Clinical significance of circulating tumor cells in peripheral blood from patients with gastric cancer.

BACKGROUND: The authors hypothesized that circulating tumor cells (CTCs) in patients with gastric cancer are associated with prognosis and disease recurrence. In this study, they evaluated CTCs in gastric cancer and clarified the clinical impact of CTCs. METHODS: In total, 265 consecutive patients with gastric cancer were enrolled. Fourteen patients were excluded from the analysis, including 12 patients who another cancer and 2 patients who refused the treatment. The remaining 251 patients were divided into 2 groups: 148 patients who underwent gastrectomy (the resection group) and 103 patients who did not undergo gastrectomy (the nonresectable group). Peripheral blood samples were collected before gastrectomy or chemotherapy. A proprietary test for capturing, identifying, and counting CTCs in blood was used for the isolation and enumeration of CTCs. RESULTS: CTCs were detected in 16 patients (10.8%) from the resection group and in 62 patients (60.2%) from the nonresectable group. The overall survival rate for the entire cohort was significantly lower in patients with CTCs than in those without CTCs (P < .0001). In the resection group, relapse-free and overall survival in patients with CTCs was significantly lower than in patients without CTCs (P < .0001). It was noteworthy that the expression of CTCs was an independent factor for determining the overall survival of patients with gastric cancer in multivariate analysis (P = .024). In the nonresectable group, the overall survival rate was significantly lower in patients with CTCs than in those without CTCs (P = .0044). CONCLUSIONS: The evaluation of CTCs in peripheral blood may be a useful tool for predicting tumor progression, prognosis, and the effect of chemotherapy in patients with gastric cancer.

Feasibility of sentinel node navigation surgery after noncurative endoscopic resection for early gastric cancer.

BACKGROUND AND AIM: Recently, the use of additional surgery after noncurative endoscopic resection has gradually increased due to the rapid spread of endoscopic treatments in selected patients with early gastric cancer. Sentinel node navigation surgery (SNNS) has also been recognized as a minimally invasive surgery with personalized lymphadenectomy in early gastric cancer. Here, we assessed the feasibility of SNNS after noncurative endoscopic resection for early gastric cancer. METHODS: Sixteen patients with early gastric cancer, in whom additional surgery had been indicated due to noncurative endoscopic resection, were enrolled. They underwent a gastrectomy with standard lymphadenectomy. One day before surgery, (99m) technetium-tin colloid was endoscopically injected into the submucosa around the tumor. After surgery, the uptake of radioisotope in dissected lymph nodes was measured using Navigator GPS. Then, all dissected lymph nodes were investigated by hematoxylin-eosin staining and immunohistochemistry using an antihuman cytokeratin monoclonal antibody. RESULTS: Hematoxylin-eosin staining demonstrated lymph node metastasis in two (12.5%) of 16 patients and in three (0.8%) of 382 nodes. However, immunohistochemistry showed that none of the patients had lymph node micrometastasis. Sentinel nodes (SNs) were identified in all patients. The mean number of SNs was 3.1 (range, 1-6). Among two patients with lymph node metastasis, the SNs, at least, contained positive nodes. Accordingly, the false-negative and accuracy rates were 0% and 100%, respectively. CONCLUSION: Our results indicate that SNNS may have potential as a further minimally invasive surgery in early gastric cancer patients after noncurative endoscopic resection.

[Outcomes of advanced gastric cancer patients treated with chemoradiation therapy].

We retrospectively analyzed 20 patients with advanced gastric cancer treated with chemoradiation(CRT). The patients consisted of 16 males and 4 females, 17(85%)of whom received intensive chemotherapy prior to CRT. Radiation was administered concurrently at 40 to 55 Gy according to the purpose of treatment. Sixteen patients received low dose CDDP and S-1. Of 8 patients who had measurable disease, one obtained CR and 3 obtained PR by the CRT. Fifteen percent of the distinct adverse effects of CRT were grade 3 leucopenia and 30% of them were grade 3 nausea. The 2-year-survival of patients who received CRT with curative intent was 91%, significantly higher than the percentage of those with palliative intent. Four patients who received R0 surgery following CRT are postoperatively healthy without symptoms of relapse. In conclusion, even though, 75% of the patients were already given chemotherapy prior to CRT, good outcomes were achieved unexpectedly. The combination of CRT and surgery may be a useful tool for chemo-resistant, locally advanced gastric cancer.

Cancerous HLA class I expression and regulatory T cell infiltration in gastric cancer.

BACKGROUND: Since antitumor immune reactions between tumors and intratumoral immunocytes have been verified in several human tumors, immunological therapeutic strategies must be considered to obtain the proper efficacy of tumor shrinkage under these conditions. Human leukocyte antigen (HLA) class I expression in cancer cells and degree of infiltration of regulatory T cells (Tregs) in the stroma have been regarded as important markers of antitumor immune reactions in the context of independent immunological mechanisms. In the current study, we investigated HLA class I expression and Treg cells infiltration in gastric cancer and discussed the clinical implications of this combinatory analysis in gastric cancer. PATIENTS AND METHODS: A total of 141 gastric cancer patients who received R0 gastrectomy at Kagoshima University Hospital were studied. Immunohistochemically, in 141 gastric cancer patients, HLA class I expression and Treg cell infiltration in cancerous tissue were evaluated using HLA class I (EMR8-5) and forkhead box p3 (FOXP3) monoclonal antibodies. The correlation between clinical factors and tumor-infiltrating Treg cells was analyzed. RESULTS: HLA class I expression was positively associated with depth of tumor invasion (P < 0.05). Infiltration of Foxp3-positive cells did not correlate with any clinicopathological markers. HLA class I expression had no association with Treg cell infiltration (r = 0.04). A better postoperative outcome was associated with fewer numbers of Treg infiltration (P = 0.034). A combination of HLA and Treg analysis may lead to a more accurate prediction of postoperative outcome (P = 0.02). CONCLUSIONS: Two different antitumor immunological markers, Treg infiltration and HLA class I expression, affected clinicopathological factors in gastric cancer by different mechanisms. Thus, an immunological combination of HLA class I expression and Treg cell infiltration may more accurately predict postoperative outcome. Immunological balance needs to be restored after evaluation of each immunological deficit in gastric cancer.

Expression of stanniocalcin 1 as a potential biomarker of gastric cancer.

OBJECTIVE: We investigated stanniocalcin 1 (STC 1) expression to assess its clinical utility as a blood marker in patients with gastric cancer and evaluated its biological impact in terms of tumor aggressiveness. METHODS: Blood specimens from 93 patients with gastric cancer and 21 normal healthy volunteers were assessed by quantitative reverse transcription-polymerase chain reaction for STC 1 mRNA expression. RESULTS: The relative numbers of STC 1 mRNA copies were significantly higher in gastric cancer cell lines and in blood specimens from patients with gastric cancer than in blood specimens from healthy volunteers (p = 0.0001 and p = 0.003, respectively). The sensitivity and specificity of STC 1 mRNA expression for discriminating patients with gastric cancer from healthy volunteers were 69.9 and 71.4%, respectively. Furthermore, the sensitivity for STC 1 mRNA was higher than that for serum carcinoembryonic antigen and carbohydrate antigen 19-9. The presence of STC 1 expression was significantly correlated with depth of tumor invasion and tumor stage (p = 0.032 and p = 0.013, respectively). CONCLUSION: Our data strongly suggest that STC 1 is a potentially useful blood marker for predicting biological tumor aggressiveness in patients with gastric cancer.

Clinical significance of circulating tumor cells in the response to trastuzumab for HER2-negative metastatic gastric cancer.

PURPOSE: The prognosis of metastatic gastric cancer has improved due to trastuzumab in patients with HER2 positive. Circulating tumor cells (CTCs) have been examined as a prognostic predictor in gastric cancer. The clinical advantage of trastuzumab was examined in gastric cancer patients with HER2-negative tumor tissues and HER2-positive CTCs. METHODS: A total of 105 patients with metastatic or recurrence gastric cancer were enrolled. All patients were examined HER2 expression in CTC using the CellSearch system in blood specimens. RESULTS: CTCs were detected in 65 of 105 patients (61.9%) and 61 patients were divided into three groups: Group A (n = 27), histological HER2-positive; Group B (n = 17), histological HER2-negative and HER2-positive CTCs; and Group C (n = 17), HER2-negative on histology and CTCs. Patients received capecitabine plus cisplatin. Groups A and B were additionally treated by trastuzumab. There was no relationship between tumor tissues and CTCs in HER2 expression. Even if group B had no histological HER2 expression, group B showed a good prognosis as same as group A, and group C had a significantly worse overall survival than groups A and B. The multivariate analysis demonstrated that HER2-expression on CTCs was an independent prognostic factor for both overall and progression-free survival. CONCLUSION: The present results indicate the potential clinical utility of trastuzumab combined chemotherapy in patients with HER2-positive CTCs even if they are histologically HER2-negative.

[Combination chemotherapy resulting in complete response of huge lymph node metastases in undifferentiated gastric cancer--case report].

A 67-year-old male was admitted to Kagoshima University Hospital and received distal gastrectomy with D1 lymph node dissection under the diagnosis of early gastric cancer. Five years later, a retroperitoneal tumor 12 cm in diameter was detected by abdominal CT. Although the tumor was curatively resected, rapid recurrence was identified in the same retroperitoneal space. Chemoradiation therapy (radiation 50 Gy and bleomycin) for residual tumor was performed, but the tumor rapidly grew. The patient was given cisplatin (CDDP) and gemcitabine (GEM) following CPT-11 treatment. The recurred tumor was remarkably shrunken and completely regressed after eight courses of the chemotherapy. The retroperitoneal tumor was finally diagnosed as lymph node relapse from undifferentiated gastric cancer. This rare case of undifferentiated gastric cancer showed a complete lymph node response following combination chemotherapy of CDDP and GEM. Combination chemotherapeutic regime with CDDP and GEM seems to be useful for treatment of undifferentiated gastric cancer.

Roux-en-Y Plus Distal Jejunal Pouch After Total Gastrectomy: A Prospective Study.

BACKGROUND/AIM: We previously described the safety of distal jejunal pouch with Roux-en-Y reconstruction after total gastrectomy. The present prospective study evaluated its clinical benefit. PATIENTS AND METHODS: Forty-five patients with gastric cancer were preoperatively assigned to groups who underwent Roux-en-Y reconstruction with jejunal pouch (PRY) (n=23) or without pouch (RY) (n=22). Age, sex, grade of lymph node dissection, splenectomy and mode of laparotomy were analyzed, and body mass index (BMI), volume of food intake at one sitting and blood chemistry (total protein, hemoglobin, iron and cholesterol) were periodically assessed in both groups. RESULTS: Post-surgical mortality and severe morbidity did not occur. Three and four patients in the PRY and RY groups, respectively, died of gastric cancer recurrence during the study. BMI at six months after surgery was significantly higher in the PRY than in the RY group (p<0.05). The percentage of food intake at one year after the procedure was significantly higher in the PRY than in the RY group (p<0.05). CONCLUSION: The distal jejunal pouch ameliorated postoperative weight loss and increased food intake. A distal jejunal pouch with PRY reconstruction may confer significant clinical advantages after total gastrectomy. The long-term clinical benefit of this procedure should be evaluated.

Clinical implication of CXCL12 expression in gastric cancer.

PURPOSE: Recent research has revealed that tumor cells expressing chemokine receptors have a crucial impact on patient survival. However, there is no information regarding chemokine expression in gastro-intestinal cancer. This study immunohistochemically investigated CXCL12 expression in gastric cancer and evaluated its association with clinical factors, including patient prognosis. METHOD: A total of 185 gastric cancer patients receiving curative gastrectomy were assessed. CXCL12 expression was evaluated by immunohistochemical analysis. Tumors with CXCL12-positive cancer cells were regarded as CXCL12 positive, and according to the degree of CXCL12 expression, patients were divided into three groups (weak, 31 cases; moderate, 27 cases; strong, 20 cases). Correlations between CXCL12 expression and clinical factors in gastric cancer were then determined. RESULTS: CXCL12 was found in the cellular membrane of cancer cells. Seventy-four of 185 patients were classified into the CXCL12-positive group. Patients were divided into three groups according to the positivity of CXCL12 expression. Significant associations between CXCL12 and lymph node metastases (p < 0.05), depth of invasion (p < 0.01), lymphatic invasion (p < 0.01), tumor diameter (p < 0.05), and clinical stage (p < 0.01) were seen. Univariate analysis revealed that the CXCL12-positive group had significantly poorer surgical outcome than the CXCL12-negative group (p < 0.01). Multivariate analysis revealed CXCL12 to be an independent prognostic factor in gastric cancer (p = 0.02). CONCLUSION: Cancerous CXCL12 positivity was determined to be an independent prognostic factor in gastric cancer, with CXCL12-positive gastric cancer showing more-aggressive behavior. Autocrine CXCL12 secretion from tumor cells may activate CXCR-4 on the tumor cells, which may be related to of the viability of distant metastases.

The successfully curative treatment of advanced gastric adenocarcinoma with multiple liver metastases and paraaortic lymph node metastases by salvage operation following the biweekly paclitaxel and S-1 combination chemotherapy: a case report.

We report the case of 67-year-old man who was given a diagnosis of advanced gastric adenocarcinoma. Complete response of multiple liver and paraaortic lymph node metastases occurred in this patient after combination chemotherapy with systemic injection of paclitaxel and oral administration of novel dihydropyrimidine- dehydrogenase- inhibitory fluoropyrimidine (S-1). Following 7 courses of the biweekly paclitaxel and S-1 combination chemotherapy, the patient underwent total gastrectomy with D3 extended lymph node dissection. According to the operative findings, the tumor was curatively removed along with the liver metastases and paraaortic lymph node metastases. Biopsy of the liver was performed and the pathological diagnosis indicated no gastric adenocarcinoma cells. The pathological report showed that the lymph node metastases had completely disappeared with single exception and minute cancerous lesions were identified in the gastric mucosa and submucosa. Therefore, the histological efficacy was evaluated as Grade 2. For postoperative chemotherapy, oral S-1 administration only was chosen. However, 6 months later, biweekly paclitaxel and S-1 combination chemotherapy was administered in sequence as a second adjuvant chemotherapy because the serum level of the tumor marker was elevated. The patient is fine and has not shown any recurrence at other sites 37 months after surgery. Salvage surgery following paclitaxel and S-1 chemotherapy may be feasible for patients with advanced gastric cancer and complete regression of distant metastases. Biweekly paclitaxel and S-1 combination chemotherapy has been used safely and its administration may be continued for a long time in an outpatient clinic setting for the treatment of advanced gastric cancer.

Prognostic value of CCR7 expression in gastric cancer.

BACKGROUND/AIMS: Chemokine receptor CCR7 is a key molecule for migration of lymphocytes and dendritic cells into lymph nodes. Expression of CCR7 in tumor cells has been reported in malignancies, and CCR7 expression in tumor cells has been investigated in vitro and in vivo. However, there is little information regarding the clinical implications of CCR7-positive gastric cancer. METHODOLOGY: A total of 224 gastric cancer patients who underwent curative surgery in Kagoshima University Hospital were enrolled. CCR7 expression in the primary tumor was detected by immunohistochemically. Patients showing more than 10% positivity for CCR7 were defined as having high CCR7 expression, as previously reported. RESULTS: CCR7 expression was detected in cytoplasm and membrane of tumor cells and inflammatory cells in the tumor nest. CCR7-positive patients exhibited deeper tumor invasion, more frequent lymph node metastasis, higher rates of lymphatic invasion (p < 0.01) and more venous invasion (p < 0.05) than CCR7-negative patients. Multivariate regression analysis showed that the most significant clinical factor for CCR7 was lymph node metastasis followed by lymphatic invasion. CCR7-positive gastric cancer patients had significantly poorer surgical outcomes than CCR7-negative patients (p < 0.01). However, CCR7 was not selected as an independent prognostic factor. CONCLUSIONS: Our results suggest that CCR7 expression in gastric cancer is related to the onset of preferential conditions for lymphatic spread, such as lymph node metastasis. Although CCR7 expression is not an independent prognostic factor, it may show strong correlations with other lymphatic factors. CCR7 expression of preoperative biopsy specimen can predict lymph node metastasis because of the close correlation with lymphatic factors.

[Clinical efficacy of biweekly paclitaxel and S-1 regimen for 14 gastric cancer patients with liver metastases].

We evaluated efficacy of biweekly paclitaxel and S-1 for advanced gastric cancer patients with liver metastases. A total of 14 patients had multiple liver metastases. None of whom received chemotherapy before the current regimen. The patients were given 80 mg-130 mg/m(2) of paclitaxel every two weeks and 80 mg of S-1 during the first two weeks. Chemotherapeutic efficacy for liver metastases was 50%. The 3-year-survival rate of the 14 patients was 50%, which was significantly higher than that of historical control patients (p<0.01). Two patients received gastrectomy with curative intent. Histological exploration revealed disappearance of liver metastases. In conclusion, biweekly paclitaxel+S-1 regimen was one of the promising therapies for advanced gastric cancer patients with liver metastases.

Clinical significance of nuclear expression of spleen tyrosine kinase (Syk) in gastric cancer.

Spleen tyrosine kinase (Syk) expression was immunohistochemically examined in 250 gastric cancer patients. The rate of positive Syk expression was 42.4%. Syk expression was significantly associated with T1 tumors, lymphatic invasion, venous invasion and lymph node metastasis (P<0.0001). The 5-year survival rate was significantly higher among patients with nuclear Syk expression than among those who were negative for Syk expression (P=0.0003). However, Syk expression was not an independent prognostic factor. Loss of Syk expression was closely related to the malignant property of gastric cancer in the context of tumor depth and lymph node metastasis, especially in early gastric cancer.

A phase I combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer.

The aim of the current study was to determine the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of a combination of paclitaxel and S-1 in patients with advanced gastric cancer. Fifteen patients were enrolled. The dose for S-1 was set at 80 mg/m2/day (days 1-14), while the dose for paclitaxel increased by 10 mg/m2 for every three patients, with a starting dose of 100 mg/m2 and was given biweekly on day 1 and 15. There was no severe toxicity (grade 4) recorded in patients receiving up to 120 mg/m2 of paclitaxel. Leukopenia/neutrophilia with grade 1 to 3 occurred in six patients up to level 3. At 130 mg/m2 of paclitaxel, grade 4 leukocytopenia and neutropenia events and grade 3 diarrhea developed in one out of three patients. One patient in another group of three patients that were enrolled at level 3, developed grade 4 granulocytopenia with fever (a body temperature higher than 38 degrees C) and grade 3 leukocytopenia. Eight patients, out of a total of 15, showed a partial response, resulting in an objective response rate of 53%. Five patients received gastrectomy. Median survival time was 428 days and the 1 year survival rate was 53%. Biweekly paclitaxel/S-1 combination chemotherapy could be safely used for the treatment of advanced gastric cancer. The recommended doses for a phase II study with paclitaxel and S-1 are 120 mg/m2 and 80 mg/m2, respectively.

HLA-G expression in gastric cancer.

BACKGROUND: Ectopic HLA-G expression in tumor cells may indicate immune escape from the host immune defense via the inhibitory receptor on natural killer (NK) cells. However, there is little information on HLA-G expression in gastric cancer. PATIENTS AND METHODS: HLA-G expression was immunohistochemically analyzed in 115 gastric cancer patients and the clinical implications of its expression in gastric cancer were assessed. Moreover, NK cell infiltration into the primary tumor was evaluated using anti-CD57 antibodies. RESULTS: The HLA-G-positive group had a more differentiated histology, less nodal invasion and earlier clinical stage than the HLA-G-negative group and these differences were significant. The 5-year survival rate in the HLA-G-positive group was 78%, which was significantly higher than that in the HLA-G-negative group (51%). NK cell infiltration into the tumor tended to be negatively correlated with HLA-G expression. CONCLUSION: Our results suggest a high frequency of HLA-G expression in early gastric cancer. However, this may not be directly related to aggressive tumor behavior via escape from the host antitumor immune defense. Further investigation is required.

Down-regulation of Gadd45 expression is associated with tumor differentiation in non-small cell lung cancer.

BACKGROUND: Evidence suggests that the growth arrest and DNA damage-inducible gene 45 (Gadd45) is an effective indicator of poor prognosis or malignant potential in solid tumors. The purpose of this study was to determine the gene expression patterns and clinical relevance of Gadd45 in tumor specimens of non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Using a quantitative real-time RT-PCR method, the mRNA expression of Gadd45 was analyzed in tumor and paired normal-appearing tissues of 66 patients with NSCLC. The gene expression data for each patient were matched to the clinicopathological parameters. RESULTS: Gadd45 mRNA expression was detectable in all (100%) specimens analyzed. The overall median mRNA expression level of Gadd45 was approximately 10-fold lower in tumor tissues than in matching normal lung tissues (p < 0.001). High intratumoral Gadd45 expression was significantly associated with a poorer histological grading (p = 0.041). CONCLUSION: The significant decrease in Gadd45 expression in tumors compared with normal tissue and its association with histological grading suggest a role for Gadd45 in the differentiation pathway of NSCLC.

Biological aggressiveness of alpha-fetoprotein (AFP)-positive gastric cancer.

BACKGROUND/AIMS: Alpha-fetoprotein (AFP)-positive gastric cancer (APGC) which occupied well-defined gastric cancer entity, reportedly has an aggressive behavior with hematogenous metastasis. However, little information regarding the clinicopathological and biological behaviors of APGC is available due to the small size of reported series. METHODOLOGY: We retrospectively analyzed the clinical features of APGC in 556 patients with gastric cancer who underwent preoperative measurement of serum AFP levels and gastrectomy in Kagoshima University Hospital. APGC was regarded as any cancer with preoperative serum AFP levels above the cutoff level of 5 ng/mL. Clinicopathological features of APGC were assessed using the General Rules of Gastric Cancer. Of the 556 patients, 97 patients underwent immunohistochemical evaluation of AFP expression in the primary tumor. Both p53 and MIB-1 expression were examined at the same time and compared with AFP expression. Biological aggressiveness of APGC was estimated. RESULTS: Serum AFP positivity was detected in 4.3% of cases (range, 0-2202 ng/mL). Patients were divided into 25 APGC patients and 531 non-APGC patients. APGC displayed deeper tumor invasion, increased nodal involvement, increased venous invasion, and increased CEA concentrations compared to gastric cancer in non-APGC. Surgical outcomes for APGC were significantly worse than those for non-APGC (p < 0.05). All recurrences in patients with APGC involved hepatic metastasis. Abnormalities of p53 were more frequent for APGC than for non-APGC (p < 0.05). CONCLUSIONS: APGC was strongly associated with hematogenous factors such as venous invasion, hepatic metastasis and aggressive biological factors (p53 abnormalities). Considering the aggressive biological behavior of APGC, we must closely follow up for patients with such tumor, including postoperative adjuvant therapy.

P53 and MIB-1 expression in gastrointestinal stromal tumor (GIST) of the stomach.

BACKGROUND/AIMS: Routine clinical approaches for evaluating the risk of recurrence in patients with gastrointestinal stromal tumor (GIST) of the stomach have been limited. Some biomolecular markers may yield more useful information in identifying patients having a higher risk of recurrence. In the current retrospective study, we selected MIB-1 and p53 expression as markers to detect at-risk patients. METHODOLOGY: We enrolled 31 gastric GIST patients who underwent gastrectomy at Kagoshima University Hospital. Patients were classified into two groups based on mitosis and tumor diameter. p53 and MIB-1 expression in the primary tumor were detected immunohistochemically. RESULTS: The patients were classified as having a malignant GIST (20 cases), a benign GIST (11 cases). MIB-1 labeling index (LI) varied from 1 to 32% (average 7.8%). The MIB-1 LI for malignant GISTs was 6.3 +/- 6.4%, which was significantly higher than the 3.2 +/- 2.5% observed for benign GISTs (p < 0.01). The 3 patients positive for p53 died as a result of GIST recurrence. CONCLUSIONS: In addition to routine pathological evaluation, expression of p53 and MIB-1 may provide more accurate information regarding the risk of GIST recurrence. Especially, p53 expression of the tumor may indicate patients having a high risk of recurrence.

[Combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer].

In the present article, we report the results of phase I/II combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer. In the phase I study, we could determine the recommended dose for the phase II study with paclitaxel and S-1 to be 120 mg/m2 and 80 mg/m2, respectively. The side effect was not so severe. The overall response was 53%. In conclusion, biweekly paclitaxel and S-1 administration can be safely combined for the treatment of advanced gastric cancer. This combined therapy represents a novel and active treatment regimen with low toxicity and can be defined as safe and effective. Now we are analyzing the result of the phase II study.

Overexpression of survivin mRNA is associated with a favorable prognosis following neoadjuvant radiochemotherapy in esophageal cancer.

Survivin is a member of the inhibitor of apoptosis (IAP) gene family known to be involved in resistance to chemo- and radiation therapy. We examined the potential of quantitative survivin mRNA expression to predict histopathologic tumor response and prognosis following neoadjuvant radiochemotherapy (cis-platinum, 5-FU, 36 Gy) in patients with locally-advanced esophageal cancer (cT2-4, Nx, M0). Tumor (T) and normal tissue (N) samples from 51 patients were collected by endoscopic biopsy prior to treatment. Survivin mRNA expression was analyzed by quantitative real-time RT-PCR assays. Histomorphologic regression was defined as a major response when resected specimens contained <10% of residual vital tumor cells or if a pathologically complete response was achieved. Some 7/51 patients had progressive disease and 44/51 proceeded to surgical resection. Of 44 resected tumors, 17 (31.4%) showed a major and 27 (61.4%) showed a minor histopathologic response; the survival rates were significantly different (p<0.01). Median absolute survivin expression was 5.1 in the tumor and 2.4 in corresponding normal tissue samples (Wilcoxon, p<0.001). Median relative (T/N ratio) survivin mRNA expression was 1.7. Survivin mRNA expression levels did not show a significant association with histomorphologic regression. Relative survivin mRNA expression of a T/N ratio >1 indicated a favorable prognosis (log-rank, p<0.003). Expression levels of survivin mRNA in pretherapeutic biopsies did not predict the extent of histomorphologic tumor regression following preoperative radiochemotherapy for esophageal cancer. However, overexpression of survivin mRNA in pretreatment biopsies (T/N ratio >1) was associated with superior survival probabilities.