title: Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors.
abstract: OBJECTIVE
  The predictive role of the quantification of thymidylate synthase (TS) in tumors treated with antifolate drugs, such as 5-fluorouracil (5-FU), has been extensively reported in a variety of human tumors. Neuroendocrine tumors (NET) represent potential targets of antifolate agents, but no data on TS expression level in these tumors are currently available.
  
  
  METHODS
  A series of 116 NETs were collected, including 58 gastroenteropancreatic (GEP) and 58 lung NETs. In 24 well-differentiated GEP neuroendocrine carcinomas (WD-NEC), a 5-FU-based treatment was given. Total RNA was extracted from microdissected paraffin blocks. TS mRNA quantification was done by real-time PCR, whereas protein expression was evaluated by immunohistochemistry.
  
  
  RESULTS
  By means of both quantification by real-time PCR and immunohistochemistry, a higher TS expression in pulmonary small cell lung cancer and large cell NEC compared with typical and atypical carcinoids was observed (P < 0.01). Similarly, in GEP tumors, a higher TS expression in poorly differentiated carcinomas than both WD-NEC and benign tumors (P < 0.01) was found. In patients with WD-NEC treated with 5-FU, high TS mRNA levels were associated with shorter time to progression (P = 0.002) and overall survival (P = 0.04). This negative prognostic role was confirmed in multivariate analysis adjusting for major prognostic variables (P = 0.01). No association between TS mRNA and survival was observed in WD-NEC patients not receiving 5-FU.
  
  
  CONCLUSIONS
  This study, for the first time, (a) reports the differential TS expression in the spectrum of NETs and (b) indicates TS as a possible predictive marker of treatment efficacy in WD-NEC patients treated with 5-FU.
authors.affiliation: Thoracic Oncology Unit, Pathology Division, Department of Clinical and Biological Sciences, University of Torino, San Luigi Hospital, Torino, Italy. paolo.ceppi@unito.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Ceppi
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrero
authors.forename: Luisella
authors.initials: L
authors.lastname: Righi
authors.forename: Ida
authors.initials: I
authors.lastname: Rapa
authors.forename: Rosj
authors.initials: R
authors.lastname: Rosas
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.forename: Luigi
authors.initials: L
authors.lastname: Dogliotti
authors.forename: Giorgio V
authors.initials: GV
authors.lastname: Scagliotti
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D004067:Digestive System Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005472:Fluorouracil / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D005472:Fluorouracil