Quality of life following esophagectomy with three-field lymphadenectomy for carcinoma, focusing on its relationship to vocal cord palsy.

To clarify the quality of life of patients who underwent esophagectomy for carcinoma by right thoracotomy, laparotomy and cervical anastomosis, 116 patients who were cancer free at the time of mailing a questionnaire were analyzed. A significant decrease in vital capacity for 3 years postoperatively, as well as in the percentage of ideal body weight, between 3 and 5 years were observed in 57 patients with three-field lymphadenectomy. Patients' quality of life undergoing three-field dissection was worse than those with less radical lymphadenectomy (59 cases) in terms of the performance status and difficulty in talking at 60 months or more postoperatively. Around 20% of all patients reported severe hoarseness due to permanent recurrent nerve paralysis, resulting in poor quantity of food intake at 24 months or less postoperatively and restricted daily activity and difficulty in talking at 60 months or more after the operation. When a patient suffers from vocal cord insufficiency caused by permanent paralysis of the recurrent nerve, early treatment before discharge from the hospital should be performed to improve the quality of life of such a patient.

Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases.

Urokinase-type plasminogen activator receptor (uPAR) plays a central role in the plasminogen activation cascade and participates in extracellular matrix degradation, cell migration and invasion. We evaluated the expression level of uPAR mRNA and the presence of isolated tumour cells (ITCs) in bone marrow (BM) and peripheral blood (PB) in gastric cancer patients and clarified its clinical significance. We assessed specific uPAR mRNA expression by quantitative real-time reverse transcriptase- polymerase chain reaction (RT-PCR) in BM and PB in 846 gastric cancer patients as well as three epithelial cell markers, carcinoembryonic antigen (CEA), cytokeratin (CK)-19 and CK-7. The uPAR mRNA expression in bone marrow and peripheral blood expressed significantly higher than normal controls (P<0.0001). The uPAR mRNA in BM showed concordant expression with the depth of tumour invasion, distant metastasis, and the postoperative recurrence (P=0.015, 0.044 and 0.010, respectively); whereas in PB, we observed more intimate significant association between uPAR expression and clinicopathologic variables, such as depth of tumour invasion, the distant metastasis, the venous invasion and the clinical stage (P=0.009, 0.002, 0.039 and 0.008, respectively). In addition, the uPAR mRNA expression in PB was an independent prognostic factor for distant metastasis by multivariate analysis. We disclosed that it was possible to identify high-risk patients for distant metastasis by measuring uPAR mRNA especially in peripheral blood at the timing of operation in gastric cancer patients.

CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer.

Although CD133 has been shown to be a marker for cancer stem cells in various tumours, its expression in pancreatic cancer has not yet been clinically reported. In this study, we investigated the relationship between CD133 expression and clinicopathological factors in pancreatic cancer. Pancreatic head carcinoma specimens from 80 patients who underwent surgical resection were immunohistochemically assessed for CD133, vascular endothelial growth factor (VEGF)-C, CXCR4, CD34, Ki-67, and cytokeratin (CK) expressions. Sixty percentage (48/80) of specimens were CD133-positive, with less than 15% cells per specimen expressing the marker. CD133-positive cells were found at the peripheral site of adenocarcinoma glandular structures and were negative for CK. There was a significant correlation between CD133 expression and clinicopathological factors, including histological type, lymphatic invasion, and lymph node metastasis (P=0.0215, 0.0023, and 0.0024, respectively). Vascular endothelial growth factor-C expression was also significantly correlated with CD133 expression (P=0.0002). Consequently, the 5-year survival rate of CD133-positive patients was significantly lower than that of CD133-negative patients (P=0.0002) and multivariate analysis revealed that CD133 expression was an independent prognostic factor (P=0.0103). These results suggest that CD133 expression in pancreatic cancer was significantly associated with lymphatic metastasis, VEGF-C expression, and prognosis.

The role of salvage surgery for recurrence of esophageal squamous cell cancer.

AIM: A consensus treatment strategy for recurrent esophageal squamous cell cancer (ESCC) has not been established. The purpose of the present study was to analyse the mode of recurrence, and evaluate the role of surgical salvage treatment in recurrence of ESCC. METHODS: Recurrence was detected in 131 of 367 consecutive patients with ESCC. We retrospectively analysed the mode of recurrence and treatment for recurrence. Recurrence was divided into four types; lymph node, hematogeneous, mixed and local. Treatments were classified into four groups; chemotherapy alone (C group), radiation therapy +/- chemotherapy (R group), surgery +/- other therapy (S group), and no therapy (N group). RESULTS: Of the 131 recurrences, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 43, 44, 40 and 4, respectively. The number of patients in the C, R, S, N groups was 35, 35, 24 and 37, respectively. Of the 24 patients who received surgical treatment for recurrence, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 11, 6, 6 and 1, respectively. The number of lesions in hematogeneous recurrence was 2 or less. The survival rate from recurrence to death in the C, R, S and N groups was 0, 3.9, 6.7 and 0%, respectively. A statistically significant difference was found in these groups (p < 0.0001). CONCLUSIONS: Salvage surgery is one of the useful treatment tools for resectable metastatic lesions. In such cases, the number of lesions, recurrent sites and effectiveness of chemotherapy and/or radiotherapy should be carefully evaluated.

Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma.

BACKGROUND: Platelet-derived endothelial cell growth factor (PD-ECGF) is known to promote the development of new blood vessels, which are fundamental to tumor growth and metastasis. We previously found that thymidine phosphorylase (dThdPase) and PD-ECGF are the same protein. PURPOSE: We retrospectively examined the expression of dThdPase in primary colorectal carcinomas, its association with angiogenesis and clinicopathologic findings, and its prognostic value. METHODS: Tissues were obtained from the tumors of 163 patients whose colorectal carcinomas were completely removed by surgery. Microvessels assessed by immunostaining endothelial cells for factor VIII were counted on a 400x field in the most active areas of neovascularization within the tumor. We purified the monoclonal antibody against dThdPase and studied the expression of dThdPase in the same serial sections used for the detection of factor VIII. Those who carried out microvessel counting and dThdPase expression assessment had no knowledge of clinicopathologic findings. The significance of dThdPase in the prognosis of patients with colorectal carcinomas was also examined in the survival analysis of mortality follow-up data covering the period between 1984 through 1991. Reported P values are from two-sided tests of statistical significance. RESULTS: The mean microvessel count (+/- standard deviation) in dThdPase-positive colorectal carcinoma specimens (17.5 +/- 7.2) was higher (P < .001) than that in dThdPase-negative carcinoma specimens (9.3 +/- 5.5). The dThdPase positivity was in accordance with the microvessel count. dThdPase positivity showed highly significant statistical associations with tumor size, extent of invasion, lymph node metastasis, lymphatic invasion, and venous invasion. Cox regression analysis revealed that dThdPase expression was prognostic for poor disease outcome after adjustment for Dukes' stage and microvessel count. CONCLUSIONS: These findings suggest that higher levels of dThdPase expression in colorectal carcinomas are associated with more extensive angiogenesis, poor clinical and laboratory findings, and unfavorable clinical outcome. IMPLICATIONS: Inhibition of dThdPase in human colorectal carcinomas might improve prognosis for some patients.

Multidrug resistance and the lung resistance-related protein in human colon carcinoma SW-620 cells.

BACKGROUND: Lung resistance-related protein (LRP), the major vault protein in humans, is sometimes overexpressed in multidrug-resistant cells. Because cells transfected with the LRP gene did not express the multidrug-resistant phenotype, we investigated whether LRP is involved in multidrug resistance. METHODS: SW-620 cells, a human colon carcinoma cell line, alone or transfected with an expression vector carrying a LRP-specific ribozyme or with an empty vector, were treated with sodium butyrate to induce differentiation. Expression of P-glycoprotein, multidrug resistance protein, and LRP in the cells was examined by northern and western blotting, and the efflux of doxorubicin in the cells or isolated nuclei was examined by fluorescence microscopy. RESULTS: A 2-week treatment with sodium butyrate induced LRP and conferred resistance to doxorubicin, vincristine, etoposide, gramicidin D, and paclitaxel (Taxol) in SW-620 cells. Insertion of either of two LRP-specific ribozymes into SW-620 cells inhibited these activities. Levels of drugs accumulating in the cells were not decreased by sodium butyrate, suggesting that the adenosine triphosphate-binding cassette transporter is not involved in sodium butyrate-induced multidrug resistance. Doxorubicin was mainly located in the nuclei of untreated cells and in the cytoplasm of sodium butyrate-treated cells. Isolated nuclei from untreated cells or sodium butyrate-treated cells incubated with anti-LRP polyclonal antibodies contained more doxorubicin than the nuclei of sodium butyrate-treated cells alone. Efflux of doxorubicin was greater from the nuclei of sodium butyrate-treated cells than the nuclei of untreated cells or of sodium butyrate-treated cells transfected with a LRP-specific ribozyme and was inhibited by an anti-LRP polyclonal antibody. CONCLUSIONS: LRP is involved in resistance to doxorubicin, vincristine, etoposide, paclitaxel, and gramicidin D and has an important role in the transport of doxorubicin from the nucleus to the cytoplasm.

A modified invasion-3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay for quantitating tumor cell invasion.

Reconstituted basement membrane matrix (Matrigel) has been utilized for in vitro assay of tumor cell invasion in recent years. In the conventional chamber for the invasion assay, however, a large number of cells passed easily through the center of the Matrigel-coated filter because the Matrigel layer could not be completely uniform by the meniscus formation. To prevent the meniscus phenomenon of the Matrigel layer, we devised a water-repellent treatment of the inside wall of the assay chamber with paraffin. Consequently, very few erythrocytes passed through the Matrigel-coated filter of this modified chamber with the erythrocyte assay, which was used to demonstrate the evenness and uniformity of the Matrigel layer on the filter. For quantitating a small number of cells which invaded through the Matrigel-coated filter by the invasion assay, a tetrazolium-based colorimetric 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assay was used. The invasive abilities of the eight different cells were determined by this invasion-3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium+ ++ bromide assay using the modified chamber with a filter coated with 70 microliters of the 0.2-mg/ml Matrigel. After 72 h of incubation, the malignant cell lines significantly exceeded the normal cell lines in the percentage of invasion (P < 0.01). Therefore, the modified invasion-3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium+ ++ bromide assay provides a simple, easily reproducible in vitro assay for quantitating tumor cell invasion.

In vitro determination of basement membrane invasion predicts liver metastases in human gastrointestinal carcinoma.

We described previously (H. Imamura, et al., Cancer Res., 54: 3620-3624, 1994) a quantitative and reproducible 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for tumor cell invasiveness that uses a water-repellent, paraffin-treated Chemotaxicell chamber to produce a uniform Matrigel layer. In the present experiments, we studied 71 human gastrointestinal carcinomas, including 53 maintained as xenografts in nude mice and 18 fresh surgical specimens. We found a correlation between metastatic behavior and the percent invasion (PI) calculated from the MTT assay. Tumors producing liver metastases had a significantly higher PI than did tumors without liver metastases (P < 0.01), and seven of nine fresh tumors with a PI greater than 1.0 showed liver metastases within 2 years. No significant correlations were noted between the PI and clinicopathological factors. In the tumor xenografts, type IV collagenase activity was significantly higher in tumors with clinically evident liver metastases than in those without liver metastases (P < 0.05). Colorectal carcinomas with liver metastases and a high PI showed higher expression of matrix metalloproteinase 9 than matrix metalloproteinase 2 as assessed by gelatin zymography. Thus, the invasion-MTT assay is clinically useful for predicting liver metastases. Type IV collagenase plays an important role in the development of liver metastases from human gastrointestinal carcinoma.

Enhanced adenovirus transgene expression in malignant cells treated with the histone deacetylase inhibitor FR901228.

The presence of coxsackie and adenovirus receptor (CAR) and alpha(v) integrin on cell surfaces is required for efficient adenovirus infection. Treatment of cells with the histone deacetylase inhibitor FR901228 (depsipeptide) increased CAR and alpha(v) integrin RNA levels in six cancer cell lines. Sodium butyrate and trichostatin A, other histone deacetylase inhibitors, caused similar increases. Cells treated with FR901228 prior to infection had a 4-10-fold increase in transgene expression from a beta-galactosidase-expressing adenoviral vector. These studies suggest that FR901228 increases the efficiency of adenoviral transgene expression and may be useful in cancer gene therapy.

Suppression of metastasis by thymidine phosphorylase inhibitor.

We developed a novel inhibitor of thymidine phosphorylase (TP), 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI), that is about 1000-fold more active than 6-amino-5-chlorouracil, one of the most potent TP inhibitors. TPI inhibited the high chemotactic motility and basement membrane invasion of KB/TP cells, a TP-positive clone transfected with Rous sarcoma virus (RSV)/TP, to the levels seen in KB/CV cells, a control clone transfected with RSV. In nude mice, oral administration of TPI suppressed not only macroscopic liver metastases of highly metastatic KB/TP cells but also the level of human beta-globin as a molecular marker of micrometastases in the livers of the mice. These findings demonstrate that TP plays a key role in the invasiveness and metastasis of TP-expressing solid tumors and suggest that TPI might be a novel antimetastatic agent for blood-borne metastasis.

MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas.

BACKGROUND: Many patients with invasive ductal carcinoma of the pancreas (IDC) have a poor outcome. MUC4 expression has been implicated as a marker for diagnosis and progression of IDC, but there are no studies of the relation between MUC4 expression and patient prognosis in IDC. AIMS: To investigate the prognostic significance of MUC4 expression in IDC. METHODS: The expression profiles of MUC4, ErbB2, p27, and MUC1 were investigated in IDC tissues from 135 patients by means of immunohistochemistry. RESULTS: MUC4 was expressed in 43 of the 135 patients with IDC (31.9%). The survival of 21 patients with high MUC4 expression (>20% of neoplastic cells stained) was significantly worse than that of the 114 patients with low MUC4 expression (<20% of neoplastic cells stained) (p = 0.0043). Univariate analysis showed that high MUC4 expression (p = 0.0061), large primary tumour status (>T2) (p = 0.0436), distant metastasis (p = 0.0383), lymphatic invasion (p = 0.0243), and surgical margins (p = 0.0333) were significant risk factors affecting the outcome of patients with IDC. Backward stepwise multivariate analysis showed that MUC4 expression (p = 0.0121), lymph node metastasis (p = 0.0245), and lymphatic invasion (p = 0.0239) were significant independent risk factors. ErbB2, p27, and MUC1 were not independent risk factors. CONCLUSIONS: This study shows that MUC4 expression in IDC is a new independent factor for poor prognosis and predicts the outcome of patients with IDC.

Endoscopic quadrantectomy for breast cancer with sentinel lymph node navigation via a small axillary incision.

A great deal of clinical experience has firmly established the concept of the sentinel lymph node (SN) in breast cancer. SN biopsy allows treatment without axillary lymphadenectomy and has made it possible to perform a surgical intervention via just a small skin incision. In partial resection of the breast (quadrantectomy), we use a double retractor to form a workspace under the skin via a small axillary incision. Resection does not require a large incision even in cases in which the cancer lesion is located in the upper inner or lower inner quadrant of the breast, as the endoscope allows the surgeon to see the workspace formed by the double retractors.

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.

Expression of thymidine phosphorylase is associated with a poor prognosis in patients with ductal adenocarcinoma of the pancreas.

Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor and has angiogenic activity. In this study, we investigated the expression of dThdPase in ductal adenocarcinoma of the pancreas and examined the correlation between dThdPase expression and clinicopathological factors and clinical outcome. dThdPase expression was demonstrated by immunohistochemistry in the cytoplasm of tumor cells in 59% of the 54 patients studied. The expression of dThdPase correlated significantly with a poor prognosis (P=0.013). Significant correlations were also observed between dThdPase expression and extrapancreatic neural plexus invasion and the presence of postoperative hepatic metastases (P=0.05 and 0.03, respectively). The average microvessel count in dThdPase-positive tumors was significantly higher than that in dThdPase-negative tumors (P < 0.0001). These findings suggest that dThdPase expression in pancreatic adenocarcinoma enhances the abilities of tumor invasion and/or metastasis through its angiogenic properties.

Expression of p21WAF1/Cip1 in the p53-dependent pathway is related to prognosis in patients with advanced esophageal carcinoma.

The proteins p53 and p21 are important components that regulate G1-S transition through the cell cycle. We immunohistochemically investigated p53 and p21 expression in 111 patients with esophageal squamous cell carcinoma. We also evaluated whether the expression of either of these proteins is a prognostic factor according to the p53-dependent and -independent pathways. The positive rates of p53 and p21 expression were 42.8 and 43.2%, respectively. Clinicopathological findings according to p53 and p21 expression did not differ significantly. The 5-year-survival rates between p21 positive and negative expression did not differ significantly in the p53-positive group. In the p53-negative group, the 5-year-survival rate of patients with p21-positive expression was 22.9%, which was significantly better than that of patients with p21-negative expression (12.7%; P<0.05). Multivariate analysis revealed that p21 expression in the p53-dependent pathway was an independent prognostic factor. Accordingly, the prognostic values of p21 expression between the p53-dependent and -independent pathways differed. Examination of p21-positive expression in the p53-dependent pathway will help to estimate the favorable prognosis of patients with advanced esophageal carcinoma.

Construction of gene therapy vectors targeting thyroid cells: enhancement of activity and specificity with histone deacetylase inhibitors and agents modulating the cyclic adenosine 3',5'-monophosphate pathway and demonstration of activity in follicular and anaplastic thyroid carcinoma cells.

Thyroid carcinoma accounts for the majority of deaths from endocrine cancers. Although effective therapies exist for well differentiated tumors, the treatment options for poorly differentiated and anaplastic tumors are much less effective. In the present study we demonstrate that the thyroglobulin (Tg) promoter can be used to direct specific expression of either luciferase or thymidine kinase in thyroid cancer cells. Furthermore, using a putative enhancer element for the Tg gene, the activity of the Tg promoter in and its specificity for thyroid cells were enhanced. In transient transfectants or in stably transfected thyroid carcinoma cells, treatment with the histone deacetylase inhibitors, depsipeptide (FR9012228) and sodium butyrate, alone or in combination with 8-bromo-cAMP, resulted in further enhancement. In experiments in which the herpes simplex virus thymidine kinase (HSV-TK) gene was driven by the Tg promoter and the putative enhancer, HSV-TK expression and ganciclovir sensitivity were augmented. Similar results were obtained in two cell lines derived from a follicular thyroid carcinoma and in two anaplastic thyroid carcinoma cell lines. In summary, we report the construction of a suicide HSV-TK vector with preferential toxicity for thyroid cells. The results in anaplastic thyroid carcinoma cells suggest that it may be of use in the full spectrum of thyroid malignancies.

Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(-) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells.

Thyroid carcinoma accounts for the majority of deaths from endocrine cancers. A major cause of treatment failure is the inability to trap iodine. Chemotherapeutic agents with differentiating properties have been tried in an attempt to increase iodine uptake. We examined the ability of the novel histone deacetylase (HDAC) inhibitor, depsipeptide (FR901228), to modulate the expression of thyroid-specific genes. Four cell lines, two derived from follicular thyroid carcinomas (FTC 133 and FTC 236) and two derived from anaplastic thyroid carcinomas (SW-1736 and KAT-4) were used. In these four cell lines, a very low concentration of depsipeptide (1 ng/mL) increased histone acetylation and expression of both thyroglobulin and the Na(+)/I(-) symporter messenger RNAs. After 3 days, messenger RNA levels approached those of a normal thyroid control. Depsipeptide induced increases in (125)I accumulation indicated that a functional Na(+)/I(-) symporter protein was induced. Transient transfections indicate that the effects are mediated at least in part by a trans-activating factor. These in vitro results suggest that depsipeptide or other histone deacetylase inhibitors might be used clinically in thyroid carcinomas that are unable to trap iodine as an adjunct to radioiodine therapy.

The activity and expression of thymidine phosphorylase in human solid tumours.

Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and has angiogenic activity. Since dThdPase seems to have an important role in angiogenesis of tumours, we measured the activity and expression of dThdPase in various tumours and the adjacent non-neoplastic tissues. We assayed dThdPase activity by spectrophotometric means, and the expression of dThdPase was examined by immunoblotting and by immunohistochemical staining using a monoclonal antibody against dThdPase. In the oesophagus, stomach, colorectum, pancreas, and lung, dThdPase activity in carcinomas was significantly higher (P < 0.05) than that in the adjacent non-neoplastic tissues. The expression level of dThdPase detected by immunoblotting correlated well with the activity of dThdPase. In the oesophagus, stomach, colorectum, gall bladder, pancreas and lung, the proportion of dThdPase-positive tumours was significantly higher (P < 0.05 or 0.01) than that of the dThdPase-positive adjacent normal tissues. In oesophageal, gastric colorectal and lung carcinomas, the proportion of dThdPase positivity in advanced carcinomas was significantly higher (P < 0.01) than that in early carcinomas. Tumour-infiltrative macrophages or lymphocytes in the lymph node, alveolar macrophages and Kupffer cells expressed high levels of dThdPase. The results indicate that dThdPase activity and expression level in many tumours are higher than those in the adjacent non-neoplastic tissues, and that dThdPase may have an important role in the proliferation of these solid tumours.

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.