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 Â dCK/RRM1 Â 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.

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.

A 47-year-old woman with neurofibromatosis type 1 suffered from general muscle weakness and watery diarrhea. Laboratory findings showed elevated muscular enzymes, severe hypokalemia and excessive production of catecholamines and vasoactive intestinal polypeptide (VIP). A computed tomography scan showed a 10 cm left adrenal mass, in which [(131)I]-metaiodobenzylguanidine scintigraphy showed high uptake. After she underwent surgical removal of the tumor, all the symptoms and signs subsided. A histological study revealed that the mass consisted of pheochromocytoma and ganglioneuroma, respectively producing catecholamines and VIP. In immunohistochemical staining of neurofibromin, pheochromocytoma and ganglion cells showed positive staining, whereas the staining was negative for nerve bundles and Schwann cells. We concluded that the patient had hypokalemic rhabdomyolysis due to watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome, which was induced by a VIP-producing composite pheochromocytoma. Composite pheochromocytoma is a neuroendocrine tumor that is composed of pheochromocytoma and ganglioneuroma, both derived from the neural crest. Deficiency of neurofibromin in Schwann cells might have played an important role in the development and the growth of the composite pheochromocytoma in this patient.

No abstract

Gaucher disease with multiple bone necrosis treated by enzyme replacement therapy and pamidronate.