Correlation between cathepsin D expression and p53 protein nuclear accumulation in oesophageal squamous cell carcinoma.

AIM: The lysosomal protease cathepsin D has been reported to be associated with tumour progression in malignant tumours. Expression of the gene encoding cathepsin D is known to be stimulated by oestrogen in mammary cancer cells. Recent experiments revealed that a p53 DNA binding site is located in the promoter region of the cathepsin D gene. This fact indicates that cathepsin D expression may correlate with p53 protein expression. The purpose of this study is to evaluate the expression patterns of the cathepsin D and p53 proteins in oesophageal squamous cell carcinoma (SCC). METHODS: In 154 patients with oesophageal SCC, expression of the cathepsin D and p53 proteins was measured in tumours by means of immunohistochemistry using monoclonal antibodies against cathepsin D (clone, 1C11) and p53 (clone, BP53-12). RESULTS: Cathepsin D was detected in tumour cells, although it was not found in normal oesophageal epithelium adjacent to carcinoma. High cathepsin D expression (positive tumour cells > 10%) was detected in 76 of 154 cases (49%) and high p53 nuclear expression (positive tumour cells > 50%) was detected in 70 cases (46%). High cathepsin D expression was significantly associated with invasive tumour growth (p = 0.002), poor prognosis (p = 0.049), and nuclear accumulation of p53 protein (p = 0.001). Overexpression of both p53 and cathepsin D was seen in 45 of the 154 cases (29.2%). In addition, there was a positive correlation between the cathepsin D index (percentage of cathepsin D positive tumour cells) and Ki-67 labelling index (percentage of Ki-67 positive tumour cells) in 154 oesophageal SCCs (rho = 0.257; p = 0.009). However, in multivariate survival analysis, cathepsin D expression by the tumours was not an independent prognostic factor in patients with oesophageal SCC (p = 0.236). CONCLUSIONS: The expression of cathepsin D by cancer cells may play an important role in the invasive growth of oesophageal SCC. Overexpression of both p53 and cathepsin D was seen frequently in tumours; p53 gene abnormalities may correlate with cathepsin D overexpression in oesophageal SCC.

[Immunohistochemical study of dihydropyrimidine dehydrogenase (DPD) and p53 in biopsied specimens of esophageal cancer before chemoradiotherapy].

We studied whether the immunohistochemical status of dihydropyrimidine dehydrogenase (DPD) and p53 can be used to predict the sensitivity to chemoradiotherapy (CRT) in patients with esophageal cancer. In 19 patients who did not undergo preoperative CRT, the immunoreactivity of DPD and p53 in biopsied specimens correlated well with those in surgically resected specimens (DPD: 100%, p53: 73%). Fifteen patients were treated with 5-FU (250-300 mg/body/day: day 1-5, 8-12), low-dose cisplatin (10 mg/body/day: day 1, 8) and radiotherapy (30-40 Gy). The response rate (CR + PR) for CRT in these patients was 40%. All tumors that showed CR or PR demonstrated low expression of DPD. However, all tumors with high DPD expression showed MR or NC. However, the expression of p53 did not correlate with the response rate for CRT. Therefore, the effect of CRT for esophageal cancer may be predicted by immunohistochemical examination of DPD in biopsied tumor specimens.

Clinicopathological significance of cathepsin D expression in gastric adenocarcinoma.

OBJECTIVE: An estrogen-regulated lysosomal protease, cathepsin D, has been detected in a variety of tissues. This proteinase has been described as closely associated with tumor progression and metastasis in malignant tumors. The purpose of this study was to determine the clinicopathological and prognostic significance of cathepsin D expression in gastric adenocarcinoma. METHODS: In a consecutive series of 478 patients with gastric carcinoma (median follow-up period: 93 months, range: 1-285 months), cathepsin D expression in tumors was quantitatively analyzed with immunohistochemistry using a monoclonal antibody against cathepsin D (clone: 1C11). The percentage of cathepsin-D-positive cancer cells (the CD index) was calculated. In addition, the amount of cathepsin-D-positive stromal cells was evaluated; three grades (high, intermediate, and low) were used for the classification. RESULTS: The mean CD index of 478 tumors was 12.8% (range: 0-100%, median: 8%). The mean CD index of diffuse-type gastric carcinomas (14.9%) was significantly higher than that of intestinal-type carcinomas (10.1%, p < 0.0001). Cathepsin D expression of cancer cells was significantly associated with the depth of tumor invasion in both types. The percentage of tumors with high cathepsin D expression in stromal cells was significantly higher in well-differentiated tumors (25.5%) than in moderately differentiated (12.8%) or in poorly differentiated tumors (19.1%). Cathepsin D expression of stromal cells was significantly associated with the depth of tumor invasion in the intestinal type, in contrast to the diffuse type. Highly expressed cathepsin D in cancer cells was associated with a poor prognosis in both types of carcinoma, but in stromal cells highly expressed cathepsin D was associated to a poor prognosis in the intestinal type only. CONCLUSION: These results indicate that cathepsin D expression in cancer cells may play an important role in tumor progression in diffuse-type gastric carcinoma, whereas in the intestinal type of carcinoma, cathepsin D expression in stromal cells may play an important role in tumor progression.

Micro-lymph node metastasis and its correlation with cathepsin D expression in early gastric cancer.

BACKGROUND AND OBJECTIVES: Limited operations for early gastric cancer (EGC) have been recommended based on data from lymph node (LN) metastasis detected by hematoxylin and eosin (HE) staining. Recently, the clinical importance of micro-LN metastasis has been reported. In this study, the indication of limited operations for EGC was re-evaluated based on the data from micro-LN metastasis detected by cytokeratin (CK) immunostaining. Also, the correlation between micro-LN metastasis and lysosomal acidic protease cathepsin D (CD) expression in primary tumors was evaluated. METHODS: A total of 5,949 LNs from 160 patients with EGC were stained by anti-CK monoclonal antibody (CAM 5.2). Also, the 160 primary EGCs were stained by CD. RESULTS: The incidence of LN metastasis increased from 7.5% (12/160) by HE-staining to 27.5% (44 of 160) by CK immunostaining. The incidence of micro-LN metastasis increased according to the depth of tumor invasion (mucosal cancer: 19% and submucosal cancer: 36.8%) and the size of tumors (< or = 1.0 cm: 5.9%, 1.1-2.0 cm: 25.6%, and > 2.1 cm: 31.7%). The CK-staining patterns were classified into the three subgroups (CK-negative, n = 116; single cell type, n = 27; and clustered type, n = 17). The occurrence of cancer recurrence was significantly higher in clustered type (17.6%) than in single cell type (3.7%) and in CK-negative (0%, P < 0.0001). The mean percentage of CD-positive cancer cells of primary tumors in clustered type (17.2%) was significantly higher than in single cell type (12.3%) and in CK-negative (7.5%, P = 0.0036). CONCLUSIONS: The acidic protease CD may play an important role of cancer metastasis in EGC. The limited operation without lymphadenectomy should be indicated for EGC with CD-negative.

Pharmacokinetics of intraoperative intrapleural cisplatin chemotherapy of various osmolarities in cases of esophageal cancer.

Intraoperative intrapleural (i.pl.) cisplatin (CDDP) treatment during thoracotomy was performed for esophageal cancers. Three patients underwent isotonic (308 mOsm/l) CDDP treatment. Hypotonic CDDP treatments with a 154 mOsm/l solution and a 62 mOsm/l solution were administered to 4 and 9 patients, respectively. The maximum concentrations (Cmax) of both total and filterable platinum in the plasma after injection of the hypotonic solution were significantly higher than those after injection of the isotonic solution. The area under the curve of concentration versus time (AUC) of the plasma of the 62 mOsm/l solution was significantly higher than that of the 154 mOsm/l and isotonic solution. Although higher levels of the Cmax may increase side-effects, the hypotonic condition of the i.pl. fluid and increased AUC in the plasma may escalate the accumulation of platinum in i.pl. cancer cells. These results suggest that hypotonic i.pl. CDDP is tolerable and may be useful for treatment of the incipient phase of pleural carcinomatosis and for prophylaxis of postoperative recurrence.

Clinicopathological findings in patients with gastric adenocarcinoma with familial aggregation.

BACKGROUND/AIMS: The clinicopathological characteristics of gastric cancer (GC) with a positive family history of site-specific GC have not been well discussed. The aim of this study was to estimate the risk of familial aggregation of GC in a hospital-based case-control study and to analyze the clinicopathological characteristics of GC with familial aggregation of GC. METHODS: Our series was comprised of 926 histologically confirmed patients with GC (588 males and 338 females) and 2,052 non-cancer outpatients between 1985 and 1996. The odds ratios (ORs), as estimators of relative risks, together with the corresponding 95% confidence intervals (CIs) for a family history of GC and for a family history of other cancers were calculated. Moreover, the clinicopathological findings of patients with GC who had a GC family history were compared with those of patients with GC who had no GC family history. RESULTS: A positive family history of GC was associated with a statistically significant increase in the risk of GC (OR = 2.15; 95% CI = 1.77-2.63), while no association was observed between the risk of GC and a family history of other cancers (OR = 1.11; 95% CI = 0.91-1.36). The incidence of a multifocal occurrence of GCs was higher in patients with a family history of GC (19.4%) than in patients without a family history of GC (12%, p = 0.005). The risk (OR) of occurrence of multiple cancers in the stomach in patients who had a family history of GC was 1.77 (95% CI = 1.19-2.64). CONCLUSIONS: Our results suggest that a family history of GC seemed to be a risk factor for the development of GC. Further, a family history of GC was found to be associated with a multifocal occurrence of GC.

Randomized comparison of two preoperative methods for preparation of the colon: oral administration of a solution of polyethylene glycol plus electrolytes and total parenteral nutrition.

BACKGROUNDS/AIMS: Two colon preparation methods were compared for their efficacy. The comparison was carried out between whole bowel irrigation using polyethylene glycol-electrolyte lavage solution (PEG-ELS) and total parenteral nutrition (TPN). METHODOLOGY: Twenty-six consecutive patients suffering from colorectal cancer without apparent obstruction were randomly divided into two groups. Twelve patients received 2 litres of PEG-ELS one day before the operation following two tablets of sennoside (24 mg) two days before the operation without restriction of food until PEG-ELS. Fourteen patients received magnesium citrate (34 g) and sennoside (24 mg) on the day before the operation with 7 days' TPN and fasting. RESULTS: The average time of defecation was 9 in the PEG-ELS group and 5 in the TPN group (p < 0.001), with little difference between the necessary times to complete defecation (PEG-ELS: 280 min. vs. TPN: 260 min.). However, although half of the PEG-ELS group complained of side effects of abdominal fullness the overall incidence of side effects in both groups were the same of 50%. There were no significant changes between the data of blood test and routine chemistry before and after the bowel preparation in both groups. The purity of the colorectum judged at operation in both groups were excellent, no residue at all, except in one patient of the TPN group. The total bacterial counts of the rectal samples obtained at operation of PEG-ELS group were fewer than that of TPN group but not statistically significant. CONCLUSION: Colon preparation using PEG-ELS is just as good as the 7-days' TPN treatment and fasting, and exceeds from the standpoint of saving time.

[Flow cytometric measurement of p53 protein and DNA content in colorectal carcinomas with liver metastasis].

To investigate the possible relation between p53 protein, DNA content and liver metastasis of colorectal cancer, overexpression of p53 and DNA content were measured by flowcytometer in 113 primary lesions, which included 34 cases with simultaneous liver metastasis and 79 cases with curative resection, and 25 metastatic lesions of the liver. Overexpression of p53 and DNA aneuploidy were found in 44 (38.9%) and 77 (68.1%) of 113 primary lesions, respectively. However, p53 protein and DNA aneuploidy were unrelated to the clinicopathological findings, such as liver metastasis, venous invasion and lymph node metastasis. Comparing the overexpression of p53 protein between primary and metastatic lesions, p53 protein was recognized in 18 (72.0%) of 25 metastatic lesions of the liver. Incidence of p53 protein was significantly higher in metastatic lesions of the liver than in primary lesions (p < 0.01). On the other hand, p53 protein was found in 27 (60.0%) of 45 diploid lesions and in 35 (37.6%) of 93 aneuploid lesions. There was a significant difference in p53 protein between diploid and aneuploid tumors (p < 0.05). These results suggest that p53 protein may not correlate with the occurrence of liver metastasis and might be produced in the metastatic lesion of the liver after metastasis.