Mutations in the ST7/RAY1/HELG locus rarely occur in primary colorectal, gastric, and hepatocellular carcinomas.

Human cancers frequently show a loss of heterozygosity on chromosome 7q31, which indicates the existence of broad-range tumour-suppressor gene(s) at this locus. Truncating mutations in the ST7 gene at this locus are seen frequently in primary colon cancer and breast cancer cell lines. Therefore, the ST7 gene represents a novel candidate gene for the tumour suppressor at this locus. However, more recent studies have reported that ST7 mutations are infrequent or absent in primary cancer and cell lines. To ascertain the frequency of mutations of the ST7 gene in cancer cells, we examined mutations in the ST7 coding sequence in 48 colorectal, 48 gastric, and 48 hepatocellular carcinomas using polymerase chain reaction-single-strand conformational polymorphism and direct sequencing. We detected somatic mutations, which were located near the exon-intron junction in intron 8, in only three out of 144 cases. We conclude that mutations in the ST7 gene are rare in primary colorectal, gastric, and hepatocellular carcinomas.

A case of esophageal sarcomatoid carcinoma with molecular evidence of a monoclonal origin.

A case of polypoid tumor of the esophagus consisting of a sarcomatous tumor partly covered with superficial squamous cell carcinoma is described. The sarcomatous component consisted of anaplastic spindle and pleomorphic tumor cells that mimicked malignant fibrous histiocytoma (MFH). Both the sarcomatous and carcinomatous components were positive for p53 immunohistochemically. Further molecular analysis revealed that the two components had the same somatic mutation in the p53 gene. These results suggest a monoclonal origin of this biphasic tumor.

Hypertension as a paraneoplastic syndrome in hepatocellular carcinoma.

We report a 66-year-old man with hepatocellular carcinoma who was positive for hepatitis B surface antigen, and was hospitalized because of hypoglycemia and hypertension. His plasma renin activity was normal (2.3 ng/ml per h), but concentrations of angiotensin I (>2500 pg/ml) and II (86 pg/ml) were high. Increased angiotensin I level at sites proximal and distal from the confluence of the hepatic vein and the inferior vena cava indicated that the hypertension was provoked by overproduction of angiotensin I from the hepatocellular carcinoma. Previous reports of patients with hepatocellular carcinoma with hypertension due to abnormality of renin-angiotensin system are reviewed.

Mutation analysis of transforming growth factor beta type II receptor, Smad2, and Smad4 in hepatocellular carcinoma.

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII), Smad2, and Smad4 genes have been detected in several human cancers. However, there are no reports of mutation analysis of the entire coding regions in these genes in hepatocellular carcinoma, and the roles of these genes in hepatocarcinogenesis remain unknown. We screened 30 hepatocellular carcinomas for mutations of these genes using polymerase chain reaction single-strand conformation polymorphism. We detected no mutations, but did find 3 cases of loss of heterozygosity of chromosome 17p13.1. These results suggest that mutations of the TGFbetaRII, Smad2, and Smad4 genes are rare, and that genetic instability is uncommon in human hepatocellular carcinoma.

Low MIB-1 labeling index in anti-HCV positive hepatocellular carcinoma.

It has been reported that hepatitis C virus-related hepatocellular carcinoma (HCC) patients survive longer than hepatitis B virus-related patients. In this study, since HCC patients positive for anti-HCV antibody had significantly longer disease-free survival (p<0.05), we evaluated the proliferative activity of 58 resected HCCs and the status of their viral infections. Ki-67 (MIB-1) immunostaining, argyrophilic nucleolar organizer regions and c-myc gene amplification were examined as parameters of proliferation, and p53 overexpression was examined in relation to clinicopathologic features and prognosis. Thirty-nine patients with HCC (67%) were positive for anti-HCV antibody alone, five (9%) were negative for both anti-HCV and HBV antibodies, two (3%) were positive for both anti-HCV and HBV antibodies, and 12 (21%) had HBsAg alone. HCC patients with anti-HCV antibody had a lower MIB-1 labeling index (LI) than HCC patients negative for the antibody (p<0.05), irrespective of the serum HBsAg status. However, there was no significant correlation between anti-HCV antibody and other proliferative parameters. MIB-1 could simply be related to cellular proliferation. On the other hand, the other parameters may be related to tumor progression as well as proliferation. HCV-related HCC does have lower proliferative activity and a better prognosis.

[Hepatocellular carcinoma following interferon therapy].

We experienced six patients with resected hepatocellular carcinoma (HCC) following interferon (IFN) therapy. Hepatitis virus C-RNA in polymerase chain reaction was positive in all patients prior to the IFN therapy. HCV-RNA became negative in two patients following IFN therapy, and was re-positive at the time of detection of HCC. In histological studies prior to the IFN therapy, pre-cirrhosis was diagnosed in four out of six patients and chronic active hepatitis 2B (CAH2B) in one according to the Europian classification. In non-cancerous portion of the liver, cirrhosis developed in five patients, and CAH2B in one. There was no significant correlation among the interval of HCC detection following IFN therapy, tumor size, tumor location, and histological findings. Patients should be carefully followed up by serum alpha fetoprotein levels or ultrasonography of the liver during and following IFN therapy.

Evaluation of the therapeutic effect of TAE on primary liver cancer.

The therapeutic effect of transcatheter arterial chemoembolization (TAE) performed on 31 patients with primary liver cancer was evaluated using the following procedures: (1) the alpha-fetoprotein (AFP) reduction rates and prognoses were analyzed according to the tumor reduction rates (TR), and (2) the AFP reduction rates and prognoses were also analyzed according to the tumor necrosis rates (TN) estimated by regarding every region with Lipiodol retention as being necrotic. The following results were obtained. The AFP level was 400 ng/ml or higher in 15 patients (48%). Their AFP reduction rates were as favorably high as 65.4%-99.8% (mean, 88.1%), and the AFP level was normalized in 3 patients. The cumulative survival rates after the initial treatment were relatively high, i.e., 78.4% in the 1st year, 58.1% in the 2nd year, and 38.7% in the 3rd year. These results suggested the effectiveness of the TAE treatment undertaken in this study. Regarding the TR, the tumor was reduced in size by 50% or more in only 5 patients (16%), and most patients had a TR of less than 25%. On the other hand, the majority, 25 patients (81%), had a TN ranging between 50% and less than 100%, including 7 who had a TN ranging between 50% and less than 90% and 18 who had a TN ranging between 90% and less than 100%. There was no significant correlation between the AFP reduction rate and the TN or TR. Regarding evaluation of the cumulative survival rates by TR and TN, the 1-year survival rate was lower in patients having a TR of less than 25% than in those having a TR of 25% or more. Patients having a TN of less than 50% showed a poor outcome as compared with those having a TN of 50% or more. Although the TR was found to be less than 50% in a majority of the patients when the therapeutic effect of TAE on the liver cancer was evaluated according to the TR, many of these patients showed a good outcome. Thus, the conventional efficacy evaluation, in which a tumor reduction of 50% or more is considered to be effective, should be reconsidered. On the other hand, the TN was found to be 50% or more in most of the patients, suggesting the necessity of a more detailed classification of TN. In relation to the survival rate, patients having a TN of less than 50% showed a poor outcome.

Antitumor effect of RBS (rice bran saccharide) on ENNG-induced carcinogenesis.

We examined whether orally administered RBS (rice bran saccharide), prepared from rice bran by hot water extraction, increases immunocompetence, inhibits gastrointestinal carcinogenesis with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) or shows an antitumor effect. After the administration of RBS, phytohemagglutinin (PHA)- and pokeweed mitogen (PWM)-stimulated blastogenesis of lymphocytes derived from the mesenteric lymph nodes and peripheral blood was enhanced, and the helper/suppressor T-cell ratio was elevated, and migration activity of peritoneal macrophages was also increased in rats treated continuously with ENNG. ENNG-induced gastrointestinal carcinomas were observed in 43% of those administered RBS (ENNG-RBS) as compared with 88% in the control (ENNG) and 94% in the prednisolone (PRD) group (ENNG-PRD). The 12-month survival rate of rats bearing gastrointestinal cancer was 58% in the ENNG-RBS group as compared with 25% in the ENNG group and 15% in the ENNG-PRD group. RBS prevented the reduction in immunocompetence in the course of carcinogenesis, suppressed carcinogenesis, and prolonged the survival of rats with gastrointestinal cancer. Antitumor activities of RBS are thought to be a kind of host mediated action. The growth inhibition ratio of transplantable ENNG-induced cancer in Wistar rats was 42.1% in the RBS and 51.8% in the 5-FU group. Since little is known about the potent antitumor activity of alpha-glucan, it would be interesting to consider the relationship between the structure and the biological activities of polysaccharides.

Anti-tumor effects of the oral administration of the streptococcal preparation OK-432 (PICIBANIL)--the inhibition of carcinogenesis and growth in rats with ENNG-induced gastrointestinal tumors.

We examined whether the Streptococcal preparation OK-432, an immunopotentiating agent, increases immunocompetence of the gut-associated lymphoid system (GALS), inhibits gastrointestinal carcinogenesis, and has an anti-tumor effect. 14C-labelled OK-432 was orally and intraperitoneally administered to rats, and the distribution of the agent in various organs then serially evaluated. The concentration of OK-432 in Peyer's patches and mesenteric lymph nodes was higher after oral administration than after intraperitoneal administration, and showed a biphasic pattern peaking at 30 minutes and 5 hours following administration, in the Peyer's patches. With regard to immunocompetence, PHA- and PWM-stimulated blastogenesis of lymphocytes derived from the mesenteric lymph nodes and peripheral blood enhanced, and the helper/suppressor T-cell ratio was elevated after the oral administration of OK-432. Moreover, chemotactic activity of peritoneal macrophages was also increased. ENNG-induced gastrointestinal carcinogenesis was observed in 60 per cent of the rats orally administered OK-432 as compared with 88 per cent of the controls. The 13-month survival rate of the rats with gastrointestinal cancer was 50 per cent in those administered OK-432 as compared with 25 per cent in those administered OK-432 as compared with 25 per cent in the controls. When administered orally, the agent prevented reduction in immuno-competence in the course of carcinogenesis, suppressed carcinogenesis, and prolonged the survival of animals with cancer without any of the side effects associated with injection. The oral administration of OK-432 is thus considered to be an effective non-specific immunotherapy against gastro-intestinal malignancies.

[Factors affecting death at home in bedridden elderly people].

To examine factors which affect death at home in bedridden elderly people, relatives of bedridden elderly people, in three areas of Japan, who had died, were interviewed, and demographic, medical, social and familial factors were compared between 136 persons who died at home and 132 persons who died in the hospital. 1) In all three geographical areas, significantly more subjects who died at home had physicians who made home visits than in those who died at hospital (p less than 0.01). 2) The mean age at death was significantly higher in the elderly people who died at home than in those who died in the hospital in all three areas (p less than 0.01). 3) The results of multiple logistic regression analysis indicated that physician's home visits and death age were significantly related independently to death at home. This relation was independent of confounding factors such as residential area, disease type, or use of social services.