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.

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.

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.

A phase II, randomized study of aprepitant in the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapies in colorectal cancer patients.

The present study aimed to study the efficacy of aprepitant in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC) for colorectal cancer (CRC), and comprised a multicenter, phase II, open-label, randomized, parallel comparative study conducted as part of the Kagoshima aprepitant study for colon cancer in Japan. Patients with advanced or recurrent CRC were treated with standard MEC regimens (FOLFOX, XELOX or FOLFIRI) and received either standard chemotherapy [5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) + dexamethasone] or aprepitant regimen chemotherapy (5-HT3 RA + reduced-dose dexamethasone + aprepitant). The primary endpoint of the present study was the proportion of patients who achieved a complete response (CR) during the overall, acute, and delayed phases of the first planned chemotherapy cycle. Secondary endpoints were complete protection, the proportions of patients without emetic episodes or nausea, patients with no more than moderate nausea during the overall, acute and delayed phases, and the time to treatment failure. The CR rates in the overall, acute and delayed phases were similar in the aprepitant and the standard-regimen groups. Additionally, there were no significant differences in secondary endpoints between the two groups. In summary, aprepitant in combination with 5-HT3 RA and reduced-dose corticosteroids was well tolerated and effective in preventing CINV associated with moderately emetogenic antitumor agents in Japanese patients with CRC.

Mutations in the mitochondrial DNA D-Loop region occur frequently in adenocarcinoma in Barrett's esophagus.

Mitochondrial DNA (mtDNA) is known for high mutation rates caused by lack of protective histones, inefficient DNA repair systems, and continuous exposure to mutagenic effects of oxygen radicals. We examined the frequency of mutations in the mtDNA D-Loop region in 20 patients with Barrett's carcinoma and associated Barrett's epithelium by automated DNA sequencing. Mutations were detected in eight of 20 (40%) patients in tumor and/or tumor-associated Barrett's epithelium. In six of eight positive cases, the mutations were detected only in the tumor, one of eight showed mutations in tumor and Barrett's epithelium, and one of eight only in Barrett's epithelium. The degree of dysplasia in Barrett's epithelium was classified low-grade in one and high grade in the two specimens. There was no association of mtDNA D-Loop mutations with histopathological stage of disease or tumor grading. We present the first study of frequent occurrence of mutations in the mtDNA D-Loop regions in adenocarcinomas in Barrett's esophagus. Furthermore, this study supports the hypothesis that oxidative damage might be a mechanism for the induction of adenocarcinoma in Barrett's esophagus. Since mutations were identified in tumor-associated dysplastic Barrett's epithelium, they also might become a marker for the malignant potential of Barrett's epithelium.

High specificity of quantitative excision repair cross-complementing 1 messenger RNA expression for prediction of minor histopathological response to neoadjuvant radiochemotherapy in esophageal cancer.

PURPOSE: The excision repair cross-complementing 1 (ERCC1) gene is coding for a nucleotide excision repair protein involved in the repair of radiation- and chemotherapy-induced DNA damage. We examined the potential of quantitative ERCC1 mRNA expression to predict minor or major histopathological response to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, and 36 Gy of radiation) followed by transthoracic en bloc esophagectomy in patients with locally advanced esophageal cancer (cT(2-4), N(x), M(0)). EXPERIMENTAL DESIGN: Tissue samples were collected by endoscopic biopsy before treatment. RNA was isolated from biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Relative mRNA levels (tumor/normal ratios) were calculated as (ERCC1/beta-actin in tumor)/(ERCC1/beta-actin in paired normal tissue). ERCC1 expression levels were correlated with the objective histopathological response in resected specimens. Histomorphological regression was defined as major response when resected specimens contained <10% of residual vital tumor cells or in case a pathologically complete response was achieved. RESULTS: Twelve of 36 tumors showed a major histopathological response, and 24 of 36 showed a minor histopathological response. Relative expression levels of ERCC1 of >1.09 were not associated with a major histopathological response (sensitivity, 62.5%; specificity, 100%) and 15 of 24 patients with minor histopathological response to the delivered neoadjuvant radiochemotherapy could be unequivocally identified. This association of dichotomized relative ERCC1 mRNA expression and histopathological response was statistically significant (P < 0.001). CONCLUSIONS: Relative expression levels of ERCC1 mRNA determined by quantitative real-time reverse transcriptase-PCR appear highly specific to predict minor response to our neoadjuvant radiochemotherapy protocol in patients with locally advanced esophageal cancer and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number (42%) of patients.

Evaluation of colloid size for sentinel nodes detection using radioisotope in early gastric cancer.

The purpose of this study was to investigate the relationship between colloid size and the detection of sentinel nodes (SN) in early gastric cancer. Three size of 99mTechnetium-tin colloids (500, 100 and 50 nm) were preoperatively injected into the submucosa under endoscopic control. Lymph node metastasis and micrometastasis was examined. RI-uptake in the hottest nodes and the total RI-uptake in the hot nodes were highest in the size of 100 nm. At least one lymph node metastasis, including micrometastasis, was included in the hot nodes. RI-labeled colloid size was one of the important factors to detect SN in early gastric cancer.

Disseminated cancer cells in the blood and expression of sialylated antigen in gastric cancer.

BACKGROUND: In gastric cancer, disseminated cancer cells (DCC) can be detected in peripheral blood using bio-molecular techniques. It is known that patients having DCC exhibit a high occurrence of postoperative relapse in gastrointestinal cancer. However, more than half of gastric cancer patients having positive DCC do not show cancer relapse. Sialylated Lewis antigens are considered to be crucial molecules in the metastasis of disseminated cancer. The current study investigated whether combination analysis of DCC and sialylated Lewis antigen are useful in estimating the recurrence risk of gastric cancer. PATIENTS AND METHODS: Subjects were 106 consecutive gastric cancer patients who underwent curative gastrectomy. DCC in the peripheral blood were detected using the carcinoembryonic antigen (CEA)-mRNA by RT-PCR method. Sialylated Lewis antigen expression (sLeA and sLeX) of the primary tumor was assessed immunohistochemically. RESULTS: Of 106 gastric cancer patients, 43 (40%) were positive for DCC. Immunohistochemically, 53 (50%) and 49 (46%) patients were positive for sLeA and sLeX, respectively. The presence of DCC did not correlate with sLeA and sLeX expression in gastric cancer. Postoperative tumors were present in 19 patients (7 hematogenous and 12 non-hematogenous), 12 of which were positive for DCC. Six sLeA-positive patients (26%) with DCC and 13 sLeX-positive patients (57%) with DCC suffered from postoperative recurrence of gastric cancer. The p value of CEA-mRNA and sLeX combination analysis was more significant (p<0.01) than that of CEA-mRNA alone (p=0.02). CONCLUSION: Analyzing both DCC and sLeX expression in gastric cancer may enable more accurate prediction of postoperative recurrence.

Clinical significance of circulating tumor cells in blood by molecular detection and tumor markers in esophageal cancer.

BACKGROUND: The clinical significance of circulating tumor cells in the blood during surgery has not been elucidated in esophageal squamous cell carcinoma (ESCC). We evaluated the relationship between circulating tumor cells and clinicopathologic findings, compared with that of serum squamous cell carcinoma (SCC) antigen and carcinoembryonic antigen (CEA), in ESCC. METHODS: Blood samples from 54 consecutive patients were obtained from the peripheral artery and the superior vena cava at three points in time: immediately before surgery, and before and after tumor resection. CEA-specific reverse transcriptase-polymerase chain reaction (RT-PCR), which can quantify circulating tumor cells in blood, was performed. The preoperative values of serum SCC antigen and CEA were also obtained for all patients. RESULTS: CEA messenger RNA (CEA mRNA) was detected in the blood of 31 out of 54 patients (57.4%). CEA mRNA positivity was detected most frequently after tumor resection and correlated with nodal status and stage grouping. The incidence of total recurrence and blood-borne recurrence was significantly greater in patients with CEA mRNA positivity than in those with CEA mRNA negativity (P =.036 and.0026, respectively). Preoperative serum levels of SCC antigen and CEA did not correlate with clinicopathologic findings and tumor recurrence. CONCLUSIONS: CEA mRNA detected by RT-PCR was more predictive of tumor recurrence than serum tumor markers. Effective adjuvant therapy is recommended for patients with CEA mRNA positive expression.

Lymph node micrometastasis and lymphatic mapping determined by reverse transcriptase-polymerase chain reaction in pN0 gastric carcinoma.

BACKGROUND: The purposes of this study were to examine lymph node micrometastasis (LMM) by reverse transcriptase-polymerase chain reaction (RT-PCR) method, and clarify the initial nodes involved by metastatic disease according to tumor location. METHODS: We examined 312 lymph nodes obtained from 50 patients with node-negative gastric carcinoma. RT-PCR and immunohistochemistry were performed. The clinical characteristics of LMM were investigated, and the map of LMM was made according to tumor location. RESULTS: The number of patients and LMM detected by RT-PCR was 14 and 17 and by immunohistochemistry was 7 and 8, respectively. RT-PCR was a more sensitive method than immunohistochemistry. LMM by RT-PCR correlated with depth of tumor invasion and lymphatic invasion. Regarding pT1 tumor, 9 patients with LMM had tumors that were of the macroscopically depressed type and 2 cm or more in diameter. According to the lymphatic map, right pericardial lymph nodes and lymph nodes along the lesser curvature were the initial nodes involved in the upper third of the stomach. Right pericardial lymph nodes, lymph nodes along the lesser curvature, and infrapyloric nodes were more important initial metastatic sites in the middle third of the stomach, and lymph nodes along the lesser curvature and infrapyloric nodes in the lower third. CONCLUSIONS: We demonstrated the relationship between LMM and clinicopathologic factors, especially in pT1 tumor. The mapping of LMM may prove useful for selecting the optimal treatment.

Infiltration of antitumor immunocytes into the sentinel node in gastric cancer.

The sentinel node (SN) is regarded as the first drainage lymph node, and tumor cells are considered likely to directly affect the SN. However, few reports have identified differences between SNs and non-SNs in cancer patients. Subjects in this study included 27 patients with gastric cancer who underwent curative operation and intraoperative detection of SNs by radioisotope methods. The mean number of SNs was 3.2 (range 1 to 5). Degree of infiltration of natural killer cells, dendritic cells, MIB-1 labeling index, and CD3-zeta expression of lymphocytes in SNs and non-SNs were examined by means of immunohistochemical methods. Degree of infiltration was compared according to depth of invasion and between SNs and non-SNs. Patients with early-stage cancer displayed a greater degree of infiltration of MIB-1 labeling index and CD3-zeta expression than patients with pT2 or pT3 lesions (P<0.05). The MIB-1 labeling index in SNs was significantly lower than that in non-SNs (P<0.05). However, no significant difference was observed in infiltration of natural killer cells, dendritic cells, or CD3-zeta. Morphologic changes of dendritic cells in SNs were not definite. Our results suggest that SNs in gastric cancer might not be suppressed, unlike in breast cancer and melanoma. SN paralysis may depend on tumor- and organ-specific characteristics or exogenous stimulation from the gastric mucosa. Studies in progress will help to identify immunologic paralysis of the SN in various types of cancer. Attention must therefore be paid to organ specificity.

Bone marrow micrometastasis detected by RT-PCR in esophageal squamous cell carcinoma.

The clinical implications of bone marrow micrometastases (BMM) detected by RT-PCR in esophageal squamous cell carcinoma (ESCC) have not been elucidated. We evaluated the relation between the presence of BMM, both before and after surgery, and clinicopathologic findings in patients with ESCC. Bone marrow samples from 48 patients with ESCC were obtained from the iliac crest before and after surgery. After total RNA was extracted from each bone marrow sample, carcinoembryonic antigen (CEA)-specific RT-PCR was performed. BMM was detected by RT-PCR in 10 of the 48 patients. Four patients each had positive signals only before or only after surgery and 2 patients had positive signals both before and after surgery. There were no significant differences in clinicopathologic factors, including neoadjuvant therapy, between patients with BMM and without BMM. To date, the rates of recurrent disease in patients with BMM and without BMM are 80% (8/10) and 50% (19/38), respectively, a difference which is not significant. The 4-year survival rates of patients with BMM and without BMM are 10.0% and 47.3%, respectively. Recurrence and survival rates were poorer in patients with RT-PCR positivity, although the differences were not significant. A larger study is required to clarify the clinical impact of BMM.

Clinical significance of CEA-mRNA expression in peritoneal lavage fluid from patients with gastric cancer.

Peritoneal dissemination is one of the most common modes of gastric cancer recurrence even after curative resection. Cytological examination of peritoneal lavage fluid is useful for detection of free cancer cells in the peritoneal cavity. However, some patients with negative cytological findings have peritoneal metastases of their gastric cancer. The purpose of the present study was to investigate the incidence and clinical significance of metastases harbored in the peritoneal cavity of patients with gastric carcinoma. Peritoneal lavage fluid was collected from the left subphrenic or Douglas cavities of 136 gastric cancer patients without macroscopic peritoneal metastases and 31 patients with benign disease. Peritoneal lavage fluid was examined by both conventional cytological examination (Papanicolaou and Giemsa staining), and carcinoembryonic antigen (CEA)-specific reverse transcription-polymerase chain reaction (RT-PCR). Among 136 gastric cancer patients, 5 patients (3.6%) were positive for free cancer cells by cytological examination and 30 (22.1%) were positive by RT-PCR. A difference in positivity between the left subphrenic and Douglas cavity was found in 18 patients by RT-PCR. The frequency of RT-PCR results increased according to lymph node metastases, lymphatic invasion, depth of tumor invasion and stage grouping. The incidence of peritoneal recurrence was significantly higher in patients with positivity than those with negativity by RT-PCR (p<0.0001). Among cytologically negative patients, survival was significantly shorter in patients with positive than in those with negative CEA-mRNA expression (p<0.0001). The technique of RT-PCR was more sensitive than cytological examination in the detection of cancer cells and prediction of peritoneal recurrence. Adjuvant therapy may be advisable for the gastric cancer patients with positive findings of peritoneal lavage by RT-PCR.

Histological differences in the invasion of advanced esophageal and gastric carcinoma beyond the esophago-gastric junction.

BACKGROUND: The esophago-gastric junction (EGJ) has several unique anatomical and histological features. We investigated the histological differences between esophageal squamous cell carcinoma with invasion of the gastric wall (esophageal group of patients) and gastric carcinoma with invasion of the esophageal wall (gastric group of patients).METHODS: Thirty-six patients in the esophageal group and 83 patients in the gastric group were histologically examined in regard to the mode of invasion. The pattern of tumor invasion beyond the EGJ was classified as continuous or discontinuous.RESULTS: The discontinuous pattern was more frequently seen in the esophageal group than in the gastric group. In the gastric group, however, the distance invaded beyond the EGJ was significantly greater in tumors with the discontinuous pattern than in those with the continuous pattern ( P < 0.01). Gastric mucosal invasion at the EGJ was not seen in 36% of the esophageal group, whereas tumor infiltration into the esophageal mucosal layer at the tip beyond the EGJ was found in 60% of the gastric group. The incidence of invasion deeper than the muscularis propria in the gastric and esophageal groups was 18% and 58%, respectively ( P < 0.0001).CONCLUSION: The histological characteristics of esophageal or gastric carcinoma beyond the EGJ should be taken into consideration in diagnosis and surgical procedures.

CD3 zeta expression of regional lymph node and peripheral blood lymphocytes in gastric cancer.

BACKGROUND AND AIM: Impaired expression of the CD3 zeta chain in T cells associated with T cell anergy has been reported in cancer patients. However, few studies have investigated CD3 zeta expression in regional lymph node lymphocytes (LAL) in cancer patients. This study aims to confirm CD3 zeta expression levels by lymph node and peripheral blood lymphocytes (PBL) in gastric cancer patients and to discuss the clinical implications of intranodal or peripheral blood expression of CD3 zeta in gastric cancer. PATIENTS AND METHODS: Twenty-two gastric cancer patients were enrolled. Macroscopically non-metastatic compartment 1 LNL (C1LNL), compartment 2 LNL (C2LNL) and PBL were surgically obtained. Two-color flow cytometry was then used to quantify the levels of CD3 zeta expression in C1LNL, C2LNL and PBL. RESULTS: Impaired CD3 zeta expression was confirmed in 9.5% of C1LNL, 8.9% of C2LNL and 4.2% of PBL. There was a significant difference in CD3 zeta expression levels between C1LNL and PBL (p<0.01). CD3 zeta expression in PBL was significantly correlated with depth of invasion but not nodal involvement. Distinct differences between the respective lymph node compartments were not identified. CONCLUSION: Immunological paralysis following CD3 zeta impairment may occur more frequently in LNL than in PBL in gastric cancer. Identifying such patients during the perioperative period using flow cytometric methods will increase the efficacy of cytokine therapy aiming to normalize CD3 zeta expression levels.

Paraaortic lymph node micrometastasis and tumor cell microinvolvement in advanced gastric carcinoma.

BACKGROUND: Paraaortic lymph node dissection in advanced gastric carcinoma is controversial. The purpose of this study was to investigate the incidence and significance of micrometastasis (MM) or tumor cell microinvolvement (TCM) in these critical lymph nodes.METHODS: A total of 2339 lymph nodes, including 390 paraaortic nodes, obtained from 47 patients with advanced gastric carcinoma were examined immunohistochemically, using cytokeratin antibody.RESULTS: Lymph node metastasis was found in 95 of the 390 paraaortic nodes of 14 patients by routine histological examination. MM or TCM was immunohistochemically detected in 45 of the 295 negative paraaortic lymph nodes from 15 of 33 patients (MM, n = 5; TCM, n = 10). The 5-year-survival rate in the paraaortic node-negative group and cytokeratin-positive group was significantly higher that that of the hematoxilin and eosin-positive group. The total number of lymph node metastases by hematoxylin and eosin staining and the pathological lymph node compartments, by cytokeratin-positive nodes, were prognostic factors by multivariate analysis.CONCLUSIONS: We demonstrated a high rate of MM or TCM in the paraaortic lymph nodes and suggest that such harbored metastases are related to the prognosis of patients with advanced gastric carcinoma. On the basis of this study, a multi-institutional study should be considered.

Biological properties of biopsy specimens are useful for predicting lymph node micrometastasis in esophageal carcinoma.

BACKGROUND: Some studies have reported on lymph node micrometastasis (MM) by RT-PCR. We attempted to predict MM by biological means using preoperative biopsy specimens. MATERIALS AND METHODS: Lymph nodes from 60 patients with esophageal carcinoma were examined by routine histological examination and CEA-specific RT-PCR. The biopsy specimens were immunohistochemically examined using p53, cyclin D1 (CD1) and desmoglein 1 (DG1) antibodies. RESULTS: Of 659 lymph nodes, 53 (8.0%) nodes were positive according to histological examination and 158 (24.0%) had MM by RT-PCR. The percentage of patients with lymph node metastasis according to histological examination and RT-PCR was 65.0% and 81.7%, respectively. CD1 and DG1 expression correlated with MM, whereas p53 expression did not. MM was frequently detected in the tumors with CD1-positive, DG1-negative or reduced expression. CONCLUSION: The expression of CD1 and DG1 in biopsy specimens may offer useful information on lymph node metastasis, including MM in esophageal carcinoma.

Tumor-associated macrophage (TAM) infiltration in gastric cancer.

BACKGROUND: Tumor-associated macrophages (TAMs) are defined as macrophages that migrate into the tumor stroma. TAMs are known to directly or indirectly affect immune suppression. TAMs have not previously been reported in gastric cancer. MATERIALS AND METHODS: Using anti-CD68 antibodies, we immunohistochemically evaluated TAM infiltration in 97 gastric cancer patients who underwent tumor resection. Furthermore, CD3-zeta chain expression of tumor infiltrating lymphocytes (TILs) from the same section was also examined. According to the degree of TAM infiltration, 97 patients were divided into two groups (high TAM group, more than 200 positive cells; low TAM group, less than 200 positive cells). Clarification of the clinicopathological features of TAM-positive gastric cancer was attempted. RESULTS: TAM infiltration in the tumor nest ranged from 0 to 621 cells (average 187). The degree of infiltration positively correlated with depth of invasion, nodal status and clinical stage. Patients in the high TAM group had lower CD3-zeta expression by TILs than patients in the low TAM group. CD3-zeta expression by TILs negatively correlated with infiltration of TAMs (p < 0.01). Patients with a high TAM count had poorer surgical outcomes than those with a low TAM count. CONCLUSION: From the results of the current study, TAM infiltration may be used as a prognostic marker in gastric cancer. Negative correlation between TAM infiltration and CD3-zeta expression by TILs suggests that TAMs may be responsible for the immunological inactivity of T cells in gastric cancer.