title: Systemic changes of tryptophan catabolites via the indoleamine-2,3-dioxygenase pathway in primary cervical cancer.
abstract: OBJECTIVE
  Induction of tryptophan catabolism is mediated by inflammatory mechanisms including up-regulation of the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO). This leads to the formation of mediators collectively referred to as kynurenines. Kynurenines are involved in various diseases such as renal failure, sepsis and cancer. We aimed to investigate whether systemic levels of kynurenines are induced in primary cervical cancer (PCC).
  
  
  METHODS
  Tryptophan, serotonin, kynurenine, kynurenic acid, quinolinic acid and estimated IDO activity were determined using tandem mass spectrometry for serum samples of 20 PCC patients (mean age: 45.1±11.3 years, FIGO-stage: 1b1-2b) prior to radical abdominal surgery. Data were compared to those from 40 healthy controls. Receiver operating curve (ROC) analyses were performed.
  
  
  RESULTS
  Mean tryptophan (22.7±15.1 vs. 18.9±3.5 μM; p=0.27) and kynurenine levels (2.25±0.7 vs. 2.59±0.25 μM; p=0.1) were unchanged in PCC patients when compared to controls. Estimated IDO activity (kynurenine level × 100/tryptophan: 11.8±4.5 vs. 14.1±2.4; p=0.04) and mean levels of kynurenic acid (0.25±0.06 vs. 0.55±0.23 μM; p<0.0001) were significantly lower in PCC patients compared to controls, while mean levels of quinolinic acid (0.35±0.07 vs. 0.24±0.09 μM, p<0.0001) were significantly higher. The ratio of quinolinic acid to kynurenic acid (Q/K) differed significantly between patients with and those without cancer (p<0.0001). When this index was >0.95, the sensitivity and specificity for identification of PCC patients were 100% and 90%, respectively (AUC=0.981, 95% CI=0.907-0.999; positive likelihood ratio +10.0).
  
  
  CONCLUSIONS
  PCC is associated with increased systemic levels of quinolinic acid and reduced levels of kynurenic acid. In our study population, the Q/K allowed identification of PCC patients with a high level of accuracy. The prognostic power and relevance of this novel proposed index remains to be elucidated in further larger prospective studies.
authors.affiliation: Department of Gynecology and Obstetrics, Charité, Virchow Campus Clinic-University Hospital, Augustenburger Platz 1, 13353 Berlin, Germany. chfotopoulou@gmail.com
authors.forename: Christina
authors.initials: C
authors.lastname: Fotopoulou
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.forename: Rene
authors.initials: R
authors.lastname: Pschowski
authors.forename: Stephan
authors.initials: S
authors.lastname: VON Haehling
authors.forename: Grazyna
authors.initials: G
authors.lastname: Domanska
authors.forename: Elena-Ioana
authors.initials: EI
authors.lastname: Braicu
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fusch
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
authors.forename: Joerg C
authors.initials: JC
authors.lastname: Schefold
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008875:Middle Aged; D014364:Tryptophan / Q000097:blood*; D002583:Uterine Cervical Neoplasms / Q000097:blood* / Q000201:enzymology
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan