title: Expression level of dihydropyrimidine dehydrogenase is associated with clinical outcome in patients with T1G3 bladder cancer treated with Bacillus Calmette-Guerin.
abstract: BACKGROUND
  Recently, it has been shown that 5-fluorouracil (5-FU) with a strong dihydropyrimidine dehydrogenase (DPD) inhibitor elicits a significant response in bladder cancer with a high level of DPD. However, only a few studies investigated the association between the level of the enzyme that regulates the metabolism of 5-FU and prognosis in bladder cancer. Furthermore, to our knowledge, there has also been no such report in T1G3 bladder tumors treated with BCG. Therefore, we evaluated enzymes that regulate the metabolism of 5-FU in T1G3 tumors treated with BCG immunotherapy using the Danenberg tumor profile (DTP) method, a highly accurate measurement of RNA from paraffin-embedded specimens.
  
  
  METHODS
  This study included 28 patients with T1G3 bladder cancer, each of whom underwent complete transurethral tumor resection and BCG intravesical instillation at our institution. The median follow-up period was 39 months (range, 3 to 159 months). The DTP method was used to analyze the mRNA expression of 3 enzymes related to 5-FU: DPD, orotate phosphoribosyltransferase (OPRT), and thymidylate synthase (TS).
  
  
  RESULTS
  Among the 28 patients, 13 developed recurrences (46.4%) and 5 experienced disease progression (17.9%). An elevated DPD mRNA level was significantly associated with recurrence (p = 0.048) and progression (p = 0.045). However, TS and OPRT mRNA levels were not significantly associated with any other clinical features or outcomes. Furthermore, the high DPD group had a significantly lower recurrence-free survival rate than the low DPD group (p = 0.047). Among patients with low DPD, the 2- and 5-year recurrence-free survival rates were 88.9% and 74.1%, respectively; while among patients with high DPD, the corresponding rates were 61.3% and 36.8%, respectively. TS and OPRT were not significantly associated with recurrence-free survival rates.
  
  
  CONCLUSIONS
  DPD is significantly associated with recurrence and progression among T1G3 bladder cancer patients treated with BCG.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ide
authors.affiliation: Department of Urology and Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. eiji-k@kb3.so-net.ne.jp.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Shuji
authors.initials: S
authors.lastname: Mikami
authors.forename: Akira
authors.initials: A
authors.lastname: Miyajima
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
mesh_terms: D000368:Aged; D001500:BCG Vaccine / Q000627:therapeutic use*; D001483:Base Sequence; D017931:DNA Primers; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000628:therapy*
chemical_list: D001500:BCG Vaccine; D017931:DNA Primers; D042943:Dihydrouracil Dehydrogenase (NADP)