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  • 1
    In: Neuro-Oncology, 2016, Vol. 18(8), pp.1035-1036
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: BBA - Reviews on Cancer, January 2013, Vol.1835(1), pp.61-75
    Description: Brain metastases (BM) occur in 20% to 40% of patients with cancer and result in significant morbidity and poor survival. The main therapeutic options include surgery, whole brain radiotherapy, stereotactic radiosurgery and chemotherapy. Although significant progress has been made in diagnostic and therapeutic methods, the prognosis in these patients remains poor. Furthermore, the poor penetrability of chemotherapy agents through the blood brain barrier (BBB) continues to pose a challenge in the management of this disease. Preclinical evidence suggests that new targeted treatments can improve local tumor control but our clinical experience with these agents remains limited. In addition, several clinical studies with these novel agents have produced disappointing results. This review will examine the knowledge of targeted therapies in BM. The preclinical and clinical evidence of their use in BM induced by breast cancer, non-small cell lung cancer and melanoma will be presented. In addition, we will discuss the role of antiangiogenic and radiosensitising agents in the treatment of BM and the current strategies available to increase BBB permeability. A better understanding of the mechanism of action of these agents will help us to identify the best targets for testing in future clinical studies.
    Keywords: Brain Metastases ; Targeted Therapies ; Angiogenesis ; Radiotherapy ; Blood–Brain Barrier ; Biology ; Chemistry
    ISSN: 0304-419X
    E-ISSN: 1879-2561
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(12), p.e0168113
    Description: Antiangiogenic treatment of glioblastomas with Bevacizumab lacks predictive markers. Myoinositol (MI) is an organic osmolyte, with intracellular concentration changes depending on the extracellular osmolality. Since Bevacizumab markedly reduces tumor edema and influences the tumor microenvironment, we investigated whether the MI concentration in the tumor changes during therapy.We used 1H-magnetic resonance spectroscopy to measure the MI concentrations in the tumor and contralateral control tissue of 39 prospectively recruited patients with recurrent glioblastomas before and 8-12 weeks after starting therapy. 30 patients received Bevacizumab and 9 patients were treated with CCNU/VM26 as control. We performed a survival analysis to evaluate MI as a predictive biomarker for Bevacizumab therapy.MI concentrations increased significantly during Bevacizumab therapy in tumor (p 〈 .001) and control tissue (p = .001), but not during CCNU/VM26 treatment. For the Bevacizumab cohort, higher MI concentrations in the control tissue at baseline (p = .021) and higher differences between control and tumor tissue (delta MI, p = .011) were associated with longer survival. A Kaplan-Meier analysis showed a median OS of 164 days for patients with a deltaMI 〈 1,817 mmol/l and 275 days for patients with a deltaMI 〉 1,817 mmol/l. No differences were observed for the relative changes or the post treatment concentrations. Additionally calculated creatine concentrations showed no differences in between subgroups or between pre and post treatment measurements.Our data suggest that recurrent glioblastoma shows a strong metabolic reaction to Bevacizumab. Further, our results support the hypothesis that MI might be a marker for early tumor cell invasion. Pre-therapeutic MI concentrations are predictive of overall survival in patients with recurrent glioblastoma treated with Bevacizumab.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(6), p.e0155315
    Description: Leptomeningeal dissemination of a primary brain tumor is a condition which is challenging to treat, as it often occurs in rather late disease stages in highly pretreated patients. Its prognosis is dismal and there is still no accepted standard of care. We report here a good clinical effect with a partial response in three out of nine patients and a stable disease with improvement on symptoms in two more patients following systemic anti-angiogenic treatment with bevacizumab (BEV) alone or in combination with chemo- and/or radiotherapy in a series of patients with leptomeningeal dissemination from primary brain tumors (diffuse astrocytoma WHO°II, anaplastic astrocytoma WHO°III, anaplastic oligodendroglioma WHO°III, primitive neuroectodermal tumor and glioblastoma, both WHO°IV). This translated into effective symptom control in five out of nine patients, but only moderate progression-free and overall survival times were reached. Partial responses as assessed by RANO criteria were observed in three patients (each one with anaplastic oligodendroglioma, primitive neuroectodermal tumor and glioblastoma). In these patients progression-free survival (PFS) intervals of 17, 10 and 20 weeks were achieved. In three patients (each one with diffuse astrocytoma, anaplastic astrocytoma and primitive neuroectodermal tumor) stable disease was observed with PFS of 13, 30 and 8 weeks. Another three patients (all with glioblastoma) were primary non-responders and deteriorated rapidly with PFS of 3 to 4 weeks. No severe adverse events were seen. These experiences suggest that the combination of BEV with more conventional therapy schemes with chemo- and/or radiotherapy may be a palliative treatment option for patients with leptomeningeal dissemination of brain tumors.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    In: Journal of Neurochemistry, February 2018, Vol.144(4), pp.421-430
    Description: Since there is growing evidence that a switch to glycolysis is one mechanism to evade anti‐angiogenic treatments, we asked whether ablation of oxidative phosphorylation is sufficient to induce bevacizumab resistance in glioma. LNT‐229 cells without functional mitochondria (rho cells) had a glycolytic phenotype and reduced reactive oxygen species. Hypoxia‐induced cell death was nearly abolished in rho cells. Mice carrying rho‐tumours were resistant against bevacizumab, additional treatment with the glycolysis inhibitor 2‐deoxy‐D‐glucose re‐established their sensitivity. Our results suggest that independency of oxidative phophorylation is sufficient to induce resistance against bevacizumab, and inhibition of glycolysis might be a therapeutic approach.
    Keywords: Bevacizumab ; Glioma ; Glycolysis ; Hypoxia Resistance ; Oxidative Phosphorylation
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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  • 6
    Language: German
    In: NeuroTransmitter, 1/2014, Vol.25(1), pp.38-44
    ISSN: 1436-123X
    Source: Springer (via CrossRef)
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(5), p.e0127123
    Description: Current pathological diagnostics include the analysis of (epi-)genetic alterations as well as oncogenic pathways. Deregulated mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in a variety of cancers including malignant gliomas and is considered a promising target in cancer treatment. Monitoring of mTORC1 activity before and during inhibitor therapy is essential. The aim of our study is to provide a recommendation and report on pitfalls in the use of phospho-specific antibodies against mTORC1-targets phospho-RPS6 (Ser235/236; Ser240/244) and phospho-4EBP1 (Thr37/46) in formalin fixed, paraffin embedded material.Primary, established cell lines and brain tumor tissue from routine diagnostics were assessed by immunocyto-, immunohistochemistry, immunofluorescent stainings and immunoblotting. For validation of results, immunoblotting experiments were performed. mTORC-pathway activation was pharmacologically inhibited by torin2 and rapamycin. Torin2 treatment led to a strong reduction of signal intensity and frequency of all tested antibodies. In contrast phospho-4EBP1 did not show considerable reduction in staining intensity after rapamycin treatment, while immunocytochemistry with both phospho-RPS6-specific antibodies showed a reduced signal compared to controls. Staining intensity of both phospho-RPS6-specific antibodies did not show considerable decrease in stability in a timeline from 0-230 minutes without tissue fixation, however we observed a strong decrease of staining intensity in phospho-4EBP1 after 30 minutes. Detection of phospho-signals was strongly dependent on tissue size and fixation gradient. mTORC1-signaling was significantly induced in glioblastomas although not restricted to cancer cells but also detectable in non-neoplastic cells.Here we provide a recommendation for phospho-specific immunohistochemistry for patient-orientated therapy decisions and monitoring treatment response.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Strahlentherapie und Onkologie, 2011, Vol.187(11), pp.722-728
    Description: Byline: Johanna Gerstein (1), Kea Franz (2), Joachim P. Steinbach (3), Volkert Seifert (2), Claus Rodel (1), Christian Weiss (1,4) Keywords: Glioblastoma multiforme; radiochemotherapy; temozolomide; Glioblastoma multiforme; Radiochemotherapie; Temozolomid Abstract: Background The objective of this retrospective analysis was to assess long-term outcome and prognostic factors of unselected patients treated for glioblastoma (GB) at a single center with surgery, standard radiotherapy (RT), and concomitant temozolomide (TMZ). From 1999--2005, the institutional protocol included surgery and RT with TMZ. From 2005 on, adjuvant TMZ was routinely added. Patients and Methods Between April 1999 and September 2009, 181 patients with GB were treated with RT (60 Gy in 30 fractions) and concomitant TMZ (75 mg/m.sup.2/day throughout RT). Biopsy only had been performed in 53 patients (29.3%), 128 patients (70.7%) had undergone resection, which was complete based on postoperative MRI in 51 patients (28.2%). Adjuvant TMZ was applied in 67 of 181 patients (37%). Results Median overall survival (OS) and progression-free survival (PFS) were 15.0 (95% CI, 13.1--16.8) and 7.2 months (95% CI, 5.9--8.5), respectively. After complete resection, partial/subtotal resection and biopsy, median OS was 23.20, 14.75, and 7.89 months (p 〈 0.001), respectively. In multivariate Cox proportional hazards regression models, extent of resection (p 〈 0.0001), Karnofsky's performance score (p 〈 0.0001) and adjuvant TMZ (p = 0.001) were significant independent prognostic factors for OS. RT with concomitant TMZ was well tolerated in the majority of patients and could be completed as scheduled in 146 patients (80.7%), while 11 patients (6.1%) discontinued RT. Another 35 patients (19.3%) interrupted concomitant chemotherapy. Conclusion RT with concomitant TMZ is a feasible regimen with acceptable toxicity in routine practice. Our data are compatible with a beneficial effect of adjuvant TMZ on OS and PFS. Abstract (German): Hintergrund Ziel dieser retrospektiven Analyse einer monoinstitutionellen Serie war es, Langzeitergebnisse sowie Prognosefaktoren nach Operation und simultaner Radiochemotherapie (RCT) mit Temozolomid (TMZ) zu untersuchen. Zwischen 1999 und 2005 erfolgte nach Operation eine RCT mit TMZ seit 2005 wurde routinemassig eine adjuvante TMZ-Chemotherapie hinzugefugt. Patienten und Methoden Von 04/1999 bis 9/2009, wurden 181 GB-Patienten mit einer kombinierten RCT (60 Gy in 30 Fraktionen) mit TMZ 75 mg/m.sup.2/Tag wahrend der RT behandelt. Eine alleinige Biopsie lag bei 53 Patienten (29,3 %) vor. 128 Patienten (70,7 %) wurden reseziert davon erreichten 51 Patienten (28,2 %) nach Massgaben eines postoperativen MRT eine komplette Resektion. Eine adjuvante TMZ-Therapie erhielten 67 der 181 Patienten (37 %). Ergebnisse Das mediane Gesamtuberleben (GU) und das progressionsfreie Uberleben (PFU) lag bei 15,0 (95 %-CI: 13,1--16,8 Monate) bzw. 7,2 Monaten (95 %-CI: 5,9--8,5 Monate). Nach kompletter Resektion, partieller/subtotaler Resektion bzw. Biopsie betrug das mediane GU 23,2 bzw. 14,75 und 7,89 Monate (p 〈 0,001). In der multivariaten Analyse waren Resektionsstatus (p 〈 0,0001), Karnofsky-Index (p 〈 0,0001) und adjuvante TMZ-Therapie (p = 0,001) unabhangige prognostische Faktoren. Von der Mehrzahl der Patienten wurde die kombinierte RCT gut vertragen und konnte bei 146 Patienten (80,7 %) vollstandig durchgefuhrt werden. Bei 11 Patienten (6,1 %) wurde die RT abgebrochen. Bei weiteren 35 Patienten wurde die konkomitante Chemotherapie unterbrochen. Schlussfolgerung Die kombinierte RCT mit TMZ ist in der klinischen Routine ein gut vertragliches Therapieregime mit einer akzeptablen Toxizitat. Die adjuvante Chemotherapie mit TMZ war mit einer Verbesserung des GU und PFU assoziiert. Author Affiliation: (1) Department of Radiotherapy and Oncology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany (2) Department of Neurosurgery, Johann Wolfgang Goethe University, Frankfurt/Main, Germany (3) Dr. Senckenberg Institute of Neurooncology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany (4) Department of Radiation Therapy and Oncology, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt/Main, Germany Article History: Registration Date: 01/01/2011 Received Date: 25/10/2010 Accepted Date: 16/06/2011 Online Date: 28/10/2011
    Keywords: Glioblastoma multiforme ; radiochemotherapy ; temozolomide
    ISSN: 0179-7158
    E-ISSN: 1439-099X
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  • 9
    In: Brain, 2017, Vol. 140(10), pp.2623-2638
    Description: Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Thiepold et al. report that mTOR complex 1 activation defines a tumour subgroup that is metabolically vulnerable. These results could help identify patients likely to benefit from metabolically active therapies such as anti-angiogenic treatment. Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from EGFR via mammalian target of rapamycin complex 1 (mTORC1) is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways in glioblastomas. Therefore, epidermal growth factor receptor and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that epidermal growth factor receptor and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting from hypoxia-induced cell death. We hypothesized that conversely mTORC1 activation sensitizes glioma cells to hypoxia-induced cell death. As a model for mTORC1 activation we used gene suppression of its physiological inhibitor TSC2 (TSC2sh). TSC2sh glioma cells showed increased sensitivity to hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway. Mechanistically, mTORC1 upregulated the first and rate limiting enzyme of the pentose phosphate pathway, G6PD. Furthermore, an increase in oxygen consumption in TSC2sh cells was detected. This appeared to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PPARGC1A and PPARGC1B (also known as PGC-1α and -β). The finding that mTORC1 activation causes an increase in oxygen consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify glioblastoma patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGFA-targeting antibody bevacizumab in future clinical evaluations.
    Keywords: Glioma ; Mtor ; Hypoxia ; Starvation ; Oxygen
    ISSN: 0006-8950
    E-ISSN: 1460-2156
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  • 10
    Language: English
    In: Cancer Research, 04/15/2013, Vol.73(8 Supplement), pp.3967-3967
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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