title: The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response.
abstract: BACKGROUND
  Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblastoma (GBM) biology, do not influence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response.
  
  
  METHODS
  The relationship between TS growth and clinical outcome was investigated in 52 GBMs treated with surgical resection followed by radiotherapy and temozolomide (TMZ). The effect on TS of radiation (6 to 60 Gy) and of TMZ (3.9 μM to 1 mM) was related with patients' survival.
  
  
  RESULTS
  Generation of TS was an independent factor for poor overall survival (OS) and poor progression-free survival (PFS) (P < .0001 and P = .0010, respectively). Growth rate and clonogenicity of TS predicted poor OS. In general, TS were highly resistant to both radiation and TMZ. Resistance to TMZ was stronger in TS with high clonogenicity and fast growth (P < .02). Shorter PFS was associated with radiation LD50 (lethal dose required to kill 50% of TS cells) >12 Gy of matched TS (P = .0484). A direct relationship was found between sensitivity of TS to TMZ and patients' survival (P = .0167 and P = .0436 for OS and PFS, respectively). Importantly, values for TMZ half-maximal inhibitory concentration <50 μM, which are in the range of plasma levels achieved in vivo, identified cases with longer OS and PFS (P = .0020 and P = .0016, respectively).
  
  
  CONCLUSIONS
  Analysis of TS holds translational relevance by predicting the response of parent tumors to radiation and, particularly, to TMZ. Dissecting the clonogenic population from proliferating progeny in TS can guide therapeutic strategies to a more effective drug selection and treatment duration.
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Quintino Giorgio
authors.initials: QG
authors.lastname: D'Alessandris
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Daniele
authors.initials: D
authors.lastname: Runci
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Mariachiara
authors.initials: M
authors.lastname: Buccarelli
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Tonia
authors.initials: T
authors.lastname: Cenci
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Michele
authors.initials: M
authors.lastname: Signore
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Louis
authors.initials: L
authors.lastname: Stancato
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Olivi
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Larocca
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ricci-Vitiani
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Institute of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide
keywords: cancer stem cells; glioblastoma; radiotherapy; temozolomide; treatment outcome