Bio


Hiroyuki Shimada, MD, PhD, FRCPA (Hon), is Professor of Pathology and of Pediatrics at the Stanford University Medical Center. He was born in Tokyo, Japan, and completed MD (1973) and PhD (1982) at the Yokohama City University School of Medicine, Yokohama, Japan, and also completed his pathology training at the Children's Hospital (now the Nationwide Children’s Hospital) and the Ohio State University, Columbus, Ohio, USA (1988). Before moving to the Stanford University in 2019, he was Professor of Pathology (Clinical Scholar) at the University of Southern California Keck School of Medicine and working at the Children’s Hospital Los Angeles.
Dr. Shimada was Chair of the International Neuroblastoma Pathology Committee (1999-2017) and the founder of the International Neuroblastoma Pathology Classification (INPC). As Director of the COG (Children’s Oncology Group) Neuroblastoma Pathology Reference Laboratory (since 2001), he has been actively reviewing pathology samples of ~700 neuroblastoma cases per year from United States, Canada, Australia, and New Zealand. Pathology review results according to the INPC have been providing critical information for patient stratification and protocol assignment in the COG international neuroblastoma clinical trials.

Clinical Focus


  • Pathology
  • neuroblastoma

Academic Appointments


Honors & Awards


  • Enid Gilbert-Barness Prize, Society for Pediatric Pathology (2018)
  • Honorary Fellowship, Royal College of Pathologists of Australasia (2012)
  • Eleanor Humpherys Visiting Professorship, University of Chicago (2005)
  • Lotte Straus Prize, Society for Pediatric Pathology (1989)

Professional Education


  • Residency:Nationwide Children's Hospital (1988) OH
  • Board Certification: Pathology, Japanese Society of Pathology (1981)
  • Medical Education:Yokohama City University School of Medicine (1973) Japan

All Publications


  • Replicating and identifying large cell neuroblastoma using high-dose intra-tumoral chemotherapy and automated digital analysis. Journal of pediatric surgery Taylor, J. S., Sha, L., Ikegaki, N., Zeki, J., Deaton, R., Harris, J., Coburn, J., Yavuz, B., Sethi, A., Shimada, H., Kaplan, D. L., Gann, P., Chiu, B. 2019

    Abstract

    PURPOSE: Large cell neuroblastomas (LCN) are frequently seen in recurrent, high-risk neuroblastoma but are rare in primary tumors. LCN, characterized by large nuclei with prominent nucleoli, predict a poor prognosis. We hypothesize that LCN can be created with high-dose intra-tumoral chemotherapy and identified by a digital analysis system.METHODS: Orthotopic mouse xenografts were created using human neuroblastoma and treated with high-dose chemotherapy delivered locally via sustained-release silk platforms, inducing tumor remission. After recurrence, LCN populations were identified on H&E sections manually. Clusters of typical LCN and non-LCN cells were divided equally into training and test sets for digital analysis. Marker-controlled watershed segmentation was used to identify nuclei and characterize their features. Logistic regression was developed to distinguish LCN from non-LCN.RESULTS: Image analysis identified 15,000 nuclei and characterized 70 nuclear features. A 19-feature model provided AUC >0.90 and 100% accuracy when >30% nuclei/cluster were predicted as LCN. Overall accuracy was 87%.CONCLUSIONS: We recreated LCN using high-dose chemotherapy and developed an automated method for defining LCN histologically. Features in the model provide insight into LCN nuclear phenotypic changes that may be related to increased activity. This model could be adapted to identify LCN in human tumors and correlated with clinical outcomes.

    View details for DOI 10.1016/j.jpedsurg.2019.08.022

    View details for PubMedID 31519361

  • Down-regulation of MYCN protein by CX-5461 leads to neuroblastoma tumor growth suppression Taylor, J. S., Zeki, J., Ornell, K., Coburn, J., Shimada, H., Ikegaki, N., Chiu, B. W B SAUNDERS CO-ELSEVIER INC. 2019: 1192–97
  • Down-regulation of MYCN protein by CX-5461 leads to neuroblastoma tumor growth suppression. Journal of pediatric surgery Taylor, J. S., Zeki, J., Ornell, K., Coburn, J., Shimada, H., Ikegaki, N., Chiu, B. 2019

    Abstract

    PURPOSE: MYCN oncogene amplification is an independent predictor of poor prognosis in neuroblastoma. CX-5461 is a small molecular inhibitor that prevents initiation of ribosomal RNA (rRNA) synthesis by RNA Pol I, down-regulating MYCN/MYC proteins. We hypothesize that neuroblastoma tumor growth can be suppressed by CX-5461.METHODS: MYCN-amplified (KELLY, IMR5) and nonamplified (SY5Y, SKNAS) neuroblastoma cells were treated with CX-5461. MYCN/MYC expression after 24-48 h was determined by Western blot. Orthotopic neuroblastoma tumors created in mice using KELLY cells were treated with CX-5461-loaded silk films implanted locally. Tumor growth was monitored using ultrasound. Histologic evaluation of tumors was performed.RESULTS: IC50 for KELLY, IMR5, SY5Y, and SKNAS cells to CX-5461 was 0.75 muM, 0.02 muM, 0.8 muM, and 1.7 muM, respectively. CX-5461 down-regulated MYCN and MYC proteins at 0.25-1.0 muM on Western blot analysis. CX-5461-loaded silk film released 23.7±3 mug of the drug in 24 h and 48.2±3.9 mug at 120 h. KELLY tumors treated with CX-5461-loaded film reached 800 mm3 after 7.8±1.4 days, while those treated with control film reached the same size on 5.1±0.6 days (p=0.03). CX-5461-treated tumors showed collapse of nucleolar hypertrophy and MYCN protein downregulation.CONCLUSION: We demonstrated that local delivery of CX-5461 via sustained release platform can suppress orthotopic neuroblastoma tumor growth, especially those with MYCN/MYC overexpression.

    View details for PubMedID 30879743

  • Anti-CD105 Antibody Eliminates Tumor Microenvironment Cells and Enhances Anti-GD2 Antibody Immunotherapy of Neuroblastoma with Activated Natural Killer Cells. Clinical cancer research : an official journal of the American Association for Cancer Research Wu, H. W., Sheard, M. A., Malvar, J., Fernandez, G. E., DeClerck, Y. A., Blavier, L., Shimada, H., Theuer, C. P., Sposto, R., Seeger, R. C. 2019; 25 (15): 4761–74

    Abstract

    We determined whether elimination of CD105+ cells in the tumor microenvironment (TME) with anti-CD105 antibodies enhanced anti-disialoganglioside (GD2) antibody dinutuximab therapy of neuroblastoma when combined with activated natural killer (aNK) cells.The effect of MSCs and monocytes on antibody-dependent cellular cytotoxicity (ADCC) mediated by dinutuximab with aNK cells against neuroblastoma cells was determined in vitro. ADCC with anti-CD105 mAb TRC105 and aNK cells against MSCs, monocytes, and endothelial cells, which express CD105, was evaluated. Anti-neuroblastoma activity in immunodeficient NSG mice of dinutuximab with aNK cells without or with anti-CD105 mAbs was determined using neuroblastoma cell lines and a patient-derived xenograft.ADCC mediated by dinutuximab with aNK cells against neuroblastoma cells in vitro was suppressed by addition of MSCs and monocytes, and dinutuximab with aNK cells was less effective against neuroblastomas formed with coinjected MSCs and monocytes in NSG mice than against those formed by tumor cells alone. Anti-CD105 antibody TRC105 with aNK cells mediated ADCC against MSCs, monocytes, and endothelial cells. Neuroblastomas formed in NSG mice by two neuroblastoma cell lines or a patient-derived xenograft coinjected with MSCs and monocytes were most effectively treated with dinutuximab and aNK cells when anti-human (TRC105) and anti-mouse (M1043) CD105 antibodies were added, which depleted human MSCs and murine endothelial cells and macrophages from the TME.Immunotherapy of neuroblastoma with anti-GD2 antibody dinutuximab and aNK cells is suppressed by CD105+ cells in the TME, but suppression is overcome by adding anti-CD105 antibodies to eliminate CD105+ cells.

    View details for DOI 10.1158/1078-0432.CCR-18-3358

    View details for PubMedID 31068371

  • MYC-family protein overexpression and prominent nucleolar formation represent prognostic indicators and potential therapeutic targets for aggressive high-MKI neuroblastomas: a report from the children's oncology group. Oncotarget Niemas-Teshiba, R., Matsuno, R., Wang, L. L., Tang, X. X., Chiu, B., Zeki, J., Coburn, J., Ornell, K., Naranjo, A., Van Ryn, C., London, W. B., Hogarty, M. D., Gastier-Foster, J. M., Look, A. T., Park, J. R., Maris, J. M., Cohn, S. L., Seeger, R. C., Asgharzadeh, S., Ikegaki, N., Shimada, H. 2018; 9 (5): 6416–32

    Abstract

    Neuroblastomas with a high mitosis-karyorrhexis index (High-MKI) are often associated with MYCN amplification, MYCN protein overexpression and adverse clinical outcome. However, the prognostic effect of MYC-family protein expression on these neuroblastomas is less understood, especially when MYCN is not amplified. To address this, MYCN and MYC protein expression in High-MKI cases (120 MYCN amplified and 121 non-MYCN amplified) was examined by immunohistochemistry. The majority (101) of MYCN-amplified High-MKI tumors were MYCN(+), leaving one MYC(+), 2 both(+), and 16 both(-)/(+/-), whereas non-MYCN-amplified cases appeared heterogeneous, including 7 MYCN(+), 36 MYC(+), 3 both(+), and 75 both(-)/(+/-) tumors. These MYC-family proteins(+), or MYC-family driven tumors, were most likely to have prominent nucleolar (PN) formation (indicative of augmented rRNA synthesis). High-MKI neuroblastoma patients showed a poor survival irrespective of MYCN amplification. However, patients with MYC-family driven High-MKI neuroblastomas had significantly lower survival than those with non-MYC-family driven tumors. MYCN(+), MYC-family protein(+), PN(+), and clinical stage independently predicted poor survival. Specific inhibition of hyperactive rRNA synthesis and protein translation was shown to be an effective way to suppress MYC/MYCN protein expression and neuroblastoma growth. Together, MYC-family protein overexpression and PN formation should be included in new neuroblastoma risk stratification and considered for potential therapeutic targets.

    View details for PubMedID 29464082

    View details for PubMedCentralID PMC5814222

  • Dose Escalation Study of No-Carrier-Added I-131-Metaiodobenzylguanidine for Relapsed or Refractory Neuroblastoma: New Approaches to Neuroblastoma Therapy Consortium Trial JOURNAL OF NUCLEAR MEDICINE Matthay, K. K., Weiss, B., Villablanca, J. G., Maris, J. M., Yanik, G. A., DuBois, S. G., Stubbs, J., Groshen, S., Tsao-Wei, D., Hawkins, R., Jackson, H., Goodarzian, F., Daldrup-Link, H., Panigrahy, A., Towbin, A., Shimada, H., Barrett, J., LaFrance, N., Babich, J. 2012; 53 (7): 1155-1163

    Abstract

    (131)I-metaiodobenzylguanidine (MIBG) is specifically taken up in neuroblastoma, with a response rate of 20%-37% in relapsed disease. Nonradioactive carrier MIBG molecules inhibit uptake of (131)I-MIBG, theoretically resulting in less tumor radiation and increased risk of cardiovascular toxicity. Our aim was to establish the maximum tolerated dose of no-carrier-added (NCA) (131)I-MIBG, with secondary aims of assessing tumor and organ dosimetry and overall response.Eligible patients were 1-30 y old with resistant neuroblastoma, (131)I-MIBG uptake, and cryopreserved hematopoietic stem cells. A diagnostic dose of NCA (131)I-MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. The treatment dose of NCA (131)I-MIBG (specific activity, 165 MBq/μg) was adjusted as necessary on the basis of critical organ tolerance limits. Autologous hematopoietic stem cells were infused 14 d after therapy to abrogate prolonged myelosuppression. Response and toxicity were evaluated on day 60. The NCA (131)I-MIBG was escalated from 444 to 777 MBq/kg (12-21 mCi/kg) using a 3 + 3 design. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/μL within 28 d or platelets to greater than 20,000/μL within 56 d, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions.Three patients each were evaluable at 444, 555, and 666 MBq/kg without DLT. The dose of 777 MBq/kg dose was not feasible because of organ dosimetry limits; however, 3 assigned patients were evaluable for a received dose of 666 MBq/kg, providing a total of 6 patients evaluable for toxicity at 666 MBq/kg without DLT. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight patients had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. Four of 15 patients had a complete (n = 1) or partial (n = 3) response, 1 had a mixed response, 4 had stable disease, and 6 had progressive disease.NCA (131)I-MIBG with autologous peripheral blood stem cell transplantation is feasible at 666 MBq/kg without significant nonhematologic toxicity and with promising activity.

    View details for DOI 10.2967/jnumed.111.098624

    View details for Web of Science ID 000306164600033

    View details for PubMedID 22700000

  • Outcome analysis of non-high-risk neuroblastoma patients enrolled on Children's Oncology Group trials P9641 and A3961 Meany, H., Attiyeh, E. F., Naranjo, A., Twist, C., London, W. B., Villablanca, J., Schmidt, M., Baker, D., Strother, D. R., Shimada, H., Matthay, K. K., Cohn, S., Maris, J. M., Park, J. R. AMER SOC CLINICAL ONCOLOGY. 2012
  • Current Treatment Protocols Have Eliminated the Prognostic Advantage of Type 1 Fusions in Ewing Sarcoma: A Report From the Children's Oncology Group JOURNAL OF CLINICAL ONCOLOGY van Doorninck, J. A., Ji, L., Schaub, B., Shimada, H., Wing, M. R., Krailo, M. D., Lessnick, S. L., Marina, N., Triche, T. J., Sposto, R., Womer, R. B., Lawlor, E. R. 2010; 28 (12): 1989-1994

    Abstract

    PURPOSE Ewing sarcoma family tumors (ESFTs) exhibit chromosomal translocations that lead to the creation of chimeric fusion oncogenes. Combinatorial diversity among chromosomal breakpoints produces varying fusions. The type 1 EWS-FLI1 transcript is created as a result of fusion between exons 7 of EWS and 6 of FLI1, and retrospective studies have reported that type 1 tumors are associated with an improved outcome. We have re-examined this association in a prospective cohort of patients with ESFT treated according to current Children's Oncology Group (COG) treatment protocols. METHODS Frozen tumor tissue was prospectively obtained from patients diagnosed with ESFT, and reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine translocation status. Analysis was confined to patients with localized tumors who were diagnosed after 1994 and treated according to COG protocols. Translocation status was correlated with disease characteristics, event-free survival (EFS), and overall survival (OS). Results RT-PCR identified chimeric fusion oncogenes in 119 of 132 ESFTs. Eighty-nine percent of identified transcripts were EWS-FLI1, and of these, 58.8% were type 1. Five-year EFS and OS rates for patients with type 1 and non-type 1 fusions diagnosed between 2001 and 2005 were equivalent (type 1: EFS, 63% +/- 7%; OS, 83% +/- 6%; non-type 1: EFS, 71% +/- 9%; OS, 79% +/- 8%). CONCLUSION Current intensive treatment protocols for localized ESFT have erased the clinical disadvantage that was formerly observed in patients with non-type 1 EWS-FLI1 fusions.

    View details for DOI 10.1200/JCO.2009.24.5845

    View details for Web of Science ID 000276764000006

    View details for PubMedID 20308669

    View details for PubMedCentralID PMC2860404

  • Mouse mesenchymal stem cells expressing PAX-FKHR form alveolar rhabdomyosarcomas by cooperating with secondary mutations CANCER RESEARCH Ren, Y., Finckenstein, F., Abdueva, D. A., Shahbazian, V., Chung, B., Weinberg, K. I., Triche, T. J., Shimada, H., Anderson, M. J. 2008; 68 (16): 6587–97

    Abstract

    Alveolar rhabdomyosarcomas (ARMS) are highly malignant soft-tissue sarcomas that arise in children, adolescents, and young adults. Although formation and expression of the PAX-FKHR fusion genes is thought to be the initiating event in this cancer, the role of PAX-FKHR in the neoplastic process remains largely unknown in a progenitor cell that is undefined. We hypothesize that PAX-FKHR determine the ARMS progenitor to the skeletal muscle lineage, which when coupled to the inactivation and/or activation of critical cell signaling pathways leads to the formation of ARMS. Because a number of studies have proposed that mesenchymal stem cells (MSC) are the progenitor for several of the sarcomas, we tested this hypothesis in MSCs. We show that PAX-FKHR induce skeletal myogenesis in MSCs by transactivating MyoD and myogenin. Despite exhibiting enhanced growth in vitro, the PAX-FKHR-expressing populations do not form colonies in soft agar or tumors in mice. Expression of dominant-negative p53, or the SV40 early region, elicits tumor formation in some of the PAX-FKHR-expressing populations. Additional activation of the Ras signaling pathway leads to highly malignant tumor formation for all of the populations. The PAX-FKHR-expressing tumors were shown to have histologic, immunohistochemical, and gene expression profiles similar to human ARMS. Our results show the critical role played by PAX-FKHR in determining the molecular, myogenic, and histologic phenotype of ARMS. More importantly, we identify MSCs as a progenitor that can give rise to ARMS.

    View details for DOI 10.1158/0008-5472.CAN-08-0859

    View details for Web of Science ID 000258548200015

    View details for PubMedID 18701482

  • Primary and metastatic rhabdomyosarcoma in the breast: Neoplasms of adolescent females, a report from the intergroup rhabdomyosarcoma study MEDICAL AND PEDIATRIC ONCOLOGY Hays, D. M., Donaldson, S. S., Shimada, H., Crist, W. M., Newton, W. A., Andrassy, R. J., Wiener, E., Green, J., Triche, T., Maurer, H. M. 1997; 29 (3): 181-189

    Abstract

    The occurrence of rhabdomyosarcoma (RMS) primary in or metastatic to breast has been regarded as an uncommon event, associated with an unfavorable outcome. Records of 26 patients with diagnoses of breast RMS, either primary or secondary, entered in the Intergroup Rhabdomyosarcoma Study (IRS) (1972-1992) were reviewed and compared with data regarding 47 similar patients in published reports. Of the 26 IRS cases, the histologic subtype was alveolar in 24, embryonal in 1, and not determined in 1. All were female with ages ranging from 11.5 to 20.2 years (median, 15.2 years; mode, 14-16 years). This compact age distribution of both primary (n = 7) and metastatic (n = 19) breast RMS was seen in previously reported series. Among the 19 cases of RMS with initial dissemination to breast, primary tumor sites, were extremity (n = 8), nasopharynx/paranasal sinuses (n = 7), and trunk (n = 4). IRS treatment was risk-based according to site and extent of disease. Four of 7 patients with primary RMS remain disease free 2.9 to 7 years post diagnosis. Among 19 patients with RMS initially metastatic to breast, including 7 in IRS clinical group IV at original diagnosis, three are disease free at 7.6, 15.7 and 17.0 years. Conclusions: primary or metastatic RMS in breast is almost confined to adolescent females having tumors with alveolar histology. Approximately one-half of the patients with primary breast disease and 15% of those with metastatic breast disease as an initial recurrence are long-term survivors.

    View details for Web of Science ID A1997XH25700004

    View details for PubMedID 9212842