An incremental positivity of telomerase was observed during hepatocarcinogenesis. The use of this assay in 21-G-needle biopsy specimens may be useful in clinical examination.

HARUSHIGE NAKATSUKASA, KOUZOU ASHIDA, TOSHIHIRO HIGASHI, SOUHEI OHGUCHI, SO TSUBOI, NAOKI HINO, KAZUHIRO NOUSO, YOSHIAKI URABE, NOBUYUKI KINUGASA, KEIGO YOSHIDA, SHUJI UEMATSU, MASAHIKO ISHIZAKI, YOSHIYUKI KOBAYASHI, AND TAKAO TSUJI Hepatocellular carcinoma (HCC) is one of the most prevaThe cellular distribution of tissue inhibitor of melent malignancies in Japan and China, and frequently occurs talloproteinases (TIMP)-1, and TIMP-2 was studied by in hepatitis B or C virus-related chronic hepatitis or cirrhousing in situ hybridization in surgically removed husis. In particular, cirrhosis has been regarded as a high-risk man hepatocellular carcinomas (HCCs) and cholandisease state for developing HCCs. A unique feature of HCC giocellular carcinomas (CCCs). The purpose of this development is the occurrence of the tumor in fibrotic or cirstudy was to characterize the potential involvement rhotic liver that contains abundant extracellular matrices of TIMPs in the development of HCCs and CCCs. All (ECMs). Therefore, the capacity of HCC to degrade the surHCCs and CCCs expressed TIMPs. The distribution rounding ECMs may be an important trait for growth, invaof transcripts for TIMPs in the tumors was mostly sion, and metastasis. homogeneous. Expression of TIMPs in cancer cellsThe characteristic features of malignant tumors are the was more intense than that in the surrounding noninvasion to cross tissue boundaries and the metastasis to cancerous liver (either, cirrhosis, chronic hepatitis, distant organs. Many steps that occur during cancer invasion or normal), and expression of TIMP-1 was stronger and metastasis require specific interactions between maligthan that of TIMP-2. Expression of TIMPs varied nant cells and the ECMs, 1 particularly in regard to HCC and among HCC nodules, but there was no obvious associcirrhotic liver. Multiple humoral factors are involved in this ation between the expression level of TIMPs and difprocess: matrix metalloproteinases (MMPs), tissue inhibitor ferentiation stages or invasiveness of the HCCs. Tranof metalloproteinases (TIMPs), and various cytokines. An imscripts for TIMPs were clearly demonstrated in the balance between TIMPs and MMPs may be an important metastatic HCC nodules in the lung. Expression of factor in tumor invasion and metastasis. TIMP-1 in CCC was strong, and small nodules of CCC Three members of the TIMP family have been described. 2 were recognized in the liver. ImmunohistochemicalEach TIMP is the product of a separate gene. TIMP-1 is a 28-study for TIMP-1 revealed a consistent staining of the kd glycoprotein, whereas TIMP-2 is a 21-kd nonglycosylated TIMP-1 protein with the transcripts. In the perituprotein. Between TIMP-1 and TIMP-2, there is 37% amino moral histologically normal liver, which was not inacid identity and 65.6% overall homology. 3 TIMP-3 has been fected with either hepatitis B or C virus, expression identified as a 21-kd protein and shares an amino acid seof TIMP-1 was found in various cell types, but that of quence homology of 40% with TIMP-1 and 45%...

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Streptococcal agent OK-432 was administered a t maintenance levels with conventional inductive chemotherapeutic agents to stage 111 and I V lung cancer patients. Survival rates were longer in patients treated with OK-432 than in patients treated without OK-432. An enhancement of lymphocyte blastogenic activity and a delayed PPD skin reaction were found i n patients treated by OK-432. A low grade fever was present as a side effect of this agent in some patients. T h e results suggest that OK-432 may be a useful immunotherapeutic agent i n combination with induction chemotherapy in reducing host damage in advanced stages of lung cancer. Cancer 37:2201-2203. 1976. KAMOTO ET AL.'s8 DEVELOPED STREPTOCOC-0 cal agent OK-432 and suggested that this agent destroyed cancer cells. This drug has been shown to have a positive effect in a limited number of patients with leukemia and car-cinoma but no conclusions could be drawn as to the relationship between dose and effect.*Vs Our previous studies4~5~"J have suggested that OK-432 may have a mild anticancer response but the principal effect of this agent appeared to be on cell-mediated action and on reticuloendothelial function, and n o effect was observed on humoral immunity. I n our earlier studies485 tumor cells were implanted in mice pretreated with OK-432. Host resistance to implanted tumors continued after drug administration for at least 1 week. I n these mice, pretreatment with OK-432 accompanied by concomitant treatment with either cyclophosphamide or irradiation resulted in reduced survival time compared with pre-treatment by OK-432 alone. T h e length of host survival appeared to be related directly

To determine the role of telomere‐mediated gene stability in hepatocarcinogenesis, we examined the telomere length of human liver with or without chronic liver diseases and hepatocellular carcinomas (HCC). The mean telomere restriction fragment (TRF) length of normal liver (n=13), chronic hepatitis (n=11), liver cirrhosis (n=24) and HCC (n=24) was 7.8±0.2, 7.1±0.3, 6.4±0.2 and 5.2±0.2 kb, respectively (mean±standard error). TRF length decreased with a progression of chronic liver diseases and that in HCC was significantly shorter than that in other chronic liver diseases (p<0.05). The ratios of TRF length of HCC to that of corresponding surrounding liver of well differentiated (n=7), moderately differentiated (n=10) and poorly differentiated (n=4) HCCs were 0.83±0.06, 0.75±0.05 and 0.98±0.09, respectively. The ratio of poorly differentiated HCC was significantly higher than that of moderately differentiated HCC (p<0.05). A comparison between the size and telomere length ratio of moderately differentiated HCCs revealed a decrease of the ratio with size until it reached 50 mm in diameter. In contrast, the ratio increased as the size enlarged over 50 mm. These findings suggest that the gene stability of the liver cells mediated by the telomere is reduced as chronic liver disease progresses and that telomerase is activated in poorly differentiated HCC and moderately differentiated HCC over 50 mm in diameter.