This paper reports a relapsed case of acute myeloid leukemia with intracranial, testicular and intestinal tumor formation. A-56-year-old male, diagnosed as M1 on September, 1988, entered complete remission on October 14, 1988, aided by JAL-SG and AML-85 regimen. Blast cells with Auer rods demonstrated 8;21 translocation lacking 11q with 30 of 30 analyzed bone marrow cells, and the following antigen pattern: CD5+, CD19+, CD33+, CD56+, HLA-DR+. After 4 courses of post remission therapy, the maintenance therapy was discontinued because of his liver dysfunction. He was discharged on May, 1989, and was seen as an out patient. He complained of left hemiplegia and was re-admitted on September 30, 1989. Though the bone marrow was in complete remission on September 4th, CT scan and MRI demonstrated intracranial tumor formation. Bone marrow relapse occurred on October 27th, eventually resulting in his death on November 18th. Autopsy showed intracranial, testicular and intestinal tumor formation and blast cell invasion into the liver, spleen and kidneys. We analyzed the characteristics of 14 cases with intracranial tumor formation previously reported. The focal neurological symptoms reflecting the intracranial tumor mass effect were considered to be important initial signs. CT scan was a useful tool for diagnosis. The average age of the 14 cases was 38, 9 and the male/female ratio was 9:5. Six of 9 cases, diagnosed by FAB classification, were M2 and one of the 6 cases in whom chromosomes of blast cells were examined had t(8;21). Though irradiation seemed effective for the reduction of tumor mass, the patients' prognosis was poor.(ABSTRACT TRUNCATED AT 250 WORDS)

A 31-year-old Japanese male who complained of low-grade fever, fatigue and generalized lymphadenopathy had shown an increase in peripheral white cell count, and 84% of peripheral blood cell and 76% of nuclear bone marrow cells consisted of small cleaved lymphoblastic abnormal cells with or without barely visible nucleoli. Cytogenic study of cervical lymph node biopsy specimens showed a t(14;18)(q32;q21) chromosome translocation. Histologically the lymph node cells were classified according to the International Working Formulation as follicular small cleaved-cell lymphoma. Molecular analysis of DNA fragments of peripheral lymphocytes revealed both J-H gene and bcl-2 oncogene rearrangements. Immunophenotypes of peripheral lymphocytes, bone marrow cells and lymph node cells expressed a clonally distinct B-cell population bearing surface immunoglobulin-G, kappa-chain, CD-10, CD-19, CD-20, CD-21 and OKIa-1 antigens. We diagnosed this case as follicular lymphoma in the leukemic phase,

Recently, nuclear DNA contents of various human tumors were studied, and DNA aneuploidy was thought to have prognostic significance in many kinds of malignant tumors. Although the same significance was reported in thyroid carcinoma, the anaplastic thyroid carcinoma which is one of the most aggressive tumor in human malignant neoplasms, not always shows DNA aneuploidy. Therefore, using 3 xenografts established from 3 patients with anaplastic thyroid carcinomas, we investigated their growth activity, DNA ploidy and chromosome abnormalities. Two of these xenografts grew relatively fast in nude mice showing diploid or near diploid state in a flow cytometric study, and also, showed many structural abnormalities in chromosome analysis by the G-banding technique. The remaining one xenograft showed slower growth and aneuploidy, and had extensive numerical but less structural variability in its chromosomal constitution. These results indicate that some tumors showed DNA diploidy and have structural chromosome abnormalities and also suggest that the prognostic value of quantitative DNA measurement is limited in such tumors.

Chemically-induced hepatic carcinogenesis is a suitable model to investigate multistep process of carcinogenesis, because preneoplastic and neoplastic lesions develop in a sequential manner. The process is initiated by emergency of "genetically altered cells" or "initiated cells" which have a potential to progress to hepatocellular carcinomas. The cells can clonally expand under the effect of tumor promoters or carcinogens. Clonal expansion will increase the probability that a cell undergoes further genetic changes. By this stepwise manner, a cell may acquire neoplastic properties such as independence to growth factors, invasive growth, loss of antigenicity, metastatic capacity, etc. The author reviewed the recent advance in studies on oncogenes, tumor suppressor genes and growth factor genes concerning to rodent hepatic carcinogenesis.

During the last decade, the influences of genetic factors on individual drug metabolizing capacity in humans have been characterized in fairly great detail at the molecular level. Debrisoquine/sparteine and mephenytoin polymorphisms are now known to be derived from defects in the human liver of specific forms of microsomal CYP (P450 or previously termed cytochrome P-450), CYP2D6 and CYP2C9 (2C18), respectively. In these polymorphisms, clear ethnic differences are observed in the incidence of poor metabolizers (PM). Although debrisoquine PM is detected in high incidence (5-10%) in Caucasians, little was found in Japanese. In contrast, mephenytoin PM is detected in higher percentages in Japanese (15-25%) than in Caucasians (3-7%). In this mini-review, current understanding of the molecular mechanisms of both types of polymorphism and structural relationships of CYP2D6 and CYP2C9 substrates are shown. Relationships between specific phenotypes and cancer risks or disease are also discussed.

Cell dispersion and motility are thought to be important steps in the invasion of tumor cells. The molecular mechanisms responsible for the induction of cell dispersion and motility remain unclear. Several factors affecting cell motility have been discovered. Among them, scatter factor (SF), a mesenchymal cell-derived protein, dissociates epithelial cell colonies into individual cells and stimulates the migration of epithelial cells. Purified SF promotes the invasiveness into collagen matrices of a number of human carcinoma cell lines, suggesting that SF is involved in the invasion of tumor cells. Recently, SF has been found to be identical to hepatocyte growth factor. Moreover, the c-met proto-oncogene product (the c-met protein) possessing a tyrosine kinase domain was identified as a receptor for SF. Three possible mechanisms have been postulated in which a tumor cell might increase its invasive potential through enhanced motility via SF and its receptor. First, in a cell already expressing the c-met protein, an unexpressed SF gene might be activated, leading to synthesis and secretion of the factor which could then initiate active motility in an autocrine fashion. Second, the tumor cell expressing the c-met protein may release a factor that affects surrounding mesenchymal cells, promotes synthesis and release of SF. The tumor cell would be stimulated in a paracrine fashion. Finally, the tumor cell may be exposed to SF already released by surrounding cells but may not be able to respond because it is partially or completely deficient in the c-met protein. Induction and increased expression of the c-met gene would result in the invasive phenotype of the tumor cell. Studies on these possible mechanisms will be required to elucidate the involvement of SF in the invasion of tumor cells.

Interferon alpha (IFN alpha) has been used in the treatment of chronic myelogenous leukemia (CML). The initial trial was made in 1983 by Talpaz et al. Their first report suggested that IFN alpha treatment could achieve high hematological remission. The cause of the effect was unclear, but may be mediated through interaction cell surface membrane and inhibitory protein production. IFN alpha was related to some T cell immunity, and could be taken to be Ph1 positive cell inhibition by normal T cell. Although IFN alpha therapy has limited use with get Ph1 negative hematopoiesis, intensive treatment of this kind is needed to minimize Ph1 clone, using various therapy combination with IFN alpha.

We treated 70 patients with acute promyelocytic leukemia (APL) with daily oral 45 mg/m2 all-trans retinoic acid (ATRA) in 2 multi-institutional prospective studies. Of 63 evaluable patients, 21 were resistant to initial induction chemotherapy, 10 were resistant to salvage chemotherapy after relapse, 17 were in the first relapse, 4 in the second relapse, 4 in the third relapse, and 7 were previously untreated. In the first study with ATRA from China, 18 (82%) of 22 evaluable patients achieved CR within 8 to 53 days with a median of 29 days. Initial peripheral leukemia cell counts were significantly less in the CR cases (p < 0.01). They were less than 100/cmm in 17 of 18 CR cases, and more than 200/cmm in all failure cases. Patients achieving CR received standard consolidation and maintenance chemotherapies, and the 16-month predicted continuing CR rate is 60%. Based on the first study, in the second study with ATRA from Hoffmann-La Roche AG, if initial peripheral leukemia cell counts were more than 200/cmm, chemotherapy was first given and then ATRA was started. Of 41 evaluable patients, 36 (88%) achieved CR within 11 to 91 days with a median of 34 days. Of 3 patients who received preceding chemotherapy due to high leukemia cell counts, 2 achieved CR. Morphological evidence of differentiation was noted in all CR cases, with Auer rods in mature segmented neutrophils in 13 cases. The clinical signs of DIC decreased rapidly within a few days and disappeared in CR cases. Toxicities attributable to ATRA were minimal and included cheilitis, xerosis, dermatitis, gastrointestinal disorders, bone pain, liver damage and high serum triglyceridemia.

We had studied the histogenesis and p21 expression in ovarian tumor induced by 7,12-dimethylbenz(a)anthracene (DMBA). The present study was done to elucidate point mutation of the ras gene in tumors. Cases with immunohistological p21 expression; 3 adenomas, 5 adenocarcinomas and 2 sarcomas were examined by polymerase chain reaction (PCR). 1) The products of PCR were confirmed the presence of amplified sequences by electrophoresis. 2) No point mutation of H-ras (Codon 12,61) or K-ras (Codon 12,61) genes was found in the ovarian tumors induced by DMBA. 3) These results suggested that the mutational activation of ras genes in tumorigenesis was dependent on another mechanism.

DNA ploidy and DNA content of two surgically resected sclerosing hemangioma of the lungs were examined by flow cytometry. Cell kinetics were analyzed by using DNA index and the proliferation index. Both cases were diploid, and their proliferation indices were 22.91 and 25.53, respectively, suggesting that they are benign tumors.

The exact role of hepatitis B virus (HBV) in hepatocarcinogenesis is not known. We generated HBV x gene transgenic mice under the hypothesis that the viral transactivator may alter the host gene expression and lead to the development of hepatocellular carcinoma. The x gene under its own regulatory element caused progressive histopathological changes specifically in the transgenic mouse liver, beginning with multifocal foci of altered hepatocytes, followed by the appearance of neoplasia. This finding shows, for the first time, the direct involvement of HBV in the development of liver cancer. Analyses of events that follow the expression of the x gene suggest that the x gene acts at the early stage of carcinogenesis in the liver.

Hepatocyte growth factor (HGF) is a highly potent growth stimulator of hepatocytes and c-met proto-oncogene has recently been identified as its high-affinity receptor. Since the c-met gene expression is found in many types of cells, carcinogenic and/or transforming activity through autocline or paracline mechanism of HGF-c-met/HGFR system has become point of interest. By transfecting HGF into a unique immortalized mouse hepatocytes (MLE-10), which expresses c-met at high level, we were able to first demonstrate transforming activity of HGF by autocline mechanism.

The X gene product of hepatitis B virus (HBV) has a trans-activation function. The AP-1, AP-2, kappa B-like, and C/EBP-like sequences, and the 26-bp element in HBV enhancer were identified as X-responsive elements. Although the X protein possesses a transcriptional activation domain, it doesn't bind to the X-responsive elements. However, CREB/ATF-2 becomes able to bind to a CRE-related sequence in the 26-bp element once it complexes with X protein. In addition, X protein was shown to have amino acid sequences homologous to the essential domain of Kunitz-type serine protease inhibitors and directly interacted with the protease, tryptase TL2. Results suggest that X protein modulates the tryptase TL2 activity, which may be involved in the proteolytic cleavage of cellular transcription factors.