title: Quantitation of glucose uptake in tumors by dynamic FDG-PET has less glucose bias and lower variability when adjusted for partial saturation of glucose transport.
abstract: BACKGROUND
  A retrospective analysis of estimates of tumor glucose uptake from 1,192 dynamic 2-deoxy-2-(18F)fluoro-D-glucose-positron-emission tomography [FDG-PET] scans showed strong correlations between blood glucose and both the uptake rate constant [Ki] and the metabolic rate of glucose [MRGluc], hindering the interpretation of PET scans acquired under conditions of altered blood glucose. We sought a method to reduce this glucose bias without increasing the between-subject or test-retest variability and did this by considering that tissue glucose transport is a saturable yet unsaturated process best described as a nonlinear function of glucose levels.
  
  
  METHODS
  Patlak-Gjedde analysis was used to compute Ki from 30-min dynamic PET scans in tumor-bearing mice. MRGluc was calculated by factoring in the blood glucose level and a lumped constant equal to unity. Alternatively, we assumed that glucose consumption is saturable according to Michaelis-Menten kinetics and estimated a hypothetical maximum rate of glucose consumption [MRGlucMAX] by multiplying Ki and (KM + [glucose]), where KM is a half-saturation Michaelis constant for glucose uptake. Results were computed for 112 separate studies of 8 to 12 scans each; test-retest statistics were measured in a suitable subset of 201 mice.
  
  
  RESULTS
  A KM value of 130 mg/dL was determined from the data based on minimizing the average correlation between blood glucose and the uptake metric. Using MRGlucMAX resulted in the following benefits compared to using MRGluc: (1) the median correlation with blood glucose was practically zero, and yet (2) the test-retest coefficient of variation [COV] was reduced by 13.4%, and (3) the between-animal COVs were reduced by15.5%. In statistically equivalent terms, achieving the same reduction in between-animal COV while using the traditional MRGluc would require a 40% increase in sample size.
  
  
  CONCLUSIONS
  MRGluc appeared to overcorrect tumor FDG data for changing glucose levels. Applying partial saturation correction using MRGlucMAX offered reduced bias, reduced variability, and potentially increased statistical power. We recommend further investigation of MRGlucMAX in quantitative studies of tumor FDG uptake.
authors.affiliation: Department of Biomedical Imaging, Genentech, Inc,, South San Francisco, CA, 94080, USA. williams.simon@gene.com.
authors.forename: Simon-Peter
authors.initials: SP
authors.lastname: Williams
authors.forename: Judith E
authors.initials: JE
authors.lastname: Flores-Mercado
authors.forename: Ruediger E
authors.initials: RE
authors.lastname: Port
authors.forename: Thomas
authors.initials: T
authors.lastname: Bengtsson