Boards, Advisory Committees, Professional Organizations

  • Board certified member, The Japanese society of internal medicine (2007 - Present)

Professional Education

  • Doctor of Medicine, Oita University (2003)
  • Residency, Kyushu University Hospital, JPN (2004)
  • Residency, Hamanomachi Hospital, JPN (2005)
  • Fellowship, Kyushu University Hospital, JPN, Oncology (2006)
  • Doctor of Philosophy, Kyushu University (2012)
  • Fellowship, Kyushu University Hospital, JPN, Oncology (2012)

Stanford Advisors


All Publications

  • Analysis of Adverse Events of Bevacizumab-containing Systemic Chemotherapy for Metastatic Colorectal Cancer in Japan. Anticancer research Isobe, T., Uchino, K., Makiyama, C., Ariyama, H., Arita, S., Tamura, S., Komoda, M., Kusaba, H., Shirakawa, T., Esaki, T., Mitsugi, K., Takaishi, S., Akashi, K., Baba, E. 2014; 34 (4): 2035-40


    Bevacizumab (BV) is widely used in chemotherapy for metastatic colorectal cancer (mCRC). Although specific adverse events have been observed, their risk factors have not been clarified.178 mCRC patients who underwent chemotherapy were retrospectively examined and correlations between possible risk factors and adverse events were analyzed.87 out of 178 patients were treated with BV-containing chemotherapy. Possible risk factors for BV-related adverse events were: remaining primary tumor, current bleeding, history of arterial thromboembolism (ATE), hypertension, and proteinuria, and these were observed in 22%, 2%, 7%, 16%, and 8% of patients, respectively. Patients with hypertension prior to chemotherapy developed significantly worse hypertension (p=0.018). Gastrointestinal bleeding occurred in 3 out of 18 patients with residual primary tumor (16.7%) and 6 out of 63 patients with no primary tumor (8.7%) (p=0.385).Pre-existing hypertension appears to be a risk factor for BV-related deterioration of hypertension.

    View details for PubMedID 24692744

  • miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. eLife Isobe, T., Hisamori, S., Hogan, D. J., Zabala, M., Hendrickson, D. G., Dalerba, P., Cai, S., Scheeren, F., Kuo, A. H., Sikandar, S. S., Lam, J. S., Qian, D., Dirbas, F. M., Somlo, G., Lao, K., Brown, P. O., Clarke, M. F., Shimono, Y. 2014; 3


    MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression.

    View details for DOI 10.7554/eLife.01977

    View details for PubMedID 25406066

  • Human STEAP3 maintains tumor growth under hypoferric condition EXPERIMENTAL CELL RESEARCH Isobe, T., Baba, E., Arita, S., Komoda, M., Tamura, S., Shirakawa, T., Ariyama, H., Takaishi, S., Kusaba, H., Ueki, T., Akashi, K. 2011; 317 (18): 2582-2591


    Iron is essential in cellular proliferation and survival based on its crucial roles in DNA and ATP synthesis. Tumor cells proliferate rapidly even in patients with low serum iron, although their actual mechanisms are not well known. To elucidate molecular mechanisms of efficient tumor progression under the hypoferric condition, we studied the roles of six-transmembrane epithelial antigen of the prostate family member 3 (STEAP3), which was reported to facilitate iron uptake. Using Raji cells with low STEAP3 mRNA expression, human STEAP3-overexpressing cells were established. The impact of STEAP3 expression was analyzed about the amount of iron storage, the survival under hypoferric conditions in vitro and the growth of tumor in vivo. STEAP3 overexpression increased ferritin, an indicator of iron storage, in STEAP3-overexpressing Raji cells. STEAP3 gave Raji cells the resistance to iron deprivation-induced apoptosis. These STEAP3-overexpressing Raji cells preserved efficient growth even in hypoferric mice, while parental Raji cells grew less rapidly. In addition, iron deficiency enhanced STEAP3 mRNA expression in tumor cells. Furthermore, human colorectal cancer tissues exhibited more STEAP3 mRNA expression and iron storage compared with normal colon mucosa. These findings indicate that STEAP3 maintains iron storage in human malignant cells and tumor proliferation under the hypoferric condition.

    View details for DOI 10.1016/j.yexcr.2011.07.022

    View details for Web of Science ID 000295909200004

    View details for PubMedID 21871451

  • Effective monotherapy with amrubicin for a refractory extrapulmonary small-cell carcinoma of the liver. Case reports in medicine Isobe, T., Yanai, S., Kusaba, H., Yada, S., Kuroda, Y., Tamiya, S., Matsumoto, T., Baba, E., Harada, M. 2009; 2009: 538081-?


    Small-cell carcinoma of the liver is a rare neoplasm, and no standard treatment for it has yet been established. A 72-year-old man with an extensive disease stage of small-cell carcinoma of the liver was treated with systemic chemotherapy consisting of cisplatin and etoposide (PE) followed by irinotecan. Although the masses were markedly decreased once after the sixth course of PE, amrubicin monotherapy as third-line chemotherapy was started because the hepatic masses had increased again. The administration of amrubicin was repeated in 8 courses with regression of the disease, resulting in a 26-month survival since the first-line chemotherapy was started. This is the first case report of a refractory EPSCC successfully treated with amrubicin.

    View details for DOI 10.1155/2009/538081

    View details for PubMedID 19718248

  • Autoimmune thrombocytopenia with clonal expansion of CD8-positive T cells after autologous peripheral blood stem cell transplantation for diffuse large B-cell lymphoma BONE MARROW TRANSPLANTATION Isobe, T., Tanimoto, T. E., Nakaji, G., Miyamoto, T., Yamasaki, S., Takase, K., Numata, A., Fukuda, T., Nagafuji, K., Inaba, S., Harada, M. 2005; 35 (3): 315-316

    View details for DOI 10.1038/sj.bmt.1704750

    View details for Web of Science ID 000226543300016

    View details for PubMedID 15568035

  • Organoid Culture of Human Cancer Stem Cells. Methods in molecular biology (Clifton, N.J.) Shimono, Y., Mukohyama, J., Isobe, T., Johnston, D. M., Dalerba, P., Suzuki, A. 2016


    Organoid culture is a three-dimensional culture method that enables ex vivo analysis of stem cell behavior and differentiation. This method is also applicable to the studies on stem cell characters of human cancer stem cells. The components of organoid culture include Matrigel® and a culture medium containing growth factor cocktails that mimic the microenvironments of organ stem cell niches. Here, we describe the basic methods for the organoid culture of dissociated or FACS-sorted human cancer stem cells. Then, we introduce a method to dissociate the organoids for serial passage and propagation.

    View details for DOI 10.1007/7651_2016_13

    View details for PubMedID 27654995

  • Amrubicin monotherapy for patients with extrapulmonary neuroendocrine carcinoma after platinum-based chemotherapy. Cancer chemotherapy and pharmacology Nio, K., Arita, S., Isobe, T., Kusaba, H., Kohashi, K., Kajitani, T., Tamura, S., Hirano, G., Mitsugi, K., Makiyama, A., Esaki, T., Ariyama, H., Oda, Y., Akashi, K., Baba, E. 2015


    Extrapulmonary neuroendocrine carcinomas (EPNEC) are rarely observed and are associated with poor outcomes. Based on the clinicopathological similarity, treatment used for small cell lung carcinoma has also been employed for EPNEC, but the response to such therapy has not been well examined. The goal of this study was to investigate amrubicin (AMR) monotherapy as a salvage therapy for EPNEC arising from digestive organs.Patients with EPNEC of the digestive organs who had prior platinum-based chemotherapy and were subsequently treated with AMR between July 2005 and December 2013 at any one of four institutions were retrospectively examined to characterize the safety and efficacy of AMR.Thirteen patients (ten males, three females; median age 64 years) were examined. Primary cancer sites included stomach (n = 6), rectum (n = 3), esophagus (n = 2), liver (n = 1) and pancreas (n = 1). Prior irinotecan- and etoposide-containing chemotherapies were used in ten and six patients, respectively. Median initial dose of AMR was 40 mg/m(2)/day for three consecutive days, and median of treatment cycles was 4 (range 1-9). The objective response rate (ORR) was 38.5 %. Median progression-free survival (PFS) and overall survival (OS) were 107 (range 22-275) and 215 days (range 71-535), respectively. Common severe adverse events (grade 3/4) were neutropenia (84.6 %) and febrile neutropenia (30.8 %). Patient with longer platinum-free interval (>90 days) exhibited longer PFS and OS than those with shorter platinum-free interval (190 vs. 63 days and 348 vs. 145 days, respectively).AMR showed evidence of clinical activity and safety when used for the treatment of EPNEC. It might be especially useful for populations with sensitive relapse.

    View details for DOI 10.1007/s00280-015-2706-y

    View details for PubMedID 25702050

  • Systemic chemotherapy for metastatic non-mucinous appendiceal adenocarcinoma: a case report and literature review International Cancer Conference Journal Tsuchihashi, K., Takayoshi, K., Uchino, K., Shirakawa, T., Kumagai, H., Tamura, S., Komoda, M., Isobe, T., Kusaba, H., Aishima, S., Akashi, K., Baba, E. 2013; 2 (1): 36-40
  • Human Nanog pseudogene8 promotes the proliferation of gastrointestinal cancer cells EXPERIMENTAL CELL RESEARCH Uchino, K., Hirano, G., Hirahashi, M., Isobe, T., Shirakawa, T., Kusaba, H., Baba, E., Tsuneyoshi, M., Akashi, K. 2012; 318 (15): 1799-1807


    There is emerging evidence that human solid tumor cells originate from cancer stem cells (CSCs). In cancer cell lines, tumor-initiating CSCs are mainly found in the side population (SP) that has the capacity to extrude dyes such as Hoechst 33342. We found that Nanog is expressed specifically in SP cells of human gastrointestinal (GI) cancer cells. Nucleotide sequencing revealed that NanogP8 but not Nanog was expressed in GI cancer cells. Transfection of NanogP8 into GI cancer cell lines promoted cell proliferation, while its inhibition by anti-Nanog siRNA suppressed the proliferation. Immunohistochemical staining of primary GI cancer tissues revealed NanogP8 protein to be strongly expressed in 3 out of 60 cases. In these cases, NanogP8 was found especially in an infiltrative part of the tumor, in proliferating cells with Ki67 expression. These data suggest that NanogP8 is involved in GI cancer development in a fraction of patients, in whom it presumably acts by supporting CSC proliferation.

    View details for DOI 10.1016/j.yexcr.2012.04.011

    View details for Web of Science ID 000306820200001

    View details for PubMedID 22677041

  • Improvement of quality of life and survival using self-expandable metal stent placement for severe malignant stenosis of the gastric body: a case report. Journal of medical case reports Kumagai, H., Nio, K., Shirakawa, T., Uchino, K., Kusaba, H., Isobe, T., Komoda, M., Tamura, S., Maeyama, R., Nagai, E., Akashi, K., Baba, E. 2012; 6 (1): 315-?


    Advanced gastric carcinoma often decreases quality of life because of upper gastrointestinal tract stenosis. Self-expandable metal stents have been thought to be an effective, minimally invasive treatment for stenosis. However, the effectiveness of self-expandable metal stent placement for carcinomatous stenosis of the gastric body and antrum has not been clarified, and there have been few reports of such cases.A 74-year-old Japanese woman developed stenosis of the gastric body and antrum caused by advanced gastric cancer during first-line chemotherapy. She developed weight loss and poor nutrition due to inadequate intake. Self-expandable metal stent placement for stenosis of the gastric body and antrum ameliorated her symptoms rapidly and improved her general condition and quality of life. Eight days after self-expandable metal stent placement, second-line chemotherapy could be administered safely. Oral intake and nutritional status were maintained for 117 days after self-expandable metal stent placement, and she died of gastric cancer 176 days after self-expandable metal stent placement and initiation of second-line chemotherapy.Self-expandable metal stent placement for carcinomatous stenosis in the gastric body and antrum could be an effective therapeutic strategy for patients with inadequate oral uptake. It may provide rapid improvement of the patient's general condition and oral intake with minimal complications, comparatively long-term symptom relief, and a survival benefit by allowing second-line chemotherapy.

    View details for DOI 10.1186/1752-1947-6-315

    View details for PubMedID 22992342

  • Irinotecan-based combination chemotherapy for metastatic small intestinal adenocarcinoma ONCOLOGY LETTERS Shibata, Y., Baba, E., Ariyama, H., Arita, S., Isobe, T., Kusaba, H., Mitsugi, K., Nakano, S., Akashi, K. 2010; 1 (3): 423-426
  • Schedule-dependent synergistic interaction between gemcitabine and oxaliplatin in human gallbladder adenocarcinoma cell lines ANTI-CANCER DRUGS Makiyama, A., Qin, B., Uchino, K., Shibata, Y., Arita, S., Isobe, T., Hirano, G., Kusaba, H., Baba, E., Akashi, K., Nakano, S. 2009; 20 (2): 123-130


    To define the most effective combination schedule of gemcitabine and oxaliplatin (L-OHP), we investigated the in-vitro interaction between these drugs in a panel of four human gallbladder adenocarcinoma cell lines (HAG-1, GB-d1, NOZ, and G-415). Cytotoxic activity was determined by the WST-1 assay. Different schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation and apoptosis were evaluated by flow cytometry. Simultaneous and sequential treatments of gemcitabine followed by L-OHP exhibited synergistic effects in all four cell lines, whereas the reverse sequence largely showed an antagonism. Gemcitabine exclusively arrested cells at the G0/G1 phase, and L-OHP at the G2/M phase, as measured by flow cytometric analyses. Apoptosis was most prominent when cells were treated simultaneously or in a sequence gemcitabine followed by L-OHP, producing apoptosis in treated cells (27-30%). In contrast, the reverse sequence yielded only 6-7% induction of apoptosis, the rate being not significantly different from those induced by each drug singly. Moreover, this sequence dependence was further confirmed by the experiment, which compared the number of HAG-1 cells 7 days after these combination schedules. These findings suggest that the interaction of gemcitabine and L-OHP is highly schedule dependent, with the most efficacious interaction observed in either simultaneous combination or in a sequence combination of gemcitabine followed by L-OHP.

    View details for DOI 10.1097/CAD.0b013e3283218080

    View details for Web of Science ID 000263125500007

    View details for PubMedID 19209029

  • B cell activation regulates exosomal HLA production EUROPEAN JOURNAL OF IMMUNOLOGY Arita, S., Baba, E., Shibata, Y., Niiro, H., Shimoda, S., Isobe, T., Kusaba, H., Nakano, S., Harada, M. 2008; 38 (5): 1423-1434


    Exosomes are nanovesicles produced constitutively and inducibly by several types of cells. They are generated as intraluminal vesicles of multivesicular bodies and express MHC and several endosomal/lysosomal proteins. In spite of their potential role in cellular immunity, the regulatory mechanisms of exosome production are largely unknown. In this study, we have established a novel ELISA system to quantify exosomal HLA using a combination of anti-HLA class I and anti-HLA-DR mAb. We found that exosomal HLA production of B cells was enhanced by contact with CD4(+) T cells. Neutralizing anti-CD154 (CD40L) mAb inhibited this effect, and a soluble CD40L significantly increased production of exosomal HLA in B cells. In addition, B cell stimulation via BCR and TLR9 enhanced their production while IL-4 stimulation alone failed to do so. Strikingly, an inhibitor of the classical NF-kappaB pathway drastically inhibited exosomal HLA production in stimulated B cells, indicating that the classical NF-kappaB pathway is critical for exosomal HLA production in B cells. Together, these findings suggest a pivotal role of B cell activation in exosomal HLA production in vivo.

    View details for DOI 10.1002/eji.200737694

    View details for Web of Science ID 000256073400026

    View details for PubMedID 18425730

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