Y Kawachi

Tokyo Medical and Dental University, Edo, Tokyo, Japan

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Publications (43)64.1 Total impact

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    ABSTRACT: Thymidylate synthase (EC 2.1.1.45) and thymidine kinase (EC 2.71.21) are key enzymes involved in de novo and salvage pathways for pyrimidine nucleotide synthesis. Both enzyme activities are increased in rapidly proliferating normal, fetal and neoplastic tissues. In a previous study, the activities of thymidylate synthase and thymidine kinase were relatively predominant in the poorly-and well-differentiated types of a gastric cancer. In the present study of patients with colorectal cancer, the serum thymidine kinase activities are elevated in cases at a clinically late stage, and in cases with a recurrence and a distant metastasis associated with abundant blood supply, i.e. metastasis to the liver, lung and bone. Well-differentiated colorectal cancer shows higher thymidine kinase activity than moderately-well-differentiated type as was previously shown in gastric cancer patients. Furthermore, neoadjuvant chemotherapy using the 5-fluorouracil derivative UFT demonstrates a stronger suppression of increased activities of thymidylate synthase in the tumorous tissues than in the non-tumorous mucosa.
    No preview · Article · Jan 2002 · Anticancer research
  • Tetsuya Tada · Tsutomu Suzuki · Yasuyuki Kawachi

    No preview · Article · Jan 2001 · Nihon Rinsho Geka Gakkai Zasshi (Journal of Japan Surgical Association)
  • Yasuyuki Kawachi · Tetsuya Tada · Katsuyoshi Hatakeyama

    No preview · Article · Jan 2001 · Nihon Rinsho Geka Gakkai Zasshi (Journal of Japan Surgical Association)
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    ABSTRACT: Thymidylate synthase and thymidine kinase are key enzymes involved in de novo and salvage pathways for pyrimidine nucleotide synthesis. Colorectal carcinogenesis induced with 1,2-dimethylhydrazine in rats enhanced mRNA expression levels of both enzymes, resulting in the increase of both enzyme activities and bromodeoxyuridine-immunoreactive S-phase cells. Poorly and well differentiated adenocarcinomas of the colorectum showed the relative elevation of activities of thymidylate synthase and thymidine kinase, respectively. These results indicate that the relationship between de novo and salvage pathways for pyrimidine nucleotide synthesis may depend on the histopathological grades of cell differentiation.
    No preview · Article · Nov 1999 · Oncology Reports
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    ABSTRACT: In this study we investigated which type of T cells: high T-cell receptor (TCRhigh, cells of thymic origin) or intermediate TCR (TCRint, cells of extrathymic origin), expanded in the liver and other organs, resulting in the induction of graft-versus-host disease (GVHD) with minor lymphocyte stimulating (M1s) disparity. When 6.5 Gy-irradiated BALB/c (H-2d M1s-1b2a) mice were injected with interleukin-2 receptor beta-chain(-) (IL-2Rbeta(-)) CD3high cells purified from the spleen of B10.D2 (H-2d M1s-1b2b) mice, IL-2Rbeta(+)CD3high cells expanded in the liver and other organs of recipient mice. The majority of these cells were found to be IL-2Ralpha(-)Mel-14(-)CD4(+)Vbeta3(+) in GVHD mice. The CDR3 region in their TCR-alphabeta (i.e. N-Dbeta-N) was polyclonal, although there were skewed usages of Vbeta3 and Jbeta2.4. The majority of cells were confirmed to be of donor origin by the individual discrimination method, namely, they originated from isolated IL-2Rbeta(-)CD3high cells. Interestingly, these T cells lacked cytotoxicity against both a natural killer (NK)-sensitive target and thymocytes with M1s disparity and nondisparity. Another important finding was that activated granulocytes expanded at generalized sites in GVHD mice. The present results raise the possibility that M1s disparity is mainly recognized by TCRhigh cells with unique properties but that direct effector cells that induce GVHD might not be such T cells but rather accompanied granulocytes.
    Preview · Article · Apr 1999 · Scandinavian Journal of Immunology
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    ABSTRACT: Thymidylate synthetase and thymidine kinase are key enzymes involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively. Weekly injections of 1,2-dimethyl-hydrazine induced high incidence of colorectal adenocarcinomas in rats. An increased activity of thymidylate synthetase was found in the poorly differentiated adenocarcinomas of the chemically induced rat colorectal tumors. Six-week oral administration of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil (UFT) reduced the total number of colorectal tumors, with the reduction of thymidylate synthetase activity in the poorly-differentiated type, though the mRNA expression of thymidylate synthetase and thymidine kinase differed little between the groups with or without UFT treatment. These results indicate that the long-term oral administration using UFT suppresses colorectal carcinogenesis and the growth of the poorly-differentiated type tumors.
    No preview · Article · Jan 1999 · Anticancer research
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    ABSTRACT: It is believed that self-reactive forbidden T-cell clones are generated by 'failure' of the pathway of T-cell differentiation in the thymus, if it is disturbed. We examined how such forbidden clones are generated under immunosuppressive conditions. Mice were treated with an injection of deoxyspergualin, FK506, or cycloporin A. From day 3, the number of cells yielded by various organs decreased. Because of the resistance of intermediate (int) T-cell receptor (TCR) cells (i.e. TCRint cells), they became more prominent in proportion than TCRhigh cells. TCRhigh cells are conventional T cells generated through the mainstream in the thymus, whereas TCRint cells are primordial T cells generated by the extrathymic pathway or an alternative intrathymic pathway. Similar to untreated mice, forbidden V beta 3+ and V beta 11+ clones in C3H/He (Mls-1b2a) mice were confined to TCRint cells after treatment; there was no leakage of forbidden clones into TCRhigh cells in the thymus and periphery. In parallel with the increase in the proportion of TCRint cells, the proportion of forbidden clones also increased under immunosuppressive states, especially in the liver. Liver mononuclear cells isolated from treated mice still had the potential to mediate autologous killing. The present results suggest that the generation of self-reactive clones is highly restricted to the pathways of TCRint cell differentiation even under immunosuppressive conditions.
    Preview · Article · Jun 1997 · Immunology
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    ABSTRACT: Thymidylate synthetase (TS) and thymidine kinase (TK) are key enzymes in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively. A high incidence of colorectal adenocarcinomas with varied grades of cell differentiation can be induced by 1,2-dimethylhydrazine (DMH) in rats. The marked increases of TS and TK activities were found in the poorly and well-differentiated adenocarcinomas of the colon, respectively. Oral administration of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil (UFT) markedly reduced the number and accumulated area of colonic carcinomas, and TS activity in the poorly differentiated adenocarcinomas. A potential balance between the de novo and the salvage pathways for pyrimidine nucleotide synthesis was suggested to be related with the histopathological grades of cell differentiation. Suppression of colonic TS activity by UFT administration reduced the colonic carcinogenesis and the potency of the poorly differentiated adenocarcinomas of the colon.
    No preview · Article · Feb 1997 · Cancer Detection and Prevention
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    ABSTRACT: Neonatally thymectomized (NTx) mice fall victim to such autoimmune diseases as gastritis and pancreatitis with aging. Self-reactive T cell clones are known to be consistently generated through TCR intermediate (i.e. TCRint) cell differentiation in normal mice (i.e. via the extrathymic pathways and an alternative intrathymic pathway). It was investigated whether the generation of such clones in NTx mice follows this rule or whether they are generated by default via mainstream T cell differentiation in the thymus. The majority of T cells generated in NTx mice were TCRint cells in all organs tested. In contrast to athymic mice, which carry only TCRint cells with aging, a leaky appearance of high TCR (i.e. TCRhi) cells emerged in the lymph nodes and other organs of NTx mice. Self-reactive clones estimated by anti-Vbeta monoclonal antibodies in conjunction with the Mls system were confined to TCRint cells in all tested organs, including a target organ, the stomach, in NTx mice. A leaky population of TCRhi cells did not contain a significant number of self-reactive clones. Moreover, such self-reactive clones among TCRint cells in NTx mice with autoimmune disease were shown to be nonanergic in the proliferation assay. The present results suggest that the generation of self-reactive clones is totally due to TCRint cell differentiation, although it is still undetermined whether the expanding TCRint cell population is generated via the extrathymic pathway or an alternative intrathymic pathway. It is shown here not to be due to a failure of the TCRhi cell-differentiation pathway in NTx mice.
    No preview · Article · Dec 1996 · European Journal of Immunology
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    ABSTRACT: Morphological and phenotypic characterization in previous studies has indicated that intermediate (int) T-cell receptor (TCR) cells or T natural killer (TNK) cells may stand at an intermediate position between NK cells and high TCR cells of thymic origin in phylogenetic development. In this study, a functional study on cytotoxic activity against various tumour targets was performed in each purified subset. When a negative selection method entailing in vivo injection of anti-asialo GM, antibody or anti-interleukin (IL)-2R beta monoclonal antibody (mAb) was applied, IL-2R beta 1 CD3 NK cells were found to have the highest NK activity while IL-2R beta 1 int CD3 (or TCR) cells had a lower level of the NK activity. High CD3 cells (freshly isolated) did not have any such activity. Sorting experiments further revealed that the NK function mediated by int CD3 cells was augmented when they were exposed to anti-CD3 mAb. anti-TCR alpha beta, or anti-TCR-delta mAb. This phenomenon was not observed in NK cells and high CD3 cells. More importantly, when anti-CD3 mAb (or anti-TCR mAb) was added to the assay culture, int CD3 cells became cytotoxic against even NK-resistant tumour (Fc gamma R-. Fas+) targets. Liver mononuclear cells or int CD3 cells exposed to anti-CD3 mAb for 6 hr showed an elevated level of perforin in their cytoplasms. The present results suggest that int CD3 cells are usually non-cytotoxic against various tumours but become functional after being stimulated via the TCR CD3 complex.
    Full-text · Article · Oct 1996 · Immunology
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    ABSTRACT: Extrathymic T cells can be easily distinguished from thymus-derived T cells, in terms of their expression levels of TCR (or CD3) and IL-2 receptor β-chain (IL-2Rβ). In this study, we examined how extrathymic T cells and thymus-derived T cells were activated in various organs during viral infection. When C3H/He mice were intraperitoneally inoculated with herpes simplex virus (HSV) of type 1-GC+ strain at a sublethal dose, 3 × 104PFU/mouse, the number of mononuclear cells (MNC) in the liver and spleen was stable but that of thymocytes decreased gradually up to 7 days after infection. However, a striking change of lymphocyte subsets was seen in the liver, namely, an increase in the proportion of NK cells (CD3-IL-2Rβ+) and extrathymic T cells (CD3-intermediate+ IL-2Rβ+-) on day 3 and 7. Reflecting this change, γδ T cells and double-negative CD4-8- T cells, which are components of extrathymic T cells, became elevated on day 3. Pre-elimination of NK cells and intermediate CD3 cells by an in vivo injection of anti-IL-2Rβ mAb made mice susceptible to death by infection. All irradiated (6Gy) mice also became susceptible to death, but 1 × 107 adoptive transfer of liver MNC, but not of splenic MNC, obtained from HSV-immunized mice was effective in preventing death (50%). The experiment in which mice were treated with anti-asialoGM1 antibody showed that NK cells were much more important for early phase protection than were intermediate CD3 cells. MNC were also isolated from the lung, the major target organ, in HSV-infected mice. Intermediate CD3 cells and granulocytes increased in this organ. These results suggest that a serial induction of primitive lymphocytes such as NK cells and extrathymic T cells may be crucial for early protection from viral infection.
    Preview · Article · Feb 1996 · Biomedical Research
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    ABSTRACT: It has been established that, even after syngeneic bone marrow transplantation, animals treated with immunosuppressive drugs may suffer from graft-versus-host disease, showing autoimmune-like symptoms. Although the major effector cells are known to be T-cell subsets, detailed characterization of such T cells remains to be investigated. In the present study, we characterized them, especially as to whether they are thymus-derived T cells or extrathymic T cells, and how self-reactive clones were distributed among the above T-cell subsets. BALB/c mice (Mls-1b2a) were irradiated (9 Gy), subjected to bone marrow transplantation, and then treated with cyclosporin A (CsA) for 6 weeks. From 2 weeks after the cessation of CsA, these mice displayed signs of GVH disease. The major target organs included the liver and colon. Two-color staining for CD3 and IL-2R beta was applied to identify CD3-IL-2R beta+ NK cells, CD3-intermediate +IL-2R beta+ cells (i.e., intermediate CD3 or TCR cells of extrathymic origin) and CD3-high+IL-2R beta- cells (i.e., high CD3 cells of thymic origin). It was demonstrated that the major expanding lymphocytes were intermediate TCR cells and that self-reactive clones (V beta 3+ and V beta 11+ cells in this strain of mice) were confined to this population. Interestingly, these self-reactive clones had ability to respond to immobilized anti-V beta 3 and anti-V beta 11 mAbs. Liver MNC in mice with GVH disease which contained the highest proportion of intermediate TCR cells were able to mediate the adoptive transfer of GVH disease to other irradiated (6.5 Gy) mice. Intermediate TCR cells also showed potent cytotoxic activity against syngeneic leukemia cells. These results suggest that intermediate TCR cells are the major effector cells for the induction of syngeneic GVH disease.
    No preview · Article · Jan 1996 · Cellular Immunology
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    ABSTRACT: Since the incidence of acute appendicitis seems to vary with weather, we investigated the underlying mechanism. When 112 patients who had undergone appendectomy were classified into three groups according to atmospheric pressure at the time of onset, gangrenous cases (high infiltration of granulocytes) were much greater in frequency than catarrhal cases (no infiltration of granulocytes) at high pressure. At low pressure, the situation was the reverse. The variation of granulocytes and lymphocytes in the blood as related to atmospheric pressure and heart rate was examined in healthy donors. Granulocytosis was seen with increased sympathetic activity (high heart rate) at high pressure, whereas lymphocytosis was seen with increased parasympathetic activity (low heart rate) at low pressure. Taken together with the results from patients, in which gangrenous cases showed granulocytosis in the blood as well as in the appendix while catarrhal cases showed lymphocytosis in the blood and appendix, it is presumed that granulocytosis induced by increased sympathetic activity might be related to the onset of gangrenous appendicitis. Experimental results using human and mouse materials indicated that catecholamines induce granulocytosis via their adrenergic receptors. Even in gangrenous cases, bacteria were not detected in the vicinity of granulocytes in the appendix by electron microscopy. The present results seem to shed important light on the etiology of suppurative diseases.
    Preview · Article · Jan 1996 · Biomedical Research
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    ABSTRACT: Extrathymic T cells exist in the liver and are often seen in close contact with Kupffer cells in the hepatic sinusoids. Since selective depletion of Kupffer cells has become possible by using liposome-encapsulated clodronate, it was investigated whether elimination of Kupffer cells influences the level of extrathymic T cells in the liver. Extrathymic T cells were identified as interleukin-2 receptor β-chain (IL-2Rβ) intermediate TCR (TCRint) cells by two-color staining for CD3 or T cell receptor (TCR) and IL-2Rβ. The elimination of Kupffer cells did not significantly affect levels of TCRint cells up to 7 days after treatment. We then examined monocyte colony stimulating factor (M-CSF)-deficient op/op mice (low levels of Kupffer cells). Extrathymic T cells both in the liver and spleen of these mice were detected at a level comparable to that of control mice. Since extrathymic T cells in the liver are sometimes located in the parenchymal space, the relationship between extrathymic T cells and hepatocytes was then examined. Electron microscopy revealed that some hepatic T cells adhered directly to hepatocytes. When hepatocytes were damaged by a single injection of CCl4, hepatocyte death and subsequent hepatic fibrosis were induced. Beginning 3 days after injection, CD3int cells, but not other type of cells, decreased prominently. Purified CD3int cells, as well as whole lymphocytes in the liver, were cytotoxic against syngeneic hepatoma. In parallel with the above-mentioned hepatic damage, the cytotoxic activity of lymphocytes against such targets was impaired in the liver. These results suggest that extrathymic generation of TCRint cells and their acquisition of cytotoxic function are relatively independent of Kupffer cells, but are dependent on hepatocytes.
    No preview · Article · Dec 1995 · European Journal of Immunology
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    T Okada · T Iiai · Y Kawachi · T Moroda · Y Takii · K Hatakeyama · T Abo
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    ABSTRACT: Human T cells carrying natural killer (NK) markers, CD57 or CD56 antigens, appear to be distinguishable from other T cell subsets in terms of their granular lymphocyte morphology and their numerical increase in patients with AIDS and in recipients of bone marrow transplantation. At the beginning of this study, we observed that CD57+ T cells as well as CD56+ T cells were abundant at tumour sites in many patients with colorectal cancer. Since all these findings for CD57+ T cells are quite similar to those of extrathymic T cells seen in mice, we investigated how CD57+ T cells are distributed to various immune organs in humans. They were found to be present mainly in the bone marrow and liver, but to be completely absent in the thymus. Similar to the case of extrathymic T cells in mice, they were observed to consist of double-negative CD4-8- subsets as well as single-positive subsets (preponderance of CD8+ cells), and to contain a considerable proportion of gamma delta T cells. These features are striking when compared with those of CD57- T cells, which are characterized by an abundance of CD4+ subsets and alpha beta T cells. Not only at tumour sites but also in the peripheral blood, some patients with colorectal cancer displayed elevated levels of CD57+ cells. These results suggest that CD57+ T cells may be of extrathymic origin, possibly originating in the bone marrow and liver, and may be associated with tumour immunity, similar to another extrathymic population of CD56+ T cells in humans.
    Full-text · Article · Nov 1995 · Clinical & Experimental Immunology
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    ABSTRACT: Experiments to date have revealed a population of T cells that carry intermediate (int) levels of TCR (or CD3) and express IL-2R beta-chain (IL-2R beta) in mouse liver. Such int TCR cells also reside in other immune organs, although in low numbers. On the other hand, NK1.1+ T cells with int TCR do reside in the thymus and other peripheral organs. To determine the relationship of two types of cells, we characterized int CD3 cells and NK1.1+ T cells throughout the organs in terms of the phenotype, V beta repertoire, and morphology. Although both IL-2R beta+ T cells and NK1.1+ T cells are classified as int CD3 cells, NK1.1+ T cells are present within int CD3 cells. The majority of int CD3 cells in the liver and thymus were NK1.1+, whereas the minority of such cells in the spleen, lymph nodes, and bone marrow were NK1.1+. Among int CD3 cells, double-negative (DN) CD4-8- cells and/or CD4+ were abundant in NK1.1+ subset, whereas CD8+ cells were generally abundant in NK1.1- subset. Self-reactive V beta+ clones estimated by the M1s system were distributed to both NK1.1+ and NK1.1- subsets. High CD3 cells in the thymus and other organs contained neither DN cells nor forbidden clones. Int CD3 cells had the morphology of granular or agranular lymphocytes carrying perforin. Among int CD3 cells, NK1.1+ subset had a higher level of perforin-positive cells than NK1.1- subset. These results clearly demonstrate the relationship between int TCR cells and NK1.1+ T cells in various organs.
    Full-text · Article · Oct 1995 · The Journal of Immunology
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    ABSTRACT: T cells expressing high levels of the T cell receptor (TCRhigh) differentiate in the major intrathymic pathway and then distribute to the peripheral immune organs, whereas T cells expressing intermediate levels of the TCR (TCRint) differentiate in both extrathymic pathways and an alternative intrathymic pathway and localize in unique sites, including the liver and thymic medulla. Since TCRint cells constitutively express interleukin-2 receptor beta-chain (IL-2R beta), two-color staining for CD3 (or TCR) and IL-2R beta clearly distinguished IL-2R beta+ CD3int (or TCRint) cells from IL-2R beta-, CD3high cells. CD3int cells may be considered to be primordial T cells based on their phenotype, morphology and other functional properties. In this study, using anti-V beta mAb in conjunction with the endogenous superantigen Mls, the distribution of self-reactive clones among T cells generated in all of the above pathways was investigated in mice. Self-reactive T cell clones were confined to IL-2R beta+, CD3int cells, in all of the organs tested. A significant proportion of self-reactive clones was never identified among CD3high cells in the thymus and peripheral immune organs in either young (8 week old) or old (50 week old) mice. Possibly reflecting their self-reactivity, CD3int cells, but neither NK cells nor CD3high cells had a potent cytotoxic effect against a syngeneic hepatoma in the presence of anti-CD3 mAb. These results raise the possibility that CD3int cells seen in the liver and thymus might belong to a similar primordial lineage of T cells, and that self-reactive clones are not generated through the major intrathymic pathway, but only through extrathymic pathways and an alternative intrathymic pathway.
    No preview · Article · Aug 1995 · European Journal of Immunology
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    T Iiai · M Kimura · Y Kawachi · K Hirokawa · H Watanabe · K Hatakeyama · T Abo
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    ABSTRACT: Autoimmune MRL-lpr/lpr (lpr) mice were previously demonstrated to have an abnormal proliferation of intermediate T-cell receptor (TCR) cells of extrathymic origin in the liver. Despite this situation, thymectomy in lpr mice resulted in amelioration of autoimmune disease. To understand the underlying mechanism, we investigated associated T-cell differentiation in the thymus and other organs of these mice. When the disease was evoked, T cells with extrathymic properties, i.e. intermediate TCR-alpha beta cells expressing double-negative (DN) CD4-8- phenotype and interleukin-2 (IL-2) receptor beta-chain, became prominent not only in the liver, but also in the thymus. Such thymic T cells mainly resided in the medulla. A small-scale localization of such T cells was seen in the thymic medulla even in normal control mice. There was a heterogeneity among intermediate TCR cells in terms of the composition of DN cells and the expression of CD2 and B220 antigens, depending on the organs and the sites in the same organ. Intermediate TCR cells in the liver, thymus and autoimmune target organs (e.g. kidney) contained a high proportion of the active form (CD2+B220-), while intermediate TCR cells accumulating in peripheral organs, the spleen and lymph nodes, were mainly of the inactive form (CD2-B220+). The active form had an ability to proliferate in response to IL-2 and SEB, whereas the inactive form did not. The present results suggest that the proliferation of intermediate TCR cells occur at multiple sites; this may explain the effect of thymectomy, namely, the retarded onset of disease, in lpr mice.
    Full-text · Article · May 1995 · Immunology
  • T Iwama · H Tomita · Y Kawachi · K Yoshinaga · S Kume · H Maruyama · Y Mishima
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    ABSTRACT: The relative risk of periampullary carcinoma is high in patients with familial adenomatous polyposis (FAP). We examined the possibility of local treatment of the ampullary lesion of these patients in an early stage. From August 1991 to April 1993, 37 patients with FAP underwent endoscopic examination and biopsy of the ampulla. Local excision of the ampulla was performed in seven patients. Two of the seven patients were diagnosed with carcinoma in situ; the ages of the patients were 35 and 46 years. A 38-year-old woman had ampullary carcinoma infiltrating into the muscle of the sphincter of Oddi. These three cases showed a protruding change or deformity of the ampulla endoscopically. The laboratory data, cholangiogram, and abdominal ultrasonography were within normal limits. The superficial change of the ampulla along with the young age of the patients were considered to be factors that warranted further observation. Postoperative complications in two cases were treated successfully. Indications for local excision of the ampulla of patients with FAP would be protruding change of the ampulla, biopsy showing adenoma with severe atypia or carcinoma, in situ, no jaundice with or without subclinical abnormality of laboratory data, no apparent dilatation in the bile duct, and age of more than 35 years.
    No preview · Article · Nov 1994 · Journal of the American College of Surgeons
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    ABSTRACT: To investigate the effect of intra-arterial injection of mitoxantrone emulsified with ethiodized oil, forty-eight patients with hepatocellular carcinoma were evaluated. After the treatment, ten of the patients underwent hepatectomy. In the thirty-eight unresected cases, there were 15 (39%) partial responses, which continued 1.2 to 11.8 months (mean, 5.8 months). The 1- and 2- year survival rates were 67% and 38%, respectively. The response rate was higher in cases with tumor under 5 cm in diameter. In the remaining 10 resected cases, the necrotic areas in main nodules ranged from 65% to 100% (mean, 85%). This treatment might be applied effectively to patients with small hepatocellular carcinoma.
    No preview · Article · Oct 1994 · Gan to kagaku ryoho. Cancer & chemotherapy