Schedule-dependent combined sensitivity testing of anti-cancer agents in human gastric carcinoma cell lines.

The efficacy of combination chemotherapy for gastric carcinoma has been unsatisfactory, although the prognosis of advanced and recurrent disease has improved with the introduction of cisplatin (CDDP). This study examines the effect of the anti-cancer therapies CDDP, doxorubicin (ADM) and etoposide (VP-16) on the cell cycle and their cytotoxicity against two gastric carcinoma cell lines: MKN-28 (well differentiated) and MKN-45 (poorly differentiated). The treatments have different cytocidal mechanisms, and they were studied in dual combinations. For all combinations studied, cytotoxicity against MKN-45 was higher than against MKN-28. For ADM plus CDDP, or ADM plus VP-16, cytotoxicity was higher in patients pretreated with ADM than other regimens. The highest anti-tumour activity against both cell lines was obtained with ADM followed by CDDP (we have obtained good clinical results with this regimen). Schedule-dependent combined sensitivity testing of anti-cancer agents will be useful for the clinical application of therapies.

Advanced gastric cancer with multiple lymph node metastasis successfully treated with etoposide, adriamycin and cisplatin.

Gastric cancer usually shows poor sensitivity to chemotherapy, and the presence of lymph node metastases is associated with extremely poor prognosis, especially when the number of such nodes is more than 10. We report here a case of advanced gastric cancer with histopathologically confirmed metastases in 15 regional lymph nodes, in which the recurrent tumor was sensitive to combination chemotherapy. Distal gastrectomy with lymphadenectomy was performed for the primary tumor. A hard (recurrent) tumor was detected in the upper abdomen 5 months postoperatively. Abdominal CT revealed two tumors measuring 3.5 x 1.8 and 3.3 x 2 cm in diameter at the front of the pancreatic head, which suggested recurrence. Etoposide, adriamycin and cisplatin (EAP) chemotherapy (20 mg/kg adriamycin, 100 mg/kg etoposide and 50 mg/kg cisplatin (CDDP)) was administered every 6 weeks. The tumors regressed and became undetectable on CT after four cycles. At that stage, CDDP was replaced with 400 mg/kg carboplatin, which was administered every 1 or 2 months. The patient had no recurrence 8 years after surgery. For treatment of advanced gastric cancer with multiple lymph node metastases, a wide resection of the tumor should be performed followed by treatment of the residual tumor cells with a suitable combination chemotherapy taking into consideration the characteristics of the tumor and the condition of the host. We present a patient with gastric cancer and histopathologically confirmed metastases in 15 regional lymph nodes, who was successfully treated by surgery followed by EAP adjuvant chemotherapy. The patient remains alive and well at 8 years after surgery.

The prognostic advantage of preoperative intratumoral injection of OK-432 for gastric cancer patients.

To investigate, by a multi-institutional randomized trial, the prognostic significance of the augmentation of tumour-infiltrating lymphocytes (TILs) by preoperative intratumoral injection of OK-432 (OK-432 it), a bacterial biological response modifier, in patients with gastric cancer. The 10-year survival and disease-free survival were examined and analysis of the factors showing survival benefit was performed. 370 patients who had undergone curative resection of gastric cancer were enrolled in this study and followed up for 10 years postoperatively. Patients were randomized into either an OK-432 it group or a control group. Ten Klinishe Einheit (KE) of OK-432 was endoscopically injected at 1 to 2 weeks before the operation in the OK-432 it group. Both groups received the same adjuvant chemoimmunotherapy consisting of a bolus injection of mitomycin C (0.4 mg kg(-1) i.v.) and administration of tegafur and OK-432 from postoperative day 14 up to 1 year later. Tegafur (600 mg day(-1)) was given orally and OK-432 (5 KE/2 weeks) was injected intradermally for a maintenance therapy. The TILs grades in resected tumour specimens and presence of metastasis and metastatic pattern in dissected lymph nodes were examined. Multivariate analysis was performed to determine the efficacy of OK-432 it on prognostic factors. All patients were followed up for 10 years. The overall 5- and 10-year survival rates and disease-free survival rates of the OK-432 it group were not significantly higher than those of the control group. However, OK-432 it significantly increased the 5- and 10-year survival rates of patients with stage IIIA + IIIB, moderate lymph node metastasis (pN2), and positive TILs. OK-432 it was most effective at prolonging the survival of patients who had both positive TILs and lymph node metastasis. The OK-432 it group with positive TILs showed a significant decrease in metastatic lymph node frequency and in the number of lymph node micro- metastatic foci when compared to the control group. This study showed that only one time preoperative OK-432 it, particularly when it triggers TILs, is effective for reduction of regional lymph node metastasis. OK-432 it probably acts partly by eliminating micro-metastatic foci in lymph nodes. Preoperative intratumoral injection of OK-432 is technically very easy and has no serious adverse effects, so it is a promising form of neoadjuvant immunotherapy for advanced gastric cancer.

[A case of nonresectable scirrhous type gastric cancer successfully treated by low-dose cisplatin (CDDP), 5-fluorouracil (5-FU) and pirarubicin (THP)].

There have been few effective chemotherapeutic regimens for scirrhous type gastric cancer. Recently, the usefulness of combined cancer agent chemotherapy based on the concept of biochemical modulation has been reported. For example sequential MTX and 5-FU therapy, low-dose CDDP plus 5-FU, and the like. In this paper, we report the usefulness of low-dose CDDP plus 5-FU therapy in combination with pirarubicin (THP) for inoperable scirrhous type gastric cancer. A 32-year-old man who was suffering from scirrhous type gastric cancer with pyloric stenosis was treated with this regimen. Eight weeks after the start of therapy, his gastric capacity and lumen diameter had clearly increased, and he was taking ordinary meals. Ascites had also completely disappeared. CR has now been continued about 7 months. This regimen is considered to be promising for scirrhous type gastric cancers with a poor prognosis.

Lymphovascular and neural invasion in low-lying rectal carcinoma.

We have previously demonstrated that lymphovascular infiltration was correlated with an increased risk for developing lymph node metastasis in rectal adenocarcinomas confined within the submucosal layer. In another study, lymphovascular infiltration was also correlated with poor prognosis for patients with advanced rectal cancers. Considerations that low rectal tumors have an increased risk to develop recurrence and neural invasion have been recently implicated with a more localized pattern of tumor spread. We therefore assessed the lymphovascular and neural invasion in 65 specimens from patients with low rectal cancers who underwent curative operation to determine its implications in the treatment and prognosis. Lymphovascular invasion was noted in 60%, and neural invasion was found in 27% of the cases. Five-year survival rates (Kaplan-Meier method) were significantly decreased in patients with lymphovascular invasion (31 vs. 67%; p < 0.01) or neural invasion (30 vs. 58%; p < 0.01). Neither lymphovascular nor neural invasion was noted in Dukes' stage A tumors. There was no recurrence or distant metastasis in these patients. However, lymphovascular and neural invasion increased with tumor stage. Local recurrence and distant metastasis occurred respectively in three and four, and five and five patients with Dukes' B and C tumors, respectively. Both Dukes' B and C cases with local recurrence had a higher incidence of neural invasion as compared with the disease-free group. These results suggest that postoperative assessment of venous and neural invasion may provide valuable information to better determine which patients with low rectal cancers would benefit from adjuvant treatment.

Endoscopic sphincterotomy assisted by percutaneous transhepatic choledochal tube: a preliminary report.

We report a method of endoscopic retrograde sphincterotomy in patients in whom the optimal viewing of the papilla of Vater is hardly obtained. Percutaneous transhepatic cholangiodrainage (PTCD)-tube is placed under ultrasonographic guidance. PTCD-tube coming out of the papilla of Vater is observed by the endoscope and the guide wire inside the shpincterotome is inserted into the PTCD-tube. Sphincterotome is advanced into the common bile duct by the guidance of the guide wire and PTCD-tube. Sphincterotomy is performed in a usual fashion. Two patients with previous history of gastrectomy underwent this procedure with successful results. This method should be tried when usual method of EST is difficult and unsuccessful.

A case of traumatic neuroma of the gallbladder in the absence of previous surgery and cholelithiasis.

We experienced a patient with traumatic neuroma of the gallbladder with no history of gallbladder surgery or cholelithiasis. A 74-year-old man was referred to our department after a gallbladder tumor was incidentally discovered during a preoperative screening examination for prostate hypertrophy. Ultrasonography, MRI, CT and endoscopic retrograde cholangiography revealed a protuberant lesion of the gallbladder. Laparoscopic cholecystectomy was attempted but adhesion between the liver and duodenum forced us to convert to open laparotomy. Cholecystectomy and adjacent liver tissue resection was performed. Diagnosis was made by frozen histology during operation. It revealed no malignancy. Postoperative pathological examination revealed traumatic neuroma associated with inflammation. To our knowledge, this is the first reported case of gallbladder neuroma without a history of gallstones or surgery in the English and Japanese literature since 1980. This traumatic neuroma should be considered in a differential diagnosis in treating gallbladder neoplasm, even in the absence of an operative history or cholelithiasis.

Serum levels of circulating intercellular adhesion molecule 1 in hepatocellular carcinoma.

BACKGROUND/AIMS: This is a comparative study of the relationship between. MATERIAL AND METHODS: Serum levels of circulating intercellular adhesion molecule-1 (cICAM-1) were measured by ELISA assay in four patients with chronic hepatitis (CH), 16 with liver cirrhosis (LC), 38 with hepatocellular carcinoma (HCC), and in nine healthy controls. RESULTS: No significant difference in cICAM-1 levels was observed between LC and HCC. The cICAM-1 level in HCC did not correlate with tumor markers but correlated well with tumor size. cICAM-1 level in HCC Stage III + IV was significantly higher than that of Stage I, and was higher in HCC with liver metastasis as opposed to HCC without metastasis. Furthermore, the cICAM-1 level of HCC decreased significantly after hepatectomy. CONCLUSION: These findings showed a close relationship between cICAM-1 and the progress of intrahepatic metastasis of HCC, indicating a possibility for using cICAM-1 as a prognostic marker.

The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers.

We previously reported that introduction of the wild-type p53 gene into human cancer cells with deleted p53 enhanced apoptosis induced by chemotherapy [Fujiwara et al. (1994) Cancer Res 54:2287]. This suggests that p53 status could be a potent determinant of the therapeutic efficacy of DNA-damaging cancer therapy. We analyzed 24 patients with gastric or colorectal cancer for p53 mutations and apoptotic changes in surgical specimens. Out of 11 patients with gastric cancer, 3 were treated with chemotherapeutic drugs before resection; 5 of 13 patients with colorectal cancer had 30 Gy radiation prior to surgery. p53 mutations were detected in 4 cases of gastric cancer (36.4%) and in 6 cases of colorectal cancer (46.2%) by immunohistochemical staining. The preoperative DNA-damaging therapies increased the number of apoptotic cells in wild-type-p53-expressing tumors; tumors with mutant p53, however, significantly showed fewer apoptotic cells compared with those expressing wild-type p53. The p53-inducible WAF1/CIP1 protein was immunohistochemically observed in wild-type-p53-containing tumors, whereas mutant-p53-expressing tumors expressed no detectable WAF1/CIP1. Taken together, we conclude that p53 mutations are associated with the poor response of chemotherapy and radiotherapy.

Asymptomatic membranous obstruction of the inferior vena cava due to large intrahepatic collaterals.

This paper presents a case of asymptomatic membranous obstruction of the inferior vena cava with a rare hemodynamic pattern consisting of large intrahepatic venous connections between the right inframembranous and the middle supramembranous hepatic vein. These remarkably large collaterals obviated significant enlargement of the azygous venous system and the development of a Budd-Chiari syndrome.

Needle tract implantation of hepatocellular carcinoma after ultrasonically guided needle liver biopsy: a case report.

Cancer spread along the needle tract following fine needle biopsy is reported to be a rare complication. We report a case of subcutaneous implantation of hepatocellular carcinoma (HCC) following ultrasonically (US)-guided fine needle liver biopsy. The patient, a 53-year-old male was found to have a HCC at the medial segment of the liver confirmed by fine needle biopsy. Three year and four months after segmentectomy, the patient felt a subcutaneous growing lump at the previous biopsy site. The tumor was resected and confirmed histologically as HCC. We herein document other reports of such an occurrence following fine needle biopsy of HCC in Japan and consider this problem in liver biopsies.

Expression of Fas antigen and Bcl-2 protein in hepatocellular carcinoma.

Fas antigen (ag) is a cell surface protein known to trigger apoptosis in a variety of cells upon specific antibody binding. On the other hand, Bcl-2 protein, an oncogene product located at the mitochondrial inner surface, prolongs cell survival by blocking apoptosis. In this study we examined the expression of Fas ag and bcl-2 protein in 17 cases of hepatocellular carcinoma (HCC) to determine their role on HCC. By flow cytometric analysis, mean (SD) value of the expression of Fas ag on hepatocytes derived from normal liver, diseased liver (chronic hepatitis or liver cirrhosis) and HCC was 5.8 (4.7)%, 10.3 (6.9)%, and 24.0 (18.2)%, respectively. Fas ag expression on hepatoma cells was significantly greater than normal and diseased liver cells. The expression of Bcl-2 protein in normal liver, diseased liver and HCC was 4.3 (8.5)%, 0.8 (2.5)% and 2.1 (3.4)%, respectively, and the difference was not significant. These results suggest that induction of apoptosis may be a possible therapy against HCC.

31P nuclear magnetic resonance evaluation of rat liver preserved in UW solution.

A persistent problem in orthotopic liver transplantation is primary nonfunction (PNF) of the hepatic allograft. In an attempt to reduce the incidence of graft failure, the feasibility of pretransplant assessment of graft viability was investigated by 31P nuclear magnetic resonance (NMR) spectroscopy. The level of adenosine triphosphate (ATP) was measured as an indicator of liver function by 31P NMR spectroscopy after a 30 min normothermic reperfusion following cold-storage in University of Wisconsin (UW) solution. The mean +/- SD beta-ATP/Pi ratio after preservation for 0, 12, 24 or 48 h was 1.40 +/- 0.34, 0.85 +/- 0.27, 0.64 +/- 0.14 and 0.38 +/- 0.09, respectively. Significance was observed between 12h and 24h and between 12h and 48h of preservation. These results correlated well with the morphological changes in endothelial cells and sinusoidal lining cells examined by transmission electron microscopy. It is suggested strongly that microcirculatory disturbances due to endothelial cell injury impairs the recovery of ATP levels after reperfusion, and that ATP determination by 31P NMR spectroscopy, as a non-invasive modality, may help in the prediction of PNF after liver transplantation.

An analysis of DNA ploidy pattern of hepatocellular carcinoma.

To determine whether a relationship exists between DNA ploidy and the prognosis of hepatocellular carcinoma (HCC), flow cytometric DNA analysis was performed in paraffin-embedded specimens obtained from 44 patients with HCC who underwent hepatectomy. There were 26 diploid (59%) and 18 aneuploid (41%) tumors. No correlation was shown between DNA ploidy pattern and patient age, sex, liver cirrhosis, hepatitis B virus antigen and serum alpha-fetoprotein level. The ploidy pattern had no significant correlation with the presence of vascular invasion or intrahepatic metastasis. Only Edmondson's grade was well correlated with the ploidy pattern. We noted a significant correlation between survival rates and the presence of vascular invasion or intrahepatic metastasis (p < 0.05). In contrast, no significant correlation was found between DNA ploidy pattern and the prognosis of HCC. The results of this study indicate that DNA ploidy pattern may not be a useful indicator for the prognosis of HCCs after hepatic resection, unlike the results of gastric and colon cancers.

[In vivo comparative study of the pharmacokinetics of chemotherapeutic agents infused via hepatic artery or portal vein against hepatic metastases. DRC Group].

Recently, the treatment for hepatic metastasis has been performed by injection of chemotherapeutic agents via hepatic artery. Although this therapeutic procedure has been contributing to a relatively higher response rate, the resulting increased response has not significantly improved prognosis. So, we assessed the infusion of chemotherapeutic agents via portal vein in rabbits and compared the results with those from arterial infusion. Two weeks after inoculation of VX-2 tumor cells into the liver, subcapsularly, injection of chemotherapeutic agents as well as sampling of the livers was started. The rabbits were allocated into two groups, an arterial infusion group and a portal vein infusion group. They received a single shot of mitomycin C (MMC, 1.7 mg/kg), or 5-fluorouracil (5-FU, 9.5 mg/kg) or cisplatin (CDDP, 1.6 mg/kg) injected by infusion pump for 1 h. The drug concentration into the normal liver and intratumorally was measured by HPLC method for 5-FU and MMC, and by flameless atomic absorption spectrometry for CDDP. Either drug concentration in the liver or tumor did not substantially differ between the two groups. This experiment revealed that portal vein infusion can contribute as much drug concentration intratumorally as by arterial infusion.

Immunotherapy by a slow delivery system of interleukin-2 in mice models.

A sustained release system for interleukin-2 (IL-2), and IL-2 mini-pellet (IL-2 mp), was developed by fusing IL-2 into a needle shaped collagen. Serum concentration of IL-2 after a single subcutaneous injection of the IL-2 mp into C57BL/6 mice remained elevated longer than after an injection of aqueous IL-2. IL-2 in the serum became undetectable by 6h after a subcutaneous injection of 1 x 10(6) unit of IL-2 in phosphate-buffered saline (PBS). In contrast, after a single subcutaneous injection of IL-2 mp containing the same amount of IL-2, the concentration of IL-2 increased to its maximum at 6h after injection, then began to decrease gradually. IL-2 was detected even on the third day after a single subcutaneous injection of one IL-2 mp. Augmentation of NK activity and generation of IL-2 activated killer cells were observed in the spleen from day 1--day 3 after a single subcutaneous injection of IL-2 mp into C57BL/6 mice. This activation was not observed following a single subcutaneous injection of the same amount of IL-2 in PBS. Adoptive immunotherapy by a single subcutaneous injection of IL-2 mp followed by intravenous injections of in vitro cultured IL-2 activated killer cells showed better results in decreasing the number of metastases of Lewis lung carcinoma in C57BL/6 mice than immunotherapy using IL-2 solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant fibrous histiocytoma of the liver--a case report.

A case of surgically confirmed primary malignant fibrous histiocytoma of the liver is presented. A 35-year-old man was admitted to hospital with an epigastric mass. No abnormal laboratory findings, including tumor markers, were detected. Ultrasound and computed tomography showed the main tumor in the left lateral segment and a daughter nodule in the posterior segment of the liver. Arteriography demonstrated a slightly hypervascular mass in the left lateral segment. Histological examination of the resected tumor showed bundles of spindle cells with a focal storiform pattern, which were intermingled with bizarre giant cells, therefore a diagnosis of malignant fibrous histiocytoma was made.

[Immune response in cancer patients treated with adjuvant immunochemotherapy].

In order to evaluate the immune response in cancer patients treated with adjuvant immunochemotherapy, a committee was organized in Japanese research Society for Surgical Cancer Immunology. Skin reactions, subsets of PBL, HLA, immunosuppressor (IAP), Immunoactivity (NK activity and lymphoblastogenesis with PHA), general nutritional condition and performance status were picked up and discussed as to how these reactions influence the prognosis of patients. For example, 395 cases of gastric cancer (excluded stage I, non-chemotherapy and absolute non-curative resection) collected from the committee's hospital were divided into two groups, according to a statistical "cut off point", i.e., more than 5.9g/dl of TP, 4.0g/dl of Alb, and 1500/mm3 of PBL, and values less than these. The five-year survival rate was significantly high in the former group. In the group that kept high counts of these parameters after operation, the 5-year survival rate was significantly high in cases which received immunotherapy. In conclusion, immunoparameters paralleled to the stage of disease and prognosis. When the parameters remained at high levels after operation, the immunotherapy group showed good survival compared to the non-immunotherapy group. Immunotherapy is not valuable in patients with high IAP levels and poor nutritional condition.