Yasuharu Tokuyama

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

Clinicopathological features of hepatocellular carcinoma evaluated by vascular endothelial growth factor expression

Aim:  To evaluate the significance of the expression of vascular endothelial growth factor (VEGF), its correlation with clinicopathological variables were studied in the tissue of hepatocellular carcinoma (HCC) and surrounding liver.

Strategy for synchronous and multiple liver metastasis.

BACKGROUND/AIMS Surgical indications for resection of synchronous metastasis from colorectal cancer (CRC) and the optimal timing of hepatectomy are still controversial and widely debated. METHODOLOGY Synchronous and multiple metastatic liver tumors were detected in 57 patients since May 2005. Our treatment policy was to perform hepatectomy if the resection could be done with no limit on size and number of tumors. However, if curative resection could not be done, chemotherapy was begun and timing for the possibility of a radical operation was planned immediately. RESULTS In 37 patients whose tumors were located only in the liver, primary tumor resection was performed in 16 patients and after tumor-decreasing by chemotherapy, in 7 patients. In 20 patients in whom chemotherapy was performed first, after controlling the distant metastasis, hepatectomy was performed in 3 patients and staged hepatectomy was performed in 10. Recurrence was detected after hepatectomy in 75.0% of simultaneous resection cases and in 70.0% of staged cases. In the recurrence cases, early detection after tumor resection occurred in 58.3% of the simultaneous and 14.2% of the staged. CONCLUSIONS The present data show that neoadjuvant chemotherapy does not increase the risk of postoperative complications or the surgical difficulties of hepatectomy for colorectal metastases.

Mucinous cystic neoplasm of the pancreas in a male patient

Mucinous cystic neoplasms (MCNs) make up a morphologic family of similar appearing tumors arising in the ovary and various extraovarian organs such as pancreas, hepatobiliary tract and mesentery. MCNs of the pancreas occur almost exclusively in women. Here, we report a rare case of MCN in a male patient. A 39-year-old man was admitted to our hospital with the chief complaint of back pain. Abdominal computed tomography revealed a multilocular cyctic mass 6.3 cm in diameter in the pancreatic tail. In addition, the outer wall and septae with calcification were demonstrated in the cystic lesion. On magnetic resonance imaging , the cystic fluid had low intensity on T1-weighted imaging and high intensity on T2-weighted imaging. Endoscopic retrograde cholangio-pancreatography (ERCP) showed neither communication between the cystic lesion and the main pancreatic duct nor encasement of the main pancreatic duct. Endoscopic ultrasonography revealed neither solid component nor thickness of the septae in the cystic lesion. Consequently, we performed distal pancreatectomy with splenectomy under the diagnosis of cystic neoplasia of the pancreas. Histopathologically, the cystic lesion showed two distinct component: an inner epithelial layer and an outer densely cellular ovarian-type stromal layer. Based on these findings, the cystic lesion was diagnosed as MCN.

Liver Abscess after Common Hepatic Artery Embolization for Delayed Hemorrhage Following Pancreaticoduodenectomy: A Case Report

A 55-year-old man underwent pancreaticoduodenectomy for bile duct carcinoma in March 2009. The patient developed anastomotic leakage and had a short episode of hemorrhage from the drainage tubes with spontaneous disappearance. CT and upper endoscopy did not reveal the source of bleeding. A massive life-threatening hemorrhage occurred on the 18th postsurgical day. Emergency angiography showed a 2.7-cm pseudoaneurysm of the gastroduodenal artery stump, and hepatic artery embolization was performed. After embolization, an abscess appeared in segments 2/3 of the liver without involving the right lobe. We treated conservatively by drainage and antibiotics. During the course of therapy after embolization, the patient experienced several episodes of high fever but did not develop hepatic failure. On the 68th day after embolization, the abscess had penetrated to the lesser sac, which was immediately treated by percutaneous drainage. Anastomotic leakage was treated by continuous irrigation from the drain, for which complete resolution was achieved by the 34th day after embolization. The patient was discharged 101 days after embolization. Imaging and the clinical course demonstrate a unique mechanism of abscess formation after embolization.

Ileal perforation in a patient with high spinal cord injury: report of a case.

Assessing abdominal complications in patients who have previously suffered high spinal cord injury is very difficult because the resultant loss of sensory, motor, and reflux function of the abdominal wall can mask the typical signs of acute abdomen such as tenderness, muscle rigidity, and peritoneal rebound pain. We recently diagnosed a small intestinal perforation in a 77-year-old man with a C6–7 spinal cord injury sustained 14 years earlier. The patient was correctly diagnosed as having an acute abdominal condition, despite palsy of abdominal wall sensation. An emergency laparotomy was done and a 40-cm length of affected ileum, about 180 cm distal to the Treitz ligament, including a 1-cm perforation, was resected, followed by an end-to-end anastomosis. We report this case to raise awareness of the need for appropriate diagnosis and early surgical treatment of abdominal complications in spinal-cord-injured patients.

A Case Report of Intraductal Papillary-Mucinous Neoplasm of the Pancreas Showing Morphologic Transformation during Followup Periods.

A 64-year-old man underwent MRCP for further examination of gallbladder stones and IPMN of branch-type (IPMN-Br) was pointed out. Yearly MRCP had revealed the gradual increase of the cystic components, marked dilation of the main pancreatic duct (MPD), and filling defects in the MPD. After follow-up for three years, he underwent pancreatoduodenectomy. Histologically, the dilated MPD and connecting dilated branch ducts were filled with nodular growth of tumor cells consisting of gastric-type adenoma with pyloric gland-like structures. In the MPD, a transition from gastric-type adenoma to intestinal-type carcinoma was observed. In addition, in a dilated branch duct, some components of intestinal-type carcinoma with marked arborizing structures were observed. A minimally invasion was observed around branch ducts. Immunohistochemistry revealed diffuse nuclear accumulation of PCNA and Ki67 in the tumor cells of branch dusts. Our observations suggest that the secondary infiltration to the MPD of IPMN-Br and IPMN-Br possesses malignant potential for microinvasion.

Successful Surgical Resection for Peritoneal Implantation of Hepatocellular Carcinoma at the Paracardial Portion

Peritoneal implantation from hepatocellular carcinoma has been rarely reported. It may occur at various sites. Here we present a surgically resected case of peritoneal implantation to the diaphragm from hepatocellular carcinoma. A 50-year-old woman underwent right hemihepatectomy extended to a medial part of Couinaud segment IV for hepatocellular carcinoma in May 2000. In December 2008, the elevation of alpha-phetoprotein and the appearance of a heterogeneously enhanced mass, with dimensions of 9 × 7 cm, and adjacent to the remnant liver and pericardium suggested intrahepatic recurrence with markedly enhanced growth. After transcatheter arterial embolization, surgical resection under laparotomy combined with median sternotomy was selected. Samples of pericardial fluid showed no malignancy after cytological examination. At the superior border of the tumor, the confluence of pericardium and diaphragm was displaced, but the tumor itself showed a generally expanding but not invasive growth. The resected tumor showed moderately differentiated hepatocellular carcinoma whose pathology revealed a peritoneal implantation to the diaphragm. The patient is in good health without any postoperative complications or any further sign of recurrence.