title: Clinical significance of tryptophan metabolism in the nontumoral hemisphere in patients with malignant glioma.
abstract: α-(11)C-methyl-L-tryptophan (AMT) PET allows evaluation of brain serotonin synthesis and can also track upregulation of the immunosuppressive kynurenine pathway in tumor tissue. Increased AMT uptake is a hallmark of World Health Organization grade III-IV gliomas. Our recent study also suggested decreased frontal cortical AMT uptake in glioma patients contralateral to the tumor. The clinical significance of extratumoral tryptophan metabolism has not been established. In the present study, we investigated clinical correlates of tryptophan metabolic abnormalities in the nontumoral hemisphere of glioma patients.
  
  
  METHODS
  Standardized AMT uptake values (SUVs) and the uptake rate constant of AMT (K [mL/g/min], a measure proportional to serotonin synthesis in nontumoral gray matter) were quantified in the frontal and temporal cortex and thalamus in the nontumoral hemisphere in 77 AMT PET scans of 66 patients (41 men, 25 women; mean age ± SD, 55 ± 15 y) with grade III-IV gliomas. These AMT values were determined before treatment in 35 and after treatment in 42 patients and were correlated with clinical variables and survival.
  
  
  RESULTS
  AMT uptake in the thalamus showed a moderate age-related increase before treatment (SUV, r = 0.39, P = 0.02) but decrease after treatment (K, r = -0.33, P = 0.057). Women had higher thalamic SUVs before treatment (P = 0.037) and higher thalamic (P = 0.013) and frontal cortical K values (P = 0.023) after treatment. In the posttreatment glioma group, high thalamic SUVs and high thalamocortical SUV ratios were associated with short survival in Cox regression analysis. The thalamocortical ratio remained strongly prognostic (P < 0.01) when clinical predictors, including age, glioma grade, and time since radiotherapy, were entered in the regression model. Long interval between radiotherapy and posttreatment AMT PET as well as high radiation dose affecting the thalamus were associated with lower contralateral thalamic or cortical AMT uptake values.
  
  
  CONCLUSIONS
  These observations provide evidence for altered tryptophan uptake in contralateral cortical and thalamic brain regions in glioma patients after initial therapy, suggesting treatment effects on the serotonergic system. Low thalamic tryptophan uptake appears to be a strong, independent predictor of long survival in patients with previous glioma treatment.
authors.affiliation: PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan Department of Pediatrics, Wayne State University, Detroit, Michigan.
authors.forename: David O
authors.initials: DO
authors.lastname: Kamson
authors.affiliation: PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan.
authors.forename: Tiffany J
authors.initials: TJ
authors.lastname: Lee
authors.affiliation: PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Varadarajan
authors.affiliation: Department of Radiology, Wayne State University, Detroit, Michigan Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Robinette
authors.affiliation: PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan Department of Pediatrics, Wayne State University, Detroit, Michigan Department of Radiology, Wayne State University, Detroit, Michigan Department of Neurology, Wayne State University, Detroit, Michigan.
authors.forename: Otto
authors.initials: O
authors.lastname: Muzik
authors.affiliation: PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan Department of Radiology, Wayne State University, Detroit, Michigan.
authors.forename: Pulak K
authors.initials: PK
authors.lastname: Chakraborty
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan Department of Neurology, Wayne State University, Detroit, Michigan.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Barger
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan Department of Neurosurgery, Wayne State University, Detroit, Michigan; and Department of Oncology, Wayne State University, Detroit, Michigan.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Mittal
authors.affiliation: PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan Department of Pediatrics, Wayne State University, Detroit, Michigan Karmanos Cancer Institute, Detroit, Michigan Department of Neurology, Wayne State University, Detroit, Michigan juhasz@pet.wayne.edu.
authors.forename: Csaba
authors.initials: C
authors.lastname: Juhász
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D007737:Kynurenine / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods; D011379:Prognosis; D016016:Proportional Hazards Models; D012701:Serotonin / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives / Q000378:metabolism*
chemical_list: D012701:Serotonin; D007737:Kynurenine; C028129:tryptophan methyl ester; D014364:Tryptophan
keywords: PET; brain; glioma; survival; tryptophan metabolism