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Xue, Song, Man Hu, Jinming Yu, Bingjie Fan, and Ji Ma. "Correlation of PD-L1 with VEGF and KI-67 index in patients with primary glioma." Journal of Clinical Oncology 35, no. 7_suppl (March 1, 2017): 94. http://dx.doi.org/10.1200/jco.2017.35.7_suppl.94.
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94 Background: The treatment strategies for glioma, especially glioblastoma multiforme, are not effective. The programmed death ligand 1 (PD-L1) immune escape and increased angiogenesis may be two of the underlying sources of treatment resistance. However, the relationship between these pathways in human glioma is still unknown. Methods: Data for 64 patients with primary glioma recorded from June 2007 to December 2013 in Shan Dong Cancer Hospital were immunohistochemically evaluated for the expressions of PD-L1, VEGF, MMP-9 and KI-67 index. Image ProPlus software was used to quantify the mean optical density (MOD) of the immunohistochemical image. Results: PD-L1 expression was observed in 65.22% of low-grade glioma and 90.24% of high-grade glioma, respectively. The whole expression rate of PD-L1 in glioma was 81.25%. The expression of PD-L1 is significantly related to pathological grade ( p <0.001), VEGF ( p= 0.017) and KI-67 index ( p= 0.009). The mean of PD-L1 MOD in High-grade group was 0.1144±0.02754, higher than that in low-grade group, 0.005129±0.001441 ( p= 0.004). In addition, Expression of VEGF, MMP-9 and KI-67 was significantly different between low-grade and high-grade gliomas ( p= 0.008, 0.04, 0.004 for VEGF, MMP-9 and KI-67, respectively). When analyzed as a continuous variable, the expressions of PD-L1 was positively correlated with VEGF (r = 0.392, p= 0.001) and KI-67 (r = 0.388, p= 0.001). Conclusions: These data suggest, for the first time, that PD-L1 play an important role in glioma angiogenesis and proliferation potential, providing the possibility for considering additional combinations of targeted VEGF therapies and anti-PD-L1 immunotherapy for the treatment of human brain glioma.
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Badu, S. K. "The role of angiogenic factors eNOS / VEGF in the treatment of anaplastic glioma." Vestnik nevrologii, psihiatrii i nejrohirurgii (Bulletin of Neurology, Psychiatry and Neurosurgery), no. 11 (October 20, 2022): 883–92. http://dx.doi.org/10.33920/med-01-2211-07.
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Introduction: Anaplastic gliomas (AG) account for 6–15 % of all primary brain tumors. These include: anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligoastrocytoma (AOA), and rarer forms — anaplastic pleomorphic xanthoastrocytoma and anaplastic ganglioma. According to the data on these factors, endothelial nitric oxide synthase (eNOS) is promising in terms of the prognostic value of the course of the tumor process. It was reported that a number of vascular VEGF factors interact with eNOS, contributing to the formation of an intra-tumor vascular network, which can create conditions for uneven prolonged hypoxia, leading to the emergence of more stable tumor cells. Its role in the development of a higher anaplasia level has not been studied in isolation, which determines the relevance of this study. The prognostic role of changes in endothelial nitric oxide synthase (eNOS) in the continued growth and malignant transformation of anaplastic gliomas was studied. Results: Histological samples of brain tumors of 22 patients at the University Clinic in Nizhny Novgorod from 2017 to 2019 were examined and verified for the presence of high-grade III glioma, according to the data of the World Health Organization. The average age of the patients was 50.7 years. The material was obtained as a result of surgical removal of recurrent tumors after chemo and radiotherapy. Discussion: The microenvironment of anaplastic glioma plays an essential role in its pathogenesis. More importantly, angiogenesis, which causes the supply of glioma cells with oxygen, growth factors, nutrients, and hormones, is a significant process of tumor dissemination and growth. The degree of microvascular proliferation and angiogenesis was associated with poor survival rate, transition from a lower grade to a high grade, and relapse. In high-grade glioma, such as anaplastic glioma, neoangiogenesis is an important physiological process that provides adequate blood supply for the proliferation, survival, and invasion of glioma cells. Conclusion: The high mortality rate in gliomas underscores the urgent need for effective treatment. The glioma pathogenesis is complex and can be caused by various mechanisms, as evidenced by abnormal activation of tumor angiogenesis and mutation of isocitrate dehydrogenase. VEGF acts as a regulator of angiogenesis and is widely recognized as a critical factor in glioma development and progression. Our results suggest that VEGF and eNOS inhibition may be an effective way to control and/or block endothelial barrier damage and prevent tumor progression.
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Peles, Einat, Zvi Lidar, Amos J. Simon, Rachel Grossman, Dvora Nass, and Zvi Ram. "Angiogenic Factors in the Cerebrospinal Fluid of Patients with Astrocytic Brain Tumors." Neurosurgery 55, no. 3 (September 1, 2004): 562–68. http://dx.doi.org/10.1227/01.neu.0000134383.27713.9a.
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Abstract OBJECTIVE: Gliomas account for most primary brain tumors in adults, and survival correlates with the grade and vascularity of the tumor. The degree of tumor-related angiogenesis seems to be a significant predictor of tumor progression, recurrence, and metastatic spread in a variety of malignant diseases, including brain tumors. Our study's objective was to quantify the levels of two angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), in the cerebrospinal fluid (CSF) and serum of patients with gliomas and to correlate these levels with tumor grade, vascularity, and overall survival. METHODS: Twenty-six patients with the diagnosis of cerebral glioma (19 high-grade, 7 low-grade) comprised the study group. Ten patients with communicating hydrocephalus served as controls. Levels of VEGF and bFGF in the CSF and serum were determined using enzyme-linked immunosorbent assay analysis. Tumor vascularity was graded qualitatively using immunohistochemical staining for CD34. Nonparametric statistical techniques were used for data analysis. RESULTS: Median levels of bFGF and VEGF in the CSF were significantly higher in patients with high-grade glioma as compared with patients with low-grade glioma or hydrocephalus (bFGF levels, 52, 26, and 24 ng/ml, respectively, P < 0.0001; VEGF levels, 17.6, 7.2, and 8.3 ng/ml, respectively, P < 0.005). A significant correlation was found comparing CSF levels of bFGF with levels of VEGF (P < 0.001). The levels of the angiogenic factors in the CSF correlated with the degree of tumor vascularity and were adversely associated with patient survival. Serum levels of the angiogenic factors showed no correlation to tumor grade, vascularity, or survival. CONCLUSION: Our data suggest that CSF levels of bFGF and VEGF may serve as an additional marker for tumor grading and vascularity and may help predict survival.
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Newton, Herbert B. "Bevacizumab: Review of Development, Pharmacology, and Application to Brain Tumors." Clinical Medicine. Therapeutics 1 (January 2009): CMT.S2042. http://dx.doi.org/10.4137/cmt.s2042.
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Bevacizumab is a humanised monoclonal antibody targeted to the vascular endothelial growth factor (VEGF). VEGF is the ligand for VEGF receptors (VEGFR), which are important for the development and maintenance of the angiogenic phenotype in high-grade solid tumors, including malignant gliomas. An overview of angiogenesis, VEGF, VEGFR, and the pharmacology of bevacizumab will be presented. Bevacizumab is active in pre-clinical testing against glioma tissue cultures and xenograft models. In the clinical setting, in combination with irinotecan and other chemotherapy agents, it has shown significant activity in patients with glioblastoma multiforme (GBM) and other brain tumors. Objective responses on neuro-imaging have been noted in 30%-60% of reported cases. Prolongation of progression-free survival and overall survival have also been suggested in many reports. Treatment of bevacizumab is associated with potential side effects, including thromboembolic disorders, fatigue, intracranial hemorrhage, proteinuria, hypertension, and bowel perforation.
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BITERGE-SUT, Burcu. "A comprehensive analysis of the angiogenesis-related genes in glioblastoma multiforme vs. brain lower grade glioma." Arquivos de Neuro-Psiquiatria 78, no. 1 (January 2020): 34–38. http://dx.doi.org/10.1590/0004-282x20190131.
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Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.
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Vasconcelos, Vivian Castro Antunes, Gustavo Jacob Lourenço, Angelo Borsarelli Carvalho Brito, Victor Leal Vasconcelos, Marcos Vinicius Calfat Maldaun, Helder Tedeschi, Suely Kaue Nagashi Marie, Sueli Mieko Oba Shinjo, and Carmen Silvia Passos Lima. "Associations of VEGFA and KDR single-nucleotide polymorphisms and increased risk and aggressiveness of high-grade gliomas." Tumor Biology 41, no. 9 (September 2019): 101042831987209. http://dx.doi.org/10.1177/1010428319872092.
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Angiogenesis, induced by the vascular endothelial growth factor A through its ligation to the vascular endothelial growth receptor 2, has been described as a crucial point in high-grade glioma development. The aim of this study was to evaluate the influence of VEGFA–2578C/A, −2489C/T, −1154G/A, −634G/C, and −460C/T, and KDR–604T/C, −271G/A, +1192G/A, and +1719A/T single-nucleotide polymorphisms on risk and clinicopathological aspects of high-grade glioma. This case–control study enrolled 205 high-grade glioma patients and 205 controls. Individuals with VEGFA–2578 CC or CA, VEGFA–1154 GG, VEGFA–634 GC or CC, and VEGFA–460 CT or TT genotypes were under 2.56, 1.53, 1.54, and 1.84 increased risks of high-grade glioma, compared to others, respectively. And 1.61, 2.66, 2.52, 2.53, and 2.02 increased risks of high-grade glioma were seen in individuals with VEGFA–2578 CC plus VEGFA–1154 GG, VEGFA–2578 CC or CA plus VEGFA–634 GC or CC, VEGFA–2578 CC or CA plus VEGFA–460 CT or TT, VEGFA–1154 GG or GA plus VEGFA–634 GC or CC, and VEGFA 634 GC or CC plus VEGFA–460 CT or TT combined genotypes, respectively, when compared to others. The “CAGT” haplotype of KDR single-nucleotide polymorphisms was more common in patients with grade IV than in those with grade III tumors, and individuals carrying this haplotype were at 1.76 increased risk of developing grade IV tumors than others. We present, for the first time, preliminary evidence that VEGFA–2578C/A and VEGFA–1154G/A single-nucleotide polymorphisms increases high-grade glioma risk, and “CAGT” haplotype of the KDR gene alters high-grade glioma aggressiveness and risk of grade IV tumors in Brazil.
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Степанов, И. А., В. А. Белобородов, and М. А. Шамеева. "Molecular and cellular mechanisms of glioblastoma resistance to vascular endothelial growth factor inhibitors." ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia», no. 3() (September 16, 2020): 137–45. http://dx.doi.org/10.25557/0031-2991.2020.03.137-145.
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Представлен обзор современных источников литературы, посвященных изучению молекулярных и клеточных механизмов резистентности глиобластомы к антиангиогенным лекарственным средствам. Ангиогенез представляет собой важнейший патофизиологический механизм роста и прогрессирования глиобластомы за счет активного развития микрососудистой сети. Ускоренное развитие микрососудистой сети в глиобластоме происходит благодаря синтезу опухолевыми клетками большого количества фактора роста эндотелия сосудов (Vascular Endothelial Growth Factor, VEGF). Среди основных молекулярных и клеточных механизмов лекарственной устойчивости глиобластомы к анти-VEGF агентам принято относить VEGF-независимые пути ангиогенеза, активность клеток костного мозга и перицитов, а также сосудистую кооперацию, периваскулярную инвазию и феномен аутофагии. Изложены современные данные о рациональном и наиболее эффективном использовании анти-VEGF-лекарственных средств у пациентов с глиомами высокой степени злокачественности. Обозначены актуальные, остающиеся нерешенными вопросы, что обусловливает необходимость проведения дальнейших экспериментальных и клинических исследований, посвященных изучению механизмов лекарственной устойчивости глиобластомы к анти-VEGF-препаратам. This state-of-the-art review focuses on molecular and cellular factors associated with glioblastoma resistance to antiangiogenic drugs. Angiogenesis is an important pathophysiological mechanism for the growth and progression of glioblastoma facilitated by active development of microvasculature. The accelerated development of the microvascular network in glioblastoma occurs due to the synthesis of a large number of vascular endothelial growth factor (VEGF) by tumor cells Among the major molecular and cellular factors, glioblastoma drug resistance to anti-VEGF agents is commonly attributed to VEGF-independent pathways of angiogenesis, bone marrow cell and pericyte activity as well as to vascular co-option, perivascular invasion, and the phenomenon of autophagy. The authors provided current data on the rational and most effective use of anti-VEGF drugs for patients with high-grade gliomas. Relevant unsolved problems associated with drug resistance of glioblastoma to anti-VEGF drugs were highlighted.
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Kikuchi, Ryogo, Ryo Ueda, Katsuya Saito, Shunsuke Shibao, Hideaki Nagashima, Ryota Tamura, Yukina Morimoto, et al. "A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma." Journal of Clinical Medicine 8, no. 2 (February 20, 2019): 263. http://dx.doi.org/10.3390/jcm8020263.
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High-grade gliomas (HGGs) carry a dismal prognosis despite current treatments. We previously confirmed the safety and immunogenicity of a vaccine treatment targeting tumor angiogenesis with synthetic peptides, for vascular endothelial growth factor receptor (VEGFR) epitopes in recurrent HGG patients. In this study, we evaluated a novel vaccine therapy targeting not only tumor vasculature but also tumor cells, using multiple glioma oncoantigen (GOA)/glioma angiogenesis-associated antigen (GAAA) peptides in HLA-A2402+ recurrent/progressive HGG patients. The vaccine included peptide epitopes from four GOAs (LY6K, DEPDC1, KIF20A, and FOXM1) and two GAAAs (VEGFR1 and VEGFR2). Ten patients received subcutaneous vaccinations. The primary endpoint was the safety of the treatment. T-lymphocyte responses against GOA/GAAA epitopes and treatment response were evaluated secondarily. The treatment was well tolerated without any severe systemic adverse events. The vaccinations induced immunoreactivity to at least three vaccine-targeted GOA/GAAA in all six evaluable patients. The median overall survival time in all patients was 9.2 months. Five achieved progression-free status lasting at least six months. Two recurrent glioblastoma patients demonstrated stable disease. One patient with anaplastic oligoastrocytoma achieved complete response nine months after the vaccination. Taken together, this regimen was well tolerated and induced robust GOA/GAAA-specific T-lymphocyte responses in recurrent/progressive HGG patients.
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Gilbert, M. R., M. Wang, K. Aldape, A. Lassman, A. G. Sorensen, T. Mikkelson, M. Groves, M. Werner-Wasik, W. Regine, and M. Mehta. "RTOG 0625: A phase II study of bevacizumab with irinotecan in recurrent glioblastoma (GBM)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2011. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2011.
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2011 Background: Angiogenesis is a hallmark of GBM, making the tumor vasculature an attractive therapeutic target. In gliomas, vascular endothelial growth factor (VEGF) promotes both angiogenesis and invasion of tumor cells. Bevacizumab is a humanized monoclonal antibody against VEGF-A that rapidly reduces the concentration of VEGF in the circulation. Irinotecan may enhance efficacy by synergistic tumor endothelial cell death or improved tumor delivery of the chemotherapy via “normalized” tumor vasculature. Prior studies of this combination demonstrated high radiographic response and 6-month progression free (6-mPFS) rates. This study was designed to determine the efficacy and safety of this regimen in the cooperative group setting. Methods: Eligibility included age ≥ 18, centrally confirmed GBM or gliosarcoma, progressive or recurrent disease. Enzyme-inducing anticonvulsants were not allowed. Treatment was intravenous bevacizumab 10 mg/kg and irinotecan 200 mg/m2 every 2 weeks. Accrual goal was 57 eligible patients. Primary endpoint was 6-mPFS rate where an estimate of ≥ 35% would define efficacy (15% improvement over historical data). Results: Full enrollment (57) was achieved, median age was 57, median KPS was 80; all had prior radiation and temozolomide treatment. The 6m-PFS rate was 37% (95% CI: 24–50%), with 21 of 57 patients progression-free at 6 months. Moderate toxicity was noted with 21(37%) grade 3, seven (12%) grade 4, and one (<2%) treatment-related death (intracranial hemorrhage). There were six episodes of venous thrombosis, 14 episodes of grade 3 or 4 hematologic toxicity, predominantly lymphopenia (7), and neutropenia (4), no opportunistic infections or febrile neutropenia were noted. Other toxicities included fatigue (9), diarrhea (2), and hypertension (2). Conclusions: These results, in the cooperative group context, corroborate the efficacy of the bevacizumab and irinotecan combination for recurrent GBM with the 6m-PFS surpassing the predetermined efficacy threshold. Previously described toxicities were confirmed with a moderately high rate of venous thrombosis, one intracranial hemorrhage, and moderate hypertension. Studies to determine the contribution of the cytotoxic agent to efficacy and the role of bevacizumab in newly diagnosed GBM are planned. [Table: see text]
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Friedland, D. M., S. A. Ali, A. Ahmad, M. Rahman, G. Bejjani, and M. Braffet. "Bevacizumab plus irinotecan therapy in relapsed, heavily pre-treated malignant glioma: A case series." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 12500. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.12500.
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12500 Background: Endothelial proliferation has been recognized as a marker of high grade or aggressive glioma in several grading classifications and it has been demonstrated that the degree of microvascularity as assessed by the endothelial cell/capillary density correlates well with the biologic aggressiveness of these tumors. These features suggest that high grade gliomas are a suitable target for angiogenesis inhibiting therapies. Bevacizumab (B) is a humanized IgG1 monoclonal antibody to VEGF that has been shown to have activity in malignant gliomas when combined with irinotecan (CPT-11), a topoisomerase 1 inhibitor. Methods: We report a case series of 10 patients with recurrent, heavily pre-treated malignant glioma who were treated with the combination of B and CPT-11. Nine patients had WHO grade 4 tumors while one had a grade 3 lesion. All patients had failed standard therapy with primary resection followed by adjuvant chemotherapy and radiation. Most had also failed additional resection, chemotherapy and radiation after their initial relapse. The mean number of failed therapies in addition to adjuvant therapy prior to starting B and CPT-11 was 3 (range 1–6) and the median ECOG performance status was 2 (range 1–3). Nine patients were started on B at a dose of 5 mg/kg every 2 weeks and were given CPT-11 at a dose of 125 mg/m2 every week for 3 weeks with 1 week off. The tenth patient received B at a dose of 10 mg/kg but with CPT-11 at 125 mg/m2 every 2 weeks. Results: This regimen was well tolerated with no CNS hemorrhages or >grade 1 bleeding. One patient had treatment held for repair of an anal fissure but then had it restarted. One patient had a DVT while on therapy. The objective response rate was 80% (8 PR and 2 SD).The median progression- free interval on treatment is 25 weeks with 5 patients still having a response at the time of this report. In patients with progressive disease, the median time to progression is 25 weeks. The median overall survival has not been reached, and exceeds 6 months. There has been one death due to disease progression. Conclusion: The combination of B and CPT-11 is safe and has excellent activity even in this relapsed, heavily pre-treated population of patients with high grade malignant glioma, most of whom would not be candidates for clinical trials. No significant financial relationships to disclose.
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Narayana, A., S. Chheang, E. Knopp, N. Peccerelli, J. Babb, G. Johnson, M. Gruber, J. Allen, D. Zagzag, and M. Law. "Comparing cerebral blood volume and vascular permeability measurements with tumor volume measurements following anti-angiogenesis therapy in recurrent gliomas." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2030. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2030.
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2030 Background: Dynamic susceptibility contrast-enhanced MRI (DSC MRI) is emerging as an important adjunctive biomarker to assess the effectiveness of anti-angiogenic therapies in the treatment of brain tumors. The purpose of our study is to compare changes in relative cerebral blood volume (rCBV) and in perfusion-permeability index (KTrans) with those of tumor volume measurements (T1c, T2/Flair) in predicting tumor therapeutic response in recurrent high-grade gliomas treated with bevacizumab, an anti-VEGF monoclonal antibody. Methods: 11 patients were treated with one to four cycles of bevacizumab and CPT-11. Their histological diagnoses were: glioblastoma multiforme (n=7), anaplastic astrocytoma (n=2), anaplastic oligodendroglioma (n=1), and diffuse pontine glioma (n=1). All patients had baseline DSC MRI scans prior to the administration of bevacizumab and were followed clinically and radiographically with both conventional and DSC MRI. Mixed model regression was used to compare the pre-treatment and post-treatment levels of each response measure. Results: There were statistically significant reductions in both actual rCBV measurements and T1c enhancement following treatment with bevacizumab and CPT-11. The pretreatment rCBV and T1c rates of change (as determined per 100 days) correlated significantly with time (p values are 0.0229 and 0.0014, respectively), while only the post treatment rCBV demonstrated significant rate of change (p value = 0.0001), suggesting that rCBV may reflect the effects of bevacizumab better than tumor volume. However, when the changes in rate from pre- to post-treatment status were considered, both rCBV and T1c demonstrated significance (p= 0.0001, 0.0157, respectively). There was a trend towards females having higher mean levels of KTrans than males at the same time point relative to treatment onset, but the result was not statistically significant (p=0.072). Conclusions: rCBV as measured from DSC MRI can be used as a surrogate biomarker to determine therapeutic response to bevacizumab. This may influence the neurosurgical risk/benefit equation as well as alter the aggressiveness of the post-operative adjuvant therapy in patients with recurrent gliomas. No significant financial relationships to disclose.
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Neyns, B., C. Chaskis, M. Dujardin, H. Everaert, J. Sadones, N. N. Nupponen, and A. Michotte. "Phase II trial of sunitinib malate in patients with temozolomide refractory recurrent high-grade glioma." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2038. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2038.
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2038 Background: High-grade gliomas (HGG) are characterized by neo-angiogenesis. Sunitinib is a small molecule tyrosine kinase inhibitor that inhibits multiple receptors (including VEGFR, PDGFR, and c-Kit). We investigated sunitinib for the treatment of patients (pts) with temozolomide (TMZ) refractory recurrent HGG. Methods: Pts were recruited according to a 2-stage phase II design and received a daily dose of 37.5 mg sunitinib. T1 ± Gd and T2 weighted MRI images were obtained after 4 and 8 weeks of sunitinib and q8 weeks thereafter. We assessed the antiangiogenic effect by calculating the cerebral blood volume (CBV) and cerebral blood flow (CBF) from dynamic susceptibility (DSC) based perfusion MRI and determined the lesion-to-normal-white matter CBV (CBVLTN) and CBF (CBFLTN) ratios. Uptake of fluorinated fenyl-methyl-alanine within the CNS was assessed by PET at baseline and reassessed in responding pts. Results: 21 pts were enrolled (median age 43 [range 34–71]; M/F 15/6; KPS 90–80: 11 pts, KPS 70–60: 10 pts). All pts had PD following surgery, RT and TMZ. A total of 142 treatment weeks (range 2–84) were evaluated; 81% of the administrations were at the 37,5 mg-, 19% at the 25 mg dose level. Most frequent AEs were: skin toxicity (gr2, n = 1; gr 3, n = 1), fatigue (gr 2, n = 4), hypertension (gr 2, n = 3), diarrhea (gr 2, n = 2), mucositis (gr 3; n = 1), afebrile- (gr 2, n = 3) and febrile neutropenia (gr 3, n = 1; gr 4, n = 1), thrombocytopenia (gr 2, n = 4; gr 3, n = 1; gr 4, n = 1), and lymphocytopenia (gr 2, n = 2; gr 3, n = 4). Decrease in CBVLTN and CBFLTN was observed in 6/14 evaluable pts after 4 weeks of sunitinib, 5/19 evaluable pts had SD on T1±Gd after 8 weeks; one pt experienced a marked clinical improvement with a reduction in the tumor metabolism on PET. After a median follow-up of 11 months, median TTP and -OS are1,6 and 3,8 months respectively. Three pts with a secondary glioblastoma (age <40 year) had an objective PR when administered CCNU at PD under sunitinib (with a TTP of 2, 8 and +9 mths respectively). Characterization of the VEGFR, PDGFR, and Kit gene copy numbers and protein expression in the tumors is ongoing. Conclusions: Sunitinib at a continuous daily dose of 37.5 mg has a transient antiangiogenic effect in pts with recurrent HGG but is of insufficient clinical benefit to warrant further investigation as a single agent. [Table: see text]
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Gillespie, David L., Maria T. Aguirre, Sandhya Ravichandran, Lisa L. Leishman, Claudia Berrondo, Joseph T. Gamboa, Libo Wang, et al. "RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model." Journal of Neurosurgery 122, no. 2 (February 2015): 331–41. http://dx.doi.org/10.3171/2014.10.jns132363.
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OBJECT High-grade gliomas are the most common form of adult brain cancer, and patients have a dismal survival rate despite aggressive therapeutic measures. Intratumoral hypoxia is thought to be a main contributor to tumorigenesis and angiogenesis of these tumors. Because hypoxia-inducible factor 1α (HIF-1α) is the major mediator of hypoxia-regulated cellular control, inhibition of this transcription factor may reduce glioblastoma growth. METHODS Using an orthotopic mouse model with U87-LucNeo cells, the authors used RNA interference to knock down HIF-1α in vivo. The small interfering RNA (siRNA) was packaged using a novel multifunctional surfactant, 1-(aminoethyl) iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide] (EHCO), a nucleic acid carrier that facilitates cellular uptake and intracellular release of siRNA. Stereotactic injection was used to deliver siRNA locally through a guide-screw system, and delivery/uptake was verified by imaging of fluorescently labeled siRNA. Osmotic pumps were used for extended siRNA delivery to model a commonly used human intracranial drug-delivery technique, convection-enhanced delivery. RESULTS Mice receiving daily siRNA injections targeting HIF-1α had a 79% lower tumor volume after 50 days of treatment than the controls. Levels of the HIF-1 transcriptional targets vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), c-MET, and carbonic anhydrase-IX (CA-IX) and markers for cell growth (MIB-1 and microvascular density) were also significantly lower. Altering the carrier EHCO by adding polyethylene glycol significantly increased the efficacy of drug delivery and subsequent survival. CONCLUSIONS Treating glioblastoma with siRNA targeting HIF-1α in vivo can significantly reduce tumor growth and increase survival in an intracranial mouse model, a finding that has direct clinical implications.
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Zhukova, Nataliya, Kiri Chan, Kathryne Walshe, Peter A. Downie, and Paul Wood. "LGG-42. BEVACIZUMAB-ASSOCIATED SECONDARY AMENORRHEA AND PREMATURE OVARIAN FAILURE IN ADOLESCENT FEMALE PATIENTS WITH LOW-GRADE CNS DISEASE." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii374. http://dx.doi.org/10.1093/neuonc/noaa222.421.
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Abstract Compelling body of evidence exists to use bevacizumab, a humanized monoclonal anti-VEGF antibody, in selected paediatric patients with low-grade CNS tumours. Common toxicities of bevacizumab, hypertension, proteinuria, epistaxis, mucosal perforation, decreased wound healing are well reported. However, the effect of bevacizumab on female ovarian function and long-term fertility is still being documented. Current evidence for bevacizumab-associated decline in ovarian function is largely from breast and colon cancer cohorts where exposure to multimodal chemotherapy confounds causative relationships. Fertility counseling and oocyte cryopreservation is currently offered as standard of care to post-pubertal females at high risk of infertility due to high-dose radiation and chemotherapy. Adolescent females with low-grade CNS tumours on bevacizumab represent a unique population which could potentially be at high risk for infertility. We report 2 cases of adolescent girls treated with bevacizumab as a single agent and in combination with vinblastine for NF2-associated vestibular schwannomas and brainstem glioma respectively. Both patients were post-pubertal with established menstrual cycles and normal baseline FSH/LH/oestradiol/AMH values prior to commencement of therapy. They became amenorrhoeic shortly after starting of therapy with levels of FSH/LH/oestradiol suggestive of premature ovarian failure. One patient has remained asymptomatic, whereas the other has developed profound post-menopausal symptoms interfering with quality of life which necessitated commencement of hormone-replacement therapy. Appropriate pretreatment fertility investigation and consultation should be offered to all post-pubertal females starting on bevacizumab. Further research into the long-term effects of gonadal toxicity in both females and males with drugs inhibiting angiogenesis is needed.
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Park, Young Nyun, Young-Bae Kim, Kyung Moo Yang, and Chanil Park. "Increased Expression of Vascular Endothelial Growth Factor and Angiogenesis in the Early Stage of Multistep Hepatocarcinogenesis." Archives of Pathology & Laboratory Medicine 124, no. 7 (June 1, 2000): 1061–65. http://dx.doi.org/10.5858/2000-124-1061-ieoveg.
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Abstract Background.—Hepatocellular carcinoma (HCC) is known to receive its blood supply principally from the hepatic arteries. Recent studies have reported differences in the vascular supply, especially arterial supply among low- and high-grade dysplastic nodules (DNs) (also referred to as adenomatous hyperplasia and macroregenerative nodules) and HCCs. Increased expression of vascular endothelial growth factor (VEGF) has been reported in HCC. In addition, VEGF may play an important role in the early phases of hepatocarcinogenesis. Methods.—We immunohistochemically stained 7 low-grade DNs, 8 high-grade DNs, 11 early HCCs, 17 small HCCs, and 21 advanced HCCs with antibodies against VEGF, α-smooth muscle actin (to identify unpaired arteries, ie, arteries not accompanied by bile ducts, indicative of angiogenesis), CD34 (as a marker of sinusoidal capillarization), and proliferation cell nuclear antigen. Results.—Expression of VEGF was found in the hepatocytes and HCC cells. The degree of VEGF expression increased gradually according to the stepwise development of hepatocarcinogenesis. It was higher in high-grade DNs and early HCCs than in low-grade DNs. The hepatocytes and HCC cells adjacent to peliosis and fibrous septa showed stronger VEGF expression. Angiogenesis, unpaired arteries, and sinusoidal capillarization developed from low-grade DNs and gradually increased. It was highest in HCCs. The proliferation cell nuclear antigen labeling indexes of hepatocytes and HCC cells also increased gradually as hepatocarcinogenesis progressed. Small HCCs showed a higher status of neoangiogenesis and cell proliferation activity than advanced HCCs. The degree of VEGF expression was correlated with angiogenesis and cell proliferation activity. Conclusion.—We conclude that VEGF plays a significant role in angiogenesis, growth, and development of HCC.
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Pelloso, Luis Arthur F., Daniella Marcia Maranhao Bahia Kerbauy, Juliana Correa da Costa Ribeiro, Leonardo Caires Santos, Cesar Cilento Ponce, Maria Regina Regis Silva, and L. F. Chauffaille de Lourdes Maria. "Angiogenesis in Myelopoliferative Neoplasms." Blood 116, no. 21 (November 19, 2010): 5049. http://dx.doi.org/10.1182/blood.v116.21.5049.5049.
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Abstract Abstract 5049 Introduction: New blood vessel formation (angiogenesis) is a multistep process that involves extracellular matrix remodeling, endothelial cell migration and proliferation, capillary differentiation and anastomosis formation. Angiogenesis has a key role in tumor growth and spread. Vascular endothelial growth factor (VEGF) is a positive regulatory cytokine and has a key, rate-limiting dose in promoting tumor angiogenesis. Abnormal VEGF expression has been described in acute leukemias as well as lymphomas. The available data in chronic myeloproliferative neoplasms (MPN) suggests that microvascular density (MVD) and VEGF expression are involved in angiogenesis process. Aim: The aim of this study was to evaluate MVD, VEGF expression and its correlation with clinical parameters. Material and Methods: The study was performed according to the regulation of the Ethics comitee. We included 41 patients with newly diagnosed MPN and 6 controls [28 PV, 23 PMF, 6 secondary eryhtrocytosis] from 2006 through 2009. G-band karyotype, FISH analysis (chromosomes 5, 7, 8 and 20) and JAK2V617F mutation were done according to standard techniques. Two experienced pathologists assessed morphology on hematoxylin-eosin stained slides, bone marrow fibrosis on Gomori silver slides and fibrosis was determined according to Thiele criteria (Thiele et al 2005). Bone marrow MVD was visualized in paraffin tissue sections using CD34 immunohistochemical staining and classified using a score system 0–4. Immunoexpression of VEGF was done in bone marrow core biopsies. A VEGF score was based on VEGF-positive megakaryocytes vs VEGF-immunohistochemistry staining. Statistical analysis was done using Chi-square test. Results: Most of PV patients had a low MVD (grade 0+1) (73%), whereas the majority of PMF patients had high MVD (grade 2+4) (76 %). MVD score was higher in PMF than PV (median grade 3 vs 1, respectively p=0.8). There were no differences in MVD score (both PV and PMF) according to JAK2V617F mutation status (respectively p=0.79 and p=0.8). Interestingly, PV and PMF patients with high MVD presented high platelet count (315 vs 694 × 109/L in PV, 664 vs 985 ×109/L in PMF); and a high incidence of thrombosis (18.1 vs 50% in PV p=0.9; and 0 vs 26.3% in PMF). VEGF score was higher in PV than PMF (median score 3 vs 2 p=0.22). Thus, PV and PMF patients with low MVD presented a higher rate of abnormal karyotype than high MVD patients (18% vs 0 in PV; 33 vs 10,5% in PMF p=0.0002). We combined data and analyzed together PV and PMF patients who presented low MVD and high MVD. High MVD patients (n=23) were older than low MVD group (68 vs 59 p=0.77), had low hemoglobin value (12.5 vs 18.5g/dL p=0.10), presented high platelet count (738 vs 351 × 109/L) and had a high incidence of thrombosis (30.4 vs 15.3% p=0.98) but there was no difference in VEGF score (median score 3 p=0.39). There was a correlation of high MVD and advanced fibrosis in (r=0.54 Pearson test). Low and high MVD patients had similar JAK2V617F rate mutation (61.5 vs 60.8%, p=0.4) and low MVD patients presented a slightly higher incidence of abnormal cytogenetic findings (31 vs 6.6%). There was no correlation with MVD and VEGF score (r=0.34), age (r=0.17), platelet count (r=0.27). There were no differences in VEGF score according to JAK2V617F mutation status. There was a correlation between VEGF score (grade 2+3) and the occurrence of massive splenomegaly in PV patients (r=0.52 Pearson test). PV patients who presented advanced fibrosis had a high platelet compared to mild fibrosis (567 vs 1031× × 109/L). There were no changes in platetet count regarding to fibrosis degree in PMF. Discussion and Conclusions: According to our results we found increase of platetet count and thrombosis in patients with high MVD. VEGF score did not relate to MVD findings neither thrombosis. The occurrence of high MVD correlated with high platelet count and thrombosis, suggest that MVD mechanisms may determine clonal changes and influence platelet differentiation and survival. Probably other biological interactions such as abnormal signaling network in bone marrow may play a role in determining MVD changes in MPN. This question remains to be further validated and investigated in other studies. Our current data show that stromal abnormalities were correlated with thrombosis and raise the question of the evolutive changes in the hematopoietic stem cell leading to abnormal changes in bone marrow during the course of the disease. Disclosures: No relevant conflicts of interest to declare.
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Byrne, G. J., and N. J. Bundred. "Surrogate Markers of Tumoral Angiogenesis." International Journal of Biological Markers 15, no. 4 (October 2000): 334–39. http://dx.doi.org/10.1177/172460080001500411.
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Background Angiogenesis is a prerequisite for tumor growth and metastasis. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on endothelial cells as a result of vascular endothelial growth factor (VEGF) stimulation. Purpose To determine if measurement in serum of VEGF or VCAM-1 provides an accurate measure of tumor angiogenesis. Methods VCAM-1 and VEGF were measured in the serum of women with early and advanced breast cancer by ELISA. Levels were compared to levels of VCAM-1 and VEGF in women with normal breasts and levels of the endothelial glycoprotein von Willebrand factor. Levels of VEGF and VCAM-1 in women with early breast cancer were correlated with established clinicopathological prognostic markers and intratumoral microvessel density (IMD). Results In early breast cancer serum VCAM-1 correlated closely with the microvessel density in tumors (r=0.61, p<0.001). Women with lymph node-positive and high-grade tumors had higher levels of serum VCAM-1 than women with lymph node-negative and low-grade tumors. Serum VEGF demonstrated no correlation with established prognostic features or IMD. Levels of VCAM-1 and VEGF were raised in women with advanced breast cancer. Conclusion Serum VCAM-1 is a surrogate marker of angiogenesis in breast cancer and its measurement may help in the assessment of antiangiogenic drugs currently in phase II trials.
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Cheng, Quan, Anliu Tang, Zeyu Wang, Ning Fang, Zhuojing Zhang, Liyang Zhang, Chuntao Li, and Yu Zeng. "CALD1 Modulates Gliomas Progression via Facilitating Tumor Angiogenesis." Cancers 13, no. 11 (May 30, 2021): 2705. http://dx.doi.org/10.3390/cancers13112705.
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Angiogenesis is more prominent in anaplastic gliomas and glioblastoma (GBM) than that in pilocytic and diffuse gliomas. Caldesmon (CALD1) plays roles in cell adhesion, cytoskeletal organization, and vascularization. However, limited information is available on mechanisms underlying the effect of CALD1 on the microvascular facilitation and architecture in glioma. In this study, we explored the role of CALD1 in gliomas by integrating bulk RNA-seq analysis and single cell RNA-seq analysis. A positive correlation between CALD1 expression and the gliomas’ pathological grade was noticed, according to the samples from the TCGA and CGGA database. Moreover, higher CALD1 expression samples showed worse clinical outcomes than lower CALD1 expression samples. Biofunction prediction suggested that CALD1 may affect glioma progression through modulating tumor angiogenesis. The map of the tumor microenvironment also depicted that more stromal cells, such as endothelial cells and pericytes, infiltrated in high CALD1 expression samples. CALD1 was found to be remarkably upregulated in neoplastic cells and was involved in tumorigenic processes of gliomas in single cell sequencing analysis. Histology and immunofluorescence analysis also indicated that CALD1 associates with vessel architecture, resulting in glioma grade progression. In conclusion, the present study implies that CALD1 may serve as putative marker monitoring the progress of glioma.
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Eoli, Marica, Cristina Rabascio, Lucia Cuppini, Elena Anghileri, Serena Pellegatta, Angelica Calleri, Patrizia Mancuso, Paola Porrati, Francesco Bertolini, and Gaetano Finocchiaro. "Plasma levels of IL-8 and g-CSF in high-grade gliomas treated with bevacizumab." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 2083. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.2083.
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2083 Background: Bevacizumab, an anti-VEGF antibody, has shown significant activity in high grade gliomas (HGG). However, tumor recurrence inevitably occurs. Methods: We treated 63 recurrent HGG patients with poor prognostic factors with bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m2) every 2 weeks, and investigated IL-12, IL-13, IL-17, FGF basic, G-CSF, MIP-1b, PDGF-beta, plasma levels before starting treatment and every 8 weeks by Bioplex. Ten age- and sex-matched healthy controls were used for comparison. Results: After a median follow-up of 27 weeks, median OS and PFS were 33 and 18 weeks, respectively. PFS at 6 and 12 months were 32% and 12%, respectively. OS at 6 months was 60%. Toxicity was mild. Baseline higher amounts of IL-13 (48±174 pg/ml vs 3.44±0.9 pg/ml, p=0.0001) and lower amounts of MIP-1b (35.3±20.9 pg/ml vs 67.2±18.8 pg/ml, p=0.0002), PDGF-beta (1585.5±1585 pg/ml vs 7098±1585 pg/ml, p=0.0001) and VEGF (27±39.8 pg/ml vs 54.5±32 pg/ml, p=0.001) were detected in patients than in healthy controls. In a cohort of 15 non-responders (patients who progressed 8 weeks after treatment onset), baseline IL-8 (15.7±10.8 pg/ml vs 10.9±9.4 pg/ml, p=0.03) and G-CSF (113.3±54 pg/ml vs 84.9±59.2 pg/ml, p=0.03) were significantly higher than in patients responding to treatment. In the same cohort no significant reduction of VEGF and other cytokines was observed after 8 weeks of treatment, while a decrease of plasma VEGF was observed in the remaining patients (26±32 pg/ml vs 13.3±28.5 pg/ml, p=0.001). Furthermore, in a cohort of 22 long-term responders (patients who progressed after more than 18 weeks of treatment), levels of VEGF decreased after 8 weeks of treatment when compared to baseline, whereas no difference was observed in baseline levels (23.9±22.6 pg/ml vs 9.8±9.4 pg/ml, p=0.001). Conclusions: Data suggest that high levels of IL-8 and G-CSF at baseline associated with a lack of VEGF decrease after 8 weeks of treatment identify patients who are resistant to bevacizumab. This hypothesis should be tested in a large number of patients.
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Utami, Dini Andri, Salmiah Agus, Yenita, and Husna Yetti. "The Correlation of VEGF Expression with Grade of Differentiation and Lymphovascular Invasion in Bladder Infiltrating Urothelial Carcinoma." Majalah Patologi Indonesia 31, no. 2 (May 1, 2022): 409–16. http://dx.doi.org/10.55816/mpi.v31i2.499.
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Background
Urothelial carcinoma is the most common malignancy in the bladder with an incidence up to 95% and 70-85% of them are bladder infiltrating urothelial carcinoma. To improve the management of bladder urothelial carcinoma, prognostic factors are required. One such factor is angiogenesis, which affects growth, development and metastasis. Vascular endothelial growth factor (VEGF) is the main pro-angiogenic factor to control angiogenesis. Expression of VEGF is correlated with progression of bladder infiltrating urothelial carcinoma, such as grade and lymphovascular invasion. The aim of this study was to determine the correlation of VEGF expression with grade of differentiation and lymphovascular invasion in bladder infiltrating urothelial carcinoma.
Methods
This research was a retrospective observational cross sectional study with 48 cases of bladder infiltrating urothelial carcinoma in four Anatomical Pathology Laboratory in West Sumatera 2018 and 2019. Samples were reevaluated of HE slide for grade of differentiation and lymphovascular invasion. VEGF expressions in tumor cell s were analyzed using immunohistochemistry staining. Bivariate statistical analysis used Fisher's Exact test and value p<0.05 was considered significant.
Results
Bladder infiltrating urothelial carcinoma high grade had more positive VEGF expression (91.7%), while low grade had more negative VEGF expression (58.3%). Lymphovascular invasion positive was mostly found with positive VEGF expression (75%). Statistical analysis showed significant correlation between VEGF expression with grade of differentiation (p=0.001) and lymphovascular invasion (p=0.004).
Conclusion
The conclusion was VEGF expression had significant correlation with grade of differentiation and lymphovascular invasion of bladder infiltrating urothelial carcinoma.
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Tamura, Ryota, Yukina Morimoto, Mizuto Sato, Tetsuro Hikichi, Kazunari Yoshida, and Masahiro Toda. "A Pilot Study of the Adverse Events Caused by the Combined Use of Bevacizumab and Vascular Endothelial Growth Factor Receptor-Targeted Vaccination for Patients with a Malignant Glioma." Vaccines 8, no. 3 (September 2, 2020): 498. http://dx.doi.org/10.3390/vaccines8030498.
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Anti-angiogenic therapy, targeting vascular endothelial growth factor (VEGF)-A/VEGF receptors (VEGFRs), is beneficial for tumor growth prevention in a malignant glioma. A simultaneous blockade using both bevacizumab (Bev), which targets circulating VEGF-A, and a multi-kinase inhibitor on VEGFRs was more effective for advanced solid cancers, including melanoma and renal cell carcinoma. However, previous clinical trials demonstrated a high adverse event rate. Additionally, no studies previously assessed treatment efficacy and safety using both VEGF-A and VEGFR-targeted agents for malignant gliomas. We had conducted clinical trials investigating VEGFRs peptide vaccination in patients with malignant gliomas, in which the treatment exhibited safety and yielded therapeutic effects in some patients. The combined use of Bev and VEGFRs vaccination may enhance the anti-tumor effect in malignant gliomas. In this pilot study, the adverse event profile in patients treated with Bev after the vaccination was investigated to establish this treatment strategy, in comparison to those treated with Bev collected from the published data or treated with the vaccination alone. In our previous clinical studies on patients with malignant gliomas, Bev was administered to 13 patients after VEGFRs vaccinations. One patient had a Grade 4 pulmonary embolism. Two patients had Grade 2 cerebral infarctions. There were no significant differences in the adverse event rates among patients treated with Bev, with the vaccination, or with Bev after the vaccination. Although careful observation is imperative for patients after this combination treatment strategy, VEGFRs-targeted vaccination may coexist with Bev for malignant gliomas.
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Cheng, Ling-Gang, Wen He, Hong-Xia Zhang, Qian Song, Bin Ning, Hui-Zhan Li, Yan He, and Song Lin. "Intraoperative Contrast Enhanced Ultrasound Evaluates the Grade of Glioma." BioMed Research International 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/2643862.
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Objective. The aim of our study was to investigate the value of intraoperative contrast enhanced ultrasound (CEUS) for evaluating the grade of glioma and the correlation between microvessel density (MVD) and vascular endothelial growth factor (VEGF).Methods. We performed intraoperative conventional ultrasound (CUS) and CEUS on 88 patients with gliomas. All of the patients have undergone surgery and obtained the results of pathology. All patients have undergone intraoperative CUS and CEUS to compare the characteristics of different grade gliomas and the results of CUS and CEUS were compared with pathological results.Results. The time to start (TTS) and time to peak (TTP) of low grade glioma (LGG) were similar to those of edema and normal brain surrounding glioma. The enhanced extent of LGG was higher than that of the normal brain and edema. The TTS and TTP of high grade glioma were earlier than those of the edema and normal brain surrounding glioma. The enhancement of HGG was higher than that of LGG. The absolute peak intensity (API) was correlated with MVD and VEGF.Conclusion. Intraoperative CEUS could help in determining boundary of peritumoral brain edema of glioma. Intraoperative CEUS parameters in cerebral gliomas could indirectly reflect the information of MVD and VEGF.
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Vredenburgh, J. J., A. Desjardins, J. E. Herndon, J. Quinn, J. Rich, S. Sathornsumetee, H. S. Friedman, D. Reardon, S. Gururangan, and A. Friedman. "Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and irinotecan for treatment of malignant gliomas." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 1506. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.1506.
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1506 Background: The prognosis for recurrent malignant gliomas is poor, with a median survival <12 months, median progression-free survival <12 weeks and response rates <20%. Malignant gliomas have high concentrations of VEGF receptors, and the higher the VEGF receptor concentration, the worse the prognosis. Bevacizumab is a humanized IgG1 monoclonal antiblody to VEGF, which is synergistic with chemotherapy for most malignancies. Irinotecan is a topoisomerase 1 inhibitor, and has modest activity against recurrent malignant gliomas. Methods: We report a FDA approved phase II trial of bevacizumab and irinotecan for the treatment of recurrent malignant gliomas. 32 patients were enrolled, 23 with grade IV tumors (glioblastoma multiforme) and 9 with grade III tumors (anaplastic astrocytomas or oligodendrogliomas). All the patients had progressive disease and every patient had received prior radiation therapy and chemotherapy. Patients were treated every other week with bevacizumab 10 mg/kg and irinotecan 125 mg/m2 for patients not taking enzyme inducing anti-epileptic drugs or 340 mg/m2 for patients taking enzyme inducing anti-epileptic drugs. Results: The regimen was well tolerated with no CNS hemorrhages or >grade 1 systemic hemorrhages. Four patients were taken off study for thrombotic complications, 2 pulmonary emboli, 1 deep venous thrombus, and one thrombotic stroke. Two patients were discontinued secondary to grade 2 proteinuria and three were discontinued because they required non-neurosurgical surgery, appendectomy, repair of anal fissures and hip stabilization. The response rate was 63% (19 PRs and 1 CR). The median progression-free survival is 24 weeks. The median overall survival has not been reached, and exceeds 6 months. There have been ten deaths due to disease progression. Conclusions: The combination of bevacizumab and irinotecan is safe and one of the most active regimens against malignant gliomas. [Table: see text]
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Khorana, A. A., C. W. Francis, C. K. Ryan, M. B. Taubman, Y. C. Hu, and S. A. Ahrendt. "Tissue factor, angiogenesis and thrombosis in pancreatic cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 4001. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4001.
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4001 Background: Coagulation proteins are commonly activated in pancreatic cancer and are closely linked to regulation of angiogenesis. We investigated tumor cell expression of tissue factor (TF), the prime initiator of coagulation, and its association with parameters of angiogenesis, venous thromboembolism (VTE) and survival. Methods: Tissue cores from a bi-institutional retrospective series of patients consecutively resected between January 1994 and February 2002 and followed for a median period of 16 months were used to build a pancreatic cancer tissue microarray. TF expression was graded semiquantitatively using immunohistochemistry (IHC)(grade 0:negative, grade 1: 1- 33% positive, grade 2: 34- 66% positive and grade 3: > 66% cells positive) in pancreatic intraductal dysplasia (n=5) and resected pancreatic cancer (n=122). Study endpoints included correlation of TF with VEGF expression by IHC, microvessel density (MVD), clinical VTE and survival in resected patients. Patients with history of VTE, on anticoagulation or with inadequate follow-up were excluded from analysis of VTE outcomes (n=33). Results: TF expression was observed in all specimens with intraductal dysplasia and 108 resected pancreatic cancers (89%) but not in uninvolved pancreas. Sixty-six patients (54%) with resected pancreatic cancer were found to have high TF expression (defined as ≥ grade 2, the median score), and 56 patients (46%) had low or no TF expression. Tumors with high TF expression were more likely to also express VEGF (80% versus 27% with low TF expression, p<0.0001). Tumors with high TF expression had a higher median MVD (8 versus 5/tissue core with low TF expression, p=0.01). Resected patients with high TF expression had a VTE rate of 20% compared to 5.5% in patients with low TF expression (p=0.04). Median survival in tumors with high TF was 17.9 months versus 12.6 months in those with low TF (p=0.16). Conclusions: TF expression appears to occur early in pancreatic cancer pathogenesis. This is the first report describing an association of TF expression with VEGF expression, increased MVD and clinical VTE in resected pancreatic cancer, confirming the linkage of thrombosis and angiogenesis. Targeting TF in pancreatic cancer could affect both neoplastic and thrombotic outcomes. No significant financial relationships to disclose.
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Papassotiriou, Gerasimos-Petros, Evangelos Terpos, Efstathios Kastritis, Maria Gkotzamanidou, Filia Apostolakou, Evangelos Eleutherakis-Papaiakovou, and Meletios Athanasios Dimopoulos. "High Circulating Vascular Endothelial Growth Factor Receptor-1 Correlates with Increased Microvessel Density and Inferior Survival in Newly-Diagnosed Patients with Multiple Myeloma Who Receive Frontline Therapy with Novel Agent-Based Regimens." Blood 118, no. 21 (November 18, 2011): 5082. http://dx.doi.org/10.1182/blood.v118.21.5082.5082.
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Abstract Abstract 5082 Vascular Endothelial Growth Factor Receptor-1 (VEGF-R1) is a receptor tyrosine kinase specific for the angiogenic factors VEGF-A, VEGF-B and placenta growth factor (PlGF), which is also a member of the VEGF family. In contrast to VEGF, the role of PlGF and VEGFR-1 in neovascularization is less clear. Angiogenesis is increased in patients with multiple myeloma (MM) and correlated with inferior outcome in several studies. The role of PlGF and VEGFR-1 has not been evaluated in MM. Therefore, we measured the circulating levels of PlGF and VEGFR-1: i) in 64 patients with newly diagnosed myeloma: 16 with asymptomatic disease (7M/9F; median age 59 years, range 37–82 years) and 48 with symptomatic myeloma (30M/18F; median age 70 years, range 45–89 years; ii) in 8 patients with MGUS (4M/4F; median age 72 years, range 39–84 years); and iii) in 20 healthy, gender and age-matched controls. PlGF and sVEGFR-1 were measured in serum samples using an electrochemiluminescence immunoassays (ECLIA) on a cobas e411 immunology analyzer (Roche Diagnostics, Mannheim, Germany). We also explored possible correlations between PlGF and VEGFR-1 circulating levels with clinical and laboratory values of the patients including microvessel density (MVD) of the bone marrow trephine biopsies and survival. Immunohistochemical identification of microvascular endothelial cells was performed in the trephine biopsies of MGUS and MM patients using a human monoclonal antibody against CD34 (DAKO A/S, Glostrup, Denmark). In each biopsy sample, microvessels were counted in at least 3 independent hot spots per section and the MVD of a bone marrow specimen was calculated as the mean value of all independent readings and recorded as the number of microvessels per ×400 field. When the microvessel count was 1–2, angiogenesis was characterized as low grade, while intermediate grade angiogenesis was defined by the presence of a microvessel count of 3–6 and high grade angiogenesis by the presence of microvessel count ≥7. Compared to controls, patients with symptomatic MM had elevated circulating PlGF (median: 19.5 pg/ml, range: 6.7–91.3 pg/ml vs. 16.1 pg/ml, 10.9–25.0 pg/ml of control group; p<0.01) and elevated VEGFR-1 levels (88.6 pg/ml, 51.5–320 pg/ml vs. 73.3 pg/ml, 62.9–100.8 pg/ml; p<0.001). Patients with MGUS and asymptomatic MM had no differences compared to controls for PlGF and VEGFR-1. In myeloma patients there was a strong correlation between circulating PlGF and VEGFR-1 levels (r=0.62, p=0.009 for asymptomatic patients and r=0.36, p=0.01 for symptomatic MM). PlGF also correlated with IL-6 (r=0.68, p<0.01) and high sensitivity CRP (r=0.5031, p<0.01) in MM patients. Of 16 patients with asymptomatic myeloma, 11 (68%) had low grade angiogenesis in the trephine biopsies and 5 (31%) intermediate grade angiogenesis; no one had high grade angiogenesis. There was no difference for PlGF levels between patients with low and intermediate grade angiogenesis in asymptomatic myeloma. However, patients with asymptomatic myeloma and intermediate grade angiogenesis had elevated VEGFR-1 (98.3 pg/ml, 87.1–148.9 pg/ml) compared to patients with low grade angiogenesis (72.3 pg/ml, 63.7–95.8 pg/ml). Similar results were obtained for patients with symptomatic myeloma. Of those, 18 (37%) had low grade angiogenesis in the trephine biopsies, while 20 (41%) had intermediate grade and 10 (20%) high grade angiogenesis. The median values and ranges of VEGFR-1 for low, intermediate and high grade angiogenesis were: 75.1 pg/ml (51.5–109.1 pg/ml), 94.2 pg/ml (61.2–143.8 pg/ml) and 151.8 pg/ml (103.7–320.0 pg/ml), respectively (p-ANOVA<0.0001). All patients with symptomatic myeloma received frontline therapy with novel agent-based regimens: 25 with lenalidomide-based regimens, 16 with thalidomide-based regimens and 7 with bortezomib-based regimens. The median follow-up period was 18.8 months and 8/47 patients have died. The probability of survival was 86% at 1 year and 78% at 2 years. In the univariate analysis the VEGFR-1 as a continuous variable correlated with higher risk of death (HR: 1.011, 95% CI: 1.004–1.018, p=0.003). In conclusion our study suggests that myeloma patients have increased circulating PlGF and VEGFR-1. High levels of VEGFR-1 correlated with increased angiogenesis and inferior survival, supporting a significant role of VEGFR-1 in the biology of angiogenesis in MM. Disclosures: No relevant conflicts of interest to declare.
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Fine, Howard A., William D. Figg, Kurt Jaeckle, Patrick Y. Wen, Athanassios P. Kyritsis, Jay S. Loeffler, Victor A. Levin, et al. "Phase II Trial of the Antiangiogenic Agent Thalidomide in Patients With Recurrent High-Grade Gliomas." Journal of Clinical Oncology 18, no. 4 (February 14, 2000): 708. http://dx.doi.org/10.1200/jco.2000.18.4.708.
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PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.
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Shpon’ka, I. S., and T. V. Shynkarenko. "Diagnostic value of microvessel structure in brain glial tumors." I.P.Pavlov Russian Medical Biological Herald 25, no. 3 (October 15, 2017): 350–61. http://dx.doi.org/10.23888/pavlovj20173350-361.
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Diffuse gliomas are the most common primary brain tumors with a disproportionately high mortality rate. Characteristics of microvessels are of high diagnostic and prognostic significance, however, the results of previous studies are controversial. The aim of the work is to evaluate the features of angiogenesis in diffuse gliomas on the basis of determining the qualitative and quantitative microvascular characteristics. Also important is their relationship with the histological type of tumor. Microvascular density (μm-1), total vascular area (%), total lumen area (%) and the mean diameter of microvessels (μm) were measured and calculated in diffuse brain gliomas (n=76) using GFAP-negative status of endothelium in the presence of exclusively GFAP-positive tumor cells. Proliferation of microvessels was evaluated using proliferation index of vascular epithelium (Ki-67). The possibility of routine evaluation of the angiogenesis in diffuse gliomas using GFAP and Ki-67 markers was defined. We revealed significant correlation between features of the neoplastic microvasculature and WHO Grade.
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Kuzman, James A., Boris G. Naraev, Anna M. Button, Megan I. Samuelson, Michael J. Goodheart, Barry DeYoung, Thomas M. O'Dorisio, and Thorvardur Ragnar Halfdanarson. "Expression of vascular endothelial growth factor receptor (VEGF-R) and CD31 receptor (CD31-R) in high-grade neuroendocrine carcinoma of the uterine cervix (cNEC) and its association with prognosis." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e15580-e15580. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e15580.
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e15580 Background: High-grade cNEC is uncommon cancer, and the optimal treatment is unclear. It is not known if cNEC expresses surface proteins related to angiogenesis. The aim of this study is to evaluate the expression of proteins involved in angiogenesis, as well as their possible association with clinical outcomes. Methods: Expression of VEGF-R and CD31-R was analyzed with standard immunohistochemical methods in tumor specimens from 16 patients with cNEC seen at our institution from 1977 to 2010. CD31-R expression was estimated by analyzing microvessel density using a CD31 specific antibody. Intensity and percentage of cells expressing VEGF-R was determined. Univariate survival analysis was performed using a Cox Proportional Hazard Model. Results: VEGF-R was expressed in 15 out of 16 specimens whereas CD31-R was expressed in all specimens. Increased VEGF-R expression correlated with shortened survival but the association was not statistically significant (p=0.0544, hazard ratio=1.514, CI=0.992-2.309). A one unit increase in VEGF-R expression correlated with increase in the risk of death by 51.4%. CD31-R expression showed no significant association with survival (p=0.9638,CI=0.865-1.165). Conclusions: VEGF-R and CD31-R are expressed by most cNECs. Increased VEGF-R, but not CD31-R, expression may be associated with worse survival. Further exploration of the role of angiogenesis in cervical NETs is warranted.
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Butta, Shristi, Mallika Pal, Suman Ghosh, and Manoj Kumar Gupta. "The role of vascular endothelial growth factor in predicting the tumor dynamics of meningiomas." International Journal of Research in Medical Sciences 9, no. 11 (October 28, 2021): 3397. http://dx.doi.org/10.18203/2320-6012.ijrms20214423.
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Background: Meningiomas are the most common tumors of the central nervous system with variable tumor dynamics. Histopathology is the gold standard but has its own constraints in predicting the tumor behavior. As intra- tumoral hypoxia leads to neo angio angiogenesis and subsequent tumor growth we envisage to establish the role of vascular endothelial growth factor (VEGF) in predicting the tumor dynamics of meningiomas.Methods: This observational, descriptive, longitudinal follow up study included 38 patients and spanned over a period of 2 years. Surgical samples were grossed and histo-pathologically analyzed and subsequently immune-histochemically categorized. Cases showing VEGF positivity were subjected to yearly follow up to ascertain the number of recurrent cases.Results: Majority of our cases belonged to WHO grade I (84.21%). The 73.68% were females. The 63.16% were aged >50 years. The 42.1 % of the total cases revealed moderate to strong VEGF expression. Majority of grade II and grade III meningiomas showed moderate to strong VEGF expression. However, a subgroup of grade I meningiomas also revealed a high immune-expression of VEGF (31.25%). Statistically significant association was found between VEGF expression and WHO grade (p=0.0001). On follow up 34.21% of the cases showed recurrence. Significant association was found between VEGF expression and recurrence of the tumor s (p=0.0005).Conclusions: VEGF has a role in ascertaining the high-risk grade I meningiomas that have a potential to recur as well as grade II and grade III meningiomas that show adverse patient prognosis.
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Świdrowska, Joanna, Piotr Smolewski, Jerzy Stańczyk, and Elżbieta Smolewska. "Serum Angiogenesis Markers and Their Correlation with Ultrasound-Detected Synovitis in Juvenile Idiopathic Arthritis." Journal of Immunology Research 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/741457.
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Synovial angiogenesis is considered to be an important early step in the pathogenesis of juvenile idiopathic arthritis (JIA). In this study we assessed levels of angiogenic markers in serum or synovial fluid and their possible relevance to disease activity or degree of ultrasound signs of synovial inflammation and angiogenesis in early JIA. The concentration of vascular endothelial growth factor (VEGF), its soluble receptors 1 and 2 (sVEGF-R1, sVEGF-R2), and angiopoietins 1 and 2 (ANG-1, ANG-2) were evaluated in 43 JIA patients and 23 healthy controls. Synovial angiogenesis was assessed by means of Power-Doppler Ultrasonography (PDUS), according to the fourth-grade vascularity scale. VEGF and its receptors’ (sVEGF-R1, sVEGF-R2) serum levels were significantly higher in JIA patients (p=0.002). We found large variation in serum ANG-1 and ANG-2 levels. The PDUS imaging identified increased synovial microvascular blood flow in 15 (35.7%) examined JIA children. Intensity of joint vascularization correlated with higher serum VEGF and its levels was lowest in grade 0 and highest in grade 3 (p<0.007andp<0.001, resp.). In conclusion, the high correlation between synovial microvascular blood flow, serum angiogenic proteins, and symptoms of synovitis may indicate its important role in pathogenesis of JIA.
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Restucci, B., S. Papparella, P. Maiolino, and G. De Vico. "Expression of Vascular Endothelial Growth Factor in Canine Mammary Tumors." Veterinary Pathology 39, no. 4 (July 2002): 488–93. http://dx.doi.org/10.1354/vp.39-4-488.
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Vascular endothelial growth factor (VEGF) is a dimeric protein that stimulates angiogenesis in vitro and in vivo by inducing endothelial cell proliferation and migration. In this immunohistochemical study, VEGF-immunolabeled cells were counted in a series of 10 benign and 40 malignant canine mammary tumors. The morphologic pattern of VEGF positivity (intensity of immunolabeling and VEGF granule size and distribution) was also evaluated. A low number of cells weakly positive for VEGF with few and small granules polarized to the luminal pole was detected in benign neoplasms. In contrast, in malignancies a high number of VEGF-positive cells had strong immunolabeling, often with large granules found diffusely in the cytoplasm. This level of immunolabeling was more pronounced in the less differentiated, more malignant phenotypes (grade 3). Macrophages, which can synthesize VEGF, were strongly positive. Stromal and myoepithelial cells were negative. VEGF data were correlated statistically with intratumoral microvessel density (number of newly formed microvessels) and both measures were greater in less differentiated malignant neoplasms, demonstrating that angiogenesis and malignancy increase together. VEGF appears to be a powerful angiogenic factor in canine mammary tumors.
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Rynda, A. Yu, V. E. Olyushin, D. M. Rostovtsev, Y. M. Zabrodskaya, and G. V. Papayan. "Fluorescent diagnostics with chlorin e6 in surgery of low-grade glioma." Biomedical Photonics 10, no. 4 (February 4, 2022): 35–43. http://dx.doi.org/10.24931/2413-9432-2021-10-4-35-43.
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Intraoperative fluorescence diagnostics of high-grade gliomas is widely used in neurosurgical practice. This work analyzes the possibilities of fluorescence diagnostics for low-grade gliomas (LGG) using chlorin e6 photosensitizer. The study included patients with newly diagnosed LGG, for whom chlorin e6 was used for intraoperative fluorescence control at a dose of 1 mg/kg. During the operation, the fluorescence intensity of various areas of the putative tumor tissue was analyzed using the RSS Cam – Endo 1.4.313 software. Tissue samples with various degrees of fluorescence intensity were compared with the results of their histopathological analysis (WHO tumor diagnosis, Ki-67 index, P53, VEGF). Fluorescence was detected in more than half of the cases, but in most cases had a focal character and low fluorescence intensity. The fluorescence intensity directly correlated with the data of histopathological examination of tumor tissues (Ki-67 index (p=0.002), expression of P53 (p=0.0015) and VEGF (p=0.001)). The sensitivity of the method for LGG surgery was 72%, the specificity was 56,7%. Intraoperative fluorescence diagnostics with chlorin e6 can be used in LGG surgery, especially to visualize intratumoral areas with a higher degree of anaplasia.
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Eppenberger, U., W. Kueng, J. M. Schlaeppi, J. L. Roesel, C. Benz, H. Mueller, A. Matter, et al. "Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients." Journal of Clinical Oncology 16, no. 9 (September 1998): 3129–36. http://dx.doi.org/10.1200/jco.1998.16.9.3129.
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PURPOSE To compare the prognostic impact of tumor angiogenesis factors (vascular endothelial growth factor [VEGF], angiogenin, and basic fibroblast growth factor [bFGF]), tumor proteolysis factors (urokinase-type plasminogen activator [uPA] and plasminogen activator inhibitor-1 [PAI-1]), and conventional tumor markers (stage, grade, and steroid receptors) in early breast cancer. PATIENTS AND METHODS In the primary clinical study, tumor angiogenesis and other factors were detected in frozen biopsies from 305 primary breast tumors. VEGF expression was assessed by chemiluminescence immunosorbent assay (ICMA); angiogenin, bFGF, uPA, and PAI-1 by enzyme-linked immunosorbent assay (ELISA); and steroid receptors (estrogen receptor [ER] and progesterone receptor [PgR]) by enzyme immunoassay (EIA). In the validating clinical study, another set of 190 node-negative primary breast tumor samples were collected at a separate institution. RESULTS Univariate analysis of the primary study showed that VEGF levels were positively correlated with recurrence (P < .001). Angiogenin levels were positively correlated with disease relapse (P < .005) for the overall collective group, but not within the node-negative subset. No significant correlations were found between tumor bFGF levels and patient survival. In multivariate regression analysis, the only independent predictors of relapse-free survival (RFS) were VEGF, uPA, and lymph node status. In the validation set, the distribution of VEGF and uPA values were similar to those in the primary study; low expression of both VEGF and uPA identified patients with a < or = 20% likelihood of recurrence within 7 years. CONCLUSION Separate primary and validating clinical studies concur that tumor VEGF level is the most important prognostic parameter among several markers of tumor angiogenesis and proteolysis.
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Burgess, E. R., R. L. I. Crake, E. Phillips, H. R. Morrin, J. A. Royds, M. C. M. Vissers, B. A. Robinson, and G. U. Dachs. "P16.11 Vitamin C levels and the hypoxic pathway in human glioma tissues." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii57—ii58. http://dx.doi.org/10.1093/neuonc/noab180.201.
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Abstract BACKGROUND Gliomas are the most common brain cancer and survival is poor, with 11–15 months for high-grade glioblastoma patients, despite treatment. Gliomas are hypoxic tumours, which increases with tumour grade. Under hypoxia, the transcription factor hypoxia inducible factor-1 (HIF) accumulates and upregulates expression of genes involved in tumour development and progression. HIF-1 levels and activity are controlled by HIF hydroxylases which target HIF-1α for degradation and prevent co-activation. HIF hydroxylases are part of the 2-oxoglutarate (2-OG)-dependent dioxygenase enzyme family, that require 2-OG and oxygen as substrates and ascorbate and iron as co-factors. The role of ascorbate in regulating the hypoxic pathway in cancer is of interest, with previous research showing reduced HIF pathway activity with increasing tumour ascorbate levels. Brain tissue has one of the highest ascorbate levels in the body, and is one of the last to become depleted under deficiency, indicating an important role for ascorbate in this tissue. One previous study has analysed ascorbate levels in 11 human glioblastoma patients, and showed lower ascorbate in tumour tissue compared to normal brain tissue. There have been no studies investigating the relationship between ascorbate levels and the hypoxic pathway in human glioma tissues. MATERIAL AND METHODS Human glioma tissues (n = 39), obtained from the Cancer Society Tissue Bank Christchurch (ethics approval H19/163), were processed for ascorbate and hypoxic pathway proteins (HIF-1α, CA-IX, BNIP3, HKII, GLUT1 and VEGF). Ascorbate levels were quantified by HPLC-ED, and proteins were measured by Western blotting and ELISA. Spearman’s correlations were used to identify relationships between ascorbate and HIF pathway proteins. RESULTS Of the samples, 64% were GBM. Ascorbate was significantly lower in GBM compared to low-grade gliomas (p = 0.04). VEGF was significantly higher in GBM compared to astrocytomas (p = 0.01). Increased tumour ascorbate was associated with lower VEGF and CA-IX proteins. HIF-1α and BNIP3 protein were positively associated, and VEGF was positively associated with HKII and CA-IX. VEGF inversely associated with BNIP3, and CA-IX inversely associated with HKII. The hypoxic pathway score (calculated from protein levels of members of the hypoxic pathway) was reduced in tumours with higher ascorbate but this did not reach significance (p = 0.2). CONCLUSION This is the first study to show that ascorbate levels were reduced in high-grade gliomas compared to low-grade. Some members of the hypoxic pathway were associated with ascorbate levels. The overall hypoxic pathway score did not significantly correlate with ascorbate and increased numbers of samples are required to confirm any associations. Other variables, such as IDH-1 mutation status of the tumours may affect the correlation and will be analysed next.
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Belfort-Mattos, Patrícia Napoli, Gustavo Rubino de Azevedo Focchi, Julisa Chamorro Lascasas Ribalta, Tatiana Megale De Lima, Carmen Regina Nogueira Carvalho, Fernanda Kesselring Tso, and Neila Maria De Góis Speck. "Immunohistochemical Expression of VEGF and Podoplanin in Uterine Cervical Squamous Intraepithelial Lesions." Disease Markers 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/8293196.
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VEGF and podoplanin (PDPN) have been identified as angiogenesis and/or lymphangiogenesis regulators and might be essential to restrict tumor growth, progression, and metastasis. In the present study, we evaluate the association between the expression of these markers and CIN grade. Immunohistochemistry was performed in 234 uterine cervical samples using conventional histologic sections or TMA with the monoclonal antibodies to VEGF (C-1 clone) and podoplanin (D2-40 clone). Positive-staining rates of VEGF in 191 CIN specimens were significantly associated with histological grade (P<0.001). Negative and/or focal immunostaining for PDPN were more frequent in CIN 3 (P=0.016). We found that patients with CIN 3 more frequently had strong and more diffuse staining for VEGF and diminished staining for PDPN (P=0.018). Strong and more diffuse VEGF immunoexpressions in CIN 2 and CIN 3 were detected when compared to CIN 1. Negative and/or focal PDPN immunoexpression appear to be more frequent in CIN 3. Moderate to strong VEGF expression may be a tendency among patients with high-grade lesions and diminished PDPN expression.
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Carvalho, Maria Isabel, Isabel Pires, Marlene Dias, Justina Prada, Hugo Gregório, Luis Lobo, and Felisbina Queiroga. "Intratumoral CD3+ T-Lymphocytes Immunoexpression and Its Association with c-Kit, Angiogenesis, and Overall Survival in Malignant Canine Mammary Tumors." Analytical Cellular Pathology 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/920409.
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In this study 80 malignant CMT were submitted to immunohistochemical detection of CD3, c-kit, VEGF, and CD31, together with clinicopathological parameters of tumor aggressiveness. CD3+ T-cells and c-kit overexpression revealed a positive correlation with VEGF (r= 0.503,P< 0.0001;r= 0.284,P= 0.023 for CD3 and c-kit, resp.) and CD31 (r= 0.654,P< 0.0001;r= 0.365,P= 0.003 for CD3 and c-kit, resp.). A significant association (P= 0.039) and a positive correlation (r= 0.263,P= 0.039) between CD3 and c-kit were also observed. High CD3/VEGF, c-kit/VEGF, and CD3/c-kit tumors were associated with elevated grade of malignancy (P< 0.0001 for all groups), presence of intravascular emboli (P< 0.0001 for CD3/VEGF and CD3/c-kit;P= 0.002 for c-kit/VEGF), and presence of lymph node metastasis (P< 0.0001 for all groups). Tumors with high CD3/VEGF (P= 0.006), c-kit/VEGF (P< 0.0001), and CD3/c-kit (P= 0.002) were associated with poor prognosis. Interestingly high c-kit/VEGF tumors retained their significance by multivariate analysis arising as independent prognostic factor.
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Di Stefano, Anna Luisa, Giuseppe Lombardi, Jaime Gallego Perez-Larraya, Blandine Boisselier, Marianne Labussiere, Francois Ducray, Vittorina Zagonel, Caroline Cheneau, Jean-Yves Delattre, and Marc Sanson. "Association of VEGFA SNP rs2010963 with prognosis and prediction of vascular toxicity of bevacizumab in recurrent glioblastomas." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2028. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2028.
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2028 Background: VEGFA has become an attractive target in high grade gliomas but there is no predictor of response or toxicity to anti-VEGF therapy. We investigated here the association between functional single nucleotide polymorphism (SNP) +405 G>C (rs2010963), located in 5’ untranslated terminal region of VEGFA gene, survival, response to bevacizumab (BVZ), and vascular toxicity. Methods: The rs2010963 was analyzed in blood DNA using a Taqman SNP Genotyping Assay and confronted to Progression Free Survival (PFS), Overall Survival (OS) in the general population of gliomas, and -for the glioblastomas (GBM) treated with BVZ at recurrence- with Response, PFS, and thrombo-hemorragic events. Results: In the general population of 954 gliomas stratified per grade (362 grade 2, 269 grade 3, 323 grade 4) there was no association between rs2010963 and OS or PFS. In the population of 123 recurrent GBM treated with BVZ, we observed a favourable trend in PFS associated with the C allele of rs2010963 (5.4 vs 4.2 months, p = 0.07). Most importantly the CC genotype was associated with the occurrence of thrombo-hemorragic events (6/16 vs 2/107 in CG+GG, p <0.0001). Conclusions: Our data suggest that rs2010963 status has not prognostic significance in gliomas, but is associated with vascular events in recurrent GBM treated with BVZ. The impact of rs2010963 on response to BVZ needs to be further investigated.
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Sponghini, A. P., F. Platini, D. Rondonotti, M. Giavarra, F. Patrucco, M. E. Negru, and R. Soffietti. "Efficacy and safety of the VEGF inhibitor bevacizumab in combination with fotemustine for high-grade gliomas." Annals of Oncology 26 (October 2015): vi140. http://dx.doi.org/10.1093/annonc/mdv348.24.
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Goli, K. J., A. Desjardins, J. E. Herndon, J. N. Rich, D. A. Reardon, J. A. Quinn, S. Sathornsumetee, D. A. Bota, H. S. Friedman, and J. J. Vredenburgh. "Phase II trial of bevacizumab and irinotecan in the treatment of malignant gliomas." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2003. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2003.
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2003 Background: Recurrent malignant gliomas have low response rates to current treatments. Malignant gliomas have high concentrations of VEGF receptors which are poor prognostic indicators. Bevacizumab is a humanized IgG1 monoclonal antibody to VEGF, which is synergistic with chemotherapy for most malignancies. Irinotecan is a topoisomerase 1 inhibitor with modest activity against recurrent malignant gliomas. Methods: We report the mature data for our FDA approved phase II trial of bevacizumab and irinotecan for the treatment of recurrent malignant gliomas. We enrolled 68 patients (35 with grade IV tumors and 33 with grade III tumors.) All patients had progressive disease and received prior radiation therapy and temozolomide. The first 32 patients were treated every other week with bevacizumab 10 mg/kg and irinotecan 125 mg/m2 (non EIAED) or 340 mg/m2 (EIAED). The last 36 patients were treated with irinotecan 125 mg/m2 (non EIAED) or 350 mg/m2 (EIAED) on days 1, 8, 22, and 29 and bevacizumab 15 mg/kg on days 1 and 22. Results: The regimen was well tolerated. Only 1 CNS hemorrhage occurred after 10 cycles of treatment. Eight patients were taken off study for thrombotic complications (four PE, two DVT, one TTP, one thrombotic stroke) and 2 of these patients died (one with PE and one with thrombotic stroke). Two patients were discontinued secondary to grade 2 proteinuria and 3 were discontinued because they required non-neurosurgical surgery. The response rate was 59% (38 PRs and 2 CRs). In Grade IV, the median PFS was 23 weeks (95% confidence intervals 17–34). The 6 month PFS was 43% (95% confidence intervals 29%-63%), the median overall survival was 40 weeks (95% confidence intervals 34–50). In grade III patients the median PFS was 42 weeks, the 6 month PFS was 61% (95% confidence intervals 46%-80%), the medial overall survival was 60 weeks (95% confidence intervals 37%-73%). The follow-up for the second cohort is short with similar efficacy and more toxicity. Conclusion: The combination of bevacizumab and irinotecan is safe and demonstrates superior activity against malignant gliomas. [Table: see text]
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Sathornsumetee, Sith, Yiting Cao, Jennifer E. Marcello, James E. Herndon, Roger E. McLendon, Annick Desjardins, Henry S. Friedman, Mark W. Dewhirst, James J. Vredenburgh, and Jeremy N. Rich. "Tumor Angiogenic and Hypoxic Profiles Predict Radiographic Response and Survival in Malignant Astrocytoma Patients Treated With Bevacizumab and Irinotecan." Journal of Clinical Oncology 26, no. 2 (January 10, 2008): 271–78. http://dx.doi.org/10.1200/jco.2007.13.3652.
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Purpose The combination of a vascular endothelial growth factor (VEGF) –neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy. Patients and Methods In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2α were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers. Results Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016). Conclusion In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.
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Fuchs, Quentin, Marina Pierrevelcin, Melissa Messe, Benoit Lhermitte, Anne-Florence Blandin, Christophe Papin, Andres Coca, Monique Dontenwill, and Natacha Entz-Werlé. "Hypoxia Inducible Factors’ Signaling in Pediatric High-Grade Gliomas: Role, Modelization and Innovative Targeted Approaches." Cancers 12, no. 4 (April 15, 2020): 979. http://dx.doi.org/10.3390/cancers12040979.
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The brain tumor microenvironment has recently become a major challenge in all pediatric cancers, but especially in brain tumors like high-grade gliomas. Hypoxia is one of the extrinsic tumor features that interacts with tumor cells, but also with the blood–brain barrier and all normal brain cells. It is the result of a dramatic proliferation and expansion of tumor cells that deprive the tissues of oxygen inflow. However, cancer cells, especially tumor stem cells, can endure extreme hypoxic conditions by rescheduling various genes’ expression involved in cell proliferation, metabolism and angiogenesis and thus, promote tumor expansion, therapeutic resistance and metabolic adaptation. This cellular adaptation implies Hypoxia-Inducible Factors (HIF), namely HIF-1α and HIF-2α. In pediatric high-grade gliomas (pHGGs), several questions remained open on hypoxia-specific role in normal brain during gliomagenesis and pHGG progression, as well how to model it in preclinical studies and how it might be counteracted with targeted therapies. Therefore, this review aims to gather various data about this key extrinsic tumor factor in pHGGs.
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Nandhu, Mohan S., Bin Hu, Susan E. Cole, Anat Erdreich-Epstein, Diego J. Rodriguez-Gil, and Mariano S. Viapiano. "Novel Paracrine Modulation of Notch–DLL4 Signaling by Fibulin-3 Promotes Angiogenesis in High-Grade Gliomas." Cancer Research 74, no. 19 (August 19, 2014): 5435–48. http://dx.doi.org/10.1158/0008-5472.can-14-0685.
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Graner, Michael W. "Roles of Extracellular Vesicles in High-Grade Gliomas: Tiny Particles with Outsized Influence." Annual Review of Genomics and Human Genetics 20, no. 1 (August 31, 2019): 331–57. http://dx.doi.org/10.1146/annurev-genom-083118-015324.
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High-grade gliomas, particularly glioblastomas (grade IV), are devastating diseases with dismal prognoses; afflicted patients seldom live longer than 15 months, and their quality of life suffers immensely. Our current standard-of-care therapy has remained essentially unchanged for almost 15 years, with little new therapeutic progress. We desperately need a better biologic understanding of these complicated tumors in a complicated organ. One area of rejuvenated study relates to extracellular vesicles (EVs)—membrane-enclosed nano- or microsized particles that originate from the endosomal system or are shed from the plasma membrane. EVs contribute to tumor heterogeneity (including the maintenance of glioma stem cells or their differentiation), the impacts of hypoxia (angiogenesis and coagulopathies), interactions amid the tumor microenvironment (concerning the survival of astrocytes, neurons, endothelial cells, blood vessels, the blood–brain barrier, and the ensuing inflammation), and influences on the immune system (both stimulatory and suppressive). This article reviews glioma EVs and the ways that EVs manifest themselves as autocrine, paracrine, and endocrine factors in proximal and distal intra- and intercellular communications. The reader should note that there is much controversy, and indeed confusion, in the field over the exact roles for EVs in many biological processes, and we will engage some of these difficulties herein.
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Linderholm, B., B. Tavelin, K. Grankvist, and R. Henriksson. "Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma." Journal of Clinical Oncology 16, no. 9 (September 1998): 3121–28. http://dx.doi.org/10.1200/jco.1998.16.9.3121.
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PURPOSE The prognostic value of vascular endothelial growth factor (VEGF) protein, known to stimulate endothelial growth and angiogenesis, was evaluated in node-negative breast carcinoma (NNBC) and compared with established prognostic factors. PATIENTS AND METHODS In 525 consecutive patients with primary invasive NNBC (T1-2N0M0; tumor, node, metastasis stage), of whom 500 patients did not receive any systemic therapy, the cytosolic levels of VEGF165 were measured by using a quantitative enzyme-linked immunosorbent assay. The median follow-up was 46 months. Univariate and multivariate analyses were performed. RESULTS VEGF level was significantly inversely correlated with estrogen receptor (ER) positivity but positively associated with tumor size and histologic grade. Patients with VEGF levels above the median value (2.40 pg/microg of DNA) showed a significantly shorter survival time (P=.0012) than patients with levels less than the median value, also when analyzed as a continuous variable (P=.0277). Tumor size, grade, and ER expression were all statistically significant for overall survival in univariate analyses (P=.0069, P=.014, and P < .001, respectively). Multivariate analysis showed that VEGF level was the strongest predictor of overall survival (P=.0199). Histologic grade was also an independent predictor of survival (P=.0477). Among the 381 patients with ER-positive tumors, a group in general considered to have a good prognosis, we found a significant reduction in survival for those with levels of VEGF greater than the median value (P=.0009). CONCLUSION The results suggest that the level of VEGF165 protein is an independent, strong prognostic factor for survival in patients with NNBC, especially in the subgroup of patients with ER positivity. Thus, cytosolic VEGF165 might be useful to select patients for adjuvant systemic therapy.
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Mohile, N. A., L. E. Abrey, S. C. Lymberis, S. Karimi, B. L. Hou, and P. H. Gutin. "A pilot study of bevacizumab and stereotactic intensity modulated re-irradiation for recurrent high grade gliomas." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2028. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2028.
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2028 Background: Bevacizumab is a humanized monoclonal antibody directed at vascular endothelial growth factor A (VEGF-A). Preclinical studies suggest that inhibition of VEGF-A improves glioma response to radiotherapy. The concurrent use of bevacizumab and cranial radiotherapy has not been investigated. The objective of this study is to determine the safety of this combination. Methods: Patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytomas (AA) less than 3.5 cm received bevacizumab (10 mg/kg IV) every 2 weeks. MRI after cycle 1 (28 days) was done to reassess response and for RT planning. Patients then received stereotactic intensity modulated radiation therapy (IMRT): 30Gy in 5 fractions over 15 days. Bevacizumab treatment, given every 2 weeks, was administered during radiotherapy and continued until tumor progression. Brain MRI to assess response was performed after odd cycles. MR T1 and T2* perfusion were performed at baseline and after cycle 1. Results: 12 patients (10 GBM, 2 AA) with median age 53 (range, 30–61) and median KPS 90 (range, 80–100) received a median of 5.5 cycles of bevacizumab. In 1 patient, stereotactic IMRT could not be delivered safely to tumor. Grade III events occurred in 10 patients including hypertension, headache, seizures, neutropenia, hyponatremia and hypophosphatemia. There were no grade IV or V events, no dose limiting toxicities and no intracranial hemorrhage. 7/12 patients had objective responses (3 CR and 4 PR). In 5, SD was the best reported response. At last follow up, ten patients remain on study; 2 have come off for PD. Estimated 6 month PFS is 76%. MR perfusion imaging demonstrated a decrease in mean perfusion values after 1 cycle of bevacizumab. Conclusions: Bevacizumab in combination with RT is safe and well tolerated. Imaging responses and duration of disease control suggest that this regimen is active in this subset of recurrent glioma patients. Further investigations to determine efficacy and possible synergy of bevacizumab with radiotherapy are warranted. [Table: see text]
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Atukeren, Pinar, Ahmad Kunbaz, Okan Turk, Rahsan Kemerdere, Mustafa Onur Ulu, Nursel Turkmen Inanir, and Taner Tanriverdi. "Expressions of Endocan in Patients with Meningiomas and Gliomas." Disease Markers 2016 (2016): 1–5. http://dx.doi.org/10.1155/2016/7157039.
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Objective. Endocan has been shown to be a marker for several cancers and may show degree of malignancy. The aim of this study is to assess tissue levels of endocan in common brain tumors, namely, meningiomas, low-grade gliomas (LGGs), and high-grade gliomas (HGGs).Patients and Methods. Endocan was assayed by commercially available enzyme linked immunosorbent assay (ELISA) kits in a total of 50 brain tumors (20 meningiomas, 19 LGGs, and 20 HGGs) and 15 controls. The results were compared to control brain tissues.Results. Each tumor group showed significant higher levels of endocan compared to controls (p<0.05). In addition, endocan levels showed steady increase from the least (meningiomas) to the most (HGGs) malignant tumors and positive correlation was noted between the degree of malignancy and endocan level (p=0.0001).Conclusion. Endocan, a vital molecule for angiogenesis, is expressed in common brain tumors and results suggest that endocan could be a marker for malignancy.
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Liana, Nana, Noza Hilbertina, Loli Devianti, and Husna Yetti. "The Association of VEGF Expression with Degree of Differentiation and Lymphovascular Invasion in Colorectal Adenocarcinoma." Majalah Patologi Indonesia 31, no. 1 (January 4, 2022): 368–75. http://dx.doi.org/10.55816/mpi.v31i1.490.
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BackgroundColorectal carcinoma is the third most common malignancy in the world. Colorectal carcinoma is a heterogeneous tumor withdifferent clinical pathologic features and prognostic values. For the same tumor-stage, patients could have difference prognosis andit has been suggested that the angiogenesis might be correlated with the prognosis, especially expression of vascular endothelialgrowth factor (VEGF) as the main pro-angiogenic factor. High VEGF expression in colorectal adenocarcinoma is associated withincreased blood vessels in invasive tumor area, cell proliferation and metastases. However, relation VEGF expression with thedegree of differentiation and lymphovascular invasion is not known.MethodsThis was a retrospective observational study with cross sectional approach. Samples were obtained from 39 paraffin blocks withdiagnosis adenocarcinoma not otherwise specific (NOS) in four Anatomical Pathology Laboratory in West Sumatera 2018 andevaluated for degree of differentiation and lymphovascular invasion. VEGF expressions in tumor cell were analyzed usingimmunohistochemistry staining. Bivariate statistical analysis used Fisher's Exact test and value p<0.05 was considered significant.ResultsColorectal adenocarcinoma with high grade differentiation entirely had high VEGF expression (100%), while low gradedifferantiation with high VEGF expression was 60.7%. Lymphovascular invasion positive was mostly found with high VEGFexpression (80.6%). Statistical analysis showed significant association between VEGF expression with degree of differentiation(p=0.017) and lymphovascular invasion (p=0.028).ConclusionThe conclusion was VEGF expression had significant association with degree of differentiation and lymphovascular invasion ofcolorectal adenocarcinoma.
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Weiss, Sarah A., Maneka Puligandla, Lucia Jilaveanu, Naomi B. Haas, Xin Victoria Wang, Christopher Zito, Marta Boeke, et al. "Microvessel density as a prognostic marker in high-risk renal cell carcinoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 4565. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.4565.
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4565 Background: Increased vascularity is a hallmark of renal cell carcinomas (RCC), particularly clear cell RCC. The vascular endothelial growth factor (VEGF) pathway, implicated in tumor angiogenesis, is dysregulated in RCC. The phase 3 trial ECOG-ACRIN E2805 enrolled 1,943 patients (pts) with resected high-risk RCC (pT1b high grade to pT4 any grade or N any). Pts were randomized to adjuvant sunitinib, sorafenib, or placebo. Our aim was to determine the prognostic and predictive role of microvessel density (MVD), VEGF receptors, and ligands in nephrectomy specimens. Methods: We obtainedpre-treatment primary RCC tissue from 822 pts and built tissue microarrays using 3 cores from each sample. Using quantitative immunofluorescence we measured tumor MVD (area of CD34-expressing cells) and intensity of the VEGF/VEGF-R family (VEGF-R1, R2, R3 and VEGF-A, B, C, D) in tumor cells. We tested for association with disease-free survival (DFS) and overall survival (OS) by the stratified log-rank test. Associations with treatment arm and clinicopathologic variables were determined. Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (p = 0.021, HR 0.63) and for pts treated in the placebo group (p = 0.014). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p = 0.060). High VEGFD expression overall was associated with shorter OS (p = 0.027) but not for placebo (p = 0.16). Yet high MVD was not associated with improved DFS (p = 1.00). High MVD correlated with above-median age ( > 56) (p = 0.032), Fuhrman grade I/II (p < 0.001), clear cell histology (p < 0.001), and absence of necrosis (p < 0.001) but not with gender, sarcomatoid features, lymphovascular invasion, or tumor size. In multivariable analysis, MVD remained independently associated with improved OS for the entire cohort (p = 0.013). Conclusions: High MVD in nephrectomy specimens of high-risk RCC pts is associated with improved OS, regardless of treatment arm. MVD is thus an independent prognostic, rather than predictive, biomarker. Further studies should assess whether incorporating MVD into clinical models will predict outcome in resected high-risk RCC pts and if MVD can be used for pt selection for adjuvant therapy.
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Lawrence, Johnathan E., Nicholas J. Cook, Richard A. Rovin, and Robert J. Winn. "Leptin Promotes Glioblastoma." Neurology Research International 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/870807.
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The hormone leptin has a variety of functions. Originally known for its role in satiety and weight loss, leptin more recently has been shown to augment tumor growth in a variety of cancers. Within gliomas, there is a correlation between tumor grade and tumor expression of leptin and its receptor. This suggests that autocrine signaling within the tumor microenvironment may promote the growth of high-grade gliomas. Leptin does this through stimulation of cellular pathways that are also advantageous for tumor growth and recurrence: antiapoptosis, proliferation, angiogenesis, and migration. Conversely, a loss of leptin expression attenuates tumor growth. In animal models of colon cancer and melanoma, a decline in the expression and secretion of leptin resulted in a reduction of tumor growth. In these models, positive mental stimulation through environmental enrichment decreased leptin secretion and improved tumor outcome. This review explores the link between leptin and glioblastoma.
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Lai, Chien-Rui, Hisao-Hsien Wang, Hsin-Han Chang, Yu-Ling Tsai, Wen-Chiuan Tsai, Chen-Ray Lee, Chih-Ying Changchien, Yu-Chen Cheng, Sheng-Tang Wu, and Ying Chen. "Enhancement of Farnesoid X Receptor Inhibits Migration, Adhesion and Angiogenesis through Proteasome Degradation and VEGF Reduction in Bladder Cancers." International Journal of Molecular Sciences 23, no. 9 (May 9, 2022): 5259. http://dx.doi.org/10.3390/ijms23095259.
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(1) Background: Bladder cancer is a malignant tumor mainly caused by exposure to environmental chemicals, with a high recurrence rate. NR1H4, also known as Farnesoid X Receptor (FXR), acts as a nuclear receptor that can be activated by binding with bile acids, and FXR is highly correlated with the progression of cancers. The aim of this study was to verify the role of FXR in bladder cancer cells. (2) Methods: A FXR overexpressed system was established to investigate the effect of cell viability, migration, adhesion, and angiogenesis in low-grade TSGH8301 and high-grade T24 cells. (3) Results: After FXR overexpression, the ability of migration, adhesion, invasion and angiogenesis of bladder cancer cells declined significantly. Focal adhesive complex, MMP2, MMP9, and angiogenic-related proteins were decreased, while FXR was overexpressed in bladder cancer cells. Moreover, FXR overexpression reduced vascular endothelial growth factor mRNA and protein expression and secretion in bladder cancer cells. After treatment with the proteosome inhibitor MG132, the migration, adhesion and angiogenesis caused by FXR overexpression were all reversed in bladder cancer cells. (4) Conclusions: These results may provide evidence on the role of FXR in bladder cancer, and thus may improve the therapeutic efficacy of urothelial carcinoma in the future.