title: Initial evidence that blood-borne microvesicles are biomarkers for recurrence and survival in newly diagnosed glioblastoma patients.
abstract: The purpose of this pilot study was to determine whether blood-borne microvesicles from newly diagnosed glioblastoma patients could be used as biomarkers. We collected 2.8 mL blood from 16 post-operative patients at the time that they were being simulated for chemoradiation therapy (radiation with concurrent temozolomide). Two additional samples were collected during chemoradiation therapy and a final sample was collected at the end of chemoradiation therapy. Patients continued with the therapy suggested by their physicians, based on tumor conference consensus and were followed for recurrence and overall survival. Microvesicles were isolated using serial centrifugation and stained for surface markers (Annexin V for phosphotidyl serine, CD41 for platelets, anti-EGFR for tumor cells, and CD235 for red blood cells). Flow cytometry analysis was performed. Our findings provide initial evidence that increases in Annexin V positive microvesicle levels during chemoradiation therapy are associated with earlier recurrence and shorter overall survival in newly diagnosed glioblastoma patients. The effect is dramatic, with over a four-fold increase in the hazard ratio for an individual at the 75th versus the 25th percentile. Moreover the pattern of Annexin V positive microvesicles remain significant after adjustment for confounding clinical variables that have previously been shown to be prognostic for recurrence and survival. Inclusion of neutrophil levels at the start of chemoradiation therapy in the model yielded the largest attenuation of the observed association. Further studies will be needed to verify and further investigate the association between these two entities.
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. sydevans@mail.med.upenn.edu.
authors.forename: Sydney M
authors.identifier: http://orcid.org/0000-0002-0216-1014
authors.initials: SM
authors.lastname: Evans
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Putt
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lustig
authors.affiliation: Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Lage
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Dewight
authors.initials: D
authors.lastname: Williams
authors.affiliation: Department of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Arati
authors.initials: A
authors.lastname: Desai
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Wolf
authors.affiliation: Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Brem
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Koch
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D055252:Cell-Derived Microparticles / Q000473:pathology*; D059248:Chemoradiotherapy; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000175:diagnosis / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor
keywords: Biomarker; Circulating vesicles; Exosomes; Glioblastoma; Microvesicles; Outcome