Yoshiyuki Yanai

Vascular endothelial growth factor C promotes lymph node metastasis in a rectal cancer orthotopic model.

PurposeVascular endothelial growth factor C (VEGF-C), a novel member of the vascular endothelial growth factor family, is a relatively specific lymphangiogenic growth factor. It has been suggested that increased expression of VEGF-C in primary tumors is correlated with lymph node metastasis. We conducted this study to determine whether VEGF-C directly affects lymphangiogenesis and lymph node metastasis in colorectal cancer.MethodsFor an accurate analysis and clear visualization of metastases, the rectal cancer cell line, DLD1, was engineered to stably express green fluorescent protein (GFP) (DLD1/GFP). We implanted DLD1/GFP cells overexpressing VEGF-C orthotopically into the rectal walls of nude mice.ResultsLymph node metastasis was confirmed in all (100%) of the mice bearing DLD1/GFP-VEGF-C tumors, but in only 25% of the mice bearing control tumors. There were more lymph node metastases per mouse in the mice bearing DLD1/GFP-VEGF-C tumors than in the mice bearing control tumors. There were no differences in cell growth and motility in vitro or in the resulting tumor volume from the implanted cells between the two groups. Immunohistochemical staining revealed that VEGF-C induced the growth of lymphatic vessels, which were enlarged in the tumor periphery and contained tumor cell emboli.ConclusionThese results suggest that VEGF-C-induced lymphangiogenesis mediates tumor spread and the formation of lymph node metastasis.

A Novel, Easy, and Safe Technique to Repair a Stoma Prolapse Using a Surgical Stapling Device

A stoma prolapse is one of the late complications and often occurs when the stoma is made in an emergency situation. This complication is not lethal, but causes irritable stoma, skin trouble, and difficulty in stoma care. We herein report the case of a 48-year-old female with an end colostomy that was created as an emergency operation 4 months before. On admission, her colostomy protruded approximately 20 cm from the skin with marked redness, swelling, and erosion; it was impossible to treat manually. We repaired the prolapse successfully in a simple procedure with a Proximate Linear Cutter 100. Briefly, under mild sedation, the instrument was diagonally inserted into the prolapsed stoma and applied twice on both sides. Then, the base of each divided tissue was stapled and cut with the same device. Finally, the prolapse was completely repaired without major bleeding and severe pain. We have applied this novel technique successfully in 5 further cases, and there have been no complications or recurrences. This technique can be performed without spinal or general anesthesia and seems to be a very useful procedure for patients with prolapse of a stoma.

Giant peritoneal loose body in the pelvic cavity: report of a case.

This report describes a giant peritoneal loose body in the pelvic cavity. A 63-year-old man who was asymptomatic underwent a routine medical examination, which revealed a tumor in the pelvic space. Computed tomography and magnetic resonance imaging showed a smooth-surfaced mass with two marked calcifications in the central position. Preoperatively, we suspected a calcified leiomyoma originating from the wall of the sigmoid colon; however, at laparoscopic surgery we extracted a hard, egg-shaped mass 5 cm in diameter, with detached appendices epiploicae. Histological examination revealed that this peritoneal loose body was made up of thick layers of fibrous tissue with a few cellular components, and necrotic fat tissue in the central position. Small peritoneal loose bodies are occasionally found during laparotomy or autopsy, but such a large one is very unusual.

A novel nude mouse model of liver metastasis and peritoneal dissemination from the same human pancreatic cancer line.

Introduction Recently, several mice models have been used for investigating cancer metastasis. However, there are no metastatic and peritoneal dominated variants from the same parental cell line. Aim and Methodology To elucidate the mechanisms of metastasis, we established highly liver metastatic and peritoneal disseminated models in nude mice, and then characterized several factors related to metastasis in these cells. We established a series of well-characterized sublines that showed metastatic potentials to different organ sites of nude mice. Two sublines were selected sequentially from the parental pancreatic cancer cell line, HPC-4, resulting in a highly liver metastatic cell line, HPC-4H4, and a highly peritoneal disseminated cell line, HPC-4P4a. Using these three cell lines, we investigated several biologic properties and mRNA levels of differentially expressed genes involved in cancer metastasis. Results The tumorigenicity, the motile activity, and the adhesive activity of metastatic sublines were higher than those of parental HPC-4 cells. Macroscopic and microscopic findings and the DNA ploidy pattern were the same among the three cell lines. In addition, HPC-4H4 cells expressed clearly higher levels of vascular endothelial growth factor and IL-8 expression than did HPC-4P4a cells. In fluorescence-activated cell sorter analysis of adhesion molecules, the expression of integrin-&agr;2 was enhanced in HPC-4 cells, integrin-&agr;v&bgr;5 was enhanced in HPC-4H4 cells, and integrin-&agr;3 was enhanced in HPC-4P4a cells. Osteopontin, vascular endothelial growth factor, and hepatocyte growth factor were among the genes that were upregulated in HPC-4H4 cells compared with HPC-4P4a cells. HPC-4P4a cells did not metastasize to the liver by intrasplenic injection. Conversely, HPC-4H4 cells metastasized remarkably to the peritoneum by intraabdominal injection. Conclusion These sublines are the first reported liver metastatic and peritoneal disseminated models derived from the same parental cell lines. The results of our study suggest that the process of hematogenous metastasis is not the same as that of peritoneal dissemination.

Induction of heat shock protein-70 (hsp-70) by intraarterial administration of geranylgeranylacetone

IN TRANSPLANTATION, the principal problems are ischemia-reperfusion injury, preservation injury, rejection, infection, and graft-versus-host disease (GVHD), etc. Of these, ischemia-reperfusion/preservation injury is especially important, because it can cause primary nonfunction and its improvement is thereby crucial for the success of organ transplantation. Recently, there have been reports that showing that induction of heat shock protein (hsp) protects against ischemia-reperfusion injury and preservation injury. However, the mechanisms of this protective effect remain unknown and, as yet, a nontoxic clinical procedure for induction of hsp remains unavailable. In this study, we focused on geranylgeranylacetone (GGA), which is an antiulcer drug developed in Japan and used clinically for the treatment of gastric ulcer and gastritis. Its protective effects in other organs as well as the stomach have been reported; for instance, in one study, an improved histologic status in subjects with chronic hepatic injury was seen. It has been suggested that GGA may exert cytoprotective action through an increase of prostaglandin E2, 7 maintenance of cNOS activity, or induction of hsp. Therefore, in this study we investigate whether intraarterial administration of GGA to rats could induce expression of hsp-70 in various organs.

Inhibitory effect of endothelin A receptor blockade on tumor growth and liver metastasis of a human gastric cancer cell line

BackgroundWith metastatic progression, gastric cancer is incurable. Using a DNA microarray, we performed differential gene expression analysis of established highly metastatic gastric cancer cell lines and compared the findings with those from a low-metastatic parental cell line. The results demonstrated that the endothelin A receptor (ET-A) gene was the only one from the highly metastatic cell lines that was generally up-regulated.MethodsTo investigate the role that ET-A plays in gastric cancer metastasis, we studied the effect of an ET-A-selective antagonist, YM598, on cell proliferation, tumor growth, and liver metastasis of the highly liver metastatic cell line AZ-H5c, established from the low metastatic human gastric cancer cell line AZ-521.ResultsAn in vivo study using nude mice demonstrated that YM598 had a significant growth inhibition effect on AZ-H5c at doses of 0.5–10.0 mg/kg. The liver metastatic rate was also significantly reduced by YM598: control, 83.3%; 1 mg/kg dosage, 16.7%; 10 mg/kg, 20%; and pretreatment at 1 mg/kg, 16.7%. There was no evidence of gross toxicity resulting from the YM598 treatment.ConclusionThe ET-A blockade by YM598 had a strong inhibitory effect against tumor growth and liver metastasis of the gastric cancer cell lines. These data suggest that YM598 has potential as a novel therapeutic agent for inhibiting liver metastasis of gastric cancer.

Gastric T-cell lymphoma associated with hemophagocytic syndrome

BackgroundLymphoma-associated hemophagocytic syndrome (LAHS) occurs in mostly extra nodal non-Hodgkins lymphoma. LAHS arising from gastrointestinal lymphoma has never been reported. Here we report a case of gastric T-cell lymphoma-associated hemophagocytic syndrome.Case presentationA 51-year-old woman presented with pain, redness of breasts, fever and hematemesis. Hematological examination revealed anemia. Gastroscopy revealed small bleeding ulcers in the stomach and the computed tomography scan showed liver tumor. She underwent total gastrectomy for gastrointestinal bleeding and the histopathology revealed gastric T-cell lymphoma. She continued to bleed from the anastomosis and died on the 8th postoperative day. Autopsy revealed it to be a LAHS.ConclusionsIf Hemophagocytic syndrome (HPS) occurs in lymphoma of the gastrointestinal tract, bleeding from the primary lesion might be uncontrollable. Early diagnosis and appropriate treatment are needed for long-term survival.

Gene Expression Screening Using a cDNA Macroarray to Clarify the Mechanisms of Peritoneal Dissemination of Pancreatic Cancer

Abstract.Purpose: Pancreatic cancer is associated with the poorest prognosis of any digestive cancer due to the high incidence of peritoneal dissemination, which is the cause of death in most cases. To determine the mechanisms of peritoneal dissemination in pancreatic cancer, we established a mouse model of high peritoneal dissemination. Methods: A novel highly peritoneal-disseminating cell line was established from the human pancreatic cancer cell line; CAPAN-1. The new cell line, CAPAN-1P4a, was established from CAPAN-1 by repeated in vivo selection (four times) of the tumor cell line. To clarify the candidate genes implicated in peritoneal dissemination of pancreatic cancer, global gene expression screening was done using a cDNA macroarray. Results: CAPAN-1P4a cells showed 100% metastasis 3 weeks after injection and high reproducibility in the inoculated mice. Twenty-seven genes were upregulated and 14 genes were downregulated in CAPAN-1P4a cells compared with CAPAN-1 cells. The genes differentially expressed in the two cell lines were included as tumor suppressor/apoptosis genes, regulatory transcription factor, membrane receptors, cell adhesion protein, membrane receptors, and so on. Conclusions: Our established CAPAN-1P4a model offers a new means of conducting global gene expression analysis of pancreatic cancer cells with peritoneal dissemination and it has the potential to provide new insights into the mechanism of peritoneal dissemination in human pancreatic cancer.