[The fourth report from Sapporo Tsukisamu Hospital - chemotherapy and its regimen as second choice for patients with early gastric cancer].

Surgical treatments for early gastric cancer, such as endoscopic procedures, are currently performed as standard therapy. However, when surgery is not possible due to physical or mental conditions, effective chemotherapy with minimum side effects is a second choice, although a suitable regimen has yet to be recommended. We thus retrospectively evaluated the Int FP regimen for 10 early gastric cancer patients. The results show an efficacy ratio of 100% (CR 8 cases, PR 2 cases). The two PR cases subsequently underwent surgical treatment. The 1-, 3-, and 5-year survival rates of all cases were 100%, 90% and 60%, respectively. The 1-, 3-, and 5-year survival rates of patients with chemotherapy alone were 100%, 87.5% and 50%, respectively, although none of the patients died of cancer (5-year survival rate of 100%). One out of the 8 CR cases relapsed 7 months after achieving CR. This patient then received chemotherapy with the same regimen, achieving a second CR and survived for 66 months without disease. All cases developed hematological toxicities, although they were all under grade 2 except for 2 cases which were grade 3 (decrease of WBC or Hb). Non-hematological toxicities were seen in 7 cases, all under grade 2. These results, although from a limited number of subjects, indicated that the IntFP regimen is safe and may contribute to achieving pathological CR and long-term survival of patients with early gastric cancer.

[The third report from Sapporo Tsukisamu Hospital--chemotherapy for patients with advanced gastric cancer (peritoneal dissemination, peritonitis carcinomatosa)].

Recently, it became possible to reduce the size of tumors in patients with advanced or relapsed gastric cancer by chemotherapy with the combination of several kinds of anti-cancer drugs which are all effective and allowed for use with gastric cancer patients. However, chemotherapy alone can not cure patients with advanced gastric cancer that was shown to improve median survival time (MST), compared with patients provided with the best supportive care (BSC). According to reports from Europe, US and Japan,the MST of patients with advanced gastric cancer and those with peritoneal expansion treated by chemotherapy is almost 7-12 months and 5-6 months,respectively, both of which are short and unsatisfactory. From March 2002, we started to treat patients with advanced gastric cancer (stage IV) with a new regimen; intermittent dosage of 5-FU (-->S-1), CDDP and paclitaxel utilizing the difference of cell cycle between normal and cancer cells (intermittent FP . weekly PTX). In the present study, therefore, we analyzed advanced gastric cancer patients with peritoneal expansion (9 cases, 4 with cancerous peritonitis) treated with this regimen. The results were as follows. The one-and 2-year survival rate was 55.6% and 27.8%, respectively, and the MST was 14 months. Four patients (44.4%) had hematological toxicities over grade 3. All of them had anemia (3 cases) and neutropenia (3 cases). Toxicities of thrombocytopenia were all under grade 1 and nonhematological toxicities were all under grade 2, which were clinically manageable. These results, although the sample was small, suggested that this may contribute to the extension of survival time of patients with stage IV advanced gastric cancer with peritoneal expansion.

[The second report from Sapporo Tsukisamu hospital--chemotherapy for patients with advanced colorectal cancer].

The remedy,especially recent chemotherapy,against colorectal cancer is improving median survival time (MST) of patients with Stage IV advanced colorectal cancer. According to other reports,however,it seems to be difficult to improve it longer than 20 months. In May 2002, we devised a new regimen by intermittent dosage of 5-FU (-->S-1), CDDP and paclitaxel utilizing the difference of cell cycle between normal and cancer cells, and thirteen patients with advanced colorectal cancer (Stage IV) were treated with this regimen. As a result, a satisfactory efficacy rate of 53.8%, 1-year survival rate of 69 .2%, 2-year survival rate of 53.9%, 3-year survival rate of 44.9%, 5-year survival rate of 17.9%, and MST 36 months were achieved. Five patients had hematological toxicities over grade 3 (38.5%) and most of them were anemia (3 cases) and neutropenia (5 cases). Thrombocytopenia and gastroenterological toxicity were all under grade 2. Adverse effects related to this regimen were clinically manageable. These results, although for a limited number of patients, indicated that this may contribute to the extension of survival time of patients with Stage IV advanced colorectal cancer.

[The first report from Sapporo Tsukisamu Hospital--chemotherapy and chemoradiotherapy for patients with advanced pancreatic cancer].

The remedy, especially chemotherapy, for advanced pancreatic cancer is hardly ever successful in terms of efficacy rate and survival period, because it is virtually unable to contribute to the improvement of median survival time (MST). Thus,we devised a new intermittent dosage regimen utilizing the cell cycle difference of normal GI tract, bone marrow cell and pancreatic cancer cell, making use of 5-FU (-->S-1), CDDP and paclitaxel in March 2002. Ten patients with advanced pancreatic cancer (4 in Stage IVa and 6 in Stage IVb) were treated with this new regimen. As a result, an efficacy ratio of 50.0% and a 1-year survival ratio of 60.0% were achieved. However, 2-year survival ratio of 12.0% was low, and there was no 3-year survivor. The MST was 19 months as of December 31, 2006. All of the non-hematological toxicities were under grade 2. Eight patients had hematological toxicities over grade 3 and most of them were anemia and neutropenia. Only 2 cases had thrombocytopenia. Although adverse effects related to this regimen were clinically manageable, it was difficult to improve MST of patients with advanced pancreatic cancer with chemotherapy alone including this regimen. Hence, we devised another regimen with the joint use of radiotherapy along with the same chemotherapy regimen in January 2003. Twenty patients with advanced pancreatic cancer (Stage IV) were treated with this regimen. It is presently under way, and an efficacy ratio of 35.0%, 1-year survival ratio of 86.3% and 2-year survival ratio of 64.0% were obtained by May 2005, showing that this may contribute to the extension of survival time of Stage IV pancreatic cancer patients.

[Long-term repeatable chemotherapy for patients with advanced pancreatic cancer].

At present, the advanced pancreatic cancer is known to be one of the most resistant malignancies on chemotherapy. To improve the efficacy of chemotherapy, we shifted the aim of chemotherapy from a tumor regression to long-term survival, and sought for a repeatable regimen with little toxicity. Some of the novel (repeatable) regimens used a combination of 5-FU/S-1, CDDP and paclitaxel performed for 10 patients with advanced pancreatic cancer (4 cases of Stage IVa and 6 cases of Stage IVb). As a result, the survival ratios of one and two years were 85.7% and 22.9%, respectively. The efficacy rate was 50% (5 cases of PR and 5 cases of NC). Hematological adverse reactions over grade 3 were observed in 8 out of 10 cases, although the decrease of platelet count was observed only in 2 cases (grade 3 and 4). The majority of hematological adverse reactions over grade 3 were leukocytepenia and anemia which were easy to control safely. All of non-hematological adverse reactions were observed under grade 2 and did not disrupt the maintenance of chemotherapy.

Ethanol induces transforming growth factor-alpha expression in hepatocytes, leading to stimulation of collagen synthesis by hepatic stellate cells.

BACKGROUND: Liver fibrosis often develops in alcoholic liver diseases without accompanying inflammation; however, the underlying mechanism is unclear. Using ethanol-exposed human HepG2 hepatoblastoma cells as a model for alcoholic liver diseases, we previously found that ethanol exposure causes HepG2 cells to secrete an approximately 6,000 Da nonheparin-binding polypeptide that stimulates collagen synthesis in human IMR-90 fibroblasts. The aim of the current study was to characterize and identify this factor. METHODS: Concentration of type I procollagen peptide and transforming growth factor (TGF)-alpha was assessed by enzyme-linked immunosorbent assay. TGF-alpha protein expression was examined by Western blot. Type I collagen messenger RNA expression in rat hepatic stellate cells was assessed by reverse transcription-polymerase chain reaction. RESULTS: The collagen-stimulating activity in conditioned media from ethanol-exposed HepG2 cells to stimulate type I procollagen peptide synthesis of IMR-90 cells was specifically inhibited by addition of anti-TGF-alpha antibodies. Western blot analysis showed increased TGF-alpha protein expression in ethanol-treated HepG2 cells. TGF-alpha in conditioned medium from ethanol-exposed HepG2 cells stimulated type-I collagen messenger RNA expression in rat hepatic stellate cells. CONCLUSIONS: These results suggest that TGF-alpha derived from ethanol-exposed hepatocytes may contribute to the development of hepatic fibrosis in alcoholic liver diseases.