CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer.

Although CD133 has been shown to be a marker for cancer stem cells in various tumours, its expression in pancreatic cancer has not yet been clinically reported. In this study, we investigated the relationship between CD133 expression and clinicopathological factors in pancreatic cancer. Pancreatic head carcinoma specimens from 80 patients who underwent surgical resection were immunohistochemically assessed for CD133, vascular endothelial growth factor (VEGF)-C, CXCR4, CD34, Ki-67, and cytokeratin (CK) expressions. Sixty percentage (48/80) of specimens were CD133-positive, with less than 15% cells per specimen expressing the marker. CD133-positive cells were found at the peripheral site of adenocarcinoma glandular structures and were negative for CK. There was a significant correlation between CD133 expression and clinicopathological factors, including histological type, lymphatic invasion, and lymph node metastasis (P=0.0215, 0.0023, and 0.0024, respectively). Vascular endothelial growth factor-C expression was also significantly correlated with CD133 expression (P=0.0002). Consequently, the 5-year survival rate of CD133-positive patients was significantly lower than that of CD133-negative patients (P=0.0002) and multivariate analysis revealed that CD133 expression was an independent prognostic factor (P=0.0103). These results suggest that CD133 expression in pancreatic cancer was significantly associated with lymphatic metastasis, VEGF-C expression, and prognosis.

Clinical significance of midkine expression in pancreatic head carcinoma.

Midkine (MK) is a heparin-binding growth factor and a product of a retinoic acid-responsive gene. Midkine is overexpressed in many carcinomas and thought to play an important role in carcinogenesis. However, no studies have been focussed on the role of MK in pancreatic carcinoma. This study sought to evaluate the clinical significance of MK expression in pancreatic head carcinoma, including the relationship between immunohistochemical expression and clinicopathologic factors such as prognosis. Immunohistochemical expression of MK and CD34 was evaluated in pancreatic head carcinoma specimens from 75 patients who underwent surgical resection. Midkine was expressed in 53.3% of patients. Midkine expression was significantly correlated with venous invasion, microvessel density, and liver metastasis (P=0.0063, 0.0025, and 0.0153, respectively). The 5-year survival rate was significantly lower for patients positive for MK vs patients negative for MK (P=0.0073). Multivariate analysis revealed that MK expression was an independent prognostic factor (P=0.0033). This is the first report of an association between MK expression and pancreatic head carcinoma. Midkine may play an important role in the progression of pancreatic head carcinoma, and evaluation of MK expression is useful for predicting malignant properties of pancreatic head carcinoma.

Phase-I trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent radiotherapy in patients with unresectable pancreatic cancer.

In this phase-I trial, we evaluated the safety of S-1, a novel oral fluoropyrimidine anticancer agent, combined with external-beam radiotherapy (EBRT) to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) in unresectable pancreatic cancer patients. Patients had histologically proven unresectable locally advanced or metastatic pancreatic cancer. S-1 was administered orally twice daily. External-beam radiotherapy was delivered in fractions of 1.25 Gy x 2 per day, totalling 50 Gy per 40 fractions for 4 weeks. S-1 was given at five dose levels: 60 mg m(-2) day(-1) on days 1-7 and 15-21 (level 1), 1-14 (level 2), and 1-21 (level 3a) and 80 mg m(-2) day(-1) on days 1-21 (level 3b) and 1-28 (level 4). We studied 17 patients: dose levels 1 (four patients), 2 (four patients), 3a (three patients), 3b (three patients), and 4 (three patients). One patient in level 1 (grade 3 vomiting) and two patients in level 4 (grade 4 neutropenia and grade 3 anorexia) showed DLT. No DLT was seen for levels 2, 3a, and 3b. Clinical effects by computed tomography included 5 partial responses (35%), 11 cases of stable disease, and one case of progressive disease. CA19-9 levels of less than half the starting values were observed in 8 of 16 (50%) patients. S-1 at a dose of 80 mg m(-2) day(-1) given on days 1-21 is safe and recommended for phase-II study in patients with locally advanced and unresectable pancreatic cancer when given with EBRT.

Magnetic compression anastomosis for benign obstruction of the common bile duct.

Advances in interventional radiology have made possible magnetic compression anastomosis between the bile duct and the small intestine as a novel treatment. A 70-year-old man who had undergone subtotal gastrectomy for gastric cancer 2 years previously experienced recurring cholangitis with high fever and jaundice. Diagnostic evaluation subsequently demonstrated complete obstruction of the common bile duct which was attributed to recurrent cholangitis. A parent magnet was placed endoscopically into the afferent loop of the duodenum through the gastrojejunostomy with Billroth II reconstruction. The daughter magnet attached to a guide wire was placed in the obstructed common bile duct through a percutaneous transhepatic cholangiographic drainage tube. Two magnets were immediately attracted towards each other transmurally, and anastomosis was established on day 32 after the procedure. This novel method of magnetic compression anastomosis has the advantages of noninvasiveness and simplicity, as well as being a well-tolerated procedure for indications such as biliary obstruction.

Hand-assisted laparoscopic distal pancreatectomy with minilaparotomy for distal pancreatic cystadenoma.

Two patients with cystic tumors of the pancreas treated by laparoscopic distal pancreatectomy are presented. The first patient was a 34-year-old woman with a 6-cm cystadenoma of the tail of the pancreas treated with a complete laparoscopic distal pancreatectomy. After mobilization of the distal pancreas and spleen, the pancreas was transected proximally together with the splenic artery and vein using an endoscopic linear stapler. The second patient was a 71-year-old woman with a 6-cm cystadenoma of the body of the pancreas, treated by hand-assisted laparoscopic distal pancreatectomy with minilaparotomy because the tumor was adjacent to the portal vein and celiac axis. Using an upper median minilaparotomy, dissection of the gastrocolic ligament, division of the splenic artery, and transection and closure of the pancreas were performed. Division of the splenic vein and mobilization of the distal pancreas and spleen were performed via a hand-assisted laparoscopic approach. There were no postoperative complications (such as pancreatic fistulas) in either patient, and the postoperative courses were uneventful. The patients returned to normal activity within 1 week after the operation. Complete laparoscopic and hand-assisted laparoscopic distal pancreatectomy are preferable to conventional open surgery for benign tumors of the pancreas because of their less-invasive nature. Additionally, in tumors of the body of the pancreas, hand-assisted laparoscopic distal pancreatectomy might have the advantages of laparotomy and laparoscopy in terms of handling the splenic artery and vein just below the minilaparotomy site, suggesting an easier and safer procedure than complete laparoscopic distal pancreatectomy. Therefore, hand-assisted laparoscopic distal pancreatectomy can be recommended as a useful alternative to complete laparoscopic distal pancreatectomy for selected patients with benign tumors of the body and tail of the pancreas.

Length and quality of survival following external beam radiotherapy combined with expandable metallic stent for unresectable hilar cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: Hilar cholangiocarcinoma is a morbid disease with a poor prognosis because resection cannot be performed in many cases. The purpose of this study was to evaluate whether external beam radiotherapy (RT) combined with expandable metallic biliary stent (EMS) affects the length and quality of survival of patients with unresectable hilar cholangiocarcinomas. METHODS: Fifty-one patients with unresectable hilar cholangiocarcinoma were retrospectively reviewed. Thirty patients received external beam radiotherapy combined with EMS (EMS+RT group), 10 patients were treated with EMS alone (EMS group), and the remaining 11 patients underwent percutaneous transhepatic biliary drainage alone (PTBD group). The length and quality of survival were analyzed and compared among the three groups. RESULTS: The mean survival of 6.4 months in the EMS group was significantly longer than that of 4.4 months in the PTBD group (P < 0.05). The EMS+RT group with a mean survival of 10.6 months had a significantly longer survival than the EMS group (P < 0.05). The average of the monthly Karnofsky scores of 74.9 in the EMS+RT group and 68.1 in the EMS group, as a parameter of quality of survival, was significantly higher than that of 57.7 in the PTBD group (P < 0.01). The number of hospital days per month of survival was significantly smaller in the EMS+RT and EMS groups than in the PTBD group (10.4, 14.2 vs. 27.3 days; P < 0.001). The EMS+RT group had a longer stent patency than the EMS group (mean: 9.8 vs. 3.7 months; P < 0.001). CONCLUSIONS: These results indicate that external radiotherapy combined with metallic biliary endoprosthesis can increase the length and quality of survival and consequently provide a definite palliative benefit for patients with unresectable hilar cholangiocarcinoma.

Ultrasonically activated scalpel is an effective tool for cutting the pancreas in biliary-pancreatic surgery: experimental and clinical studies.

The ultrasonically activated scalpel, a new tool for cutting and coagulating tissue, uses high-frequency ultrasonic vibrations, and has been widely employed in the field of laparoscopic surgery. We evaluated its usefulness for cutting the pancreas in biliary-pancreatic surgery. We planned experimental and clinical studies using an ultrasonically activated scalpel (harmonic scalpel) for cutting the pancreas. The harmonic scalpel was set up at a power level of 3 (75% of full power) in the knife mode. In the experimental study, using dogs, cutting of the pancreas with the harmonic scalpel resulted in significantly less bleeding and significantly less histological tissue damage to the cut stumps than cutting of the pancreas with an electric or a regular scalpel. In the clinical study: (1) the hemostatic effect of the harmonic scalpel was excellent or good in any condition of the pancreas; (2) of 50 stumps of the main pancreatic duct cut with the harmonic scalpel, the stump was easily found in 48 (96%), while ultrasonography was necessary to find the remaining 2 stumps in soft pancreas; (3) in 41 anastomoses (29 soft and 12 hard pancreas) there were no postoperative pancreatic fistulae. These results indicate that the ultrasonically activated scalpel is an effective tool for cutting the pancreas in biliary-pancreatic surgery.

Spindle cell carcinoma of the pancreas.

We experienced a rare case of spindle cell carcinoma of the pancreas. The patient was a 74-year-old man who complained of abdominal pain and loss of weight. Ultrasonographic scans revealed a hypoechoic solid mass in the head of the pancreas, 4 cm in diameter, with a high echoic spot suggestive of central necrosis or hemorrhage. The mass was hypodense on enhanced computed tomographic scans and hypovascular on angiograms. At laparotomy, the tumor had invaded to the mesocolon, but dissemination and distant metastasis were not found. We therefore performed pylorus-preserving pancreatoduodenectomy and ascending colectomy. The patient was discharged on postoperative day 26 after an uneventful recovery. Two months later, he was readmitted because of ascites, with positivity of spindle cells shown on cytology; he died on day 92 after surgery. In the resected specimen, the tumor had a mostly sarcomatous component, consisting of spindle-shaped cells, and a small glandular component. Immunohistochemically, both components were positive for cytokeratin and epithelial membrane antigen, but negative for vimentin and desmin. The tumor was diagnosed as a spindle cell carcinoma of the pancreas. Perineural invasion, lymphatic permeation, and blood vessel invasion were found, but lymph node metastasis was not found. Although a curative operation was performed, the outcome in this patient was very poor.

Gastric acidity following pancreaticogastrostomy with pylorus-preserving pancreaticoduodenectomy.

Pancreaticogastrostomy (PG) has been reintroduced and employed occasionally as a useful alternative to pancreaticojejunostomy (PJ) after Whipple resection or pylorus-preserving pancreaticoduodenectomy (PPPD). Although the physiologic alteration in the stomach is important for the correlation between gastric and pancreatic functions, the actual intragastric pH profile after PG is still unclear. This study was conducted to investigate the physiologic changes in gastric pH and serum gastrin and secretin levels before and after PPPD reconstructed with PG (PPPD-PG) in humans. Twenty-four hour continuous intragastric pH and serum gastrin and secretin levels in the fasting state were examined in 25 patients who had undergone PPPD-PG. No peptic ulcer was detected after the operation. After PG, serum gastrin and secretin levels were unchanged. Twenty-four hour gastric pH monitoring revealed two distinct patterns during the nocturnal period before the operation: patients with acid-type secretion (n = 11) exhibited a persistent acid pH, whereas those with alkaline-type secretion (n = 14) had cyclic variations between an acid and an alkaline pH value. After PG, in both acid- and alkaline-type patients, median pH and percentages of time that the gastric pH was less than 4 (% pH < 4) and more than 6 (% pH > 6) did not change, and circadian pH patterns also remained unchanged. These results suggest that PPPD-PG has little influence on gastric acidity, and the neurohumoral relation between the stomach, duodenum, and pancreas is preserved after PG. Therefore, physiologically, PG can be recommended as a reconstructive procedure after PPPD.

Mucin core protein expression in extrahepatic bile duct carcinoma is associated with metastases to the liver and poor prognosis.

BACKGROUND: Curative resection does not guarantee long term survival for the patient with extrahepatic bile duct carcinoma because of the possibility of metastases to the liver (LM). Expression of mucin core protein-1 (MUC1), sialyl-Le(x), and sialosyl-Tn in bile duct carcinoma was determined and compared with LM and prognosis. METHODS: Immunohistochemical expression of MUC1, sialyl-Le(x), and sialosyl-Tn in 73 extrahepatic bile duct tumors was analyzed using the DF3, FH6, and TKH2 monoclonal antibodies, respectively. Scoring was based on the percentage of immunoreactive cells: negative, low expression (25%). RESULTS: High expression of MUC1, sialyl-Le(x), and sialosyl-Tn was observed in 68.5%, 34.2%, and 54.8%, respectively. of 73 cases. Patients with tumors showing high expression of MUC1 had a higher rate of LM (48.9%) and a significantly shorter survival period (median survival time, 17.8 months) compared with patients with tumors showing low (incidence of LM, 9.1%; median survival time, >100 months) or negative (incidence of LM, 11.1%; median survival time, 52.9 months) expression of MUC1 (P < 0.01). However, the survival period of patients with tumors showing high, low, or negative expression of sialyl-Le(x) or of sialosyl-Tn did not differ significantly. High MUC1 expression correlated with LM by logistic regression analysis and emerged as an independent prognostic factor in stepwise multivariate analysis. CONCLUSIONS: The results of the current study demonstrate that high expression of MUC1 correlates with LM and poor outcome in patients with extrahepatic bile duct carcinoma.

Analysis of the N-terminal polypeptide of the capsid precursor protein and the ORF3 product of feline calicivirus.

The N-terminal unique polypeptide region of the capsid precursor protein of feline calicivirus (FCV) and the protein encoded by ORF3 of FCV were expressed as fusion proteins with glutathione S-transferase to analyze the expressed products in FCV-infected cells. Immunoblot analysis using a serum from a cat experimentally infected with FCV indicated relatively high immunogenicity of the N-terminal polypeptide in FCV-infected cats, as compared with the ORF3 protein. Specific antisera were prepared by immunization to mice with the fused proteins and used in immunoblot analysis. A 14 kD product corresponding to the N-terminal polypeptide and a 10 kD polypeptide of the ORF3 product were identified in the FCV-infected cells but not detected in the purified particles. No neutralization activity against FCV was detected in these antisera. The proteins identified as polypeptides of 14 kD and 10 kD in this study may have functions as non-structural proteins.

Molecular detection of circulating cancer cells during surgery in patients with biliary-pancreatic cancer.

BACKGROUND: It remains unclear whether surgical treatment for biliary-pancreatic cancers provokes the hematogenous dissemination of cancer cells. The aim of this study was to detect circulating cancer cells in the blood stream before and during tumor resection for biliary-pancreatic cancer. METHODS: We analyzed blood samples obtained perioperatively from the portal vein, peripheral artery, and superior vena cava, using a carcinoembryonic antigen (CEA)-specific nested reverse transcriptase-polymerase chain reaction. RESULTS: CEA-mRNA expression was detected in the blood of 21 (52.5%) of 40 patients with biliary-pancreatic cancer. The patients with detectable CEA-mRNA expression included 8 (42.1%) of 19 with bile duct cancers and 13 (61.9%) of 21 with pancreatic cancers. CEA-mRNA expression was not detected in blood obtained from 15 healthy volunteers and 15 patients with benign disease. The positive rate of CEA-mRNA of advanced clinical stage (TNM pStage III and IV) showed higher than that of early stage (pStage I and II; P <0.05). Tumor resection increased significantly the positive rates of CEA-mRNA in the blood stream of three kinds of vessel. CONCLUSIONS: Surgical procedures provoke the hematogenous dissemination of cancer cells perioperatively. Therefore, new strategies during operations to prevent liver metastases are needed to improve the survival of patients with biliary-pancreatic cancer.

Clinical and biological features of t1 ductal adenocarcinoma of the pancreas.

BACKGROUND/AIMS: The impact of tumor size on tumor development and long-term prognosis is still controversial for patients with ductal adenocarcinoma of the pancreas. We investigated the clinicopathological and biological features of ductal adenocarcinoma limited to the pancreas without direct histological extrapancreatic invasion (t1 tumor). METHODOLOGY: The clinical records of 86 patients who underwent surgery for ductal adenocarcinoma of the pancreas were reviewed to determine clinical features, histopathological findings, operative management and outcomes. Immunohistochemical staining of the p53 tumor suppressor gene (p53) was performed for the resected specimens. RESULTS: Only 10 (12%) of the 86 resected ductal adenocarcinomas of the pancreas were t1 tumors. Six of the 10 patients with t1 tumors survived for more than 5 years. The rates of nodal metastasis (10%) and neural plexus invasion (0%) in t1 tumors were significantly lower than those in non-t1 tumors, although the rates of blood-borne metastasis (30%) and p53 expression (50%) in t1 tumors were the same as those in non-t1 tumors. CONCLUSIONS: Curative resection contributes to a satisfactory long-term prognosis of patients with t1 tumor of the pancreas as a result of the low rates of both nodal metastasis and neural plexus invasion associated with this procedure. In patients with t1 tumor of the pancreas, a satisfactory long-term prognosis can be assured as a result of the low rates of both nodal metastasis and neural plexus invasion associated with curative resection.

Liver metastases after curative resection in patients with distal bile duct cancer.

BACKGROUND: Curative resection cannot ensure long-term survival for patients with distal bile duct cancer. The aim of this study was to determine the most frequent mode of recurrence after curative resection and to analyse its risk factors. METHODS: Clinical details for 64 consecutive patients with distal bile duct cancer who underwent surgical resection between 1980 and 1997 were reviewed. Modes of recurrence and clinicopathological findings were analysed based on the residual tumour (R) classification. RESULTS: The overall actuarial 5-year survival rate was 32 per cent. Of 42 patients undergoing R0 resection 10 were alive at 5 years, of 17 having R1 resection one was alive at 5 years, and none of the five patients having R2 resection survived for 5 years (R0 versus R1, P = 0.02). In the R0 group, the incidence of liver recurrence (14 of 42 patients) was similar to that in the R1 resection group (six of 17), although there were fewer lymph node and peritoneal recurrences than in patients who had R1 resection (P < 0.05). The high-risk factor for liver metastasis was microscopic vascular involvement. Important factors for survival were lymph node metastasis, microscopic vascular involvement and age. In addition, microscopic vascular involvement was the only independent factor for survival in the R0 group. CONCLUSION: R0 resection provided significant survival benefit but had no effect on liver recurrence. Therefore, new agents or strategies to prevent liver metastasis are necessary for improvement of survival.

Expression of thymidine phosphorylase is associated with a poor prognosis in patients with ductal adenocarcinoma of the pancreas.

Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor and has angiogenic activity. In this study, we investigated the expression of dThdPase in ductal adenocarcinoma of the pancreas and examined the correlation between dThdPase expression and clinicopathological factors and clinical outcome. dThdPase expression was demonstrated by immunohistochemistry in the cytoplasm of tumor cells in 59% of the 54 patients studied. The expression of dThdPase correlated significantly with a poor prognosis (P=0.013). Significant correlations were also observed between dThdPase expression and extrapancreatic neural plexus invasion and the presence of postoperative hepatic metastases (P=0.05 and 0.03, respectively). The average microvessel count in dThdPase-positive tumors was significantly higher than that in dThdPase-negative tumors (P < 0.0001). These findings suggest that dThdPase expression in pancreatic adenocarcinoma enhances the abilities of tumor invasion and/or metastasis through its angiogenic properties.

Comparison of relapse and long-term survival between pylorus-preserving and Whipple pancreaticoduodenectomy in periampullary cancer.

BACKGROUND: Whether long-term survival and type of recurrence in periampullary cancer are influenced by the type of surgical procedure or not is still obscure. The purpose of this review was to analyze the results at a single institution. METHODS: Between 1982 and 1996, 113 consecutive patients with either distal bile duct or ampullary cancers underwent either pylorus-preserving pancreaticoduodenectomy (PPPD) or the Whipple procedure. The median follow-up was 30 months (range 12 to 150). Patient records were reviewed to determine type of recurrence and survival. RESULTS: In distal bile duct or ampullary cancers, comparison of actuarial survival curves between PPPD and the Whipple operation revealed no significant differences. Even in node-positive patients, the 5-year survival rates did not differ significantly between those undergoing PPPD or the Whipple operation. Tumor recurrence was not correlated with the operative method, although among types of tumor recurrence, the rate of blood-borne metastasis was higher in distal bile duct or ampullary cancers. CONCLUSIONS: PPPD is an acceptable alternative to the Whipple procedure in the treatment of periampullary cancer. Long-term survival and type of recurrence were not influenced by these types of surgical procedures.

Gastric acid secretion and gastroduodenal pH after pancreaticogastrostomy in dogs.

Pancreaticogastrostomy has been reintroduced as a useful alternative procedure to pancreaticojejunostomy after Whipple resection or pylorus-preserving pancreaticoduodenectomy because of the very low incidence of leakage and disruption. In this study, gastric acid secretion, serum gastrin level, and 24-hr dual gastroduodenal pH after pancreaticogastrostomy were examined on the assumption that a canine model was a pylorus-preserving pancreaticoduodenectomy. Basal acid output (BAO), maximal acid output (MAO), and dual gastroduodenal pH were measured in eight dogs with gastric fistula. After pancreaticogastrostomy, BAO levels showed a slight increase significantly, but MAO levels showed no change. Serum gastrin levels in the fasting and postprandial states showed the similar patterns between before and after surgery. In the 24-hr dual gastroduodenal pH monitoring, gastric pH and duodenal pH also did not change in the fasting and postprandial states. These results suggested that the maintenance of the normal gastric pH after pancreaticogastrostomy was caused by a little increase of BAO, and the neurohumoral relationship between the stomach, duodenum, and pancreas was preserved even after pancreaticogastrostomy. Therefore, the pancreaticogastrostomy is a recommendable reconstructive procedure physiologically after pylorus-preserving pancreaticoduodenectomy.

Modified pancreaticogastrostomy following pancreaticoduodenectomy.

A modified pancreaticogastrostomy without gastrotomy was performed in 46 patients undergoing pancreaticoduodenectomy for malignant or benign disease. Postoperative complications related to the modified pancreaticogastrostomy occurred in one patient (2%). Operative mortality was 4% and was unrelated to the pancreaticogastrostomy itself. During the first postoperative year, four patients died of causes unrelated to the original disease process, and nine patients died of recurrent carcinoma. The remaining 31 patients were alive and well at a mean follow-up of 20 months. Results of postoperative gastroscopy were normal in all patients studied. A modified pancreaticogastrostomy without gastrotomy is a safe and effective procedure for pancreatic reconstruction in pancreaticoduodenectomy.