Tohru Takahashi

Expression of c-kit and kit Ligand in Human Colon Carcinoma Cells

To determine whether c-kit and kit ligand (KL) mRNAs could be expressed in human epithelial tumors, reverse transcriptase-polymerase chain reaction and Northern blot analysis were performed. KL mRNA was shown to be expressed in a variety of epithelial tissues and cell lines. The expression of c-kit mRNA was then examined in hepatocellular and colon carcinoma cell lines. While hepatocellular carcinoma cell lines did not express c-kit mRNA as far as we could ascertain, 2 of 5 colon carcinoma cell lines showed the expression of both c-kit and KL mRNAs. Furthermore, the expression of c-kit in these cells was demonstrated at the protein level by flow cytometry. These data suggest that c-kit and KL may play an important role as an autocrine loop in the proliferation of some colon carcinoma cells.

Increased invasiveness of MUC1 and cDNA-transfected human gastric cancer MKN74 cells

MUC1 mucin is an anti‐adhesion molecule expressed in a wide variety of tumors. To examine whether MUC1 mucin is involved in tumor invasion, we have prepared MUC1 transfectants using the human gastric cancer cell line MKN74 and performed an in vivo tumor assay by transplanting these into nude mice. Tumor weight at 71 days after s.c. injection of transfectants was measured, showing that the in vivo growth of MUC1 transfectants was increased compared to that of mock transfectants. Furthermore, MUC1‐transfectant tumors invaded into the muscle layer, whereas mock‐transfectant tumors did not. In vitro invasion, adhesion to extracellular matrix components and phagokinetic track motility were then evaluated to analyze the mechanisms for the in vivo invasiveness of the transfectants. MUC1 transfectants exhibited an increased in vitro invasiveness, decreased binding to laminin, fibronectin, type I collogen and type IV collagen and increased motility. These effects of MUC1 mucin over‐expression in MKN74 cells were abolished by the treatment of transfectants with an inhibitor of O‐glycan biosynthesis, benzyl‐α‐GalNAc. Our data suggest that MUC1 mucin could be related to the increased invasive ability of MKN74 cells, whereas O‐glycan might play an essential role. Int. J. Cancer 76:377–382, 1998.© 1998 Wiley‐Liss, Inc.

MUC1 Mucin Core Protein Binds to the Domain 1 of ICAM-1

Background: MUC1 is aberrantly expressed on a variety of epithelial tumors. We have reported that MUC1 plays important roles in separation from primary site, invasion into the stromal tissue, and protection from immune responses. The aim of this study is to determine the precise binding of MUC1 to intercellular adhesion molecule 1 (ICAM-1) that accelerates the cancer metastasis. Methods: A cell aggregation assay between MUC1 cDNA transfectants and ICAM-1 expressing cells was employed. An anti-MUC1 antibody, anti-ICAM-1 antibody or synthetic peptide of MUC1 core protein was added to the assay to inhibit the cell aggregation. Results: MUC1 transfectants showed a significantly higher aggregation rate compared to the control cells. This aggregation was further enhanced by the inhibition of O-glycan biosynthesis. It was inhibited by either an anti-MUC1 antibody recognizing the tandem repeat domain of MUC1 core protein or an anti-ICAM-1 antibody identifying domain 1. It was also inhibited by a synthetic MUC1 peptide of 40 amino acids corresponding to two tandem repeats. Conclusions: The results revealed that a tandem repeat domain of MUC1 mucin core protein binds to domain 1 of ICAM-1, suggesting a potential role of MUC1- ICAM-1 interaction in the metastasis of epithelial tumors.

Incidence and Risk of Postherpetic Neuralgia after Varicella Zoster Virus Infection in Hematopoietic Cell Transplantation Recipients: Hokkaido Hematology Study Group

To assess the incidence of and risk factors associated with postherpetic neuralgia (PHN) after hematopoietic cell transplantation (HCT) varicella zoster virus (VZV) infection, we conducted a retrospective chart review of 418 consecutive patients who underwent HCT between April 2005 and March 2007. The male/female ratio was 221/197, median age at HCT was 47 years (range: 0-69 years), and autologous/allogeneic/syngeneic HCT ratio was 154/263/1. Seventy-eight patients developed VZV infection after HCT. Sixty-two patients had localized zoster, 11 patients had disseminated zoster (rash like chicken pox), and 4 patients had visceral zoster. All cases were treated with acyclovir (ACV) or valacyclovir (VACV), and there was no VZV infection-related death. Twenty-seven (35%) of the 78 patients with VZV infection suffered PHN after resolution of VZV infection. Multivariate analysis showed that advanced age is the only risk factor in autologous HCT (P = .0075; odds ratio [OR] = 1.14; 95% confidence interval [CI], 0.97-1.33). On the other hand, advanced age (P = .0097; OR = 1.06; 95% CI, 1.01-1.12), male gender (P = .0055; OR = 12.7; 95% CI, 1.61-100.1), and graft-versus-host disease (GVHD) prophylaxis with a tacrolimus-based regimen (P = .0092; OR = 9.56; 95% CI, 1.44-63.3) were associated with increased risk of PHN in allogeneic HCT. This study for the first time clarified the risk of PHN in HCT recipients.

Mucins and Immune Reactions to Mucins in Ulcerative Colitis

Ulcerative colitis (UC) is an inflammatory bowel disease of undetermined etiology. Mucins, mainly produced by goblet cells, protect colon cells from various kinds of stress. Alteration in the quality or quantity of mucins may be the cause of the disease. Another possible cause is immune reactions to colonic cells. Anti-MUC1 antibodies were detected in the sera of patients with UC. Antibodies would destroy the colonic cells through antibody-dependent cell-mediated cytotoxicity. We reviewed the significance of mucins as well as humoral and cellular immunity in the pathogenesis of UC.

ENHANCEMENT OF REACTIVITY OF ANTI-MUC1 CORE PROTEIN ANTIBODY AND KILLING ACTIVITY OF ANTI-MUC1 CYTOTOXIC T CELLS BY DEGLYCOSYLATION OF TARGET TISSUES OR CELLS

Abstract: MUC1 mucin core protein contains an important tumor-associated peptide antigen that can induce cytotoxic T cells (CTLs) in vivo, although this antigen is generally masked by mucin-type glycans. To reveal the precise expression pattern of MUC1 protein in normal and neoplastic gastric tissues, we performed immunohistochemical staining of periodic acid-treated tissue sections with an anti-MUC1 core protein monoclonal antibody (mAb), MUSE11. In non-cancerous tissues, the deep portion of fundic glands and the luminal surface were predominantly immunostained in normal and metaplastic glands, respectively. In cancerous tissues, the incidence of positivity for MUC1 protein varied from 67% to 88%, depending on histological type. This frequent expression of MUC1 protein in cancer tissues after periodic acid treatment suggested that deglycosylation may be of use for exposing the target antigen of anti-MUC1 CTLs. Accordingly, we then examined the effect of benzyl-α-GalNAc, an inhibitor of O-glycan biosynthesis, on the expression of MUC1 protein and sensitivity to an anti-MUC1 CTL line, designated TS, in gastric cancer JRST cells. After incubation with benzyl-α-GalNAc, the reactivity of mAb MUSE11 with JRST cells and their sensitivity of TS were clearly increased. These findings suggest that deglycosylation may offer an important strategy for enhancing anti-tumor immunity in patients with gastric cancer.

A Multicenter Retrospective Study of Mogamulizumab Efficacy in Adult T-Cell Leukemia/Lymphoma.

Micro‐Abstract Mogamulizumab recently became available for the treatment of adult T‐cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab for ATL treatment in patients in Japan and found that mogamulizumab is an effective therapeutic strategy in ATL. Some concern exists that the use of mogamulizumab in patients undergoing hematopoietic stem cell transplantation patients might cause severe graft‐versus‐host disease. Determining the optimum number of mogamulizumab administrations should be a priority for future studies. Background: Mogamulizumab, a defucosylated humanized monoclonal antibody targeting C‐C chemokine receptor 4, recently became available for the treatment of adult T‐cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab in ATL treatment in patients on Hokkaido Island, Japan. Materials and Methods: A total of 125 patients with ATL treated from January 2010 to December 2014 in 20 hospitals affiliated with the Hokkaido Hematology Study Group were enrolled in the present retrospective study. Results: Of the 125 ATL patients, 62 (46.6%) presented with the acute type, 51 (38.3%) with the lymphoma type, and 12 (9.0%) with the chronic type; the latter group included 7 unfavorable chronic cases. The median age at diagnosis was 68 years (range, 35‐86 years). The median survival for those with acute, lymphoma, and unfavorable chronic types was 302, 279, and 921 days, respectively. Advanced age, high lactate dehydrogenase level, poor performance status (3‐4), and the existence of B symptoms were unfavorable prognostic factors for overall survival (OS). Survival rate calculated from the day of diagnosis was significantly higher in patients treated with mogamulizumab. The OS of individuals receiving hematopoietic stem cell transplantation (HSCT) was superior to that of the non‐HSCT group. The median interval between the last mogamulizumab dose and allogeneic HSCT was 38 days (range, 21‐53 days). Of the 22 HSCT recipients who were not treated with mogamulizumab, overall acute graft‐versus‐host disease (aGVHD) and grade III‐IV aGVHD occurred in 12 (54.5%) and 3 (13.6%) patients, respectively. However, overall aGVHD and grade III‐IV aGVHD developed in 8 (88.9%) and 3 (33.3%) of the 9 HSCT recipients treated with mogamulizumab, respectively. Conclusion: Mogamulizumab improves OS in patients with ATL, although its use in HSCT patients might trigger severe GVHD. Determining the optimal pre‐HSCT mogamulizumab treatment regimen is thus a priority.

Fatal acute hepatic failure induced by danazol in a patient with endometriosis and aplastic anemia

We describe a 47-year-old woman with severe aplastic anemia with genital bleeding who developed acute severe hepatitis after the administration of danazol while she was receiving cyclosporin. She had been diagnosed with severe aplastic anemia 1 year previously and, while hospitalized, had received methyl prednisolone pulse therapy, which was not successful. She was then referred to our hospital. She was treated with antithymocyte globulin, cyclosporin, granulocyte colony-stimulating factor, and methyl prednisolone; a good response was achieved after 3 months of this therapy. Subsequently, oral administration of cyclosporin was continued, but she was readmitted to our hospital when pancytopenia gradually developed and the genital bleeding recurred. Danazol was administered for pancytopenia and endometriosis. Four days after the first administration of danazol, epigastric pain occurred, and the danazol was stopped. Eighteen days after the first danazol administration, very severe hepatic injury occurred abruptly. The patient died of hepatic failure. Postmortem examination revealed centrilobular massive necrosis of the liver. Danazol was implicated as the agent responsible for causing the hepatic failure. Drug interactions between danazol and cyclosporin may cause adverse effects.

Severe hemorrhage from gastric vascular ectasia developed in a patient with AML.

Gastrointestinal hemorrhage is a troublesome complication in patients with hematologic diseases. Gastrointestinal bleeding in patients with acute leukemia may be the result of chemotherapy, coagulopathy, or infection. Herein, we report a case of acute myelogenous leukemia (AML) that developed severe hemorrhage from gastric vascular ectasia (GVE) lesions, which were fully resolved after achieving a complete remission (CR). A possible relationship between AML and the development of GVE was suspected. A 70-year-old man was admitted to our hospital in September 2005, because a diagnosis of acute leukemia was suspected. A few days before admission, he was presented to another hospital because of worsening fatigue and allegedly having tarry stools. He had anemia (hemoglobin concentration was 7.6 g/dL) and severe thrombocytopenia (platelet count was 2000/ L). He was transferred to our hospital after 2 units of packed red blood cells and 15 units of concentrated platelet plasma were transfused. He had a history of acute myocardial infarction at the age of 63. Physical examination disclosed no abnormal findings except for anemia and petechiae in the trunk. A peripheral blood examination revealed that the leukocyte count was 7300/ L with 48% blasts, the hemoglobin concentration was 9.7 g/dL, and the platelet count was 66,000/ L. Liver function test results were normal. Occult blood of the feces was negative. A bone marrow aspiration revealed the proliferation of blasts without maturation in 50.3% of all nucleated cells and in 93.2% of non-erythroid cells. Only a few blasts had Auer rods or azure granules. More than half of the blasts were positive for peroxidase staining. Thus, a diagnosis of AML without maturation (M1 phenotype according to the FrenchAmerican-British classification) was made. The blasts were Severe Hemorrhage from Gastric Vascular Ectasia Developed in a Patient with AML

De novo CD5-Positive Diffuse Large B Cell Lymphoma Solely Presenting as Multiple Subcutaneous Nodules

Lymphomas may involve the subcutaneous tissue as a manifestation of generalized disease. However, they rarely present with multiple involvement of the subcutaneous fat tissue without other sites of the disease. We describe a patient with CD5+ diffuse large B cell lymphoma (DLBL) that was confined to the subcutaneous tissue. A 74-year-old woman with rheumatoid arthritis was admitted because of multiple subcutaneous nodules. The patient had not been treated with cytotoxic drugs or methotrexate. The biopsied specimen disclosed diffuse infiltration of large cells with a starry sky-like appearance. The cells were positive for CD5, CD19, CD20, CD25, IgM, λ-chain, and negative for CD10, CD23 or cyclin D1. Thus a diagnosis of CD5+ DLBL was made. The patient was treated with a modified CHOP protocol and complete remission was achieved.