Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, -2, and -3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas

Baumgarten, Peter; Blank, Anna-Eva; Franz, Kea; Hattingen, Elke; Dunst, Maika; Zeiner, Pia S.; Hoffmann, Katharina; Bähr, Oliver; Mäder, Lisa; Goeppert, Benjamin; Machein, Márcia Regina; Seifert, Volker; Steinbach, Joachim P.; Plate, Karl H.; Harter, Patrick N.; Mittelbronn, Michel

doi:10.1093/neuonc/nov288

Cited by 38 publications

(28 citation statements)

References 48 publications

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“…We only analyzed treatment‐naive patients at first diagnosis; recurrent glioma patients were excluded. During preparation of TMAs (previous descriptions of the cohort and TMA preparation ), we carefully selected representative tissue samples on whole mount sections consisting of vital tumor regions and avoiding marked necrotic areas. To rule out intraindividual differences, up to three repeated cores of the same patients were included in the TMAs.…”

Section: Methodsmentioning

confidence: 99%

“…For IHC analyses, the following antibodies were used: anti‐leukocyte common antigen CD45 (Dako, Hamburg, Germany; M0701, dilution for IHC 1:2000), anti‐CD68 (Dako; M0876, dilution for IHC 1:200), anti‐CD163 (Leica Biosystems, Novocastra, Nußloch, Germany; NCL‐CD163, dilution for IHC 1:50), anti‐CD206 (abcam; ab117644, dilution for IHC 1:100), anti‐Iba1 (Wako, Neuss, Germany; 019‐19741, dilution for IHC 1:1000) and anti‐MHCII (Dako; M0775, dilution for IHC 1:1000). IHC were performed according to standardized protocols using Discovery XT automated immunostainer (Ventana Medical Systems, München, Germany) as previously published and analyzed using a light microscope (BX41, Olympus, Hamburg, Germany).…”

Section: Methodsmentioning

confidence: 99%

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Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas

et al. 2019

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While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma‐associated microglia/macrophages (GAMs), on patients’ clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I–IV). Furthermore, we analyzed a cohort of 241 IDH1R132H‐non‐mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high‐grade astrocytomas by CD11b‐based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT‐PCR and bioinformatic analyses. A higher amount of CD68‐, CD163‐ and CD206‐positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro‐inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti‐inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2‐like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H‐non‐mutant GBMs.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas

et al. 2019

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“…However, no such clinically established, generally accepted biomarker does exist today. Like in other tumor entities, the simple expression of angiogenic target molecules, and also patterns of tumor vascularization, did not predict response to bevacizumab [29]. This lack of a predictive biomarker is clearly in sharp contrast to most other molecular therapies in oncology and might indeed be one explanation for the failure of anti-angiogenic therapies to prolong OS in unselected patients with malignant glioma.…”

Section: Can We Better Select Patients With Biomarkers?mentioning

confidence: 72%

Anti-Angiogenics: Their Role in the Treatment of Glioblastoma

2018

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Angiogenesis is a hallmark of glioblastomas, but anti-angiogenic therapies have fallen short of the initial expectations to relevantly change the clinical course of the disease. Only one agent, the anti-vascular endothelial growth factor (VEGF)-A antibody bevacizumab, has shown meaningful efficacy in controlled clinical trials in glioblastoma, so far. In primary and recurrent glioblastoma, this efficacy is, however, limited to prolonging progression-free survival and to generating some additional palliative benefits, without affecting overall survival in the total population of glioblastoma patients. Here, we give an overview of the current status of anti-angiogenic therapy in glioblastoma, including how it is currently used in the clinic. Furthermore, we discuss avenues of biomarker research aiming to identify those glioblastoma patients with a higher likelihood of profiting from anti-VEGF-A therapies (and to identify those who will not). Together with novel anti-angiogenic treatment targets and combination regimens under development today, those might improve the current clinical benefits from this class of drugs in glioblastoma.

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“…Similar immunohistochemistry protocols for different antibodies have been previously published. [3] Foreign body fragments are indicated by asterisks…”

Section: Case Presentationmentioning

confidence: 99%

Cerebral foreign body granuloma in brain triggering generalized seizures without obvious craniocerebral injury: A case report and review of the literature

et al. 2016

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Background:Intracerebral foreign body granuloma is rarely reported. We present the case of a male patient with a cerebral foreign body granuloma.Case Description:Initial admission of a 67-year-old male patient was after an aphasia followed by secondary generalized seizures. Cranial computed tomography (CCT) showed a metal-dense, wedge-shaped foreign body in the range of the frontal sinus on the left side, breaking through the frontal sinus, and creating a connection to the frontal cerebral lobe. The patient did not report previous trauma or accident. A concomitant inflammatory response could not be excluded in CCT imaging. In clinical examination, the patient showed no sensorimotor deficit. Operative resection and dural reconstruction was performed. Several tiny, metal-like foreign-body fragments and one stone-like body could be detected and removed. Histopathological examination showed an intracerebral granuloma with areas of acute granulocytic inflammatory reaction.Conclusion:Cerebral foreign body granuloma is a rare entity without initially provoking clinical symptoms, and causing clinical symptoms even years after the initial event. In most reported cases, wooden or metallic bodies are reported. In addition, hemostatic materials and non-resorbable cotton sheets can cause intracerebral granuloma. There is a high risk of infection with a high mortality rate in case of an existent intracranial abscess. In case of first presentation of seizures, a foreign body should be kept in mind if a traumatic injury cannot be reported. Therefore, possible foreign bodies provoking clinical symptoms such as seizures should always be radiologically excluded, and if present and operatively accessible, removal should be done as soon as possible.

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Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, -2, and -3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas

Abstract: Since our data indicate that beneficial response to bevacizumab treatment is independent of the expression of VEGF-A and its (co-) receptors, further investigation is needed to decipher the underlying mechanisms of antiangiogenic treatment response.

Cited by 38 publications

References 48 publications

Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas

Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas

Anti-Angiogenics: Their Role in the Treatment of Glioblastoma

Cerebral foreign body granuloma in brain triggering generalized seizures without obvious craniocerebral injury: A case report and review of the literature

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