Development and external validation of a nomogram for overall survival after curative resection in serosa-negative, locally advanced gastric cancer.

BACKGROUND: Few nomograms can predict overall survival (OS) after curative resection of advanced gastric cancer (AGC), and these nomograms were developed using data from only a few large centers over a long time period. The aim of this study was to develop and externally validate an elaborative nomogram that predicts 5-year OS after curative resection for serosa-negative, locally AGC using a large amount of data from multiple centers in Japan over a short time period (2001-2003). PATIENTS AND METHODS: Of 39 859 patients who underwent surgery for gastric cancer between 2001 and 2003 at multiple centers in Japan, we retrospectively analyzed 5196 patients with serosa-negative AGC who underwent Resection A according to the 13th Japanese Classification of Gastric Carcinoma. The data of 3085 patients who underwent surgery from 2001 to 2002 were used as a training set for the construction of a nomogram and Web software. The data of 2111 patients who underwent surgery in 2003 were used as an external validation set. RESULTS: Age at operation, gender, tumor size and location, macroscopic type, histological type, depth of invasion, number of positive and examined lymph nodes, and lymphovascular invasion, but not the extent of lymphadenectomy, were associated with OS. Discrimination of the developed nomogram was superior to that of the TNM classification (concordance indices of 0.68 versus 0.61; P < 0.001). Moreover, calibration was accurate. CONCLUSIONS: We have developed and externally validated an elaborative nomogram that predicts the 5-year OS of postoperative serosa-negative AGC. This nomogram would be helpful in the assessment of individual risks and in the consideration of additional therapy in clinical practice, and we have created freely available Web software to more easily and quickly predict OS and to draw a survival curve for these purposes.

Inverse correlation between NKG2D expression on CD8+ T cells and the frequency of CD4+CD25+ regulatory T cells in patients with esophageal cancer.

Although malignant diseases are known to be associated with immune suppression, detailed mechanisms of this phenomenon are still unknown. NKG2D is an activating cell surface receptor expressed by natural killer (NK) cells and CD8+ T cells, and it has been reported that NKG2D engagement is extremely important for T cell activation. In the current study, NKG2D expression on CD8+ T cells and the frequency of CD4+ CD25+ regulatory T (Treg) cells were determined by multicolor flow cytometry to investigate one of the mechanisms responsible for immune evasion in esophageal cancer patients. NKG2D expression on CD8+ T lymphocytes in esophageal cancer patients was significantly lower than in those of normal controls. NKG2D expression in T3/T4 esophageal cancer was significantly lower than that in T1/T2 esophageal cancer. CD8+ T cells from patients with lymph node metastasis expressed significantly lower NKG2D than those without lymph node metastasis. Moreover, significantly lower NKG2D expression was observed in stage III/IV cancer in comparison with stage I/II. The frequency of CD4+CD25+ Treg cells in esophageal cancer patients was significantly higher than those in normal controls. NKG2D expression on CD8+ T cells was significantly inversely correlated with the frequency of CD4+CD25+ Treg cells in esophageal cancer patients. Our data indicates that decreased NKG2D expression on CD8+ T cells is correlated with disease severity. Decreased NKG2D expression and an increase in Treg cells may be one of the key mechanisms responsible for immune evasion in esophageal cancer.

Continuous infusion of 5-fluorouracil with versus without low-dose, consecutive administration of cisplatin in advanced colorectal cancer. A prospective randomized phase II study.

Recently, the treatment of advanced gastric cancer by continuous infusion of 5-fluorouracil (5-FU) with low-dose cisplatin (CDDP) has improved efficacy without severe toxicities. The possible effectiveness of 5-FU+low-dose CDDP for colorectal cancer (CRC) is intriguing. One hundred fifty-five patients with far-advanced CRC including at least one measurable lesion were enrolled in a prospective randomized clinical trial funded by the Japanese Foundation for Multidisciplinary Treatment of Cancer. These patients were assigned to the two arms to assess the value of low-dose CDDP when added to a continuous intravenous infusion of 5-FU at a dose of 300 mg/m(2)/24 hrs in a one-week cycle consisting of 5 days of treatment and 2 days of rest for at least 12 weeks. CD-DP was given intravenously at a dose of 3 mg/m(2) on days 1-5 and days 8-12, and then at a dose of 7 mg/m(2) twice a week. Three patients were excluded from the trial. The response rate in the 5-FU+low-dose CDDP arm (n=75) was significantly higher than that in the 5-FU arm (n=77) (25.3% vs. 11.7%; P = 0.037). There was no significant difference in the median overall survival time between the 5-FU+low-dose CDDP arm and the 5-FU arm (479 and 491 days, respectively). Grades 3/4 toxicities occurred infrequently in both arms. The quality of life was almost the same between the arms. Low-dose CDDP improved the response rate while keeping toxicities within clinically acceptable limits. However, this combined treatment did not confer a survival advantage over treatment with continuous infusion of 5-FU alone for patients with far-advanced CRC; that might be attributable to the short CDDP administration setting of 12 weeks.

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.

Significant correlation between micrometastasis in the lymph nodes and reduced expression of E-cadherin in early gastric cancer.

BACKGROUND: E-cadherin has been recognized as an important factor associated with tumor metastasis. However, the relationship between micrometastasis in the lymph nodes and the expression of E-cadherin in the primary tumor in gastric cancer remains unclear. METHODS: Two consecutive sections of 4522 lymph nodes from 162 patients with early gastric cancer were prepared for simultaneous hematoxylin and eosin (H&E) and cytokeratin (CK) staining. Sections of primary tumors from 135 of these patients were prepared for E-cadherin immunostaining. RESULTS: The incidence of lymph node involvement was significantly increased, from 6.8% (11/162 patients) by H&E staining, to 27% (43/162 patients) by CK immunostaining (P < 0.0001). Micrometastasis in the lymph node was found in 32 of 151 (21%) patients who had no lymph node metastasis evidenced by H&E staining. Micro-lymph node metastasis was frequently found in tumors with a diameter more than 1.0 cm, of those that were poorly differentiated, deeply invaded, showed lymphatic on vascular invasion, and in those that showed reduced expression of E-cadherin. Loss of expression of E-cadherin in the primary tumor was closely correlated with micro-lymph node metastasis. Patients with tumors with micro-lymph node metastasis detected by CK immunostaining had a significantly lower 5-year survival rate (P < 0.01) than those without such metastases. CONCLUSION: Tumors more than 1.0 cm in diameter and those that exhibit poor differentiation, deep invasion (i.e., to the submucosa), lymphatic or vascular invasion, and reduced expression of E-cadherin are risk factors for lymph node metastasis in early gastric cancer. Thus, it is recommended that cancers confined to the mucosa (m-cancers) that are more than 1.0 cm in diameter should not be treated with limited surgery without lymphadenectomy.

[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.

The expression of thymidine phosphorylase suppresses spontaneous apoptosis of cancer cells in esophageal squamous cell carcinoma.

OBJECTIVE: Thymidine phosphorylase (TP) is an enzyme which converts thymidine to thymine. TP is expressed in a variety of human carcinomas and is known to be a potent angiogenic factor. A recent in vitro study indicated that TP is involved in the intracellular apoptotic signal transduction pathway. The aim of this study was to investigate the correlations between the expression of TP, microvessel density (MVD) and the occurrence of spontaneous apoptosis in esophageal squamous cell carcinoma (ESCC). METHODS: The expression of TP, intratumoral MVDs and percentages of apoptotic cancer cells, expressed by the apoptotic index (AI), of 155 tumors from 155 patients with ESCC were analyzed by immunohistochemistry and compared. RESULTS: Positive TP expression in cancer and stromal cells was detected in 89 (57.4%) and 104 (67.1%) cases, respectively. The mean MVD and mean AI of the 155 tumors were 288/mm(2) (range: 36-668/mm(2)) and 2.1% (range: 0-20.4%). The mean MVD of 104 tumors with TP-positive stromal cells (336/mm(2)) was higher than that of 51 tumors with TP-negative stromal cells (188/mm(2), p < 0.001). However, the mean MVD of 89 tumors with TP-positive cancer cells (293/mm(2)) did not differ from that of 66 tumors with TP-negative cancer cells (280/mm(2), p = 0.509). On the other hand, the mean AI of 89 tumors with TP-positive cancer cells (1.2%) was lower than that of 66 tumors with TP-negative cancer cells (3.4%, p < 0.001). However, the mean AI of 104 tumors with TP-positive stromal cells (1.9%) did not differ from that of 51 tumors with TP-negative stromal cells (2.6%, p = 0.058). No significant correlation between the MVDs and the AIs was observed (rho = -0.067, p = 0.409). CONCLUSION: In ESCC, TP may play an important role in tumor progression by increasing microvessels and suppressing apoptosis of cancer cells.

[Clinical significance of molecular biological detection of micrometastases in gastric carcinoma].

Micrometastases are considered to be a cause of recurrence after curative surgery for gastric cancer. It is important to clarify the clinicopathologic characteristics of micrometastases in the lymph nodes and peritoneal cavity to determine the treatment options in gastric cancer. Two consecutive sections of lymph nodes from patients with various cancers were examined by simultaneous staining with ordinary hematoxylin and eosin (H & E) and immunostaining with anti-cytokeratin antibody, respectively. Micrometastases in the lymph nodes were found in 18% of mucosal cancer, 25% of submucosal cancer, and 65% of T3 (serosal) cancers pecimens, with cancer-free nodes examined by H & E staining. A reduced 5-year survival rate was demonstrated in patients with nodal micrometastases among those with submucosal cancer and those with T3 cancer and cancer-free nodes examined by H & E staining. Molecular biological detection (MBD) of micrometastasis in lavage cytology specimens was performed by RT-PCR of carcinoembryonic antigen mRNA or telomerase activity assay. MBD protocols revealed micrometastases in cases with negative cytology results. Survival analysis demonstrated peritoneal recurrences in MBD-positive cases, whereas there was no recurrence in MBD-negative cases. Peritoneal micrometastases detected by MBD protocols appear to be a significant risk factor for recurrence. Therefore indications for lymph node dissection and postoperative chemotherapy should be determined based on the findings of micrometastases in gastric cancer.

Prognostic factors in patients with advanced gastric cancer treated by noncurative resection: a multivariate analysis.

BACKGROUND/AIMS: The relationship between prognostic factors and survival time after noncurative gastric resection in patients with advanced gastric cancer was examined by a retrospective review of data on 364 patients. METHODOLOGY: There were 168 patients without metastasis to the liver or peritoneum (group A), 127 with peritoneal metastasis and no liver metastasis (group B), 50 with liver metastasis and no peritoneal metastasis (group C) and 19 with synchronous liver and peritoneal metastases (group D). Patients were primarily treated with the following 3 drugs: the fluorinated pyrimidines, cisplatin, and mitomycin C. RESULTS: Patients in group D had a very poor prognosis as compared with the other groups. Multivariate analysis using the Cox's proportional hazard model adjusted for sex, age, and other covariants indicated that lymph node metastasis, lymph node dissection, and fluorinated pyrimidines for group A, cisplatin for group B, and lymph node dissection for group C were independent prognostic factors. An analysis of patients excluding cases who died within 30 days after surgery revealed that lymph node dissection for group A, lymph node dissection and cisplatin for group B, and lymph node dissection for group C were independent prognostic factors. CONCLUSIONS: Treatment protocol specific for the residual disease may improve the survival of patients with advanced gastric cancer treated by noncurative resection.

Postoperative morbidity and mortality after gastrectomy for gastric carcinoma.

BACKGROUND/AIMS: Surgical technique and postoperative care for gastric cancer have significantly improved in recent years. However, whether postoperative morbidity or mortality rates after gastrectomy for gastric cancer were reduced or not in recent years was unclear. In this study, we analyzed the chronological changes of postoperative morbidity and mortality rates, and we analyzed risk factors for postoperative morbidity and mortality in patients undergoing gastrectomy for carcinomas of the stomach. METHODOLOGY: A total of 887 patients with gastric cancer were gastrectomized in our hospital between January 1985 and December 1996. The patients were divided into three groups on the basis of chronology. The first group included patients treated over the period 1985 to 1988 (n = 324); the second group, 1989 to 1992 (n = 300); and the third group, 1993 to 1996 (n = 263). Postoperative morbidity rates and mortality rates were compared among the three groups. Also, significant risk factors affecting postoperative morbidity and in-hospital mortality were analyzed by the multiple logistic regression analysis. RESULTS: Postoperative complications were detected in 95 patients (10.7%) and in-hospital mortality rate was 2.4% (21/887). Postoperative morbidity rates were 10.5%, 11%, and 10.6% in the first, second, and third groups, respectively and postoperative mortality rates were 2.5%, 2%, and 2.7%, respectively. These postoperative morbidity and mortality rates were not different between the groups (P = 0.979 and P = 0.866). The most common postoperative complication was anastomotic leakage (56/95, 58.9%). Significant risk factors affecting in-hospital mortality were Stage IV (P = 0.006) and noncurative gastric resection (P = 0.004). However, the extent of lymph node dissection, combined resection, or the existence of preoperative complications were not significant risk factors of in-hospital mortality by multiple logistic regression analysis. CONCLUSIONS: These results indicate that patients with far-advanced gastric cancer might have a high risk of postoperative mortality. In noncurative operations for patients with advanced gastric cancer, unnecessary lymph node dissection or combined resection should be avoided.

Correlation between spontaneous apoptosis and the expression of angiogenic factors in advanced gastric adenocarcinoma.

The aim of this study was to investigate whether angiogenic factors influence the occurrence of spontaneous apoptosis in advanced gastric cancer. The apoptotic indices (AIs) of 97 tumors from 97 patients with advanced gastric cancer (pT3, pN0, pM0, Stage II) were analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) method. Intratumoral microvessel densities (IMVDs) of tumors stained with anti-CD34 monoclonal antibody were quantified under x 200 magnification using computer-assisted image analysis. The expressions of angiogenic factors, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (dThdPase), transforming growth factor-alpha (TGF-alpha), and p53 were analyzed immunohistochemically and compared with IMVDs and AIs. The mean IMVD of the 97 tumors was 365/mm2 (range 147-990/mm2). The mean AI of tumors was 2.1% (range 0-11.3%). A significant inverse correlation between the AIs and the IMVDs was shown (p = -0.278, P = 0.0064). The mean IMVDs of tumors with high expressions of dThdPase, TGF-alpha, or p53 were significantly higher than those of tumors with low expressions of these factors. The mean AI of tumors with high expressions of dThdPase was significantly lower than that of tumors with low expressions of dThdPase (P = 0.023). However, no significant correlations were detected between AIs and the expression levels of VEGF, TGF-alpha, or p53. In gastric cancer, dThdPase may play an important role in tumor progression by increasing microvessels and by suppressing apoptosis of cancer cells.

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.

Prediction of survival period for patients with postoperative recurrence after curative resection for advanced gastric carcinoma.

BACKGROUND/AIMS: Although many studies have attempted to clarify the prognostic indicators for gastric carcinoma, there have been few studies regarding the factors that correlate with the survival period of patients with postoperative recurrence. METHODOLOGY: Among 504 advanced gastric adenocarcinoma patients who had undergone curative gastrectomy, 188 patients who had died of recurrence were used in this study. RESULTS: Univariate analysis indicated that age, the presence of lymph node metastasis and blood vessel invasion, the number of positive lymph nodes, and gastrectomy significantly correlated with the survival period. Multivariate analysis indicated that the length of the survival period was independently influenced by the number of positive lymph nodes and blood vessel invasion. The survival time of patients with less than 3 positive lymph nodes and no accompanying blood vessel invasion was significantly longer than that of other patients. CONCLUSIONS: The number of positive lymph nodes and the presence of blood vessel invasion are the most important factors predicting the survival period of patients with postoperative recurrence after curative resection for advanced gastric carcinoma.

Angiogenesis, angiogenic factor expression and prognosis of gastric carcinoma.

It is known that the growth and metastasis of malignant tumors depends on neovascularization. It has also been suggested that the degree of tumor angiogenesis is related to clinical outcome in several tumor types. This is true for gastric carcinoma, where tumor angiogenesis is closely correlated with prognosis and hematogenous metastasis. Several types of angiogenic factors have been investigated in gastric cancer. In the current review, the correlation between angiogenesis / angiogenic factor expression and prognosis in gastric cancer is discussed. Moreover, the potential clinical applications of antivascular, anti-angiogenic and angiostatic agents for the treatment of gastric carcinoma are summarized.

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.

Combined resection of invaded organs in patients with T4 gastric carcinoma.

BACKGROUND: To understand the efficacy of gastrectomy combined with the resection of other organs and to refine the indications for this type of surgery, the records of 156 patients with carcinoma of the stomach directly invading adjacent organs or structures (T4 gastric carcinoma) were analyzed retrospectively. METHODS: The patients were divided into three groups, as follows: in group A, curative resection was performed by the combined resection of invaded organs or structures; in group B, although combined resection was performed, curative resection could not be performed because of the extent of lymph node metastasis, liver metastasis, and/or peritoneal metastasis; in group C, combined resection was not performed. RESULTS: In patients with peritoneal or liver metastasis, there was no significant difference in prognosis among the three groups. In patients without peritoneal and liver metastasis, the prognosis of group A was significantly better than that of group B or group C, irrespective of the extent of lymph node metastasis or the number of invaded organs. In these group A patients, the 5-year survival rates of those with localized tumors and no lymph node metastasis, those with localized tumors and lymph node metastasis, those with infiltrating tumors and no lymph node metastasis, and those with infiltrating tumors and lymph node metastasis were 100%, 56.2%, 57.1%, and 13.6%, respectively. CONCLUSIONS: Combined resection of involved organs should be carried out with curative intent in patients with localized gastric cancer or infiltrating gastric cancer without lymph node metastasis.

Combined analysis of p53 and retinoblastoma protein expressions in esophageal cancer.

BACKGROUND: p53 gene mutation and abnormal p53 protein expression, also loss of the retinoblastoma gene and protein expression are frequently associated with esophageal squamous cell carcinoma (ESCC). Recently, the prognostic significance of the combined analysis of p53 protein and retinoblastoma protein (pRB) has been reported in non-small cell lung cancer. However, in ESCC, the prognostic significance of the combined analysis of these proteins remains unclear. In this study, we immunohistochemically analyzed the p53 protein and pRB expressions in surgically resected ESCC, and we evaluated the prognostic significance of the combination of these proteins. METHODS: We analyzed p53 protein and pRB expressions immunohistochemically in 191 surgically resected ESCC cases. Overexpression of p53 and loss of pRB were considered abnormal. RESULTS: Overexpression of p53 protein was detected in 79 patients (41%) and decreased pRB nuclear staining occurred in 82 (43%). The Kaplan-Meier survival curve showed that absence of pRB expression was significantly associated with shortened survival (p = 0.001), whereas expression of p53 was not significantly associated with survival. Moreover, p53 and pRB status individually were not independent prognostic factors in multivariate survival analysis. With respect to pRB and p53, the tumors could be grouped into four categories: p53-/pRB+ (31%); p53-/pRB- (27%); p53+/pRB+ (26%); and p53+/pRB- (16%). Favorable prognosis was observed in patients with p53-/pRB+ tumors. Multivariate analysis showed p53-/pRB+ status to be an independent prognostic factor. CONCLUSIONS: The combination of p53 protein loss and pRB expression was associated with good prognosis in patients with ESCC.

Expression of thymidylate synthase in relation to survival and chemosensitivity in gastric cancer patients.

Expression of thymidylate synthase (TS) has been studied as a prognostic factor and mechanism of drug resistance in gastric cancers. The relationship between TS expression in surgically resected specimens and clinicopathological factors was examined in 216 gastric cancer patients. Immunohistochemical demonstration of the protein was achieved using an anti-TS polyclonal antibody. Positive TS staining was observed in 50 patients (23.1%). Lymph node metastasis was more frequent in patients with TS-positive tumors than in those with TS-negative tumors (P<0.01). Patients were followed for more than 5 years and survival was examined. In 163 patients who received fluorouracil (FU)-based chemotherapy, the overall 5-year survival rate was 41.8% for patients with TS-positive tumors and 57.0% for patients with TS-negative tumors (P<0.01). In the 53 patients who did not receive chemotherapy, these figures were 25.6% and 79.5%, respectively (P<0.05). In patients with T3 gastric cancer who were treated with curative gastrectomy, however, FU-based chemotherapy did not affect survival of either patients with TS-positive tumors or with TS-negative tumors. Multivariate analysis also revealed TS expression to be a significant variable for predicting postoperative survival (P<0.05). These results indicate that TS expression can be used as an independent prognostic factor for patients with gastric cancer. However, TS expression is not a major predictor of the efficacy of FU-based chemotherapy.

Nuclear profiles of cancer cells reveal the metastatic potential of gastric cancer.

Nuclear profiles have been reported as useful prognostic predictors in various cancers. Data from computerized morphometry are objective and can be quickly derived using conventional microscopic analysis, but image analysis of nuclear features has only rarely been applied to investigations of gastric cancer. The aim of this study was to evaluate the correlation between one of these morphological nuclear features and the clinicopathological parameters in patients with gastric cancer. The morphometric nuclear feature (nuclear area) was analysed in 400 patients with gastric cancer. In each case, 300 cancer nuclei on routine haematoxylin and eosin-stained slides were analysed through the use of a computer-assisted image analysis system which traced the nuclear profiles (magnificationx400) on a computer monitor. The morphometric data were compared with the patients' clinicopathological status and survival rate. The mean nuclear area (NA) of cancer cells from 400 cases of gastric cancer was 47.2 microm(2). The NAs of cancer cells from tumours with microvessel invasion (lymphatic or venous invasion), lymph node metastasis or hepatic metastasis at the time of operation were significantly larger than those of cancer cells from tumours without such invasion or metastases. Cytokeratin (CK) immunostaining was performed on 2577 lymph nodes from 91 patients with advanced gastric cancer (pT3, pN0, pM0, stage II) to detect micrometastases. CK-positive lymph nodes were detected in 350 of 2577 lymph nodes (13. 6%) and in 62 of 91 patients (68.1%). The mean NA of cancer cells from 62 tumours with micrometastases (44 microm(2)) was larger than that of cancer cells from 29 tumours without micrometastases (38.8 microm(2), p=0.043), and a significant positive correlation was detected between the NAs of cancer cells from 91 tumours and the number of micrometastatic lymph nodes of 91 patients (rho=0.278, p=0. 008). Cancer cells with large NA correlated strongly with haematogenous and lymph node recurrence or relapse after gastrectomy and the NA of cancer cells was identified as an independent prognostic factor in gastric cancer. Nuclear morphometry is an objective, reproducible, and technically uncomplicated procedure. The NA of cancer cells correlates closely with the metastatic potential of gastric cancer. Nuclear morphometry may therefore be useful for the selection of patients who are at risk of haematogenous or lymph node metastatic recurrence after surgery.