IMSUT Hospital Department of Advanced Medical Science 先端診療部

201 IMSUT Hospital Department of Advanced Medical Science 先端診療部 Professor Naohide Yamashita, M.D., Ph.D. 教授医学博士山下直秀 Associate Professor Naoya Kato. M.D., Ph.D. 准教授（併任）医学博士加藤直也 Lecturer Yasuro Matsubara, M.D., Ph.D. 講師（併任）医学博士松原康朗 Clinical Associate Naoyuki Iso-O M.D., Ph.D. 病院講師（併任）医学博士磯尾直之 Clinical Associate Hideki Ohno M.D., Ph.D. 助教医学博士大野秀樹 Clinical Associate Atai Watanabe M.D., Ph.D. 助教医学博士渡邉直 Department of Advanced Medical Science was established in September 1997. Our aim is to contribute to the performance and the development of advanced therapeutic approach to the diseases. We have been participating in the potentially important clinical trials and the several projects in line with our principles. Our research projects are (1) Antigen-specific induction of allogeneic umbilical cord or peripheral blood-derived cytotoxic T lymphocytes, (2) Analysis of the effect of Heli- cobacter pylori eradication on non-ulcer patients, (3) Treatment of drug-resistant H. pylori infection, (4) Effect of H. pylori eradication on the expression of microR- NAs in gastric mucosa, (5) Analysis of the role of leptin in hematological malignancies and parallel study on using umbilical cord blood-derived cytotoxic T lymphocytes as therapeutic strategy for hematological disorders, (6) Early diagnosis of cardiotoxicity in chemotherapy-treated patients, (7) Analysis of the potential therapeutic advantages of cell lysate from human placenta in promoting impaired cutaneous wound healing, and (8) application of 5-aminolevulinic acid for cancer therapy 1. Induction of tumor antigen-specific cytotoxic 2. Analysis of the effect of Helicobacter pylori T lymphocytes from allogeneic umbilical cord eradication on non-ulcer patients blood or peripheral blood Ohno H. et al. Fujita S. et al. Recent reports showed that eradication of H. py- We are pursuing the possibility of using adoptive lori has prophylactic effect on the development of transfer of cytotoxic T lymphocytes (CTLs) as a gastric cancer. The guideline of the Japanese Society treatment for solid tumors. Using cryopreserved for Helicobacter Research strongly recommended umbilical cord blood or peripheral blood as the the eradication therapy for all H. pylori-positive pa- source of lymphocytes, we were able to induce the tients including non-ulcer patients. Therefore, we expansion of CTLs using combination of certain T set up outpatient clinic for the eradication therapy cell growth factors and tumor antigen-specific to prevent H. pylori associated disease such as gas- stimulation. Currently we are developing a more tric cancer. But it is unclear that H. pylori eradica- efficient protocol to induce HLA-restricted tumor tion therapy can improve gastrointestinal symp- antigen-specific CTL using modified bead-based ar- toms of non-ulcer patients. We are investigating the tificial antigen presenting cell (aAPC) system. long-term effects of H. pylori eradication on non-ul- 202 cer patients. 6. Early diagnosis of cardiotoxicity in chemotherapy-treated patients. 3. Treatment of drug-resistant H. pylori infection Watanabe A. et al. Matsubara Y., Ohno H. et al. Cardiotoxicity due to chemotherapy may occur The number of patients who failed to respond acutely or even several years after completion of first- and second-line H. pylori eradication therapy the treatment for cancer. Since cancer patients sur- is gradually increasing because of drug resistance vive longer than the past due to the advances of in Japan. However, there is currently no standard anti-cancer drugs, cardiotoxicity associated with third-line eradication therapy. We are investigating chemotherapeutic regimens such as anthracyclines various third-line regimens to establish effective H. becomes a more significant issue in these days. pylori eradication therapy. Once chemotherapy-induced cardiotoxicity is established, its recognition is easy. However, methods 4. Effect of H. pylori eradication on the expres- for detection of potentially high risk patients with sion of microRNAs in gastric mucosa normal cardiac function have not been established yet. The objective of this study is to determine Ohno H. et al. whether echocardiographic measurements of myo- cardial deformation induced by increased preload, H. pylori infection is a significant risk factor for i.e. stress echocardiography, could predict the de- gastric cancer. Recent study reported the prophylac- velopment of chemotherapy-induced cardiotoxicity tic effect of H. pylori eradication on the develop- in patients with hematologic malignancy. ment of metachronous gastric cancer after endo- scopic resection. However, the development of gas- 7. Analysis of the potential therapeutic advan- tric cancer after successful eradication of H. pylori tages of cell lysate from human placenta in has been reported in some cases and the mecha- promoting impaired cutaneous wound healing nism of it remains unclear. To elucidate the mecha- nism, we are investigating changes of expression Zhang X. et al level of genes such as microRNAs in gastric mucosa after H. pylori eradication therapy. One of the major factors responsible for the ap- pearance of chronic wounds is the impairment of 5. Understanding the pathophysiology of leptin cytokine released by local fibroblasts and inflamma- in hematological malignancies and explora- tory cells, which can result in reduced angiogenesis. tion of therapeutic alternatives for hemato- A high level amount of VEGF secreted by human logical malignancies using umbilical cord placenta-derived cell was discovered in our previ- blood-derived cytotoxic T lymphocytes. ous study. Currently, we are examining therapeutic effects of the cell lysate from placenta on excisional Lam Q.L.K. et al. skin wound healing. The objective of this study is to determine whether we can use the cell lysate for The objective of our research is to study the role treatment of non-healing chronic wounds in clinic. of leptin in the survival and activity of multiple We are trying to determine cytokines included in myeloma with consideration of the bone marrow the cell lysate. By applying the cell lysate in vitro microenvironment. We will analyze how leptin acts and in vivo, we examined its effects on the prolif- directly on myeloma cell growth, and explore alter- eration and migration of various type cells; and its native mechanisms of its potential action through effects on enhancing of cutaneous wound healing in acting on the bone marrow stroma. In parallel stud- mice skin excisional wound model. ies, we actively explored therapeutic alternatives for hematological malignancies using available re- 8. An application of 5-aminolevulinic acid for sources in our laboratory including cryopreserved cancer therapy umbilical cord blood. We have successfully devel- oped methods to isolate and expand cytotoxic T Kimura Y. et al. lymphocytes from either cryopreserved or fresh umbilical cord blood, and we have been testing the 5-aminolevulinic acid (ALA) is a heme precursor feasibility of different strategies to derive tumor- andcommoninthehumanbody.Onceabsorbed specific cytotoxic T lymphocytes. Future success of and converted by the heme biosynthetic pathway, our study will potentially be novel addition to the 5-ALA becomes photoactive PpIX (protoporphyrin existing cancer therapies. IX), which accumulates preferentially in tumors cells and can be detected by light exposure. Thus, we hypothesize that PpIX accumulation could be 203 enhanced by adding exogenous 5-ALA so that tu- nuclear cells (PBMCs) in the presence of PpIX. Cur- mors or circulating tumor cells (CTCs) are detected rently, we are planning a clinical study to detect among normal cells by a photodetector such as CTCs in the PBMCs of patients with cancer. For the fluorescence activated cell sorting (FACS). In addi- latter propose, we have established the ex vivo DC tion, the detected and recovered tumor cells could culture and have confirmed that the resulting DCs be used as tumor associated antigen for cancer vac- are functional in terms of inducing antigen specific cine, including peptide and dendritic cell (DC) can- cytotoxic T cells (CTLs). Nest, we will test whether cervaccines.Fortheformerpurpose,wehavees- DCs are able to induce CTC-specific immune reac- tablished the experimental conditions where CTCs tions in humans using CTC-derived tumor anti- are detected within human peripheral blood mono- gens. Publications Narumoto O1, Niikura Y, Ishii S, Morihara H, Oka- K, Kawaoka Y. Differences in cytokine produc- shiro S, Nakahari T, Nakano T, Matsumura H, tion in human macrophages and in virulence in Shimamoto C, Moriwaki Y, Misawa H, Yamashi- mice are attributable to the acidic polymerase ta N, Nagase T, Kawashima K, Yamashita N. Ef- protein of highly pathogenic influenza A virus fect of secreted lymphocyte antigen-6/urokinase- subtype H5N1. J Infect Diseas. 207: 262-71, 2013 type plasminogen activator receptor-related pep- Mashima H, Ohno H, Yamada Y, Sakai T, Ohnishi tide-1 (SLURP-1) on airway epithelial cells. Bio- H. INSL5 may be a unique marker of colorectal chem Biophys Res Commun. 438: 175-9, 2013 endocrine cells and neuroendocrine tumors. Bio- Sakabe S, Takano R, Nagamura-Inoue T, Yamashita chem Biophys Res Commun. 432: 586-92, 2013 N, Nidom CA, Quynh Le MT, Iwatsuki-Horimoto 204 IMSUT Hospital Department of Medicine (Department of Hematology/Oncology) 内科（血液腫瘍内科） Professor Arinobu Tojo, M.D., D.M.Sc. 教授医学博士東條有伸 Associate Professor Satoshi Takahashi, M.D., D.M.Sc. 准教授医学博士高橋聡 Associate Professor Kaoru Uchimaru, M.D., D.M.Sc. 准教授医学博士内丸薫 Assistant Professor Koichiro Yuji M.D., D.M.Sc. 助教医学博士湯地晃一郎 Assistant Professor Nobuhiro Ohno, M.D. 助教大野伸広 Assistant Professor SeikoKatoM.D.,D.M.Sc. 助教医学博士加藤せい子 Assistant Professor Takaaki Konuma M.D., D.M.Sc. 助教医学博士小沼貴晶 Assistant Professor Muneyosi Futami M.D., D.M.Sc. 助教医学博士二見宗孔 Assistant Professor Seiichiro Kobayashi M.D., D.M.Sc. 助教医学博士小林誠一郎 We have been challenging to cure intractable hematological disorders such as leukemia and lymphoma mainly with the aid of hematopoietic stem cell transplan- tation (HSCT).

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