title: Spatial heterogeneity of low-grade gliomas at the capillary level: a PET study on tumor blood flow and amino acid uptake.
abstract: Many low-grade gliomas (World Health Organization grade II) respond to chemotherapy. Cerebral blood flow (CBF) and microvessel density may be critical for drug delivery. We used PET with (18)F-fluoro-ethyl-l-tyrosine (FET) to measure the spatial distribution of the amino acid carrier, which is located at the brain capillaries, and (15)O-H(2)O to measure tumor CBF.
  
  
  METHODS
  Seventeen patients with low-grade glioma were studied. Region-of-interest (ROI) analysis was used to quantify tumor tracer uptake, which was normalized to cerebellar uptake (tumor-to-cerebellum ratio). "Active" tumor was defined as tumor having a radioactivity concentration that was at least 110% of the cerebellar activity. This threshold provided measures of active tumor volume, global and peak tumor CBF, and (18)F-FET uptake. Trace ROIs were applied to create voxelwise profiles of CBF and (18)F-FET uptake across tumor and brain. Standard MRI sequences were used for spatial correlations.
  
  
  RESULTS
  Fourteen of 17 tumors showed increased global CBF and (18)F-FET uptake. Active tumor volumes ranged between 3 and 270 cm(3) for (18)F-FET and between 1 and 41 cm(3) for CBF. Global (18)F-FET uptake in tumors corresponded to CBF increases (Spearman rank rho = 0.771, P < 0.01). The volumes of increased CBF and (18)F-FET uptake spatially coincided and were also correlated (rho = 0.944, P < 0.01). Trace ROIs showed that irrespective of increased (18)F-FET uptake at the tumor periphery, CBF increases were more confined to the tumor center. Within individual tumors, spatial heterogeneity was present. Particular tumors infiltrating the corpus callosum showed low CBF and (18)F-FET uptake in this tumor region. The patterns observed with PET were not reflected on MRI of the tumors, all of which presented as homogeneous non-gadolinium-enhancing lesions.
  
  
  CONCLUSIONS
  Low-grade gliomas are heterogeneous tumors with regard to the distribution of amino acid uptake and CBF. Both are coupled in the tumor center. At the tumor periphery, where tumor infiltration of surrounding brain occurs, CBF may be low irrespective of increased (18)F-FET uptake. An ongoing study is investigating the effect of chemotherapy on these observations.
authors.affiliation: PET Center, Division of Nuclear Medicine, University Hospital, Zürich, Switzerland.
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Wyss
authors.forename: Silvia
authors.initials: S
authors.lastname: Hofer
authors.forename: Martin
authors.initials: M
authors.lastname: Hefti
authors.forename: Esther
authors.initials: E
authors.lastname: Bärtschi
authors.forename: Catrina
authors.initials: C
authors.lastname: Uhlmann
authors.forename: Valerie
authors.initials: V
authors.lastname: Treyer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Roelcke
mesh_terms: D000328:Adult; D026905:Amino Acid Transport Systems / Q000378:metabolism; D001932:Brain Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000378:metabolism; D002196:Capillaries / Q000000981:diagnostic imaging / Q000378:metabolism; D002531:Cerebellum / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D005462:Fluorine Radioisotopes; D005910:Glioma / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000000981:diagnostic imaging / Q000378:metabolism; D008875:Middle Aged; D010103:Oxygen Isotopes; D010104:Oxygen Radioisotopes; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014867:Water
chemical_list: D026905:Amino Acid Transport Systems; D005462:Fluorine Radioisotopes; C117289:O-(2-fluoroethyl)tyrosine; D010103:Oxygen Isotopes; D010104:Oxygen Radioisotopes; D019275:Radiopharmaceuticals; D014867:Water; D014443:Tyrosine