Kenichi Sunayama

Urokinase receptor and vascular endothelial growth factor are synergistically associated with the liver metastasis of colorectal cancer

Considering recent findings that the urokinase plasniinogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor‐1 and ‐2 (PAI‐1, PAI‐2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI‐1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute Synergistically to the liver metastasis of colorectal cancer.

Orthotopic implantation of a colon cancer xenograft induces high expression of cyclooxygenase-2

The aim of the present study is to investigate the relation of cyclooxygenase (COX)-2 with liver metastasis. Pieces of human colon cancer xenograft were implanted orthotopically (CI), as well as intraperitoneally, and subcutaneously. Liver metastasis developed most frequently, and the COX-2 expression of both mRNA and protein of the tumors was the most dominant in the CI group. In contrast, the expression of COX-1 or vascular endothelial cell growth factor mRNAs had no significant differences among the groups. The intensity of COX-2 mRNA was negatively correlated with the apoptotic index. In conclusion, COX-2 plays an important role in organ-specific metastasis of the colon cancer.

Aggressive angiomyxoma of the perineum originating from the rectal wall.

Aggressive angiomyxoma (AA) is a rare mesenchymal tumor that preferentially involves the pelvic and perineal regions, and is characterized by frequent local recurrences. We describe here a case of large AA in a 31-year-old woman. The patient was admitted to our hospital with a mass in the perineal region, associated with severe menstrual pain. Although her past medical history was unremarkable, she had spotty pigmentation on the lips. Magnetic resonance imaging showed a large mass in the abdominal pelvis traversing the pelvic diaphragm just to the right of the anus, and the border between the tumor and the rectal wall was indistinct. Pathology examination of a frozen intraoperative specimen suggested AA, and, therefore, we completely resected the tumor, using a combined abdominoperineal approach. The tumor was attached to the right wall of the rectum and the pelvic diaphragm between the anus and the puborectalis. The patient recovered uneventfully and there has not been any evidence of local recurrence for 3 years postoperatively. We consider that abdominoperineal resection may be an appropriate treatment for a large AA infiltrating to the perirectal tissues, because the high recurrence rate of this disease has been attributed to incomplete surgical excision.

Simultaneous imaging of membrane antigen and the corresponding chromosomal locus in pathology archives

A new procedure for the simultaneous staining of membranous antigens, such as tyrosine kinase‐type cell surface receptor HER2 (c‐erbB2), and the corresponding chromosome (chromosome 17 for c‐erbB2) in the same cell for use in examining pathology archives is presented. A multistep procedure involving microwave‐assisted fluorescence in situ hybridization and immunofluorescence yielded cell images having c‐erbB2 on the membrane and genomic signals from the chromosome 17 centromere and the c‐erbB2 locus. Furthermore, a combination of microwave‐assisted chromogenic in situ hybridization and immunohistochemistry found colorized signals from both chromosome 17 centromere in the nuclei and c‐erbB2 on the membranes of individual cells. Quantitative image analysis further confirmed the presence of a significantly stronger c‐erbB2 immunoreactivity on cells containing three or more signals from chromosome 17 than from those with less than three signals. It was possible to extend the constellation of cell surface markers and corresponding chromosomes or locus‐specific makers to several other genes including CDH1. In this case, the disappearances of CDH1 expression, a CDH1 locus signal, and a centromere enumeration probe (CEP) 16 signal were simultaneously demonstrated in the less‐adhesive tumor cells. Thus, it is believed that this procedure might pave the way for exploiting pathology archives for the genotype–phenotype analysis of individual cells.

Beneficial effect of deletion variant of hepatocyte growth factor for impaired hepatic regeneration in the ischemically damaged liver

This study was conducted to determine the influence of hepatic ischemia and reperfusion (HIR) injury on liver regeneration and the effect of the deletion variant of hepatocyte growth factor (dHGF) under these conditions. Male Sprague-Dawley rats were subjected to 60 minutes of total hepatic ischemia, and two-thirds hepatectomy was performed just before reperfusion. Animals received intravenous administration of either vehicle buffer (vehicle control group) or dHGF (1 mg/kg) (HGF group) at the end of the period of hepatic ischemia and again 6 hours after reperfusion. At 8 hours after hepatectomy, plasma HGF levels in the vehicle control group were significantly lower than those in the nonischemic controls. Plasma aspartate transaminase levels in the vehicle control group reached 3,462 +/- 1,039 IU/L, but levels in the HGF group were significantly inhibited to 1,849 +/- 605 IU/L. The relative liver weight in the vehicle control group was significantly greater than in the HGF group, a finding that was implicated in focal liver necrosis with sinusoidal congestion. Less histological damage was observed in the HGF group. Twenty-four hours after hepatectomy, an increase in the relative liver weight in nonischemic controls and in the HGF group was higher than that in vehicle control group, and the 5-bromo-2?deoxyuridine (BrdU) labeling index in the HGF group was 23% versus 18% in the nonischemic controls. Administration of dHGF significantly improved the 7-day survival to 82% versus 40% in the vehicle control group. dHGF has potential benefit as a pharmacological agent to ameliorate impairment of the hepatic microcirculation and to potentiate a regeneration response in the ischemically damaged liver after hepatectomy and/or liver transplantation.

Diverticulitis Causing a High Serum Level of Carbohydrate Antigen 19-9: Report of a Case

Abstract We report herein a rare case of diverticulitis causing a high serum level of carbohydrate antigen (CA) 19-9. A 52-year-old man was admitted to our hospital with lower abdominal pain. Laboratory data showed evidence of inflammation and a high serum level of CA 19-9 (370 U/ml). Computed tomography demonstrated thickening of the wall of the sigmoid colon. He was diagnosed as having diverticulitis of the sigmoid colon and was treated with antibiotics. Although his symptoms improved, the presence of a malignancy such as colorectal cancer could not be completely ruled out because of the persistently high serum level of CA19-9. A laparotomy was performed and the sigmoid colon was found to be adherent to the bladder. Under a diagnosis of diverticulitis, a sigmoidectomy was performed. Pathological examination revealed diverticulitis of the sigmoid colon, but there was no evidence of malignancy in the resected specimen. The serum CA19-9 level decreased to normal postoperatively and immunohistochemical staining revealed CA19-9 antigen in the cytoplasm of the diverticular epithelium. Therefore, a possible explanation for the high level of this tumor marker was diverticulitis of the sigmoid colon.

Platelet-Activating Factor, a Critical Mediator in the Pathogenesis of Dextran Sulfate Sodium-Induced Colitis in Rats

AbstractPURPOSE: Disorder of mucosal immunity based on an imbalance between proinflammatory and anti-inflammatory cytokines is believed to be a major factor in the pathogenesis of ulcerative colitis. Platelet-activating factor potentially stimulates the production of proinflammatory cytokines and recruits inflammatory cells. The aim of this study was to determine whether and to what extent platelet-activating factor plays a role in the pathogenesis of ulcerative colitis. METHODS: Using dextran sulfate sodium-induced colitis in rats as a model of ulcerative colitis, we analyzed the composition of cellular infiltrates and the local tissue expression of messenger ribonucleic acid for cytokine-induced neutrophil chemoattractant and tumor necrosis factor-alpha. To directly assess the impact of platelet-activating factor on the development of colitis, we also determined the efficacy of a specific platelet-activating factor receptor antagonist for preventing dextran sulfate sodium-induced colitis. RESULTS: The activity of colitis was well correlated with the upregulation of cytokine-induced neutrophil chemoattractant and tumor necrosis factor-alpha messenger ribonucleic acid in local tissues and infiltration of cytokine-induced neutrophil chemoattractant-positive neutrophils and ED1-positive macrophages. The platelet-activating factor receptor antagonist effectively ameliorated colitis, along with causing a decrease in the tissue cytokine-induced neutrophil chemoattractant messenger ribonucleic acid level and a decline in neutrophil and macrophage infiltration. However, the antagonist did not alter tissue levels of tumor necrosis factor-alpha messenger ribonucleic acid. CONCLUSION: Platelet-activating factor plays a critical role in the pathogenesis of dextran sulfate sodium-induced colitis through recruitment of cytokine-induced neutrophil chemoattractant-positive neutrophils and macrophages and/or stimulation of cytokine-induced neutrophil chemoattractant release from activated neutrophils. The tissue level of tumor necrosis factor-alpha messenger ribonucleic acid does not closely reflect the activity of colitis.

A Case of Colonic Perforation Complicated with Acute Pancreatitis.

急性膵炎における合併症として大腸穿孔をともなうことはまれである. われわれは急性膵炎が原因と考えられた横行結腸穿孔例を経験し手術によりこれを救命しえたので報告する. 症例は48歳の男性で, 発熱と全身倦怠感を認め検査のため入院となった. 腹部超音波検査, CT検査にて後腹膜膿瘍を疑い, 注腸造影検査を施行したところ横行結腸において腸管外への造影剤の漏出が認められたため, 後腹膜膿瘍および大腸穿孔と診断し緊急手術を行った. 開腹すると後腹膜は膨隆し切開にて多量の膿の排出を認め, 横行結腸に穿孔を認めた. 術式は横行結腸, 下行結腸切除と人工肛門造設ならびに後腹膜ドレナージを行った. 切除した大腸の穿孔部位の炎症所見は漿膜側において顕著で組織学的にpericolitisおよびmarginal arteryの血栓を認め, 急性膵炎による虚血性変化が大腸穿孔の原因と考えられた.