Detection of circulating cancer cells after a gastrectomy for gastric cancer.

PURPOSE: In this study, we evaluated the correlation between the postoperative detection of circulating cancer cells and the risk of recurrence in patients with gastric cancer. METHODS: Total RNA was extracted from 1.5 ml of peripheral blood from 59 patients with gastric cancer and 15 patients with cholecystolithiasis (control) before and after operation. Carcinoembryonic antigen (CEA) messenger RNA (mRNA) was used as a probe to detect gastric cancer cells in samples using a real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Carcinoembryonic antigen mRNA-positive cells were not found in the peripheral blood of the control patients either before or after operation, nor in the peripheral blood of the gastric cancer patients before operation. However, CEA and mRNA-positive cells were detected in 46% of the patients just after a gastrectomy, though these circulating cancer cells disappeared from peripheral blood within 2 postoperative days. In 55 patients who underwent a curative operation, the risk for cancer recurrence (10/30; 33%) in 30 patients who did not show circulating cancer cells postoperatively was higher than that for cancer recurrence (3/25; 12%) in 25 patients with positive for circulating cancer cells (P = 0.064). As a result, the presence of blood circulating tumor cells just after surgery tends to correlate with a low rate of tumor recurrence in patients operated on for gastric cancer. CONCLUSION: These findings indicate that a gastrectomy may spread gastric cancer cells into the peripheral blood from primary tumors; however, such circulating cancer cells may be destroyed within a short time. The detection of circulating cancer cells may therefore be a marker for a possibly better prognosis in patients with gastric cancer.

[Clinical significance of micrometastasis in lymph nodes and microinvasion in primary lesion in submucosal gastric cancer].

OBJECTIVE: To clarify the clinicopathologic characteristics of micrometastasis in lymph nodes and microinvasion in primary lesion for the treatment options with regard to submucosal gastric cancer. METHODS: 1945 lymph nodes and 68 primary tumors resected from 79 patients with submucosal gastric cancer were examined. Two consecutive sections were prepared for simultaneous staining with HE and immunostaining with anti-cytokeratin antibody (CAM 5.2), respectively. RESULTS: The incidence of nodal involvement in 79 patients with submucosal gastric cancer was increased from 13% (10/79 patients) by HE staining to 34% (27/79 patients) by cytokeratin immunostaining. Micrometastasis in the lymph nodes were found in 17 of 69 patients (25%) with cancer-free nodes examined by HE staining. Microinvasion to the muscularis properia was found in 11 of 68 patients (16%) who were histologically diagnosed as submucosal gastric cancer. Survival analysis demonstrated a worse 5-year survival in the patients with micrometastasis in lymph nodes (82%) and with microinvasion to muscularis properia (73%). A higher incidence of nodal involvement was found in submucosal cancers of large size (> 2 cm; 43%), a depressed type (48%), lymphatic invasion (73%), and deeper submucosal invasion (submucosal 3; 53%). A higher incidence of microinvasion was found with the diffused-type carcinoma (33%). CONCLUSIONS: Cytokeratin immunostaining is useful for detecting micrometastasis and microinvasion in submucosal gastric cancer. Tumor size, microscopic type, lymphatic invasion, and the depth of submucosal invasion are strongly associated with lymph node involvement. Micrometastasis in lymph nodes and microinvasion in primary lesion indicate an unfavorable outcome of the patients with submucosal gastric cancer.

Laparoscopic-assisted intraperitoneal chemotherapy for patients with scirrhous gastric cancer.

BACKGROUND: The prognosis for patients with scirrhous gastric cancer (SGC) is extremely poor. To improve the patients' prognosis, laparoscopic-assisted intraperitoneal chemotherapy (IPC) was introduced for SGC. In this study, we analyzed whether IPC reduced the number of cancer cells in the peritoneal cavity of patients or changed the gene expression levels of cytokines in the peritoneal cavity. We also investigated whether IPC improved the prognosis of patients with SGC. METHODS: Total RNA was extracted from 50 ml of peritoneal wash from 11 SGC patients before and after cisplatin-based IPC. The gene expression levels of survivin, c-myc, transforming growth factor-beta (TGF-beta), interleukin-2 (IL-2), IL-6, and IL-12 were analyzed using real-time reverse transcription-polymerase chain reaction (RT-PCR) assays. Also, carcinoembrionic antigen (CEA) messenger RNA (mRNA) was used to identify the number of gastric cancer cells in peritoneal washes by the real-time RT-PCR method. The gene expression levels of cytokines and the number of cancer cells in the peritoneal cavity were compared before and after cisplatin-based IPC treatment. RESULTS: Before IPC, the gene expression of IL-2 from peritoneal washes of patients was significantly suppressed compared to the controls (p = 0.029); however, other gene expression levels did not differ. In 7 cases, more than 90% of the cancer cells were removed from the peritoneal cavity after cisplatin-based IPC. These 7 cases were named the IPC effective group, and the remaining 4 cases were named the IPC ineffective group. In the IPC effective group, elevated IL-2 and IL-6 genes were detected in 5 (71%) and in 6 (86%) after IPC. The correlation between IPC effectiveness and elevated gene expression after IPC (IL-2: p = 0.137, and IL-6: p = 0.044) was observed. However, the 50% survival period of the IPC effective group (9 months) was not different from that of that of the IPC ineffective group (6 months, p = 0.267). CONCLUSION: IPC effectiveness may correlate with elevation of gene expression of inflammatory cytokines, such as IL-2 and IL-6 in the peritoneal cavity after IPC. However, the prognostic benefits of IPC for SGC patients remain unclear.

COX-2 correlates with F-box protein, Skp2 expression and prognosis in human gastric carcinoma.

The expression of cyclooxygenase (COX)-2 is induced by growth factors, tumor promoters and cytokines, and is correlated with carcinogenesis, tumor progression and inhibition of apoptosis. To clarify the pathological significance of COX-2, we examined the effect of a selective COX-2 inhibitor, NS398, on two human gastric carcinoma cell lines, MKN-45 and KATO-III, and the expression of Skp2, P27/Kip1 and COX-2 protein in human gastric carcinomas. NS398 inhibited cell growth in a time- and dose-dependent manner and exerted cell cycle arrest in the G0/G1 phase without induction of apoptosis in MKN-45, but had no effect in KATO-III. In MKN-45, NS398 induced up-regulation of P27/Kip1 and down-regulation of COX-2, cyclin D1 and Skp2. Immunohistochemistry using 63 surgically resected gastric carcinomas disclosed that COX-2 expression was correlated with Skp2 expression and that P27/Kip1 expression was inversely correlated with COX-2 and Skp2 expression. High levels of COX-2 or Skp2 were significantly correlated with poor survival (P=0.02 and P=0.004). Our results suggested that: a) NS398 induced inhibition of cell proliferation through cell cycle arrest and suppressed the expression of Skp2 in COX-2-expressing gastric carcinoma cells, and b) COX-2 contributes to the expression of Skp2 and poor survival in human gastric carcinomas.

Management protocol for scirrhous gastric cancer.

BACKGROUND: The prognosis for patients with scirrhous gastric cancer (SGC) is extremely poor. However, the management protocol for this type of cancer has not been well discussed. In this study, we retrospectively evaluated the management of SGC and we introduced a new treatment protocol for SGC. PATIENTS AND METHODS: Between 1991 and 2001, 58 patients with SGC were treated. Thirty-nine, who underwent gastrectomy, were divided into 3 sub-groups according to peritoneal metastasis (P) and peritoneal washing cytology (CY) status [P(-)/CY(-), P(-)/CY(+), and P(+)/CY(+)]. The survival rates of these 3 sub-groups were compared with patients who did not have a gastrectomy (n=19), retrospectively. From 2002, we started a new treatment protocol for SGC. Laparoscopic diagnosis of P or CY and intraperitoneal chemotherapy (IPC) were performed before performing laparotomy on 10 patients with SGC. RESULTS: The 5-year survival rate of the 19 patients in P(-)/CY(-) was 11.6%. The survival rates of patients with P(-)/CY(+) or patients with P(+)/CY(+) were no different from patients who did not have gastrectomy (pleural effusion or ascites negative). In 10 patients who were treated with the new protocol, 7 with P(-)/CY(-) underwent gastrectomy after IPC and 3 with P(+)/CY(+) underwent repeated IPC. CONCLUSION: Gastrectomy may not have prognostic benefit for patients with SGC with CY(+). Thus, we recommend laparoscopic diagnosis of peritoneal metastasis or peritoneal cytology before performing laparotomy on these patients.

Lymph node metastasis of gastric cancer: comparison of Union International Contra Cancer and Japanese systems.

BACKGROUND: The pN classification of gastric cancer (GC) in the Japanese system (Japanese Gastric Cancer Association; JGCA) is based on the site and distance of metastatic nodes from the primary tumour. Union International Contra Cancer (UICC) has recently proposed a classification system based on the number of nodes involved (TNM-1997). The aim of the present study is to assess which classification system is more suitable for providing a prognosis in advanced GC with lymph node metastasis. METHODS: A total of 224 patients who underwent curative gastrectomy (R0: UICC-TNM and Resection A and B: JGCA) and D2 lymphadenectomy between 1990 and 1999, and diagnosed as pT2, pT3 and pT4 GC were enrolled. Patients were followed until the end of 2002. The disease-free survival rates of patients were compared between the two-stage systems (UICC-TNM and JGCA). RESULTS: Using the JGCA system, there was a significant difference between the two survival curves (pN0 and pN1, P = 0.025; pN1 and pN2, P < 0.001; pN2 and pN3, P = 0.031), but the 5-year survival rate of 27 pN2 patients (32.7%) was not significantly different from that of 14 pN3 patients (34.3%, P = 0.994) using the UICC-TNM. In 47 patients with JGCA pN2, the 5-year survival rate of 18 patients with UICC-TNM pN1 (42.9%) was not significantly different from that of 18 patients with UICC-TNM pN2 (25.2%, P = 0.422) or from that of 11 patients with UICC-TNM pN3 (24.2%; P = 0.383). CONCLUSIONS: The JGCA system is more suitable for estimating the prognosis of Japanese patients with advanced GC than the UICC-TNM.

Gene expression levels of cytokines in peritoneal washings from patients with gastric cancer.

Peritoneal seeding is frequently detected in patients with gastric cancer. The peritoneal cavity is a compartment in which the immunologic host-tumor interaction can occur. Here, we investigated the gene expression levels of cytokines, and compared these gene expressions with the progression of gastric cancer. Total RNA was extracted from 50 ml of peritoneal washings from 78 patients with gastric cancer and 11 noncancerous patients. The gene expression levels of transforming growth factor-beta (TGF-beta), interleukin (IL)-2, IL-6 and IL-12 were analyzed by real-time reverse transcription-polymerase chain reaction. The gene expression levels of TGF-beta and IL-12 in 16 patients with peritoneal seeding (peritoneal metastasis or free cancer cells) did not differ from those in controls (n = 11) and stage I and II (n = 43) patients. However, the relative gene expression level of IL-2 in patients with peritoneal seeding (0.9) was lower than that in controls (1.4, p = 0.066) and stage I and II patients (1.4, p = 0.036). In contrast, the relative gene expression level of IL-6 in patients with peritoneal seeding (3.3) was higher than that in control (2.4, p = 0.064) and stage I and II patients (2.6, p = 0.065). Low IL-2 gene and high IL-6 gene expressions in the peritoneal cavity may correlate with cancer development in the peritoneal cavity in patients with gastric cancer.

Responses of cytokines and coagulation-fibrinolytic states to surgical stress following esophagectomy.

BACKGROUND/AIMS: Surgery for esophageal cancer is one of the most invasive treatments in gastrointestinal surgery. The aim of this study was to analyze perioperative kinetics of coagulation-fibrinolytic states in comparison with cytokines in order to investigate biological responses to surgical stress in patients undergoing esophagectomy. METHODOLOGY: Serum or plasma samples of 20 patients with esophageal cancer who had undergone esophagectomy were collected during the perioperative period. Serial concentrations of cytokines (IL-6, IL-8, IL-10), PMN-E, and coagulation-fibrinolytic agents (TAT and PIC) were measured and analyzed. RESULTS: There were significant increases in concentrations of both inflammatory and anti-inflammatory cytokines during the operative and postoperative courses. TAT and PIC levels also increased significantly intra- and postoperatively. The TAT/PIC ratio was elevated simultaneously with a predominance of inflammatory cytokines over anti-inflammatory ones. CONCLUSIONS: In addition to the profile of cytokines, the TAT/PIC ratio seems to be a sensitive and useful indicator in evaluating biological responses to surgical stress.

Expression of dihydropyrimidine dehydrogenase in cancer cells but not in stromal cells predicts the efficacy of fluorouracil treatment in patients with gastric carcinoma.

BACKGROUND: It is not known whether immunohistochemical quantification of dihydropyrimidine dehydrogenase (DPD) in cancer cells, stromal mononuclear cells and normal glands predicts the efficacy of fluorouracil (FU) derivatives inpatients with T3 gastric adenocarcinoma. MATERIALS AND METHODS: The levels of DPD in cancer cells, stromal cells and normal glands were measured immunohistochemically in 111 patients with T3 gastric carcinoma. Adjuvant chemotherapy with oral UFT (uracil/tegafur[4:1]) was administered to 95 patients for more than 1 year after surgery. RESULTS: Forty-two (37.8%) patients demonstrated high DPD expression in the cytoplasm of their cancer cells. In patients with low DPD expression in cancer cells, the 5-year survival rates were 64.5% in patients given FU and 42.8% in those not given FU (p=0.014). Neither stromal cells nor normal glands affected the efficacy of FU treatment in relation to their DPD expression. CONCLUSION: DPD expression in cancer cells but not in stromal cells could be a predictor of the efficacy of FU chemotherapy in patients with T3 gastric carcinoma.

Lymph node metastasis at the splenic hilum in proximal gastric cancer.

We performed splenectomy on patients with macroscopic advanced gastric cancer located at the proximal part of the stomach to achieve complete D2 lymphadenectomy. The aim of this study was to clarify the survival benefit of splenectomy in the treatment of gastric cancer. The clinical records of 225 patients who underwent total gastrectomy with splenectomy for gastric cancers involving the proximal part of the stomach were analyzed retrospectively. Nodal involvement at the splenic hilum (no. 10) was detected in 47 cases (20.9%). All of these cases were macroscopically diagnosed as positive for serosal invasion or regional lymph node metastasis at the time of surgery. In considering the lymphatic pathway from the primary tumor to no. 10 lymph nodes, metastasis at lymph nodes along the lesser curvature (no. 3), the short gastric vessels, or the gastroepiploic vessels (no. 4) may be good indicators of no. 10 lymph node metastasis. The overall survival of 47 patients with positive no. 10 lymph nodes was extremely poor. However, when curative surgery was performed, the survival of no. 10 positive patients was not different from that of no. 10 negative patients. Thus, for patients with advanced gastric cancer located in the proximal part of the stomach, D2 lymphadenectomy with splenectomy is recommended when patients show macroscopic evidence of serosal invaded tumor with regional lymph node metastasis.

Cyclooxygenase-2 expression in human gastric tubular adenomas and carcinomas; correlation with intratumoral microvessel density and apoptotic index.

BACKGROUND: Cyclooxygenase (COX)-2 plays an important role in carcinogenesis in various human malignancies. This study examined the relationship among COX-2 expression, angiogenesis and apoptosis in human gastric adenoma and carcinoma. MATERIALS AND METHODS: We examined the expression of COX-2 in 30 tubular adenomas and 11 carcinomas, comparing it with intratumoral microvessel density (IMVD) and apoptotic index (AI) by immunohistochemistry and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxygenin nick-end labeling (TUNEL) procedure. RESULTS: Immunohistochemistry demonstrated positive expression of COX-2 in 15 (50.0%) adenomas and in 50 (53.1%) carcinomas, respectively. The frequency of COX-2 expression was significantly higher in intestinal-type carcinomas than in diffuse-type, regardless of the tumor stage. The IMVD was significantly higher in the early and advanced carcinomas than in the adenomas and also higher in the COX-2-positive adenomas and carcinomas than in the negative ones. The AI was significantly higher in the adenomas than in the carcinomas and also in the COX-2-negative adenomas and intestinal-type early carcinomas than in their positive counterparts, respectively (p < 0.05). The IMVD and AI showed significant inverse correlation in both the adenomas (p=0.02, r=-0.64) and carcinomas (p=0.04, r=-0.18). CONCLUSION: COX-2 expression might be an early event in gastric tumorigenesis and provide a preferential advantage for tumor cell proliferation because of its vascular-rich microenvironment and escape from tumor cell apoptosis, especially in intestinal-type gastric carcinomas.

Neoangiogenesis in patients with gastric carcinoma in relation to the expression of vascular endothelial growth factor and thymidine phosphorylase.

BACKGROUND: We investigated the prognostic significance of microvessel density and the relationship between the expression of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP), and angiogenesis in patients with gastric carcinoma. MATERIALS AND METHODS: The expression of VEGF and TP, and the microvessel density were examined by immunohistochemistry in patients with gastric carcinoma invading the serosa. RESULTS: The prognosis of patients with low microvessel density in the cancerous tissue was significantly better than that of patients with high microvessel density. A multivariate analysis showed that microvessel density, lymph node metastasis and tumor size were independent prognostic indicators. VEGF was expressed in tumor cells and TP was expressed in both tumor cells and infiltrating cells. VEGF expression in tumor cells and TP expression in infiltrating cells significantly correlated with microvessel density. However, microvessel density was not correlated with TP expression in tumor cells. Combined analysis based on VEGF expression in tumor cells and TP expression in infiltrating cells revealed that microvessel density was the highest in VEGF-positive and TP-positive tumors and the lowest in VEGF-negative and TP-negative tumors. Microvessel density is an independent prognostic indicator in patients with gastric carcinoma invading the serosa. CONCLUSION: VEGF expression in tumor cells and TP expression in infiltrating cells may indicate the microvessel density.

Expression of Mcl-1 and p53 proteins predicts the survival of patients with T3 gastric carcinoma.

BACKGROUND: The expression of myeloid cell leukemia 1 (Mcl-1) and p53 proteins was investigated for clinicopathological and prognostic significance in patients with gastric carcinoma. METHODS: Mcl-1 protein was immunohistochemically examined in 182 patients with gastric carcinoma. The overexpression of p53 was also analyzed in T3 gastric carcinomas. RESULTS: The expression of Mcl-1 was detected in 127 (69.8%) patients with gastric carcinoma. Mcl-1 was detected significantly more frequently in the undifferentiated type ( P < 0.05) and in the advanced stage of disease ( P < 0.05). The prognosis of patients with an Mcl-1-positive tumor was significantly worse than that of those with an Mcl-1-negative tumor ( P < 0.05). Multivariate analysis revealed that the expression of Mcl-1 was an independent prognostic factor, as were lymph node metastasis and tumor size. There was no significant relationship between the expression of Mcl-1 and p53. In patients with T3 gastric carcinoma who underwent curative surgery; however, Mcl-1(-)/p53 (-) tumor demonstrated the best postoperative survival rate, whereas Mcl-1(+)/p53(+) tumor had the worst. CONCLUSION: The expression of Mcl-1 is an indicator of tumor progression and postoperative recurrence in patients with gastric carcinoma. Combined analysis of Mcl-1 and p53 proteins may accurately predict the survival of patients with T3 gastric carcinoma.

Immunohistochemical dihydropyrimidine dehydrogenase expression is a good prognostic indicator for patients with Dukes' C colorectal cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is an enzyme that catabolizes 5-fluorouracil (5-FU), which is widely used for chemotherapy in patients with advanced colorectal cancer (CRC). However, the clinical importance of tumor dihydropyrimidine dehydrogenase (DPD) expression in patients with CRC treated with 5-FU remains unclear. MATERIALS AND METHODS: We investigated DPD activities in normal mucosa (N) and tumors (T) by enzyme-linked immunosorbent assay (ELISA) in 64 surgically resected patients with Dukes' C CRC who were treated orally with postoperative adjuvant FU-based chemotherapy. We also immunohistochemically investigated DPD expression in these specimens. The clinicopathological importance of DPD activity and expression was evaluated in the patients. RESULTS: Positive DPD expression was detected in 28 tumors (43.8%) and tumor DPD activity significantly correlated with tumor DPD immunoreactivity (p=0.0121). Further, tumor DPD activity and immunoreactivity also correlated with lymph node metastatic status (p=0.0409). The disease-free survival rate of patients with positive-tumor DPD expression was significantly worse than that of patients with negative-tumor DPD expression (39.3% vs. 72.2%, p=0.0127). However, DPD activity in tumors or normal mucosa did not correlate with patient prognosis. Tumor DPD expression appeared to be an important poor prognostic factor in patients with Dukes' C CRC by multivariate analysis (p=0.013). CONCLUSION: Immunohistochemical DPD expression in tumors is a useful prognostic parameter in patients with Dukes' C CRC treated with postoperative adjuvant FU-based chemotherapy.

Clinical significance of the loss of KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in esophageal squamous cell carcinoma.

PURPOSE: Lymph node metastasis is the most important predictor of prognosis in esophageal squamous cell carcinoma (ESCC). Recently, KiSS-1 was cloned as a human metastasis suppressor gene, and an orphan G-protein-coupled receptor (hOT7T175) was identified as the endogenous receptor of the KiSS-1 product. However, the clinical importance of KiSS-1 and hOT7T175 gene expression in ESCC remains unclear. EXPERIMENTAL DESIGN: In this study, total RNA was extracted from tumors and noncancerous epithelia of 71 patients with ESCC who underwent surgical esophageal resection. The expression levels of KiSS-1, hOT7T175, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNAs were analyzed quantitatively by real-time reverse transcription-PCR and compared with the clinical findings. RESULTS: The mean KiSS-1:GAPDH and hOT7T175:GAPDH ratios of the tumors were 1.2 and 0.3 and were at the same levels as those in the noncancerous epithelia. The loss of KiSS-1 and hOT7T175 gene expression was detected in 38% and 61% of tumors. Loss of KiSS-1 and/or hOT7T175 gene expression was not correlated with tumor size or degree of tumor invasion but was found to be a significant predictor of lymph node metastasis. CONCLUSIONS: Loss of KiSS-1 or hOT7T175 gene expression may be an important biomarker for detection of lymph node metastasis in ESCC.

Protein and gene expression of tumor-associated antigen RCAS1 in esophageal squamous cell carcinoma.

RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is expressed on the tumor cell membrane and induces apoptosis on infiltrated immune lymphocytes. RCAS1 has been reported to correlate with the escape of tumor cells from host immune surveillance, and with poor prognosis. However, the clinical importance of RCAS1 protein and gene expression in esophageal squamous cell carcinoma (ESCC) has not been well investigated. In the present study, RCAS1 gene and protein expression levels were evaluated and compared with clinical findings in 67 patients with ESCC. Expression levels of RCAS1 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) messenger RNAs (mRNAs) from tumors and non-cancerous epithelia were analyzed quantitatively by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RCAS1 protein expression was analyzed by immunohistochemistry. The mean RCAS1/GAPDH ratio of tumors (0.7) was not different from that of non-cancerous epithelia (0.7, p=0.715). RCAS1 immunoreactivity was detected in 19 tumors (28.4%). The mean RCAS1/GAPDH ratio of tumors with RCAS1 protein positive (0.6) did not differ from tumors without RCAS1 expression (0.8, p=0.131). RCAS1 gene and protein expressions did not correlate with tumor size, depth of invasion, lymph node metastasis, or patient prognosis. Thus, RCAS1 gene or protein expression may not correlate with tumor progression in ESCC.

Quantitative reverse transcriptase polymerase chain reaction analysis for KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in hepatocellular carcinoma.

PURPOSE: KiSS-1 has been cloned as a human metastasis suppressor gene and an orphan G-protein-coupled receptor (hOT7T175) identified as the endogenous receptor of the KiSS-1 product. In the present study, we evaluated the clinical importance of KiSS-1 and hOT7T175 gene expression in hepatocellular carcinoma (HCC). METHODS: The expression levels of KiSS-1, hOT7T175 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) messenger RNAs (mRNAs) were analyzed quantitatively by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 60 surgically resected HCCs. The KiSS-1/GAPDH and hOT7T175/GAPDH ratios of tumors were compared with clinicopathological findings. RESULTS: Loss of KiSS-1 mRNA expression was not detected in HCCs. The mean KiSS-1/GAPDH ratio did not change between non-cancerous cirrhotic livers and carcinomas. On the other hand, the average hOT7T175/GAPDH ratios increased from non-cancerous livers (0.08) to carcinomas (0.48). Overexpression of KiSS-1 and hOT7T175 genes was recognized in 6 tumors, which were in an advanced stage and showed poor survival. CONCLUSION: Overexpression of KiSS-1 and hOT7T175 genes was frequently observed and correlated with HCC progression; thus, the possibility that overexpressed KiSS-1 and hOT7T175 peptides mediate growth signals into cancer cells in HCCs is suggested.

Survivin gene expression positively correlates with proliferative activity of cancer cells in esophageal cancer.

OBJECTIVE: The correlation between survivin gene expression and the occurrence of spontaneous apoptosis, proliferative activity of cancer cells, tumor angiogenesis, and abnormal p53 nuclear accumulation was evaluated in esophageal cancer. METHODS: A total of 57 patients, on whom surgical esophageal resection had been performed between 1993 and 2000, were enrolled in this study. Total RNA was extracted from tumors and noncancerous epithelia. Expression levels of survivin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) messenger RNA (mRNA) were analyzed quantitatively by real-time reverse transcriptase polymerase chain reaction (quantitative PCR). The proliferative activity of cancer cells, apoptotic cancer cells, microvessel density, and abnormal p53 nuclear accumulation were analyzed in these tumors. RESULTS: The expression level of tumor survivin mRNA described as survivin/GAPDH (s/G) ratio was higher than that of noncancerous tissue (p = 0.0003), but did not correlate with lymph node metastasis, with the depth of tumor invasion, with the occurrence of apoptosis or with tumor angiogenesis. However, the tumor s/G ratio positively correlated with the proliferative activity and p53 nuclear accumulation in cancer cells. The 5-year survival rate of 53 patients was 37% (we excluded 4 patients who died from operative complications from this survival study). The 5-year survival rate of 27 patients with a high tumor s/G ratio (28.6%) was lower than that of 26 patients with a low tumor s/G ratio (46.2%, p = 0.041). High tumor s/G ratio was detected as an important prognostic factor independent of tumor stage. CONCLUSION: Detection of survivin mRNA by quantitative PCR provided us with important prognostic and biological information regarding esophageal cancer patients.

Combination chemotherapy of S-1 and low-dose cisplatin for advanced gastric cancer.

BACKGROUND: A previous phase II study showed that S-1 (TS-1) was effective for advanced gastric cancers and had mild toxicity. The present study aimed to evaluate the efficacy and feasibility of this novel anticancer drug combined with low-dose cisplatin (CDDP). METHODS: Fifteen patients with unresectable and recurrent gastric cancer were enrolled. S-1 was administered orally twice daily after meals, at a standard dose of 80 mg/m2 per day according to the late phase II trial protocol. One course consisted of 28 days' consecutive administration followed by 14 days' rest. Five or 10 mg CDDP was infused three times each week (days 1, 3, 5) during S-1 administration on hospitalization, and once each week (day 1) at the outpatient clinic. Patients' backgrounds, response rates, response durations, and time to progression were investigated. RESULTS: None of the 15 patients had a complete response and 8 had a partial response. Therefore, the overall response rate was 53% (8/15). For site efficacy, the response rate was 50% (5/10) for the primary lesion, 50% (3/6) for liver metastasis, and 39% (5/13) for lymph node metastasis. The median response duration of the 8 responders was 4 months, and the time to progression was 3.3 months. Adverse reactions appeared in 60% (9/15). The incidence of adverse reactions of grades 3 and 4 was 13% (2/15) and 0%, respectively. As for hematological toxicity, grade 3 leukopenia was observed in 2 patients (2/15), but decreased hemoglobin level and thrombocytopenia did not appear. Although gastrointestinal adverse reactions appeared in 40% (6/15), all reactions were grades 1 and 2. Because of the mild toxicity, most patients were treated at the outpatient clinic. CONCLUSIONS: Combination chemotherapy of S-1 and low-dose CDDP is expected to be a useful chemotherapy for advanced gastric cancer.