title: Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma.
abstract: Patients with recurrent glioblastoma often exhibit regions of diffusion restriction following the initiation of bevacizumab therapy. Studies suggest that these regions represent either diffusion-restricted necrosis or hypercellular tumor. This study explored postmortem brain specimens and a population analysis of overall survival to determine the identity and implications of such lesions.
  
  
  
  Postmortem examinations were performed on 6 patients with recurrent glioblastoma on bevacizumab with progressively growing regions of diffusion restriction. ADC values were extracted from regions of both hypercellular tumor and necrosis. A receiver operating characteristic analysis was performed to define optimal ADC thresholds for differentiating tissue types. A retrospective population study was also performed comparing the overall survival of 64 patients with recurrent glioblastoma treated with bevacizumab. Patients were separated into 3 groups: no diffusion restriction, diffusion restriction that appeared and progressed within 5 months of bevacizumab initiation, and delayed or stable diffusion restriction. An additional analysis was performed assessing tumor O6-methylguanine-DNA-methyltransferase methylation.
  
  
  
  The optimal ADC threshold for differentiation of hypercellularity and necrosis was 0.736 × 10-3mm2/s. Progressively expanding diffusion restriction was pathologically confirmed to be coagulative necrosis surrounded by viable tumor. Progressive lesions were associated with the worst overall survival, while stable lesions showed the greatest overall survival (P < .05). Of the 40% of patients with O6-methylguanine-DNA-methyltransferase methylated tumors, none developed diffusion-restricted lesions.
  
  
  
  Progressive diffusion-restricted lesions were pathologically confirmed to be coagulative necrosis surrounded by viable tumor and associated with decreased overall survival. Stable lesions were, however, associated with increased overall survival. All lesions were associated with O6-methylguanine-DNA-methyltransferase unmethylated tumors.
authors: From the Departments of Neurosurgery (H.S.N., W.M.M.).
authors: H S
authors: 0000-0002-3515-278X
authors: HS
authors: Nguyen
authors: Radiology (N.M., S.L.H., S.D.R., K.M.S., P.S.L.).
authors: N
authors: 0000-0003-0777-1142
authors: N
authors: Milbach
authors: Radiology (N.M., S.L.H., S.D.R., K.M.S., P.S.L.).
authors: S L
authors: 0000-0002-2519-3473
authors: SL
authors: Hurrell
authors: Pathology (E.C.).
authors: E
authors: 0000-0003-3642-6532
authors: E
authors: Cochran
authors: Neurology (J.C.).
authors: J
authors: 0000-0002-6122-8573
authors: J
authors: Connelly
authors: Radiation Oncology (J.A.B., C.J.S.).
authors: J A
authors: 0000-0002-3686-1940
authors: JA
authors: Bovi
authors: Radiation Oncology (J.A.B., C.J.S.).
authors: C J
authors: 0000-0001-7653-9713
authors: CJ
authors: Schultz
authors: From the Departments of Neurosurgery (H.S.N., W.M.M.).
authors: W M
authors: 0000-0003-1281-5250
authors: WM
authors: Mueller
authors: Radiology (N.M., S.L.H., S.D.R., K.M.S., P.S.L.).
authors: S D
authors: 0000-0002-4136-9352
authors: SD
authors: Rand
authors: Radiology (N.M., S.L.H., S.D.R., K.M.S., P.S.L.).|Biophysics (K.M.S., P.S.L.), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: K M
authors: 0000-0001-6402-2602
authors: KM
authors: Schmainda
authors: Radiology (N.M., S.L.H., S.D.R., K.M.S., P.S.L.) plaviole@mcw.edu.|Biophysics (K.M.S., P.S.L.), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: P S
authors: 0000-0002-9602-6891
authors: PS
authors: LaViolette
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D005260:Female; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009336:Necrosis / Q000000981:diagnostic imaging / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000401:mortality / Q000473:pathology*; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D000068258:Bevacizumab