Yasuhiro Nakano

To identify predictive molecular markers for gemcitabine resistance, we investigated changes in the expression of four genes associated with gemcitabine transport and metabolism during the development of acquired gemcitabine resistance of pancreatic cancer cell lines. The expression levels of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), RRM1, and RRM2 mRNA were analysed by real-time light cycler-PCR in various subclones during the development of acquired resistance to gemcitabine. Real-time light cycler-PCR demonstrated that the expression levels of either RRM1 or RRM2 progressively increased during the development of gemcitabine resistance. Expression of dCK was slightly increased in cells resistant to lower concentrations of gemcitabine, but was decreased below the undetectable level in higher concentration-resistant subclones. Expression of hENT1 was increased in the development of gemcitabine resistance. As acquired resistance to gemcitabine seems to correlate with the balance of these four factors, we calculated the ratio of hENT1 x dCK/RRM1 x RRM2 gene expression in gemcitabine-resistant subclones. The ratio of gene expression decreased progressively with development of acquired resistance in gemcitabine-resistant subclones. Furthermore, the expression ratio significantly correlated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single gene expression level correlated with the sensitivity. These results suggest that the sensitivity of pancreatic cancer cells to gemcitabine is determined by the ratio of four factors involved in gemcitabine transport and metabolism. The ratio of the four gene expression levels correlates with acquired gemcitabine-resistance in pancreatic cancer cells, and may be useful as a predictive marker for the efficacy of gemcitabine therapy in pancreatic cancer patients.

BACKGROUND AND AIMS: Although branch duct intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas without mural nodules are frequently observed in asymptomatic subjects, the natural history of these lesions has never been studied. The aim of this study was to elucidate the natural history of branch duct IPMNs without mural nodules. METHODS: Eighty-two patients who had no apparent mural nodules on initial examination were selected for follow-up. All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography, and were followed-up by regular examinations once or twice a year. Serial changes of the maximum cystic diameter and the appearance of mural nodules were studied during the observation periods ranging from 14 to 148 months (median, 61 months). RESULTS: Nine (11.0%) of 82 patients exhibited obvious progression of cystic dilatation (median, 59 months). Of these nine patients with cystic enlargement, six continued with regular follow-up examinations. Three cases underwent surgical resection, and were pathologically diagnosed as adenoma in two and borderline in one. Four patients (4.9%) showed newly developed mural nodules in dilated branch ducts (median, 105 months). Histological analysis revealed three cases classified as adenoma and one as carcinoma in situ. None of the remaining 69 patients (84.1%) showed any changes in dilated branch ducts (median, 57 months). CONCLUSIONS: Most branch duct IPMNs without mural nodules remained unchanged during long-term follow-up. Although follow-up with careful examination is required to detect newly developed mural nodules in dilated branch ducts, branch duct IPMNs without mural nodules can be followed-up without surgery.

Objective: Although branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) are slow-growing tumors with a favorable prognosis, the synchronous occurrence of pancreatic ductal adenocarcinomas (PDAs) in patients with BD-IPMNs has been reported. This study was aimed to elucidate the development of PDAs in long-term follow-up patients with BD-IPMNs. Methods: We investigated 89 BD-IPMN patients who had no mural nodules and followed them up conservatively at least 2 years (median follow-up, 64 months; range, 25-158 months). All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography. We calculated the standardized incidence ratio (SIR) from the vital statistics compiled by the Ministry of Health, Labor, and Welfare of Japan. Results: Among the 89 patients, 4 cases of PDAs distant from BD-IPMN were observed in 552 patient-years of follow-up (7.2 per 1000 patient-years). The expected number was 0.25, and the SIR of PDAs was 15.8 (95% confidence interval [CI], 4.3-40.4; P = 0.00014). Subgroup analyses showed that the incidence of PDAs was significantly increased in patients 70 years or older (SIR 16.7; 95% CI, 3.4-48.7; P = 0.0008) and in women (SIR 22.5; 95% CI, 2.7-81.1; P = 0.0037). Conclusions: Patients with BD-IPMNs are at a high risk for PDAs. During the follow-up, careful examination is required to detect the development of PDAs in patients with BD-IPMNs. Abbreviations: IPMN - intraductal papillary mucinous neoplasm, PDA - pancreatic ductal adenocarcinoma, ERCP - endoscopic retrograde cholangiopancreatography, MRCP - magnetic resonance cholangiopancreatography, EUS - endoscopic ultrasonography, CT - computed tomography, SIR - standardized incidence ratio