Biological and clinical significance of hepatocyte growth factor in breast cancer

Hepatocyte growth factor (HGF) is a mesenchyme- or stroma-derived multipotent factor that regulates the growth, motility, and morphogenesis of various types of cells, including cancer cells. We investigated the effect of HGF on human breast cancer cells, and measured the concentration of HGF in the sera of breast cancer patients. When BT-20 cells were stimulated with HGF, the transmigration of cancer cells was markedly accelerated. In a checkboard assay, pronounced chemotaxic locomotion of BT-20 cells is expressed, corresponding to HGF concentrations. HGF treatment of BT-20 cells resulted in enhanced expression of alpha 2, alpha 3 and beta 1 integrin subunits, and augmented the binding activity to immobilized collagen. The c-met protein was expressed on the cancer cells in 48 of the 97 (49.5%) breast cancer primary tumors. In the serum, the advanced and recurrent cancer group showed a high level of this protein in comparison with the other patient groups. The mean value of serum HGF was 0.65 ng/ml in patients with distant metastases and 0.27 ng/ml in those with no such evidence. Thus, the HGF concentration becomes significantly elevated in the sera of patients with distant metastases. These findings suggest that HGF is involved in invasion and metastasis of breast cancer, and that serum HGF is useful as a tumor marker with a close correlation to the metastatic state of breast cancer.     

Cytosol and serum concentration of cytokeratin subunit-19 fragment (cyfra-21-1) in breast-cancer

Cytokeratin 19 is a subunit of cytokeratin intermediate filament. CYFRA 21-1 is a new tumor marker using monoclonal antibodies which recognize a fragment of cytokeratin 19. CYFRA 21-1 was measured in cytosol of breast cancer tissues or in sera of patients with breast cancer or benign breast diseases to study the significance of this protein as a tumor marker. The cytosol concentration of CYFRA 21-1 was elevated in cancerous tissue compared to that in adjacent noncancerous tissue, and correlated with the tumor stage or the estrogen receptor status. In the serum, the mean value and positive rate for CYFRA 21-1 (assuming 2.2 ng/ml as the cut-off value) were 0.61 ng/ml (0%) in benign breast diseases, 0.98 ng/ml (6.7%) in stage I/II primary breast cancer, 75.67 ng/ml (60.0%) in stage III/IV primary breast cancer, 45.28 ng/ml (60.0%) in recurrent breast cancer, and 0.64 ng/ml (2.6%) in those with no evidence of recurrence. From the above, we concluded that CYFRA 21-1 could be a tumor marker with high specificity in breast cancer.     

Adhesion molecules involved in pleural dissemination of esophageal cancer cells

Pleural dissemination is a common cause of recurrence after surgery of patients with esophageal cancer. Very little is known about the biochemical processes involved in the initial attachment of cancer cells to pleural mesothelial cells. The authors conducted in vitro and in vivo studies to assess the role of adhesion molecules in this process, using 2 cell lines derived from human esophageal cancer. TE-1 cells, which pronouncedly express CD44H, adhered to the monolayers of mesothelial cells more firmly than T.Tn cells. On the other hand, the adhesion of TE-I cells to mesothelial cells was markedly inhibited by antibodies to CD44H or the beta(1) integrin subunit, and more strongly blocked by using a combination of the two antibodies. These antibodies inhibited the dissemination of TE-1 cells in the pleural cavity of nude mice. The findings suggest that CD44 and integrin play important roles in the initial attachment of esophageal cancer cells to mesothelial cells.     

Targeted Gene Transfer for Adenocarcinoma Using a Combination of Tumor-specific Antibody and Tissue-specific Promoter

We have developed a highly specific gene transfer method for adenocarcinoma using a monoclonal antibody against tumor-specific antigen coupled with a plasmid containing the carcinoembryonic antigen (CEA)-specific promoter. The chimeric CEA promoter (CC promoter), which contained an enhancer from the immediate early gene of cytomegalovirus and the CEA promoter, achieved 4- to 5-fold higher transgene expression in CEA-producing cells than the original CEA promoter while maintaining CEA specificity. Furthermore, a complex of a monoclonal antibody against Lewis Y antigen (LYA), the CC promoter-containing plasmid and cationic liposomes (DOTAP) achieved specific gene expression in CEA-producing and LYA-positive adenocarcinoma cell lines that was 200-fold more efficient than in CEA-non-producing and LYA-negative cell lines during a short in vitro incubation. This strategy may be applicable for clinical gene therapy.     

Mean systolic ejection rate after aortocoronary bypass graft surgery

In 62 patients with coronary artery disease who underwent aortocoronary bypass graft surgery, we measured the mean systolic ejection rate invasively at rest and during upright exercise before and several months after operation. After bypass surgery, mean systolic ejection rate did not show any change at either supine or sitting rest and at submaximal exercise levels of walking on a treadmill. At maximal exercise, only patients with complete revascularization showed a significant increase in heart rate from 105 to 147 (+40%) and mean systolic ejection rate from 339 ml/sec to 404 ml/sec (+19%, P less than 0.001). Patients with incomplete revascularization did not show a substantial change in these variables. Beta-blocker withdrawal did not affect the result significantly.     

Prediction of maximal cardiac output in preoperative patients with coronary artery disease

Of 100 patients (89 men, 11 women) studied preoperatively to determine their aerobic and hemodynamic profiles at rest and during upright treadmill exercise. The mean maximal cardiac output (CO), measured using the direct Fick principle, was 57 ± 14% of average normal values. The reduction in maximal heart rate (63 ± 13% of normal) was a greater factor in the reduction in CO than stroke volume (88 ± 16% of normal). Maximal oxygen consumption (V?O₂max) was 48 ± 15% of normal and the greater reduction in V?O₂₂max compared with CO was due to lower peripheral extraction in the coronary patients. Variables that correlated with maximal CO in a univariate analysis included angina severity (r = ?0.45), V?O₂₂max (r = 0.67), maximal heart rate (r = ?0.31), left ventricular dysfunction (r = ?0.45), maximal systolic blood pressure (r = ?0.31) and number of vessels with ≥ 50% diameter reduction (r = ?0.3). Resting ejection fraction did not correlate with maximal CO. In a multivariate analysis, 4 variables correlated significantly (r = 0.77) with maximal CO: in order, V?O₂₂max, number of vessels with ≥ 50% stenosis, magnitude of ST depression and sex.     

Clinical outcomes of a novel therapeutic vaccine with Tax peptide‐pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study

Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type‐I (HTLV‐I)‐infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV‐I Tax‐specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti‐ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate‐ to high‐risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax‐specific CTL responses were observed with peaks at 16–20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide‐pulsed DC vaccine is a safe and promising immunotherapy for ATL.