Kinya Baba

Analysis of MT1‐MMP and MMP2 expression in human gastric cancers

Membrane‐type 1 matrix metalloproteinase (MT1‐MMP) is a presumed activator of MMP2, which is one of the major proteinases in tumor cell invasion. In this study, we determined the clinico‐pathologic significance of MT1‐MMP expression in 68 human gastric carcinomas. The tumor‐normal ratio (T/N ratio) of MT1‐MMP expression was determined by reverse transcription‐polymerase chain reaction analysis. To visualize the localization of MT1‐MMP, an immunohistochemical study was performed. In addition, a gelatin zymography was done to examine the activation ratio of MMP2, and a correlation between MT1‐MMP expression and activation of MMP2 was studied. The expression of MT1‐MMP mRNA was higher in tumor tissue than in corresponding normal tissue in most cases. The mean value of the T/N ratio was 4.8. Twenty cases with T/N ≥ 4.8 showed significantly deeper invasion and higher frequency of lymph node metastasis than 48 cases with T/N < 4.8. MT1‐MMP expression was an independent factor influencing both tumor invasion of the gastric wall and lymph node metastasis. Although MT1‐MMP expression was not an independent prognostic factor, the patients with T/N ≥ 4.8 showed a significantly worse prognosis than those with T/N < 4.8. An immunohistochemical study demonstrated that MT1‐MMP expression was mainly recognized in the tumor cells. There was a significant correlation between MT1‐MMP expression and activation of MMP2. Our findings suggest that: 1) the expression of MT1‐MMP may influence prognosis via tumor invasion of the gastric wall and lymph node metastasis, and 2) MT1‐MMP activation of MMP2 may be clinically relevant in gastric carcinoma tumors. Int. J. Cancer 74:316‐321, 1997.

Endoscopic diagnosis of early carcinoma of the esophagus using Lugol's solution

Small esophageal lesions, particularly intraepithelial cancers, are extremely difficult to detect. We used Lugols iodine solution with panendoscopic examination to detect the presence and spread of small squamous cell carcinomas of the esophagus. Serial histologic specimens of the surgically removed esophagus from 32 patients with Lugols combined endoscopic diagnosis of early esophageal carcinoma were examined to determine the correlation between endoscopic and histologic findings. All of the early staged carcinomas clearly remained unstained by Lugols solution. We believe that the application of Lugols solution will greatly aid in instances when a suspicious mucosal lesion is noted, when the margin of the lesion is unclear, or when there is suspicion that a mucosal lesion may have been overlooked.

Hyperthermia combined with chemotherapy and irradiation for patients with carcinoma of the oesophagus—A prospective randomized trial

From 1988 to 1990, 53 patients with squamous cell carcinoma of the thoracic oesophagus underwent subtotal oesophagectomy after either preoperative hyperthermo-chemoradiotherapy (HCR therapy) or chemoradiotherapy without hyperthermia (CR therapy), in a prospective randomized trial carried out to examine the effects of hyperthermia given preoperatively. The two groups (27 patients given HCR therapy and 26 given CR therapy) were found to be comparable with regard to prognostic factors of age, site of carcinoma, TNM stage, etc. Following preoperative evaluation by an upper GI series and endoscopy, a subtotal oesophagectomy was done for all 53 patients. All the resected specimens, including the lymph nodes, were histopathologically examined, and the effects of preoperative treatment were evaluated by findings in the upper GI series and endoscopy, as well as based on the histopathology of the excised tissues. There were no viable cancer cells in the resected specimens of seven patients in the HCR therapy group (26.9%) and of two patients in the CR therapy group (7.7%). In addition, no hyperthermia complications were observed. The study suggests that preoperative HCR therapy may be a more beneficial therapy than preoperative CR therapy in patients with squamous cell carcinoma of the oesophagus who undergo a subtotal oesophagectomy.

Efficient induction of antitumor cytoxic T lymphocytes from a healthy donor using HLA-A2-restricted MAGE-3 peptide in vitro

Abstract The antigenic peptides encoded by tumor-rejection antigen genes, MAGE-1 and -3, have been identified, and various methods have been utilized for the in vitro induction of MAGE-specific, cytotoxic T lymphocytes (CTL) from peripheral blood mononuclear cells (PBMC) using synthetic peptides. However, all of these methods are technically demanding and thus have a relatively limited usefulness. We herein report a simple and efficient method for the in vitro induction of specific CTL by using the HLA-A2-restricted MAGE-3 peptide from the PBMC of a healthy donor. CTL responses could thus be efficiently induced from unseparated PBMC by stimulation with freshly isolated, peptide-pulsed PBMC as antigen-presenting cells and by using interleukin-7 and keyhole limpet hemocyanin for the primary culture. The induced CTL could thus recognize and lyse not only HLA-A2 target cells pulsed with the peptide but also HLA-A2 tumor cells expressing MAGE-3, in an HLA-class-I-restricted manner. This simple method may, therefore, become a useful tool for investigating the potential peptides for tumor antigens as well as for developing various immunotherapeutic approaches for human malignant tumors.

Apoptosis in antibody-dependent monocyte-mediated cytotoxicity with monoclonal antibody 17-1a against human colorectal carcinoma cells : enhancement with interferon γ

Abstract Antibody-dependent cell-mediated cytotoxicity (ADCC) has been considered to be one of the main effector mechanisms by which unconjugated monoclonal antibody (mAb) 17-1A can exert an antitumor effect in vivo. Since the apoptotic pathway as well as the necrotic pathway have been shown to be utilized in various cytotoxic effector mechanisms, we investigated the role of apoptosis in ADCC mediated by monocytes (ADMC) using mAb 17-1A as an antibody and the human colorectal carcinoma cell line, COLO205, as target cells in vitro. The implications of the apoptosis during ADMC was demonstrated by means of both a DNA fragmentation assay and a TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay. Furthermore, interferon γ (IFNγ) was also found to enhance the induction of apoptosis significantly. The addition of superoxide dismutase did not reduce the level of the apoptosis, although superoxide anion (O2–) was observed to be produced. However, the release of tumor necrosis factor α (TNFα) was significantly enhanced during ADMC, while, in addition, apoptosis was significantly inhibited by the addition of anti-TNFα antibody. These findings indicated that apoptosis might be implicated in ADMC with mAb 17-1A, which was augmented by IFNγ, while, in addition, TNFα may also be one of the major mediators of apoptosis.

Analysis of ornithine decarboxylase messenger ribonucleic acid expression in colorectal carcinoma.

PURPOSE: Ornithine decarboxylase (ODC) is a rate-limiting enzyme for polyamine synthesis. An elevated protein level of ODC was observed in the tumors. There has been, however, little information reported so far on the expression of ODC messenger ribonucleic acid (mRNA) in clinical colorectal carcinomas.In vitrostudies disclosed that the transcriptions of the ODC gene is regulated by the c-mycgene. METHODS: The expression of ODC and c-mycmRNA in biopsy specimens obtained from both tumor tissue and the corresponding normal tissue was examined by the reverse transcriptase polymerase chain reaction method in 40 cases of colorectal carcinoma. RESULTS: The expression of ODC mRNA was observed in both tumor tissue and normal tissue. The tumor to normal ratio of ODC mRNA was higher in cases with deeply invasive tumors than in cases with shallow tumors, and it was also higher in Dukes B or C cases than in Dukes A cases. There was a significant correlation between the tumor to normal ratio of c-mycmRNA and that of ODC mRNA in each case. CONCLUSIONS: These findings suggested that 1) the study of the expression of ODC mRNA may be useful for preoperatively predicting more advanced disease of colon carcinoma, and 2) there was a significant correlation between expression of ODC and c-mycmRNA in the clinical samples, which was similar to the findings of a previousin vitrostudy.

Platelet Aggregability and the Occurrence of Anastomotic Leakage after Esophageal Reconstruction

In 21 patients who had undergone resection and reconstruction for esophageal carcinoma, the postoperative platelet aggregability was measured and the correlation between the occurrence of anastomotic leakage and platelet aggregability was investigated. There was no statistical difference in the clinical features of the patients between those with (n = 5) and without (n = 16) anastomotic leakage. Platelet aggregability was measured by the turbidimetric method from blood samples taken preoperatively, and at 1, 3, and 7 postoperative days (POD). The average values of platelet aggregability in patients without anastomotic leakage were 81.2, 70.4, 80.1, and 81.8%, while those with leakage were 81.3, 47.6, 52.3, 70.6% preoperatively, and 1, 3, and 7 POD, respectively. Thus, platelet aggregability significantly decreased in patients with anastomotic leakage on the first postoperative day (p < .05), and then gradually recovered postoperatively as time passed. Therefore, the measurement of platelet aggregability is considered to be one of the parameters predicting the occurrence of anastomotic leakage, and a prevention in the decrease of platelet aggregability as well as its activation could become a treatment for preventing anastomotic leakage.

A complete response of an advanced oesophageal carcinoma treated with hyperthermic chemotherapy: a case report

A 56-year-old Japanese man with an advanced squamous cell carcinoma in the middle oesophagus was treated with a combination of hyperthermia, intravenous infusion of cisplatin (CDDP) and oral administration of oily bleomycin(BLM)-polyacrylate paste. After performing six sessions of hyperthermia treatment conducted at 42-45 degrees C for 30 min with 150 mg of CDDP and 180 mg of BLM, a subtotal oesophagectomy and lymph node dissection were performed. A histopathological study of the resected specimen showed no residual viable cancer cells either in the oesophagus or in the dissected lymph nodes. There were no side effects or perioperative complications and the patient is now healthy and leading a normal life 10 months after operation without undergoing any further treatment, at the time of writing. The effect of small amounts of CDDP and the oral application of oily BLM were thought to be strongly enhanced by hyperthermia in the treatment of oesophageal squamous carcinoma, and this regimen is therefore recommended as a safe and effective strategy, especially for preoperative treatment.

Histopathologic Investigation of Squamous Epithelial Dysplasia and Carcinoma of the Esophagus

Squamous epithelial dysplasia is frequently encountered in the esophagus with squamous cell carcinoma, and several studies have suggested its significance as a precancerous lesion.