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Background: The suppression of apoptosis is an important factor in tumor progression in hepatocellular carcinoma (HCC). However, to the authors knowledge the clinicopathologic importance of the expression of apoptosis-related genes (bcl-2, bax, and survivin) in HCC remains unclear. In the current study, the authors investigated the correlation between expression of apoptosis-related genes and the occurrence of spontaneous apoptosis in HCC. In addition, the prognostic significance of the expression of apoptosis-related genes in patients with HCC was analyzed., Methods: Tissue samples were obtained through surgical resection of the liver in 53 patients with HCC and 5 patients without HCC. The expression levels of bcl-2, bax, survivin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA were analyzed using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The bcl-2/bax ratio and survivin/GAPDH ratio of the tumors were compared with clinicopathologic findings. In addition, apoptotic tumor cells and the proliferative activity of tumor cells were detected using immunohistochemistry., Results: The bcl-2/bax ratios of the tumors were not different from those of noncancerous liver tissue samples obtained from regions distant from the tumors and were not found to correlate with apoptosis or with clinical importance in HCC. In contrast, the survivin/GAPDH ratios of the tumors were significantly higher than those of noncancerous liver tissue and demonstrated a negative correlation with apoptosis and a positive correlation with the proliferative activity of tumor cells. Moreover, patients who had tumors with a high survivin/GAPDH ratio were found to have a high incidence of disease recurrence., Conclusions: The real-time RT-PCR method appears to be a useful technique with which to detect reliable gene expression in tissues, and the detection of survivin mRNA expression by this method may be a useful marker for identifying patients with HCC who have a high risk of disease recurrence., (Copyright 2002 American Cancer Society.)

Background: The objective of this study was to assess the prognostic value of detecting circulating tumor cells in the tumor drainage blood and peripheral blood of patients with colorectal carcinoma., Methods: A total of 53 patients with advanced colorectal carcinoma were studied. Tumor drainage blood and peripheral blood samples that were obtained during surgery were examined for carcinoembryonic antigen (CEA) mRNA using reverse transcriptase-polymerase chain reaction (RT-PCR)., Results: In spiking experiments, the assay indicated a sensitivity limit of 1 carcinoma cell per 10(6) cells. CEA mRNA was detected in the tumor drainage blood of 36 of 53 patients (68%) and in the peripheral blood of 18 of 53 patients (34%). The rate of detection in both tumor drainage blood and peripheral blood was significantly higher in patients with lymph node metastasis, lymphatic invasion, or vascular invasion (P < 0.05). Among those patients who underwent potentially curative resection, the 2-year disease free survival rate of patients whose tumor drainage or peripheral blood was negative for CEA mRNA was significantly better than that of patients who showed CEA mRNA positivity of either sample (tumor drainage blood: 100% vs. 57%; P < 0.05; peripheral blood: 74% vs. 50%; P < 0.01), although the follow-up thus far has been only 9-30 months., Conclusions: The presence of CEA mRNA in the blood is a useful indicator of circulating tumor cells, and it is one of the determinant prognostic factors for patients with colorectal carcinoma. Moreover, the absence of CEA mRNA in tumor drainage blood was found to be a superior marker for disease free survival compared with that in peripheral blood.

Background: Nuclear profiles have been reported to be useful prognostic predictors in various cancers. Data from computerized morphometry are objective and are quickly obtained by conventional microscopic analysis. However, this image analysis of nuclear features has been only rarely applied to investigations of colorectal adenocarcinoma. The aim of this study was to evaluate the correlation between the morphologic nuclear features and clinicopathologic parameters in cases of colorectal adenocarcinoma., Methods: Morphometric nuclear features (nuclear area, perimeter, and shape) were analyzed in 343 patients with colorectal carcinoma and in 57 patients with colorectal adenoma. In each case, 300 nuclei of carcinoma or adenoma cells were analyzed on routine hematoxylin and eosin stained slides by means of a computer-assisted image analysis system that involved tracing the nuclear profiles (magnification x400) on a computer monitor. The morphometric data were compared with patients' survival, clinicopathologic status, and DNA ploidy pattern of tumors., Results: The mean nuclear area (NA) enlarged from normal colorectal mucosa to adenoma and carcinoma (normal mucosa: n = 343, mean NA = 19 micrometer(2); adenoma: n = 57, mean NA = 34 micrometer(2); mucosal carcinoma: n = 15, mean NA = 45 micrometer(2); P < 0.001). In 343 colorectal carcinomas, NAs of cancer cells in tumors with lymphatic invasion, venous invasion, lymph node metastasis, or hepatic metastasis were significantly larger than those of cancer cells in tumors without such factors. The mean NA of DNA aneuploid tumors was larger than that of DNA diploid tumors (P < 0.001). The nuclear area of cancer cells was determined to be one of the independent prognostic factors in multivariate analysis (P < 0.001). Moreover, the large nuclear area of cancer cells was recognized as one of the risk factors of metachronous hematogenic metastasis in patients after curative surgery., Conclusions: Data from computerized morphometry are objective and can be obtained rapidly by conventional microscopic analysis. The nuclear area of cancer cells appears to predict 1) the ability of cancer cells to invade the microvessels in the colorectal wall and 2) the ability of cancer cells to metastasize to the lymph nodes or liver. Therefore, nuclear morphometry is beneficial in mass screening to select patients who are at risk of hematogenic or lymph node metastatic recurrence after curative surgery for colorectal carcinoma., (Copyright 1999 American Cancer Society.)

Background: Transforming growth factors beta (TGFs beta) are involved in a variety of important cellular functions, including cell growth and differentiation, adhesion, migration, extracellular matrix formation, and immune function. Moreover, it has been reported that TGFs beta are correlated with angiogenesis. However, the role of TGF-beta as an angiogenic factor in gastric carcinoma is still unclear., Methods: TGF-beta1 expression was determined in 101 patients with gastric carcinoma by immunohistochemical procedures, and this expression was compared in the current study with both the expression of vascular endothelial growth factor (VEGF), which is thought to be the most potent angiogenic factor, and microvessel density, to evaluate the effect of TGF-beta1 on the angiogenesis of gastric carcinoma tissues., Results: TGF-beta1 expression was detected in 23 tumors (22.8%). TGF-beta1 expression was more frequent in differentiated than in undifferentiated gastric carcinoma. Furthermore, TGF-beta1 expression was significantly correlated with the depth of invasion and the stage of disease. There was a close correlation between TGF-beta1 expression and VEGF expression. There was no correlation between TGF-beta1 expression and microvessel density, whereas VEGF expression was significantly correlated with microvessel density. With regard to prognosis, the 5-year survival rate was 55.9% for patients with TGF-beta1 positive tumors and 67.0% in patients with TGF-beta1 negative tumors. Accordingly, the prognosis for patients with TGF-beta1 negative tumors was significantly better than that for patients with TGF-beta1 positive tumors. Multivariate analysis indicated that lymph node metastasis, tumor size, and TGF-beta1 expression were independent prognostic factors., Conclusions: These results suggest that TGF-beta1 might be associated with tumor progression by indirectly stimulating angiogenesis through the up-regulation of VEGF expression in gastric carcinoma., (Copyright 1999 American Cancer Society.)

Background: Spontaneous apoptosis has been detected in gastric carcinoma. However, the clinicopathological significance of this remains unclear. The objective of this study was to investigate the correlation between spontaneous apoptosis and the clinicopathologic and biologic characteristics of advanced gastric carcinoma. In addition, the prognostic significance of spontaneous apoptosis of tumors was evaluated., Methods: The occurrence of apoptotic cell death (apoptotic index [AI]) in 97 patients with advanced gastric carcinoma was analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling method. The Ki-67 labeling index (LI), expression of p53 and p21, DNA ploidy pattern, microvessel density (MVD), density of dendritic cells (DCs) in tumors, and degree of lymphocytic infiltration (LI) of the tumors were compared with the AI for each patient. In addition, the prognostic significance of AI was evaluated in these patients., Results: The mean AI of the 97 tumors was 2.05% (range, 0-11.31%). Statistical analyses revealed significant correlations between the AIs and the Ki-67 LIs (P = 0.0004) and between the AIs and the density of DCs (P = 0.0007), as well as an inverse correlation between the AIs and the intratumoral MVD (P = 0.0064). In addition, the AI of 47 tumors with high grade LI (2.94+/-2.51%) was significantly higher than that of 50 tumors with low grade LI (1.22+/-0.93%) (P<0.0001). However, the authors failed to find a significant correlation between the AIs and expression of p53 and p21 and the DNA ploidy pattern. In 93 surviving patients, the 5-year survival rate of 45 patients who had tumors with high AIs (> or =1.47; 82%) was significantly better than that of 48 patients who had tumors with low AIs (<1.47; 60%) (P = 0.0264)., Conclusions: The findings of the current study suggest that the tumors with low neovascularization and high local immunoreactivity may regulate their progression by apoptosis. Moreover, less extensive apoptosis in gastric adenocarcinoma may contribute to disease progression and could be correlated with a poorer prognosis.

Background: In this study, the authors examined the correlations among enhancement of apoptosis, changes in cell cycle distribution, and expression of Ki-67 in human colorectal carcinoma cells during different durations of preoperative treatment with 5-fluorouracil (5-FU)., Methods: Forty-one patients with advanced colorectal carcinoma were divided into 4 groups, which received intravenous 5-FU at 500 mg/body/day preoperatively for 3 days (n = 11), 5 days (n = 13), 7 days (n = 9), or 10 days (n = 8). Patients were further divided into two subgroups according to the DNA ploidy pattern of their tumors, i.e., diploid or aneuploid. Apoptotic cells were stained by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. The expression of Ki-67 was examined by immunohistochemical staining. Flow cytometry was used to analyze changes in cell cycle distribution., Results: Apoptosis of cancer cells was mostly increased in the 7-day group (apoptotic index [Al]: 18.3+/-1.7%] compared with that of the 3-day, 5-day (AI: 11.3+/-2.3% and 13.2+/-2.8%, respectively) (P < 0.01), or 10-day (Al: 16.2+/-2.1%) (P < 0.05) groups. The expression of Ki-67 was reduced with increasing prolongation of 5-FU administration, from 55.2+/-2.1% in the 3-day group to 38.1+/-2.7% in the 10-day group. The authors also assessed the S-phase fraction (SPF) of cancer cells to evaluate changes in cell cycle distribution caused by 5-FU. All tumor samples from patients treated by 5-FU showed S-phase accumulation. The ratio of SPF (after 5-FU/before 5-FU) was higher in the 5-day group (2.35+/-0.78) than in the 3-day (1.71+/-0.48), 7-day (1.68+/-0.55), or 10-day (1.20+/-0.20) groups (P < 0.05). DNA ploidy pattern of the tumor had no influence on the enhancement of apoptosis, the increased ratio of SPF, or the decrease in proliferative activity of colorectal carcinoma cells induced by 5-FU., Conclusions: S-phase accumulation preceded apoptotic cell death when intravenous 5-FU was administered continuously to human colorectal carcinoma cells.

Background: The expression of variant isoforms of CD44 is correlated with the ability of tumor cells to metastasize in some clinical carcinomas. In this study, the serum concentration of soluble splice isoforms of CD44 that shared exon variant 6 (sCD44v6) were measured and the histologic expression of CD44v6 in tumors from patients with gastric carcinoma examined., Methods: Serum samples were obtained from 102 patients with primary gastric carcinoma before surgery and serum levels of sCD44v6 were determined with an enzyme-linked immunoadsorbent assay. The expression of CD44v6 in tumors was examined by immunohistochemical staining., Results: Both the serum concentration of sCD44v6 and its expression in tumors were associated significantly with the depth of invasion of the tumor, lymph node metastasis, and clinical stage in patients with diffuse type gastric carcinoma. Among patients with gastric carcinoma, the serum level of sCD44v6 was higher in those with CD44v6 positive tumor cells than in those with CD44v6 negative tumor cells. The serum level of sCD44v6 was a prognostic indicator in patients with diffuse type gastric carcinoma, as was the histologic expression of CD44v6. However, neither CD44v6 nor sCD44v6 was a predictor of survival time in patients with intestinal type gastric carcinoma., Conclusions: It appears that CD44v6 and sCD44v6 are related to the progression of diffuse type gastric carcinoma. An elevated serum level of sCD44v6 may be useful as a prognostic indicator in patients with diffuse type gastric carcinoma.

Background: The authors examined whether expression of p21 (waf1/cip1/sdi1) and p53 protein was related to survival, rates in patients with advanced gastric carcinoma., Methods: The expression of p21 and p53 protein was analyzed by immunohistochemistry in 93 patients with advanced gastric carcinoma with serosal invasion and lymph node metastasis. All patients underwent curative surgery. The probability of survival was calculated by the Kaplan-Meier method and compared by the generalized Wilcoxon test., Results: Various levels of p21 and p53 immunoreactivities in carcinoma cells were detected in 30 (32%) and 60 (65%), respectively, of 93 samples. There was no correlation between p21 and p53 expression. The 5-year survival rate of patients with p21 expression was 69.4%, which was significantly better than that of patients without p21 expression (38.1%; P < 0.05). However, p53 protein expression did not correlate with patient survival., Conclusions: Expression of p21 protein may be a better prognostic factor than p53 protein expression in patients with advanced gastric carcinoma.

Background: It has been reported that anticancer drugs induce apoptosis, thus it is considered that apoptosis may be important in cancer chemotherapy. The authors examined whether the administration of 5-fluorouracil (5-FU) enhanced apoptosis of gastric carcinoma cells, and investigated the relationship between apoptosis and the expression of Ki-67 and the Bax gene., Methods: Twenty patients with gastric carcinoma were divided into 2 groups. Ten patients received continuous intravenous 5-FU at 500 mg/body weight/day for 7 days preoperatively whereas the other 10 did not receive any chemotherapy or radiotherapy, and served as controls. For detection of apoptotic cells, apoptotic indices were examined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) method. The expression of Ki-67 and the Bax gene were examined by immunohistochemical staining., Results: Apoptosis of gastric carcinoma cells increased significantly to 6.1 +/- 3.6% in the 5-FU-treated group compared with the controls (3.2 +/- 1.8%; P < 0.05). The level of expression of Ki-67, a marker of cell proliferation, was inversely correlated with the extent of TUNEL staining that was specific for apoptosis. The percentage of cells that were immunopositive for Ki-67 fell to 50.8 +/- 7.3% of the apoptotic area in the 5-FU-treated group compared with 57.5 +/- 6.9% in the controls (P < 0.05). There was no significant correlation between frequency of apoptotic cells and the level of expression of the Bax gene., Conclusions: The authors demonstrated enhanced apoptosis in gastric tumors after continuous intravenous infusion of 5-FU for 7 days. This result suggests that it may be possible to evaluate the effects of chemotherapy by detecting apoptotic cells.

Background: Apoptotic cell death plays an important role in the proliferation and turnover of cells in various tumors. The relationship between apoptosis and cell proliferation was studied to determine each of their roles in colorectal carcinogenesis., Methods: Apoptotic cells were identified by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. The occurrence of apoptosis was examined in colorectal cancer that had invaded the submucosa. Specimens were obtained from 38 cases of cancer with adenoma and 29 cases of cancer de novo. Apoptotic indices (AIs) as percentages of TUNEL-positive cells relative to the number of tumor cells and Ki-67 labeling indices (PI) were investigated. The relationship between the frequency of apoptosis and the expression of p53 and c-myc proteins was also investigated., Results: In cancer with adenoma, the ratio of AI/PI in adenoma cells was significantly higher than that of cancer cells (P < 0.0001). Mean AIs of cancer with adenoma were significantly higher than those of cancer de novo particularly in the flat-type cancers (P < 0.05). Among p53 negative tumors, the ratio of AI/PI for cancer de novo was significantly lower than that for cancer with adenoma (P < 0.05). AI of cancer de novo was lower than that of cancer with adenoma in cases with overexpression of c-myc protein (P < 0.05), whereas there was no significant difference in the ratio of AI/PI between cancer de novo and cancer with adenoma., Conclusions: Colorectal carcinogenesis is related to the inhibition of apoptosis and to the augmentation of proliferative activity both in cancer with adenoma and in cancer do novo. A reduction of the rate of apoptosis as compared with that of cell proliferation might explain the rapid-growing nature of cancer de novo particularly in cases with the flat-type appearance.

Background: Dendritic cells (DC), including epidermal Langerhans cells, are potent antigen-presenting cells that can carry and present tumor antigens to helper T-cells. An immunohistochemical study was performed to clarify the relationship between the extent of infiltration by DCs in primary gastric cancer and that in the regional lymph nodes., Methods: Paraffin blocks were prepared for staining with antibody against S-100 protein in 121 cases of gastric cancer. Infiltration of S-100 protein-positive DCs was evaluated in the primary tumor and in the peritumoral, primary, secondary, and tertiary nodes., Results: The extent of infiltration by DCs into the regional lymph nodes decreased significantly with an increasing distance of the nodes from the primary tumor. Correlation of the extent of such infiltration was observed among the peritumoral, primary, secondary, and tertiary nodes. However, the extent of infiltration into the primary tumor did not correlate with that into the primary, secondary, and tertiary nodes. Infiltration by DCs of the peritumoral nodes correlated with that of the tumor, particularly when lymph node metastasis was absent. There was no significant difference in the extent of infiltration into the peritumoral nodes even when lymph nodes were involved. However, infiltration of DCs increased in the primary and secondary nodes when the primary nodes were involved., Conclusion: Infiltration of DCs may be regulated in the primary lesion of gastric cancer. The peritumoral lymph nodes serve as transmitters of DCs from the primary tumor to the regional lymph nodes. DCs in the regional lymph nodes are important for establishing immunologic defense mechanisms in cases of gastric cancer when metastasis is absent or limited to the primary nodes.

Background: The microwave tissue coagulator (2450 MHz) has been used clinically in the treatment of hepatocellular carcinoma (HCC) to transection of the liver parenchyma and has proven an excellent method for hemostasis. There are, however, few reports on the application of this coagulator to the induction of tumor necrosis., Methods: Microwave tissue coagulation (MTC) was applied at laparotomy in eight patients with nonresectable multiple HCCs. All patients were treated with a combination of resection or intrahepato-arterial chemotherapy and MTC. A total of 222 bouts of MTC were applied to 21 tumors, the largest of which was 65 mm in largest dimension. The monopolar needle electrode was inserted directly into the tumor and the procedure was repeated at approximately 5 mm intervals., Results: Levels of alpha-fetoprotein in serum were found to have decreased in all patients one month after surgery with MTC. Contrast-enhanced computerized tomography (CT) showed the complete absence of blood flow in all tumors subjected to MTC. Needle biopsy one month after MTC confirmed tumor necrosis in all cases. All patients are alive at the time of this report, with the longest survival period being 24 months. In three of eight patients, new tumors were confirmed by angiographic CT at sites separate from the treated tumors. MTC resulted in fewer adverse effects on liver function and less extensive inflammatory reactions than liver resection., Conclusion: Intraoperative MTC appears to be an effective method for inducing local tumor necrosis, and may be of use in combination with palliative surgery for multiple HCC when radical liver resection is not feasible.

Background: Continuous hyperthermic peritoneal perfusion (CHPP) with a solution that contained 10 micrograms/ml mitomycin C was devised initially as a method for intraperitoneal thermochemotherapy. The authors conducted a randomized clinical trial to evaluate the efficacy of CHPP as a prophylactic treatment for prevention of peritoneal recurrence of gastric cancer with serosal invasion., Methods: Between January 1983 and October 1986, 82 patients with gross serosal invasion but no gross peritoneal metastasis were divided by random sampling into two groups before undergoing potentially curative surgery for gastric cancer: 42 patients were scheduled to receive CHPP, whereas 40 were not scheduled to receive this treatment. CHPP was administered immediately after closing the abdomen after gastric resections while the patients were still on the operating table under general anesthesia., Results: The 5-year survival rate (64.2%) of patients in the CHPP group was higher than that (52.5%) of patients in the control group although the difference was not significant. Of several patterns of cancer recurrence, peritoneal recurrence was more frequent in the control group than in the CHPP group. The mortality rate from peritoneal recurrence in the case of patients in the CHPP group was much lower than that of patients in the control group (P = 0.0854). CHPP did not induce anastomotic breakdown or chemical peritonitis after surgery., Conclusions: The results indicate that CHPP is effective in preventing peritoneal recurrence of gastric cancer with serosal invasion, which is highly likely to reappear in the peritoneum.

Background: This study evaluated the prognosis of patients with carcinoma in the gastric remnant stump after distal gastrectomy for benign disease (stump cancer)., Methods: Twenty patients with resected stump cancer were studied and compared with 266 patients with resected primary cancer in the upper third of the stomach (primary cancer)., Results: The percentages of lymph nodes with metastases located at the lesser curvature and the left gastric artery, respectively, were 50.0% and 25.2% in patients with primary cancer and 15.0% and 5.0% in patients with stump cancer. In patients with remnant gastric cancer, lymph node metastases at jejunal mesentery near anastomotic site were found in 2 of 20 (10.0%). The 5-year survival rates were 62.1% and 52.5% for patients with curatively resected primary cancer (n = 203) and stump cancer (n = 17), respectively, and there was no statistical difference between the two groups. There was a distinct difference in terms of patterns of recurrence between patients with curatively resected primary cancer and those with stump cancer. The percentages of peritoneal and hematogenic metastases, respectively, were 40.6% and 31.3% in primary cancer and 0% and 83.3% in stump cancers., Conclusion: The lymph flow from the remnant stomach seems to be changed by the initial operation, and as a result, in stump cancer, metastatic lymph nodes are located at different places from those associated with primary cancer. Even when curative surgery is performed in patients with stump cancer, it is important to follow up patients and check for possible metastasis to the liver.

The effects of intercepting a part of the enterohepatic circulation of bile acids by ileal resection or bypass on the quantitative and qualitative changes of fecal bile acids were investigated in rats, and the relationship of these changes to the development of DMH-induced colon cancer was studied. The daily fecal total bile acid level was increased in all intercepted groups, especially those with long resection and exclusion. Total bile acid levels played a greater role in the development of DMH-induced colon cancer than did primary or secondary bile acid levels individually. Our findings suggest that bile acid acts as a promoter in the development of colon cancer.

We examined the relationship between the spatial extent of invasion of the gastric serosa in patients with gastric carcinoma and their postoperative 5-year survival rate. At the time of surgical resection of gastric cancer, intraperitoneal free cancer cells were detected by lavage of the Douglas cavity in 135 of 309 (44%) patients with gross evidence of serosal invasion. Examination of the relationship between the presence of intraperitoneal free cancer cells and serosal area invaded by the tumor revealed that only 22% of cases with an area of serosal invasion 10 cm2 or less were positive for free cancer cells, but such cells were found in 72% of cases with an area of serosal invasion greater than 20 cm2. The 5-year survival rate was 31% in patients with an area of serosal invasion of less than 10 cm2, whereas the rate was only 8% in patients with an area of serosal invasion greater than 20 cm2. Not only the presence of serosal invasion by a tumor but also the spatial extent of the invasion are significant factors that influence the prognosis of patients with gastric carcinoma.

Mucosal dysplasia and carcinoma infiltrating the submucosal layer were induced in rats with dimethylhydrazine. The nuclear DNA content of the cells was measured, and the correlation between the DNA distribution pattern and histopathologic findings was evaluated. In mild and moderate dysplasias, histograms of the nuclear DNA content showed a narrow range of distribution with a sharp peak in the diploid area. In severe dysplasia, however, there was wide distribution and no peak value; this was reminiscent of carcinoma. Based on the findings of this report, the authors suggest that severe dysplasia be regarded as intramucosal carcinoma.

The authors reviewed the medical records of 1005 patients with multiple colorectal cancers (763 synchronous and 242 metachronous) to study the number and site of the tumors, their preoperative detectability, and the results of treatment. Concurrent advanced cancers were found in 35.1%, concurrent advanced and early cancers in 59.0%, and concurrent early cancers in 5.9% of patients with synchronous malignancy. In 60.1% of these patients, the existence of multiple lesions was diagnosed preoperatively; coexisting early cancers were often overlooked. In patients with metachronous malignancy, early cancers were less frequent than in patients with synchronous malignancy. The cumulative 5-year survival rate in curatively operated patients was 70.4% for synchronous malignancy and 66.5% for metachronous malignancy, similar to that for colon cancer in general.