The Japanese integrated staging score using liver damage grade for hepatocellular carcinoma in patients after hepatectomy.

AIMS: The new Japanese staging system for hepatocellular carcinoma (HCC), the Japan integrated staging (JIS) score, accounts for both Child-Pugh classification and Japan tumour node metastasis (TNM) staging. However, in HCC patients who undergo hepatectomy, liver function is relatively good and a better prognostic classification of hepatic function is necessary. METHODS: The present study was designed to analyse the modified JIS score using liver damage grade by the Liver Cancer Study Group of Japan instead of the Child-Pugh classification (using the category indocyanine green retention rate at 15 min [ICG(R15)] instead of encephalopathy), and to compare the Japan TNM stage in 101 patients who underwent resection of HCC. RESULTS: The liver damage grade showed significantly better discrimination of disease-free and overall survival than did the Child-Pugh classification. The modified JIS score system showed significant differences of disease-free and overall survivals in each score and this system was superior for discriminating survivals compared with the TNM staging. CONCLUSIONS: The combined staging system of hepatic function, particularly ICG(R15), and tumour stage provides a better prediction of prognosis. The JIS score using the liver damage grade was a useful predictor of prognosis of HCC patients who underwent hepatic resection.

Long-term outcomes of radical surgery after gasless video endoscopic transanal excision of T1/T2 rectal cancers.

AIMS: We aim to clarify the long-term outcomes after an additional radical operation following gasless video endoscopic transanal rectal tumour excision (gasless VTEM) of 'high-risk' T1 and T2 rectal cancer. METHODS: Gasless VTEM involves modification of transanal endoscopic microsurgery (TEM) by incorporating a standard laparoscopic video camera without a CO(2) insufflation system. This study between 1993 and 2003 included six men and five women with a median age of 64 years (range, 36-79). Specimens resected by gasless VTEM revealed (1) high-risk T1 carcinomas with one of the following histological types: poorly differentiated, lymphovascular invasion, and massive invasion of the submucosa (submucosal invasion greater than 200-300 microm from the muscularis mucosa) and (2) T2 carcinomas. RESULTS: Eight patients had a high-risk T1 carcinoma and three patients had a T2 carcinoma. In two patients with a high-risk T1 carcinoma, a residual tumour was found in the specimen resected by the additional radical surgery. At a median follow-up of 86.5 months (range, 63.2-110.5), none of the patients developed tumour recurrence. Although one patient died with cancer at another organ site (hilar cholangiocarcinoma of the liver) 87 months after the additional radical surgery, the other 10 patients are alive and disease free. CONCLUSIONS: This study revealed favorable long-term outcomes after additional radical surgery following gasless VTEM in patients with high-risk T1 and T2 carcinomas.

Platelet-derived endothelial cell growth factor expression is an independent prognostic factor in colorectal cancer patients after curative surgery.

AIMS: Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic factor that undergoes increased expression in colorectal carcinomas, but its prognostic value is a topic of debate. The aim of this study is to clarify the prognostic value of PD-ECGF expression in colorectal carcinomas. METHODS: PD-ECGF expression was measured by enzyme-linked immunosorbent assay in frozen materials from 134 colorectal cancer patients who had received curative resections. Patients were divided into high expression and low expression groups based upon selected cut-off value. Correlations among PD-ECGF expression, clinicopathologic features, and disease-free interval were studied by univariate and multivariate analysis. To evaluate the origin of PD-ECGF, serial sections of the 134 tumours were stained for PD-ECGF and CD68. RESULTS: PD-ECGF expression in the normal mucosa was 34.4+/-15.5 (Units/mg protein) and the cut-off value was 65.4 (mean+2SD). There were no significant correlations between clinicopathological features and PD-ECGF expression. The disease-free interval for the high PD-ECGF expression group was significantly longer than that of the low expression group (P=0.05). A multivariate Cox's regression analysis revealed that high PD-ECGF expression is an independent factor for better outcome. In immunohistochemical study, almost all tumour cells were negative for PD-ECGF, but stromal macrophages were predominantly positive for PD-ECGF. CONCLUSIONS: The PD-ECGF expression originated from stromal macrophages was a predictor for favorable outcome after curative resections for colorectal cancer.

Minilaparotomy may be independently associated with reduction in inflammatory responses after resection for colorectal cancer.

OBJECTIVES: A minilaparotomy approach (skin incision less than 7 cm) to resection of colon cancer is technically feasible, but objective data supporting its benefit are scarce. The aim of this study was to clarify whether minilaparotomy is independently associated with a reduction in the acute inflammatory response after resection of colorectal cancer. DESIGN: Thirty-one patients who underwent surgical resection of colorectal cancer using minilaparotomy or conventional laparotomy were included in this nonrandomized prospective study. Inflammatory responses were evaluated with serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels. RESULTS: In both the minilaparotomy and conventional laparotomy groups, serum IL-6 and CRP levels significantly increased 24 h after the operation (1POD) compared to preoperative levels (p < 0.0001 and p < 0.0001, respectively). Median serum levels of IL-6 and CRP in the minilaparotomy group were significantly lower at 1POD versus the conventional group (p = 0.0066 and p = 0.0033, respectively). Multivariate analyses showed that a smaller increase in serum IL-6 or CRP levels at 1POD [less than 75th percentile (112.9 or 10.6 mg/ml, respectively)] was independently related to only minilaparotomy. CONCLUSIONS: These data in this nonrandomized trial suggest that minilaparotomy may be independently associated with reduced inflammatory responses in colorectal cancer resection.

Modified CLIP using PIVKA-II for evaluating prognosis after hepatectomy for hepatocellular carcinoma.

AIMS: The new staging system proposed by the Cancer of the Liver Italian Program (CLIP) for hepatocellular carcinoma (HCC) accounts for both liver dysfunction and tumour characteristics. The present study was designed to analyze UICC TNM stage, CLIP and modified CLIP in 91 patients who underwent hepatic resection for HCC. METHODS: In the modified CLIP, scoring of AFP was replaced by that of protein induced by vitamin K absence or antagonist II (PIVKA-II; predictive value, > or = 400 mAU/ml). RESULTS: After hepatic resection, 54 patients developed recurrent tumours. High PIVKA-II was a significant determinant of recurrence (p<0.05). However, a high score of the modified CLIP as well as those other staging systems did not correlate with tumour-recurrence rate. Univariate analysis showed that high TNM score, CLIP score and our modified CLIP score were significant predictors of poor prognosis. Multivariate Cox's analysis revealed that high PIVKA-II and high modified CLIP score were associated with higher risk for disease-free and overall survival as well as high TNM stage. CONCLUSIONS: Compared with the original CLIP, our modified CLIP was a better predictor of prognosis of HCC patients who underwent hepatic resection.

Gasless, video endoscopic transanal excision for carcinoid and laterally spreading tumors of the rectum.

BACKGROUND: The aim of this study is to determine whether gasless, video endoscopic transanal-rectal tumor excision (gasless VTEM) is a valid treatment for rectal carcinoid and laterally spreading tumors (LST). METHODS: Eighty-four patients with an adenoma, adenocarcinoma (Tis/T1), or carcinoid tumor of the rectum were divided into three groups: (i) LST ( n = 17 patients), (ii) carcinoid ( n = 11), and (iii) control with other types of tumors ( n = 56). RESULTS: The LST group had a longer median operating time than in the control group, whereas the carcinoid group had a shorter operating time. Two patients (11.7%) in LST group developed peritoneal entry during the operation, while 2 patients (3.6%) in the control group experienced postoperative complications. During a median follow-up length of 55.2 months, one patient in the LST group developed a recurrence. CONCLUSIONS: Gasless VTEM is a simple, minimally invasive procedure used to treat LST and carcinoid tumors of the rectum. However, resection for the LST group had a high risk of peritoneal entry during operation.

Chromosomal imbalances associated with acquired resistance to fluoropyrimidines in human colorectal cancer cells.

The chromosomal aberrations underlying the development of resistance to fluoropyrimidines have not yet been identified. To characterise the genomic changes that induce the development of resistance to fluoropyrimidines, we used comparative genomic hybridisation (CGH) to analyse and compare the parent DLD-1 human colorectal cancer cell line and two cell lines, DLD-1/5-FU and DLD-1/FdUrd, which were resistant to 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd), respectively. Both resistant cell lines showed a genetic aberration derived from the parental cell line DLD-1. Losses of 3p and 3q were also detected as additional genetic changes in the two resistant cell lines. Both resistant cell lines showed decreased orotate phosphoribosyltransferase (OPRT) activity, which is associated with the activity of the uridine monophosphate (UMP) synthase gene (3q13). These results suggested that the loss of 3q might be a genetic change responsible for the decreased OPRT activity and fluoropyrimidine cytotoxic response in cancer cells. Amplification of 18p11.2-p11.3 containing the thymidine synthase (TS) gene (18p11.32) was observed only in the DLD-1/FdUrd-resistant cell line, which overexpresses TS. These findings suggested that 18p amplification represents a genetic change associated with the overexpression of the TS protein. Our results indicate that chromosomal aberrations identified by CGH could explain, at least in part, acquired fluoropyrimidine resistance.

Long-term outcomes of intragastric endoscopic mucosal resection using a modified buess technique for early gastric cancer.

BACKGROUND/AIMS: The aim of this study was to clarify long-term outcomes of endoscopic mucosal resection (EMR) using a modified Buess technique for mucosal gastric cancer. METHODS: The procedure included en bloc mucosal resection using a Buess-type rectoscope into the gastric lumen via a temporary gastrostomy under video camera guidance. We reviewed 5 patients who underwent this procedure between 1995 and 1997 with a single mucosal cancer of the stomach that was unsuitable for en bloc excision by endoscopic snare diathermy. RESULTS: All tumors were superficial elevated types (type 0-IIa) located in the middle third and posterior wall of the stomach. Median maximum tumor diameter was 2.2 (range 1.1-3.5) cm. There was no operative mortality. One patient developed a hemorrhagic gastric ulcer postoperatively. All tumors histologically showed curative potential of the mucosal resection without margin involvement. During a median follow-up period of 64 (50-77) months, none of the patients developed local recurrence. One patient had an early gastric cancer that metachronously developed at another stomach site. CONCLUSION: Intragastric EMR using a modified Buess technique appears to be a useful treatment for cure of mucosal gastric cancer for a limited group of patients unsuitable for complete en bloc excision by endoscopic snare diathermy.

Increased expression of sialyl Lewis(x) antigen in penetrating growth type A early gastric cancer.

Early gastric cancer can be divided morphologically into two categories, penetrating growth type-A (Pen-A type) and other growth types (non-Pen-A types). Sialyl Lewis(x) antigen has been demonstrated to play an important role in tumor metastasis by serving as a functional ligand in the cell adhesion system. The aim of this study is to ascertain whether or not sialyl Le(x) antigen expression correlates with tumor growth patterns of early gastric carcinoma. An immunohistochemical assay was performed using monoclonal antibody CSLEX1 in 12 Pen-A type and 79 non-Pen-A type cancers. Scoring was based on the percentage of immunoreactive cells: negative, low expression (< or = 25%), and high expression (> 25%). Lymph node metastasis was found more frequently in Pen-A type than non-Pen-A type cancers (P=0.0004). Furthermore, sialyl Le(x) antigen high expression was detected more often in Pen-A type cancers (7 out of 12; 58.3%) than non-Pen-A type cancers (13 out of 79; 16.5%) (P=0.0036). Multivariate logistic regression analysis showed that these variables are related independently to the Pen-A type and the non-Pen-A type tumor growth patterns. These data suggest that the difference in sialyl Le(x) antigen expression between the Pen-A type and non-Pen-A type tumor growth patterns of early gastric cancer may, at least partially, reflect different biological behavior during tumor progression.

Evaluation of sialyl Lewis(a), sialyl Lewis(x), and sialyl Tn antigens expression levels as predictors of recurrence after curative surgery in node-negative colorectal cancer patients.

This study aimed to determine whether sialyl Lewis(a) (Le(a)), sialyl Lewis(x )(Le(x)), or sialyl Tn antigen expression could identify a subset of node-negative colorectal cancer patients that are at high risk for recurrence after curative surgery. Tumor tissue samples from 90 patients with node-negative colorectal cancer, who had undergone surgical resection, were analyzed immunohistochemically for the expression of each antigen. Patients were classified as having low or high antigen expression depending on whether more or less than 40% of the field showed positive staining. The main outcome measure for each variable was disease-free interval. Sialyl Le(a), sialyl Le(x), and sialyl Tn antigens were expressed in 53 (58.9%), 41 (45.6%), and 34 (37.8%) carcinomas, respectively. The median follow-up was 83.5 months. Patients with high sialyl Le(x) expression had shorter disease-free intervals than those with low sialyl Le(x) expression (P = 0.0041); the expression of sialyl Le(a) or sialyl Tn antigens did not show a significant relationship with disease-free survival. Cox's regression analysis revealed that sialyl Le(x) expression was an independent predictor for disease-free survival, separate from T factor or tumor location. High sialyl Le(x) expression may be useful in identifying a subset of node-negative colorectal cancer patients who are at high risk for recurrence.

Surgical technique and outcome of gasless video endoscopic transanal rectal tumour excision.

BACKGROUND: Transanal endoscopic microsurgery (TEM) is unpopular because of its high cost and most surgeons' unfamiliarity with microscopic surgery. This report describes an experience with a modification of TEM, gasless video endoscopic transanal rectal tumour excision (gasless VTEM), which incorporates a standard laparoscopic video camera and requires no carbon dioxide insufflation system. METHODS: One hundred and one patients with 105 rectal tumours underwent gasless VTEM between 1993 and 2000. RESULTS: Histological examination revealed 18 adenomas, 75 carcinomas (Tis, 47; T1, 23; T2, five), 11 carcinoid tumours and one lymphoma. The median height above the dentate line and maximum tumour diameter was 5.0 (range 2-14) cm and 2.0 (range 0.4-8.0) cm respectively. The peritoneal cavity was opened intraoperatively in two patients. The median operating time was 53 (range 15-202) min. Bleeding, suture dehiscence and transient incontinence developed after operation in four patients. There was no operative death. Median hospital stay was 5 (range 1-21) days. Eleven patients with T1/T2 staging underwent subsequent radical resection. The median duration of follow-up was 52.3 months. One patient with a carcinoma developed a recurrence. CONCLUSION: Gasless VTEM is a feasible, safe and minimally invasive procedure for the treatment of selected rectal adenomas and early carcinomas. The suggested modifications may make the procedure more widely available.

Expression of ABH/Lewis-related antigens as prognostic factors in patients with breast cancer.

PURPOSE: The prognostic value of altered blood group factor and Lewis-related carbohydrate antigen expression in breast cancers has not been fully determined. METHODS: To this end, breast carcinoma samples from 87 radical mastectomy patients with primary cancer were analyzed by immunohistochemistry for the ABH factors, Le(a), sialyl Le(a), Le(x), and sialyl Le(x). RESULTS: It was found that ABH, Le(a), sialyl Le(a), Le(x), and sialyl Le(x) antigens were expressed in 25 (21.8%), 26 (22.6%), 26 (22.6%), 36 (31.3%), and 37 specimens (32.2%), respectively. Tumors with lymph node metastasis expressed Le(x) or sialyl Le(x) antigens more frequently than those without lymph node metastasis ( P=0.0020 or P=0.039, respectively). The survival time of patient s after surgery was significantly shorter for those whose tumors expressed Le(x) or sialyl Le(x) than for those without Le(x)- or sialyl Le(x)-positive tumors ( P=0.0028 and P=0.0029, respectively). Cox's multiple regression analysis revealed that sialyl Le(x) expression was an independent prognostic factor for patient survival regardless of primary tumor (T factor) and lymph node (N factor) status (hazards ratio, 3.80). CONCLUSIONS: Thus, expression of sialyl Le(x) antigen in tumor cells is associated with poor prognosis in patients with breast cancer and must be considered in the design of future therapeutic trials.

Pre-operative serum levels of sialyl Tn antigen predict liver metastasis and poor prognosis in patients with gastric cancer.

AIMS: To clarify the prognostic value of preoperative serum levels of sialyl Tn antigen (STN) for survival of gastric cancer patients. METHODS: Pre-operative serum levels of STN, sialyl Lewis(a)antigen (CA19-9) and carcinoembryonic antigen (CEA) were examined in 180 patients who underwent resection of gastric cancer. Patients were divided into high and low antigen groups on the basis of a selected diagnostic-based cut-off value. Correlation between high antigen serum levels, established clinicopathologic factors and prognosis was examined by univariate and multivariate analysis. RESULTS: Twenty-eight patients (15.6%) were classified as high STN; 37 (20.6%) as high CA19-9; and 33 (18.3%) as high CEA. The survival time of the high STN, CA19-9 or CEA group was shorter than that of the respective low-antigen group (P<0.0001, P=0.0008 or P=0.0002, respectively). Patients with stage III/IV tumours with high STN had a shorter survival time that those with low STN (P=0.0004). Cox's regression with multiple covariates showed that high serum STN is an independent factor predicting a worse outcome in gastric cancer patients. Multiple logistic regression analysis revealed that high serum STN is an independent predictor for the development of liver metastasis. CONCLUSIONS: Pre-operative high serum levels of STN predict both liver metastasis and poor prognosis after resection for gastric cancer.

Measurement of serum hyaluronic acid level during the perioperative period of liver resection for evaluation of functional liver reserve.

BACKGROUND AND AIM: The serum hyaluronic acid (HA) concentrations reflect the degree of hepatic fibrosis and sinusoidal endothelial cell damage. The HA concentrations were examined to evaluate liver damage during the perioperative period of hepatectomy. METHODS: The HA level of serum samples from 79 patients who underwent a hepatectomy was measured, and the results were compared to conventional liver function tests, the degree of fibrosis, liver regeneration and complications. RESULTS: Hyaluronic acid concentrations correlated with the severe fibrosis or histological activity index, and also correlated with liver function tests including transaminase level, platelet counts, prothrombin time activity, indocyanine green retention rate at 15 min (ICG R15), liver activity at 15 min by technetium-99m galactosyl human serum albumin scintigraphy (LHL 15), and portal pressure. The HA level postoperatively correlated with liver function, especially with total bilirubin. Hyaluronic acid levels at day 28 postoperatively correlated with ICG R15 and LHL 15. The hyaluronic acid level before surgery and at day 28 postoperatively correlated with the regeneration of remnant liver in major hepatectomy. The HA levels were significantly higher in patients with hepatic failure or prolonged ascites. CONCLUSION: Our results indicate that the measurement of the HA level is useful for monitoring liver damage or predicting complications associated with liver surgery.

Instability of chromosome 17 and the p53 locus in non-familial colorectal cancer with multiple primary malignancies.

Recently, two different mechanisms of genetic instability have been demonstrated in the carcinogenesis of colorectal cancer. Microsatellite instability is an important genetic event for carcinogenesis in hereditary non-polyposis colorectal cancer, proximal colon cancer, and multiple colorectal carcinoma. To examine the association among chromosomal instability and multiple primary malignancies (MPM) in colorectal cancer, fluorescence in situ hybridization using a chromosome 17-specific probe, p53 cosmid probe, and/or an alpha satellite DNA probe was performed in 184 patients with colorectal cancer. The proportion of aneusomy 17 in MPM was significantly higher than that of single cancers (SC) (46.1+/-8.0% and 39.0+/-10.3%, respectively; p<0.01). Multiple numerical aberrations of chromosome 17 in MPM occurred more often than those of SC (64.3% and 22.9%, respectively; p<0.01). The mean frequency of p53 deletion was also higher in MPM (70.4+/-16.7%) compared with SC (53.4+/-18.1%, p<0.05). The frequency of chromosome 17 translocation was significantly greater in tumors with MPM (4/6; 67%) than in SC (3/23; 13%, p<0.05). The frequency of p53 locus translocation was also significantly greater in tumors with MPM (4/6; 67%) than in SC (0/23; 0%, p<0.01). These results suggested that numerical and structural aberrations of chromosome 17 and the p53 locus are important genetic events associated with carcinogenesis in non-familial colorectal cancer with MPM.

Minilaparotomy wound edge protector (Lap-Protector): a new device.

Laparoscopic-assisted or minimally invasive surgery involving minilaparotomy is occasionally complicated by infection of the minilaparotomy wound caused by intestinal bacteria. Furthermore, when this procedure is performed to excise colorectal or gastric cancer, tumor recurrence may develop in the minilaparotomy wound. In an attempt to minimize the risk of these complications, we developed a new, easy-to-use device which we named the "Lap-Protector." Minilaparotomy was performed using the Lap-Protector in 28 patients with colon cancer and eight patients with early gastric cancer who underwent minimally invasive surgery between January and September, 1999. During a median follow-up period of 15.9 (range 12.4-21.0) months, none of the 36 patients showed any sign of wound infection or tumor recurrence in the minilaparotomy wound. These results indicated that the Lap-Protector is a safe and useful device that may help to prevent infections and cancer cell contamination of the minilaparotomy wound.

Prognostic value of carcinoembryonic antigen (CEA) in tumor tissue of patients with colorectal cancer.

To establish the prognostic value of carcinoembryonic antigen (CEA) concentration in tumor tissue (T-CEA), normal colonic mucosa (N-CEA) and pre-operative serum (S-CEA), we studied 79 patients who underwent resections for colorectal cancer. The patients were separated into groups reflecting laboratory values lower or higher than a diagnostic value (S-CEA) or the median value of the entire population (T-CEA, N-CEA). A high S-CEA predicted for more advanced stage (p = 0.028), whereas no association was noted between stage and CEA concentration for T-CEA and N-CEA groups. The high S-CEA and T-CEA groups had a worse clinical outcome (p=0.0036 and p=0.024, respectively), while survival of high versus low N-CEA groups did not differ. By Cox's regression analysis, high T-CEA concentration was an independent variable for poor outcome (Hazard ratio, 3.15), while S-CEA and N-CEA were not. In conclusion, a high T-CEA concentration was the only independent predictor of poor outcome after resection for colorectal cancer.

Prognostic factors in hepatic metastases of colorectal carcinoma: immunohistochemical analysis of tumor biological factors.

The present study was designed to provide a systemic analysis of prognosis in 62 patients who underwent hepatic resection for colorectal liver metastasis. The analyzed factors included microvessel counts stained by CD34 and expression of two adhesion molecules, E-cadherin and CD44 variant exon 6-(v6) in these tumors. No significant factors related to recurrence were identified and only negative expression of CD44v6 tended to correlate with recurrence (P = 0.075). A short disease-free period to recurrence was noted in patients with high CEA levels (>10 ng/ml) and H2/3 classification. A short surgical margin, H2/3 classification, high microvessel counts (>60/field, x200), and negative expression of CD44v6 and E-cadherin tended to be associated with poor prognosis. A high microvessel count was the most significant prognostic factor by multivariate Cox proportional hazards regression model. Hepatic resection without tumor exposure and a careful follow-up in cases identified with poor prognostic factors are necessary.

Evaluation of metastatic potential of gastric tumors by staining for proliferating cell nuclear antigen and chromosome 17 numerical aberrations.

BACKGROUND: Aberrations in chromosome 17 are important in carcinogenesis. We recently reported that numerical aberrations in chromosome 17 were associated with tumor progression in gastric cancer. The aim of this study was to determine the biological characteristics of gastric tumor cells with chromosome 17 numerical aberrations. METHODS: Gastric tumor sections (n = 105) and metastatic lymph nodes (n = 16) were stained simultaneously for PCNA (proliferating cell nuclear antigen) and chromosome 17 centromere. Cancers were classified as follows: Group 1: PCNA(+) and numerical chromosomal aberration(+); Group 2: PCNA(-) and numerical chromosomal aberration(+); Group 3: PCNA(+) and numerical chromosomal aberration(-); and Group 4: PCNA(-) and numerical chromosomal aberration(-). RESULTS: The frequency of Group 1 cells correlated with lymphatic invasion (P < .0001), lymph node metastasis (P < .0001), and venous invasion (P < .01). The frequency of these cells in gastric lesions was lower than in metastatic lymph nodes (P < .01). Logistic regression analysis identified the depth of invasion followed by the frequency of Group 1 cells were two of the most significant independent factors that could predict lymph node metastasis and lymphatic invasion. CONCLUSIONS: The frequency of gastric tumor cells positive for PCNA and chromosome 17 numerical aberrations may be an indicator of the metastatic potential of gastric cancers.