Takashi Marutsuka

Extensive intraoperative peritoneal lavage and chemotherapy for gastric cancer patients with peritoneal free cancer cells.

Abstract.The effects of extensive intraoperative peritoneal lavage (EIPL) for gastric cancer patients with peritoneal free cancer cells were investigated. This study was based on 22 consecutive patients with peritoneal free cancer cells, among 663 patients who underwent curative surgical treatment for advanced gastric cancer. The 22 patients were followed up for 2 years or until death. These patients were divided into three groups: group 1, patients with no additional intraoperative therapy (from 1989 to 1992; n = 8); group 2, patients with intraoperative intraperitoneal chemotherapy alone (from 1992 to 1995; n = 7); and group 3, patients with EIPL followed by intraoperative intraperitoneal chemotherapy (from 1996 to 1999; n = 7). Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that viable cancer cells were not detected after the eighth EIPL in a gastric cancer patient with numerous intraperitoneal free cancer cells. In group 3, 4 of the 7 patients survived for more than 2 years, including 3 with cancer-free status, whereas no patient survived cancer-free in groups 1 and 2. The peritoneal recurrence rates and cancer-specific 2-year survival rates in groups 1, 2, and 3 were 100%, 85.7% and 42.9%; and 0%, 14.3%, and 57.1%, respectively. The 2-year survival rate of group 3 was significantly higher than that of group 1 (P = 0.017) and that of group 2 (P = 0.025). In a subset analysis, patients with peritoneal free gastric cancer cells but no macroscopic dissemination showed a statistically significant improvement in survival those treated with EIPL compared with those not treated with EIPL.

Irinotecan plus low-dose cisplatin for α-fetoprotein-producing gastric carcinoma with multiple liver metastases: Report of two cases

Abstract.α-Fetoprotein (AFP)-producing gastric carcinoma generally causes multiple liver metastases and has an extremely poor prognosis. There is no standard chemotherapy for this disease. Two recent consecutive patients who had AFP-producing gastric carcinoma were treated with a novel chemotherapy regimen: irinotecan hydrochloride (100 mg/body over 90 min) plus low-dose cisplatin (10 mg/body) by intravenous infusion. Treatment was done weekly during admission and once every 2 weeks on an outpatient basis. Both patients had multiple liver metastases with high serum levels of AFP, and one demonstrated resistance to 5-fluorouracil. In both patients, liver metastases showed a dramatic complete response to chemotherapy, and the serum AFP levels returned to normal. No significant toxicities were observed. These preliminary results suggest that the present regimen may cause fewer side effects while retaining its synergistic antitumor activity. This regimen may therefore be worth trying as first-line chemotherapy for patients with metastatic AFP-producing gastric carcinoma.

A New Procedure of Percutaneous Microwave Coagulation Therapy Under Artificial Hydrothorax for Patients with Liver Tumors in the Hepatic Dome

Abstract Percutaneous microwave coagulation therapy (PMCT) has been widely used as an effective minimal invasive therapy for small liver tumors. The occurrence of a sonographic masked space due to the presence of the lung, however, has become a major obstacle to visualizing the whole tumor in the hepatic dome. To facilitate the use of PMCT for liver tumors in the hepatic dome, we developed PMCT in combination with the artificial hydrothorax method (percutaneous transdiaphragmatic MCT: PTD-MCT). Our new approach for PMCT to the hepatic tumors located in Couinauds segments VIII or VII just under the diaphragm resulted in a successful treatment. The separation of the lung from the diaphragm by the infusion of saline into the pleural cavity enabled us not only to visualize the whole tumor in the hepatic dome to accurately target the tumor, but also helped us to avoid injuring the lung. PTD-MCT is therefore strongly recommended for the treatment of liver tumors in the hepatic dome.

Adopting Extensive Intra-operative Peritoneal Lavage (EIPL) as the Standard Prophylactic Strategy for Peritoneal Recurrence

EIPL (extensive intra-operative peritoneal lavage) therapy was developed as a prophylactic strategy for peritoneal recurrence, with the goal of improving the quality of life and survival span for advanced gastric cancer patients with peritoneal free cancer cells. The purpose of this article is to review the therapys contribution to a remarkable improvement in the 5-year survival for patients with positive lavage cytology on prospective randomized controlled clinical trials. We also advocate for the adoption of the EIPL as the optimal treatment protocol for advanced gastric cancer.

Gastric and intestinal phenotypes of gastric carcinoma with reference to expression of brain (fetal)-type glycogen phosphorylase

Purpose. Although reports have suggested that differentiated gastric carcinomas have different phenotypes, i.e., gastric and intestinal type, this classification is complicated and can be confusing. Our previous studies have demonstrated a close relationship between carcinogenesis in differentiated-type gastric cancer and the expression of brain (fetal)-type glycogen phosphorylase (BGP). The purpose of this study was to investigate the relationship between the mucin phenotype of gastric carcinoma and BGP expression. Methods. Ninety-six specimens of gastric carcinoma were studied using specific anti-BGP antibody. Correlation of BGP expression with intestinal and gastric phenotypes was determined with the anti-mucin antibodies, HGM, CD10, and MUC2. Results. BGP was expressed in 82.6% (38/46) of differentiated type and in 24.0% (12/50) of undifferentiated type carcinomas. The incidence of BGP positivity was significantly greater in the differentiated-type carcinoma than in the undifferentiated type (P < 0.001). The proportions of gastric, mixed and intestinal types in differentiated and undifferentiated gastric carcinomas were 13.0%, 47.8%, and 39.2%, and 56.0%, 32.0%, and 12.0%, respectively. In both differentiated and undifferentiated types, the phenotype of gastric and intestinal mucin expression corresponded very well with BGP expression, that is, more than 90% of carcinomas with gastric type did not express BGP, whereas approximately 90% of carcinomas with intestinal type did express BGP. Conclusions. The classification of gastric and intestinal phenotypes of gastric carcinoma in terms of BGP expression was simpler and clearer than such classification in terms of mucin immunohistochemistry. It is suggested that BGP is a useful biomarker for the classification of intestinal and gastric type carcinoma of the human stomach, including classification from the carcinogenetic point of view.

Can the peritoneal recurrence be prevented after curative surgery

Although advances in diagnosis and surgical techniques have improved the conditions of patients with gastric cancer, peritoneal recurrence is still the most frequent cause of death, and the prognosis of patients with peritoneal metastasis of gastric cancer is extremely poor [1, 2]. In patients with pancreatic cancer, besides, one of the major features is its early peritoneal recurrence as well as liver metastasis after curative surgical treatment [3]. The most likely cause of peritoneal recurrence in patients with serosa-invasive gastric cancer is the presence of intra-peritoneal free cancer cells from the serosal surface of the primary cancer and their implantation on the peritoneum. Furthermore, it has been proved that lymph node dissection opened the lymphatic channel and spread viable cancer cells into the peritoneal cavity, using CEA and CK20 specific ultra-rapid quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in combination with an automated mRNA extractor [4]. This CEA and CK20 specific RTPCR study demonstrated that free cancer cells were

Establishment of a rapid procedure for one-step real-time reverse transcription-polymerase chain reaction in combination with automated mRNA extraction: a clinical application to intra-operative molecular diagnosis of cancer cells

Reverse transcription-polymerase chain reaction (RT-PCR) technique is extremely useful for sensitive detection of cancer cells, but it requires at least 8 h. If the precise information on the cancer spread based on RT-PCR is available during surgery, we can give the optimal therapy to each patient during operation. We aimed to establish the ultra-rapid procedure of RT-PCR for application to the intra-operative diagnosis. We have established a one-step real-time RT-PCR using LightCycler with hybridization probes, in combination with automated mRNA extraction on MagNA Pure LC. The method can be completed in only 70 min after sampling and has a comparable sensitivity to conventional RT-PCR and/or two-step real-time RT-PCR with a wide (10–106) dynamic range. When this method was applied to the intra-operative detection of free cancer cells in peritoneal lavage, the results were available during operation in all cases. We could detect cancer cells more effectively compared to conventional cytology and RT-PCR. This protocol is easily accomplished, delivers rapid, sensitive and reproducible results, and is therefore applicable to intra-operative diagnosis.

Peritoneal metastasis after operation for non-serosa-invasive gastric carcinoma and a prophylactic strategy for peritoneal dissemination

Abstract The established ultra-rapid quantitative RT-PCR system for intraoperative detection of intraperitoneal free cancer cells, the elucidated cause of peritoneal recurrence after curative operation for patients with non-serosa-invasive gastric cancer, and the extensive intraperitoneal lavage (EIPL) therapy for the prophylaxis of peritoneal recurrence from the results of evaluation using the ultra-rapid quantitative RT-PCR system were reviewed. We established ultra-rapid RT-PCR protocol that enables diagnosis of intraperitoneal cancer spread about 70 min, using LightCycler method in combination with automated mRNA extractor. Both the carcinoembryonic antigen (CEA) and cytokeratin (CK)20 messenger RNA (mRNA) in intraperitoneal lavages after lymph node dissection were identified in three (14.2%) and four (26.7%) patients with submucosal (SM) and muscularis propria (MP) tumors, respectively. Although peritoneal metastasis occurs in some patients with early gastric carcinoma, the reasons have not been fully established. These results clarified that peritoneal metastasis after operation for non-serosal-invasive gastric cancer was caused by opening lymphatic channels during lymph node dissection allowing the spread of viable cancer cells into the peritoneal cavity. Furthermore, EIPL method was performed in five cases with serosa-invasive (SE) gastric carcinoma, and its efficacy was evaluated by the quantitative RT-PCR. The quantitative RT-PCR demonstrated that EIPL reduced free cancer cells from 3.8×10 5 ±1.4×10 5 to 2.8±1.5 cells/100 ml of lavage by from six to eight washes, and they disappeared after the seventh to ninth wash. In conclusion, an ultra-rapid quantitative RT-PCR system for intraoperative detection of intraperitoneal free cancer cells was established for clinical use. It is suggested that the combination with the novel rapid detection system with the intraoperative therapy of EIPL can be a useful prophylactic strategy for peritoneal metastasis from gastric carcinoma.

Proposal of genetic pathways of de novo colorectal carcinomas

Abstract Our recent study has demonstrated that brain (fetal)-type glycogen phosphorylase (BGP) positive foci (BGP foci) have a vital role in the de novo colorectal carcinogenesis. This paper reviewed the investigation on the genetic alternations in the BGP foci and the clarification of the mechanisms of de novo colorectal carcinogenesis. De novo colorectal carcinomas with invasion into submucosa or superficial muscularis propria were selected from resected specimens. Investigations of the p53, K-ras and APC mutations were performed in the BGP foci, BGP negative colorectal mucosa and de novo colorectal carcinoma. No K-ras mutation was observed in all of the cases. Mutations of p53 and APC were 14 (50.0%) and 9 (32.1%) in de novo colorectal carcinomas, and 11 (39.3%) and 1 (3.6%) in BGP foci, respectively. Both p53 and APC mutations were detected in 8 and 1, p53 mutation alone in 6 and 10, APC mutation alone in 1 and 0 out of 28 de novo colorectal carcinomas and BGP foci, respectively. Our sequential studies propose that the two major pathways, i.e., the p53–APC pathway and the p53 alone pathway in the de novo colorectal carcinogenesis.