Seiji Akiyama

The possible antiproliferative potency of human recombinant interferon-beta (hIFN-beta) towards ten human esophageal cancer cell lines was examined in comparison with the activity of the factor towards human malignant melanoma cell lines. The cell growth of esophageal cancer cell lines was inhibited by hIFN-beta in a dose- and time- dependent manner. The 50% inhibitory concentrations (IC50) of hIFN-beta on nine cell lines out of ten ranged between 23 to 332 IU/ml of culture medium. The remaining cell line, T.Tn, was less sensitive to the interferon (IC50, 611 IU/ml). Under the same culture conditions, the melanoma cell lines tested differed markedly in their sensitivity to hIFN-beta. When the esophageal cancer cells were treated with 5-fluorouracil (5-FU) in the presence of a low concentration of hIFN-beta, the effectiveness of 5-FU was markedly enhanced. In particular, the rate of growth inhibition of T.Tn cells was more than the added potencies of 5-FU and hIFN-beta indicating that the interferon is an effective biomodulator of 5-FU. All these data suggest that combination therapy with hIFN-beta and the anticancer drug 5-FU would be beneficial for the treatment of carcinoma of the esophagus.

Recent evidence shows that the presence of promoter hypermethylation of tumor suppressor genes has been demonstrated in the serum DNA of patients with various cancers such as lung, liver, and head and neck cancer. We have examined promoter hypermethylation of the p16 gene in esophageal squamous cell carcinoma (SCC) using methylation-specific PCR to detect tumor DNA in the serum. Aberrant promoter methylation of the p16 gene was detected in 31 of 38 (82%) esophageal SCCs. Subsequently, we tested for promoter methylation in the paired serum DNA of 31 patients with a p16 alteration in the primary tumor. We found that 7 of these 31 (23%) patients had the same methylation changes in the serum DNA. This result indicates that promoter methylation present in the tumors of esophageal SCC patients can be detected in the serum of the same patient and that this approach can potentially be used for the screening and monitoring of the disease.

An animal experimental study was performed to clarify the preventive effect of oral HCFU (1-hexylcarbamoyl-5-fluorouracil) on hepatic metastasis. A total of 180 BALB/C mice received intraportal injection of Colon26 cancer cells followed by oral daily administration of HCFU to 5 groups divided according to the dose of HCFU, ranging from 0 (controls) to 7.5 mg/Kg for 21 days. These groups were independently assigned to 3 sets to investigate survival rates and degree of hepatic metastasis. Mean survivals in the treated groups were statistically longer than the controls except the 7.5 mg/Kg group. HCFU 7.5 and 5 mg/Kg groups showed the minimum liver weight on the 12th and 16th day, respectively these were significantly smaller than those of controls (p < 0.0001 in both). It is considered that oral HCFU could effectively suppress hepatic metastasis of the colon26 cancer cells and prolong the life of animals. This finding suggests the promising clinical application of oral HCFU for colorectal cancer after curative resection.

Several microsatellite polymorphisms located in the tumor necrosis factor locus on the chromosomal region 6p21.3 in the major histocompatibility complex region have been associated with malignant neoplasms and autoimmune diseases. In this study, we focused on the polymorphisms of tumor necrosis factor a and d from gastrointestinal carcinoma patients to ascertain whether they can be useful to predict these neoplasms. We examined esophageal, gastric, and colorectal cancers (47, 53, 77 patients, respectively), and 213 normal controls. To compare the microsatellite polymorphisms of tumor necrosis factor a, d in Japanese individuals, dioxyribonucleic acids were extracted from normal mucosa (cancer patients) and from peripheral blood monocytes (the normal controls) by polymerase chain reaction. The frequency of tumor necrosis factor a3 allele was significantly higher in gastric cancer (P = 0.012) and that of tumor necrosis factor d7 allele was significantly higher in the colorectal cancer than the normal controls (P = 0.037). That of tumor necrosis factor a10 was significantly lower in the gastric cancer than the normal controls (P = 0.008). Microsatellite polymorphisms of tumor necrosis factor a and d might be significantly correlated with carcinogenesis of specific neoplasms, and may be useful for predicting these cancers.

We examined AIS status in digestive tract cancers and found that all eight esophageal cancer cell lines (100%) showed AIS/TA-AIS gene overexpression, whereas 1 of 12 (8%) gastric cancer and 0 of 14 (0%) colon cancer cell lines showed AIS/TA-AIS gene expression. We then confirmed that the AIS gene, not the TA-AIS gene, was dominantly expressed in esophageal cancers by reverse transcription-PCR. AIS protein was also expressed in AIS gene-positive cell lines. Subsequently, we tested AIS gene expression in paired esophageal normal tissues and cancers. Twenty-five of 39 (64%) primary esophageal cancers demonstrated an obviously higher expression of AIS gene compared to paired normal tissues. Moreover, high AIS gene expression was significantly associated with lymph node metastases in esophageal cancer (P = 0.0271). These results suggested that AIS may be useful as a marker for advanced esophageal cancer.

The Japan Research Society for Appropriate Cancer Chemotherapy set out to summarize the present status of chemosensitivity testing for antitumor agents in Japan. Two different questionnaires were sent to 122 and 94 institutes, respectively, whilst responses were received from 87 (71.3%) and 41 (43%) institutes, respectively. The results showed that chemosensitivity tests were performed in 42 institutes where a total of 2 in vivo and 10 in vitro different assays were performed. Actual cases of chemosensitivity detected by the tests varied from 1 to 368 cases/year/institute with a median of 15 cases and mean +/- standard deviation of 48 +/- 65 cases. The total number of tested cases increased from 1,747 cases in 1993 to 1,934 cases in 1994 and to 2,147 cases in 1995, resulting in an average of 1,891 cases year. The assays used included the adenosine triphopsphate inhibition assay,/the collagen droplet embed drug response assay, the fluorescent dye assay, the growth chamber assay, the histoculture drug response assay, human tumor clonogenic assay, the MTT assay (SDI test), the nuclear damage assay, the nude mouse model, the subrenal capsule assay and the thymidine incorporation assay (scintillation assay). The correlation of in vitro and in vivo results revealed 215 true positive (S/S), 246 false positive (S/R), 45 false negative (R/S) and 595 true negative (R/R) cases, resulting in rates of 47% for true positives and 93% for true negatives, with a 74% accuracy. We concluded that chemosensitivity testing is widely applied in this country and has a high accurate predictive value for advanced carcinomas.

This is a case report of a 37-year-old Japanese married female with laryngeal sarcoma, treated by direct electric current so as to obtain remission for more than 4 years without signs of recurrence. Due to her hoarseness and laryngeal numb feeling she underwent a laryngeal examination including a biopsy, resulting in a diagnosis of sarcoma. She refused a total laryngectomy and was given Cobalt treatment of 40 Grey. In the following several months, no improvement was observed, objectively or subjectively. In Nagoya University Hospital the patient then received direct electric current therapy of 36 Coulombs through two platinum electrodes inserted into the tumor under a CT guide, pericutaneously. Two months later, as the hoarseness remained in spite of some improvement, she underwent another session of direct electric current therapy of 14.4 Coulombs through the platinum electrodes by bronchoscope-guided direct insertion. Her hoarseness soon disappeared thereafter and there was a regression of the tumor in 6 months. She did well thereafter without any signs of recurrence for 4 years. Clinical treatment of solid tumors with electric treatment with direct electric current has been done in more than 8,000 cases with CR in 25% of all cases and PR in 50%. Its mechanism, however, remains unclear. In our experimental animal studies, apoptosis was observed. It is considered that this electric therapy using direct electric current will be recognized as one method to treat solid tumors.

Background and Objectives Since 1993, we have performed preoperative embolization therapy (PET) in an attempt to augment the blood flow of the gastric tube and prevent anastomotic leakage after esophageal resection. The clinical effects and complications associated with PET are reported. Methods The femoral artery was punctured and the left gastric artery, right gastric artery, and splenic artery underwent embolization, leaving the right gastroepiploic artery as the only patent feeding artery for the stomach. PET was performed in 54 patients, and data concerning blood flow of the stomach before and after the construction of the gastric tube were available in 51 patients. Of the 25 patients who were operated in the same period without undergoing PET, similar data were available in 20 patients. Results In the group of patients who underwent PET, the blood flow of the gastric tube after its construction was 67% of the value measured at the upper part of the stomach just after opening the abdominal cavity. For those who were not pretreated by PET, it declined to 33%. Conclusions PET for esophageal cancer is a safe procedure that contributes to the decrease in the frequency of anastomotic dehiscence after esophageal operation, owing to the augmented tissue blood flow of the upper portion of the stomach following the construction of gastric tubes. J. Surg. Oncol. 1998;69:219–223.

The enhanced effects due to the combined use of oral administration of S-1 and intraperitoneal administration of Cisplatin (CDDP) were examined with gastric cancer xenografts (NUGC 4). S-1, a new anticancer drug, was daily administered at 10 mg/kg (qld x 5 x 3 weeks). 5-FU level in blood was 1 microgram/ml at two hours after the treatment. Antitumor activity was not found in mice with only the CDDP treatment. But antitumor activity by S-1 and daily low-dose (1 mg/kg) or intermittent treatment (5 mg/kg) of CDDP showed better results than daily S-1 treatment. The daily low-dose CDDP treatment showed similar efficacy to the intermittent administration at the same total dose, but the daily low-dose CDDP treatment was better in the light of toxicities. These results suggest that treatment with S-1 and daily low-dose CDDP was effective for gastric cancer.