title: Increased Activity of the Immunoregulatory Enzyme Indoleamine-2,3-Dioxygenase with Consecutive Tryptophan Depletion Predicts Death in Patients with Neuroendocrine Neoplasia.
abstract: OBJECTIVE
  Data from a considerable number of malignancies demonstrate that depletion of the essential amino acid tryptophan via induction of the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO) serves as an important tumour escape strategy and is of prognostic importance. Here we investigate the predictive value of the activity of IDO as well as levels of tryptophan and respective downstream catabolites in a large cohort of patients with neuroendocrine neoplasms (NEN).
  
  
  METHODS
  142 consecutive Caucasian patients (62 male, aged 60.3 ± 11.9 years) with histologically confirmed NEN were systematically analysed in a retrospective blinded end point analysis. Patients were followed up for a mean period of about 3.9 ± 1.9 years. Clinical outcome, levels of established biomarkers, and tryptophan degradation markers (assessed using tandem mass spectrometry) including estimated IDO activity were recorded. Cox proportional hazards regression models were performed for the assessment of prognostic power.
  
  
  RESULTS
  We found that baseline tryptophan levels were significantly lower and IDO activity was significantly increased in non-survivors. The risk for death inclined stepwise and was highest in patients in the upper tertile of IDO activity. Cox proportional regression models identified IDO activity as an independent predictor of death.
  
  
  CONCLUSIONS
  In this retrospective analysis, we observed that baseline activity of the immunoregulatory enzyme IDO was significantly increased in non-survivors. IDO activity was identified as an independent predictor of death in this cohort of NEN patients. Whether IDO activity or tryptophan depletion serves to guide future therapeutic interventions in NEN remains to be established.
authors.affiliation: Department of Hepatology and Gastroenterology, Charité Campus Mitte [CCM and Campus Virchow Clinic (CVK)], Charité, University Medicine Berlin, Berlin, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Pschowski
authors.forename: Ulrich-Frank
authors.initials: UF
authors.lastname: Pape
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fusch
authors.forename: Christian
authors.initials: C
authors.lastname: Fischer
authors.forename: Henning
authors.initials: H
authors.lastname: Jann
authors.forename: Alexander
authors.initials: A
authors.lastname: Baur
authors.forename: Ruza
authors.initials: R
authors.lastname: Arsenic
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Stephan
authors.initials: S
authors.lastname: von Haehling
authors.forename: Marianne
authors.initials: M
authors.lastname: Pavel
authors.forename: Joerg C
authors.initials: JC
authors.lastname: Schefold
mesh_terms: D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000097:blood*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000175:diagnosis* / Q000201:enzymology* / Q000276:immunology / Q000401:mortality*; D012189:Retrospective Studies; D014364:Tryptophan / Q000097:blood*
chemical_list: D015415:Biomarkers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan