BACKGROUND To identify the role of survivin, a novel inhibitor of apoptosis (IAP) in colorectal tumorigenesis, the authors investigated tissue expression of survivin in human colorectal tumors including 43 hyperplastic polyps, 171 adenomas with low dysplasia, 42 adenomas with high dysplasia, and 60 carcinomas in adenoma, and examined whether the expression of survivin correlated with tumor cell apoptosis, proliferation, and angiogenesis, which is known to initiate the imbalance between cell proliferation and apoptosis. METHODS Immunohistochemical staining for the paraffin sections by using the monoclonal antibodies, survivin, p53, bcl‐2, Ki‐67, and CD34, was performed by the standard avidin‐biotin‐peroxidase technique. The apoptotic cells were detected by terminal deoxynucleotidyl transferase–mediated dUTP‐biotin nick end labeling method, using an Apop Tag in situ detection kit. RESULTS The immunoreactivity of survivin significantly increased in the transition from adenoma with low dysplasia to high dysplasia/carcinoma (P < 0.001). Similar changes in protein expression were observed for p53 but not for bcl‐2, which was expressed throughout the colorectal tumorigenesis. This transition was associated with a significant decrease in the apoptotic index (AI) and significant increases in the Ki‐67 labeling index (LI) and microvessel density (MVD; P < 0.001 for both). The expression of survivin inversely correlated with AI and was positively correlated with Ki‐67 LI and MVD (P < 0.001 for both). CONCLUSIONS These results suggest that, like p53, survivin plays an important role in transition from adenoma with low dysplasia to high dysplasia during human colorectal tumorigenesis. Cancer 2001;91:2026–32. © 2001 American Cancer Society.

ObjectiveTo analyze the survival predictors of patients undergoing hepatectomy for colorectal liver metastasis to determine useful indicators for therapy selection. Summary Background DataAlthough recurrence develops in more than two thirds of patients undergoing hepatectomy for colorectal liver metastasis, preoperative characteristics that might predict such recurrence have yet to be clearly identified. MethodsClinicopathologic data of 85 consecutive patients with colorectal cancer who underwent a curative resection of primary lesions and metastatic liver diseases at one institute were analyzed using the multivariate method with respect to both the metastatic state and the primary lesion. ResultsMultivariate analysis indicated that the aggressiveness of the primary tumor, early liver metastasis, and a large number of liver metastases were the characteristics that could be detected before hepatectomy and that independently indicated a worse survival. A three-ranked classification based on these coefficients (H-staging) was significantly related to both the recurrence rate within 6 months (7% in H-stage A, 30% in B, and 44% in C) and the 5-year survival rates (55%, 14%, and 0% respectively). An additional scoring system (HЈ-staging) based on the aggressiveness of the primary tumor and the level of carcinoembryonic antigen 1 to 3 months after hepatectomy was found to be related to the mode of subsequent recurrence and surgical resectability of the recurrent foci. ConclusionsH-staging can provide useful prognostic information for the treatment of liver metastasis. HЈ-staging could also help in predicting the possible mode of recurrence after hepatectomy and in determining the most suitable mode of additional therapy. Further multiinstitutional studies based on a large collective database will confirm the utility of these two staging systems.Hepatic resection is at present the treatment of choice for patients with colorectal metastases because it offers a reasonable chance of long-term survival.1 Nevertheless, because recurrence develops in many patients in a short period after hepatectomy, an improved set of indicators for surgical treatment is needed. Numerous investigators have reported the significance of several prognostic parameters, including liver-related characteristics (number, 2,3 distribution, 4 tumor diameter, 5,6 macroscopic type, 7 and satellite metastases 1 ), the time to liver metastasis, 1 the existence of extrahepatic disease, 8 the extent of liver resection, 1,3-6 age, 5 level of carcinoembryonic antigen (CEA), 3,5 and stage of the primary tumor.5 To date, however, few reliable selection criteria have been established with regard to treatment policies based on these variables. 5To assess the prognostic indicators, we reviewed a consecutive series of our patients with colorectal cancer and associated liver metastases. We examined several parameters and their relation to the prognostic outcome to determine whether any of these factors might be predictors of poor outcome and therefore useful in asse...

We comparatively investigated the extent of apoptotic cell loss in human colorectal cancers evaluated by two methods, namely the conventional terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end-labeling (TUNEL) method and immunohistochemistry for single-stranded (ss) DNA. The apoptotic index (AI) obtained with the TUNEL method was higher than that shown by the immunohistochemistry for ssDNA. However, a significant correlation in AIs evaluated by these methods was found. The AIs obtained by both methods were significantly higher in the advanced cancers than in the early cancers. Cellular proliferation activity was assessed in terms of positivity rate (PR) for expression of proliferating cell nuclear antigen (PCNA). The PR of advanced cancers was significantly higher than that of early cancers. The present results indicate that immunohistochemistry for ssDNA is useful (as is the TUNEL method) for evaluation of apoptotic tumor cells in colorectal carcinomas. In addition, it was confirmed that there is a remarkable increase of not only proliferation activity, but also tumor cell apoptosis in the process of progression of colon cancer from early to advanced stages of the disease.Key words: Apoptosis -TUNEL -Immunohistochemistry -Single-stranded DNA -Colorectal cancer Apoptosis is characterized morphologically by large chromatin fragments, 1) by extensive margination and fragmentation of the chromatin viewed electromicroscopically,2) and by a characteristic "ladder formation" of DNA fragments of about 180-200 base pairs by endonuclease activation in gel electrophoresis.3)The terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick endlabeling (TUNEL) method, which detects apoptosis and programmed cell death has been utilized to identify apoptotic cells at the single-cell level. 4) In contrast, Tomei has speculated that apoptosis involves the modification of chromatin, which results in a break-down of the supercoiling organization and the formation of individual super breaks. He has further proposed that single-stranded (ss) DNA modification in the nucleosomal linker region might constitute a critical early step in apoptosis.5) Naruse et al. showed that the antibody against ssDNA is a good marker of both drug-induced apoptosis and programmed cell death during embryogenesis. A polyclonal antibody against ssDNA has been used to immunohistochemically detect apoptotic cell death in epithelial cells. 6)There is, to our knowledge, no report on the relationship between apoptosis detected by immunohistochemistry for ssDNA and cellular proliferation activity assessed in terms of the positivity rate (PR) of proliferating cell nuclear antigen (PCNA) in colorectal carcinoma. In the present study, we investigated the extent of apoptotic cell loss in human colorectal cancers by the conventional TUNEL method and by immunohistochemistry for ssDNA. In addition, we compared the apoptotic indices (AIs) obtained by these two methods to determine whe...

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