SURROGATE MARKERS PREDICT ANGIOGENIC POTENTIAL AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA MULTIFORME
Abstract OBJECTIVE The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic and histological evidence of increased vascularity correlate with clinical grade of gliomas. However, a quantitative noninvasive assay to assess glioma vascularity and associated clini...
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| Veröffentlicht in: | Neurosurgery 2009-05, Vol.64 (5), p.819-827 |
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| creator | Greenfield, Jeffrey P. Jin, David K. Young, Lauren M. Christos, Paul J. Abrey, Lauren Rafii, Shahin Gutin, Philip H. |
| description | Abstract
OBJECTIVE
The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic and histological evidence of increased vascularity correlate with clinical grade of gliomas. However, a quantitative noninvasive assay to assess glioma vascularity and associated clinical aggressiveness has not been developed. Circulating endothelial progenitor cells are unique vascular precursors recruited from the bone marrow through the circulation to form new tumor blood vessels. These cells were measured in patients undergoing surgery for glioblastoma multiforme (GBM). We hypothesized that this might reflect the extent of tumor vascularity, predict prognosis, or be useful as an assay to assess response to antiangiogenesis therapies. In addition, we report on a novel in vitro assay to assess the proangiogenic activity within the plasma samples obtained from glioma patients.
METHODS
Fifty-six patients with various-grade gliomas had peripheral venous blood collected at the time of surgery and at subsequent visits during the follow-up period. The blood was separated into plasma and cellular fractions. The plasma was utilized in a human umbilical vein endothelial cell-based angiogenic assay. The cellular fraction containing endothelial progenitor cells was isolated, and specific cellular phenotypes were immunologically separated and counted using flow cytometry. Pathological samples were reviewed at the time of initial resection, and each patient's clinical course was monitored until the time of manuscript submission.
RESULTS
Plasma derived from peripheral blood of patients with GBM scored significantly higher on the functional angiogenic scale compared with plasma derived from patients with low-grade gliomas and from controls. In addition, all patients with GBM had measurable numbers of bone marrow-derived endothelial precursor cells coexpressing CD133 and vascular endothelial growth factor receptor 2 in their peripheral circulation at the time of tumor resection. These cells range from less than 0.1% to 1.6% of the entire circulating mononuclear white blood cell population, or approximately 200 000 cells in some patients. A statistically significant relationship was observed between the percentage of endothelial progenitor cells in the peripheral blood at the time of initial GBM resection and survival.
CONCLUSION
These studies suggest that plasma and circulating CD133+ vascular endothelial growth factor receptor 2+ proangiogenic cells are p |
| doi_str_mv | 10.1227/01.NEU.0000343742.06625.DB |
| format | Article |
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OBJECTIVE
The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic and histological evidence of increased vascularity correlate with clinical grade of gliomas. However, a quantitative noninvasive assay to assess glioma vascularity and associated clinical aggressiveness has not been developed. Circulating endothelial progenitor cells are unique vascular precursors recruited from the bone marrow through the circulation to form new tumor blood vessels. These cells were measured in patients undergoing surgery for glioblastoma multiforme (GBM). We hypothesized that this might reflect the extent of tumor vascularity, predict prognosis, or be useful as an assay to assess response to antiangiogenesis therapies. In addition, we report on a novel in vitro assay to assess the proangiogenic activity within the plasma samples obtained from glioma patients.
METHODS
Fifty-six patients with various-grade gliomas had peripheral venous blood collected at the time of surgery and at subsequent visits during the follow-up period. The blood was separated into plasma and cellular fractions. The plasma was utilized in a human umbilical vein endothelial cell-based angiogenic assay. The cellular fraction containing endothelial progenitor cells was isolated, and specific cellular phenotypes were immunologically separated and counted using flow cytometry. Pathological samples were reviewed at the time of initial resection, and each patient's clinical course was monitored until the time of manuscript submission.
RESULTS
Plasma derived from peripheral blood of patients with GBM scored significantly higher on the functional angiogenic scale compared with plasma derived from patients with low-grade gliomas and from controls. In addition, all patients with GBM had measurable numbers of bone marrow-derived endothelial precursor cells coexpressing CD133 and vascular endothelial growth factor receptor 2 in their peripheral circulation at the time of tumor resection. These cells range from less than 0.1% to 1.6% of the entire circulating mononuclear white blood cell population, or approximately 200 000 cells in some patients. A statistically significant relationship was observed between the percentage of endothelial progenitor cells in the peripheral blood at the time of initial GBM resection and survival.
CONCLUSION
These studies suggest that plasma and circulating CD133+ vascular endothelial growth factor receptor 2+ proangiogenic cells are present in the peripheral blood of patients with glioma and can be used as a surrogate biomarker to measure tumor angiogenicity. These cells can be measured at the time of diagnosis and monitored in the postoperative period. These assays can be used to predict tumor aggressiveness. Also promising is their potential to identify patients with increased angiogenic activity who might respond maximally to antiangiogenesis therapies or to assess tumor response in patients using those therapies as the use of these adjuvant molecular modalities becomes more prevalent in neuro-oncology.</description><identifier>ISSN: 0148-396X</identifier><identifier>EISSN: 1524-4040</identifier><identifier>DOI: 10.1227/01.NEU.0000343742.06625.DB</identifier><identifier>PMID: 19404145</identifier><identifier>CODEN: NRSRDY</identifier><language>eng</language><publisher>Hagerstown, MD: Oxford University Press</publisher><subject>AC133 Antigen ; Adult ; Aged ; Aged, 80 and over ; Antigens, CD - metabolism ; Biological and medical sciences ; Biological Assay - methods ; Biomarkers, Tumor - metabolism ; Blood ; Bone marrow ; Brain cancer ; Brain Neoplasms - blood ; Brain Neoplasms - mortality ; Brain Neoplasms - pathology ; Endothelial Cells - metabolism ; Endothelial Cells - pathology ; Enzyme-Linked Immunosorbent Assay - methods ; Female ; Flow Cytometry ; Follow-Up Studies ; Glioblastoma - blood ; Glioblastoma - mortality ; Glioblastoma - pathology ; Glioma ; Glycoproteins - metabolism ; Humans ; Male ; Medical prognosis ; Medical sciences ; Middle Aged ; Neovascularization, Pathologic - blood ; Neurosurgery ; Peptides - metabolism ; Plasma ; Stem Cells - metabolism ; Stem Cells - pathology ; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases ; Umbilical Veins - pathology ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor Receptor-2 - metabolism</subject><ispartof>Neurosurgery, 2009-05, Vol.64 (5), p.819-827</ispartof><rights>Copyright © 2009 by the Congress of Neurological Surgeons</rights><rights>2009 INIST-CNRS</rights><rights>Copyright © Congress of Neurological Surgeons</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-c260303d3bad56a1f8a70a3fd5eb59a8e9b42ac66b8e6264dcaa773ab8bab0a53</citedby><cites>FETCH-LOGICAL-c421t-c260303d3bad56a1f8a70a3fd5eb59a8e9b42ac66b8e6264dcaa773ab8bab0a53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21463944$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19404145$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Greenfield, Jeffrey P.</creatorcontrib><creatorcontrib>Jin, David K.</creatorcontrib><creatorcontrib>Young, Lauren M.</creatorcontrib><creatorcontrib>Christos, Paul J.</creatorcontrib><creatorcontrib>Abrey, Lauren</creatorcontrib><creatorcontrib>Rafii, Shahin</creatorcontrib><creatorcontrib>Gutin, Philip H.</creatorcontrib><title>SURROGATE MARKERS PREDICT ANGIOGENIC POTENTIAL AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA MULTIFORME</title><title>Neurosurgery</title><addtitle>Neurosurgery</addtitle><description>Abstract
OBJECTIVE
The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic and histological evidence of increased vascularity correlate with clinical grade of gliomas. However, a quantitative noninvasive assay to assess glioma vascularity and associated clinical aggressiveness has not been developed. Circulating endothelial progenitor cells are unique vascular precursors recruited from the bone marrow through the circulation to form new tumor blood vessels. These cells were measured in patients undergoing surgery for glioblastoma multiforme (GBM). We hypothesized that this might reflect the extent of tumor vascularity, predict prognosis, or be useful as an assay to assess response to antiangiogenesis therapies. In addition, we report on a novel in vitro assay to assess the proangiogenic activity within the plasma samples obtained from glioma patients.
METHODS
Fifty-six patients with various-grade gliomas had peripheral venous blood collected at the time of surgery and at subsequent visits during the follow-up period. The blood was separated into plasma and cellular fractions. The plasma was utilized in a human umbilical vein endothelial cell-based angiogenic assay. The cellular fraction containing endothelial progenitor cells was isolated, and specific cellular phenotypes were immunologically separated and counted using flow cytometry. Pathological samples were reviewed at the time of initial resection, and each patient's clinical course was monitored until the time of manuscript submission.
RESULTS
Plasma derived from peripheral blood of patients with GBM scored significantly higher on the functional angiogenic scale compared with plasma derived from patients with low-grade gliomas and from controls. In addition, all patients with GBM had measurable numbers of bone marrow-derived endothelial precursor cells coexpressing CD133 and vascular endothelial growth factor receptor 2 in their peripheral circulation at the time of tumor resection. These cells range from less than 0.1% to 1.6% of the entire circulating mononuclear white blood cell population, or approximately 200 000 cells in some patients. A statistically significant relationship was observed between the percentage of endothelial progenitor cells in the peripheral blood at the time of initial GBM resection and survival.
CONCLUSION
These studies suggest that plasma and circulating CD133+ vascular endothelial growth factor receptor 2+ proangiogenic cells are present in the peripheral blood of patients with glioma and can be used as a surrogate biomarker to measure tumor angiogenicity. These cells can be measured at the time of diagnosis and monitored in the postoperative period. These assays can be used to predict tumor aggressiveness. Also promising is their potential to identify patients with increased angiogenic activity who might respond maximally to antiangiogenesis therapies or to assess tumor response in patients using those therapies as the use of these adjuvant molecular modalities becomes more prevalent in neuro-oncology.</description><subject>AC133 Antigen</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antigens, CD - metabolism</subject><subject>Biological and medical sciences</subject><subject>Biological Assay - methods</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Blood</subject><subject>Bone marrow</subject><subject>Brain cancer</subject><subject>Brain Neoplasms - blood</subject><subject>Brain Neoplasms - mortality</subject><subject>Brain Neoplasms - pathology</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelial Cells - pathology</subject><subject>Enzyme-Linked Immunosorbent Assay - methods</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Follow-Up Studies</subject><subject>Glioblastoma - blood</subject><subject>Glioblastoma - mortality</subject><subject>Glioblastoma - pathology</subject><subject>Glioma</subject><subject>Glycoproteins - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Neovascularization, Pathologic - blood</subject><subject>Neurosurgery</subject><subject>Peptides - metabolism</subject><subject>Plasma</subject><subject>Stem Cells - metabolism</subject><subject>Stem Cells - pathology</subject><subject>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</subject><subject>Umbilical Veins - pathology</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - metabolism</subject><issn>0148-396X</issn><issn>1524-4040</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqVkV9v0zAUxS0EYmXwFZAFGm8J_p-Et7TNMos0qVJ38GY5iSN1apsSLw98-3m0YhJv-OXKvr9z75EPAJ8wCjEh0VeEwzLbhsgfymjESIiEIDxczl-BGeaEBQwx9BrMEGZxQBPx8wq8c-4BISxYFL8FVzjxBGZ8BrrNtq6rPFUZXKX196zewHWdLeVCwbTMZZVnpVzAdaWyUsm08I9L6CX38t5fZAnXqZK-tYE_pLqDeSGreZFuVLVK4WpbKHlb1avsPXjTm72zHy71GmxvM7W4C4oql4u0CFpG8GPQEoEooh1tTMeFwX1sImRo33Hb8MTENmkYMa0QTWwFEaxrjYkiapq4MQ0ynF6DL-e5p3H4NVn3qA8719r93hztMDktIhxjQRMPfv4HfBim8ei9aZzEXCSCY-Kpb2eqHQfnRtvr07g7mPG3xkg_J6ER1j4J_ZKE_pOEXs69-ONlxdQcbPcivXy9B24ugHGt2fejObY795cjmHmnjHmOn7lhOv2PgSdfs5is</recordid><startdate>20090501</startdate><enddate>20090501</enddate><creator>Greenfield, Jeffrey P.</creator><creator>Jin, David K.</creator><creator>Young, Lauren M.</creator><creator>Christos, Paul J.</creator><creator>Abrey, Lauren</creator><creator>Rafii, Shahin</creator><creator>Gutin, Philip H.</creator><general>Oxford University Press</general><general>Lippincott Williams & Wilkins</general><general>Wolters Kluwer Health, Inc</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20090501</creationdate><title>SURROGATE MARKERS PREDICT ANGIOGENIC POTENTIAL AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA MULTIFORME</title><author>Greenfield, Jeffrey P. ; Jin, David K. ; Young, Lauren M. ; Christos, Paul J. ; Abrey, Lauren ; Rafii, Shahin ; Gutin, Philip H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c421t-c260303d3bad56a1f8a70a3fd5eb59a8e9b42ac66b8e6264dcaa773ab8bab0a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>AC133 Antigen</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antigens, CD - metabolism</topic><topic>Biological and medical sciences</topic><topic>Biological Assay - methods</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Blood</topic><topic>Bone marrow</topic><topic>Brain cancer</topic><topic>Brain Neoplasms - blood</topic><topic>Brain Neoplasms - mortality</topic><topic>Brain Neoplasms - pathology</topic><topic>Endothelial Cells - metabolism</topic><topic>Endothelial Cells - pathology</topic><topic>Enzyme-Linked Immunosorbent Assay - methods</topic><topic>Female</topic><topic>Flow Cytometry</topic><topic>Follow-Up Studies</topic><topic>Glioblastoma - blood</topic><topic>Glioblastoma - mortality</topic><topic>Glioblastoma - pathology</topic><topic>Glioma</topic><topic>Glycoproteins - metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Neovascularization, Pathologic - blood</topic><topic>Neurosurgery</topic><topic>Peptides - metabolism</topic><topic>Plasma</topic><topic>Stem Cells - metabolism</topic><topic>Stem Cells - pathology</topic><topic>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</topic><topic>Umbilical Veins - pathology</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Greenfield, Jeffrey P.</creatorcontrib><creatorcontrib>Jin, David K.</creatorcontrib><creatorcontrib>Young, Lauren M.</creatorcontrib><creatorcontrib>Christos, Paul J.</creatorcontrib><creatorcontrib>Abrey, Lauren</creatorcontrib><creatorcontrib>Rafii, Shahin</creatorcontrib><creatorcontrib>Gutin, Philip H.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Neurosurgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Greenfield, Jeffrey P.</au><au>Jin, David K.</au><au>Young, Lauren M.</au><au>Christos, Paul J.</au><au>Abrey, Lauren</au><au>Rafii, Shahin</au><au>Gutin, Philip H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SURROGATE MARKERS PREDICT ANGIOGENIC POTENTIAL AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA MULTIFORME</atitle><jtitle>Neurosurgery</jtitle><addtitle>Neurosurgery</addtitle><date>2009-05-01</date><risdate>2009</risdate><volume>64</volume><issue>5</issue><spage>819</spage><epage>827</epage><pages>819-827</pages><issn>0148-396X</issn><eissn>1524-4040</eissn><coden>NRSRDY</coden><abstract>Abstract
OBJECTIVE
The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic and histological evidence of increased vascularity correlate with clinical grade of gliomas. However, a quantitative noninvasive assay to assess glioma vascularity and associated clinical aggressiveness has not been developed. Circulating endothelial progenitor cells are unique vascular precursors recruited from the bone marrow through the circulation to form new tumor blood vessels. These cells were measured in patients undergoing surgery for glioblastoma multiforme (GBM). We hypothesized that this might reflect the extent of tumor vascularity, predict prognosis, or be useful as an assay to assess response to antiangiogenesis therapies. In addition, we report on a novel in vitro assay to assess the proangiogenic activity within the plasma samples obtained from glioma patients.
METHODS
Fifty-six patients with various-grade gliomas had peripheral venous blood collected at the time of surgery and at subsequent visits during the follow-up period. The blood was separated into plasma and cellular fractions. The plasma was utilized in a human umbilical vein endothelial cell-based angiogenic assay. The cellular fraction containing endothelial progenitor cells was isolated, and specific cellular phenotypes were immunologically separated and counted using flow cytometry. Pathological samples were reviewed at the time of initial resection, and each patient's clinical course was monitored until the time of manuscript submission.
RESULTS
Plasma derived from peripheral blood of patients with GBM scored significantly higher on the functional angiogenic scale compared with plasma derived from patients with low-grade gliomas and from controls. In addition, all patients with GBM had measurable numbers of bone marrow-derived endothelial precursor cells coexpressing CD133 and vascular endothelial growth factor receptor 2 in their peripheral circulation at the time of tumor resection. These cells range from less than 0.1% to 1.6% of the entire circulating mononuclear white blood cell population, or approximately 200 000 cells in some patients. A statistically significant relationship was observed between the percentage of endothelial progenitor cells in the peripheral blood at the time of initial GBM resection and survival.
CONCLUSION
These studies suggest that plasma and circulating CD133+ vascular endothelial growth factor receptor 2+ proangiogenic cells are present in the peripheral blood of patients with glioma and can be used as a surrogate biomarker to measure tumor angiogenicity. These cells can be measured at the time of diagnosis and monitored in the postoperative period. These assays can be used to predict tumor aggressiveness. Also promising is their potential to identify patients with increased angiogenic activity who might respond maximally to antiangiogenesis therapies or to assess tumor response in patients using those therapies as the use of these adjuvant molecular modalities becomes more prevalent in neuro-oncology.</abstract><cop>Hagerstown, MD</cop><pub>Oxford University Press</pub><pmid>19404145</pmid><doi>10.1227/01.NEU.0000343742.06625.DB</doi><tpages>9</tpages></addata></record> |
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| ispartof | Neurosurgery, 2009-05, Vol.64 (5), p.819-827 |
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| subjects | AC133 Antigen Adult Aged Aged, 80 and over Antigens, CD - metabolism Biological and medical sciences Biological Assay - methods Biomarkers, Tumor - metabolism Blood Bone marrow Brain cancer Brain Neoplasms - blood Brain Neoplasms - mortality Brain Neoplasms - pathology Endothelial Cells - metabolism Endothelial Cells - pathology Enzyme-Linked Immunosorbent Assay - methods Female Flow Cytometry Follow-Up Studies Glioblastoma - blood Glioblastoma - mortality Glioblastoma - pathology Glioma Glycoproteins - metabolism Humans Male Medical prognosis Medical sciences Middle Aged Neovascularization, Pathologic - blood Neurosurgery Peptides - metabolism Plasma Stem Cells - metabolism Stem Cells - pathology Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases Umbilical Veins - pathology Vascular endothelial growth factor Vascular Endothelial Growth Factor Receptor-2 - metabolism |
| title | SURROGATE MARKERS PREDICT ANGIOGENIC POTENTIAL AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA MULTIFORME |
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