Sadatoshi Shimizu

Inhibitory effect of a selective cyclooxygenase-2 inhibitor on liver metastasis of colon cancer.

COX‐2 overexpression is recognized in various cancers, but the role of COX‐2 in the progression of cancer, including the liver metastasis of colon cancer, is not clearly understood. We examined the role of COX‐2 in the mechanism of liver metastasis of colon cancer, using a highly metastasizable colon carcinoma cell line, LM‐H3. A COX‐2 inhibitor, JTE‐522, inhibited cell proliferation and invasion of LM‐H3 in vitro and clearly reduced the number of metastatic nodules on the surface of nude mouse livers in vivo. We also examined the effects of JTE‐522 on the production of growth factors and MMPs through the use of ELISA and gelatin zymography, respectively. JTE‐522 downregulated PDGF production by LM‐H3 but had no influence on VEGF production. JTE‐522 also inhibited MMP‐2 secretion by LM‐H3. JTE‐522 downregulated PGE2 production, but the associated changes in PGE2 did not affect PDGF and VEGF production by LM‐H3. We conclude that JTE‐522 downregulated the cell proliferation and invasive potential of LM‐H3 by reducing the production of PDGF and MMP‐2 and hypothesize that these inhibitory effects on the production of PDGF and MMP‐2 can lead to inhibition of liver metastasis of colon cancer. These data indicate that the COX‐2 inhibitor JTE‐522 has a high potential for use as a clinical agent for the treatment of liver metastasis of colon cancer.

In vivo and in vitro interactions between human colon carcinoma cells and hepatic stellate cells.

Stromal reaction is important for the growth of cancer both in primary and metastatic sites. To demonstrate this reaction during the hepatic metastasis of human colon carcinoma, we histologically investigated alterations to the distribution and phenotype of hepatic stellate cells (HSCs), the only mesenchymal cells in the liver parenchyma, using a nude mouse model. Intrasplenically injected colon carcinoma LM‐H3 cells migrated into the space of Disse and underwent proliferation, in close association with hepatocytes and HSCs, at 2 days. At 14 days, HSCs were accumulated around the tumor mass and expressed α‐smooth muscle actin, a marker for HSC activation. We next investigated in vitro the growth factors involved in the interactions between LM‐H3 cells and HSCs. Conditioned medium of rat HSCs which underwent culture‐induced activation contained platelet‐derived growth factor (PDGF)‐AB, hepatocyte growth factor (HGF) and transforming growth factor (TGF)β, and could augment LM‐H3‐cell proliferation and migration. Neutralizing antibodies against PDGF‐AA and PDGF‐BB and those against PDGF‐BB and HGF inhibited proliferation and migration, respectively, of LM‐H3 cells, whereas antibody against TGF‐β had no effect. LM‐H3 cells expressed PDGF receptors‐α and ‐β and c‐met. Conditioned medium of LM‐H3 cells contained PDGF‐AB, and could enhance HSC proliferation and migration. This augmenting effect was suppressed by treatment with anti‐PDGF‐AB antibody. The present study has demonstrated that bidirectional interactions involving PDGF and HGF take place in vitro between colon carcinoma cells and HSCs, raising the possibility that similar interactions might be involved in the stromal reaction during hepatic metastasis.

Spontaneous Regression of Hepatocellular Carcinoma: Report of a Case

A spontaneous regression of hepatocellular carcinoma is an extremely rare phenomenon. A 69-year-old Japanese man with hepatitis C virus-related chronic hepatitis presented with a liver tumor. We diagnosed the tumor to be hepatocellular carcinoma in the course of spontaneous regression, by imaging studies and changes in the tumor markers. Because the possible presence of viable cancer cells could not be ruled out, we recommended surgery. He refused all treatments at first, but finally agreed to undergo surgery about 10 months after presentation. A hepatectomy was performed. Histologically, no viable tumor cells were found. In our case, the vascularity of the tumor according to the imaging findings was followed up during the clinical course. The patient is now doing well and without any evidence of recurrence at 37 months after surgery.

HER3 Overexpression as an Independent Indicator of Poor Prognosis for Patients with Curatively Resected Pancreatic Cancer

Objective: The association between human epidermal growth factor receptor 3 (HER3) overexpression and survival in patients with curatively resected pancreatic cancer was investigated. Methods: Tissue samples from 126 pancreatic cancers without hematogenous or peritoneal metastases recovered from macroscopically curative resection were fixed with formalin, embedded in paraffin and subjected to immunohistochemical staining. Semiquantitative scores of zero (no staining or staining in less than 10% of cancer cells), 1+, 2+, or 3+ were assigned to each sample based on the intensity of staining. Scores of 2+ or 3+ were defined as HER3-positive staining, i.e., HER3 overexpression. Results: HER3 overexpression was observed in 52 of the 126 tissue samples (41.3%). There were no associations between HER3 overexpression and clinicopathological factors, including tumor location, tumor size, tumor differentiation, T/N categories according to the International Union against Cancer, and serum carbohydrate antibody 19-9 level (CA19-9). Univariate analysis demonstrated the median survival time of patients with HER3 overexpression was 37.2 months, while that of patients with HER3-negative samples was 58.6 months (p = 0.008). HER3 overexpression, lymph node metastasis, and elevated serum CA19-9 level were independent predictors of poor prognosis based on multivariate survival analysis. Conclusion: A new prognostic predictor, HER3 overexpression, was identified for resected pancreatic cancer.

Ultrastructure of early phase hepatic metastasis of human colon carcinoma cells with special reference to desmosomal junctions with hepatocytes

To demonstrate ultrastructural events in the early phase of hepatic metastasis of human colon carcinoma, we intrasplenically injected a highly metastasizable, human colon carcinoma cell line LM‐H3 (1 × 10 6 cells) into nude mice, and electron microscopically investigated the hepatic metastasis. At 24 h, tumor cells adhered to the endothelial wall of terminal portal venules and periportal sinusoids. At 48–72 h, after extravasation, they deeply invaded the hepatic cell plate and the interstitial tissue of the portal tract, in which they underwent proliferation and made the metastatic foci. Tumor cells were linked with each other or with surrounding hepatocytes by desmosomes. Desmosomes were maintained during the mitosis. When invading tumor cells were exposed to the bile canaliculi, they generated microvilli on the surface. Microvilli were also formed at the luminal surface of intracytoplasmic inclusions. In the interstitial tissue of the portal tract, tumor cells were closely associated with fibroblasts. However, no junctional specializations were seen between them. The present study demonstrated that human colon carcinoma cell line LM‐H3 formed desmosomes with hepatocytes soon after invasion of the hepatic cell plate, suggesting the regulatory role of an interaction with hepatocytes in the growth of metastatic foci within the liver parenchyma.

Laparoscopic splenectomy for histiocytic sarcoma of the spleen.

Primary histiocytic sarcoma of the spleen is a rare but potentially lethal condition. It can remain asymptomatic or only mildly symptomatic for a long time. An 81-year-old woman presented with an extremely enlarged spleen. She suffered from progressive anemia and required a red blood cell transfusion once a month. Although computed tomography, ultrasonography, and magnetic resonance imaging were performed for diagnosis, a confirmed diagnosis was not obtained. Her enlarged spleen compressed her stomach, and she suffered from gastritis and a sense of gastric fullness just after meals. She underwent laparoscopic splenectomy for therapeutic and diagnostic purposes. Her post-operative course was uneventful. After surgery, her red blood cell and platelet counts increased markedly. The tumor was diagnosed as splenic histiocytic sarcoma. Post-surgical chemotherapy was not performed, and the patient died of liver failure due to liver metastasis 5 mo after surgery. Laparoscopic splenectomy is minimally invasive and useful for the relief of symptoms related to hematological disorders. However, in cases of an enlarged spleen, optimal views and working space are limited. In such cases, splenic artery ligation can markedly reduce the size of the spleen, thus facilitating the procedure. The case reported herein suggests that laparoscopic splenectomy may be useful for the treatment of splenic malignancy.

Lymphoid hyperplasia detected as a single mass in the gallbladder: report of a case

We herein report a case of lymphoid hyperplasia of the gallbladder that showed unique images on computed tomography and ultrasonography. A 42-year-old female was referred to our hospital for evaluation and treatment of a gallbladder tumor. Ultrasonography and computed tomography showed a mass in the wall of the gallbladder neck, without typical findings of benign or malignant tumors. The serum levels of tumor markers, such as carcinoembryonic antigen, carbohydrate antigen 19-9, alpha-fetoprotein, and cytokeratin 19 fragment, were all within normal limits. Laparoscopic cholecystectomy was therefore performed. There were no stones in the gallbladder. Macroscopically, the submural tumor had a clear border without a capsule and a cystic portion. Its cut surface was grayish white. Microscopically, many lymph follicles with germinal centers were recognized in the subserosal layer. The lymphocytes were morphologically normal. We diagnosed lymphoid hyperplasia with chronic cholecystitis. Lymphoid hyperplasia of the gallbladder is extremely rare.

Ultrasonic Screening of the Thyroid in Patients with Breast Complaints

From 1994 until 2002, we performed 6956 ultrasonic screenings of the thyroid for all patients who received breast examination by ultrasonography. We discovered 14 thyroid cancers (0.32%) from 4327 cases with breast complaints. The incidence of thyroid cancer with breast cancer (0.25%) was three times higher than that of thyroid cancer without breast cancer (0.73%). It was concluded that ultrasonic screening of the thyroid was useful in patients with breast complaints.

PREDICTION OF RECURRENCE AFTER ENDOSCOPIC TREATMENT FOR ESOPHAGEAL VARICES: WITH SPECIAL REFERENCE TO ESOPHAGEAL VARICEAL PRESSURE

Background: We investigated the factors influencing esophageal variceal recurrence after endoscopic treatment on the basis of 25 variceal patients who were measured for esophageal variceal pressure, which had been reported to have a close relationship to variceal rupture.

Laparoscopic Hepatectomy for Liver Cancer.

This chapter covers a range of important topics of laparoscopic hepatectomy as a novel approach toward treatment of liver cancer. Although laparoscopic hepatectomy was performed in a limited number of centers in the 1990s, technological innovations, improvements in surgical techniques and accumulation of experience by surgeons have led to more rapid progress in laparoscopic hepatectomy in the late 2000s for minimally invasive hepatic surgery. Currently, laparoscopic hepatectomy can be performed for all tumor locations and several diseases via several approaches. The laparoscopic approach can be applied to several types of resection, not only for tumors but also for liver transplantation, with equivalent or better results compared with those obtained with open surgery. Therefore, laparoscopic hepatectomy will become a standard procedure for treatment of liver cancer in the near future.