Phase I/II study of streptozocin monotherapy in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. METHODS: Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000-1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). RESULTS: Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%.Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32-40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. CONCLUSIONS: STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

A pancreaticoduodenectomy risk model derived from 8575 cases from a national single-race population (Japanese) using a web-based data entry system: the 30-day and in-hospital mortality rates for pancreaticoduodenectomy.

OBJECTIVE: To create a mortality risk model after pancreaticoduodenectomy (PD) using a Web-based national database system. BACKGROUND: PD is a major gastroenterological surgery with relatively high mortality. Many studies have reported factors to analyze short-term outcomes. SUBJECTS AND METHODS: After initiation of National Clinical Database, approximately 1.2 million surgical cases from more than 3500 Japanese hospitals were collected through a Web-based data entry system. After data cleanup, 8575 PD patients (mean age, 68.2 years) recorded in 2011 from 1167 hospitals were analyzed using variables and definitions almost identical to those of American College of Surgeons-National Surgical Quality Improvement Program. RESULTS: The 30-day postoperative and in-hospital mortality rates were 1.2% and 2.8% (103 and 239 patients), respectively. Thirteen significant risk factors for in-hospital mortality were identified: age, respiratory distress, activities of daily living within 30 days before surgery, angina, weight loss of more than 10%, American Society of Anesthesiologists class of greater than 3, Brinkman index of more than 400, body mass index of more than 25 kg/m, white blood cell count of more than 11,000 cells per microliter, platelet count of less than 120,000 per microliter, prothrombin time/international normalized ratio of more than 1.1, activated partial thromboplastin time of more than 40 seconds, and serum creatinine levels of more than 3.0 mg/dL. Five variables, including male sex, emergency surgery, chronic obstructive pulmonary disease, bleeding disorders, and serum urea nitrogen levels of less than 8.0 mg/dL, were independent variables in the 30-day mortality group. The overall PD complication rate was 40.0%. Grade B and C pancreatic fistulas in the International Study Group on Pancreatic Fistula occurred in 13.2% cases. The 30-day and in-hospital mortality rates for pancreatic cancer were significantly lower than those for nonpancreatic cancer. CONCLUSIONS: We conducted the reported risk stratification study for PD using a nationwide surgical database. PD outcomes in the national population were satisfactory, and the risk model could help improve surgical practice quality.

Familial Intraductal Papillary Mucinous Neoplasm Associated With the Germline MSH6 Missense Variant and Progression of Pancreatic cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasm (IPMN) in individuals with at least one first-degree relative with IPMN is defined as familial IPMN. However, few studies have reported on familial IPMN, its clinical characteristics, or the associated genetic factors. MATERIALS AND METHODS: We report the case of a 58-year-old woman with multifocal IPMN and a mural nodule in the pancreatic body. The patient underwent a distal pancreatectomy and developed pancreatic head cancer 1 year and 6 months postoperatively. The patient had a family history of multifocal IPMN in her father. Therefore, a genetic predisposition to IPMN and pancreatic cancer was suspected. The patient was analyzed for germline variants, and the resected IPMN was subjected to immunohistochemical and somatic variant analyses. RESULTS: Next-generation sequencing revealed a heterozygous germline missense variant in exon 5 of MSH6 (c.3197A>G; Tyr1066Cys). The pathogenicity of this variant of uncertain significance was suspected based on multiple in silico analyses, and the same MSH6 variant was identified in the patient's father's colonic adenoma. The mural nodule in the pancreatic body was pathologically diagnosed as a high-grade IPMN with ossification and somatic KRAS and PIK3CA variants. CONCLUSIONS: This case revealed a possible genetic factor for familial IPMN development and presented interesting clinicopathological findings.

Histotopographical characterization of the para-aortic lymph nodes in the area near the origin of the thoracic duct, and its relationship to nodal cancer metastasis.

Using 10 elderly cadavers without macroscopically evident tumors, we histologically examined 115 para-aortic lymph nodes located near the origin of the thoracic duct after preparation of en bloc specimens using a clearance method. The afferent and efferent sides of these nodes were usually not discriminated clearly because i) the superficial cortex (B-lymphocyte area) and deep cortex (T-lymphocyte area) were not clearly differentiated due to lack of a typical hilus, and both cortices were intermingled to form "nodular masses"; ii) each nodule with a lining of macrophages was surrounded by dilated intermediate and subcapsular sinuses; iii) the nodes were often surrounded by multiple tributaries of the thoracic duct. Moreover, the nodes sometimes involved these tributaries inside. Therefore, the nodal architecture seemed to accelerate intranodal shunt flow without filtration through the cortex. Valves of the lymphatic vessel tended to be restricted to an area immediately before drainage into the thoracic duct. Thus, lymph flow was likely to change along a network of tributaries around a node. These morphologies suggested very limited barrier function of the para-aortic node against cancer metastasis. However, we hypothesized that "better" or "worse" types of nodes are histologically identifiable when they are picked up surgically along with the surrounding tissues.

Postoperative hematological changes after spleen-preserving distal pancreatectomy with preservation of the splenic artery and vein.

BACKGROUND: The aim of this study was to determine the early postoperative hematological changes after spleen-preserving distal pancreatectomy (SpDP) with preservation of the splenic artery and vein (PSAV). METHODS: We reviewed 53 patients who underwent SpDP with PSAV (n = 21) or distal pancreatectomy with splenectomy (DPS; n = 32) for benign or low-grade malignant lesions between July 1998 and June 2010. Red and white blood cell (WBC) count, platelet count, serum hemoglobin, hematocrit, C-reactive protein, albumin level, and clinical factors were compared between the SpDP with PSAV and DPS. RESULTS: There were no significant differences in the patient characteristics between the two groups. Platelet count on postoperative day (POD) 5 and WBC count on POD 3 were significantly higher in the DPS group, and these differences continued to be significant until the 3rd month after surgery. Serum hemoglobin and hematocrit in the 1st month after surgery were also significantly higher in the SpDP with PSAV group. CONCLUSION: The hematological benefits of SpDP with PSAV include reduction of postoperative hematological abnormalities in the early postoperative phase and recovery of the serum hemoglobin and hematocrit levels in the early postoperative phase.

Surgical management of pancreatic neuroendocrine tumors.

This study outlines the surgical management and clinicopathological findings of pancreatic neuroendocrine tumors (P-NETs). There are various surgical options, such as enucleation of the tumor, spleen-preserving distal pancreatectomy, distal pancreatectomy with splenectomy, pancreatoduodenectomy, and duodenum-preserving pancreas head resection. Lymph node dissection is performed for malignant cases. New guidelines and classifications have been proposed and are now being used in clinical practice. However, there are still no clear indications for organ-preserving pancreatic resection or lymph node dissection. Hepatectomy is the first choice for liver metastases of well-differentiated neuroendocrine carcinoma without extrahepatic metastases. On the other hand, cisplatin-based combination therapy is performed as first-line chemotherapy for metastatic poorly differentiated neuroendocrine carcinoma. Other treatment options are radiofrequency ablation, transarterial chemoembolization/embolization, and liver transplantation. Systematic chemotherapy and biotherapy, such as that with somatostatin analogue and interferon-α, are used for recurrence after surgery. The precise surgical techniques for enucleation of the tumor and spleen-preserving distal pancreatectomy are described.

Dual segmental arterial supply to a single renal lobule: a study using semi-serial sections of mid-term fetuses.

OBJECTIVE: To determine which and how many segmental arteries supply a single renal lobule especially at and near the segmental border, as no data are available on the arterial supply to a single renal lobule (a pyramid and its covering cortex) at the border between renal segments. MATERIALS AND METHODS: We studied semi-serial sections (100 microm intervals; haematoxylin and eosin staining) of 26 kidneys obtained from 13 mid-term human fetuses (20-30 weeks gestation). Eleven fetuses were used for horizontal sections and two for sagittal sections. Section to section, we first traced the renal pyramids using a pen to understand the lobular configuration. RESULTS: Fusion of the medullary pyramids was usually evident along the segmental borders, except for the border between the upper and middle segments. This fusion often accompanied a pair of arcuate arteries, each of which arose from a different renal segment, but shared a common corticomedullary junction to supply a single lobule. The incidence of fusion was high along the anterior border of the posterior segment as well as the border between the apical and upper segments. When the lower segmental artery entered the parenchyma distant from the renal hilus, fusion of pyramids occurred along the border between the posterior and lower segments in association with double arcuate arteries. CONCLUSIONS: A single lobule is most likely to be shared by double segments at or near the segmental border. This morphology seems to be a result of lobule fusion during development and growth. Thus, in adults, a dual segmental supply to a single lobule seems to be more frequent than in fetuses.

Groove pancreatitis.

Groove pancreatitis is a segmental chronic pancreatitis that affects the anatomical area between the pancreatic head, the duodenum, and the common bile duct, referred to as the groove area. Most patients with groove pancreatitis are males aged 40-50 years with a history of alcohol abuse. In about 20% of patients undergoing pancreaticoduodenectomy to treat chronic pancreatitis, groove pancreatitis is detected. The clinical symptoms are weight loss, upper abdominal pain, postprandial vomiting, and nausea due to duodenal stenosis. The pathogenesis of groove pancreatitis is thought to be anatomical or functional obstruction of the minor papilla. The viscosity of pancreatic juice increases due to excessive alcohol consumption and/or smoking, leading to calcification of the pancreatic duct. According to these conditions, pancreatitis in the groove area might arise due to impaired pancreatic juice outflow. The descending part of the duodenum is usually stenotic. Severe fibrosis and scarring are evident in the groove area. Characteristic pathological findings are cystic lesions in the duodenal wall, Brunner gland hyperplasia, dilation of Santorini's duct and protein plaques in the pancreatic duct. A differential diagnosis of groove pancreatitis from peripancreatic cancer is clinically important. Cystic lesions in the duodenal wall and smooth stenosis of the bile duct are important findings of groove pancreatitis revealed by endoscopic ultrasonography, computed tomography and magnetic resonance imaging. Biopsy through the duodenum is also useful for diagnosis. Conservative treatment options include endoscopic stenting of the minor papilla, but long-term outcomes remain unclear. Pancreatoduodenectomy is a rational treatment for symptomatic groove pancreatitis.

Topographical anatomy of Spiegel's lobe and its adjacent organs in mid-term fetuses: Its implication on the development of the lesser sac and adult morphology of the upper abdomen.

At 8-16 weeks of gestation, Spiegel's lobe of the caudate lobe appears as a sac-like herniation of the liver parenchyma between the inferior vena cava and ductus venosus or Arantius' duct. In 5 of 11 fetuses at 20-30 weeks of gestation, we found that an external notch was formed into the posterior aspect of the caudate lobe by a peritoneal fold containing the left gastric artery. This notch appeared to correspond to that observed in adults, which is usually seen at the antero-inferior margin of the lobe after rotation of the lobe along the horizontal or transverse axis. However, the notch did not accompany two of the three fetuses in which the left hepatic artery originated from the left gastric artery. Notably, until 9-10 weeks of gestation, the inferior and left part of Spiegel's lobe rode over the hepatoduodenal ligament and protruded medially into the lesser sac (bursa omentalis) behind the stomach. Thus, the fetal Winslow's foramen was located at the "superior" side of the ligament. However, as seen in adults, the protruding Spiegel's lobe was located at the posterior side of the lesser omentum. Therefore, a hypothetical rotation along the transverse axis in the later stages of development seems necessary to explain this repositioning. Considering that Spiegel's lobe develops faster than surrounding structures, it is likely that the lesser sac resulting from the rotation of the gastrointestinal tract, which actively contributes to facilitate the growth of the Spiegel lobe.

Intrahepatic micrometastases around liver metastases from gastric cancer.

BACKGROUND/PURPOSE: We aimed to clarify the association between the presence of micrometastases around liver metastases from gastric cancer and the results of hepatic resection. In addition, we investigated the influence of E-cadherin and matrix metalloproteinase (MMP)-7 expression on the development of micrometastases. METHODS: Micrometastases around liver metastases were examined microscopically in 31 metastatic liver tumor specimens resected from 17 patients who had undergone hepatic resection for liver metastases from gastric cancer. E-cadherin and MMP-7 expression in the primary gastric tumor, the liver metastases, and the micrometastases were examined immunohistochemically. RESULTS: Hepatic micrometastases were present in around 48% of the liver metastases, accounting for 59% of the patients. The tumor recurrence rate in the remnant liver after hepatic resection was significantly higher, and survival significantly poorer, in patients with such micrometastases than in those without. Micrometastases tended to appear around the liver metastases that had reduced E-cadherin expression. Most of the micrometastases in the lymph ducts and sinusoids showed reduced E-cadherin expression. MMP-7 expression was not correlated with the presence of micrometastases. CONCLUSIONS: About half of the hepatic metastases from gastric cancer had seeded off micrometastases, and the presence of these micrometastases was associated with a poorer result of hepatic resection. Reduced E-cadherin expression in metastatic liver tumors may be associated with the development of micrometastases.

Fetal topohistology of the mesocolon transversum with special reference to fusion with other mesenteries and fasciae.

The developing mesocolon transversum was investigated using hematoxylin and eosin-stained semiserial sections derived from 17 human fetuses between 12 and 30 weeks of gestation. The mesocolon was attached to the mesoduodenum and greater omentum until 12 weeks. However, the fetal duodenal attachment appeared not to correspond to the right colic flexure in adults. The greater omentum and mesocolon were likely to be irregularly folded at the attachment site possibly because the developing transverse colon "ran into" and pushed up the greater omentum and pancreatic head. Lymphatic vessels invaded the indistinct fusion plane to destroy the primary configuration. Moreover, the mesocolon seemed to "seize" or take-over some parts of the splenic side of the greater omentum, but the thick gastric side containing the right gastroepiploic artery and vein remained along the greater curvature. Until 20 weeks, the left colic flexure was fixed to the pancreatic tail, and near the flexure the mesocolon also fused with the renal fascia. The left splenic end of the greater omentum was folded and fused together to form a thick ligament-like structure, i.e., the gastrocolic ligament. In addition, near the duodenojejunal junction, a peritoneal bridge was often seen containing the inferior mesenteric artery or vein. Although surgeons generally believe that the mesocolon can be gently detached from the greater omentum, the fusion plane in adults appears to be the result of secondary modification and simplification by vascular development.

Living donor liver transplantation for type II citrullinemia from a heterozygous donor.

Adult-onset type II citrullinemia (CTLN2) is a rare disorder of the urea cycle resulting in hyperammonemia, with a poor prognosis. Here we report a 48-year-old Japanese man who showed abnormal nocturnal behavior. Laboratory data indicated raised plasma concentrations of ammonia and citrulline, and a definitive diagnosis of CTLN2 was made by DNA analysis. Hyperammonemia was not improved by oral intake of branched-chain amino acids (BCAA), whereas venous infusion of BCAA was effective. Western blotting revealed heterozygotic expression of citrin protein in a liver biopsy specimen from the patient's brother. However, as symptomatic CTLN2 is very unusual in a heterozygotic carrier, we considered the brother suitable as a living-donor liver transplantation (LDLT) donor. The recipient's entire liver was removed, and replaced with the left liver graft. The plasma ammonia level remained low without infusion of BCAA after liver transplantation. From this case we conclude that venous infusion, rather than oral administration, of BCAA is useful for conservative treatment of CTLN2. However, liver transplantation is the only effective therapeutic option for CTLN2, and should be performed before irreversible encephalopathy occurs. Use of a graft from heterozygotic donors is permissible treatment for CTLN2.

A case of mucinous cystic neoplasm of the gallbladder.

The patient was a 70-year-old woman in whom examination revealed a high level of carbohydrate antigen 19-9. Abdominal ultrasonography and computed tomography (CT) revealed a multilocular cystic lesion compressing the gallbladder. CT indicated the presence of a multilocular cystic tumor (67 × 68 × 72 mm) in contact with the right hepatic lobe. Intraoperative findings indicated that the cyst diameter was 8.5 × 6.0 cm, and the cyst was continuous with the gallbladder. The gallbladder was resected along with the cyst. The cyst was multilocular and originated from the cystic duct and gallbladder wall. The cyst wall contained cuboidal to columnar mucin-producing epithelial cells and ovarian-like stroma (OS). The final diagnosis was mucinous cystic neoplasm (MCN) of the gallbladder with low-grade dysplasia. In the 2010 WHO classification of tumors of the digestive system, MCN have been newly defined as a type of hepatobiliary tract epithelial neoplasms. MCN of the gallbladder with OS is extremely rare. Only three cases have been published in the literature. The presence of OS is necessary for diagnosis of MCN.

S-1 induced discoid lupus erythematosus-like lesions and long-term complete response for para-aortic lymph node recurrence of pancreatic ductal adenocarcinoma: a case report.

BACKGROUND: Metastatic recurrence after resection of pancreatic cancer is considered to be an incurable disease, and discoid lupus erythematosus (DLE)-like lesions are known as a side effect of fluorouracil agents. We report a very rare case of metastatic recurrence of pancreatic cancer in a Japanese man with DLE-like lesions in which long-term complete response was achieved through S-1 monotherapy. CASE PRESENTATION: A 65-year-old man who had undergone distal pancreatectomy with splenectomy for pancreatic body cancer and had received adjuvant gemcitabine developed postoperative para-aortic lymph node recurrence 17 months after surgery. S-1 monotherapy was started. About 2 weeks after starting this treatment, he developed an erythematous rash on the face and scalp. DLE was diagnosed by skin biopsy. The eruptions were aggravated by the administration of S-1 and improved during periods of respite from S-1. Yet as CA19-9 was reduced by almost half 1 month after starting S-1 chemotherapy, S-1 chemotherapy was continued at a reduced dose. CA19-9 decreased to within a normal range within 6 months after starting S-1 chemotherapy, and a reduction in lymph node metastasis was detected through imaging. The patient is still alive without recurrence or metastasis 113 months after surgery. CONCLUSIONS: Even in patients with S-1-induced DLE-like lesions, continuation of S-1 is possible if the dose and duration of S-1 are appropriately regulated and medical therapy is administered for the skin lesions. Further investigation into the possible correlation between skin rash and clinical benefit in connection with S-1 is strongly warranted.

Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein.

Preservation of the spleen at distal pancreatectomy has recently attracted considerable attention. Since our first successful trial, spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for tumors of the pancreas and chronic pancreatitis has been performed more frequently. The technique for spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein are outlined. The splenic vein is identified behind the pancreas and within the thin connective tissue membrane. The connective tissue membrane is cut longitudinally above the splenic vein. An important issue is to remove the splenic vein from the body of the pancreas toward the spleen, since a different approach may be very difficult. The pancreas is preferably removed from the splenic artery toward the head of the pancreas itself. This procedure is much easier than removing the pancreas from the vein side. One patient had undergone distal gastrectomy for duodenal ulcer, with reconstruction by Billroth II technique. If distal pancreatectomy with splenectomy had been performed for the lesion of the distal pancreas at the time, the residual stomach would also have to be resected. The potential damage done to the patient by reconstruction of the gastrointestinal tract in combination with distal pancreatectomy and splenectomy would have been much greater than with distal pancreatectomy only with preservation of the spleen and residual stomach. Benign lesions as well as low-grade malignancy of the body and tail of the pancreas may be a possible indication for this procedure.

Definition of MCN (mucinous cystic neoplasm of the pancreas) and a proposal for a new concept of MRN or MSN (mucinous round or spherical neoplasm).

The differential diagnosis of IPMN and MCN is very important for clinicians. MCN is reported to develop in middle-aged females (mean age 48 years) and in the body and tail of the pancreas. Some doctors insist that ovarian-like stroma is absolutely necessary for the definition of MCN. Prompt resection of MCN after diagnosis is desirable. In contrast, about 60% of cases with branch-type IPMN do not require an operation. Therefore, one of the important goals in the differential diagnosis of MCN and branch-type IPMN is to determine the surgical indications before the operation. We believe that MCN and IPMN should be defined by imaging procedures before the operation. We suggest that a neoplasm with an appearance similar to an orange should be diagnosed as MCN, while that with an appearance similar to a bunch of grapes in MRCP should be diagnosed as branch-type IPMN. Proposal of a new concept: If the term MCN is restricted to neoplasms that exhibit ovarian-like stroma, we propose that lesions which are surrounded by a very thick capsule, and which show an orange-like appearance by imaging procedures without histological ovarian-like stroma should be called MRN (mucinous round neoplasm) or MSN (mucinous spherical neoplasm).

Neuroendocrine carcinoma of the stomach with peripancreatic lymph node metastases successfully treated with pancreaticoduodenectomy.

Neuroendocrine carcinoma of the stomach is an uncommon tumor, usually associated with highly malignant biological behavior and extremely poor prognosis. In this report, we described a case of advanced neuroendocrine carcinoma of the stomach with the peripancreatic lymph node metastases which was treated with pancreaticoduodenectomy with extended lymphadenectomy. The patient was admitted to our hospital for anemia. An upper gastrointestinal endoscopy revealed a 4x4-cm fungating tumor with its fundus locating mainly in the duodenal bulbus and extending to the gastric antrum, and tumor biopsy revealed the histological findings of adenocarcinoma. Computed tomography (CT) showed a large mass in the duodenal bulbus with regional lymph node metastases. The patient's disease was diagnosed as primary duodenal cancer with regional lymph node metastases preoperatively. During the operation, an obviously swollen lymph node on the anterior surface of the head of the pancreas 4.0 x 3.5 cm in size was found growing into the parenchyma of the pancreas head and could not be separated from the pancreas, and the swollen lymph node along the superior mesenteric vein was also hard and suspected to be a metastatic node. A pancreaticoduodenectomy with extended lymphadenectomy was performed to achieve a radical resection. Histopathologically, the origin of the primary tumor was considered as a gastric origin, and the tumor was composed of diffused small cells with a moderate mitotic index and occasional rosette formation. Immunohistochemical investigations of the neoplastic cells confirmed the tumor to be neuroendocrine carcinoma. The obvious swollen lymph node on the anterior surface of the head of the pancreas and the swollen lymph node along the superior mesenteric vein were also identified as metastatic lymph nodes. Adjuvant chemotherapy with TS-1 was administered on an out-patient basis 6 weeks after the operation. The patient is well and has now been free of symptoms of recurrence and metastasis for 8 months.

Prognostic role of angiogenesis and its correlations with thymidine phosphorylase and p53 expression in ductal adenocarcinoma of the pancreas.

BACKGROUND/AIMS: Currently, little information is available regarding the prognostic role of angiogenesis and its correlation with Thymidine phosphorylase (dThdPase) in ductal adenocarcinoma of the pancreas. In the present study, we aimed to evaluate whether tumor angiogenesis, dThdPase expression correlates with prognosis in patients after radical surgical treatment for ductal adenocarcinoma of the pancreas and to investigate the correlation between tumor angiogenesis and dThdPase expression. Furthermore, the role of p53 expression in tumor neovascularization was also examined in this study. METHODOLOGY: Tissue samples were taken from 32 patients with ductal adenocarcinoma of the pancreas after radical surgical treatment. Intratumoral microvessel density (IMVD) and dThdPase, p53 expression were examined immunohistochemically. RESULTS: Increased IMVD significantly correlated with the tumor size, lymph node metastasis and advanced TNM stage (p < 0.05, respectively). Furthermore, increased IMVD correlated withpoorer survival curve (p < 0.05). A significant correlation was present between IMVD and dThdPase expression (p < 0.001), while dThdPase expression did not correlate with prognosis. p53 expression correlated with prognosis, whereas no significant correlation was shown between p53 expression and IMVD in ductal adenocarcinoma of the pancreas. CONCLUSIONS: Tumor angiogenesis is associated with clinicopathological factors regarding tumor progression and may be an important prognostic factor in ductal adenocarcinoma of the pancreas. dThdPase plays an important role in tumor angiogenesis in ductal adenocarcinoma of the pancreas. Mutant p53 expression may not involve in tumor angiogenesis in ductal adenocarcinoma of the pancreas.