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1.  Chemoprevention of DMBA-induced mammary carcinogenesis in rats by low-dose EPA and DHA. 
British Journal of Cancer  1997;75(3):348-353.
We investigated the effects of low-dose eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the incidence and growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in rats fed a high-fat (HF) diet. We also examined the effects of these treatments on the fatty acid composition of tumour and serum. Tumour incidence was significantly decreased by the administration of low-dose EPA and DHA, whereas their inhibitory effects on tumour growth did not reach significance. Serum arachidonic acid (AA) level was decreased by the administration of low-dose EPA and tended to be decreased by the administration of low-dose DHA, whereas tumour AA levels were not changed. The administration of low-dose EPA and DHA may be useful for inhibiting the incidence of breast cancer.
PMCID: PMC2063366  PMID: 9020478
2.  Expression of 16 kDa proteolipid of vacuolar-type H(+)-ATPase in human pancreatic cancer. 
British Journal of Cancer  1996;73(12):1511-1517.
Recent studies have shown that bafilomycin A1-sensitive vacuolar-type H(+)-ATPase (V-ATPase) plays important roles in cell growth and differentiation. However, there is no published study that has focused on the expression of V-ATPase in human tumour tissues. This study was designed to examine the mRNA and protein levels for the 16 kilodalton (kDa) proteolipid of V-ATPase in human pancreatic carcinoma tissues. We first investigated the mRNA level for V-ATPase in six cases of invasive pancreatic cancers and two normal pancreases, using reverse transcription-polymerase chain reaction technique. Then, we examined immunohistochemically the level of V-ATPase protein in 49 pancreatic cancers and ten benign cystic neoplasms of the pancreas, using antisera raised against the 16 kDa proteolipid. There was a notable difference in the level of V-ATPase mRNA between normal and pancreatic carcinoma tissues, with no evident difference in the expression of the beta-actin gene. Immunohistochemically, 42 out of 46 invasive ductal cancers (92%) displayed a mild to marked immunoreactivity for V-ATPase in the cytoplasm, whereas neither non-invasive ductal cancers nor benign cystic neoplasms expressed detectable immunoreactive proteins. These findings suggest that the overexpression of V-ATPase protein is characteristic of invasive pancreatic tumours. V-ATPase may play some crucial roles in tumour progression.
PMCID: PMC2074554  PMID: 8664121
3.  Poor prognostic value of proliferating cell nuclear antigen labelling index in breast carcinoma. 
Journal of Clinical Pathology  1993;46(6):525-528.
AIM--To investigate the association between proliferating cell nuclear antigen immunostaining and various clinicopathological variables, and its prognostic value in breast carcinoma. METHODS--A monoclonal antibody PC10 was applied to formalin fixed, paraffin wax embedded tissue in 144 cases of primary breast cancer. PCNA immunostaining was scored by counting 1000 cells; the percentage of positive stained cells was recorded as the PCNA labelling index (PCNA-LI). RESULTS--The PCNA-LI varied from 0-77% with a mean of 18%. When tumours were separated on the basis of the mean value, 93 had a low PCNA-LI of less or equal than 18% and 47 a high PCNA-LI of more than 18%. There was no significant correlation between PCNA-LI and all prognostic factors included in this study. Moreover, PCNA-LI failed to show any prognostic value for overall and disease free survival. CONCLUSION--PCNA immunostaining is not correlated with clinicopathological variables and patient survival in breast cancer.
PMCID: PMC501287  PMID: 8101192
4.  Immunosuppressant FK506 induces interleukin-6 production through the activation of transcription factor nuclear factor (NF)-kappa(B). Implications for FK506 nephropathy. 
Journal of Clinical Investigation  1996;97(11):2433-2439.
FK506 is a powerful immunosuppressive drug currently in use that inhibits the activation of several transcription factors (nuclear factor (NF)-AT and NF-kappaB) critical for T cell activation. We show here that, contrary to the situation in T cells, FK506 activates transcription factor NF-kappaB in nonlymphoid cells such as fibroblasts and renal mesangial cells. We further show that FK506 induces NF-kappaB-regulated IL-6 production in vitro and in vivo, in particular in kidney. IL-6 has been shown previously to produce renal abnormalities in vivo, such as mesangioproliferative glomerulonephritis. Similar renal abnormalities were also observed in FK506-treated animals. These results thus suggest a causal relationship between FK506-induced NF-kappaB activation/IL-6 production and some of FK506-induced renal abnormalities.
PMCID: PMC507328  PMID: 8647935
5.  Rationale for extensive lymphadenectomy in early gastric carcinoma. 
British Journal of Cancer  1995;72(6):1518-1524.
The incidence of nodal metastasis in early gastric carcinoma (EGC) is 10-20%. However, the optimal nodal dissection for early gastric carcinoma has not been established. A retrospective study was conducted in 392 consecutive patients who underwent potentially curative distal gastrectomy for EGC between 1962 and 1990. Of these 295 patients treated after September 1972 were prospectively entered into an extensive lymphadenectomy protocol. These patients were compared with 97 patients with simple gastrectomy in respect of the causes of death after surgery and the 10 year disease-specific survival rate. The incidence of nodal metastasis in early gastric carcinoma patients was 13.0%. Operative mortality from extensive lymphadenectomy was almost the same as from simple gastrectomy (2.0% and 2.1% respectively). Extensive lymphadenectomy provided a significantly higher 10 year survival rate than limited lymph node dissection (97.9% vs 88.1% respectively; P < 0.005). Among patients with nodal metastasis, the survival rate following extensive lymphadenectomy was significantly higher than that after simple gastrectomy (87.5% vs 55.6%; P = 0.018). Among patients without nodal metastasis, there was no difference between the two groups in the survival rate (99.4% and 96.7% respectively; P = 0.12). Multivariate analysis using the Cox proportional hazards model disclosed two significant independent prognostic factors on disease-specific survival, the nodal involvement (risk ratio: 8.4; P < 0.0001) and the extent of lymph node dissection (risk ratio: 5.8; P < 0.005). Extensive nodel dissection appears to prevent recurrence and to improve the cancer-specific survival in EGC patients with nodal metastasis.
PMCID: PMC2034094  PMID: 8519670
6.  Expression of basic fibroblast growth factor and its receptor in human pancreatic carcinomas. 
British Journal of Cancer  1995;72(4):824-831.
We examined the expression of basic fibroblast growth factor (FGF) and FGF receptor by immunohistochemistry in 32 human pancreatic ductal adenocarcinomas. Mild to marked basic FGF immunoreactivity was noted in 19 (59.4%) of the 32 tumours examined, and 30 (93.3%) of the tumours exhibited a cytoplasmic staining pattern against FGF receptor. The tumours were divided into two groups according to the proportion of positively stained tumour cells: a low expression group (positive cells < 25%) and a high expression group (positive cells > or = 25%). No statistically significant difference in tumour size, differentiation, metastases or stage was found between the low and high basic FGF expression groups. However, a significant correlation was found between FGF receptor expression level and the presence of retroperitoneal invasion, lymph node metastasis, and tumour stage. In addition, low FGF receptor expression was significantly associated with a longer post-operative survival as compared with high FGF receptor expression, whereas there was no significant difference in post-operative survival between the low and high basic FGF expression groups. Increased expression of FGF receptor is correlated with the extent of malignancy and post-operative survival in human pancreatic ductal adenocarcinomas. Thus, overexpression of FGF receptor may prove to be a more useful prognostic marker than basic FGF expression level in pancreatic cancer patients.
PMCID: PMC2034026  PMID: 7547227
7.  Induction of oesophageal and forestomach carcinomas in rats by reflux of duodenal contents. 
British Journal of Cancer  1994;70(2):185-189.
A study was designed to determine whether oesophageal carcinomas can be induced through reflux of duodenal contents. Male Wistar rats weighing 230-250 g were divided into three groups according to the surgical procedure performed: (1) the duodenal contents were directed into the forestomach through a stoma (duodeno-forestomach reflux); (2) the duodenal contents were regurgitated into the forestomach through the glandular stomach (duodeno-glandular-forestomach reflux); and (3) a sham operation was performed as a control. Animals were fed standard CRF-1 solid food and tap water that was not exposed to carcinogens and were sacrificed 50 weeks post-operatively. While no neoplasia was observed in any of the 32 control rats, 4/11 (36%) with duodeno-forestomach reflux and 3/18 (17%) animals with duodeno-glandular-forestomach reflux developed carcinomas in the lower oesophagus and forestomach. The incidence in each group was significantly higher than in the controls (P < 0.01 and P < 0.05 respectively). Six of the seven lesions consisted of squamous cell carcinomas, and one was a mucinous adenocarcinoma. Oesophageal columnar epithelial metaplasia was observed in two (18%) of the animals with duodeno-forestomach reflux. Carcinomas were always surrounded by chronic inflammatory changes, including regenerative thickening, basal cell hyperplasia and dysplasia. Additional well-differentiated adenocarcinomas were observed in the prepyloric antrum of 6/18 (33%) animals with duodeno-glandular-forestomach reflux. These findings indicate that chronic reflux of duodenal contents may cause oesophageal carcinoma.
PMCID: PMC2033512  PMID: 8054264
8.  Pancreatic trypsinogen and cathepsin B in human pancreatic carcinomas and associated metastatic lesions. 
British Journal of Cancer  1994;69(1):152-156.
Expression of pancreatic trypsinogen and cathepsin B in 23 surgically resected pancreatic ductal adenocarcinomas was evaluated immunohistochemically, using a monoclonal antibody against human pancreatic trypsinogen and a polyclonal antibody against human cathepsin B. Fifteen of 20 invasive tubular adenocarcinomas (75%) expressed pancreatic trypsinogen in a coarse granular pattern located in the supranuclear cytoplasm of the carcinoma cells. In addition, metastatic lesions, including those in peripancreatic lymph nodes and neural plexuses, expressed pancreatic trypsinogen. In contrast, three intraductal (non-invasive) papillary adenocarcinomas did not express pancreatic trypsinogen. Cathepsin B expression was recognised in 14 of 20 invasive tubular adenocarcinomas (70%) in a fine granular pattern located diffusely in the cytoplasm of the carcinoma cells, while none of the three intraductal papillary adenocarcinomas had detectable cathepsin B. These findings suggest that pancreatic invasive ductal adenocarcinomas express pancreatic trypsinogen and cathepsin B immunoreactive peptides, raising the possibility that pancreatic trypsinogen and cathepsin B may act independently of each other in the process of carcinoma invasion and metastasis, like other different classes of proteases involved in the proteolytic modification of the matrix barrier.
PMCID: PMC1968761  PMID: 8286198
9.  Inverse association of nm23-H1 expression by colorectal cancer with liver metastasis. 
British Journal of Cancer  1993;68(5):1020-1024.
The expression of nm23-H1 mRNA and protein was studied in colorectal cancers by Northern blotting and immunohistochemistry. All 21 colorectal cancers studied by Northern blotting had increased levels of nm23-H1 mRNA relative to the adjacent normal colonic mucosa. Increased nm23-H1 protein expression was also observed in all 36 colorectal cancer cases including those studied by Northern blotting. There was no significant correlation between nm23-H1 expression and tumour histology, serosal invasion, lymphatic invasion, venous invasion, or lymph node metastasis. However, the expression of both mRNA and protein was significantly lower in tumours associated with liver metastasis than in those without such metastasis. These observations indicate that the nm23 gene may play a role in the suppression of liver metastasis of colorectal cancer.
PMCID: PMC1968746  PMID: 8217591
10.  Prognostic significance of Helix pomatia lectin and c-erbB-2 oncoprotein in human breast cancer. 
British Journal of Cancer  1993;68(3):621-626.
We investigated the prognostic significance of Helix pomatia lectin (HPA) staining on disease-free and overall survival in 120 primary breast carcinomas. HPA staining was present in 58 (48%) of these carcinomas. It was significantly associated with axillary lymph node metastases (P < 0.001) and c-erbB-2 expression (P < 0.01). A univariate study revealed that disease-free and overall survival were significantly correlated with clinical stage, tumour size, axillary lymph node metastases. HPA staining and c-erbB-2 expression. In a multivariate study, all previous prognostic indicators except HPA staining and c-erbB-2 expression were independent factors. However, stratifying the patients on the basis of HPA and c-erbB-2 status suggested that HPA +/c-erbB-2+ status was predictive of a higher incidence of axillary lymph node metastases (P = 0.000001) and a poorer overall (P < 0.0002) and a shorter disease-free (P < 0.000006) survival when compared with the other subgroups, although this combination did not provide any additional prognostic information for overall (P = 0.3544) or disease-free (P = 0.7152) survival by a multivariate analysis. For patients in whom axillary lymph node dissection has not been performed, therefore, HPA and c-erbB-2 status seems to be a powerful tool to discriminate subpopulations with a high recurrence risk and shorter survival who should undergo more aggressive therapy.
PMCID: PMC1968392  PMID: 8102537
11.  p53 immunoreaction in endoscopic biopsy specimens of colorectal cancer, and its prognostic significance. 
British Journal of Cancer  1993;68(2):399-402.
The expression of p53 protein was immunohistochemically studied in formalin-fixed paraffin-embedded biopsy specimens of 203 colorectal carcinomas by use of a monoclonal antibody specific for the p53 protein. PAb1801. p53 protein expression with its reactivity localised in nuclei was found in 121 (59.6%) of the cancers. There was no correlation of p53 immunoreactivity with histological classification, wall invasion, lymphatic invasion, venous invasion, lymph node metastases, or peritoneal metastases. p53-positive cancers were more frequently associated with liver metastasis than p53-negative ones. Patients with p53-positive tumours had significantly poorer prognoses than those with p53-negative tumours. The 5 year survival rate was 58.1% for patients with p53-positive tumours, and 76.3% for those with p53-negative tumours. In Dukes' stage C tumours, an especially good correlation was found between p53 immunoreactivity and prognosis. In addition, patients with p53-positive tumours had higher recurrence rates. The results indicate that p53 immunoreactivity may be a useful prognostic marker of colorectal cancers.
PMCID: PMC1968572  PMID: 8347496
12.  Further analysis of predictive value of Helix pomatia lectin binding to primary breast cancer for axillary and internal mammary lymph node metastases. 
British Journal of Cancer  1993;67(6):1368-1371.
We investigated the relation between Helix pomatia (HPA) staining of primary breast cancer and the presence of axillary (AX) or internal mammary (IM) metastases, and evaluated its predictive value for AX or IM metastases in comparison with the use of clinical variables. There was a significant association between the HPA staining and AX or IM metastases. When HPA staining was regarded as an indicator of AX metastases, a diagnostic accuracy of 72%, a sensitivity of 69% and a specificity of 75% were achieved. As an indicator of IM metastases, these values were 64%, 76% and 62%, respectively. In predicting the presence of AX metastases using a discriminant function with clinical AX status, location of tumour and tumour size, diagnostic accuracy, sensitivity and specificity were 79%, 69% and 87%, respectively. In predicting the presence of IM metastases using the discriminant function with clinical AX status and tumour size, these values were 74%, 71% and 75%, respectively. Therefore, it was concluded that the HPA staining may be useful, but it was equivalent with the discriminant function with clinical variables in prediction of AX or IM metastases.
PMCID: PMC1968528  PMID: 7685619
13.  Specific detection of c-erbB-2 mRNA expression in gastric cancers by the polymerase chain reaction following reverse transcription. 
British Journal of Cancer  1992;66(1):84-87.
The expression of the c-erbB-2 mRNA in human embryonic lung fibroblasts, a gastric cancer cell line, mature placenta, and 25 gastric cancer tissues was examined by using the polymerase chain reaction following reverse transcription. This technique can be used to examine c-erbB-2 mRNA expression in a small endoscopic biopsy specimen before surgery.
PMCID: PMC1977918  PMID: 1379062
14.  DNA polymerase alpha positive-cell rate in colorectal cancer and its relationship to prognosis. 
British Journal of Cancer  1992;65(3):421-424.
A total of 63 patients with colorectal cancer were studied for proliferative activity by an immunohistochemical technique using a monoclonal antibody against DNA polymerase alpha. The DNA polymerase alpha positive cell rates ranged from 24.0% to 74.6%. There was a correlation between the DNA polymerase alpha positive cell rates of biopsies and resected specimens. There was no significant correlation between DNA polymerase alpha positive cell rates and histological type, tumour size, invasion of bowel wall, lymphatic invasion, venous invasion, lymph node metastasis or peritoneal metastasis. Tumours with a high growth fraction (a DNA polymerase alpha positive cell rate greater than or equal to 42%) were more frequently associated with liver metastasis than those with a low growth fraction (a DNA polymerase alpha positive cell rate less than 42%). Patients with high growth fraction tumours had significantly poorer prognoses than those with low growth fraction tumours. The results of multivariate analysis using the proportional hazard model of Cox indicated that the DNA polymerase alpha positive cell rates, liver metastasis, and peritoneal metastasis were independent prognostic factors. The results indicate that the DNA polymerase alpha positive cell rate may be a useful prognostic marker of colorectal cancers.
PMCID: PMC1977617  PMID: 1558798
15.  Detection of the growth fraction in colorectal tumours by a monoclonal antibody against DNA polymerase alpha. 
British Journal of Cancer  1990;61(3):390-393.
The cell kinetics of 54 colorectal tumours were examined by immunohistochemical methods, using the monoclonal antibody DNA polymerase alpha which reacts with an antigen found only in proliferating cells. The rate of DNA polymerase alpha positive cells in colorectal cancer was 44.8%, a figure that was significantly higher than the 21.9% found in colorectal adenomas. The rate of DNA polymerase alpha positive cells tended to rise as the degree of differentiation decreased according to the standard histological grading criteria for colorectal cancer. Positive cells were detected in much greater numbers in tumours with liver metastasis (55.4%) than in those without metastasis (41.7%). The rate of DNA polymerase alpha positive cells for aneuploid lesions was higher than that for lesions with a diploid pattern. The determination of growth fractions with a monoclonal antibody (DNA polymerase alpha) may be a biological marker of great prognostic significance.
PMCID: PMC1971304  PMID: 2328204
16.  Human chorionic gonadotropin in colorectal cancer and its relationship to prognosis. 
British Journal of Cancer  1989;60(3):382-384.
The presence of human chorionic gonadotropin in large bowel cancers was studied immunohistochemically using an immunoperoxidase technique. HCG-positive tumour cells were present in 42 of 194 adenocarcinomas examined (22.0% of colon cancer and 21.2% of rectal cancers). On histological grading, the hCG-positive rate tended to rise as the degree of differentiation decreased. HCG was detected more frequently in cancers invading the total bowel wall (27%) than in those invading the partial wall (17.1%). Lymph node, liver or peritoneal metastases were present more frequently in hCG-positive tumours than in hCG-negative tumours. Furthermore, there was an intimate correlation between the presence of hCG-positive tumour cells and CEA doubling times in nine cases with untreated liver metastasis. The survival rate for patients with tissue hCG-positive cells was lower than for those with hCG-negative tumours. Thus, the presence of tissue hCG in colorectal cancers may be a biological marker of prognostic significance.
PMCID: PMC2247188  PMID: 2789946
17.  DNA ploidy in early gastric cancer and its relationship to prognosis. 
British Journal of Cancer  1988;58(1):81-84.
The relationship between DNA ploidy and clinical prognosis was determined in 65 patients who underwent gastroectomy for early gastric cancer. Of the 65 patients, 16 had intramucosal and 49 submucosal tumours. Five-year survival rates were 100 and 79.6% for patients with intramucosal and submucosal tumours respectively. Diploid tumours were observed more frequently among the patients with intramucosal neoplasms. Among the patients with submucosal invasion, the presence of polyploid cells (greater than or equal to 6c) in less than 10% of the malignant population was associated with a superior survival at 5 years, than those with greater than or equal to 10% of polyploid cells (92.1% vs. 36.3%). When the macroscopic type and the ploidy status were evaluated together, patients who had greater than or equal to 10% of cells with DNA greater than or equal to 6 c and a protruding type of tumour, had a 5 year survival rate of only 12.5%. Finally when factors such as the level of wall invasion, percentage of polyploid cells, type of histogram, and macroscopic type were evaluated by multiple regression analysis, macroscopic type and percentage of polyploid cells were the only significant prognostic factors. On the basis of these findings, the DNA ploidy pattern and the macroscopic type may be useful markers of patients who will develop recurrence.
PMCID: PMC2246485  PMID: 3166895

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