Significance of caveolin-1 and matrix metalloproteinase 14 gene expression in canine mammary tumours.

Canine mammary tumours (CMTs) are the most common neoplasms affecting female dogs. There is an urgent need for molecular biomarkers that can detect early stages of the disease in order to improve accuracy of CMT diagnosis. The aim of this study was to examine whether caveolin-1 (Cav-1) and matrix metalloproteinase 14 (MMP14) are associated with CMT histological malignancy and invasion. Sixty-five benign and malignant CMT samples and six normal canine mammary glands were analysed using quantitative reverse transcription-polymerase chain reaction. Cav-1 and MMP14 genes were highly expressed in CMT tissues compared to normal tissues. Cav-1 especially was overexpressed in malignant and invasive CMT tissues. When a CMT cell line was cultured on fluorescent gelatin-coated coverslips, localisation of Cav-1 was observed at invadopodia-mediated degradation sites of the gelatin matrix. These findings suggest that Cav-1 may be involved in CMT invasion and that the markers may be useful for estimating CMT malignancy.

Surgical results of patients with peritoneal carcinomatosis treated with cytoreductive surgery using a new technique named aqua dissection.

During 2004 to 2011, 81, 420, and 166 patients with colorectal cancer (CRC), epithelial appendiceal neoplasm (APN), and gastric cancer (GC) with PC were treated with cytoreductive surgery (CRS) plus perioperative chemotherapy. CRS was performed by peritonectomy techniques using an aqua dissection. Results. Complete cytoreduction was done in 62/81 (76.5%), 228/420 (54.3%), and 101/166 (60.8%) of patients with CRC, APN, and GC. The main reasons of incomplete resections were involvement of all peritoneal regions and diffuse involvement of small bowel. The incidence (64%, 302/470) of CC-0 resection after introduction of an aqua dissection was significantly higher than before (42%, 82/197). A total of 41 (6.1%) patients died postoperatively. Major complication (grade 3-4 complications) occurred in 126 patients (18.9%). A reoperation was necessary in 36 patients (5.4%). By the multivariate analysis, PCI scores capable of serving as thresholds for favorable versus poor prognosis in each group and CC scores demonstrated as the independent prognostic factors. Conclusions. Peritonectomy using an aqua dissection improves the incidence of complete cytoreduction, and improves the survival of patients with PC. Patients with PCI larger than the threshold values should be treated with chemotherapy to improve the incidences of complete cytoreduction.

Surgical treatment for peritoneal carcinomatosis from gastric cancer.

This review describes the latest surgical treatments for peritoneal carcinomatosis (PC) arising from gastric cancer. Systemic chemotherapy is less effective against PC because of the existence of the blood-peritoneal barrier. Accordingly, perioperative intraperitoneal chemotherapy plus cytoreductive surgery (CRS) is a new trend of multidisciplinary therapy for PC. Intraperitoneally administered drugs penetrate directly into the peritoneal dissemination, resulting in the high loco-regional intensity of drugs. A new bidirectional chemotherapy called neoadjuvant intraperitoneal/systemic chemotherapy (NIPS) has been developed. After NIPS, the disappearance of PFCCs has been reported, and the incidence of complete cytoreduction has increased accordingly. Complete cytoreduction, a low peritoneal carcinomatosis index, and negative PFCCs are significant favorable prognostic factors. Hyperthermic intraperitoneal chemotherapy (HIPEC) after CRS is associated with improved survival with an acceptable postoperative mortality and morbidity. Early postoperative intraperitoneal chemotherapy (EPIC) has also contributed to improving survival after CRS.

[Resected case of pulmonary arteriovenous malformation diagnosed with a brain abscess as a clinical manifestation; report of a case].

A 63-year-old female with Rendu-Osler-Weber disease had general fatigue and right hemiparesis. A computed tomography (CT) scan of her head demonstrated an enhancing cystic mass in the left frontal lobe, and it was diagnosed as a brain abscess and then drainaged. Thereafter, a pulmonary arteriovenous malformation (PAVM) identified in the left lingular segment by chest CT scan and the PAVM was resected by partial resection of the lung.

Neoadjuvant treatment of gastric cancer with peritoneal dissemination.

AIMS: To report our experience of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) for patients having a complete resection of the primary gastric cancer and peritoneal carcinomatosis (PC). PATIENTS AND METHODS: Patients with advanced peritoneal dissemination of primary gastric cancer had the placement of a peritoneal port system. For intraperitoneal chemotherapy, 40 mg of docetaxel and 150 mg of carboplatin were introduced in 1000 ml of saline on a weekly basis. Simultaneously, 100 mg/m2 of methotrexate and 600 mg/m2 of 5-fluorouracil were infused via a peripheral vein. A minimum of two cycles and up to six cycles of NIPS were used prior to cancer resection. At surgery a complete removal of the primary gastric cancer and the peritoneal implants by peritonectomy was attempted. RESULTS: Sixty-one patients were enrolled in the study. Thirty-nine had positive intraperitoneal cytology which reverted to negative cytology after treatment in 22. Thirty-eight showed a partial response. Thirty patients came to resection and 14 patients could be made disease-free. Median survival time of all patients was 14.4 months. Patients who received a complete resection had a median survival time of 20.4 months. Grade III/IV toxicities were not found after two courses of NIPS, but did develop in seven patients after more than three courses of NIPS. CONCLUSION: NIPS can downstage large volume peritoneal dissemination of gastric cancer. When combined with gastrectomy including peritonectomy a complete surgical resection was possible in one-quarter of the patients and resulted in a prolonged survival. This combined intraperitoneal and systemic chemotherapy for PC from gastric cancer is worthy of consideration for phase III clinical investigations.

Quantitative prognostic indicators of peritoneal dissemination of gastric cancer.

There are three classifications that describe the quantitative prognostic indicators of peritoneal dissemination for gastric cancer. The Japanese classification (P1, P2, and P3, Lyon classification, (stage I, II, stage III, and stage IV), and the Peritoneal Cancer Index (PCI). Carcinomatosis with limited extent (P1/ P2) corresponds to the PCI less than 13 and the stage I and II from Lyon classification. Carcinomatosis with large extent (P3) corresponds to PCI of 13 or larger and stage III and IV from Lyon classification. PCI enables one to describe the precise distribution of peritoneal dissemination. All three classifications correlate with prognosis. With regard to the surgical cytoreduction of the primary tumor and the peritoneal dissemination, Sugarbaker proposed the classification of completeness of cytoreduction (CCR). Patients with no macroscopic residual tumor had significantly better prognosis than those with residual disease. CCR is a valuable prognostic indicator after cytoreductive surgery.

Diagnostic value of preoperative RT-PCR-based screening method to detect carcinoembryonic antigen-expressing free cancer cells in the peritoneal cavity from patients with gastric cancer.

BACKGROUND: At present the most reliable method for the diagnosis of peritoneal micrometastasis of gastric cancer is peritoneal wash cytology, but the sensitivity of this method is low. The aim of the present study was to verify whether carcinoembryonic antigen (CEA) reverse transcriptase-polymerase chain reaction (RT-PCR) assay can enhance the sensitivity and specificity of conventional cytology, and to determine how this technique can improve the accuracy of peritoneal recurrence. METHODS: The present study included 230 patients with gastric cancer. Preoperative peritoneal wash was done by a paracentesis, followed by conventional cytology, CEA measurement, and CEA RT-PCR of recovered fluid. RESULTS: The CEA RT-PCR assay yielded 40 (17%) positives, which included none of the 26 patients with benign disease. The incidence of positive cytology and CEA level in wash fluid was 19% and 15%, respectively. Logistic stepwise regression analysis revealed that lymph node status, depth of invasion, venous invasion, and the results of peritoneal cytological examination, and CEA RT-PCR assay were independently related to peritoneal recurrence. The CEA level in the wash fluid was not related to peritoneal recurrence. Peritoneal cytological examination was the most significant predictive factor for peritoneal recurrence with a sensitivity of 46%, specificity of 94% and accuracy of 73%, while the corresponding values of the CEA RT-PCR assay were 31%, 95%, and 73%. Combining cytological examination with CEA RT-PCR assay resulted in a sensitivity rate for peritoneal recurrence of 57%, an 11% improvement over that of cytology alone. CONCLUSION: The data indicate that the use of a combination of CEA RT-PCR and cytological assay is more likely to identify patients who will develop peritoneal recurrence. This may be useful for the classification of patients for the most suitable therapeutic trials.

Intraoperative chemohyperthermic peritoneal perfusion as an adjuvant to gastric cancer: final results of a randomized controlled study.

BACKGROUND/AIMS: Although the most frequent cause of death after curative resection of advanced gastric cancer is peritoneal recurrence, there was no effective therapy for the prevention of peritoneal recurrence. This randomized trial sought to determine whether intraoperative chemohyperthermic peritoneal perfusion could eliminate microscopic residual disease and thereby improve survival of patients with advanced gastric cancer. METHODOLOGY: One-hundred and thirty-nine patients with T2-4 gastric cancer underwent curative gastrectomy with extended lymphadenectomy. These patients were randomly allocated into the following three groups. Patients in the CHPP group received surgery + chemohyperthermic peritoneal perfusion, and those in the CNPP group underwent surgery + chemonormothermic peritoneal perfusion. The third group was surgery alone group. In the CHPP and CNPP groups, peritoneal cavity was perfused with 6-8 liters of heated saline at, respectively, 42-43 degrees C and 37 degrees C with 30 mg of mitomycin C and 300 mg of cisplatin by a extracorporeal circulation machine. RESULTS: Major operative complication occurred in 19% (9/48), 14% (6/44) and 19% (9/47) of the CHPP, CNPP and surgery alone group, respectively. Complication which uniquely developed after chemohyperthermic peritoneal perfusion was bowel perforation. Mortality rates of each group were 4% (2/48), 0% (0/44) and 4% (2/47) in the CHPP, CNPP and surgery alone group, respectively. Overall 5-year survival rates of CHPP, CNPP and surgery alone groups were 61%, 43% and 42%, respectively. In a subset analysis, patients with gastric cancer having serosal invasion or lymph node metastasis have shown a statistically significant improvement in survival when treated with chemohyperthermic peritoneal perfusion. However, chemonormothermic peritoneal perfusion had no survival benefit. By analyzing with Cox proportional hazard model, chemohyperthermic peritoneal perfusion emerged as an independent prognostic factor for good survival. Surgery alone had three-fold higher risk of death than chemohyperthermic peritoneal perfusion. CONCLUSIONS: Chemohyperthermic peritoneal perfusion had an efficiency for the prophylaxis of recurrence after curative resection of advanced gastric cancer, and is indicated for patients with tumor infiltrating beyond serosal layer and node positive tumor.

Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer.

S100A4 is known to be involved in cancer cell motility by virtue of its ability to activate nonmuscle myosin. E-cadherin has an important role in the homophilic cell-cell adhesion and is called an invasion suppressor gene. In the current study, we investigate the histological type and metastatic potential of gastric cancer from the aspect of the interrelationship of E-cadherin and S100A4 expression. Expression of E-cadherin and S100A4 in gastric cancer cell lines, primary gastric cancers, and their normal counterparts were analyzed by reverse transcription-PCR, Western blot, and immunohistochemical methods. S100A4 protein and E-cadherin were expressed in five of eight gastric cancer cell lines, and inverse expression of the two proteins are found in four cell lines. In the clinical specimens, E-cadherin mRNA expression in differentiated adenocarcinomas (88%, 14 of 16) was significantly more frequent than that in poorly differentiated adenocarcinomas (50%, 22 of 44; P = 0.015). Western blot analysis demonstrates that S100A4 protein expression in poorly differentiated adenocarcinomas was 1.6-fold higher than in well differentiated adenocarcinoma. Immunohistochemically, S100A4 expression was detected in 51 (55%) of 92 primary gastric cancers. Reduced expression of E-cadherin in primary tumors was found in 66 (72%) of 92 tumors. S100A4 expression in the poorly differentiated adenocarcinomas had a strong relation to positive lymph node involvement or peritoneal dissemination. Reduced E-cadherin expression showed a strong relationship with positive serosal involvement and infiltrating type. Tumors classified as a group with reduced E-cadherin and high expression of S100A4 reveal positive peritoneal dissemination, serosal involvement, and infiltrating type in the growth pattern. Furthermore, these tumors showed a strong correlation with the poorly differentiated adenocarcinoma. In contrast, tumors with preserved E-cadherin and low expression of S100A4 have a close relation to the well differentiated adenocarcinoma and a favorable prognosis. By the Cox proportional hazard model, S100A4 and E-cadherin tissue status was judged as an independent prognostic factor. S100A4 and E-cadherin tissue status may be a powerful aid in evaluating metastatic potential or the prognosis of patients with gastric cancer.

A new surgical approach (peritonectomy) for the treatment of peritoneal dissemination.

BACKGROUND/AIMS: Despite the improvements of chemotherapy and surgical techniques, treatment results of peritoneal dissemination still remain pessimistic. METHODOLOGY: During a 10-year period, 106 patients with peritoneal dissemination from gastric cancer were treated with chemo-hyperthermic peritoneal perfusion (CHPP), peritonectomy + CHPP, systemic PMUE therapy, and surgery alone in 51, 15, 13, and 27 patients, respectively. In peritonectomy, disseminated nodules were resected as much as possible in combination with the combined resection of the abdominal organs and parietal peritoneum covering diaphragm, pelvis and abdominal wall. After resection, the abdominal cavity was treated with heated saline at 42-43 degrees, containing cisplatinum (CDDP), Mitomycin C (MMC), and etoposide for 1 hour. PMUE therapy was administered with one course of i.v. infusion of 75 mg/m2 of CDDP and 30 mg/body of MMC on the 1st day, followed by etoposide 50 mg/body on the 3rd, 4th, and 5th day, and with oral intake of 400 mg/body of UFT every day from the 1st day. RESULTS: No post-operative or chemotherapeutic deaths were observed. Systemic PMUE therapy showed no survival improvement, and survival of the peritonectomy + CHPP group was the best, following CHPP, systemic PMUE and surgery alone. CONCLUSIONS: Peritonectomy and CHPP may be the best choice for the treatment of peritoneal dissemination.

Carcinosarcoma of the esophagus with metastases showing osteosarcoma: a case report and review of the literature.

Carcinosarcoma of the esophagus includes both carcinomatous and sarcomatous elements. The classification and histogenesis of carcinosarcoma is controversial. In a polypoid carcinosarcoma diagnosed in a resected esophagus the sarcomatous component was composed of dense interlacing bundles of spindle-shaped cells in the submucosa. Areas with transitional features between the two components were observed. Immuno-histochemical examination showed vimentin-positive cells in the sarcomatous areas. Subsequently, obtained autopsy specimens from the lung, kidney and iliac bone showed metastatic osteosarcoma composed of an interlacing pattern of bone or osteoid components. We suspected that the sarcomatous elements in the esophagus resulted from sarcomatous transformation of carcinoma cells, and that the metastatic lesions showed differentiation of neoplastic cells to the osteosarcoma.

Immunohistochemical study of MT-MMP tissue status in gastric carcinoma and correlation with survival analyzed by univariate and multivariate analysis.

Matrix metalloproteinase (MMP) expression is associated with advanced-stage cancer and contributes to tumor progression, invasion, and metastasis. Membrane type matrix metalloproteinase (MT-MMP) has a potential transmembrane domain at the C terminus and activates pro-MMP-2, which is mainly produced from interstitial fibroblasts. Its expression on the membrane of invasive tumor cells results in the pericellular space degradation at cell-matrix contact sites and renders cancer cells more invasive at the migration front. To elucidate the relationship between MT-MMP expression and metastasis and prognosis in gastric cancer patients, MT-MMP expression was analyzed immunohistochemically in 127 primary tumors and results were correlated with several prognostic parameters and patient's survival. MT-MMP immunoreactivity was stained on the cell membrane of cancer cells and fibroblasts in the invasion front. MT-MMP was detected in 72 tumors (57%) (MT-MMP-positive). MT-MMP expression was closely associated with macroscopically invasive type, nodal involvement, lymphatic invasion, vessel invasion, and peritoneal dissemination. Patients with MT-MMP-positive tumor had a significantly worse prognosis than those with MT-MMP-negative tumor (p<0.001). Multivariate analysis showed MT-MMP overexpression as an independent prognostic factor in gastric cancer patients. Immunohistochemical analysis for MT-MMP may be an indicator of metastatic potential or the prognosis of gastric cancer patients.

[A fatal case of aggressive-phase multiple myeloma with ileus and invasion into extramedullary organs].

A 62-year-old woman with IgA-lambda type monoclonal gammopathy had been followed up since January 1988. In March 1991, multiple myeloma (IgA-lambda) was diagnosed on the basis of bone marrow biopsy findings and increased serum IgA levels. She was treated intermittently with melphalan and prednisolone over a perioa of about 6 years, but was eventually admitted due to renal dysfunction, hypercalcemia, increased serum IgA and the formation of subcutaneous masses. During chemotherapy she underwent emergency surgery for obturative ileus. Histological examination of the resected tissues revealed invasion of myeloma cells into the small intestine and peritoneum. Despite continued chemotherapy, the patient's soft tissue masses enlarged, and new lesions appeared in other organs. In the terminal stage, lower serum IgA levels were observed despite an increase in Bence-Jones protein levels in urine. The patient died five months after admission. An autopsy found infiltration by atypical myeloma cells in multiple organs. An immunohistochemical examination revealed and increase in lambda-light chain positive cells relative to the number of alpha-heavy chain positive cells. The terminal course was considered to be representative of aggressive phase multiple myeloma. The case was rare in that the patient's ileus was caused by invasion of myeloma cells into the small intestine.

Prognostic significance of c-erbB-2 gene expression in the poorly differentiated type of adenocarcinoma of the stomach.

Prognostic significance of c-erbB-2 gene abnormalities is unclear in the poorly differentiated type of gastric carcinoma, because the abnormalities of this gene have been reported to be restricted to the differentiated type of gastric carcinoma. In this study, correlation of c-erbB-2 gene amplification/overexpression of mRNA and protein were studied in the poorly differentiated type of gastric carcinoma. c-erbB-2 gene amplification determined by the slot-blot hybridization was observed in 11 (13%) of 82 gastric cancer, and 8 of 11 tumors were poorly differentiated. In addition, c-erbB-2 mRNA expression was studied by the reverse transcriptase-polymerase chain reaction. Four (17%) of 24 tumors showed overexpression of c-erbB-2 mRNA, and all these four exhibited morphologically a poorly differentiated type. Among 157 poorly differentiated gastric cancers, 20 (13%) tumors showed immunohistochemically c-erbB-2 protein expression. These tumors had significantly higher incidences of larger tumor, serosal invasion-positive tumors, node-positive tumor, or peritoneal dissemination-positive tumor than those without c-erbB-2 expression. Furthermore, patients with c-erbB-2 protein overexpression ran poorer prognoses than those without c-erbB-2 expression. From these results, we conclude that expression c-erbB-2 tissue status may be a good prognostic indicator in poorly differentiated gastric carcinoma.

A possible role of cytokines in the formation of peritoneal dissemination.

The earliest event in the formation of peritoneal dissemination is considered through the process of the attachment of intraperitoneal free cancer cells to the submesothelial basement membrane, exposed after contraction of mesothelial cells. We studied the mechanisms of the contraction of mesothelial cells using a. highly metastatic sell line (MKN-45-P) to the peritoneum. Four hours after intraperitoneal inoculation of MKN-45-P, mouse mesothelial cells began to contract, and submesothelial basement membrane was widely exposed after 24 h. The same changes developed four hours after i.p. injection of IL-6, TNF-alpha and IL-8, and were most prominently observed in mice treated with IL-8. However, no significant changes were observed after treatment of HGF, EGF and TGF-beta. Furthermore, IL-1 alpha, IL-6, IL-8, TNF and EGF increased the number of intercellular gaps of a human mesothelial cell monolayer, which was incubated on Matrigel coated dishes. Normal mesothelial cells form a contiguous monolayer of closely apposed polygonal cells, each of which had prominent and peripheral bands of F-actin. After incubation with IL-1 alpha, IL-6, IL-8, TNF and EGF, peripheral actin bands became indistinct and the central stress fibers became numerous. However, no significant changes were found in mesothelial cells, which were treated with TGF-beta and HGF. In addition, the number of attached MKN-45-P cells on a mesothelial cell monolayer after treatment of IL-1 alpha (0.1-1 ng/ml), IL-8 (10-100 ng/ml), and TNF-alpha (100 ng/ml) was significantly larger than that of control and TGF-beta significantly reduced the number of attached cells. Concentration of IL-8 in the serum-free medium of MKN-45-P cells was high (3.4 ng/ml), but IL-1 alpha, IL-6, TNF-alpha, TGF-beta, EGF and HGF could not be detected. None of these cytokines were detected in the conditioning medium of human mesothelial cells. Based on these results, mesothelial cell contraction may be mediated by IL-1 alpha, IL-6, IL-8, TNF-alpha, and EGF, and these cytokines may be produced from cancer cells and/or intraperitoneal inflammatory cells. In contrast, TGF-beta have an inhibitory effect on the mesothelial cell contraction and attachment of cancer cells to a mesothelial monolayer. The attachment of free cancer cells on the peritoneum may be controlled with these cytokines.

Correlation of peritoneal dissemination and integrin alpha 3 expression in gastric cancer.

To clarify the interrelationship between alpha 3 integrin, subunit/E-cadherin expression and peritoneal dissemination in gastric cancer, alpha 3 integrin subunit and E-cadherin expression gas were immunohistochemically examined and were correlated with clinicopathologic parameters. Among 150 primary gastric cancers, alpha 3 integrin subunit and E-cadherin were strongly expressed in 96 (65%) and 88 (59%) tumors, respectively. Integrin alpha 3 expression was closely associated with peritoneal dissemiantion, but there was no relationship between integrin alpha 3 expression and histologic type, nodal status, macroscopic type or wall invasion. Furthermore, 22 (84%) of 26 tumors which recurred in peritoneum overexpressed integrin alpha 3 expression in primary tumors. All seven peritoneal foci obtained from peritoneal dissemination expressed integrin alpha 3 expression despite no integrin alpha 3 expression in two of these 7 primary tumors. Reduced E-cadherin expression in primary tumors was intimately associated with large tumor size (>6 cm), nodal involvement, peritoneal dissemination and positive serosal invasion. Peritoneal dissemination was most frequently found in the tumors with positive integrin alpha 3 expression and reduced E-cadherin expression. Patients with these type of tumor [E-cadherin expression (-), and integrin alpha 3 subunit (+)] showed the poorest prognosis as compared with the other groups of patients. These results indicate that upregulation of integrin alpha 3 expression and down regulation of E-cadherin might have an important role in the formation of peritoneal dissemination. These tumors have characteristics of easy detachment from the serosal surface via downregulation of E-cadherin and strong adhesion capacity to the peritoneum via up-regulation of integrin alpha 3 expression. The immunohisto-chemical combination analysis of E-cadherin and integrin alpha 3 expression on the primary gastric cancer may be a good screening method to predict peritoneal recurrence.

E-cadherin and c-met expression as a prognostic factor in gastric cancer.

E-cadherin has an important role in the cell-cell adhesion and is known as an invasion suppressor gene. The c-met, which is a receptor of hepatocyte growth factor receptor, is involved in the proliferative and motile activity in cancer cells. The invasive and metastatic capacities of gastric cancer were studied from the immunohistochemically examined expression of MET and E-cadherin. Among 127 primary gastric cancers, 47 (34%) tumors were found to have preserved E-cadherin expression and the other 84 tumors showed reduced E-cadherin expression. MET expression was found in 55 (43%) tumors. A strong correlation was found between reduced E-cadherin expression and a larger tumor, positive serosal invasion, lymph node metastases or poor prognosis. Tumors with MET expression have the tendencies to invade deeply, to metastasize in more remote lymph nodes or peritoneum and to run a poor prognosis. MET over-expression and reduced E-cadherin expression were strongly associated with lymph node metastasis, peritoneal dissemination and poor prognosis. This group of patients with simultaneously abnormal expressions of these genes had a sixfold relative risk of death, as compared with patients with tumors showing MET negative or preserved E-cadherin expression. These results indicate that immunohistochemical combined analyses of MET and E-cadherin expression may be a powerful tool for the evaluation of invasive capacity and the prognosis of gastric cancer patients.

Correlation between expression of urokinase-type plasminogen activator receptor and metastasis in gastric carcinoma.

To clarify the interrelationship between urokinase-type plasminogen activator receptor (uPAR) and the progression of gastric cancer, uPAR expression in gastric cancer was studied by the reverse transcription (RT)-PCR and immunohistochemistry. uPAR mRNA was expressed in 44 of 46 primary gastric cancers and uPAR immunoreactivity was found in 21 (14%) of 155 tumors. uPAR immunoreactivity was also observed in the fibroblast-like cells and the inflammatory cells including macrophages. The intensity of uPAR immunoreactivity of these cells was weaker than that of cancer cells. uPAR expression detected by RT-PCR may be from cancer cells and/or non-cancerous stromal cells. uPAR immunoreactivity in cancer cells was closely associated with histologic type, nodal status, and macroscopic type. The uPAR positive tumors were closely associated with the macroscopically infiltrating type, undifferentiated type and stage IV disease. Poorly differentiated carcinomas with rich intestitial fibrosis (scirrhous carcinoma) expressed uPAR with a significantly higher incidence than the other histologic types of carcinoma. Growth of scirrhous carcinoma may be a result of a concerted action of the players in the plasminogen activator system, consisting of cancer cells and stromal elements. Furthermore, there was an intimate relationship between the grade of lymph node metastasis and uPAR tissue status. Patients with a uPAR positive tumor had a significantly poorer prognosis than those with uPAR negative tumor. These results indicate that the immunohistochemical diagnosis of uPAR tissue status on the primary tumor of gastric cancer may be a good predictor for the prognosis of patients with gastric cancer.

Association of progression and reduced expression of VLA-2 in gastric cancer.

We investigated the expression of VLA-2 in gastric cancers by immunohistochemistry using anti-integrin alpha 2 and beta 1 antibodies and the data were compared with the pathological findings of each gastric cancer. The specimens were stained with an immunohistological technique for integrin alpha 2 and beta 1 subunits. Tumors, simultaneously expressing both integrin alpha 2 and beta 1 subunits were defined as positive for VLA-2. Tumors expressing either subunits of integrin alpha 2 or beta 1 or those showing reduced expression of both subunits were defined as VLA-2 negative tumors. In the 77 primary tumors, 55 (71%) were VLA-2 positive. 38 (90%) of 42 tumors showing differentiated type including tubular adenocarcinoma and papillary adenocarcinoma expressed VLA-2, whereas 19 (55%) out of 35 undifferentiated type of cancers including poorly differentiated adenocarcinoma, mucinous carcinoma and signet ring cell carcinoma stained for VLA-2. In the undifferentiated type of cancers, VLA-2 negative tumors had a significantly higher incidence of vessel invasion than VLA-2 positive ones (p<0.05). VLA-2 negative tumors showed a tendency to peritoneal dissemination, lymph node metastases, lymphatic invasion or invasion beyond the subserosal layer. In the specimens of peritoneal dissemination, VLA-2 expression rate was found in 56% (9/16), with a higher expression rate than that of primary lesions. These data indicate that reduced expression of VLA-2 may strongly associate with vessel invasion especially in the undifferentiated type of adenocarcinoma of the stomach.