Expression of MUC1 and MUC2 mucins in gastric carcinomas: its relationship with the prognosis of the patients.

Our previous immunohistochemical studies for the expression of MUC1 mucin antigen (which was detected by monoclonal antibody DF3) and MUC2 mucin antigen (which was detected by polyclonal antibody anti-MRP) in pancreatic and intrahepatic bile duct tumors demonstrated that invasive carcinoma with poor outcome showed a pattern of MUC1+ and MUC2- expression, whereas many of the noninvasive tumors with favorable outcome showed a pattern of MUC1- and MUC2+ expression. To clarify the relationship between the expression of these mucin antigens and the biological properties of gastric cancers, the expression of MUC1 and MUC2 mucin antigens was examined immunohistochemically in 136 patients with gastric cancer invading the submucosa or the deeper layer, and the survival of the antigen-positive and antigen-negative patient groups was compared using the Kaplan-Meier method. For MUC1 mucin expression, different glycoforms of MUC1 were examined using four monoclonal antibodies (NCL-MUC-1-CORE, DF3, MY.1E12, and HMFG-1). The patients with MUC1+ mucin antigen staining in the carcinoma showed significantly worse survival than those with MUC1- mucin antigen staining. In contrast, the patients with MUC2+ mucin antigen staining in the carcinoma showed significantly better survival than those with MUC2- mucin antigen staining. In conclusion, MUC1 antigen expression was associated with a poor outcome in patients with gastric cancer, irrespective of its glycosylation status, and MUC1 is thus considered to be a useful prognostic factor for poor outcome in patients. In contrast, MUC2 antigen expression is a prognostic factor associated with a favorable outcome in patients. In addition, combined evaluation of the MUC1 and MUC2 mucin staining is clinically useful to predict outcome in patients with gastric cancer.

Preserved Smad4 expression in the transforming growth factor beta signaling pathway is a favorable prognostic factor in patients with advanced gastric cancer.

The signals of the transforming growth factor beta (TGF-beta) superfamily are conveyed through cell surface serine/threonine kinase receptors to the intracellular mediators known as Smads. Activation of Smads causes their translocation from the cytoplasm to the nucleus, where they function to control gene expression. The present study analyzed the expression of Smad4 and TGF-beta1 to determine their prognostic significance in advanced gastric cancer. Of 249 cases of advanced gastric cancer, 41 had invaded the muscular layer, 114 had invaded the subserosal layer, and 94 had invaded the serosa. Anti-Smad4 and TGF-beta1 antibodies were used for immunohistochemical staining. Reduced expression of Smad4 was 75.1%, whereas positive expression of TGF-beta1 was 39.6% in gastric cancer. Smad4 expression was related to the depth of tumor invasion (P < 0.05), and TGF-beta1 expression correlated with tumor gross type (P < 0.05). Postoperative survival analysis indicated that patients who had a tumor with reduced Smad4 expression had a poorer clinical outcome than those with preserved expression (P < 0.05). Furthermore, in patients with TGF-beta1-positive tumors, survival rate was significantly better in patients with preserved Smad4 expression than in those with reduced Smad4 expression (P < 0.05). According to multivariate analysis, Smad4 expression acted as an independent prognostic factor. Smad4 expression, particularly in the TGF-beta pathway, is an effective predictor of outcome for patients with advanced gastric cancer.

Intranodal antitumor immunocyte infiltration in node-negative gastric cancers.

The status and role of immunocytes and dendritic cells in regional lymph nodes in patients with gastric cancer are examined in this study. Forty-nine patients with gastric cancer who underwent curative resection were enrolled in the present study. These patients had no lymph node metastases according to a histological examination. The infiltration of natural killer (NK) cells, dendritic cells, and MIB-1-positive immunocytes was investigated. Based on the Japanese Classification of Gastric Carcinoma, regional lymph nodes were divided into three compartments: (a) compartment 1 (lymph node station numbers 1-6); (b) compartment 2 (lymph node station numbers 7-12); and (c) compartment 3 (lymph node station numbers 14 and 16). Dendritic cells and MIB-1-positive immunocytes infiltrated compartment 1 lymph nodes in increased numbers compared with the lymph nodes of compartments 2 or 3 (P < 0.05). Conversely, intranodal NK cell infiltration did not differ significantly among the three compartments. The incidence of intranodal dendritic and MIB-1-positive cell infiltration in patients with submucosal gastric cancer was significantly higher than in patients with tumors that invaded beyond the muscularis propria. The decreased expression of these immunological markers correlated well with recurrent disease, regardless of tumor depth. The immunocyte level is higher in lymph nodes near the primary tumor (compartment 1) than in those that are distant from the tumor (compartments 2 and 3). This pertains to all three markers, i.e., NK, dendritic, and MIB-1-positive cells. Unlike dendritic and MIB-1-positive cells, intratumoral infiltration of NK cells did not correlate well with either lymph node compartment or the depth of tumor invasion. The degree of NK cell infiltration may be directly associated with antitumor effects, especially in compartment 1. A decrease in all three markers is associated with tumor recurrence.

p21 expression is a prognostic factor in patients with p53-negative gastric cancer.

The expression of p21 and p53 proteins was analyzed by immunohistochemistry in 256 patients with advanced gastric cancer. The results showed that strong, weak and negative expression of p21 were detected in 22.2 (57/256), 68.0 (174/256) and 9.8% (25/256) of the patients, respectively. p53 expression was found in 28.9% (74/256). The expression of p21 was not associated with clinicopathological features. In p53 negative tumors, p21 expression was associated with the survival of patients who underwent curative operations (P = 0.007). The 5-year survival rates were 20.1, 36.6 and 59.8% in patients with p21-negative, -weakly positive and -strongly positive tumors, respectively. In contrast, in p53-positive tumors, prognosis did not differ in spite of p21 expression. Multivariate analysis showed that p21 expression was an independent factor in patients with p53-negative tumors. These results indicate that examination of p21 expression in p53 negative tumors will be useful for estimating the prognosis of patients with advanced gastric cancer.

Invariant chain expression in gastric cancer.

Invariant chain (Ii) is a chaperone molecule that inhibits the binding of endogenous antigens to HLA class II. The tumor cell with overexpressed Ii chain is thought to escape attacking cytotoxic lymphocytes by suppressing the host immune. However, the relationship between Ii expression by the tumor and clinicopathological factors in gastric cancer remains unclear. We studied 126 patients with gastric cancer who had undergone curative gastrectomy at Kagoshima University Hospital between 1988 and 1997. In order to detect Ii and HLA-DR expression by tumor cells, immunohistochemical staining with anti-CD74 and anti-HLA-DR antibodies were performed by avidin-biotin peroxidase complex method. The 126 patients studied were divided into two groups based on Ii expression. Ii and HLA-DR were expressed both on the surface and in the cytoplasm of tumor cells and tumor infiltrating lymphocytes. A total of 48 patients were identified as Ii positive, while the remaining 78 patients were Ii negative. Ii expression negatively correlated with the depth of invasion of the tumor as well as the patients' clinical stage. Ii expression was negatively correlated with HLA-DR expression. Patients with Ii negative expression had significantly better surgical outcomes than those with Ii positive expression (P<0.05). Ii expression in gastric cancer affected surgical outcome and Ii expression was negatively correlated with depth of invasion and HLA-DR expression. Ii expression in gastric cancer may be a prognostic factor related to suppressive effects on host immune responses to tumor cells.

Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer.

Intratumoral natural killer cells (NKC) and dendritic cells (DC) may affect the clinical features of various gastrointestinal cancers. However, the relationship between intratumoral NKC and DC remains unclear. We examined 169 patients with gastric cancer who underwent gastrectomy at Kagoshima University Hospital. Immunohistochemical staining of CD57 and S-100-protein was performed to evaluate NKC and DC infiltration, respectively. A total of 25 areas containing pericancerous tissue were selected for determining the number of NKC and DC under high power microscopy (x400). Patients were classified into two groups according to NKC and DC population. Intratumoral lymphocytic infiltration was also calculated in 15 areas with a high power (x400) objective. The degree of NKC and DC infiltration was gradually decreased according to the progression of nodal involvement. Patients with many NKC infiltration had a lower positivity of lymph node metastasis and lymphatic invasion than patients with little NKC infiltration. DC infiltration was also negatively correlated with depth of invasion, lymph node metastasis and curativity. DC infiltration was positively correlated with lymphocytic infiltration (P=0.01. r=0.6). The 5-year survival rates of patients with many NKC infiltration and patients with DC many infiltration were 75 and 78%, respectively, both of which were significantly better than that of patients with little NKC and DC infiltration (P<0.05). NKC may be activated without DC or intratumoral lymphocytes. Intratumoral NKC may act as an independent immunologic effector against tumor cells, unlike DC.

Monoclonal antibodies against a human gastric cancer cell line with lung metastatic potential in nude mice define antigens with different expression between the primary and metastatic liver lesions.

SCK-29 is a tumor cell line derived from human gastric adenocarcinoma with the feature of producing lung metastases when xenografted in nude mice. Monoclonal antibodies were produced against SCK-29 tumor cells or their glycoproteins prepared by affinity chromatography on a lectin-agarose column. Five antigens defined by the monoclonal antibodies MG-1 to MG-5 were expressed in a large number of gastric or colonic adenocarcinomas. Among the antigens, MG-1 and MG-3 proved to be tumor-associated, since they were detected only occasionally in normal tissues. MG-5 antigen was often detected in normal gastric mucosa but not in other tissues. The degree of expression of MG-1. MG-3 and MG-5 antigens differed considerably in metastatic lesions. In metastatic liver lesions of gastric adenocarcinoma, expression of these MG antigens was less marked than in primary tumors. MG-1 and MG-3 antigens were abolished by neuraminidase digestion and periodate oxidation. MG-5 antigen was likely to be a protein antigen, since it was resistant to neuraminidase digestion and to periodate oxidation but was sensitive to protease digestion.

Tumorigenicity, invasion, and metastasis of human gastric cancer in nude mice.

Tumors derived from 105 patients with gastric cancer were subcutaneously heterotransplanted into nude mice in order to study their tumorigenicity and malignant behavior. Of the 105 gastric cancers, 45 were successfully transplanted (a 42.9% tumorigenesis rate). The tumorigenesis rate of Borrmann type 1 and 2 cancers (77.8%) was significantly higher than that of type 3 and 4 cancers (34.6%). Also, the tumorigenesis rate of differentiated carcinoma (57.1%) was significantly higher than that of undifferentiated carcinoma (30.9%). Spontaneous metastases from the subcutaneous tumors were observed in 5 of the 37 established tumor lines (13.5%), and macroscopic pulmonary metastases were common with one tumor line (SCK-29). Although most of the subcutaneous gastric cancers showed local expansion without distant metastasis, the same tumor cells implanted into the peritoneal cavity exhibited invasive growth and/or metastasis. Thus, the expression of a metastatic phenotype by human gastric cancer was influenced by the host microenvironment. The SCK-29 tumor line with its high metastatic potential may be useful for studies on the mechanism of blood-borne metastasis.

Clinical and pathologic features of early gastric cancer in elderly patients.

BACKGROUND/AIMS: The purpose of this study was to review the Clinicopathologic features of early gastric cancer in elderly patients. METHODOLOGY: Three hundred and seventy-two patients who underwent resection for early gastric cancer were divided into groups of patients younger and older than 70 years. The clinical and pathologic findings surgical treatment, and perioperative complications in the group of elderly patients with early gastric cancer were reviewed and compared to those of the younger group. RESULTS: Gastric cancer involving the lower third of the stomach, as well as histopathologically well-differentiated carcinomas, were significantly more prevalent in the older group. Pre-operatively, the older patients had a higher incidence of respiratory dysfunction and hypertension. D1 lymph node dissections were chosen frequently for older patients. Six older patients died within 2 months of hospitalization, while no younger patients died within this period. The mortality rate mas 11% in older patients undergoing D2 or greater extents of node dissection, although the mortality rate was only 2% in older patients undergoing a D1 or less dissection. The 5-year survival rate for older patients, including deaths unrelated to cancer, was 71%, which was significantly lower than that in the younger group. However, when only mortality from gastric cancer was considered, patient survival did not differ according to age. CONCLUSION: Given the high mortality in elderly patients unrelated to early gastric cancer, we concluded that node dissection should be limited to perigastric nodes according to tumor location in such patients.

Strategy of gastric cancer in patients 85 years old and older.

BACKGROUND/AIMS: There is little information about the clinical and pathological features of patients with gastric cancer aged 85 years old and older. METHODOLOGY: We analyzed data of 197 gastric cancer patients aged 75 years and older. The patients were dividing into three age groups and we retrospectively studied 25 gastric cancer patients aged 85 years old and older and compared their clinical courses with those of 94 patients in their late 70s and 78 patients in their early 80s. RESULTS: The patients aged 85 years and older had a significantly higher rate of symptoms on admission such as gastric outlet obstruction and progressive anemia (64%), than did the other two age groups (p<0.05). Twenty-five percent of the oldest age group did not have surgery, and none had a D2 lymph node dissection. Perioperative complications were more frequent in the oldest group than in the youngest group (p<0.05). Survival in the oldest patients was not affected by surgical resection. CONCLUSIONS: These results indicate curative gastric surgery has a less positive impact in patients aged 85 years and older than younger patients. Treatment for gastric cancer in patients 85 years old and older should emphasize the palliation of symptoms but not curative resection.

Paraaortic lymphadenectomy in patients with advanced carcinoma of the upper-third of the stomach.

BACKGROUND/AIMS: According to current TNM classification, paraaortic nodes involvement in gastric cancer is now distant metastasis. Anatomically, however, proximal gastric cancer may drain preferentially to the left-paraaortic area which represents a regional lymph-node basin. METHODOLOGY: Seventy-five patients who underwent an extended gastrectomy with paraaortic lymphadenectomy for advanced carcinoma of the upper-third of the stomach were retrospectively studied. RESULTS: Of the 75 patients, 55 (73.3%) were positive for nodal metastasis and 21 (28.0%) had paraaortic nodes involvement. Paraaortic nodes involvement tended to be left-sided (the left side of the aorta around the left renal vein) and its incidence did not increase as the overall number of infiltrated nodes increased. Five (23.8%) of the 21 patients with paraaortic nodes involvement did not have nodal metastases in the paraceliac area. Overall survival was not different whether or not paraaortic nodes involvement was present, but was dependent on the overall number of infiltrated nodes (viz. 10 vs. > 10). Eight (22.2%) of 36 patients with 1-10 infiltrated nodes had PNI, with a 5-year survival rate of 46.9%. CONCLUSIONS: Removal of lymph nodes around the left renal vein should be included during extended gastrectomy in patients with advanced carcinoma of the upper-third of the stomach. Left-paraaortic lymphadenectomy may benefit such patients if the overall number of infiltrated nodes is low (viz. 10).

Eosinophilic granuloma of the stomach mimicking gastric cancer, report of a case.

We report a rare case of eosinophilic granuloma of the stomach mimicking gastric cancer. A 49-year-old man was admitted to our hospital to undergo surgery for gastric tumor. Radiologic and endoscopic examination showed a protruding tumor with a deep ulcer at the anterior wall of the pylorus. Although malignant cells were not histologically confirmed in the biopsy specimens, subtotal gastrectomy with lymphadenectomy was performed because gastric cancer was strongly suspected. The gross appearance of the tumor seemed to be that of a gastric cancer, but the histological diagnosis was eosinophilic granuloma. If submucosal tumor of the stomach is suspected, eosinophilic granuloma should be considered as one of the differential diagnoses. Endoscopic removal of the tumor may be useful to make a precise diagnosis before surgery.

Tumor angiogenesis related to growth pattern and lymph node metastasis in early gastric cancer.

OBJECTIVE: To investigate the correlation between angiogenesis and tumor growth pattern as well as the lymph node metastasis to reveal the significance of vascularity in the early stage of gastric cancer. METHODS: 97 specimens from patients with early gastric cancer were studied by immunohistochemical method using anti-factor VIII related antigen antibody. RESULTS: Microvessel count was related to tumor growth pattern. The mean vessel count was higher in superficially spreading and penetrating types of tumors. Lymph node metastasis was correlated to microvessel count. Tumors with lymph node metastasis had higher microvessel counts than those without lymph node metastasis. CONCLUSIONS: In the early stage of gastric carcinoma, angiogenesis is correlated with tumor growth pattern and lymph node metastasis. Identification of tumors with high density of vascularization is beneficial for closer follow-up and adjuvant therapy.

[Extended gastric surgery: is paraaortic lymph node dissection essential for advanced gastric cancer?].

We retrospectively analyzed the clinicopathological findings and prognosis in patients who underwent paraaortic lymph node (No. 16) dissection. No. 16 metastasis was histologically found in 61 of 640 patients (9.5%). Almost all of the patients had tumors in the upper third of the stomach or the whole stomach. In the patients who had a total of ten or less lymph node metastases after curative resection. No. 16 metastases were found at the site of either the left or right side of the abdominal aorta. Conversely, No. 16 metastases occurred in both left and right sides of the abdominal aorta in patients with 11 or more lymph node metastases in total. The five-year survival rate of patients with histologically proven No. 16 metastasis was 21%. The indication for No. 16 lymphadenectomy should be decided by not only the number of No. 16 lymph node metastases but also by the total number of removed lymph node metastases. When D4 lymph node dissection was compared with D2 lymph node dissection in the patients without No. 16 involvement on histology, the prognosis of the former was superior to the latter in the patients with a tumor in the upper and middle part of the stomach. In order to evaluate the efficacy of prophylactic D4 lymphadenectomy, randomized clinical trial between D4 and D2 should be performed. It is also important that the indication for No. 16 lymph node dissection should be decided on the individual patients according to the objective data based on a retrospective study.

[Intraperitoneal chemotherapy in gastric cancer with peritoneal metastasis using totally implantable peritoneal access system].

Fifteen patients with peritoneal metastasis of gastric cancer were treated with mainly ip-ETP (Etoposide: i.p., THP-ADM: i.v. and CDDP: i.p.) or other drugs by the use of a totally implantable peritoneal access system. In principle, intraperitoneal drug delivery was carried out every two weeks. CDDP was administered into the intraperitoneal cavity with intravenous sodium thiosulfate delivered simultaneously to protect against cisplatin-induced nephrotoxicity. RI-scintigram showed that the intraperitoneal catheter was fully useful even six months after the operation. As a result, performance status has been improved in 12 out of 15 cases, and ascites disappeared in 3 out of 6 cases with same. Ten cases have been alive for more than 6 months after operation. There have been no severe complications (e.g., nephrotoxicity or myelosuppression) even in the cases treated at frequent intervals for more than 8 months. The findings in this study indicated that ip-ETP using totally implantable peritoneal access system is beneficial for advanced gastric cancer with peritoneal metastasis.

[Two-route chemotherapy under AT-II induced hypertension using totally implanted injection port system in liver metastases derived from digestive cancers].

Two-route chemotherapy (TRC) with intraarterial infusion of cis-diamminedichloroplatinum and intravenous infusion of sodium thiosulfate was carried out on 8 cases of digestive cancer with liver metastases, using totally implanted injection port system. The metastases occurred from gastric cancer in 3 cases and from colonic cancer in 5 cases. Computed tomography and/or ultra-sonography revealed an overall response rate of 50% (4/8). Complete response (CR) was obtained in two cases. The therapy was repeated 12 times in one case of gastric cancer with multiple liver metastases and 5 times in another rectal cancer with a solid metastatic tumor. In the latter case, a right hepatic lobectomy was performed thereafter. The histology of the hepatic tumor showed mucin lakes and necrotic lesions, and no viable cancer cells were observed. This mode of chemotherapy was therefore considered a useful measure for the treatment of liver metastases derived from digestive cancers. Furthermore, no serious side effects occurred.

[Cisplatin, 5-fluorouracil and leucovorin combination chemotherapy-added radiation therapy for advanced esophageal cancer--a case report].

Cisplatin, 5-fluorouracil and leucovorin combination chemotherapy added radiation therapy was performed for the treatment of 62-year-old male patient with advanced esophageal cancer who had liver cirrlosis. After the treatment, esophageal lesion disappeared. Only minimal side effect occurred during the treatment. Biochemical modulation chemotherapy combined with radiation therapy is useful for advanced esophageal cancer.

[Survival benefits of and indications for extended surgery for advanced gastric cancer].

The surgical management of locally advanced gastric cancer remains controversial. It is also unclear whether the postoperative survival rate could be improved by extended lymph node dissection. The aim of this paper is to determine the survival benefit of and the indications for extended surgery. Lymph node metastasis in the paraaortic area frequently occurs in locally advanced cardiac cancer. In our previous studies, the paraaortic lymph nodes above and below the left renal vein were confirmed to be the terminal destination of lymphatic flow in the upper abdominal cavity. Paraaortic lymph node dissection is essential for curarive resection in some cases of advanced gastric cancer. The 5-year survival rate in patients who undergo paraaortic lymph node dissection is nearly 15% according to the literature. Patients with metastasis of the paraaortic lymph nodes on only one side and with fewer than four involved nodes clearly benefit from paraaortic lymph node dissection. It is indicated in cases with metastasis or suspected metastasis of the left or right cardiac lymph node or N2 lymph node station. There is little survival benefit from combined resection of involved organs (T4 disease) and it should only be performed in a select group of patients. Extended surgery for locally advanced gastric cancer, however, is feasible and has acceptable operative morbidity and mortality rates.

[Surgical treatment of carcinoma of the cardia with special references to mediastinal extension and lymph node metastasis].

We retrospectively analyzed the clinicopathological findings in 141 patients with advanced cardiac cancer. According to histological type, 117 patients had an adenocarcinoma and 24 patients a squamous cell carcinoma. Curative resection was performed in 114 patients, whereas the remaining 27 patients underwent palliative resection. Preoperative endoscopic ultrasonography and abdominal ultrasound were useful for the diagnosis of esophageal invasion and lymph node metastases. Particularly, the classification of paraaortic lymph node metastasis by ultrasound was important in deciding on the surgical method. Mediastinal lymph node metastases were found histologically in 19 of 68 patients. The survival of patients with mediastinal lymph node metastasis was poor. However, among them, a favorable outcome was expected for patients with few involved nodes and if only perigastric node involvement in abdominal nodes was found. Paraaortic lymph node metastasis was found histologically in 15 of 48 patients (27.9%). Two of 35-year survivors had 5 or fewer lymph node metastases, and showed only perigastric and paraaortic node involvement. It is equally important that tumor extension and lymph node metastases in the mediastinum and abdomen should be determined in the surgical treatment of advanced carcinoma of the cardia.