title: The use of longitudinal 18F-FET MicroPET imaging to evaluate response to irinotecan in orthotopic human glioblastoma multiforme xenografts.
abstract: OBJECTIVE
  Brain tumor imaging is challenging. Although 18F-FET PET is widely used in the clinic, the value of 18F-FET MicroPET to evaluate brain tumors in xenograft has not been assessed to date. The aim of this study therefore was to evaluate the performance of in vivo 18F-FET MicroPET in detecting a treatment response in xenografts. In addition, the correlations between the 18F-FET tumor accumulation and the gene expression of Ki67 and the amino acid transporters LAT1 and LAT2 were investigated. Furthermore, Ki67, LAT1 and LAT2 gene expression in xenograft and archival patient tumors was compared.
  
  
  METHODS
  Human GBM cells were injected orthotopically in nude mice and 18F-FET uptake was followed by weekly MicroPET/CT. When tumor take was observed, mice were treated with CPT-11 or saline weekly. After two weeks of treatment the brain tumors were isolated and quantitative polymerase chain reaction were performed on the xenograft tumors and in parallel on archival patient tumor specimens.
  
  
  RESULTS
  The relative tumor-to-brain (T/B) ratio of SUV max was significantly lower after one week (123 ± 6%, n = 7 vs. 147 ± 6%, n = 7; p = 0.018) and after two weeks (142 ± 8%, n = 5 vs. 204 ± 27%, n = 4; p = 0.047) in the CPT-11 group compared with the control group. Strong negative correlations between SUV max T/B ratio and LAT1 (r = -0.62, p = 0.04) and LAT2 (r = -0.67, p = 0.02) were observed. In addition, a strong positive correlation between LAT1 and Ki67 was detected in xenografts. Furthermore, a 1.6 fold higher expression of LAT1 and a 23 fold higher expression of LAT2 were observed in patient specimens compared to xenografts.
  
  
  CONCLUSIONS
  18F-FET MicroPET can be used to detect a treatment response to CPT-11 in GBM xenografts. The strong negative correlation between SUV max T/B ratio and LAT1/LAT2 indicates an export transport function. We suggest that 18F-FET PET may be used for detection of early treatment response in patients.
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette K
authors.initials: MK
authors.lastname: Nedergaard
authors.affiliation: Department of Radiation Biology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Karina
authors.initials: K
authors.lastname: Kristoffersen
authors.affiliation: Department of Radiation Biology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Signe R
authors.initials: SR
authors.lastname: Michaelsen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Madsen
authors.affiliation: Department of Radiation Biology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Hans S
authors.initials: HS
authors.lastname: Poulsen
authors.affiliation: Department of Radiation Biology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Marie-Thérése
authors.initials: MT
authors.lastname: Stockhausen
authors.affiliation: Phase 1 Unit, Department of Oncology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Lassen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjaer
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000188:drug therapy; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis* / Q000188:drug therapy; D064593:Heterografts; D006801:Humans; D000077146:Irinotecan; D008819:Mice, Nude; D059906:Neuroimaging; D049268:Positron-Emission Tomography; D014443:Tyrosine / Q000031:analogs & derivatives*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C545932:(18F)fluoroethyltyrosine; D014443:Tyrosine; D000077146:Irinotecan; D002166:Camptothecin