Shuji Komori

Contribution of thymidylate synthase to gemcitabine therapy for advanced pancreatic cancer.

Objectives: Thymidylate synthase (TS) inhibitors activate human equilibrative nucleoside transporter 1. We evaluated the contribution of TS expression to determine a treatment method providing an effect from gemcitabine (GEM). Methods: The expression of 5-fluorouracil (5-FU) and GEM metabolic factors (5-FU: TS, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase; GEM: human equilibrative nucleoside transporter 1, deoxycytidine kinase, cytidine deaminase, 5&vprime;-nucleotidase) were studied in 7 pancreatic cancer cell lines by Western blotting, and drug resistance was evaluated by 3-[4,5-dimethylthiazol]-2,5-dephenyl tetrazolium bromide assay. The expression of 5-FU factors was observed immunohistochemically in resected pancreatic cancer specimens. Results: Gemcitabine concentrations that inhibited colony formation by 50% correlated with TS protein expression (P = 0.0169). With a 5-FU non-growth-inhibiting dose, GEM concentrations that inhibited colony formation by 50% were significantly reduced by one fourth to one tenth. Knockout of TS expression by small interfering RNA decreased resistance to GEM in the cell lines (P = 0.0019). Immunohistochemically, TS expression related to disease-free survival time of patients treated with GEM (P = 0.0224). A high expression of 5-FU factors was detected: orotate phosphoribosyltransferase: differentiated cases (P = 0.0137), lower T factor (P = 0.0411); dihydropyrimidine dehydrogenase: nerve invasion (P = 0.0188), lymph node recurrence (P = 0.0253); TS, positive N factor (P = 0.0061). Conclusions: The expression of TS provides an alternative source of substrate for DNA synthesis and positively correlates with GEM resistance and shortened patient survival. Abbreviations: GEM - gemcitabine, 5-FU - 5-fluorouracil, TS - thymidylate synthase, DPD - dihydropyrimidine dehydrogenase, OPRT - orotate phosphoribosyltransferase, hENT1 - human equilibrative nucleoside transporter 1

A case of esophageal adenocarcinoma arising from the ectopic gastric mucosa in the thoracic esophagus.

A 75-year old man was detected with a pediculate tumor in the upper esophagus. A biopsy determined that it was an adenocarcinoma. A subtotal esophagectomy with dissection of three-fields of lymph nodes was selected. The pathological study revealed it to be an esophageal adenocarcinoma arising from ectopic gastric mucosa of the fundus of the stomach. His post-operative course was uneventful and without sign of recurrence for 3.5 years.

Novel strategy with gemcitabine for advanced pancreatic cancer.

5-fluorouracil (5-FU) is widely used in chemotherapy for gastric and colorectal cancer, but gemcitabine (GEM), and not 5-FU, is approved as a standard drug for use in pancreatic cancer. Interindividual variation in the enzyme activity of the GEM metabolic pathway can affect the extent of GEM metabolism and the efficacy of GEM chemotherapy. Human equilibrative nucleoside transporter 1 (hENT1) is recognized as a major transporter of GEM into cells. In addition, a factor that activates hENT1 is the inhibition of thymidylate synthase (TS), one of the 5-FU metabolic enzymes; TS inhibition mediates depleting intracellular nucleotide pools, resulting in the activation of the salvage pathway mediated through hENT1. In this paper, the role of 5-FU in GEM-based chemotherapy for pancreatic cancer is discussed with special emphasis on enzymes involved in the 5-FU and GEM metabolic pathways and in the correlation between GEM responsiveness and the expression of 5-FU and GEM metabolic enzymes.

Preoperative diagnosis of an asymptomatic cancer restricted to the cystic duct

INTRODUCTION Even now, cystic duct cancer (CDC) as defined by Farrar is rare and has a better prognosis than gallbladder cancer, although CDC as defined by Ozden et al., the definition of which could apply to early and advanced cases of CDC, is not rare and has a poorer prognosis than the CDC defined by Farrar. PRESENTATION OF CASE A 78-year-old woman with no complaints was found to have a tumor restricted to the cystic duct. Three cytology examinations of the patients bile could not establish that the tumor was an adenocarcinoma. However, adenocarcinoma was suspected due to the hypervascularity shown on contrast-enhanced computed tomography. Cholecystectomy and extrahepatic bile duct resection with D2 lymph node dissection was performed. The pathological study revealed it to be CDC. Her postoperative course has been uneventful and without recurrence for 21 months. DISCUSSION At their first medical examination, many CDC patients are found to have such advanced spread of the cancer to adjacent organs that an extended operation might be necessary. As in our case, better patient outcome results when no lymph node or remote metastasis is present. CONCLUSION Diagnosing CDC as early as possible contributes to curative resections and favorable patient outcomes and also allows surgeons to recommend a mini-invasive procedure to their patients rather than extended resection including that of adjacent organs.