Successful conversion surgery for stage IV gastric cancer with liver metastases after second-line chemotherapy with ramucirumab and paclitaxel: a case report.

BACKGROUND: In recent years, conversion surgery after chemotherapy has been considered a promising strategy for improving the prognosis of patients with stage IV gastric cancer. However, there are few reports on conversion gastrectomy after second-line chemotherapy. Here, we report a case of long-term survival of a patient with liver metastases from gastric cancer who underwent conversion surgery after second-line chemotherapy with ramucirumab and paclitaxel. CASE PRESENTATION: A 77-year-old man complaining of weight loss was diagnosed with human epidermal growth factor receptor 2-positive gastric cancer with multiple liver metastases. Although the patient initially received trastuzumab-based chemotherapy, it was discontinued, because he experienced trastuzumab-induced infusion reactions. Thereafter, he was treated with six courses of S-1 plus cisplatin and six courses of ramucirumab plus paclitaxel as the first- and second-line regimens, respectively. The primary tumor and liver metastases remarkably shrank, and the reduction rate of the measurable metastatic liver lesions was 81.1%. According to the Response Evaluation Criteria in Solid Tumors, the patient responded partially. Therefore, he underwent total gastrectomy with D2 lymphadenectomy and partial hepatectomy of segments 3 and 4. Pathological examination revealed tumor invasion into the muscularis propria, a grade 1a histological response, and no lymph node metastases. No viable cancer cells were identified in the specimens resected from liver segments 3 and 4. Accordingly, the patient was pathologically diagnosed with stage IB (ypT2N0M0). Postoperatively, the patient received adjuvant chemotherapy with S-1 for 6 months, and he survived without recurrence for 42 months after conversion surgery. CONCLUSIONS: Conversion surgery might be clinically useful for improving survival in certain patients with gastric cancer, including those who previously received second-line chemotherapy.

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.

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.

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.

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.

Preoperative assessment of the depth of early gastric cancer invasion by transabdominal ultrasound sonography (TUS): a comparison with endoscopic ultrasound sonography (EUS).

BACKGROUND/AIMS: Transabdominal ultrasound sonography (TUS) is considered a useful diagnostic tool ascertaining depth of cancer invasion, but there are few detailed studies on its accuracy in preoperative estimations of depth of invasion in early gastric cancer (mucosal and submucosal cancer). We retrospectively analyzed the clinical efficacy of preoperative evaluation by TUS in early gastric cancer in comparison with endoscopic ultrasound sonography (EUS). METHODOLOGY: A total of 101 patients preoperatively diagnosed as early gastric cancer were enrolled in the current study. Patients were given 300cc of water subsequent to administration of an anti-peristaltic agent to facilitate filling the gastric lesion with water and TUS was performed. All patients were preoperatively examined by both EUS and TUS. RESULTS: The depth accuracy in mucosal cancer was 59% with EUS and 66% with TUS. When submucosal cancers were subdivided into shallow and deep submucosal cancers, the depth of mucosal and shallow-submucosal (SM1) cancers were correctly assessed 80% and 78% by EUS and TUS, respectively. Accuracy increased by 12% in mucosal cancer by combining EUS and TUS diagnoses. CONCLUSIONS: The diagnostic value of TUS is comparable to that of EUS in assessing depth of invasion of early gastric cancer, however, TUS had a possibility of misdiagnosing the depth of tumors located at the anterior wall. To ensure an accurate estimation of the depth of tumor invasion, it is recommended that TUS and EUS be done simultaneously.

Clinical merit of subdividing gastric cancer according to invasion of the muscularis propria.

BACKGROUND/AIMS: In TNM classification, carcinoma that has invaded the muscularis propria (mp) and cancer that has invaded the subserosa are both categorized as T2 cancer. However, some mp gastric cancer patients have a good postoperative course, similar to that of early gastric cancer patients. We performed a retrospective analysis of 74 patients with mp gastric cancer, based on the depth of mp invasion. METHODOLOGY: The clinicopathologic features of 74 cases of gastric cancer invading the mp (but no further) were subdivided according to depth of invasion, retrospectively reviewed and compared with surgical features of 165 patients with gastric cancer invading the submucosa (sm gastric cancer). For each tumor, we evaluated the degree of tumor invasion in the mp layer at a magnification of x100, using the section that showed the greatest extent of invasion. The patients were classified into 2 groups: mp1, tumor was limited to the first of the 3 mp layers; mp2, tumor had expanded beyond the first layer. RESULTS: Of the 74 mp gastric cancer patients, 30 were classified as mp1 and 44 were classified as mp2. Patients with mp1 gastric cancer had significantly more macroscopic signs of early gastric cancer, a lower frequency of lymph node metastasis, and a higher rate of operative cure than patients with mp2 gastric cancer. The incidence of lymph node metastasis among mp1 gastric cancer patients was almost equal to that of the 165 sm gastric cancer patients. The 5-year survival rate of mp1 patients was significantly better than that of mp2 patients (p<0.05), but was similar to that of the 165 sm gastric cancer patients (84%) (p<0.05). CONCLUSIONS: There were clear differences in clinical features between the mp1 and mp2 gastric cancer patients. Subdivision of mp gastric cancer according to depth of invasion may enable more precise prognosis and treatment of mp gastric cancer patients. The clinicopathological findings and surgical outcome of the mp1 patients were similar to those of the sm gastric cancer patients. Thus, mp1 patients may require treatment that is similar to treatment administered to patients with early gastric cancer.

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.

Molecular detection of free cancer cells in pleural lavage fluid from esophageal cancer patients.

The clinical significance of free cancer cells in pleural lavage fluid detected by molecular methods during surgery remains uncertain in esophageal squamous cell cancer (ESCC). We therefore evaluated the relationship between free cancer cells and clinicopathological findings, and compared the reverse transcriptase-polymerase chain reaction (RT-PCR) method with conventional cytological examination. Pleural lavage fluid from 38 consecutive patients was obtained at two time points; immediately after thoracotomy and before thorax closure. Papanicolaou and Giemsa staining as well as carcinoembryonic antigen (CEA)-specific RT-PCR were performed. The positivity rates obtained using cytological examination and CEA-mRNA expression were 5.3 and 15.8%, respectively. Positive results were observed in pleural lavage fluid after tumor resection. No significant differences in clinicopathologic factors were seen, irrespective of CEA-mRNA expression status. Among the 5 patients exhibiting CEA-mRNA positivity, 2 experienced hematogenous recurrence, 2 experienced mixed recurrence and 1 experienced pleural dissemination. With regard to mode of recurrence and mean period between surgery and relapse, no significant differences were seen between CEA-mRNA-positive and CEA-mRNA-negative patients. Although disease recurred in almost all patients exhibiting CEA-mRNA expression, due to the relatively small sample in the present study the clinical significance must be investigated further in a larger number of patients.

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.

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 impact of micrometastasis of the lymph node in gastric cancer.

Micrometastasis in regional lymph nodes has been observed immunohistochemically, but the biological and clinical roles of minute nodal invasion of carcinoma in gastric cancer remain unclear. We used the anti-cytokeratin (AE1/AE3) antibody to immunohistochemically detect nodal micrometastatic lesions that could not be identified by routine pathological examination. A total of 4203 lymph nodes were examined in 180 gastric cancer patients. Lymph node metastasis was found in 36 of the 180 patients by routine pathological evaluation. Immunohistochemically micrometastasis was detected in the lymph nodes of 19 node-negative patients. Micrometastasis was not detected in any of the mucosal gastric cancer patients who underwent lymph node dissection. Gastric cancer patients with more than six metastatic lymph nodes all had nodal micrometastasis. Patients with micrometastasis had a significantly poorer survival rate than those without micrometastasis (P < 0.05). Based on the present results the presence of lymph node micrometastasis may provide a more accurate indication for surgical outcome in gastric cancer patients at the same clinical stage.

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.

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.

Perioperative detection of circulating cancer cells in patients with colorectal hepatic metastases.

BACKGROUND/AIMS: Surgical resection is the most effective therapy for metastatic colorectal cancer to the liver. However, the selection criteria for patients who may benefit from partial hepatectomy are not fully defined. The aim of this study was to evaluate the usefulness of perioperative molecular detection of circulating cancer cells in predicting clinical outcome in patients with colorectal metastatic liver cancer. METHODOLOGY: Blood samples were obtained perioperatively from the portal vein, peripheral artery, and superior vena cava in 16 consecutive patients with colorectal liver metastases who have undergone partial hepatic resection. We analyzed circulating cancer cells using a carcinoembryonic antigen-specific nested reverse transcriptase-polymerase chain reaction. RESULTS: Positive carcinoembryonic antigen-mRNA expression was detected in 7 (43.8%) of 16 patients. Six (85.7%) of those 7 patients had hematogenous rerecurrences during the 1- to 3-year follow-up period. None of 9 negative-patients showed re-recurrence (p < 0.01). Among the 9 of 16 patients receiving postoperative adjuvant chemotherapy, no clear effect was noted regarding re-recurrence in the positive carcinoembryonic antigen-mRNA patients. CONCLUSIONS: These results suggest that the molecular detection of circulating cancer cells at the time of surgery for colorectal liver metastases could be one measure of high-risk patients for hematogenous re-recurrence after partial hepatic resection.

Clinical and pathological features in T-cell gastric lymphoma associated with human T-cell leukemia virus type 1 (HTLV-1) in comparison with B-cell gastric lymphoma.

BACKGROUND/AIMS: We investigated clinical features of T-cell gastric lymphomas associated with human T-cell leukemia virus type 1 (HTLV-1). METHODOLOGY: Ninety patients with gastric lymphoma who underwent gastrectomy were included in this study. They were divided into T-cell and B-cell gastric lymphomas according to the immunohistochemical expression of surface T-cell or B-cell markers. Clinicopathological features and surgical outcome were compared between T-cell and B-cell gastric lymphomas. Correlation between T-cell gastric lymphoma and Epstein-Barr virus, p53, MIB-1, and CD44 variant 6 on lymphoma cells was evaluated in 60 patients by in situ hybridization and immunohistochemical examination. Anti-adult T-cell leukemia antigen was evaluated in 74 patients in the blood serum were evaluated. RESULTS: Nine of the 90 patients were classified as T-cell gastric lymphoma. Patients with T-cell gastric lymphoma had significantly more nodal involvement and poorer resectability than those with B-cell gastric lymphoma. Positivity of serum anti-adult T-cell leukemia antigen was significantly higher in T-cell lymphoma patients (100%) than in B-cell lymphoma patients (41%). However, there was no significant difference in Epstein-Barr virus positivity and expression of p53, MIB-1, CD44 variant 6 between T-cell and B-cell lymphomas. The five-year-survival rate in patients with T-cell gastric lymphomas was 0% and whereas that in B-cell gastric lymphoma was 45%, there was a significant difference between the two groups (p < 0.01). Two patients with T-cell lymphoma who underwent emergency gastrectomy died in hospital during follow-up. CONCLUSIONS: The surgical outcome of patients with T-cell lymphoma with anti-adult T-cell leukemia antigen tended to be very poor, despite curative resection. Thus, intensive chemotherapy is recommended for the patients with HTLV-1 associated T-cell gastric lymphoma.

CD3-zetachain expression of intratumoral lymphocytes is closely related to survival in gastric carcinoma patients.

BACKGROUND: Impaired or reduced CD3 zeta chain (CD3-zeta) expression in T cells has been identified in various cancers and may be associated with an ineffective immune response. The clinical significance of CD3-zeta chain expression in tumor-infiltrating lymphocytes (TILs) in gastric carcinoma remains unclear. METHODS: The authors immunohistochemically investigated CD3-zeta expression in TILs in 185 patients who had undergone curative gastrectomy. CD3-zeta/CD3 epsilon (CD3-epsilon) ratios were calculated. Patients were divided into two groups: a normal CD3-zeta group (n = 121) and a reduced CD3-zeta group (n = 64). Patients with a zeta per epsilon ratio of greater than 66% were placed in the normal CD3-zeta group. RESULTS: Patients in the normal CD3-zeta group had fewer lymph node metastasis (P < 0.01) and a shallower depth of invasion (P < 0.05) than those in the reduced CD3-zeta group. The 5-year survival rate was 72% in the normal CD3-zeta group, which was significantly better than that in the reduced CD3-zeta group (55%; P < 0.01). When stratified according to clinical stage, the prognostic value was significantly different only in Stage IV patients. Multivariate analysis showed that CD3-zeta expression was an independent prognostic factor (P = 0.03) next to depth of invasion and lymph node involvement. CONCLUSIONS: Reduced CD3-zeta expression in TILs was strongly correlated with progressive disease in gastric carcinomas. CD3-zeta expression in TILs is considered an immunologic, independent prognostic marker in gastric carcinoma patients. CD3-zeta normalization with cytokine treatment may lead to prolonged survival in advanced gastric carcinoma patients.