Jun Sano

Centrosomal Kinases, HsAIRK1 and HsAIRK3, are Overexpressed in Primary Colorectal Cancers

Members of the recently identified family of Homo sapiens Aurora/Ipl1‐related kinases (HsAIRKs), homologous to chromosome segregation kinases, fly Aurora and yeast Ipl1, are highly expressed during M phase, and have been suggested to regulate centrosome function, chromosome segregation, and cytokinesis. In the present study, immunohistochemical analyses were performed of HsAIRK1 and HsAIRK3 expression in 78 primary colorectal cancers and 36 colorectal adenomas as well as 15 normal colorectal specimens. In normal colon mucosa, some crypt cells showed weak positive staining in 10 and 12 out of 15 cases for HsAIRK1 and HsAIRK3, respectively, the remaining cases being negative. Elevated expression of HsAIRK1 was observed in 53 (67.9%) of the colorectal cancers, and of HsAIRK3 in 40 (51.3%). Furthermore, colorectal adenomas showed high expression of HsAIRK1 and HsAIRK3 in 11 (30.6%) and 7 (19.4%) cases, respectively, thus being intermediate between colorectal cancers and normal colorectal mucosa. Interestingly, HsAIRK1 overexpression was significantly associated with pT (primary tumor invasion) and p53 accumulation in colorectal cancers. There was no significant correlation between proliferating cell nuclear antigen‐labeling index (PCNA‐LI) and the levels of these proteins. The results suggest that overexpression of HsAIRK1 and HsAIRK3 might be involved in tumorigenesis and/or progression of colorectal cancers.

Large solitary fibrous tumor of the retroperitoneum: report of a case.

We report an unusual case of a large solitary fibrous tumor (SFT) in the retroperitoneum. A 53-year-old man was referred to our hospital for surgical treatment of a swelling in the right flank with dull pain. Abdominal computed tomography (CT) and echograms showed a large encapsulated tumor compressing the right kidney and liver. At laparotomy, the tumor was found to be encapsulated but fixed to the capsule of the right kidney within a small area. Therefore, complete removal was achieved. The resected specimen was an encapsulated elastic hard tumor, 14 × 13 × 10 cm in size. Immunohistochemical studies revealed reactivity for CD34 and vimentin, but no staining for keratin, S-100, or Α-smooth muscle actin, confirming a diagnosis of SFT. Although SFT is usually associated with a favorable prognosis, close follow-up is recommended because of the limited information on its long-term behavior.

Antitumor Effects Induced by the Combination of TNP-470 as an Angiogenesis Inhibitor and Lentinan as a Biological Response Modifier in a Rabbit Spontaneous Liver Metastasis Model

Purpose:An angiogenesis inhibitor, TNP-470 (TNP), has shown promising results in tumor dormancy therapy, and we have been studying its antitumor effects using a rabbit spontaneous liver metastasis model. However, because inhibition was observed only at the step of micrometastasis, we examined the effects of combining TNP in the same model with a nonspecific immunopotentiator, lentinan (LNT), as a biological response modifier.Methods:The model was established by the inoculation of VX-2 tumors into the colon, and colectomy was subsequently performed, including the primary tumor. Combination (TNP + LNT) effects were evaluated in terms of the number and volume of metastatic nodules, microvessel density (MVD), expression of proliferating cell nuclear antigen (PCNA), and apoptosis, using immunohistochemical staining with anti-CD31, anti-PCNA monoclonal antibody, and the TUNEL (in situ nick end-labeling) method, respectively.Results:Angiogenesis was significantly inhibited in the TNP + LNT group, and the apoptotic index was also significantly higher than in the TNP or LNT groups. The positive expression of PCNA in the VX2 cells was reduced in the LNT alone and TNP + LNT groups, but not in the TNP alone group.Conclusion:These findings indicate that TNP-470 and lentinan could prove useful for preventing the development of metachronous liver metastases from colorectal cancers after curative resection.

Evaluation of Treatment for Synchronous Hepatic Metastases from Gastric Cancer with Special Reference to Long-Term Survivors

Abstract.Abstract.Purpose: The purpose of this study was to determine the most effective means of treating liver metastases from gastric cancer.Methods: We retrospectively examined 43 patients with liver metastases, but without peritoneal dissemination, who had received different forms of treatment.Results: The crude 5-year survival rates of patients who underwent gastrectomy with complete hepatectomy (curative gastrectomy), noncurative gastrectomy, and no gastrectomy were 33.3%, 3.7%, and 0%, respectively. The curative gastrectomy group showed the highest survival rate (not significant). The median survival of patients given hepatic artery infusion (HAI), systemic chemotherapy, and no chemotherapy were 353, 189, and 61 days, respectively. The patients given chemotherapy survived significantly longer than those not given chemotherapy. Three patients survived for more than 5 years without any signs of recurrence. The long-term survivors all had primary lesions without serosal invasion (T2) and no other noncurative factors. Two patients underwent curative gastrectomy and one underwent noncurative gastrectomy. All were given postoperative chemotherapy; as HAI in two cases, and as systemic chemotherapy in one case.Conclusion: These findings suggest that curative gastrectomy combined with HAI or systemic chemotherapy should be attempted for patients with primary tumors without serosal invasion or any other noncurative factors.

Therapeutic effect of TNP-470 on spontaneous liver metastasis of colon tumors in the rabbit.

Abstract Even though angiogenesis inhibitor is thought to be one of the promising agents in tumor dormancy therapy, its optimal administration is still unknown. Therefore, the efficient protocol using TNP-470 was examined regarding its treatment affect against spontaneous liver metastases of colon tumors in the rabbit. A spontaneous liver metastases model was established in the rabbit by the inoculation of VX-2 tumors into the subserosal space of the colon. The therapeutic effect of TNP-470 was then investigated by monitoring both the number of metastatic nodules in the liver and the microvessel density (MVD) in the tumor by immuno-histochemical staining using anti-CD31 monoclonal antibody. TNP-470 did not show any effect on the primary tumor. It was able to reduce the metastatic spread to liver when it was administered at the microscopic metastatic stage. Treatment at this stage, however, was not able to sufficiently control the disease. These results indicated that TNP-470 could efficiently cause the tumor to enter into a dormant state by inhibiting angiogenesis when it was used at the initial stage of the metastatic process in the liver. Regarding its clinical application, TNP-470 might be useful for preventing the metachronous liver metastases of colorectal cancer when it is administered as adjuvant therapy after curative surgery.

Study of a High Risk Group for Liver Metastasis of Colorectal Cancer Evaluated by Molecular Biology and Immunohistochemistry Approach.

【目的】分子生物学的側面より大腸癌肝転移高危険群の抽出を行った.【対象と結果】(1) 大腸癌48例における, RT-PCRによるMMP-9, uPA, TIMP遺伝子発現と肝転移との関連をみると, 転移群ではMMP-9とuPA発現率が有意に高率でった.(2) 異時性肝転移33例と非転移66例におけるPCNA, CD44, nm23, p53免疫染色による検討では, 転移群でPCNA-LIが有意に高く, CD44 (+), nm23 (-) が有意に多かった.(3) 肝転移65例, 無再発66例における検討では, 肝転移群でMVDが有意に高値で, VEGF染色性が有意に高かった.(4) 大腸癌52例でのCEAとCK-20を用いたRT-PCRによる癌細胞の検索では, 病期の進行とともに検出率が増加した. 遠隔転移 (-) 例でも16%(7/43) が陽性で, うち2例 (29%) に異時性肝転移が認められた.【結語】大腸癌肝転移にはMMP-9, uPA, TIMP, VEGF, MVD, PCNA, nm23, CD44などが関連しており, これらの検索がRT-PCRによる環流血中の癌細胞検出法とともに高危険群抽出に有用であると推察された.