy revealed no significant difference. Both regimens were well tolerated, with the main side effect being hematologic toxicity (grade 1–2: 8%, grade 3–4: 18%). Conclusion: These data compare favorably with published data and underline the potential of PEG-DOX in this setting. In addition, the prolonged median OS after initiation of PEG-DOX for grade III-tumors (68 weeks) merits additional focus. No significant financial relationships to disclose.

11501 Background: Temozolomide (Temodar, TMZ) recently showed promising efficacy in an EORTC trial on first-line therapy of glioblastoma (Stupp R, 2005). Pegylated liposomal doxorubicin (Caelyx, PEG-DOX) was evaluated in patients with recurrent high-grade glioma and showed an overall response rate of 40% (Hau P, 2002). Therefore, a combination of both agents seems promising. Methods: TMZ was given orally 75 mg/m2 daily during standard radiotherapy (initiation) and 150–200 mg/m2 days 1–5 in 28 days starting 4 weeks after radiotherapy (maintainance). PEG-DOX was given as a short-time infusion in a dose-escalation regimen once prior to radiotherapy and on days 1 and 15 starting 4 weeks after radiotherapy. PEG-DOX was escalated for 5 mg/m2 in groups of three patients starting with 5 mg/m2 (group 1) and a highest dose of 20 mg/m2 (group 4). Results: In the dose escalation part of this study, the regime detailed above was feasible, tolerable, and able to induce objective responses and stabilizations in patients with glioblastoma. In the first treatment group (5 mg/m2 of PEG-Dox), one out of 7 evaluable patients had a dose limiting toxicity (DLT). In the second, third and fourth treatment groups, the regimen was tolerated without DLT. Concerning efficacy in the “treated-patients” analysis of 18 patients, 1 had a partial response in MRI, and 12 patients had tumor stabilization 4 weeks after conclusion of radiotherapy. Only 5 patients progressed early. Twelve patients responded with progression free survival times of 13 to 76 weeks. One patient is still progression free after 120 weeks of treatment. Conclusion: As no DLT was observed in dose group 4, MTD was not reached and we proceed to the efficacy phase of the trial with PEG-DOX in a dose of 20 mg/m2. Seventeen patients are included so far. Results will be compared to the published study EORTC 26981/22981 (Stupp R et al., 2005) which did set a new standard in the first-line treatment of glioblastoma as survival times of more than 14 months and a 2-year overall survival of 26% were reached. Regarding the promising preliminary survival data of study RNOP-09, we expect even better results with the regimen used in this protocol. [Table: see text]

Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.