Department of Advanced Medical Science was established in September 1997.Our aim is to contribute to the performance and the development of advancedtherapeutic approach to the diseases. We have been participating in the poten-tially important clinical trials and the several projects in line with our principles.Our research projects were (1) Adaptive transfer of allogeneic umbilical cord blood-derived cytotoxic lymphocytes, (2) Analysis of the gradient expression of genes inhuman colonic mucosa, (3) Analysis of the effect of Helicobacter pylori eradicationon non-ulcer patients, (4) Effect of H. pylori eradication on the expression of mi-croRNAs in gastric mucosa, (5) Analysis of the role of Dnm3os, a non-codingRNA in skeletal development, (6) Analysis on the mechanisms of cardiac outflowtract development and (7) Analysis of the role of leptin in the pathophysiology ofmultiple myeloma.

1. Adoptive transfer of allogeneic umbilicalcord blood-derived cytotoxic lymphocytes

Fujita S., et al.

We have been making a continuous effort oninvestigating the possibility of adoptive transferof allogeneic umbilical cord blood-derived cyto-toxic T lymphocytes (CTLs) for the treatment ofhematological malignancies and solid tumors.Using cryopreserved or fresh umbilical cordblood as the source of lymphocytes, certaincombination of T cell growth factors andantigen-specific stimulation were found to beable to induce massive expansion of CTLs. Fur-ther analysis of HLA-restricted tetramers withflow cytometry revealed the functional matura-tion of ex vivo expanded CTLs. Currently weare in the process of establishing an efficientprotocol on antigen-specific CTL induction in

light of acquiring an international patent at theUniversity of Tokyo for future clinical use.

2. Analysis of the gradient expression ofgenes in human colonic mucosa

Ohno H et al.

Ulcerative colitis is characterized by continu-ous inflammation extending from rectum to oralcolonic mucosa. We speculate that the gradientexpression of genes in human colonic mucosamight be related to the disease development andprogression. We evaluated the expression levelsof genes throughout the GI tract and in othertissues by micro array and northern blot analy-sis. As a result of these analyses, some genesshowed the expression gradient to increase to-ward the distal colon. We are currently investi-gating the expression changes of these genes in

IMSUT Hospital

Department of Advanced Medical Science先端診療部

Professor Naohide Yamashita, M.D., Ph.D.Lecturer Takashi Nakaoka, M.D., Ph.D.Project Lecturer Hitomi Nagayama, M.D., D.M.Sc.Clinical Associate Hideki Ohno M.D., Ph.D.Clinical Associate Naoyuki Iso-O M.D., Ph.D.

教 授 医学博士 山 下 直 秀講 師 医学博士 中 岡 隆 志特任講師 医学博士 長 山 人 三助 教 医学博士 大 野 秀 樹助教（併任） 医学博士 磯 尾 直 之

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human intestinal diseases.

3. Analysis of the effect of Helicobacter py-lori eradication on non-ulcer patients

Ohno H et al.

Recent reports showed that eradication of H.pylori has prophylactic effect on the develop-ment of gastric cancer. The guideline of theJapanese Society for Helicobacter Researchstrongly recommended the eradication therapyfor all H. pylori-positive patients including non-ulcer patients. Therefore, we set up outpatientclinic for the eradication therapy to prevent H.pylori associated disease such as gastric cancer.But it is unclear that H. pylori eradication ther-apy can improve gastrointestinal symptoms ofnon-ulcer patients. We are investigating thelong-term effects of H. pylori eradication on non-ulcer patients.

4. Effect of H. pylori eradication on the ex-pression of microRNAs in gastric mucosa

Ohno H et al.

H. pylori infection is a significant risk factorfor gastric cancer. Recent study reported theprophylactic effect of H. pylori eradication onthe development of metachronous gastric cancerafter endoscopic resection. However, the devel-opment of gastric cancer after successful eradi-cation of H. pylori has been reported in somecases and the mechanism of it remains unclear.To elucidate the mechanism, we are investigat-ing changes of expression level of genes such asmicroRNAs in gastric mucosa after H. pylorieradication therapy.

5. Analysis of the role of Dnm3os, a non-coding RNA in skeletal development

Nakaoka T. et al.

Dnm3os, a non-coding RNA, contains threemicro RNAs; miR-199a, miR-199a＊ and miR-214,whose functions remain entirely unknown inmammals. We generated Dnm3os knock-out(KO) mouse in collaboration with Department ofPhysiological Chemistry and Metabolism, Divi-sion of Biochemistry and Molecular Biology,University of Tokyo. Dnm3os KO mice exhibitedseveral skeletal abnormalities, including cranio-facial hypoplasia, defects in dorsal neuralarches, and osteopenia. Importantly, the expres-sion of miR-199a, miR-199a＊, and miR-214 wassignificantly down-regulated in Dnm3os KO em-bryos, supporting the assumption that Dnm3os

serves as a precursor of these three miRNAs.Now, we are investigating the molecular mecha-nisms responsible for the skeletal abnormalitiesobserved in Dnm3os KO mice.

6. Analysis on the mechanisms of cardiacoutflow tract development

Nakaoka T. et al.

Malformations of the cardiovascular system inthe human account for most of the prematuredeaths caused by congenital abnormalities and,most often, are linked to abnormalities in theformation of the cardiac outflow tract. The heartdefect (hdf) mouse is a recessive lethal mutationthat arose from a LacZ reporter containing atransgene insertional mutation. The most strik-ing feature of the hdf homozygous embryo isthe immature formation of the outflow tract. Weare analyzing the second heart field and theneural crest cells, which actively contribute tothe formation of the cardiac outflow tract in hdfmouse embryos.

7. Analysis of the role of leptin in the patho-physiology of multiple myeloma

Lam Q.L.K. et al.

Leptin, originally discovered as an endocrinehormone, has recently been identified as an im-portant cytokine in modulating the immunefunction. Leptin shares high structural similarityto IL-6, while leptin receptor is related to thegp-130 signal-transducing subunit of the IL-6-type cytokine receptors. Our recent reportshowed that leptin promotes survival of periph-eral B cells via the induction of Blc-2 and CyclinD1 gene expression, and activates STAT3, Aktand NF-kappaB pathways in B cells, supportinga specific role for leptin in B cell physicology(Lam et al., PNAS 107: 13812, 2010). Further-more, myeloma cells were recently found to ex-press leptin and the leptin receptor, suggesting apossible oncogenic role of leptin in malignantplasma cell development. This evidence alto-gether pointed us to analyze the potential roleof leptin in the survival and activity of myelomacells, and how it might regulate the bone mar-row environment. The anticipated results willfacilitate a better understanding on leptin’s rolein multiple myeloma pathophysiology.

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Publications

Matsumoto K, Nagamura F, Ogami Y,Yamashita N, Kamibeppu K. (2011) Difficul-ties of Nursing Staff Involved in Phase 1 On-cology Trials in Japan. Cancer Nursing. 34:369-75.

Sakabe S, Iwatsuki-Horimoto K, Takano R, Ni-dom CA, Le MQ, Nagamura-Inoue T, Hori-moto T, Yamashita N, Kawaoka Y. (2011) Cy-tokine production by primary human macro-phages infected with highly pathogenic H5N1or pandemic H1N1 2009 influenza viruses. JGen Virol. 92: 1428-34.

Takahashi N, Nakaoka T, Yamashita N. (2012)Profiling of immune-related microRNA ex-pression in human cord blood and adult pe-ripheral blood cells upon proinflammatorystimulation. Eur J Haematol.（印刷中）.

Kawakami M, Narumoto O, Matsuo Y,Horiguchi K, Horiguchi S, Yamashita N, Sak-aguchi M, Lipp M, Nagase T, Yamashita N.(2012) The role of CCR7 in allergic airway in-flammation induced by house dust mite expo-sure. Cell Immunol（印刷中）.

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We have been challenging to cure intractable hematological disorders such as leu-kemia and lymphoma mainly with the aid of hematopoietic stem cell transplanta-tion (HSCT). No less than 30 patients per year receive allogeneic HSCT in our fa-cilities. In recent years, unrelated cord blood has been our major stem cell sourcefor recipients who have no suitable family donors in HSCT. Since 1998 we haveperformed over 350 cases of cord blood transplantation (CBT) for adult patients,which appears a distinguished experience in the world. Recent advance in identifi-cation of signaling molecules activated in a tumor-specific manner or associatedwith tumor-specific genomic recombination have disclosed many candidate thera-peutic targets in tumors. In the field of hematological malignancies, we have al-ready experienced remarkable clinical efficacies of novel therapeutic agents includ-ing tyrosine kinase inhibitors for Philadelphia-chromosome positive leukemias, RI-conjugated or non-conjugated anti-CD20 monoclonal antibodies for B cell lym-phoma and a proteasome inhibitor for multiple myeloma. We extensively applythese molecular targeted therapies for in- and out-patients. Furthermore, in recentyears, our department has been a hub facility in the greater Tokyo area for treat-ing patients with intractable adult T-cell leukemia/lymphoma.

1. Unrelated cord blood transplantation aftermyeloablative conditioning in adults withadvanced myelodysplastic syndromes.

Sato A, Ooi J, Takahashi S, Tsukada N, KatoS, Kawakita T, Tojo A

We analyzed the disease-specific outcomes ofadult patients with advanced myelodysplasticsyndrome (MDS) treated with cord blood trans-plantation (CBT) after myeloablative condition-ing. Between August 1998 and June 2009, 33adult patients with advanced MDS were treatedwith unrelated CBT. The diagnoses at transplan-

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.Associate Professor Satoshi Takahashi, M.D., D.M.Sc.Associate Professor Kaoru Uchimaru, M.D., D.M.Sc.Clinical Associate Jun Ooi, M.D.Clinical Associate Koichiro Yuji M.D., D.M.Sc.Clinical Associate Nobuhiro Ohno, M.D.Clinical Associate Seiko Kato M.D., D.M.Sc.Clinical Associate Muneyosi Futami M.D., D.M.Sc.Clinical Associate Seiichiro Kobayashi M.D., D.M.Sc.Project Research Associate Toshiro Kawakita, M.D.

教 授 医学博士 東 條 有 伸准教授 医学博士 高 橋 聡准教授 医学博士 内 丸 薫助 教 大 井 淳助 教 医学博士 湯 地 晃一郎助 教 大 野 伸 広助 教 医学博士 加 藤 せい子助 教 医学博士 二 見 宗 孔助 教 医学博士 小 林 誠一郎特任助教 河 北 敏 郎

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tation included refractory anemia with excessblasts (n＝7) and MDS-related secondary AML(sAML) (n＝26). All patients received four frac-tionated 12 Gy TBI and chemotherapy asmyeloablative conditioning. The median agewas 42 years, the median weight was 55 kg andthe median number of cryopreserved nucleatedcells was 2.51×107 cells per kg. The cumulativeincidence of neutrophil recovery at day 50 was91％. Neutrophil recovery was significantlyfaster in sAML patients (P＝0.04). The cumula-tive incidence of plt recovery at day 200 was 88％. Plt recovery was significantly faster in CMVseronegative patients (P＜0.001). The cumulativeincidence of grade II-IV acute GVHD (aGVHD)and extensive-type chronic GVHD was 67 and34％, respectively. Degree of HLA mismatchhad a significant impact on the incidence ofgrade II-IV aGVHD (P＝0.021). TRM and relapseat 5-years was 14 and 16％, respectively. Theprobability of EFS at 5 years was 70％. No fac-tor was associated with TRM, relapse and EFS.These results suggest that adult advanced MDSpatients without suitable related or unrelatedBM donors should be considered as candidatesfor CBT.

2. The impact of steroid use as a GVHD treat-ment or prophylaxis within 100 days afterCBT

Kawakita T, Tsukada N, Takahashi S, Ooi J,Kato S, Tojo A

The incidence of severe graft-versus-host dis-ease (GVHD) in cord blood transplantation(CBT) is generally low, but still exists. In our in-stitute, we use cyclosporine (CsA) and shortterm methotrexate (MTX) as GVHD prophylaxisand minimally use steroid to avoid infection orinfection-related complications. In this study, weretrospectively analyzed the clinical data to clar-ify the impact of steroid use to the outcome ofCBT. PATIENTS: We have performed 140 CBTafter myeloablative conditioning using CsA withshort term MTX as GVHD prophylaxis foradults at IMSUT between August 1998 and Oc-tober 2008. The median age was 39 (range, 16-55) years and the median number of cryopre-served nucleated CB cells was 2.38 (range, 1.21-5.69)×107/kg. Although 82 of 140 patients (59％) suffered from grade II-IV aGVHD, only 31％patients received steroid after CBT. Steroid wasused in 17 patients (12％) as a treatment formainly GVHD and the dosage of prednisolonein the treatment group were 2 mg/kg (n＝7), 1mg/kg (n＝8), and 0.5 mg/kg (n＝2). Twenty-six patients (19％) changed CsA to steroid be-cause of intolerability (20: renal dysfunction, 4:

encephalopathy, 2: others) and received 1 mg/kg (n＝4) or 0.5 mg/kg (n＝22) (alternativegroup). Overall survival in 5 years were 78％ inthe non-steroid use group, 71％ in the treatmentgroup, however 45％ in the patients with alter-native steroid use. The intolerability of CsAwithin 100 days after CBT seems to be a signifi-cant poor factor. We should modify the proce-dures including post-transplant immune modu-lation in such patients.

3. Aberrant CD3/CD7 expression in CD4＋ Tcells of HTLV-1 carriers

Kobayashi S, Ohno N, Tsuda M, Uchimaru K,Tojo A

In our recent study to purify adult T-cellleukemia-lymphoma (ATL) cells of acute-typepatients by flow cytometry, three subpopula-tions were observed in CD3 vs CD7 plot (P: CD3posiCD7posi, D: CD3dimCD7dim and N: CD3dimCD7neg).Majority of leukemia cells were enriched in theN subpopulation and the same clone was in-cluded in the D and N subpopulations, sugges-tive of clonal evolution. In this study we ana-lysed patients of indolent-type ATL and humanT-cell leukemia virus type I (HTLV-I) asympto-matic carrier (AC) to see whether the CD3 vsCD7 profile reflects progressive property ofHTLV-I infected cells. In D（％) vs N（％) plot,each patient data could be mainly categorizedinto three groups (Group 1: AC, Group 2:smoldering- and chronic-type ATL and Group 3:acute-type ATL). Intriguingly there were someexceptions (e.g. AC in Group 2). In follow-up ofsome patients, clinical disease progression corre-lated well with the CD3 vs CD7 profile. Furthermolecular (proviral load and clonality) and clini-cal data analyses lead us to propose that the CD3 vs CD7 plot reflects progression of diseasestage of HTLV-I infected patients. The CD3 vsCD7 profile will be a new indicator, along withhigh proviral load, for HTLV-I AC to forecastdisease progression. (manuscript in preparation)

4. Nation-wide survey of the management ofadult T-cell leukemia and HTLV-1 carrier

Uchimaru K

Adult T-cell leukemia (ATL) is endemic insouth-western Japan, especially in Kyushu andOkinawa islands, whereas it is considered as arare disease in the other areas of Japan. ATL isone of the most intractable hematological malig-nancies and various therapeutic approachescould be applicable. We performed nation-widesurvey for the management of ATL and HTLV-1

271

asymptomatic carrier to investigate whetherinter-district and/or inter-hospital difference ex-ists. We sent questionnaires to 1310 hematologyand dermatology departments in allover Japanand 462 replies were recovered (35.2％). Thera-peutic approach to ATL was significantly vari-able especially in acute/lymphoma, high-riskchronic type and smoldering type with skin le-sion. In Kyushu district, low dose chemothera-pies other than intensive chemotherapies wereintroduced to acute/lymphoma type ATL inmore than half of the hospitals whereas the pro-portion of those were only 29％ in the other ar-eas. Ninety-two percent and 74％ of low-risk

chronic ATL patients were followed withouttherapy in Kyushu and the other areas respec-tively. Hematopoietic stem cell transplantation(SCT) was considered to acute/lymphoma typeATL patients in almost all the hospitals but up-per limit of applicable age for SCT was signifi-cantly variable (range 45-75). These differencescould greatly affect therapies for ATL patients.Approximately 60％ of the hospitals regardedhigh-risk chronic ATL as applicable to SCT. Theapproach to high-risk chronic ATL is most vari-able in ATL subtypes. The results of the derma-tology departments will also be reported.

Publications

Kawamata T, Tojo A. Helicobacter pylori-induced thrombocytosis clinically indistin-guishable from essential thrombocythemia.Leuk. Lymphoma. 2012 Jan 31. [Epub aheadof print] PMID: 22204454

Yamagishi M, Nakano K, Miyake A, Yamochi T,Kagami Y, Tsutsumi A, Matsuda Y, Sato-Otsubo A, Muto S, Utsunomiya A, YamaguchiK, Uchimaru K, Ogawa S, Watanabe T.Polycomb-Mediated Loss of miR-31 ActivatesNIK-dependent NF-κB Pathway in Adult T-cell Leukemia and Other Cancers. Cancer Cell.21: 121-35, 2012

Ebihara Y, Takahashi S, Mochizuki S, Kato S,Kawakita T, Ooi J, Yokoyama K, Nagamura F,Tojo A, Asano S, Tsuji K. Unrelated cord

blood transplantation after myeloablative con-ditioning regimen in adolescent patients withhematologic malignancies: a single instituteanalysis. Leuk Res. 6: 128-31, 2012

Tsuda M, Ebihara Y, Mochizuki S, Uchimaru K,Tojo A, Tsuji K. Reduced dose chemotherapyfor acute promyelocytic leukemia with adultDown syndrome. Brit J Haematol. 15: 130-2,2011

Sato A, Ooi J, Takahashi S, Tsukada N, Kato S,Kawakita T, Yagyu T, Nagamura F, Iseki T,Tojo A, Asano S. Unrelated cord blood trans-plantation after myeloablative conditioning inadults with advanced myelodysplastic syn-dromes. Bone Marrow Transplant, 46: 257-61,2011

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Founded in 1981, Department of Infectious Diseases and Applied Immunology (DI-DAI) started HIV clinic in 1986. In 2011, 41 new patients with HIV infection havevisited or been admitted to our hospital and 517 patients in total are currently un-der our clinical management. The total number of in-patients with HIV-infectionduring 2011 was 46, and about 10 beds in our ward have been constantly occu-pied by patients with not only HIV-infection but also other infectious diseases.Since the number of the staff members of DIDAI is too small to care both outpa-tients and in-patients, members of the Division of Infectious Diseases and the De-partment of Infectious Disease Control join the clinic. IMSUT hospital provides themost up-to-date medical treatment to HIV-infected patients in Japan. DIDAI is alsoa treatment center for international infectious diseases such as malaria and ty-phoid fever.

1. Treatment of and clinical research on HIVinfection and related diseases.

a. Treatment of HIV infection in IMSUT hospi-tal: Statistical characteristics of HIV in-fected patients in IMSUT hospital this year

Takeshi, Fujii, Tomohiko Koibuchi, MichikoKoga1, Syoichi Shimizu, Kentaro Imai, EisukeAdachi, Michio Okame, Hidenori Sato, Toshi-yuki Miura1, Hitomi Nakamura1, TadashiKikuchi1, Takashi Odawara, and AikichiIwamoto1: 1Division of Infectious Diseases, TheAdvanced Clinical Research Center.

41 new patients with HIV-1 infection visitedour hospital this year (from January 1 to Decem-ber 31, 2011), and 517 patients in total are undermedical management in our outpatient clinic.The total number of HIV-infected inpatientsduring 2011 was 46. The number of total pa-tients declined in 1997 because a part of patientsas well as medical stuffs moved to newly estab-lished AIDS Clinical Center in InternationalMedical Center of Japan. However, the numberof patients started to increase again after 1998 inaccordance with Japanese statistics of HIV-infected patients (Fig. 1). Anti-retroviral therapy(ART) has been introduced to around 420 HIV-

IMSUT Hospital

Department of Infectious Diseases andApplied Immunology感染免疫内科

Head, Lecturer Takeshi Fujii, M.D. D.M.Sc.Professor Aikichi Iwamoto, M.D., D.M.Sc.Assistant Professor Tomohiko Koibuchi, M.D., D.M.Sc.Assistant Professor Michiko Koga, M.D., ph.D.

科長（講師） 医学博士 藤 井 毅教 授 医学博士 岩 本 愛 吉＊1

助 教 医学博士 鯉 渕 智 彦助 教 医学博士 古 賀 道 子＊1

【兼任】＊1Division of Infectious Diseases, The Advanced Clinical Research Center（先端医療研究センター感染症分野）

273

infected patients in our hospital, and most oftheir HIV viral loads have been well controlled.After one year of ART, the viral loads becomeless than 40 copies/ml in more than 90％ of pa-tients, and their CD4 cell counts increase by ap-proximately 200/µL in average. Consequently,the clinical management of HIV-infected pa-tients changed from how to treat opportunisticinfections into how to control patients withART.

2. Treatments and Clinical Research of Tropi-cal Diseases

a. Treatment of Tropical Diseases in IMSUThospital

Takeshi, Fujii, Tomohiko Koibuchi, MichikoKoga1, Syoichi Shimizu, Kentaro Imai, EisukeAdachi, Michio Okame, Hidenori Sato, Toshi-yuki Miura1, Hitomi Nakamura1, TadashiKikuchi1, Takashi Odawara, and AikichiIwamoto1: 1Division of Infectious Diseases, TheAdvanced Clinical Research Center.

Dozens of important medicines essential fortreatment of tropical or parasitic diseases are notlicensed in Japan. For instance, artesunate andinjectable quinine for falciparum malaria, in-jectable metronidazole for amebiasis,pyrimethamine and sulfadiazine for toxoplasmo-sis, etc. are not licensed. Research Group onChemotherapy of Tropical Diseases, Research onPublicly Essential Drugs and Medical Devices,Grant from the Ministry of Health, Labour andWelfare had been established to cope with thissituation. We are the central medical institutionof the research group importing and providingthese orphan drugs if needed, and colletingclinical data. This year, we imported and stored19 orphan drugs and distributed required ones

to 25 designated hospitals in all over Japan.Also we have clinics for overseas travelers. Thisyear, more than hundred of overseas travelersvisited our clinic. The reasons of their visit in-cluded prescription of malaria prophylaxis,hepatitis A/B vaccination, other general healthconsultation, or treatment of tropical diseasessuch as malaria, dengue, typhoid fever, amebia-sis, post-exposure prophylaxis of rabies and soon.

3. Creating Practice Guidelines for Treatmentof HIV-infected Patients in Japan

Tomohiko Koibuchi, Takeshi, Fujii, MichikoKoga1, Toshiyuki Miura1, Hitomi Nakamura1,Takashi Odawara, and Aikichi Iwamoto1: 1Di-vision of Infectious Diseases, The AdvancedClinical Research Center.

The Japanese guidelines for treatment of HIV-infected patients have been established since1998 with support from Ministry of Health, La-bor and Welfare. The representatives from ourdepartment have played critical roles in devel-opment of the current practice guidelines in Ja-pan. It is vital to create practice guidelines thatare specific for the unique genetic and socialbackgrounds of the HIV-infected population inJapan. In collaboration with other Japanese HIV-experts, the physicians from our department up-date the practice guidelines annually, as wedeem necessary. The guidelines are available athttp : / / www . haart-support . jp / guideline . htmand used widely by Japanese clinicians. In Ja-pan, where the number of HIV-experts are lim-ited compared to other countries, the practiceguidelines have substantially improved the stan-dard of care for the HIV-infected patients in ourcountry.

Figure 1. Number of HIV-infected outpatients in IMSUT Hospital

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4. Hepatitis B virus co-infection in HIV-infected Patients in IMSUT hospital

Tomohiko Koibuchi, Takeshi, Fujii, MichikoKoga1, Toshiyuki Miura1, Hitomi Nakamura1,Takashi Odawara, and Aikichi Iwamoto1: 1Di-vision of Infectious Diseases, The AdvancedClinical Research Center.

The rate of Hepatitis B virus (HBV) co-infection is higher in HIV-infected patients com-pared with that in the general population be-cause of common transmission routes. The per-centage of HBV surface antigen (HBsAg) posi-tive HIV-infected patients in IMSUT hospital isaround 5％. On the other hand, HBsAg positiverate in Japanese population is estimated 1.0％.HBV co-infection of HIV-infected patients accel-erates development of cirrhosis. Prevention ofHBV infection is therefore essential for HIV-infected patients. However, HIV-infected pa-tients respond poorly to HBV vaccination evenif the patients’ CD4 T-cell count is high. We re-cently reported the low response rates of HBVvaccination in HIV-infected Japanese patients;out of 12 patients received HBV vaccination atstandard schedule (0-, 1-, 6-month) in IMSUThospital, only one was a responder (HBsAb ≧10IU/L). Our data support that the strategy of im-proving the efficacy of HBV vaccination in HIV-infected patients is urgently needed.

5. Kinetics of serumβ-D-glucan after Pneumo-cystis pneumonia treatment in patientswith AIDS.

Michiko Koga1, Tomohiko Koibuchi, TadashiKikuchi1 , Hitomi Nakamura1 , ToshiyukiMiura1, Aikichi Iwamoto1 and Takeshi Fujii:1Division of Infectious Diseases, The AdvancedClinical Research Center.

The serum β-D-glucan has been demonstratedas a reliable, adjunct diagnostic marker for PCP,but its kinetics after PCP treatment is poorly un-derstood. To evaluate the correlation betweenthe levels of β-D-glucan and the clinical re-sponse, we investigate the individual transitionof the serum β-D-glucan levels after the initia-tion of PCP treatment. Seventeen PCP patientswith AIDS admitted in our hospital were ana-lyzed. All subjects showed the serum β-D-glucan levels above the cutoff value, and themedian level was 224 pg/ml〔IQR: 78-597〕at thetime of PCP diagnosis. There were no correla-tions between serum β-D-glucan levels and CRP,LDH, or AaDO2 at room air. Although therewas a downward trend of serum β-D-glucanlevel as PCP treatment was initiated, a signifi-

cant number of subjects experienced marked in-crease in the serum β-D-glucan levels despitetheir evident clinical improvement. Serum β-D-glucan level does not reflect the severity andprognosis of PCP infection, and they may not besuitable for monitoring response to treatment.

6. Long-term successful control of super-multi-drug resistant Human Immunodefi-ciency Virus type I infection by a novelcombination therapy of Raltegravir, Etravi-rine and boosted-Darunavir.

Hitomi Nakamura1, Naoko Miyazaki, NoriakiHosoya, Michiko Koga1, Takashi Odawara,Tadashi Kikuchi1, Tomohiko Koibuchi, AiKawana-Tachikawa1, Takeshi Fujii, ToshiyukiMiura1, Aikichi Iwamoto1: 1Division of Infec-tious Diseases, The Advanced Clinical ResearchCenter

Drug-resistant virus infection has been a ma-jor hurdle in the management of human immu-nodeficiency virus type 1 (HIV-1) infection. Re-cently, three novel antiretrovirals [raltegravir(RAL), etravirine (ETR), and darunavir (DRV)]were introduced into the market almost simulta-neously, and salvage regimens containing thesethree antiretrovirals have been reported to ex-hibit strong potency against drug-resistant HIV-1 infection. However, the sustainability of suchregimens remains unclear, particularly for pa-tients infected with multidrug-resistant viruses.Here we report a case of super-multidrug-resistant HIV-1 infection which has been suc-cessfully controlled by novel combination ther-apy including RAL, ETR, and DRV for over 2years, indicating that the novel combinationcould become an ultimate weapon against drug-resistant HIV infection and could alter the land-scape of HIV salvage therapy.

7. Cerebral schistosomiasis due to Schis-tosoma haematobium confirmed by PCRanalysis of the brain specimen.

Kentaro Imai, Tomohiko Koibuchi, TakashiKumagai2, Takuya Maeda3, Yoshio Osada4,Nobuo Ohta2, Michiko Koga1, Hitomi Naka-mura1, Toshiyuki Miura1, Aikichi Iwamoto1,and Takeshi Fujii: 1Division of Infectious Dis-eases, The Advanced Clinical Research Center,2Section of Environmental Parasitology, De-partment of International Health Development,Division of Public Health, Tokyo Medical andDental University, 3Department of InfectiousDiseases and Pulmonary Medicine, NationalDefense Medical College, 4Department of Im-munology and Parasitology, University of Oc-

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cupational and Environmental Health.

The case of a 25-year-old Japanese male whohad cerebral schistosomiasis by Schistosoma hae-matobium is reported here. Although serum anti-body tests showed cross-reaction with otherhelminths and no ova were excreted in urine orfeces, the existence of Schistosoma haematobium inthe brain was confirmed by PCR analysis.

8. A case of secondary syphilis presentingwith unusual complications: syphiliticproctitis, gastritis and hepatitis.

Eisuke Adachi, Tomohiko Koibuchi, MichioOkame, Hidenori Sato, Kentaro Imai, ShoichiShimizu, Giichiro Tsurita2, Naoki Oyaizu3,

Aikichi Iwamoto1 and Takeshi Fujii: 1Divisionof Infectious Diseases, The Advanced ClinicalResearch Center, 2Department of Surgery, Re-search Hospital of The Institute of Medical Sci-ence, 3Department of Laboratory Medicine, Re-search Hospital of The Institute of Medical Sci-ence

We report the first known case of syphiliswith simultaneous manifestations of proctitis,gastritis, and hepatitis. The diagnosis of syphi-litic proctitis and gastritis was established by thedemonstration of spirochetes with anti-Treponema pallidum antibody staining in bi-opsy specimens. Unusual manifestations of sec-ondary syphilis completely resolved after 4weeks of antibiotic therapy.

Publications

1. Nakamura H, Miyazaki N, Hosoya N, KogaM, Odawara T, Kikuchi T, Koibuchi T,Kawana-Tachikawa A, Fujii T, Miura T,Iwamoto A. Long-term successful control ofsuper-multidrug-resistant human immunode-ficiency virus type 1 infection by a novelcombination therapy of raltegravir, etravirine,and boosted-darunavir. J Infect Chemother.17: 105-10, 2011

2. Imai K, Koibuchi T, Kikuchi T, Koga M,Nakamura H, Miura T, Gonoi T, Yazawa K,Iwamoto A, and Fujii T, Pulmonary nocardio-sis caused by Nocardia exalbida complicatingPneumocystis pneumonia in a HIV-infectedpatient. J Infect Chemother. 17: 547-51, 2011

3. Koga M, Koibuchi T, Kikuchi T, NakamuraH, Miura T, Iwamoto A, Fujii T. Kinetics ofserum β-D-glucan after Pneumocystis pneu-monia treatment in patients with AIDS. In-tern Med. 50: 1397-401, 2011

4. Imai K, Koibuchi T, Kumagai T, Maeda T,Osada Y, Ohta N, Koga M, Nakamura H, Mi-ura T, Iwamoto A, Fujii T. Cerebral schistos-omiasis due to Schistosoma haematobiumconfirmed by PCR analysis of brain specimen.J Clin Microbiol. 49: 3703-6, 2011

5. Adachi E, Koibuchi T, Okame M, Sato H,Imai K, Shimizu S, Tsurita G, Oyaizu N,Iwamoto A, Fujii T. Case of secondary syphi-lis presenting with unusual complications:syphilitic proctitis, gastritis, and hepatitis. JClin Microbiol. 49: 4394-6, 2011

6. Takuya Maeda, Akira Ito, Yasuhito Sako,Hiroshi Yamasaki, Naoki Oyaizu, TakashiOdawara, Aikichi Iwamoto, Takeshi Fujii.Neurocysticercosis case with tuberculoma-likeepithelioid granuloma strongly suspected byserology and confirmed by mitochondrialDNA. BMJ Case Reports 2011; doi: 10.1136 /bcr.04.2011.4125

7. Iwatsuki-Horimoto K, Horimoto T, TamuraD, Kiso M, Kawakami E, Hatakeyama S, Ebi-hara Y, Koibuchi T, Fujii T, Takahashi K,Shimojima M, Sakai-Tagawa Y, Ito M, SakabeS, Iwasa A, Takahashi K, Ishii T, Gorai T,Tsuji K, Iwamoto A, Kawaoka Y. Seropreva-lence of pandemic 2009 (H1N1) influenza Avirus among schoolchildren and their parentsin Tokyo, Japan. Clin Vaccine Immunol. 18:860-6, 2011

8. Nakayama K, Nakamura H, Koga M,Koibuchi T, Fujii T, Miura T, Iwamoto A,Kawana-Tachikawa A. Imbalanced Produc-tion of Cytokines by T Cells Associates withthe Activation/Exhaustion Status of MemoryT Cells in Chronic HIV Type 1 Infection.AIDS Res Hum Retroviruses. 2011 in press

9. Fujisaki S, Yokomaku Y, Shiino T, KoibuchiT, Hattori J, Ibe S, Iwatani Y, Iwamoto A,Shirasaka T, Hamaguchi M, Sugiura W. Out-break of infections by hepatitis B virus geno-type A and transmission of genetic drug re-sistance in patients coinfected with HIV-1 inJapan. J Clin Microbiol. 49: 1017-24, 2011

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Our major goal is to cure children suffering from a variety of life-threatening hema-tological disorders. Attempting to achieve it, we continue the commitment to treat-ment and follow-up care of such children, and to clinical and laboratory researchthat ultimately will help us devise better therapeutic approaches to the diseases.Currently efforts are directed toward treatment of acute leukemia in adolescenceand young adults, establishment of novel therapies using hematopoietic or mesen-chymal stem cells (HSC or MSC, respectively), and analysis of pathogenesis ofhematopoietic disorders, especially pediatric myelodysplastic sundrome (MDS).

1. Hematopoietic stem cell transplantation forchildren with high-risk leukemia

Yasuhiro Ebihara, Shinji Mochizuki1, ShoheiYamamoto, Kohichiro Tsuji: 1Division of StemCell Processing, Center for Stem Cell Biologyand Regenerative Medicine

Although a standard regimen in hematopoeticstem cell transplatation (HSCT) has been avail-able for children with acute lymphoblastic leu-kemia (ALL) and acute myeloid leukemia(AML), it has not been standardized for thosewith rare diseases including congenital bonemarrow failure syndrome (CBMFS) and naturalkiller (NK) cell leukemia. A multi-institutionaltrial using regimens with a rationale should beproposed in a prospective manner. For CBMFS,we conducted in vitro and in vivo assays to as-sess the sensitivity of granulocyte colony-stimulating factor (G-CSF), and transplanted thepatients whose leukemic cells had a high sensi-tivity to G-CSF using a regime including G-CSF.Thus, we could avoid intensive chemotherapybefore HSCT for patients with a vulnerable nor-mal bone marrow reserve. For patients withFanconi anemia, in particular, we employed a

regimen containing fludarabine to reduce thedose of alkylating agents and irradiation toavoid the toxicity, which was otherwise likely tooccur in those patients. For patients with NKcell disease, we used a regimen combining al-kylating agents (cyclophosphamide andthiotepa) and total body irradiation based on theresults that NK leukemic cells strongly ex-pressed multidrug-registant genes. Now weplan to extend our experience in nationwide col-laborative studies.

2. Cooperative clinical trial for pediatric myel-odysplastic syndrome

Kohichiro Tsuji, Yasuhiro Ebihara, ShinjiMochizuki1, Shohei Yamamoto, Atsushi Ma-nabe2, Yuji Zaike3: 2St. Luke’s InternationalHospital, 3Department of Laboratory Medicine,Research Hospital

Pediatric MDS is a rare disease, and only 50-100 children under the age of 16 suffer from thedisease annually. The diagnosis and treatmenthave not been standardized and it should be de-termined in a nationwide manner. On behalf ofthe MDS committee of the Japanese Society of

IMSUT Hospital

Department of Pediatric Hematology-Oncology小児細胞移植科

Associate Professor Kohichiro TsujiClinical Associate Yasuhiro Ebihara

准教授 医学博士 � 浩一郎助 教 医学博士 海老原 康 博

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Pediatric Hematology, we began the pathologiccentral review in 1999 and reviewed all samplesof patients suspected of having MDS. At pre-sent, over 300 patients have been enrolled, andstandard diagnostic criteria have been proposedfor juvenile myelomonocytic leukemia (JMML),a subset of MDS. We also tested in vitro cellgrowth for patients with JMML using diagnosticsamples. The results showed that spontaneousgrowth and hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF)were observed in most children with JMML. Weproposed a cooperative trial to establish thetreatment for MDS (MDS99) and have enrolledover 100 patients from the whole country.

3. Novel approach to therapy in juvenilemyelomonocytic leukemia

Yasuhiro Ebihara, Shinji Mochizuki1, ShoheiYamamoto, Yoshitoshi Ohtsuka4, Atsushi Ma-nabe2, Yuji Zaike3, Kohichiro Tsuji: 3Depart-ment of Pediatrics, Hyogo College of Medici

JMML is a clonal myeloproliferative/myelo-dysplastic disorder of early childhood with poorprognosis. JMML cells are characterized by hy-persensitivity to GM-CSF caused by continu-ously activated GM-CSF receptor-RAS signaltransduction pathway through various molecu-lar mechanisms, resulting in spontaneous colonyformation in vitro. Bisphosphonate zoledronicacid (ZOL), a RAS-blocking compound, sup-pressed colony formation from bone marrow(BM) cells of JMML patients and normal volun-teers without and with GM-CSF, respectively, ina dose-dependent manner in clonal culture. At10 µM of ZOL, however, spontaneous colonyformation decreased, but formation of granulo-cyte (G) colonies containing only granulocytes,but no macrophages was enhanced in culture ofJMML BM cells, while granulocyte-macrophage(GM) colonies containing both granulocytes andmacrophages retained and G colony formationwas not affected in culture of normal BM cellswith GM-CSF. In suspension culture, 10 µM ofZOL also inhibited spontaneous proliferationand differentiation along monocyte/macrophagelineage of JMML BM cells, but not developmentof normal BM cells by GM-CSF assessed in cyto-chemical and flow cytometric analyses. The in-hibitory effect of ZOL on JMML cells was con-firmed at a single-clone level, and observedeven at 3 µM. The current result offers a novelapproach to therapy in JMML.

4. Establishment of therapy for acute leuke-mia in adolescence and young adults

Yasuhiro Ebihara, Shinji Mochizuki1, ShoheiYamamoto, Satoshi Takahashi5, Arinobu Tojo5,Kohichiro Tsuji: 5Division of Molecular Ther-apy, Advanced Clinical Research Center

In many area of medicine adolescents andyoung adults are regarded as a discrete groupwith specific therapeutic, psychological, educa-tional, and resource needs. In acute leukemiaage is a predictor of response. Thus, in ALLthere is a clearly poorer treatment outcome afterpuberty, while in AML, which is more commonin older adults, age is a continuous variablewith poorer outcomes in each successive decade.Much is known about other prognostic factorsand their relative incidence in each age stratum.Although there is some segregation of favorablefactors with relative youth, age usually remainsan independent factor with respect to prognosis.So far, adolescents and young adults are in-cluded in pediatric or adult-oriented treatmentprotocols, but it has been controversial whichprotocol is superior to acute leukemia in adoles-cence and young adults. We are now searchingthe most suitable therapy for them.

5. Unrelated cord blood transplantation aftermyeloablative conditioning regimen inadolescent and young adult patients withhematologic malignancies

Yasuhiro Ebihara, Shinji Mochizuki1, ShoheiYamamoto, Seiko Kato5, Toshiro Kawakita6,Jun Ooi7, Kazuaki Yokoyama5, Fumitaka Na-gamura8, Satoshi Takahashi5,, Arinobu Tojo5,,Kohichiro Tsuji: 6Division of Stem Cell Trans-plantation, Center for Stem Cell Biology andRegenerative Medicine 7Department of Hema-tology/ Oncology, Research Hospital, 8Depart-ment of Clinical Trial Safety Management, Re-search Hospital

As mentioned above, adolescents and youngadults with hematologic malignancies are dis-tinct in terms of their therapeutic requirementscompared to adults or children. However, therehave been no data defining adolescent andyoung adult patients for cord blood transplanta-tion (CBT) after conventional myeloablative con-ditioning regimen. We then reported the resultsof unrelated CBT after myeloablative condition-ing regimen in patients with hematologic malig-nancies from 15 to 20 years old. The mediantimes of myeloid and platelet engraftment were21 and 38 days, respectively. The cumulative in-cidences of acute graft-versus-host disease(GVHD) was 62.0％, all of which were grade Ior II, and that of extensive-type chronic GVHDwas 12.5％. The probabilities of overall and

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disease-free survival at 3 years were 68.2％ and48.6％, respectively, comparable to adult orchildhood cases. Therefore, adolescents andyoung adult patients with hematologic malig-nancies who have no human leukocyte antigen(HLA)-matched adult donors could be consid-ered as candidates for CBT.

6. Establishment of human BM-derived MSCfor the treatment of hemophilic arthropa-thy

Yasuhiro Ebihara, Shinji Mochizuki1, ShoheiYamamoto , Hideyuki Takedani8 , TokikoNagamura-Inoue9, Shigeyuki Wakitani10, Ari-nobu Tojo5, Hiromitsu Nakauchi11, KohichiroTsuji: 8Department of Joint Surgery, ResearchHospital, 9Department of Cell Processing andTransfusion, Research Hospital, 10Departmentof Orthopedic Surgery, Osaka City UniversityGraduate School of Medicine, 11DivisioDevisionof Stem Cell Therapy, Center for Stem CellTherapy and Regenerative Medicine

Hemophilia is a congenital disease with a lackof coagulation factors. Arthropathy is a majorcause of morbidity in the patients with hemo-philia. Approximately one third of the patientsneed the mobility assistance. Although thepathogenesis of hemophilic arthropathy (HA)still have not been precisely clarified, the de-struction of articular cartilage is the most promi-nent event in HA. Most surgical treatments forHA, such as synovectomy or total joint arthro-plasty, in Japan is performed by Department ofJoint Surgery in our hospital. So far, however,the efficacy of the treatment has been insuffi-cient. Recently it has been shown that BM con-tains MSC, which can differentiate into variousmesenchymal tissue cells, osteocytes, adipocytesand chondrocytes. Although the mechanism bywhich MSC are committed to differentiate intoeach mesenchymal tissue, the environment sur-rounding MSC plays an important role in thecommitment. We are then preparing for theclinical trial of the transplantation of autologousculture-expanded BM-derived MSC into the ar-ticular cartilage defect in the HA patients.

Publications

Tsuda, M., Ebihara, Y., Mochizuki, S., Uchimaru,K., Tojo, A. and Tsuji, K. Reduced dose che-motherapy for acute promyelocytic leukemiawith adult Down syndrome. Br. J. Haematol.155: 130-132, 2011.

Iwatsuki-Horimoto, K., Horimoto, T., Tamura,D., Kiso, M., Kawakami, E., Hatakeyama, S.,Ebihara, Y., Koibuchi, T., Fujii, T., Takahashi,K., Shimojima, M., Sakai-Tagawa, Y., Ito, M.,Sakabe, S., Iwasa, A., Takahashi, K., Ishii, T.,Gorai, T., Tsuji, K., Iwamoto, A. andKawaoka, Y. Sero-prevalence of pandemic(H1N1) 2009 influenza A virus among school-children and their parents in Tokyo, Japan.Clin. Vaccine Immunol. 18: 860-866, 2011.

Ma, F., Yang, W. and Tsuji, K. Regenerativemedicine based on human ES and iPS cells. InStem Cells in Medicine. Edited by Isobe. K.(Transworld Research Network, Kerala). pp51-70, 2011.

Ma, F., Yang, W., Ebihara, Y. and Tsuji, K. Gen-eration of blood cells from human embryonicstem cells and their possible clinical utiliza-tion. In Embryonic Stem Cells. Edited by At-wood, C. (Intech, Vienna), pp 239-250, 2011.

Kato, M., Koh, K., Kikuchi, A., Toyama, D.,Mochizuki, S., Uchisaka, N., Nagatoshi, Y.,Tanaka, R., Oh-Ishi, T., Nozawa, K., Oguma,

E. and Hanada, R. Case series of pediatricacute leukemia without a peripheral blood ab-normality, detected by magnetic resonanceimaging. Int. J. Hematol. 93: 787-790, 2011.

Yamamoto, S., Ikeda, H., Toyama, D., Hayashi,M., Akiyama, K., Suzuki, M., Tanaka, Y.,Watanabe, T., Fujimoto, Y., Hosaki, Y., Nishi-hira H. and Isoyama, K. Quality of long-termcryopreserved umbilical cord blood units forhematopoietic cell transplantation. Int. J. He-matol. 93: 99-105, 2011.

Ma, F., Gu, Y., Nishihama, N., Ebihara, Y. andTsuji, K. Differentiation of human embryonicand induced pluripotent stem cells in cocul-ture with murine stromal cells. In Human Em-bryonic and Induced Pluripotent Stem Cells:Lineage-specific Differentiation Protocols,Springer Protocol Handbooks. Edited by Ye,K., Jin, S. (Springer Science, New York), pp266-335, 2011.

Ebihara, Y., Takahashi, S., Mochizuki, S., Kato,S., Kawakita, T., Ooi, J., Yokoyam, K., Naga-mura, F., Tojo A, Asano, S. and Tsuji, K. Un-related cord blood transplantation aftermyeloablative conditioning regimen in adoles-cent and young adult patients with hema-tologic malignancies: a single institute analy-sis. Leuk. Res., in press.

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We participate in cutting edge science of autoimmune, rheumatic and allergic dis-eases and novel treatments for patients with these disorders. In addition to con-ventional drug studies aimed to improve the efficacy and safety of current thera-pies, we are going to carry out experimental protocols of particular interest for pa-tients not responding to conventional therapy and to perform the translational re-search.

I. Study on CD26 molecule in normal immuneresponse and in patients with immune-mediated diseases

Osamu Hosono, Kei Ohnuma, NoritadaYoshikawa, Hiroshi Kawasaki , HirotoshiTanaka, Chikao Morimoto. (Department ofRheumatology and Allergy), Akiko Souta-Kuribara, (Division of Clinical Immunology)

CD26 is a T cell costimulatory molecule aswell as an activation antigen with dipeptidylpeptidase IV (DPPIV) enzyme activity in its ex-tracellular region that is preferentially expressedon memory T cells. The soluble form of CD26(sCD26) is present in serum and recombinantsoluble CD26 can enhance peripheral blood Tcell proliferation induced by the recall antigen.We demonstrated that CD26 binds Caveolin-1on antigen presenting cells, and that followingCD26-caveolin-1 interaction on recall antigen-loaded monocytes, caveolin-1 is phosphorylated,with linkage to NF-κB activation, followed by

upregulation of CD86. In addition, reducedcaveolin-1 expression on monocytes inhibits CD26-mediated CD86 upregulation and abrogatesCD26 effect on recall antigen-induced T cell pro-liferation, and immunohistochemical studies re-vealed an infiltration of CD26＋ T cells in thesublining region of rheumatoid synovium andhigh expression of caveolin-1 in the increasedvasculature and synoviocytes of the rheumatoidsynovium. Taken together, these results stronglysuggest that CD26-caveolin-1 interaction plays arole in the upregulation of CD86 on recallantigen-loaded monocytes and subsequent en-gagement with CD28 on T cells, leading toantigen-specific T cell activation such as the T-cell-mediated antigen-specific response in rheu-matoid arthritis (RA).

Currently we are focusing on the translationalresearch of utilization of anti-CD26 monoclonalantibody (mAb) as well as recombinant solubleCD26 for treatment of malignant tumors,immune-mediated disorders and immune defi-ciency diseases. A phase I/II, non-randomized,

IMSUT Hospital

Department of Rheumatology and Allergyアレルギー免疫科

Professor Chikao Morimoto, M.D., D.M.Sc.Associate Professor Hirotoshi Tanaka, M.D., D.M.Sc.Lecturer Osamu Hosono, M.D., D.M.Sc.Project Lecturer Satoshi Iwata, M.D., D.M.Sc.Assistant Professor Hiroshi Kawasaki, M.D., D.M.Sc.Assistant Professor Noritada Yoshikawa, M.D., D.M.Sc.Assistant Professor Kei Ohnuma, M.D., D.M.Sc.

教 授 医学博士 森 本 幾 夫准教授 医学博士 田 中 廣 壽講 師 医学博士 細 野 治特任講師 医学博士 岩 田 哲 史助 教 医学博士 河 崎 寛助 教 医学博士 吉 川 賢 忠助 教 医学博士 大 沼 圭

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open-label, multi-center, dose-escalation study ofYS110 (humanized anti-CD26 mAb which wedeveloped) is being performed in patients withCD26-positive advanced refractory mesothe-lioma or CD26-positive solid tumors by Dr EricAngevin as principal investigator (Institut Gus-tave Roussy, Villejuif, France). Hopefully wewill perform phase I/II clinical trial utilizing hu-manized CD26 mAb for the treatment of theabove diseases in Japan.

a. Clinical significance of soluble CD26/DPPIV in various disease conditions

(i) Soluble CD26/DPPIV in autoimmune andother immune-mediated disorders

Our previous studies demonstrated that CD26-caveolin-1 interaction plays a role in theupregulation of CD86 on recall antigen-loadedmonocytes and subsequent engagement withCD28 on T cells, leading to antigen-specific Tcell. Possible substrates of CD26/DPPIV includeseveral critical cytokines and chemokines. CD26could modulate function of several cytokinesand chemokines such as RANTES (CCL5), SDF-1α (CXCL12) and glucagons-like peptide 1(GLIP-1) through its DPPIV enzyme activity. We haveshown that the DPPIV enzyme activity ofplasma sCD26 was low in HIV-1-infected indi-viduals, and was inversely correlated with HIV-1 RNA, and that the in vitro addition of recom-binant sCD26 could enhance purified proteinderivative-induced lymphocyte proliferation.These DPPIV enzyme activity of sCD26 in HIV-1-infected individuals contributes to the im-munopathogenesis of HIV infection. Further-more, we have shown that serum levels of sCD26 and its specific DPPIV activity were signifi-cantly decreased in SLE and were inversely cor-related with SLE disease activity index score,but not with clinical variables or clinical subsetsof SLE. Serum levels of sCD26 may be involvedin the pathophysiology of SLE, and appear to beuseful as a new disease activity measure forSLE.

We had examined sCD26 and its specificDPPIV activity in serum of patients with inflam-matory bowel diseases (IBD), such as Crohn’sdisease or ulcerative colitis in collaboration withGastrointestinal Unit, School of Medicine, KeioUniversity, and also in sera and synovial fluidfrom patients with RA. The DPPIV activity wasreduced in patients with IBD and was signifi-cantly lower in patients with Crohn’s diseasecompared to with ulcerative colitis (P＜0.05).We found significant decrease of serum sCD26and its specific DPPIV activity. These findingsindicate that CD26 may be potentially importantfor the pathophysiology of IBD and RA. Fur-

thermore, we have investigated autoantibodiesagainst CD26 in serum using ELISA and West-ern blotting methods. We have not found anti-CD26 autoantibody which could reduce DPPIVactivity so far. We plan to examine the effect ofTNF-α blocking therapy (infliximab, etanercept,adalimumab), IL-6 blocking therapy (tocilizu-mab) and costimulatory signal blocking therapy(abatacept) on serum levels of sCD26/DPPIV inpatients with RA and its clinical significance.(ii) Soluble CD26/DPPIV in malignancies asso-

ciated with asbestos exposureCD26 /DPPIV is able to cleave selected bio-

logical factors to alter their functions and regu-lates topoisomerase II α level in hematologicmalignancies, affecting sensitivity to doxorubicinand etoposide. Expressed on various tissues, CD26 is involved in the development of certain hu-man cancers. We have shown CD26 is highlyexpressed on the cell surface of malignant meso-thelioma and that a newly developed human-ized anti-CD26 mAb has an inhibitory effect onmalignant mesothelioma cells in both in vitroand in vivo experiments.

We examined sCD26 and its specific DPPIVactivity in serum and pleural effusion of pa-tients with asbestosis in collaboration withOkayama Rosai Hospital. Serum levels of sCD26and its specific DPPIV activity was significantlyreduced in patients with both malignant meso-thelioma and primary lung cancer associatedwith asbestos exposure compared to patientswith pleural plaque. As there seems to be a rela-tionship between pleural CD26/DPPIV andprognosis in mesothelioma, we have done themeasurement of more samples and serial studiesto confirm their clinical significance. We arenow analyzing their clinical significance, espe-cially their association with prognosis of meso-thelioma.(iii) Effect of humanized anti-CD26 mAb on

measurement of soluble CD26/DPPIVIn our ELISA for measuring soluble CD26/

DPPIV we used two different mouse anti-CD26mAbs (5F8, 1F7) which could not interfere eachother. Administration of our newly developedhumanized anti-CD26 mAb (YS110) could formimmune complex with sCD26, which mightblock binding of the detecting antibody (1F7) toserum sCD26. We confirm the interference ofhumanized anti-CD26 mAb with anti-CD26mAb (1F7) for detecting sCD26 in our ELISA.Therefore, instead of 1F7 we selected anotheranti-CD26 mAb (9C11) which recognize the epi-tope different from humanized anti-CD26 mAb(YS110) and 5F8. In clinical trial utilizing hu-manized CD26 mAb (YSCMA-EU-0001) wecould measure serum sCD26/DPPIV without in-terference of administered anti-CD26 humanized

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mAb (YS110).

b. CD26-based molecular target therapy forgraft-versus-host disease in hematopoieticstem cell transplantation

Graft-versus-host disease (GVHD) remains amajor cause of morbidity and mortality in allo-geneic hematopoietic stem cell transplantation(alloHSCT). In GVHD, mature donor T cells thataccompany the stem cell graft attack recipienttissues, especially the skin, liver, gastrointestinaltract, and lung. Therefore, all patients undergo-ing alloHSCT receive GVHD prophylaxis to im-pair T cell function; however, treatment to pre-vent GVHD can be deleterious since mature do-nor T cells play a critical role in mediating re-constitution of the adaptive immune system. Re-cipients of alloHSCT are thus at great risk forinfections, particularly when prolonged im-munosuppression is required for treatment ofGVHD. Although the role of CD26/DPPIV inGVHD needs to be studied in more detail, treat-ment with a murine antibody against humanCD26 was reported to have an effect in patientswith steroid-resistant acute GVHD following al-loSCT (Bacigalupo A., et al., Acta Haematol1985:73:185, de Meester, et al., Immunobiology1993:188:145). To examine the efficacy of CD26-targeting therapy in GVHD more profoundly,we established mouse GVHD model using hu-man peripheral blood lymphocytes (huPBL)(xenograft GVHD mouse model; x-GVHD). Af-ter NOD/LtSz-scid or NOD/Cg-Prkdcscidil2rgtm1Sug/Jic mice were injected with appropri-ate numbers of huPBL, mice show symptoms ofGVHD such as loss of weight, loss of hair, dete-rioration of activity, and thinning of ear pads.Histopathological examination revealed that CD3＋CD26＋ human lymphocytes were infiltratedin the skin, intestinal mucosa, salivary gland,lung and liver of the x-GVHD mice. In thismouse model, humanized anti-CD26 monoclo-nal antibody (mAb) was injected two weekslater of onset of x-GVHD, and the symptoms ofGVHD were improved after ten injections of hu-manized anti-CD26 mAb. Moreover, x-GVHDwas observed to be suppressed when human-ized anti-CD26 mAb was prophylactically ad-ministered. Taken together, it may be possiblethat the full therapeutic potential of alloSCT willbe realized by approaches that aim to minimizeGVHD by targeting CD26-mediated T cell regu-lation.

II. Development of novel therapy to over-come intractable disorders in rheumaticdiseases via targeting transcriptional ap-paratus

Hirotoshi Tanaka, Noritada Yoshikawa (De-partment of Rheumatology and Allergy), Nori-aki Shimizu, Takako Maruyama, Chikao Mori-moto (Division of Clinical Immunology).

We are interested in the mechanism of eu-karyotic gene expression and development ofnovel therapy and/or drugs that target tran-scriptional machineries. For this purpose, our re-cent work is mainly focused on conditionalregulation of transcription factors including theglucocorticoid receptor. Our recent achievementis now been applied in clinical settings in theIMSUT Hospital.

Glucocorticoid hormones are effective in con-trolling inflammation and immunity, but under-lying mechanisms are largely unknown. It hasbeen shown that both positive and negativeregulation of gene expression is necessary forthis process. The genes whose activity is nega-tively modulated in the anti-inflammatory proc-ess code for several cytokines, adhesion mole-cules. Most of them do not carry a classicalbinding site for regulation by the GR, but haveinstead regulatory sequences for transcriptionfactors such as AP-1 or NF-κB. Consideringvarious severe side effects of glucocorticoids, itmay be pharmacologically important to dissoci-ate these negative regulatory function of the GRfrom induction of genes for metabolic enzymes,expression of which have been shown to bepositively regulated by the GR. We propose thata certain class of compounds (surprisingly, someof them are non-steridal chemicals) may dissoci-ate transactivation and transrepression functionof the GR and offer opportunities for the designof such compounds that could function more ef-fectively as antiinflammatory drugs. In this line,we are developing novel therapeutic strategy.On the other hand, we have developed an effi-cient system to screen out the target genes ofGR in glucocorticoid-responsive tissues, and areworking with clarification of tissue-specific ef-fects of glucocorticoids.

(i) Development of Dissociating Ligand forthe GR

The GR function could be differencially regu-lated by ligands. We have recently shown thatnot only synthetic glucocorticoids but also cer-tain bile acids could differentially modulate GRfunction. Moreover, the effects of those com-pounds are indicated to be ascrived to theligand binding domain of the receptor. In thisline, we are going to isolate the dissociatingligand that preferencially promotes transrepres-sion function of the GR. Recently we have dem-onstrated that certain ligands can modulate in-

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terdomain communication of the GR, which willeventually contribute to isolation of novel cate-gory of ligands.

On the other hand, receptor specificity is an-other important aspect of novel GR regulator. Inthis line, we have shown that cortivazol is ex-tremely specific for GR and does not bind toMR. We are studying the molecular basis forthis receptor specificity of the ligand using corti-vazol as a model. Our recent microarray studydemonstrated that GR and MR have differentialrole in homeostatic regulation in non-classicalcorticosteroid target tissues including the heart.Notably, collaboration with Professor Miyano’slaboratory greatly contributed to developmentof this program.

(ii) Molecular biology of small nuclear RNAbinding protein HEXIM1

Expression of HEXIM1 is induced by treat-ment of vascular smooth muscle cells with a dif-ferentiation inducer hexamethylane bisaceta-mide. It is shown that HEXIM1 binds 7SKsnRNA and inhibits P-TEFb-mediated transcrip-tional elongation process. Physiological signifi-cance of HEXIM1 is studied using newly gener-ated transgenic mice. HEXIM1 Tg mice showcardiac resistance to elevation in pulmonary ar-terial pressure with less hypertrophic response,suggesting that HEXIM1 might be a therapeuticcandidate of pulmonary hypertension in connec-tive tissue diseases.

(iii) Clarification of tissue-specific effects ofglucocorticoids

We performed target gene identification andclarification of their biological significance incardiac muscles and skeletal muscles.1. Cardiac muscles. We found that the expres-

sion of genes that encode 2 key enzymes in acommon pathway of prostaglandin biosynthe-sis were upregulated by glucocorticoids viathe GR in cardiomyocytes: phospholipase A2group IVA (Pla2g4a ; encoding cytosoliccalcium-dependent phospholipase A2 [cPLA2]), which belongs to the class of cPLA2s thatpreferentially cleave arachidonic acid frommembrane phospholipids; and prostaglandin-endoperoxide synthase 2 (Ptgs2 ; encodingCOX2), which converts arachidonic acid intoPGH2. Importantly, ALD did not have similarstimulatory effects on these genes. The induc-tion of Pla2g4a and Ptgs2 by GR is specific forcardiomyocytes, since GR has been shown totransrepress the activation of these proinflam-matory genes in most cells. Therefore, wesought to investigate the major types of

prostanoids produced in cardiomyocytes afterexposure to glucocorticoids and to clarify theroles of these products in cardiac physiology.Among the genes for PGH2 isomerases, ex-pression of Ptgds , which encodes lipocalin-type prostaglandin D synthase (L-PGDS), wasselectively upregulated by a GR-specific ligand.Consistent with this result, PGD2 was themost prominently induced prostaglandin byGR-specific ligand stimulation of cultured car-diomyocytes and in vivo hearts. Using iso-lated Langendorff-perfused hearts and cul-tured cardiomyocytes, we demonstrated thatthe activation of L-PGDS-mediated produc-tion of PGD2 was crucial for the cardioprotec-tion against ischemia/reperfusion conferredby glucocorticoid-GR signaling. Our resultssuggest a novel interaction between gluco-corticoid-GR signaling and the arachidonicacid cascade-mediated cardiomyocyte survivalpathway. Recently, we have characterized thecardiac receptor for PGD2 and clinical appli-cation of this study is now ongoing in col-laboration with the Department of Cardiol-ogy, Keio University School of Medicine.

2. Skeletal muscle. Muscle comprises ～40％ ofbody mass and contributes not only to thestructure and movement of the body but alsoto nutrient storage and supply. In adult mam-mals, skeletal muscle hypertrophy/atrophy ischaracterized by an increase/decrease in thesize (as opposed to the number) of individualmyofibers, respectively. The control of musclemass is believed to be determined by a dy-namic balance between anabolic and catabolicprocesses. Mammalian target of rapamycin(mTOR) is a crucial component of the ana-bolic machinery for protein synthesis. Proto-typically, insulin/IGF-1 activates mTOR viathe PI3K-Akt pathway. Protein degradation inskeletal muscle cells is essentially mediatedby the activity of two conserved pathways:the ubiquitin-proteasomal pathway and theautophagic/lysosomal pathway. The ubiqui-tin-proteasomal pathway is responsible forthe turnover of the majority of soluble andmyofibrillar muscle proteins. The activity ofthis pathway is markedly increased in atro-phying muscle due to the transcriptional acti-vation of a set of E3 ligase-encoding genes, e.g., atrogin-1 and MuRF1. Autophagy alsoplays an important role in the degradation ofskeletal muscle, and is indicated to be a con-sequence of an ordered transcriptional pro-gram involving a battery of genes, e.g., LC3and Bnip3. These positive and negative path-ways are balanced in a highly coordinatedmanner for the determination of myofiber sizeand total muscle volume; however, distortion

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of this balance with a relative increase in deg-radation results in the generalized decrease ofmyofiber size and muscle atrophy (Hoffmanand Nader, Nat. Med. 2004). Pioneering stud-ies demonstrated that muscle atrophy is a re-sult of active processes that are transcription-ally controlled through the expression of aparticular gene set; the forkhead box O(FoxO) transcription factors are common com-ponents of a number of atrophy models andact as critical liaison molecules for proteindegradation and autophagy via the transcrip-tional regulation of, for example, atrogin-1,MuRF1, LC3, and Bnip3 (Mammucari et al.,2007; Sandri et al., 2004; Stitt et al., 2004; Zhaoet al., 2007). In clear contrast, it is evident thateach disease has proper signaling pathwaysto FoxOs and that other components of thecellular machinery often participate in theprogression of atrophy. Therefore, for the de-velopment of therapies against muscle atro-phy, it should be addressed how the tran-scriptional program triggered by a particularatrophy pathway is orchestrated and how thebalance of muscle protein synthesis and deg-radation is distorted in each disease.Typically, glucocorticoid-induced muscle atro-

phy is characterized by fast-twitch type II glyco-lytic muscle fiber loss with reduced or no im-pact on type I fibers. The mechanism of such fi-ber specificity is yet unknown. Previous reportssuggested that the glucocorticoid-GR system hasanti-anabolic and catabolic effects and promotesdegradation via the induction of a set of genesincluding atrogin-1, MuRF1, and myostatin. Al-though the involvement of FoxO transcriptionfactors is reported in the gene regulation ofatrogin-1 and MuRF1 under the presence of ex-cess glucocorticoids, the biochemical role of GRin the transcriptional regulation of muscle tissuehas not yet been determined. Therefore, we in-vestigated how GR-mediated gene expressioncoordinately modulates anti-anabolic and cata-bolic actions to understand the functional cou-pling of metabolism and volume regulation inmuscle.

We identified REDD1 and KLF15 genes as di-rect targets of GR. REDD1 is known to be in-duced by various stressors, including glucocorti-coid, and to inhibit mTOR activity via the se-questration of 14-3-3 and the increase of TSC1/2activity. We clearly identified the functionalGRE via the promoter analysis of REDD1 gene.On the other hand, KLF15 is a recently discov-ered transcription factor that is involved in sev-eral metabolic processes in skeletal muscle; e.g.,KLF15 transcriptionally upregulates the gene ex-pression of branched-chain aminotransferase 2(BCAT2), a mitochondrial enzyme catalyzing the

first reaction in the catabolism of branched-chainamino acids (BCAA) to accelerate BCAA degra-dation and alanine production in skeletal mus-cle. Moreover, phenotypic analysis of cardiac-specific KLF15 knockout mice revealed markedleft ventricular hypertrophy, indicating thenegative regulatory role of KLF15 on musclemass. We here demonstrated that KLF15 partici-pates in muscle catabolism via the transcrip-tional regulation of atrogin-1 and MuRF1. More-over, KLF15 affects mTOR through BCAA deg-radation and negatively modulates myofibersize. mTOR activation inhibits GR-mediatedtranscription by suppressing GR recruitmentonto target genes, strongly suggesting a mutu-ally exclusive crosstalk between mTOR and GR.Pharmacological activation of mTOR withBCAA attenuated GR-mediated gene expression,leading to the substantial restoration of musclein glucocorticoid-treated rats. We, therefore, in-dicate the critical importance of the interactionof GR and mTOR in the regulation ofmetabolism-volume coupling in skeletal muscle.Given this, we have just started the clinical trialin IMSUT hospital to verify our scenario inglucocorticoid-treated patients.

III. Clinical Trial & Survey

Osamu Hosono, Kei Ohnuma, NoritadaYoshikawa, Hiroshi Kawasaki , HirotoshiTanaka, Chikao Morimoto

We have participated the post-marketing sur-vey (Orencia�R : abatacept) since 2010 to evaluateits safety in clinical use in patients with rheuma-toid arthritis (RA). We had already performedpost-marketing survey of biologics for treatmentof rheumatoid arthritis (Remicade�R , Enbrel�R andHumira�R ). The post-marketing survey of Oren-cia�R finished in 2011. We are going to partici-pate SECURE (Safety of Biologics in Clinical Usein Japanese Patients with Rheumatoid Arthritisin the Long Term) study.

We have also participated another post-marketing survey (Rheumatrex�R : methotrexate,MTX) to evaluate the safety and efficacy of MTXdose up in RA patients treated with 8mg ofMTX per week.

IV. Medical Genome Science Program andGlobal COE Program “Center of Educa-tion and Research for the AdvancedGenome-Based Medicine”

Satoshi Iwata (Division of Clinical Immunol-ogy), Noritada Yoshikawa, Kei Ohnuma,Hiroshi Kawasaki, Osamu Hosono, HirotoshiTanaka, and Chikao Morimoto.

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We participate in Medical Genome ScienceProgram/Global COE Program. These programsinclude “Introduction of Medicine and MedicalEthics” and “Experience and Practice of Medi-cine”, especially arranged for non-M.D. post-graduates. The former is a series of lectures out-lining of medicine (history of medicine, internalmedicine, surgery, nursing, nutrition, pharma-cology, translational research, clinical psychol-ogy, and medical ethics), and the latter is aweekly round of IMSUT hospital. The atten-

dants visit Department of Radiology, LaboratoryMedicine, Blood Transfusion, Surgical Center,Nursing, Core Facility of Therapeutic vectors,BioBank Japan, and participate in ward round in1) Department of Hematology/Oncology, 2) In-fectious Diseases and Applied Immunology,Rheumatology and Allergy, and AdvancedMedical Science. These programs are indebtedto educational hospitality of many personsworking in IMSUT hospital.

Publications

Yamazaki H, Naito M, Ghani FI, Nam H Dang,Iwata S, Morimoto C. Characterization of can-cer stem cell properties of CD24 and CD26-positive human malignant mesothelioma cells.Biochemical and Biophysical Research Com-munications. In press (2012).

Aoe K, Amatya VJ, Fujimoto N, Ohnuma K,Hosono O, Hiraki A, Fujii M, Yamada T,Dang NH, Takeshima Y, Inai K, Kishimoto T,Morimoto C. CD26 overexpression is associ-ated with prolonged survival and enhancedchemosensitivity in malignant pleural meso-thelioma. Clin Cancer Res. In press (2012).

Nagashima H, Suzuki M, Araki S, Yamabe T,Muto C; Tanezumab Investigators (Hosono O,et al.). Preliminary assessment of the safetyand efficacy of tanezumab in Japanese pa-tients with moderate to severe osteoarthritisof the knee: a randomized, double-blind,dose-escalation, placebo-controlled study. Os-teoarthritis Cartilage. 19: 1405-1412, 2011.

Ohnuma K, Hosono O, Dang NH, Morimoto C.Dipeptidyl peptidase in autoimmune patho-physiology. Adv Clin Chem. 53: 51-84, 2011.

Toyokawa G, Cho H-S, Iwai Y, Yoshimatsu M,Takawa M, Hayami S, Maejima K, Shimizu N,Tanaka H, Tsunoda T, Field H, Kelly J, NealD, Ponder B, Maehara Y, Nakamura Y, andHamamoto R. The histone demethylase JMJD2B plays an essential role in human carcino-genesis through positive regulation of cyclin-dependent kinase 6. Cancer Prev Res. 4: 2051-61, 2011

Amatya VJ, Takeshima Y, Kushitani K, YamadaT, Morimoto C, Inai K. Overexpression of CD26/DPPIV in mesothelioma tissue and meso-thelioma cell lines. Oncol Rep. 26: 1369-1375,2011.

Mu SY, Shimosawa T, Ogura S, Wang H, UetakeY, Kawakami-Mori F, Marumo T, Yatomi Y,

Geller DS, Tanaka H, Fujita T. Epigeneticmodulation of the renal β-adrenergic-WNK4pathway in salt-sensitive hypertension. NatMed 17: 573-580, 2011.

Yamazaki H, Xu CW, Naito M, Nishida H,Okamoto T, Ishrat GF, Iwata S, Inukai T,Sugita K, Morimoto C. Regulation of stem cellproperties by CD9 in human B-acute lym-phoblastic leukemia. Biochem. Biophys Res.Commun. 409: 14-21, 2011

Shirakawa J, Fujii H, Ohnuma K, Sato K, Ito Y,Kaji M, Sakamoto E, Koganei M, Sasaki H,Nagashima Y, Amo K, Aoki K, Morimoto C,Takeda E, Terauchi Y. Diet-induced adiposetissue inflammation and liver steatosis areprevented by DPP-4 inhibition in diabeticmice. Diabetes. 60: 1246-5, 2011.

Shimizu N, Yoshikawa N, Ito N, Maruyama T,Suzuki Y, Takeda S, Nakae J, Tagata Y, Nishi-tani S, Takehana K, Sano M, Fukuda K, Sue-matsu M, Morimoto C, Tanaka H. Crosstalkbetween Glucocorticoid Receptor and Nutri-tional Sensor mTOR in Skeletal Muscle. CellMetab. 13: 170-82, 2011.

Abe M, Havre PA, Urasaki Y, Ohnuma K, Mori-moto C, Dang LH, Dang NH. Mechanisms ofconfluence-dependent expression of CD26 incolon cancer cell lines. BMC Cancer. 11: 51,2011.

Ghani FI, Yamazaki H, Iwata S, Okamoto T,Aoe K, Okabe K, Mimura Y, Fujimoto N,Kishimoto T, Yamada T, Xu CW, Morimoto C.Identification of cancer stem cell markers inhuman malignant mesothelioma cells. Bio-chem Biophys Res Commun. 404: 735-42,2011.がん細胞の生物学～がん幹細胞とは 山崎裕人，森本幾夫 Medical Bio，８，４０―４３，２０１１．癌幹細胞と検査医学～癌幹細胞マーカー 山崎裕人，森本幾夫 臨床検査，５５，４５８―４６３，２０１１．

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Our department was established for the application of human genome informationin clinics. In 2011, we incorporated the genetic testing laboratory in the IMSUThospital.

1. Genetic tests for the patient with malig-nant neoplasm

We reconstructed a system to perform genetictests for patients with leukemia. In the last sixmonths, we performed more than two hundredsof genetic tests including qualitative and quanti-tative evaluation of leukemic cells in the pa-tients. In addition, we have established a systemto determine c-MPL, NPM, and KRAS muta-tions, and CEP110/FGFR1 fusion gene. These ge-netic tests are contributing to precise diagnosisof malignant diseases and effect of treatment tothe patients.

2. Genetic testing using next generation se-quencer

Masao Nagasaki1, Satoru Miyano2: 1FunctionalGenomics, 2Laboratory of DNA InformationAnalysis, Human Genome Center

We started a project, the determination ofgerm-line mutations in patients suspected for fa-milial colorectal cancer, using next generationsequencer. This project was approved by institu-tional review board in 2011. One patient was en-

rolled in this study. The patient was diagnosedas familial polyposis of the colon, but conven-tional PCR-direct sequence method identified nopathogenic mutations of APC . This project isaimed to detect mutations that are undetectableby Sanger sequence method, and to identifynovel genetic alterations associated with familialtumor.

3. Genetic counseling and related activities.

Yoshinori Murakami, Yoichi Furukawa, ReikoSada, Momoyo Ohki1, Kohichiro Tsuji2, Ko-ichiro Yuji3, Noriko Fujiwara4, Masae Ono5,Shiro Ikegawa6, Toshihiro Tanaka6, MayumiTamari6, Masahiko Suzuki7, and Yusuke Naka-mura8: 1Bunkyo University, 2Department of Pe-diatric Hematology-Oncology, 3Department ofHematology-Oncology, 4Department of Nursing,5Department of Pediatrics, Tokyo Teishin Hos-pital, 6Center for Genomic Medicine, RIKEN,7Department of Neurology, Jikei Medical Uni-versity, 8Laboratory of Molecular Medicine,Human Genome Center

In IMSUT Hospital, we provide genetic coun-seling and tests to clients who are anxious about

IMSUT Hospital

Department of Applied Genomicsゲノム診療部

Professor Yoichi Furukawa M.D., Ph.D.Professor Yusuke Nakamura M.D., Ph.D.Professor Yoshinori Murakami M.D., Ph.D.

教 授 医学博士 古 川 洋 一（併任）教 授 医学博士 中 村 祐 輔（併任）教 授 医学博士 村 上 善 則（併任）

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genetic issues associated with hereditary dis-eases. In 2011, we had a total of 16 cases includ-ing familial breast cancer, Peutz-Jeghers syn-drome, familial polyposis of the colon, spi-nocerebellar degeneration, ornithine transcarba-mylase deficiency, and retinitis pigmentosa. Inthe counseling, we provided correct information

of the diseases and took psychological care ofthe clients in collaboration with clinical psy-chologists. Genetic testing was performed infour cases at clients’ request after thoughtfuldiscussion about its merit and demerit, andwritten informed consent.

Publications

1. Kaneko M, Nozawa H, Kitayama J, SunamiE, Akahane M, Yamauchi N, Furukawa Y,Nagawa H, A case of hereditary hemorrhagictelangiectasia (Osler-Weber-Rendu disease)with multiple polyps arising in the cecumand appendix. Acta Gastroenterol Belg 74(2):352-354, 2011.

2. Yamaguchi K, Sakai M, Kim J, Tsunesumi S,Fujii T, Ikenoue T, Yamada Y, Akiyama Y,Muto Y, Yamaguchi R, Miyano S, NakamuraY, Furukawa Y. MRG-binding protein con-tributes to colorectal cancer development.Cancer Sci. 102(8): 1486-92, 2011.

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The Department of Radiology works in general diagnostic radiology, neuroradiol-ogy, clinical nuclear medicine, and radiation therapy. For clinical imaging, we havea multi-detector row CT scanner, high-field MRI unit, and hybrid gamma camerasystem. We perform all examinations of CT, MRI, angiography, and nuclear medi-cine, and official reports on all the examinations are made by board-certified radi-ologists. Clinical studies are conducted in collaboration with other departments andother institutions. We also investigate the technical aspects of molecular imagingin intact small animals for its application to preclinical studies using optical imag-ing system and MRI.

Interstitial Magnetic Resonance Lymphogra-phy in Mice: Comparative Study of Gadofluo-rine 8, Gadofluorine M, and Gadofluorine P

Shigeru Kiryu, Yusuke Inoue1, Fugeng Sheng2,Makoto Watanabe, Kohki Yoshikawa3, MorioShimada3, and Kuni Ohtomo4: 1Department ofDiagnostic Radiology, Kitasato UniversitySchool of Medicine, 2Department of Radiology,Affiliated Hospital of The Academy of MilitaryMedical Sciences, Beijing, China, 3Departmentof Radiotechnical Sciences, Faculty of Radio-logical Health Sciences, Komazawa University,4Department of Radiology, Graduate School ofMedicine, University of Tokyo.

We investigated the characteristics and capa-bility of interstitial MR lymphography in miceusing gadofluorine 8, gadofluorine M, and gad-ofluorine P. Healthy mice were injected with 0.5µmol Gd gadofluorine 8, gadofluorine M, orgadofluorine P subcutaneously into the rightrear footpad, and the time courses of contrastenhancement in the lymph nodes were assessed.Moreover, we assessed the lymphatic pathway

from the right and left rear feet or tail usinggadofluorine M. Contrast enhancement wasdemonstrated for the right popliteal, right sac-ral, and right iliac lymph nodes in all mice 5min after the injection of each of the threeagents, and then decreased gradually. Enhance-ment in the lymph nojdes was still detectable 30min after the injection of gadofluorine 8 or gad-ofluorine M, it became obscure sooner after gad-ofluorine P injection. In comparison with gad-ofluorine P, the other two contrast agentsshowed mildly stronger enhancement in thelymph nodes. Clear differences were found inthe hepatobiliary and urinary kinetics of thethree agents. The injection of gadofluorine Minto various sites delineated the lymphatic path-way from the respective injection site. InterstitialMR lymphography using gadofluorine 8, gad-ofluorine M, and gadofluorine P offered clearvisualization of the lymphatic pathway inhealthy mice during a sufficient imaging timewindow. This technique allowed for repeatedassessment of the lymphatic pathway in a givenmouse, helping to reveal the mouse lymphaticsystem.

IMSUT Hospital

Department of Radiology放射線科

Associate Professor Shigeru Kiryu, M.D., D.M.Sc.Lecturer Haruyasu Yamada, M.D., D.M.Sc.Assistant Professor Makoto Watanabe, M.D., D.M.Sc.

准教授 医学博士 桐 生 茂講 師 医学博士 山 田 晴 耕助 教 医学博士 渡 邉 慎

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Long-term assessment of contrast effects ofgadofluorine M and gadofluorine P in mag-netic resonance imaging of mice.

Fugeng Sheng2, Yusuke Inoue1, Shigeru Kiryu,Makoto Watanabe, and Kuni Ohtomo.4

We investigated the long-term time course ofthe contrast effects after the intravenous injec-tion of gadofluorine M or gadofluorine P inmice. Magnetic resonance images were acquiredlongitudinally after intravenous injection of 0.1µmol Gd/g gadofluorine M into BALB/c mice.The contrast effects were also assessed in C57BL/6J mice injected with gadofluorine M, BALB/cmice injected with gadofluorine P, and BALB/cmice injected with a double dose of gadopen-tetate dimeglumine. The injection of gadofluo-rine M into BALB/c mice caused prolonged con-trast effects in the blood and other organs. Theliver enhancement was especially long-lastingand still evident 6 days after injection. Strain-related differences in contrast kinetics of gad-ofluorine M were not observed between BALB/cmice and C57BL/6J mice. In comparison withgadofluorine M, clearances from the blood, liver,and kidney were more rapid and contrast en-hancement in the spleen was generally lower forgadofluorine P. The enhancement in the gall-bladder cavity, indicating biliary excretion, wasevident only after gadofluorine P injection.Blood enhancement at 10 min was much weakerfor gadopentetate dimeglumine. Both gadofluo-rine M and gadofluorine P appear to be applica-ble to blood pool imaging and liver imaging inmice.

Distortion correction in whole-body imagingof live mice using a 1-Tesla compact mag-netic resonance imaging system.

Shigeru Kiryu, Yusuke Inoue1, YoshitakaMasutani4 , Tomoyuki Haishi5 , KohkiYoshikawa3, Makoto Watanabe, and Kuni Oh-tomo4: 5MRTechnology.

We investigated a distortion correction appli-cable to whole-body imaging of live mice. Allmagnetic resonance imaging (MRI) scans wereacquired on a compact 1-T permanent magnetunit for mouse imaging using a T1-weighted,three-dimensional (3D) fast low-angle shot se-quence. We assessed geometric distortion in MRimages of a small 3D grid phantom and deter-mined 3D image transformations for distortioncorrection. The developed distortion correctionwas applied to MR images of the 3D grid phan-tom acquired on another day, and the correctionwas validated. A two-dimensional (2D) grid

phantom was imaged with a mouse to investi-gate the applicability of the distortion correctionto whole-body mouse imaging. Obvious geomet-ric distortion was observed in the MR images ofthe 3D grid phantom. The application of the de-veloped 3D phantom-based distortion correctionreduced distortion in the images of the 3D gridphantom acquired on another day. Geometricdistortion was observed in the MR images of the2D grid phantom acquired together with themouse. The 3D phantom-based correction de-creased the distortion substantially, regardless ofmouse positioning. The developed distortioncorrection can reduce distortion in whole-bodyimaging of live mice and may enhance the capa-bilities of MRI in small animal experiments.

Gaussia luciferase for bioluminescence tu-mor monitoring in comparison with firefly lu-ciferase.

Yusuke Inoue1, Fugeng Sheng2, Shigeru Kiryu,Makoto Watanabe , HarnprasopwatRatanakanit6, Kiyoko Izawa6, Arinobu Tojo6,and Kuni Ohtomo4: 6Division of MolecularTherapy, Advanced Clinical Research Center,University of Tokyo.

Gaussia luciferase (Gluc) is a secreted re-porter, and its expression in living animals canbe assessed by in vivo bioluminescence imaging(BLI) or blood assays. We characterized Gluc asan in vivo reporter in comparison with fireflyluciferase (Fluc). Mice were inoculated subcuta-neously with tumor cells expressing both Flucand Gluc and underwent Fluc BLI, Gluc BLI,blood assays of Gluc activity, and caliper meas-urement. In Gluc BLI, the signal from the tumorpeaked immediately and then decreased rapidly.In the longitudinal monitoring, all measures in-dicated an increase in tumor burden early aftercell inoculation. However, the increase reachedplateaus in Gluc BLI and Fluc BLI despite a con-tinuous increase in the caliper measurement andGluc blood assay. Significant correlations werefound between the measures, and the correla-tion between the blood signal and caliper vol-ume was especially high. Gluc allows tumormonitoring in mice and should be applicable todual-reporter assessment in combination withFluc. The Gluc blood assay appears to provide areliable indicator of viable tumor burden, andthe combination of a blood assay and in vivoBLI using Gluc should be promising for quanti-fying and localizing the tumors.

Quantitative MR image study in neuropsy-chiatric disorders: voxel-based analysis ofdiffusion tensor data sets.

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Haruyasu Yamada, Osamu Abe7, HidenoriYamasue8, and Kiyoto Kasai8: 7Department ofRadiology, School of Medicine, Nihon Univer-sity, 8Department of Psychiatry, GraduateSchool of Medicine, University of Tokyo.

Magnetic resonance diffusion tensor imaging(DTI) has been reported to be useful in evalu-ation of the normal appearing brain in neu-ropsychiatric disorders. DTI is a unique andrelatively new technique to visualize and evalu-ate the cerebral white matter. The orientation ofwhite matter tracts can be analyzed and trackedby the methods named as diffusion tensor trac-tography or fiber tracking. Quantitative diffu-sion indices such as apparent diffusion coeffi-cient and fractional anisotropy have been used

for evaluation of the normal appearing whitematter in various diseases. Disruptions in con-nectivity may explain some of the symptoms inneuropsychiatric disorders such as schizophre-nia. The purpose of our study is to investigatediffusion anisotropy in neuropsychiatric pa-tients’ brain by voxel-based analysis of DTI andvoxel-based morphometry, using statistical para-metric mapping, tract-based spatial statistics,and other tools. Voxel-based analysis of the dif-fusion tensor data set allows a voxel-wise com-parison encompassing the whole brain withoutoperational bias or hypothesis. Our study sug-gests that the voxel-based diffusion tensoranalysis may be robust enough to perceivechanges in diffusion anisotropy in patients.

Publications

Kiryu S, Inoue Y, Sheng F, Watanabe M,Yoshikawa K, Shimada M, and Ohtomo K. In-terstitial Magnetic Resonance Lymphographyin Mice: Comparative Study of Gadofluorine8, Gadofluorine M, and Gadofluorine P. MagnReson Med Sci. (in press).

Gonoi W, Akahane M, Akai H, Hagiwara K,Kiryu S, Hayashi N, and Ohtomo K. Retro-portal main pancreatic duct with circumportalpancreas: radiographic visualization. Clin Im-aging. 35: 442-6, 2011.

Inoue Y, Masutani Y, Kiryu S, Haishi T,Yoshikawa K, Watanabe M, Shimada M, andOhtomo K. Integrated lymphography usingfluorescence imaging and magnetic resonanceimaging in intact mice. Mol Imaging. 10: 317-26, 2011.

Kiryu S, Inoue Y, Masutani Y, Haishi T,Yoshikawa K, Watanabe M, and Ohtomo K.Distortion correction in whole-body imagingof live mice using a 1-Tesla compact magneticresonance imaging system. Jpn J Radiol. 29:353-60, 2011.

Kiryu S, Inoue Y, Watanabe M, and Ohtomo K.Effect of isoflurane anesthesia and hypother-mia on the hepatic kinetics of Gd-EOB-DTPA:evaluation using MRI of conscious mice. JMagn Reson Imaging. 34: 354-60, 2011.

Inoue Y, Sheng F, Kiryu S, Watanabe M,Ratanakanit H, Izawa K, Tojo A, and OhtomoK. Gaussia luciferase for bioluminescence tu-mor monitoring in comparison with firefly lu-ciferase. Mol Imaging. 10: 377-85, 2011.

Sheng F, Inoue Y, Kiryu S, Watanabe M, andOhtomo K. Interstitial MR lymphography inmice with gadopentetate dimeglumine andgadoxetate disodium. J Magn Reson Imaging.33: 490-7, 2011.

Tomizawa N, Komatsu S, Akahane M, TorigoeR, Kiryu S, and Ohtomo K. Influence ofhemodynamic parameters on coronary arteryattenuation with 320-detector coronary CT an-giography. Eur J Radiol. 81: 230-3, 2011.

Inoue Y, Watanabe M, Kiryu S, and Ohtomo K.Quantitative effect of reducing body thicknesson visualizing murine deep abdominal lymphnodes by in vivo fluorescence reflectance im-aging. J Fluoresc. 21: 1325-9, 2011.

Sheng F, Inoue Y, Kiryu S, Watanabe M, andOhtomo K. Lymph drainage from the mam-mary glands in mice: a magnetic resonancelymphographic study with gadofluorine M.Acad Radiol. 18: 512-7, 2011.

Tomizawa N, Komatsu S, Akahane M, TorigoeR, Kiryu S, and Ohtomo K. Relationship be-tween beat to beat coronary artery motionand image quality in prospectively ECG-gatedtwo heart beat 320-detector row coronary CTangiography. Int J Cardiovasc Imaging. 28:139-46, 2011.

Akai H, Kiryu S, Matsuda I, Satou J, Takao H,Tajima T, Watanabe Y, Imamura H, KokudoN, Akahane M, and Ohtomo K. Detection ofhepatocellular carcinoma by Gd-EOB-DTPA-enhanced liver MRI: comparison with triplephase 64 detector row helical CT. Eur J Ra-diol. 80: 310-5, 2011.

Fatima Z, Ichikawa T, Motosugi U, Muhi A,Sano K, Sou H, Haradome H, Kiryu S, andAraki T. Magnetic resonance diffusion-weighted imaging in the characterization ofpancreatic mucinous cystic lesions. Clin Ra-diol. 66: 108-11, 2011.桐生茂．肝癌診療ガイドライン（日本肝臓学会２００９年）インナービジョン ２６：４２―４３，２０１１．渡辺慎，桐生茂，大友邦 術後合併症．画像診断．

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学研メディカル秀潤社 ３１：７０６―７１４，２０１１渡辺慎，大友邦 カラー図譜．今日の治療指針２０１１年版．医学書院．１０―３０，２０１１渡辺淳也，小畠隆行，山田晴耕，稲生信一，小野

留那，和田佑一，落合俊輔，野崎敦，大曽根文雄，大久保敏之．関節軟骨変性におけるT１ρmappingおよびT２mappingの評価能の検討．日本磁気共鳴医学会雑誌 ３１：７９―８０，２０１１．

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The mission of our department is to provide surgical service of malignancy and in-flammatory bowel disease and to develop and conduct clinical research and clini-cal trials in early stages (Phase I and II) on patients at the Research Hospital. Wehave also been offering diagnostic and therapeutic endoscopy, including upperand lower gastrointestinal endoscopic examinations. Novel therapies are ready tostart under cautious preparation.

1. Summary of surgical treatment in 2011

Masaru Shinozaki, Giichiro Tsurita, KeisukeHata, Yasuhiro Mizuno, Junko Takei

We performed various surgical operations.Malignancy is the leading indication for opera-tion, followed by benign diseases, such as in-flammatory bowel disease (IBD) and hernia.Among the patients with malignancy, colorec-tum is by far the leading organ in number.

Dr. Sameshima and Dr. Kawamura are willingto help us when laparoscopic colorectal surgeryis undergone. Recently, breast cancer has be-come a particular field only for highly special-ized physicians bearing knowledge in the par-ticular field. Dr. Sanuki continued the out-patient clinic and assisted our breast cancer op-erations. Dr. Tsuji and Dr. Fukatsu who belongto the University of Tokyo Hospital (Hongo),started to assist our breast clinic in 2011.

2. Summary of endoscopic examination in2011

Giichiro Tsurita, Keisuke Hata, Masaru Shino-zaki, Yasuhiro Mizuno, Junko Takei

Under cooperation with Department of Ad-vanced Medical Science, we performed 650 (9％increase compared with the number last year)upper gastrointestinal endoscopies and 639 (27％ increase) colonoscopies without major com-plications. Dr. Tsurita has been the chief of Divi-sion of Endoscopy and played the crucial role inexaminations. For the patients’ satisfaction, weaggressively perform endoscopic treatment andavoid operation as much as possible. Our twofellows (Y.M. and J.T.) have learned gastrointes-tinal endoscopic technique and have been mak-ing great progress.

3. Clinical Research.

A. The role of micro RNA and its relation tocarcinogenesis in inflammatory bowel dis-ease

Keisuke Hata, Masaru Shinozaki, Giichiro

IMSUT Hospital

Department of Surgery(Gastrointestinal and Breast Surgery)外科（主として，大腸・胃・食道・乳腺領域）

Associate Professor Masaru Shinozaki, M.D., Ph.D.Lecturer Giichiro Tsurita, M.D., Ph.D.Assistant Professor Keisuke Hata, M.D., Ph.D.

准教授 医学博士 篠 崎 大病院講師 医学博士 釣 田 義一郎助 教 医学博士 畑 啓 介

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Tsurita

Recently, micro RNA (miRNA) had beenknown to play a crucial role in post-transcriptional regulation. In inflammatorybowel disease (IBD), its etiology has not been re-vealed yet. However, interaction between mu-cosa and intraluminal bacteria and immunologi-cal response are speculated to be included atleast in the pathophysiology. There may be apossibility that abnormality in miRNA is in-volved. Furthermore, the patients with IBD aresubject to suffer from colorectal cancer due tochronic inflammation. We investigate the possi-ble relation between miRNA and carcinogenesis.

B. The problems including occurrence ofcancer after eradication of H. pylori

Keisuke Hata, Hideki Ono, Masaru Shinozaki,Giichiro Tsurita

Recently, H. pylori is attributed to the maincause of gastric cancer. However, gastric canceremerges even after eradication of H. pylori. Wefollowed the patients after eradication andfound cancer. We have sought the clinicopa-tological and molecular biological factors.

C. Whole genome sequencing of inflamma-tory bowel disease

Masaru Shinozaki, Yoichi Furukawa, KeisukeHata, Giichiro Tsurita

The progress in nucleic acid sequencing en-abled us to investigate whole genome in variousfields. Like other diseases, inflammatory boweldisease is caused not only by environmental fac-tors but also by hosts’ genetic background. Al-though several susceptibility loci have beenclarified using microsatellite difference, causa-tive genetic changes have not been disclosed.We are studying whole genome of affected indi-viduals.

D. Whole genome sequencing of colorectalcancer

Keisuke Hata, Yoichi Furukawa, Masaru Shi-nozaki, Giichiro Tsurita

We perform whole genome sequencing forcolorectal cancer under various conditions.

E. The comparison between step biopsy andtarget biopsy at surveillance colonoscopyin long-standing ulcerative colitis: a ran-domized control study

Keisuke Hata, Masaru Shinozaki, YasuhiroMizuno, Giichiro Tsurita

Patients with long-standing ulcerative colitishave increased risk of colorectal cancer. Theprognosis of symptomatic patients is extremelypoor, and surveillance colonoscopy with multi-ple biopsies is recommended for such patients.However, the methods of biopsies are differentbetween the Western countries and Japan: Nu-merous (more than 32) blind biopsies are recom-mended in the former countries, whereas targetbiopsied with restricted number are favored inJapan. Although the detection rates of dysplasia,which is known as a precancerous lesion as wellas a marker of invasive cancer, seem to be sub-stantially similar, when studies were executedseparately, no direct comparison has been at-tempted yet. We have included five patients,who were randomized to the two groups, with-out any complications.

F. Clinicopathological characteristics oflower gastrointestinal cancer associatedwith Crohn’s disease

Masaru Shinozaki, Keisuke Hata, GiichiroTsurita

In Japan, cancer in small bowel and/or largebowel associated with Crohn’s disease is rapidlyincreasing in number. In Western countries, thedistribution of cancer is similar to that of ulcera-tive colitis, and surveillance colonoscopy is donelike ulcerative colitis. However, in Japan, signifi-cant proportion of such cancer is located at peri-anal region, and the similar methodology doesnot seem sufficient for early detection. We be-lieve that the first step to solve this problem isaccumulation and analysis of such tumors.Therefore, we started to make questionnaire andsend to hospitals to clarify the clinicopathlogicalcharacteristics.

G. Cohort study for individualized postopera-tive adjuvant chemotherapy usingpyrimidine analog in stage III colon can-cer.

Giichiro Tsurita, Masaru Shinozaki, KeisukeHata

Pyrimidine analog is the basic drug of col-orectal cancer. However, the relationship be-tween enzymatic profile of CRC concerning themetabolism of pyrimidine analog and the effecton the survival has not been revealed yet.Therefore, we conducted a prospective studywhere the activity of representative enzymes of

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pyrimidine analog, e.g. thymidylate sythetase, ismeasured in the postoperative patients who re-ceive adjuvant chemotherapy.

4. Clinical research under development

We have been seeking for new projects inpartnership with basic research departments in

the Institute.

5. Clinical trials under development

In 2010, Antibody and Vaccine Center hasbeen developed at the Institute. We are planningto administer cancer related peptides undervarious situations to draw maximal effects.

Publications

1. Adachi E, Koibuchi T, Okame M, Sato H,Imai K, Shimizu S, Tsurita G, Oyaizu N,Iwamoto A, Fujii T. Case of secondary syphi-lis presenting with unusual complications:syphilitic proctitis, gastritis, and hepatitis. JClin Microbiol. 2011; 49(12): 4394-6.

2. Shuno Y, Hata K, Sunami E, Shinozaki M,Kawai K, Kojima T, Tsurita G, Hiyoshi M,Tsuno NH, Kitayama J, Nagawa H. Is surveil-lance endoscopy necessary after colectomy inulcerative colitis? ISRN Gastroenterol. 2011;2011: 509251.

3. Shinozaki M, Hata K, Matsukura M, Mizuno

Y, Takei J, Tsurita G. Portal vein thrombosisand pulmonary artery thromboembolism af-ter laparoscopic colectomy. Minim InvasiveTher Allied Technol. 2011; 20(5): 301-6.

4. Hata K, Shinozaki M, Toyoshima O,Toyoshima A, Matsumoto S, Saisho T, TsuritaG. Impact of family history of gastric canceron colorectal neoplasias in young Japanese.Colorectal Disease. (in press)

5．篠崎 大，畑 啓介，釣田義一郎．炎症性腸疾患に合併した小腸・大腸癌の特徴と外科治療．日本臨牀（in press）

294

We have been engaged in the surgical treatment of solid tumors and the immuno-therapy of various malignancies. We have also been offering diagnostic services,including endoscopic examination on upper and lower intestines. One of the goalsof our team is to provide evidence-based standard therapies including surgery,chemo-therapy, and radiation for cancer patients. However, additional emphasishas been put on the development of the novel immunological and gene therapiesin intimate collaboration with the Division of Bioengineering, Advanced Clinical Re-search Center and Core Facility for Therapeutic Vectors of Research Hospital. Wehave conducted multiple early-phase clinical trials (Phase I and II) for cancer pa-tients at Research Hospital utilizing its fundamental functions enabling clinical re-search of high quality.

I. Summary of surgical treatment and otherprocedures performed in 2011

Akihiko Itoh, Akira Kanamoto, Hideaki Ta-hara,

Team Violet has been newly established in anindependent group of the Department of Sur-gery on June 1st of 2010. This team has beentreating the patients with the diseases of gastro-

intestinal organs having the focus on, but notlimited to, hepato-biliary system and pancreas.

Surgical operations have been performed bythe team personnel on 47 cases under generalanesthesia and spinal or epidural and/or localanesthesia in 2011. As shown in Table 1, majoroperations were performed in 4 patients withmalignant diseases and in 8 patients with be-nign diseases.

IMSUT Hospital

Team Violet, Department of Surgery外科（主に肝臓，胆のう，膵臓）

Lecturer Akihiko Itoh, M.D.Professor Hideaki Tahara, M.D., D.M.Sc.Assistant Professor Akira Kanamoto, M.D., D.M.Sc.

講 師 伊 藤 精 彦教 授 医学博士 田 原 秀 晃助 教 医学博士 金 本 彰

Table 1. Major operations performed in 2011

Malignant Diseases Benign Diseaseshepato-biliary organs and pancreas

Hepatectomy 1 Cholecystecyomy 5(GIST: 1) (laparoscopic; 2)

Colon and rectumcolo-rectal resection 2

MiscellaneousLN biopsy 1 Miscellaneous procedures 3

TOTAL 4 8

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Publications

1. Kutsuna, N., Yamazaki S, Kaiga T, Inagaki. Y,Hayashi Y, Okada S, Kanamoto A, andTakayama T.: Partial MHC matched DonorCD8＋ T-Cells are Indispensable to SwitchSplenocytic Chimera. Journal of Surgical Re-search (2011 Mar 12.)

2. Yamano T, Watanabe S, Hasegawa H, SuzukiT, Abe R, Tahara H, Nitta T, Ishimaru N,Sprent J, and Kishimoto H. Ex-vivo expandedDC induce donor-specific central and periph-

eral tolerance and prolong the acceptance ofdonor skin allografts. Blood (2011 Mar 3; 117(9): 2640-8.)

3. Hikichi M, Kidokoro M, Haraguchi T, Iba H,Shida H, Tahara H & Nakamura T. Mi-croRNA regulation of vaccinia virus for en-hanced oncolytic activity and reduced patho-genicity in oncolytic virotherapy. MolecularTherapy (2011 Jun; 19 (6): 1107-15.)

Table 2. Other Surgical Treatment for Malignancy in 2011

hepato-biliary organs and pancreasTACE 16

(HCC: 14, metastatic liver cancer: 2)PTCD 3LN biopsy 8

TOTAL 27

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Department of Joint Surgery was established in 2006. Our mission is evaluationand treatment of hemophilic arthropathy. In Japan, many hospitals are able tocontrol bleeding for haemophilia by concentrates, however there are few hospitalsfocus on surgical treatments except us. Many haemophilia patients come to ourdepartment from all over Japan. We evaluate their joint condition and functionroentgenographically and physiotherapeutically and decide indication of surgicaltreatment. Many of patients will be performed joint arthroplasties and arthroscopicsynovectomy to improve their quality of life.

Surgical treatment for haemophilia

Hideyuki Takedani

From 2006 to 2011, there are 113 surgicaltreatments for hemophilia (57 for hemophilia A,16 for hemophilia B, 1 for deficiency factor VIIpatient, and 1 for Von Willebrand disease). 16 of

them have the deficiency factor antibody.In 2011, we were performed 22 surgical treat-

ments (15 for hemophilia A, 6 for hemophilia B,and 1 for Von Willebrand disease). 5 of themhave the deficiency factor antibody. 17 wereperformed total joint arthroplasties, 1 was ar-throscopic synovectomy and 4 were other surgi-cal treatments.

Publications

1) Takedani, H., Fujii, T., Kobayashi, N., Haga,S., Tatsunami, T. and Fujii, T. Inter-observerreliability of three different radiographic

scores for adult haemophilia . Haemophilia.17: 134-138, 2011.

IMSUT Hospital

Department of Joint Surgery関節外科

Lecturer Hideyuki Takedani, M.D., D.M.Sc. 講 師 医学博士 竹 谷 英 之

297

Department of Surgical Neuro-Oncology was established in 2011. All kinds ofbrain tumors, especially malignant glioma, will be treated at our department. Malig-nant glioma is incurable by standard therapy alone, therefore refined, personalizedtreatment regimens of non-standard radiation therapy and chemotherapy will beconsidered. In addition, innovative therapy such as oncolytic virus therapy will beapplied whenever possible. Based on scientific evidences and findings from basicresearch, we will conduct advanced medical practices in addition to the standardtherapy.

A clinical study of a replication-competent,recombinant herpes simplex virus type 1(G47∆) in patients with progressive glioblas-toma

Genetically engineered, conditionally replicat-ing herpes simplex viruses type 1 (HSV-1) arepromising therapeutic agents for cancer. Wehave developed a triple-mutated oncolytic HSV-1, G47∆, by introducing an additional geneticmutation to the viral genome of G207, an onco-lytic HSV-1 used in clinical trials for glioblas-toma in the United States. We have been con-ducting a phase I-IIa clinical trial of G47∆ in pa-tients with progressive glioblastoma at the Uni-versity of Tokyo Hospital. Patients with a singlelesion of recurrent glioblastoma, age 18 or older,and with a good performance status are en-

rolled. The primary end point is to access thesafety of G47∆, and the secondary end point isto access the efficacy by tumor size and progres-sion free survival. A preparation is underway tostart clinical trials of G47∆ at IMSUT Hospital.New clinical protocols to test the efficacy ofG47∆ are also in preparation.

Outpatient clinic

The outpatient clinic of the Department ofSurgical Neuro-Oncology opened in October2011. Patients with newly diagnosed glioblas-toma have been treated with high dose or stan-dard dose radiation therapy and concomitantchemotherapy. Clinical study protocols for re-current or newly diagnosed malignant gliomapatients are in preparation.

Publications

1. Ogura, M., Todo, T., Tanaka, M., Nannya, Y.,Ichikawa, M., Nakamura, F. and Kurokawa,M.: Temozolomide may induce therapy-related acute lymphoblastic leukemia. Br JHaematol 154: 663-665, 2011.

2. Koga, T., Maruyama, K., Tanaka, M., Ino, Y.,Saito, N., Nakagawa, K., Shibahara, J. andTodo, T.: Extended field stereotactic radiosur-gery for recurrent glioblastoma. Cancer (pub-lished online 16 DEC 2011 | DOI:10.1002/

IMSUT Hospital

Department of Surgical Neuro-Oncology脳腫瘍外科

Professor Tomoki Todo, M.D., Ph.D.Associate Professor Yasushi Ino, M.D., Ph.D.

教 授 医学博士 藤 堂 具 紀准教授 医学博士 稲 生 靖

298

cncr.27372).

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Our clinical practice and clinical studies have been focused on (1) anestheticmanagement in patients undergoing major surgery including joint arthroplastic sur-gery for hemophilia patients, (2) management of chronic intractable pain or im-proving the quality of life of patients with life-threatening illness (3) assessment ofthe impact of anesthesia and surgery on autonomic nervous activity, and (4) riskmanagement of medical electronic devices in Research Hospital.

1. Safety in anesthetic management, espe-cially focusing on prevention of deep veinthrombosis during total hip arthroplasty inhemophilia patients.

Management of bleeding in patients with he-mophilia has improved since the developmentof coagulation factor substitution therapy. In al-most all of the hip or knee arthroplasty, intraop-erative embolism has been detected with trans-esophageal echocardiography (TEE). But theremay have been no report on TEE findings dur-ing arthroplastic surgery in hemophilia patients.We find TEE detected variable degree of echo-genic materials in right atrium (RA) duringTHA in hemophilia patients under continuousinfusion of coagulation factor. This may suggestthat we need to consider risks not only on theside of hemorrhage but embolic events for pe-rioperative management of hemophilia patients.

2. Management of chronic intractable pain.

We organized a palliative care support teamin Research Hospital for the patients sufferingwith intractable physical and mental paincaused by life-threatening illness and/or compli-

cations of the treatments. In patients of hemato-logical malignancy with long treatment history,many of their illness have been diagnosed as re-action to severe stress and adjustment disorder,especially prolonged depressive reaction (F43,the ICD-10 classification of mental and behav-ioral disorders)

3. Assessment of the impact of anesthesiaand surgery on autonomic nervous activ-ity.

It is generally accepted that the parametersderived from power spectral analysis (PSA) ofheart rate variability (HRV) can provide a noninvasive measure of autonomic nervous activity.We have published several works on assessmentof the impact of anesthetics on autonomic nerv-ous activity during perioperative period usingreal time monitor for PSA of HRV.

4. Risk management of medical electronicdevices.

We ourselves engage in preventive mainte-nance and care of the life support machines in-cluding instruments for mechanical ventilation

IMSUT Hospital

Surgical Center手術部

Associate Professor Mieko Chinzei, M.D., M.D.Sc.Assistant Professor Reiko Shibata, M.D.Clinical Engineer Yuki Ito

准教授 医学博士 鎮 西 美栄子助 教 医学士 柴 田 玲 子

臨床工学技士 伊 藤 友 紀

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or blood purification and defibrillator. We alsosupervise physicians during clinical usage ofthese instruments. We have promoted dual-directional information system on malfunctions

or incidents of the rest of medical electronic de-vices in this hospital in collaboration with theDivision of Clinical Trial Safety Management.

Publications

Oshima N, Numao S, Chinzei M. Effectivenessof a relaxation technique at the workplaceevaluated by autonomic nervous activity and

psychological mood. J Jpn Soc Balneol Clima-tol Phys Med. 74(4): 256-262, 2011

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Division of Clinical Trial Safety Management (DCTSM) owes two major missions.One is the risk management of the Research Hospital (RH) and the other is thesupport for the conduct of clinical trials, especially for Translational Research (TR).Our roles on TR varies from the assistance for planning study design and writingprotocol to the data confirmation by Case Report Form which is managed byTranslational Research Coordinator (TRC) and the quality assurance of TRs bymonitoring/audit. To protect the right of participants into TR and to conduct TRscientifically and ethically appropriately, we have organized TRC, which consistsnurse, pharmacist, clinical laboratory technologist, dietitian, and clinical psycho-therapist.

1. Patient Safety Management of ResearchHospital

Fumitaka Nagamura, Hisako Suyama, MakikoTajima

We have engaged in the risk managementand the protection of medical incidents/acci-dents at RH. We have promoted the report sys-tem on medical incidents and accidents, andquick corresponding scheme such as “MedicalAccident-Response Meeting” and “Council ofRisk Management in the RH”. We take place atleast two seminars for staffs of RH on medicalsafety every year. Participation to these semi-nars is the obligation of workers of RH. Wehave created manuals on the risk managementand Standard Operating Procedures (SOP) onoperations of RH and revised quickly when re-quired.

2. Assistance and oversight of Clinical Trials/TRs at Research Hospital

Kazufumi Matsumoto, Kumiko Sumino, Nori-ko Fujiwara, Minako Kohno, Makiko Tajima,

Fumitaka Nagamura

The assistance of Translational (Clinical) Re-search Coordinators is indispensable for the con-duct of clinical trials, especially for TR. In 2011,we assisted the conduct of 15 clinical trials in-cluding TR. Number of the protocols are sum-marized in Table 1. Table 2 shows the numberof patients enrolled into clinical trials at RH in2011.

IMUSUT Hospital

Department of Clinical Trial Safety Management医療安全管理部

Professor Fumitaka Nagamura, M.D., D.M.Sc. 教 授 医学博士 長 村 文 孝

Table 1.

Number ofprotocol

Startedin 2011

Continuationbefore 2011 Total

TR 2 0 2

Clinical trialsfrom phar-maceuticalcompanies

3 1 4

Multi-centerstudies 2 7 9

7 8 15

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3. The Development of the Scholastic Pro-gram for the Graduate Students of Nursesin the Area of Translational Research.

Kazufumi Matsumoto, Makiko Tajima, Ku-miko Sumino, Noriko Fujiwara, FumitakaNagamura

Translational Research (TR) is the early phaseof clinical trials, which applied the develop-ments of basic researches for patients with in-curable and/or life-threatening diseases. High-educated nurses are indispensable for the con-ducts of TRs in terms of the protection of par-ticipants in TRs and the conducts of scientifi-cally appropriate TRs. We developed the scho-lastic program for the graduate students ofnurses in the area of TR. We planed and imple-mented the two-weeks program to foster the ex-pert research nurse aimed at the graduate stu-dents. It consists of the lectures on the featurepoints of TR (e.g. ethical considerations of TR,and the role of research nurse), role-plays of In-stitutional Review Board and obtaining In-formed Consent, case conference, and the expe-rience of the actual operations. We evaluatedthe reports and the questionnaires from the stu-dents to explore the degree of their understand-ings and satisfactions for this program. These re-ports and questionnaires were analyzed in ac-cordance with the qualitative method. Six stu-dents participated in the program and we evalu-ated the reports and the questionnaires. Stu-dents could understand the role of researchnurse and the necessary ability and organizationto play this role appropriately. They were satis-fied with the content and the quality of lecturesand role-plays, however, the experiences of theactual operations did not meet their demandsdue to the less acquisition of the practical exper-tise. Generally, our program meets the demandsof the students, however, the improvement of

the content on the experience of the actual op-erations is the next issue.

4. Education and training for ethics boardmembers: Is e-learning the solution?

Makiko Tajima, Fumitaka Nagamura

The Japanese Ministry of Health, Labour andWelfare recently revised the Ethical Guidelinesfor Clinical Studies. The revised guidelines re-quire education and training for members of aresearch ethics committee (REC). Some trainingprograms on ethics are offered in an e-learningformat for added convenience to learners. E-learning, also called online learning, web-basedlearning, or distance learning, has potential tobe an effective training tool. We conducted a lit-erature and internet search to assess the feasibil-ity of e-learning in REC member training. E-learning is suitable for studying bioethical prin-ciples as well as laws and regulations relevantto clinical research. It is also useful to share cri-teria for protocol review and to update informa-tion on science and technology. E-learning is es-pecially effective when the same trainingcourses are offered repeatedly and when mem-bers are unable to assemble at the same locationand same time due to geographical and tempo-ral limitations. E-learning materials are sharedamong REC members, faculty, staff, and stu-dents, and may be open to the public. Disadvan-tages of e-learning include a high dropout ratedue to lack of social interaction and the require-ment for additional human and financial re-sources. To overcome these disadvantages, con-ventional methods such as lectures, workshops,and on-the-job training (OJT) should be incorpo-rated into the training program. E-learning thatincludes the use of learning networks, such asonline discussion forums, may provide resultssimilar to those of workshops and OJT.

E-learning can be a valuable tool for RECmember training. Combining different types oftraining media, or blended learning, is recom-mended to conduct effective training.

5. Stressor Scale for Clinical Research Coor-dinators: development and psychometrictesting.

Kazufumi Matsumoto, Kumiko Sumino, Fumi-taka Nagamura

Job stress is viewed as a situation in whichworking conditions interact with individualworker characteristics and result in disruption ofpsychological or physiologic homeostasis. Clini-cal research coordinators, also known as re-

Table 2.

Number ofpatients

Enrolledin 2011

Continuationbefore 2011 Total

TR 2 0 2

Clinical trialsfrom phar-maceuticalcompanies

1 0 1

Multi-centerstudies 2 11 13

5 11 16

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search nurses, are professionals who play a cen-tral role in clinical trials. They face variousproblems associated with their responsibilities;however, few studies have reported on theirstress. To manage their stress, it is necessary toidentify the sources of stress (i.e., stressors). The56-item preliminary instrument was developedbased on literature review and expert discus-sions. A total of 589 clinical research coordina-tors in 186 hospitals in Japan were surveyed in2011. Statistical analyses on construct and con-current validity, internal consistency, and test-retest reliability were performed. A six-factor so-lution with 23 items was selected using explora-tory factor analysis: “quantitative workload,”“conflict with investigators,” “ambiguity of

work,” “conflict with other clinical research co-ordinators and with supervisors,” “demandsfrom an affiliate other than the hospital,” and“difficulty in caring for trial participants.” Con-firmatory factor analysis affirmed construct va-lidity, with a demonstrated acceptable fit be-tween the factor structure and the observeddata. All factors had significant correlations withburnout and psychological distress, which indi-cated acceptable concurrent validity. Cronbach’salpha coefficients ranged from 0.73 to 0.82.Intra-class correlation coefficients indicated al-most satisfactory test-retest reliability. Our newinstrument has acceptable validity and reliabilityfor evaluating job stressors for clinical researchcoordinators.

Publications

Matsumoto K, Nagamura F, Ogami Y, Yama-shita N, Kamibeppu K. Difficulties of NursingStaff Involved in Phase 1 Oncology Trials inJapan. Cancer Nur 34(5): 369-75, 2011.

Sato A, Ooi J, Takahashi S, Tsukada N, Kato S,Kawakita T, Yagyu T, Nagamura F, Iseki T,Tojo A, Asano S. Unrelated cord blood trans-plantation after myeloablative conditioning inadults with advanced myelodysplastic syn-dromes. Bone Marrow Transplant 46(2): 257-61,2011.

Matsumoto K, Sumino K, Fukahori H, Kitaoka,Kamibeppu K, Nagamura F. Stressor Scale forClinical Research Coordinators: developmentand psychometric testing. J Advanced Nurs-ing (in press)

Ebihara Y, Takahashi S, Mochizuki S, Kato S,Kawakita T, Ooi J, Yokoyama K, Nagamura F,Tojo A, Asano S, Tsuji K. Unrelated cordblood transplantation after myeloablative con-ditioning regimen in adolescent patients withhematologic malignancies: a single instituteanalysis. Leukemia Res (in press)中島和江，本間覚，玉木長良，金子道夫，名川弘一，原田賢治，長村文孝，大川淳，倉林亨，鳥

谷部真一，後藤百万，相馬孝博，武田裕，高橋りょう子，森崎市治郎，前田潔，江原一雅，富永隆治．国立大学附属病院における「診療行為に関連した死亡の調査分析モデル事業の利用経験とその評価」 医療の質・安全学会誌 ６�：３３２―３４５，２０１１．田嶋麻紀子，長村文孝 倫理審査委員研修におけるeラーニングの位置づけ 臨床評価 ３８：８３９―８５３，２０１１．長村文孝 トランスレーショナルリサーチにおける医学と心理学の連携 心理学ワールド５０回記念誌 ２１５―２２０，２０１１．長村文孝 臨床安全情報（有害事象）が原因で中止となった薬剤の分析 月刊ファームステージ２：３―５，２０１１．長村文孝 FDAの今後の展開 医薬品・医療機器

FDA申請・査察対応集 情報機構 ３９１―４００，２０１１．長村文孝 NICEにおける抗がん剤および抗体技術の価値評価動向 がんの新しいバイオマーカー／予測因子による個別化医療時代に求められる抗がん剤開発 技術情報協会 ３１―３８，２０１１．長村文孝 FDA対応におけるQ&A解説集 情報機構 ９―１０，１１―１３，１５―２０，２０１１．

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Our department is established in 1990, in order to manage the transfusion medi-cine and cell processing for hematopoietic stem cell transplantation. We have co-operated on a clinical and research cord blood banking with Tokyo Cord BloodBank, whose cell processing and cryopreservation facility was established the firstin IMSUT ‘Room for Clinical Cellular Technology (RCCT)’, in 1997. Now we havedeveloped RCCT as IMSUT-Cell Resource Center (IMSUT-CRC) to facilitate andsupport the advanced cell therapy projects including the regenerative medicine.Also we have been engaged to the studies for the development of various celltherapy projects together with other departments, as follows.

1. Expanded regulatory T cell therapy forGVHD, transplantation and autoimmunediseases.

Nagamura-Inoue T, Yamamoto Y, Ogami K,Tojo A

Regulatory T cells harbored the immunosup-pressive effects and were related to the patho-genesis of graft-versus-host disease (GVHD), re-jection of organ transplantation and autoim-mune disease. We developed the system of exvivo expansion of CD25＋FOXP3＋regulatory Tcells from the small amount of peripheral bloodand also cord blood (CB), to apply the immu-nological therapy.

2. Research Cord Blood Stem Cell Bank(IMSUT-Cell Resource Center):

Nagamura-Inoue T, Ishige I, Yuzawa M, Ta-mura T, Ogami K, Tojo A

“Research Cord Blood Stem Cell Bank” (for-mer named ‘Research Stem Cell Resource Bank’)was established by the support of MEXT (Minis-

try of Education, Culture, Sports, Science andTechnology) for the development of the medi-cine including Regenerative Medicine and drugdiscovery in Japan since 2004. The research CBbank provides CB units that are non-conformingfor clinical use, in processed and frozen or infresh to domestic researchers for research usevia RIKEN Bioresource Center.Visit our home page http://scb.ims.u-tokyo.ac.jp/

3. Exploring mesenchymal stem cells derivedfrom Umbilical Cord:

Nagamura-Inoue T, Yuzawa M, Tamura T,Tojo A

We have explored the umbilical cord as a newmesenchymal stem cells (MSC) source. We stud-ied the differentiation ability of cord-derivedMSC including osteocytic, chondrocytic, adipo-cytic, and also hepatic cell differentiation.

5. Institute of Medical Science, University To-kyo Cell Resource Center (IMSUT-CRC):

IMSUT Hospital

Department of Cell Processing and Transfusionセルプロセッシング・輸血部

Professor Arinobu Tojo, M.D., D.M.Sc.Lecturer Tokiko Nagamura-Inoue, M.D., D.M.Sc.

教 授 医学博士 東 條 有 伸講 師 医学博士 長 村 登紀子

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Nagamura-Inoue T, Miki Yuzawa, Ogami K,Tojo A

To promote the cell therapy related to transla-tional research, RCCT has been established in1997. Until now, the following projects had im-plemented; 1) Cord blood cell processing forbanking (for Tokyo Cord Blood Bank and Re-

search cord blood stem cell bank), 2) Dendriticcell therapies, 3) Regenerative therapy of alveo-lar bone derived from bone marrow mesenchy-mal cells, 4) Gene therapy for renal cancer. In2010, we developed and changed the name‘Room for Clinical Cellular Technology (RCCT)’to ‘IMSUT-CRC’ as for more functional broadunits for cell therapy.

Publications

Kanda J, Hishizawa M, Utsunomiya A,Taniguchi S, Eto T, Moriuchi Y, Tanosaki R,Kawano F, Miyazaki Y, Masuda M, NagafujiK, Hara M, Takanashi M, Kai S, Atsuta Y,Suzuki R, Kawase T, Matsuo K, Nagamura-Inoue T, Kato S, Sakamaki H, Morishima Y,Okamura J, Ichinohe T, Uchiyama T. Impactof graft-versus-host disease on outcomes afterallogeneic hematopoietic cell transplantationfor adult T-cell leukemia: a retrospective co-hort study. Blood. 119: 2141-8, 2012

Atsuta Y, Morishima Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S, Kai S,Sakamaki H, Kouzai Y, Kobayashi N, FukudaT, Azuma H, Takanashi M, Mori T, TsuchidaM, Kawase T, Kawa K, Kodera Y, Kato S.Comparison of unrelated cord blood trans-plantation and HLA-mismatched unrelatedbone marrow transplantation for adults withleukemia. Biol Blood Marrow Transplant. 2011Oct 15. [Epub ahead of print]

Kato K, Yoshimi A, Ito E, Oki K, Hara J, Naga-toshi Y, Kikuchi A, Kobayashi R, Nagamura-Inoue T, Kai S, Azuma H, Takanashi M,Isoyama K, Kato S; for the Japan Cord BloodBank Network. Cord Blood Transplantation

from Unrelated Donors for Children withAcute Lymphoblastic Leukemia in Japan: TheImpact of Methotrexate on Clinical Outcomes.Biol Blood Marrow Transplant. 17: 1814-21,2011

Morio T, Atsuta Y, Tomizawa D, Nagamura-Inoue T, Kato K, Ariga T, Kawa K, Koike K,Tauchi H, Kajiwara M, Hara T, Kato S; Japa-nese Cord Blood Bank Network. Outcome ofunrelated umbilical cord blood transplantationin 88 patients with primary immunodeficiencyin Japan. Br J Haematol. 154, 363-72, 2011

Sakabe S, Iwatsuki-Horimoto K, Takano R, Ni-dom CA, Le MQ, Nagamura-Inoue T, Hori-moto T, Yamashita N, Kawaoka Y. Cytokineproduction by primary human macrophagesinfected with highly pathogenic H5N1 or pan-demic H1N1 2009 influenza viruses. J Gen Vi-rol. 92,1428-34, 2011

Yuzawa M, Nagamura-Inoue T, Ishige I, OgamiK, Tamura T, Takahashi A, Kodo H, Yama-guchi S, Tojo A. Time from cord blood collec-tion to processing and temperature influencethe quality of mononuclear cell products iso-lated using a density-gradient protocol. Jap JTrans Cell Ther. 57: 139-45, 2011

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The primary function of the Core Facility for Therapeutic Vectors (CFTV) is to sup-port clinical trials that require the genetic modification and/or ex vivo manipulationof patients’ tissue or cells under current Good Manufacturing Practice (cGMP)conditions defined by FDA of USA. The CFTV is the first facility established inJapanese academia to produce genetic or cellular vectors of clinical grade. Usingthis facility, the adenoviral vector and herpes vector were prepared in CFTV forclinical use in 2011 and 2008 respectively.

1. Preparation of Standard Operating Proce-dures (SOPs)

The cGMP compliance is maintained usingwritten SOPs prepared by ourselves. The SOPscodify all aspects of laboratory activities includ-ing facility design and operations of the person-nel. The SOPs enables the staff not only to pro-duce the reagents with high quality in the stablemanners but also to help identify areas for im-provement.

2. Adoption of ISO

In order to continuously improve our activi-ties, quality management system of the CFTVhas been assessed and found to be in accor-dance with the requirements of the quality stan-dards detailed ISO9001: 2008; in the scope of de-velopment and manufacture of cell and genetherapy products.

3. Validation of CFTV

The CFTV consists of two distinct units; 1)Vector Unit, the primary viral vector productionsuite which may also function as ex vivo trans-

duction suite; 2) Cell Unit, cell processing suitecapable of generating dendritic cells for immu-notherapy and gene therapy. There are two self-contained vector production suites in the VectorUnit and two self-contained tissue culture suitesin the Cell Unit. These suites are kept Class10,000. There are many features incorporatedinto the design of this CFTV to minimize therisk of cross-contamination between products; i.e., unidirectional traffic flow, individual airlocksto each production suite, single-pass HEPA fil-tered supply air, 100 percent exhaust from thebiological safety cabinets through dedicateducts, among others. Periodical validation hasbeen performed on the facility and the equip-ments in CFTV to ensure cGMP compliance.

4. Projects in CFTV

Four projects are now in progress in theCFTV.

I. Cancer gene therapy using dendritic cellstransfected with IL-12 genes

Takafumi Nakamura, Hisako Katano, AkiraKanamoto＊, Marimo Sato＊, Hideaki Tahara:

IMSUT Hospital

Core Facility for Therapeutic Vectors治療ベクター開発室

Professor Hideaki Tahara, M.D., D.M.Sc.Project Associate Professor Takafumi Nakamura, Ph.D.Project Assistant Professor Hisako Katano, D.D.S., Ph.D.

教授（室長） 医学博士 田 原 秀 晃（併）特任准教授 生命科学博士 中 村 貴 史特任助教 歯学博士 片 野 尚 子

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＊Division of Bioengineering, Advanced ClinicalResearch Center

•Preparation of the Clinical Lot

We have been preparing the replication-defective recombinant adenoviral vector encod-ing human interleukin-12, which is an immune-stimulatory cytokine. The backbone of this vec-tor is based on the E1- and E3-deleted serotype5 adenovirus with a modified fiber, harboringan integrin-binding CDCRGDCDC-motif withinthe HI-loop of its knob protein. The IL-12 genesare driven by a CA promoter (CMV-IE enhancerwith the chicken β-actin promoter). The mastervirus seed stock (MVSS) and purified final mate-rial have been successfully prepared followingthe optimization of purified method for the pro-duction of high-titer vector.

II. Vaccine therapy with peptide-loaded den-dritic cells for advanced melanoma

Hisako Katano, Takafumi Nakamura, AkiraKanamoto＊, Marimo Sato＊, Hideaki Tahara:＊Division of Bioengineering, Advanced ClinicalResearch Center

•Preparation of Peptide-Loaded DendriticCells (DCs)

We have been supporting phase I clinical tri-als against melanoma. Based on the results ofthe basic research performed in Division of Bio-engineering, the SOPs of the DC preparationhave been written and used. The cellular re-agents have been successfully prepared in theCell Unit and offered for clinical trials withoutserious problems.

III. Oncolytic viral therapy using geneticallyengineered herpes simplex viruses formalignant brain tumors.

Tomoki Todo＊＊, Yasushi Ino＊＊, TakafumiNakamura, Hisako Katano, Hideaki Tahara:＊＊Department of Neurosurgery, GraduateSchool of Medicine, The University of Tokyo

•Manufacture of the viral vector

In collaboration with the research team, wehave been preparing oncolytic herpes simplexvirus. We have supported the establishment ofthe master and working cell banks of Vero cellsto produce genetically engineered herpes sim-plex viruses. The cGMP compliant MVSS, whichcontains a replication-competent herpes simplexvirus type 1 vector defective for the α47 gene,

was successfully produced. The purified finalproducts have been successfully prepared, ap-proved for clinical use by the authorities andare now used in phase I clinical trial for braincancer patients.

IV. Development of robotized cell culturesystem

Shigeyuki Wakitani＊＊＊, Marimo Sato＊, Taka-fumi Nakamura, Hisako Katano, Hideaki Ta-hara: ＊＊＊Department of Orthopedics, Gradu-ate School of Medicine, Osaka City University

In collaboration with Kawasaki Heavy Indus-tries, Inc., we are developing robotized cell cul-ture system which could be applied to a varietyof procedures including virus production as afunded project by NEDO.

V. Treatment of malignan pleural mesothe-lioma using replication-defective recombi-nant adenoviral vector expressing thesuppressor of cytokine signaling 3 (SOCS3).

Tetsuji Naka#, Hiroyuki Mizuguchi##, TakafumiNakamura, Hisako Katano, Hideaki Tahara:#Laboratory for Immune Signal, National Insti-tute of Biomedical Innovation, Osaka, Japan,##Laboratory of Biochemistry and MolecularBiology, Graduate School of PharmaceuticalSciences, Osaka University

•Manufacture of the viral vector for preclinicalstudies in non-human primates

In collaboration with the research team, wehave been preparing the replication-defective re-combinant adenoviral vector expressing the sup-pressor of cytokine signaling 3 (SOCS3) fortreatment of malignant pleural mesothelioma.We have supported the vector production usingthe master and working cell banks of 293 cells,which we established previously. The purifiedfinal products are to be used for preclinicalstudy in monkey.

5. Financial Support

This CFTV has been supported in large byCoordination, Support and Training Programfor Translational Research from Ministry of Edu-cation, Culture, Sports, Science and Technology(2007-2011), and Advanced Clinical ResearchCenter of IMSUT.

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Publications

Takenobu H, Shimozato O, Nakamura T, OchiaiH, Yamaguchi Y, Ohira M, Nakagawara A,Kamijo T: CD133 suppresses neuroblastomacell differentiation via signal pathway modifi-cation. Oncogene 30: 97-105, 2011.

Hikichi M, Minoru Kidokoro M, Haraguchi T,

Iba H, Shida H, Tahara H and Nakamura T:MicroRNA-based gene regulation of glycopro-tein B5R in oncolytic vaccinia virus reducesviral pathogenicity without impairing its anti-tumor efficacy. Molecular Therapy 19: 1107-1115, 2011.

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The Department of Pathology and Laboratory Medicine consists of eight divisions -clinical physiology, hematology, biochemistry, serology, bacteriology, molecular di-agnosis and pathology, and a division of flow cytometrical analysis. This Depart-ment engages in the laboratory analysis and provides information which is criticalfor patient care. While facilitating the ongoing translational research projects in theresearch hospital, the Department functions as an integrated diagnosis & monitor-ing laboratory that evaluates the safety and effectiveness of experimental thera-peutic approaches.

Overview

Our basic research strategies include the fol-lowing approaches: characterizing molecularmechanisms underlying the pathology, develop-ing a novel method to measure the disease-defining mechanism in the clinical materials andevaluating the effectiveness of molecular-targeted therapies thereby contributing to thetranslational research conducted in the institute.Integrating molecular-/biochemical-based labo-ratory assays on the solid background of patho-logical examinations enables us to evaluate theeffectiveness of experimental clinical trials andleads to correct experimental therapies that fur-ther promote translational research. Our depart-ment also functions as an integrated diagnosis &safety-monitoring laboratory as well as the divi-sion of quality control by examining/evaluatingthe safety of investigational new drugs underGMP conditions.

1. Establishment of GMP-based biosafety ex-amination laboratory (TR verification labo-ratory):

Funded by the Ministry of Education, Culture,

Sports, Science and Technology (MEXST), wehave established a laboratory, in which we ex-amine safeties of material for Translational Re-search (TR) clinical applications, such as theproducts for gene therapy and cell therapy, un-der GMP-based standards. It is now officiallycalled TR verification laboratory. For the presenttime, we are able to examine bacteria, fungi, mi-coplasma, and endotoxin contaminations by us-ing molecular and biochemical techniques. Weare planning to extend this strategy and willconduct “all-inclusive infectious agents examina-tion” facility.

2. Pathological evaluation of cancer immuno-therapy

We have initiated the analysis of surgicalspecimen obtained from the patients under can-cer immuno-therapy conducted in the researchhospital. By applying sophisticated immunohis-tochemical techniques, we now are intensivelyanalyzing materials from cases including GM-CSF-based gene therapy for renal cell carcinomaand dendritic cell-based or peptide-pulsed anti-melanoma immuno-therapy. One of our goals isto evaluate the effectiveness of the therapies and

IMSUT Hospital

Department of Pathology and Laboratory Medicine検査部

Associate Professor Naoki Oyaizu, M.D, Ph.DResearch associate Naouki Isoo, MD, Ph.D.

准教授 部長 医学博士 小柳津 直 樹助 教 医学博士 磯 尾 直 之

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to elucidate the mechanisms of anti-tumor im-mune response elicited by the therapy in situ.

3. Quantitative Evaluation of a fraction of leu-kemia cell by flow cytometry

By collaborations with Dept. Hematology, weare conducting quantitative evaluation of a frac-tion of leukemia cell from a cohort of patientswith HTLV-1 infection by flow cytometry. Byusing sophisticated gating technique, we aresuccessfully quantities ATL (adult T-cell leuke-mia) cells at subclinical stage, hence enable us todetect very early stage of overt leukemia and in-itiate proper therapy.

4. Detection of the new target molecules foradvanced cancer therapy by immune-histochemical technique: :

In recent years, advances in understanding

the molecular pathophysiology of cancer led tothe development of molecular target-baseddrugs such as Herceptin, a monoclonal antibodythat binds to her2 (human epidermal growthfactor receptor 2). Thus it is critical to detect thetarget-molecule expression in target cancer tis-sue and we are able to detect these molecules bysophisticated immune-histochemical techniques.

5. Immunopathogical analysis of hematopoie-tic cell transplantation

A number of allogeneic hematopoietic stemcell transplantation (HSCT), mainly cord bloodtransplantation, has been performed for thetreatment of hematological malignancies. Graft-versus-host disease (GVHD), a life-threateningcomplication, occurs as a complication of alloge-neic HSCT. We are also intending to develop anew way to detect GVHD and make an accurateevaluation of GVHD at our laboratory.

Publications

1. Case of secondary syphilis presenting withunusual complications: syphilic proctitis, gas-tritis, and hepatitis. Adachi E, Koibuchi T,Okame M, Sato H, Imai K, Shimizu S, TsuritaG, Oyaizu N, Iwamoto A, Fujii T. J Clin Mi-crobiol. 49: 4394-6, 2011

2. Shirai K, Inoue I, Kato J, Maeda H, MoribataK, Shingaki N, Ueda K, Deguchi H, MaekitaT, Iguchi M, Yanaoka K, Tamai H, Oka M,Kawai M, Yamaue H, Yasuoka H, NakamuraY, Iso-O N, Ichinose M. A case of a giant glu-cagonoma with parathyroid hormone-relatedpeptide secretion showing an inconsistentpostsurgical endocrine status. Intern Med. 50:1689-94, 2011

3. Kurano M, Iso-O N, Hara M, Ishizaka N,Moriya K, Koike K, Tsukamoto K. LXR ago-nist increases apoE secretion from HepG2spheroid, together with an increased produc-

tion of VLDL and apoE-rich large HDL. Lip-ids Health Dis. 10.134-144 , 2011

4. Endo Y, Suzuki M, Yamada H, Horita S,Kunimi M, Yamazaki O, Shirai A, NakamuraM, Iso-O N, Li Y, Hara M, Tsukamoto K,Moriyama N, Kudo A, Kawakami H,Yamauchi T, Kubota N, Kadowaki T, KumeH, Enomoto Y, Homma Y, Seki G, Fujita T.Thiazolidinediones enhance sodium-coupledbicarbonate absorption from renal proximaltubules via PPARγ-dependent nongenomicsignaling. Cell Metab. 13. 550-61, 2011

5. Kurano M, Iso-O N, Hara M, Noiri E, KoikeK, Kadowaki T, Tsukamoto K.Plant sterols increased IL-6 and TNF-α secre-tion from macrophages, but to a lesser extentthan cholesterol. J Atheroscler Thromb. 18: 373-83, 2011

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Department of Nursing seeks to provide high-quality nursing care and contribute tothe team approach to patient centered care to meet diversified needs, along withchanges in social circumstances and with the progress of medical science. TheCarrier Ladder System introduced in 2011 supports continuous learning and car-rier development of nurses.

One of our missions is “to bring a differenceto patient outcome by the power of nursing.”We hope to provide high-quality care so thatpatients can receive treatment without anxietyor pain, and are empowered to live valuablelife. We also make efforts to prevent infection,pressure ulcer or other complications.

In 2011, we introduced the carrier ladder sys-

tem to support active learning and developmentof nurses. Nursing skills based on good knowl-edge and evidence are also very important inpatient care. The online training tool “NursingSkills Japan” is also introduced in 2011 to sup-port nurses’ learning and brushing up theirskills.

Publications

Kobayashi, H., Takemura, Y., Kanda, K. Patientperception of nursing service quality; an ap-plied model of Donabedian’s structure-process-outcome approach theory. Scandina-vian Journal of Caring Sciences 25(3): 419-25,

2011.武村雪絵．「人を活かす」制度の考え方―人事考課の基本と師長の役割．看護管理，２２�：９４―９８，２０１２．

IMSUT Hospital

Department of Nursing看護部

Director Yukie Takemura, R.N., Ph.D.Deputy Director Kisako Sato, R.N.Nurse Manager Reiko Yamahana, R.N., C.N.S., M.Sc.

Hisako Suyama, R.N.Minayo Hisahara, R.N.Hatsuko Narita, R.N.Keiko Kawasaki, R.N.Taeko Koyane, R.N.Satomi Torisu, R.N.Mika Kogayu, R.N.

看護部長 保健学博士 武 村 雪 絵副看護部長 佐 藤 喜佐子看護師長 専門看護師 山 花 令 子看護師長 須 山 寿 子看護師長 久 原 みな代看護師長 成 田 初 子看護師長 川 崎 敬 子看護師長 小屋根 たえ子看護師長 鳥 巣 里 美看護師長 小 粥 美 香

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Conference Presentation

Fujiwara, N., Ochiai, R., Shirai, Y., Saito, Y.,Matsumoto, K., Nagamura, F., Kazuma, K.Clinical practice provided by clinical researchcoordinators in Phase I cancer research trials:a qualitative study in Japan. The 3rd AnnualConference, International Association of Clini-cal Research Nurses. 2011. 11. 16-18.織田ひとみ．脳神経叢障害予防のための載石位・頭低位の検討．第２５回日本手術看護学会年次大会．名古屋国際会議場．２０１１．１１．５．川崎敬子．看護師がする日常生活動作の把握．第４回血友病理学療法研究会学術集会．横浜ベイシェラトンホテル．２０１１．１０．２．吉田文，鎮西美栄子，山花令子，藤原紀子，武村雪絵，�橋聡，黒川陽介．オピオイド長期使用後の減量，中止に至る，離脱症状のコントロー

ルに長期間を要した一例―３年以上のモルヒネ及びフェンタニルパッチ継続使用からの離脱症例の検討．第５回日本緩和医療薬学会年会．幕張メッセ．２０１１．９．２４―２５．砂田純子，大木桃代．先輩看護師の後輩看護師指導におけるストレスとその対処に関連する介入方法の検討．日本健康心理学会第２４回大会．早稲田大学国際会議場．２０１１．９．１１―１２．

Kobayashi, H., Takemura, Y., Kanda, K. Can In-equities in Nursing Service Be Reduced byNurse Staffing?-An Analysis Based on Qualityas Perceived by Patients-. The 8th World Con-gress on Health Economics Congress. Shera-ton Centre Toronto Hotel, Toronto. 2011. 7.10-13.

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The Department of Pharmacy provides pharmaceutical care services. The presentstaff (9 pharmacists) provides a drug distribution service, complete IV admixturehyperalimentation and chemotherapy preparation services, and adequately pursuesmanagement and supply of drugs.We are also trying to contribute to propel the right use of medicines for patients.

IMSUT Hospital

Department of Pharmacy薬剤部

Director Yosuke Kurokawa 薬剤部長 黒 川 陽 介

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Department of Medical informatics is mainly engaged in information technology ofinfrastructure and operation for medical service and research in the Institute ofMedical Science (IMSUT) Hospital. IMSUT Hospital has introduced a state-of-the-art hospital information system, and every patient can receive better medical care.In addition, we play a leading role in creating infrastructure of regional medical co-operation beyond the framework of the hospital in recent years, and we are alsoplanning support for the operation of the hospital.

1. Management and operation of hospital in-formation system and network

Shigeru Kiryu, Haruyasu Yamada, MakotoWatanabe, Aki Yamauchi, Kanako Arakawa

We have engaged in the management and op-eration of the hospital information system in theIMSUT hospital. We are appropriately workingwith IT service room of IMSUT, and Informa-tion Technology Center of the University of To-kyo. We are obligated to maintain service ofhospital information system and network forbetter medical care, and to ensure the generalityand compatibility of patient medical informationinside and outside of hospitals. Our missionsare as follows:•Operational guidance, supervision, develop-

ment, operation, and management of hospitalinformation system.

•Creation and management of the network in-frastructure and environment handling thenecessary information, along with the adher-ence of information security.

•General day-to-day management on the opera-tion of hospital information system and net-work.

•Work on the review of hospital informationsystem specification.

•General office work concerning the operationof hospital information system and network.

2. Study of the development and introductionof next-generation electronic health recordsystem and network

Shigeru Kiryu, Haruyasu Yamada, MakotoWatanabe.

We aim to reform hospital information systemand to introduce electronic health record systemin IMSUT hospital.

We are also going to interconnect two hospi-tal information networks in the IMSUT hospitaland the University of Tokyo Hospital, under thecooperation with Department of Medical Infor-matics and Economics, Graduate School ofMedicine, the University of Tokyo. For the fu-ture development of translational research, themutual use of medical information is essentialbetween the two hospitals.

3. Regional medical support through the de-velopment and construction of community

IMSUT Hospital

Department of Medical Informatics医療情報部

Associate Professor Shigeru Kiryu, M.D., D.M.Sc.Lecturer Haruyasu Yamada, M.D., D.M.Sc.Assistant Professor Makoto Watanabe, M.D., D.M.Sc.

准教授 医学博士 桐 生 茂講 師 医学博士 山 田 晴 耕助 教 医学博士 渡 邉 慎

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health information network

Shigeru Kiryu, Haruyasu Yamada, MakotoWatanabe

Regional medical cooperation is very impor-tant for the future evolution of the IMSUT hos-pital. We play a leading role in creating infra-structure of regional medical cooperation be-

yond the framework of the IMSUT hospital inrecent years, and we are also planning supportfor the operation of the hospital. We are consid-ering that introduction of the electronic healthrecord network will be able to improve to intro-duce among regional clinic, hospital, and theIMSUT hospital in the regional medical coopera-tion.

Publications

None.

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