USEFULNESS OF ENDOSCOPIC TREATMENT FOR DUODENAL ADENOMA

In recent years, due to the increasing prevalence of upper gastrointestinal endoscopy, there have been an increasing number of reports on duodenal adenoma and early stage cancer. However, endoscopic techniques for the resection of duodenal adenomas are difficult, due to the anatomical features of the duodenum, and the long distance to the lesion. There have only been a few reports on the use of endoscopic techniques for duodenal adenomas compared to those focused on the stomach and large intestine. For duodenal adenomas, we used a conventional endoscope for lesions proximal to the major duodenal papilla, and a short‐type double balloon endoscope for lesions distal to the papilla. The en‐bloc resection rate was 93.8%. There was only one case of microperforation. Endoscopic manipulation is considered difficult in the deep areas of the duodenum, but double balloon endoscopy enabled stable manipulation and successful resection of the tumor in the majority of cases.     

Ongoing subclinical infection of hepatitis E virus among blood donors with an elevated alanine aminotransferase level in Japan

Ongoing subclinical infection of hepatitis E virus (HEV) has not been fully studied. In the present study, serum samples were collected from 6700 voluntary blood donors with an elevated alanine aminotransferase (ALT) level of 61-476 IU/l at a Japanese Red Cross Blood Center, and were tested for the presence of IgG, IgM and IgA classes of antibodies to HEV (anti-HEV) by in-house ELISA and HEV RNA by nested RT-PCR. Overall, 479 blood donors (7.1%) were positive for anti-HEV IgG, including 8 donors with anti-HEV IgM and 7 donors with anti-HEV IgA. Among the nine donors with anti-HEV IgM and/or anti-HEV IgA, six had detectable HEV RNA. The presence of HEV RNA was further tested in 10-sample minipools of sera from the remaining 6691 donors, and three donors including one without anti-HEV IgG were found to be positive for HEV RNA. When stratified by ALT level, the prevalence of HEV RNA was significantly higher among the 109 donors with ALT > or = 201 IU/l than among the 6591 donors with ALT of 61-200 IU/l (2.8% vs. 0.1%, P < 0.0001). The HEV isolates obtained from the nine viremic donors segregated into genotype 3, shared a wide range of identities of 85.6-98.5% and were 87.3-93.9% similar to the Japan-indigenous HEV strain (JRA1), in the 412-nucleotide sequence of open reading frame 2. This study suggests that approximately 3% of Japanese individuals with ALT > or = 201 IU/l have ongoing subclinical infection with various HEV strains.     

The Prognosis of Patients with Non-Small Cell Lung Cancer Found to Have Carcinomatous Pleuritis at Thoracotomy

Non-small cell lung cancer with carcinoma-tous pleuritis is considered to be a contraindication of surgical resection. The objective of this study was to clarify the prognosis of patients with non-small cell lung cancer in whom carcinomatous pleuritis was found at thoracotomy. A questionnaire survey on the survival of patients with carcinomatous pleuritis found at thoracotomy between January 1985 and December 1994 was conducted by the Japan Clinical Oncology Group. According to the data collected from 21 hospitals, 8 813 patients with non-small cell lung cancer underwent thoracotomy, 284 (3.2%) of whom were found to have carcinomatous pleuritis. Information on survival was available for 227 of these patients, 34 (15%) of whom underwent thoracotomy alone without resection, whereas 193 (85%) underwent surgical resection. Of the 193 resected patients, 155 had no macroscopical residual tumor apart from the carcinomatous pleuritis. The 5-year survival rate was 14%. According to a univariate analysis, female sex, the presence of adenocarcinoma, a tumor size of less than 3.0 cm, no clinical lymph node metastasis, and no macroscopical residual tumor had a significantly favorable impact on survival. A multivariate analysis revealed that the extent of clinical lymph node metastasis (P = 0.006), histology (P = 0.028), and the absence or presence of a macroscopic residual tumor after the operation (P = 0.045) were predominant prognostic factors. The 5-year survival rate of 83 patients with three positive variables was 24%. The prognosis of patients with adenocarcinoma found to have carcinomatous pleuritis at thoracotomy was not necessarily unfavorable if there was no clinically detected lymph node metastasis and no residual tumor apart from the carcinomatous pleuritis. Received: December 17, 1999 / Accepted: July 25, 2000     

Reversal of P-glycoprotein-mediated paclitaxel resistance by new synthetic isoprenoids in human bladder cancer cell line.

We isolated a paclitaxel-resistant cell line (KK47/TX30) from a human bladder cancer cell line (KK47/WT) in order to investigate the mechanism of and reversal agents for paclitaxel resistance. KK47/TX30 cells exhibited 700-fold resistance to paclitaxel and cross-resistance to vinca alkaloids and topoisomerase II inhibitors. Tubulin polymerization assay showed no significant difference in the ratio of polymerized alpha- and beta-tubulin between KK47/WT and KK47/TX30 cells. Western blot analysis demonstrated overexpression of P-glycoprotein (P-gp) and lung resistance-related protein (LRP) in KK47/TX30 cells. Drug accumulation and efflux studies showed that the decreased paclitaxel accumulation in KK47/TX30 cells was due to enhanced paclitaxel efflux. Cell survival assay revealed that verapamil and cepharanthine, conventional P-gp modulators, could completely overcome paclitaxel resistance. To investigate whether new synthetic isoprenoids could overcome paclitaxel resistance, we synthesized 31 isoprenoids based on the structure of N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB), which could reverse multidrug resistance (MDR), as shown previously. Among those examined, trans-N,N'-bis(3,4-dimethoxybenzyl)-N-solanesyl-1,2-diaminocyclohexane (N-5228) could completely reverse paclitaxel resistance in KK47/TX30 cells. N-5228 inhibited photoaffinity labeling of P-gp by [(3)H]azidopine, suggesting that N-5228 could bind to P-gp directly and could be a substrate of P-gp. Next, we investigated structural features of these 31 isoprenoids in order to determine the structural requirements for the reversal of P-gp-mediated paclitaxel resistance, suggesting that the following structural features are important for overcoming paclitaxel resistance: (1) a basic structure of 8 to 10 isoprene units, (2) a cyclohexane ring or benzene ring within the framework, (3) two cationic sites in close proximity to each other, and (4) a benzyl group with 3,4-dimethoxy functionalities, which have moderate electron-donating ability. These findings may provide valuable information for the development of P-gp-mediated MDR-reversing agents.     

Reversal of P-Glycoprotein-mediated Paclitaxel Resistance by New Synthetic Isoprenoids in Human Bladder Cancer Cell Line

We isolated a paclitaxel‐resistant cell line (KK47/TX30) from a human bladder cancer cell line (KK47/WT) in order to investigate the mechanism of and reversal agents for paclitaxel resistance. KK47/TX30 cells exhibited 700‐fold resistance to paclitaxel and cross‐resistance to vinca alkaloids and topoisomerase II inhibitors. Tubulin polymerization assay showed no significant difference in the ratio of polymerized α‐ and β‐tubulin between KK47/WT and KK47/TX30 cells. Western blot analysis demonstrated overexpression of P‐glycoprotein (P‐gp) and lung resistance‐related protein (LRP) in KK47/TX30 cells. Drug accumulation and efflux studies showed that the decreased paclitaxel accumulation in KK47/TX30 cells was due to enhanced paclitaxel efflux. Cell survival assay revealed that verapamil and cepharanthine, conventional P‐gp modulators, could completely overcome paclitaxel resistance. To investigate whether new synthetic isoprenoids could overcome paclitaxel resistance, we synthesized 31 isoprenoids based on the structure of N‐solanesyl‐N, N′‐bis(3,4‐dimethoxybenzyl)ethylenediamine (SDB), which could reverse multidrug resistance (MDR), as shown previously. Among those examined, trans‐N, N′‐bis(3,4‐dimethoxybenzyl)‐.N‐solanesyl‐l,2‐diaminocyclohexane (N‐5228) could completely reverse paclitaxel resistance in KK47/TX30 cells. N‐5228 inhibited photoaffinity labeling of P‐gp by [³H]azidopine, suggesting that N‐5228 could bind to P‐gp directly and could be a substrate of P‐gp. Next, we investigated structural features of these 31 isoprenoids in order to determine the structural requirements for the reversal of P‐gp‐mediated paclitaxel resistance, suggesting that the following structural features are important for overcoming paclitaxel resistance: (1) a basic structure of 8 to 10 isoprene units, (2) a cyclohexane ring or benzene ring within the framework, (3) two cationic sites in close proximity to each other, and (4) a benzyl group with 3, 4‐dimethoxy functionalities, which have moderate electron‐donating ability. These findings may provide valuable information for the development of P‐gp‐mediated MDR‐reversing agents.     

Combination chemotherapy with S-1 and cisplatin for non-small cell lung cancer

S-1 is a newly developed oral anti-tumor agent, which contains 5-chloro-2, 4-dihydroxypyridine and potassium oxonate to strengthen biological activities of 5-fluorouracil. Response rate of S-1 for advanced non-small cell lung cancer was reported to be 12.5-22%. Response rate of combination chemotherapy with S-1 plus cisplatin (CDDP) was reported to be 47%, and the median survival time was 11 months. Adverse events of the combination chemotherapy were milder than other combination chemotherapy described before. Therefore, S-1 plus CDDP combination chemotherapy is a future candidate for phase III clinical study.     

A prematurely terminated phase III trial of intraoperative intrapleural hypotonic cisplatin treatment in patients with resected non-small cell lung cancer with positive pleural lavage cytology: the incidence of carcinomatous pleuritis after surgical intervention

BACKGROUND: The prognosis of patients with resected non-small cell lung cancer without carcinomatous pleuritis whose intrapleural cancer cells were detected by means of a cytologic examination of pleural lavage fluid obtained immediately after a thoracotomy has been reported to be poor. METHODS: The Japan Clinical Oncology Group conducted a phase III trial for a 3-year period starting from October 1994 to determine whether intraoperative intrapleural hypotonic cisplatin treatment could effectively control pleural disease and thereby prolong the survival of these patients. The patients were randomized to receive either intraoperative intrapleural hypotonic cisplatin treatment or no treatment before closure of the open thorax. The intraoperative intrapleural hypotonic cisplatin treatment consisted of exposing the entire thorax to cisplatin (50 microg/mL) in distilled water for 15 minutes. RESULTS: Because of the slow registration pace, the study was prematurely terminated in January 1998. During the 41-month period from the start of the registration, 49 patients were entered into the study, and all were eligible. Twenty-five and 24 patients were randomly assigned to the treatment and control groups, respectively. No statistically significant difference in the overall survival and disease-free survival between the 2 groups was observed. However, the appearance of carcinomatous pleuritis was suppressed by the hypotonic cisplatin treatment (42% of the control group vs 8% of the treatment group, P =.008). CONCLUSIONS: Although the randomized trial was prematurely terminated, the intraoperative intrapleural hypotonic cisplatin treatment was found to effectively suppress the appearance of carcinomatous pleuritis in resected patients who demonstrated a positive pleural lavage cytology finding.     

Regional vulnerability to chronic hypoxia and chronic hypoperfusion in the rat brain

The purpose of this study was to compare the pathological findings of injury induced by chronic hypoperfusion and by chronic hypoxia in rat brain. Adult male Wistar rats were divided into three groups: chronic hypoperfusion (n=5), chronic hypoxia (n=5), and normal control groups (n=5). Hypoperfusion was induced by ligation of the bilateral carotid arteries under 2.5% halothane anesthesia. Chronic hypoxia was induced by keeping the animals in a chamber with an atmosphere of 10% O₂ in N₂ for 3 weeks. Twelve weeks later (chronic hypoperfusion group) and 3 weeks later (chronic hypoxia group), the animals were sacrificed and perfused through the femoral artery with a fixative containing 4% paraformaldehyde. Hematoxylin and eosin staining was done in all sections in the three groups, and the number of normal-appearing cells was counted. Normal-appearing cells in CA3 were significantly decreased in the chronic hypoperfusion group compared with those in the chronic hypoxia group, although neurons in CA1, CA2 and CA4 in both groups were equally damaged. We concluded that the CA3 hippocampus shows different vulnerabilities to chronic hypoperfusion and chronic hypoxia, possibly owing to a difference in the kinds of glutaminergic receptors.