[A case report of hepatocellular carcinoma with metastases to the lip, stomach, and colorectum].

A 79-year-old man was diagnosed with hepatocellular carcinoma in 2000 and treated with partial hepatectomy. Intrahepatic carcinoma recurred with lung metastases 7 years later. Several transcatheter arterial chemoembolizations were performed to treat the recurrence, and a right lower lobectomy was performed for lung metastasis. Twelve years after the original carcinoma diagnosis, lip and lung metastases were detected, and he was hospitalized for radiotherapy of the lung metastasis; an oral molecular-targeting drug was initiated. During the therapy, hematochezia was observed, and a colonoscopy was performed. A submucosal lesion with a blood clot measuring approximately 4mm in diameter was found in the sigmoid colon, and endoscopic mucosal resection was performed. Furthermore, an elevated lesion with a 5-mm diameter recess was observed on upper gastrointestinal endoscopy. Both lesions were diagnosed histopathologically as hepatocellular carcinoma metastases.

A case of gastric adenocarcinoma arising from a fundic gland polyp.

A rare case of gastric adenocarcinoma arising on the surface of a fundic gland polyp is reported. A 36-year-old Japanese woman was referred to our hospital for examination and treatment of a polyp that had been detected in another hospital. She did not have a history of familial adenomatous polyposis (FAP). Endoscopic examination revealed a 10-mm-diameter fundic gland polyp in the body of the stomach. The polyp had an irregular depression on its top, suggesting the presence of malignancy. Endoscopic mucosal resection was done to make a histological diagnosis. This revealed a fundic gland polyp with a tiny superficial adenocarcinoma. Atrophic changes of the gastric mucosa were mild, although Helicobacter pylori infection was positive. It is suggested that fundic gland polyps have the potential for malignant transformation.

[A case of pancreatic solid-pseudopapillary tumor without cystic component in an elderly man].

We encountered a solid pseudopapillary tumor (SPT) without any cyst component in an elderly man. A literature survey of SPT without cystic component suggested that the size and vascularity of a tumor were related to lack of cystic component. The prognosis of this disease was comparatively good, but elderly or middle aged case and cases without capsule seem to have high malignant potential.

Management of intraductal papillary-mucinous neoplasm of the pancreas: treatment strategy based on morphologic classification.

GOALS: The aim of this study was to examine and clarify the preoperative markers that are useful for differentiating between benign and malignant lesions of intraductal papillary-mucinous neoplasms (IPMN) of the pancreas, grouped according to morphologic classification. BACKGROUND: There are various stages of pathology in IPMN, ranging from benign to malignant lesions. Although the determination of appropriate treatment guidelines to deal with IPMN is a critical issue, no such guidelines have been established. PATIENTS AND METHODS: One hundred twenty cases of IPMN were classified morphologically into either main or branch duct types. We compared the morphologic classification with histopathologic diagnosis using indicators of malignancy detected by imaging such as main duct diameter, the number and diameter of cysts, and the presence or absence of mural nodules. We also examined the usefulness of pancreatic juice cytology and measurement of telomerase activity as indicators of malignancy. Finally, we performed a survival analysis on the basis of morphologic classification to determine prognosis of IPMN. RESULTS: Whereas a high incidence (64%) of malignant lesions was seen in main duct type IPMN, benign lesions were dominant (80.5%) in branch duct type IPMN. Survival analysis showed that the prognosis was significantly worse in main duct type than in branch duct type IPMN. The lesions were aggravated in all patients with main duct type who did not undergo resection, resulting in death due to progression of the pancreatic lesion. The incidence of mural nodules was a useful indicator in main duct type, whereas main duct diameter and incidence of mural nodules were useful indicators in branch duct type. Although pancreatic juice cytology showed a high accuracy rate with low sensitivity for determining malignancy, measurement of telomerase activity in this juice was very effective for differentiating between benign and malignant lesions. CONCLUSIONS: The incidence of malignant lesions was extremely high in main duct type IPMN, indicating that surgery is required in all these patients. However, to determine whether surgery is indicated in branch duct type IPMN it is necessary to obtain an appropriate image diagnosis focusing on main duct diameter and mural nodules and also to carry out cytology and measurement of telomerase activity in samples of pancreatic juice.

The effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser in bile duct carcinoma cell lines.

The signaling pathway that is initiated by binding of epidermal growth factor receptor (EGFR) and results in sustained signaling through PI3K plays an important role in a tumor's response to ionizing radiation. The current in vitro study explored both the effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser for bile duct carcinoma cell lines and ZD1839's general effects on cell growth in the same two lines. Secondly, we ensured suppression of radiation-induced phosphorylation of EGFR by ZD1839 using an immunoprecipitation technique. Furthermore, we examined radiation-induced phosphorylation of ERK, p38, JNK, and AKT with or without inhibitor with use of Western blot techniques and performed clonogenic assays to confirm radiosensitivity in the presence of a drug. ZD1839 inhibited cell growth of both cell lines and suppressed radiation-induced phosphorylation of EGFR. After exposure to radiation, there was an increase in phosphorylation of AKT as shown by Western blot. Treatment with either ZD1839 or LY294002 (the latter, a PI3K inhibitor) suppressed phosphorylation of AKT by Western blot. Both ZD1839 and LY294002 significantly suppressed colony formation by clonogenic assay; however, U0126 (a MEK1/2 inhibitor), SB203580 (a p38 inhibitor), and SP600125 (a JNK inhibitor) had no effect on colony formation. These results suggest that AKT may be a useful target molecule for enhancement of radiotherapy effect and that ZD1839 may have an important role in combination with radiotherapy for patients with bile duct carcinoma.

Fas and Fas ligand: Expression and soluble circulating levels in bile duct carcinoma.

Alteration of the Fas receptor (Fas)-/ligand (FasL) system including their soluble forms (sFas and sFasL) is thought to be one of the mechanisms preventing the immune system from rejecting the tumor cells. We investigated the tissue expression of Fas, FasL, and the alteration of sFas and sFasL in patients with bile duct carcinoma. Thirty-four samples were immunostained for Fas and FasL, and levels of sFas and sFasL in the serum of 62 patients were determined using an enzyme-linked immunoadsorbent assay. Patients with strongly positive Fas levels showed significantly better prognosis than those with weakly positive or negative Fas levels. The mean serum levels of sFas in healthy individuals were significantly higher in patients with carcinoma. However, the mean serum levels of sFasL were significantly lower in the patients with carcinoma. Serum levels of sFas and sFasL might be a significant and independent prognostic parameter in patients with bile duct carcinoma.

Induction of apoptosis by ionizing radiation and CI-1033 in HuCCT-1 cells.

CI-1033 is a quinazoline-based HER family tyrosine kinase inhibitor that is currently being evaluated as a potential anticancer agent. The present study examines the molecular mechanism by which CI-1033 induces apoptosis either as a single agent or in combination with radiation. Although CI-1033 alone did not induce apoptosis, the simultaneous exposure of cells to CI-1033 and radiation induced significant levels of apoptosis. The sequential treatment of cells with CI-1033 followed by radiation induced an even greater effect with 62.6% of cells undergoing apoptosis but this enhanced effect was not seen if cells were treated first with radiation and then CI-1033. The combination treatment induces apoptosis of HuCCT-1 via upregulation of FasL and Bid cleavage. These data suggest that modulation of the Fas-FasL pathway and activation of Bid could be useful for increasing the anti-tumor effect of CI-1033 in this type of cancer.

Gemcitabine suppresses malignant ascites of human pancreatic cancer: correlation with VEGF expression in ascites.

It has been reported that vascular endothelial growth factor (VEGF) is a potent angiogenic factor that also has the ability to increase vascular permeability. VEGF plays an important role in the development of malignant ascites in various cancers. Gemcitabine has been prescribed for patients with inoperable human pancreatic ductal carcinoma as a first-line chemotherapy. However, the response rates of patients with malignant ascites who were undergoing systemic chemotherapy were extremely limited. In the present study, we investigated the role of VEGF and the effects of gemcitabine on malignant ascites of human pancreatic ductal carcinoma. As an in vitro assay, the human pancreatic cancer cell line (SUIT-2) was incubated in DMEM supplemented with serially diluted concentrations of gemcitabine for 24 h. The expression levels of VEGF in culture media were assayed using an enzyme-linked immunosorbent assay (ELISA). As an in vivo assay, a cell suspension (1 x 10(7) cells in 100 microliters PBS) was injected into the intraperitoneal region. The mice were randomly divided into two groups (control and treated with gemcitabine). The mice were sacrificed four weeks after inoculation, the ascites volume was measured, and the extent of peritoneal dissemination was examined. The expression levels of VEGF and CD31 in peritoneal nodules were examined by immunohistochemistry. In addition, secreted VEGF protein levels were quantified using ELISA. The results show that VEGF levels in the culture medium decreased in response to gemcitabine in a dose-dependent manner. The ascites formation and peritoneal dissemination within mice were suppressed by the treatment with gemcitabine. Immunohistochemical analysis suggested that expression of VEGF and CD31 in peritoneal nodules was suppressed by gemcitabine treatment, and the VEGF protein level in ascites was significantly decreased by gemcitabine (p<0.05). These results suggest that gemcitabine controls malignant ascites and peritoneal dissemination, either directly or indirectly, via VEGF. Moreover, intraperitoneal administration of gemcitabine may be a useful therapeutic approach for patients with malignant ascites in pancreatic carcinoma.

Prognostic value of p53 and Ki-67 expression in resected or biopsy specimens of bile duct carcinoma.

For cases of inoperable bile duct carcinoma, we perform intraluminal irradiation using an 192iridium wire following endoprostheses implantation. However, the effectiveness of this procedure is uncertain, and may lead to decreased patient quality of life in some cases. Therefore, we obtained samples of bile duct carcinoma either by percutaneous transhepatic cholangioscope (PTCS) or by surgery, and studied whether expression levels of Ki-67 and p53 in these tissues could predict the effectiveness of radiotherapy (RT). Immunohistochemistry was used to determine the expression of p53 and Ki-67 in 40 resected and 18 biopsy specimens. All biopsy specimens were stage IVA according to UICC classification. Labeling indices were calculated as percentage of positively stained tumor cell nuclei of total tumor cells counted. Samples were divided into two groups according to labeling index (LI). In the resected specimens, Ki-67 LI was significantly higher in cases positive for lymphatic invasion than in negative cases (p<0.05), or advanced-stage cases (p<0.05). Also, mean Ki-67 LI was higher in tumors from cases with lymph node metastasis than without. In the biopsy specimens, a significant correlation between Ki-67 LI and the term of stent patency (p<0.05) was observed. However, there were no significant correlations between clinicopathological factors or stent patency and p53 immunoreactivity. Assessment of mean Ki-67 antigen expression, as measured by MIB-1 staining, in samples of hilar bile duct carcinoma appeared to be an important indicator of clinical behavior. Biopsy specimens obtained by PTCS may be very useful in predicting the effectiveness of RT and assist in the selection of appropriate therapies.

Expressions of angiogenic factors in pancreatic ductal carcinoma: a correlative study with clinicopathologic parameters and patient survival.

INTRODUCTION: It has been reported that angiogenic factors play an important role in proliferation and metastasis in various cancers.AIMTo investigate the expression of angiogenic factors and microvessel density (MVD) in pancreatic ductal carcinoma and to examine the correlations among expression of angiogenic factors, clinicopathologic parameters, and clinical prognosis. METHODOLOGY: Paraffin-embedded specimens from 55 patients with pancreatic ductal carcinoma were immunostained for vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), platelet-derived endothelial cell growth factor (PD-ECGF), and CD34. The correlations among the expression of individual angiogenic factors and MVD, the clinicopathologic features, and the clinical prognoses were analyzed statistically. RESULTS: Immunostaining demonstrated that 70.8% of pancreatic ductal carcinomas were positive for VEGF, 60.9% for FGF-2, and 57.2% for PD-ECGF. A significant correlation was observed between VEGF expression and MVD (p < 0.05) but not between FGF-2 or PD-ECGF and MVD. Although the expression of each angiogenic factor had no correlation with clinicopathologic features, the patients with tumors that showed high expression of VEGF and FGF-2 had significantly shorter survival times than those with low or no such expression (p < 0.05). CONCLUSIONS: These observations suggest that the expression of VEGF closely correlates with MVD and with a poor prognosis in pancreatic ductal carcinoma.