Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluate the effects of adjuvant treatment with the angiogenesis inhibitor Avastin (bevacizumab) on pathological tissue specimens of high-grade glioma. Tissue from five patients before and after treatment with Avastin was subjected to histological evaluation and compared to four control cases of glioma before and after similar treatment protocols not including bevacizumab. Clinical and radiographic data were reviewed. Histological analysis focused on microvessel density and vascular morphology, and expression patterns of vascular endothelial growth factor-A (VEGF-A) and the hematopoietic stem cell, mesenchymal, and cell motility markers CD34, smooth muscle actin, D2-40, and fascin. All patients with a decrease in microvessel density had a radiographic response, whereas no response was seen in the patients with increased microvessel density. Vascular morphology showed apparent "normalization" after Avastin treatment in two cases, with thin-walled and evenly distributed vessels. VEGF-A expression in tumor cells was increased in two cases and decreased in three and did not correlate with treatment response. There was a trend toward a relative increase of CD34, smooth muscle actin, D2-40, and fascin immunostaining following treatment with Avastin. Specimens from four patients with recurrent malignant gliomas before and after adjuvant treatment (not including bevacizumab) had features dissimilar from our study cases. We conclude that a change in vascular morphology can be observed following antiangiogenic treatment. There seems to be no correlation between VEGF-A expression and clinical parameters. While the phenomena we describe may not be specific to Avastin, they demonstrate the potential of tissue-based analysis for the discovery of clinically relevant treatment response biomarkers.
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PMID:High-grade glioma before and after treatment with radiation and Avastin: initial observations. 1877 28

Diffuse brainstem glioma carries a dismal prognosis. The current cornerstone of treatment is radiation therapy. Chemotherapy appears to be ineffective and the role of this treatment in the recurrent or progressive setting is not known. Bevacizumab and irinotecan have been reported to have shown radiographic response and improvement in progression-free survival among patients with malignant supratentorial gliomas. In this paper, we report our experience in an adult patient with progressive diffuse brainstem glioma treated with bevacizumab and irinotecan.
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PMID:Bevacizumab and irinotecan treatment for progressive diffuse brainstem glioma: case report. 1950 12

The vascular effects of antiangiogenic treatment may pose problems for evaluating brain tumor response based on contrast-enhanced magnetic resonance imaging (MRI). We used serial dynamic contrast-enhanced MRI at 12 T to assess vascular responses to antiangiogenic versus steroid therapy. Athymic rats with intracerebral U87MG human glioma (n=17) underwent susceptibility-weighted perfusion MRI with ferumoxytol, a solely intravascular ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle, followed by T1-weighted dynamic gadodiamide-enhanced MRI to measure vascular permeability. Rats were imaged before and after 24, 48, and 72 h of treatment with the antiangiogenic agent bevacizumab or the corticosteroid dexamethasone. Contrast agent extravasation was seen rapidly after gadodiamide, but not with ferumoxytol administration. Bevacizumab significantly decreased the blood volume and decreased permeability in tumors as determined by increased time-to-peak enhancement. A single dose of 45 mg/kg bevacizumab resulted in changes analogous to dexamethasone given in an extremely high dose (12 mg/kg per day), and was significantly more effective than dexamethasone at 2 mg/kg per day. We conclude that dynamic perfusion MRI measurements with ferumoxytol USPIO to assess cerebral blood volume, along with dynamic gadodiamide-enhanced MR to assess vascular permeability, hold promise in more accurately detecting therapeutic responses to antiangiogenic therapy.
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PMID:Dynamic MRI using iron oxide nanoparticles to assess early vascular effects of antiangiogenic versus corticosteroid treatment in a glioma model. 1914 91

Interleukin-6 (IL6) and vascular endothelial growth factor (VEGFA) are abundantly produced by glioma cells and contribute to malignancy by promoting angiogenesis, cell proliferation and resistance to apoptosis. We compared the effect of inhibiting IL6 and VEGF on U87-derived experimental glioma grown on the chick chorio-allantoic membrane (CAM) or in the brain of xenografted mice. Tumor growth was monitored by biomicroscopy and immunohistology. In vitro, IL6 knockdown had no effect on proliferation but substantially enhanced invasion. In the CAM experimental glioma, IL6 or VEGF knockdown reduced growth and vascularization of the tumors with a comparable efficiency, but increased invasion of residual tumor cells. In contrast, combined IL6/VEGF knockdown not only showed enhanced reduction of tumor growth and angiogenesis but also significantly prevented invasion of residual tumor cells. In mice, combining IL6 knockdown and Avastin treatment completely abrogated tumor development and infiltration. Molecular response of tumor cells to single or combined treatment was studied by transcriptomic profiling. Many cell cycle promoting genes and chromatin components were silenced in the double knockdown. In addition, specific migratory signatures detected in tumors under single IL6 or VEGF knockdown were partially erased in combined IL6/VEGF knockdown tumors. Our results show that treatment with a combination of IL6 and VEGF inhibitors brings synergistic antitumoral benefit and reduces global activity of major pathways of cell survival, proliferation and invasiveness in remaining tumor cells that may be induced by using VEGF or IL6 inhibitors alone.
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PMID:Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness. 1943 Nov 43

Malignant gliomas are rare but lethal tumors in which the mainstays of therapy remain surgery and radiation therapy. Chemotherapy currently plays a primarily adjuvant role in the management of these patients with, unfortunately, little success in the recurrent disease setting. Barriers to efficacy of standard cytotoxic agents are related to drug-delivery challenges and inherent chemoresistance. Newer agents designed as directed antiglioma therapy are being explored with exciting preliminary results. Bevacizumab and other antiangiogenic drugs are likely to play a key role in the treatment of malignant glioma, as are combinations of molecularly targeted compounds. A greater understanding of cancer biology has afforded an increasing number and variety of oncogenic targets for therapeutic development, providing hope for brain tumor patients with historically poor outcomes.
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PMID:Chemotherapy for malignant gliomas. 1946 29

Bevacizumab is an anti-vascular endothelial growth factor (VEGF) antibody with activity against recurrent malignant glioma inducing high rates of objective responses as assessed by magnetic resonance imaging (MRI). However, the mechanisms of the anti-tumor action of bevacizumab are controversial. In particular, it is unclear whether and when bevacizumab induces hypoxia in gliomas. Vascular normalization with hyperperfusion and enhanced oxygen delivery to the tumor has been suggested as an alternative mechanism. We analyzed diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps in 18 consecutive patients with recurrent malignant glioma before and after exposure to bevacizumab. Stroke-like lesions with diffusion restriction on DWI and corresponding ADC decrease were induced by bevacizumab within the previously enhancing tumor area in 13 of 18 patients. These lesions were detectable as early as 4 weeks after initiation of therapy and were maintained for up to 80 weeks. In one patient, an ADC-decreased lesion was biopsied, and histology showed atypical necrosis and nuclear hypoxia-inducible factor 1alpha upregulation but no tumor recurrence. Normalized regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) were analyzed in selected patients. Both parameters were decreased in responders with diffusion-restricted lesions. Within the tumor bed, bevacizumab induces diffusion-restricted lesions in the presence of reduced rCBF and rCBV. The cause of these alterations is unclear but may involve atypical necrosis and chronic hypoxia.
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PMID:Bevacizumab-induced diffusion-restricted lesions in malignant glioma patients. 2003 66

Agents targeting the vascular endothelial growth factor (VEGF) pathway are being used with increasing frequency in patients with recurrent high-grade glioma. The effect of more than one antiangiogenic therapy given in succession has not been established. We reviewed the efficacy of bevacizumab, a VEGF-A monoclonal antibody, in patients who progressed following prior therapy with VEGF receptor tyrosine kinase inhibitors (R-TKi). Seventy-three patients with recurrent high-grade gliomas received VEGF R-TKi (cediranib, sorafenib, pazopanib, or sunitinib) as part of phase I or II clinical trials. Twenty-four of these patients with glioblastoma progressed and received bevacizumab-containing regimens immediately after R-TKi. Those who stopped R-TKi therapy for reasons other than disease progression, or received a treatment that did not include bevacizumab, were excluded from the analysis. The efficacy of bevacizumab-containing regimens in these 24 patients was evaluated. During R-TKi therapy, 6 of 24 patients (25%) had a partial response (PR) to treatment. The 6-month progression-free survival (APF6) was 16.7% and median time-to-progression (TTP) was 14.3 weeks. Grade III/IV toxicities were seen in 13 of 24 patients (54%). Subsequently with bevacizumab salvage therapy, 5 of 24 patients (21%) had a PR, the APF6 was 12.5%, and the median TTP was 8 weeks. Five of 24 patients had grade III/IV toxicities (21%). The median overall survival (OS) from the start of R-TKi therapy was 9.2 months (range: 2.8-34.1+), whereas the median OS after bevacizumab was 5.2 months (range: 1.3-28.9+). Bevacizumab retains modest activity in high-grade glioma patients who progress on R-TKi. However, the APF6 of 12.5% in this cohort of patients indicates that durable tumor control is not achieved for most patients.
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PMID:Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors. 2015 8

Glioblastoma Multiforme (GBM) is a uniformly fatal disease with a median survival of approximately 15 months. Recent monoclonal antibody therapies such as Bevacizumab (Avastin) have been shown to be active in GBM and to prolong survival in patients with recurrent malignant glioma. Therefore, patients routinely receive intravenous (i.v.) Bevacizumab (10 mg/kg) every two weeks when they have recurred following standard therapy with chemoradiation. I.v Bevacizumab; however, can cause significant systemic side effects including bowel perforation and pulmonary embolism. In addition, the blood brain barrier (BBB) continues to provide an obstacle to the effective delivery of the antibody to the brain tumor bed. In order to overcome the BBB, and to limit the systemic toxicity of i.v. Bevacizumab, we have begun a Phase I clinical trial to test the safety of transient blood brain barrier disruption with intraarterial (IA) Mannitol followed by superselective intraarterial cerebral infusion (SIACI) of Bevacizumab. This case report describes the technical aspects of this procedure and its associated benefits and risks. This novel delivery method, which may herald the revival of Interventional Neuro-oncology, may significantly alter the way therapy is administered to patients with GBM.
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PMID:Superselective intraarterial cerebral infusion of bevacizumab: a revival of interventional neuro-oncology for malignant glioma. 2019 20

Bevacizumab, a humanized monoclonal antibody designed to inhibit vascular endothelial growth factor, is effective in combination with chemotherapy against malignant gliomas. We examined the therapeutic effects and toxicity of bevacizumab as a single agent for the treatment of recurrent malignant glioma. This is a retrospective analysis of a case series of 18 adult patients, diagnosed with recurrent WHO grade III and IV gliomas. Patients were divided into two groups: group A (n=8) received bevacizumab at a dose of 10 mg/kg every two weeks; group B patients (n=10) were treated with salvage chemotherapy of lomustine (n=4), liposomal doxorubicin (n=4), temozolomide (n=1), or the combination of procarbazine, lomustine, and vincristine (n=1). The main study outcome measure was the 12-month progression-free survival probability; the objective radiological response was a secondary endpoint. Half of the patients treated with bevacizumab remained progression-free at 12 months as compared to none in group B (log-rank p=0.0067). In addition, 7/8 patients in group A showed a radiological response as compared to 4/10 in group B. Toxicity was mild and no intracranial hemorrhage was observed. The finding that bevacizumab has significant activity as a single agent against malignant glioma is important, particularly for those patients who are unable to tolerate traditional chemotherapy.
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PMID:Bevacizumab is active as a single agent against recurrent malignant gliomas. 2033 78

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promise in treating recurrent adult high-grade glioma (HGG). However, there is very little data on recurrent or progressive pediatric HGG treated with bevacizumab. We report the results of a single institution experience using bevacizumab and irinotecan in children who relapsed or progressed following standard therapy. Twelve pediatric patients with recurrent or progressive HGG received bevacizumab at 10 mg/kg every 2 weeks with irinotecan at 125 mg/m(2). Magnetic resonance imaging (MRI) was performed prior to therapy and every 8 weeks subsequently. Ten patients had supratentorial HGG; 2 had DIPG. Radiological responses were defined according to MacDonald's criteria. Progression-free survival (PFS), overall survival (OS), and toxicities were analyzed. Ten (83.3%) patients tolerated bevacizumab without serious toxicity. Therapy was discontinued in 1 patient because of anaphylaxis. Another patient developed grade III delayed wound healing and deep vein thrombosis. Two patients (16.7%) experienced a partial response after the first MRI. No complete radiographic responses were seen. Stable disease was noted in 4 (33.3%) patients. The median PFS and OS were 2.25 and 6.25 months, respectively. A diffuse invasive recurrence pattern was noted in 5 (45.5%) patients. Treatment tolerance, toxicity, and recurrence profiles were comparable to adult HGG patients treated with bevacizumab. However, the radiological response rate, response duration, and survival appeared inferior in pediatric patients. Genetic differences in pediatric gliomas might account for this difference.
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PMID:Bevacizumab in recurrent high-grade pediatric gliomas. 2036 68


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