Molecular imaging of DNA synthesis rate of malignant brain tumor using newly developed positron labelled pharmaceutical.

• Project/Area Number: 23390344
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NARIAI Tadashi 東京医科歯科大学, 医歯(薬)学総合研究科, 准教授 (00228090)
• Co-Investigator(Kenkyū-buntansha): TOYOHARA Jun 東京都健康長寿医療センター研究所, 専門副部長 (50425659) ; MATSUMURA Akira 筑波大学, 医学医療系(人間総合科学研究所), 教授 (90241819) ; TANAKA Yoji 東京医科歯科大学, 医学部附属病院, 講師 (80323682)
• Co-Investigator(Renkei-kenkyūsha): TANAKA Yoji 東京医科歯科大学, 医学部附属病院, 講師 (80323682)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2013: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2012: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: PET / glioma / glioblastoma / thiothymidine / methionine / inflammation / inflamation / DNA / thiotymidine / 悪性グリオーマ / 転移性脳腫瘍 / DNA合成 / チオチミジン / 4DST

Outline of Final Research Achievements

4’-[methyl-11C]thiotymidine（4DST) is a newly developed positron labelled pharmaceutical by our group incorporation of which into DNA compartment of in vivo tumor was confirmed for the first time.
In the present clinical trial, we have undergone 86 scans of brain tumor or the suspects of brain tumor patients using 4DST together with 11C methionine, most widely used PET ligand for brain tumor in Japan, and compared the characteristics of 4DST imaging. Among all type of glioma, 4DST was confirmed to incorporate by reflecting proliferation rate of tumor cell more precisely than 11C methionine. 4DST was incorporated into malignant brain tumor infiltrating into the area with intact blood brain barrier. 4DST was revealed to be the most suitable PET probe to distinguish acute inflammation from malignant brain tumor. Further clinical trial is going on now.

Research Products

• [Journal Article] Comparison of 4'-[methyl-(11)C]thiothymidine ((11)C-4DST) and 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) PET/CT in human brain glioma imaging (2015)
  • Author(s): Toyota, Y. Miyake, K. Kawai, N. Hatakeyama, T. Yamamoto, Y. Toyohara, J. Nishiyama, Y. Tamiya, T.
  • Journal Title: EJNMMI Res Volume: 5 Issue: 1 Pages: 7-7
  • DOI: 10.1186/s13550-015-0085-3
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of (11)C-4'-thiothymidine, (11)C-methionine, and (18)F-FDG PET/CT for the detection of active lesions of multiple myeloma (2015)
  • Author(s): Okasaki, M. Kubota, K. Minamimoto, R. Miyata, Y. Morooka, M. Ito, K. Ishiwata, K. Toyohara, J. Inoue, T. Hirai, R. Hagiwara, S. Miwa, A.
  • Journal Title: Ann Nucl Med Volume: 29 Pages: 224-232
  • Peer Reviewed
• [Journal Article] Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2-9 versus 10 or more tumors (2014)
  • Author(s): Yamamoto, M. Kawabe, T. Sato, Y. Higuchi, Y. Nariai, T. Watanabe, S. Kasuya, H
  • Journal Title: J Neurosurg Volume: 121 Issue: Suppl_2 Pages: 16-25
  • DOI: 10.3171/2014.8.gks141421
  • Peer Reviewed
• [Journal Article] Validity of Prognostic Grading Indices for Brain Metastasis Patients Undergoing Repeat Radiosurgery (2014)
  • Author(s): Yamamoto, M. Kawabe, T. Higuchi, Y. Sato, Y. Nariai, T. Watanabe, S. Barfod, B. E. Kasuya, H.
  • Journal Title: World Neurosurg Volume: 82 Issue: 6 Pages: 1242-1249
  • DOI: 10.1016/j.wneu.2014.08.008
  • Peer Reviewed
• [Journal Article] Clinical benefit of 11C methionine PET imaging as a planning modality for radiosurgery of previously irradiated recurrent brain metastases (2014)
  • Author(s): Momose, T. Nariai, T. Kawabe, T. Inaji, M. Tanaka, Y. Watanabe, S. Maehara, T. Oda, K. Ishii, K. Ishiwata, K. Yamamoto, M.
  • Journal Title: Clin Nucl Med Volume: 39 Issue: 11 Pages: 939-943
  • DOI: 10.1097/rlu.0000000000000561
  • Peer Reviewed / Open Access
• [Journal Article] Changes in cerebral blood flow during steady-state cycling exercise: a study using oxygen-15-labeled water with PET (2014)
  • Author(s): Hiura, M. Nariai, T. Ishii, K. Sakata, M. Oda, K. Toyohara, J. Ishiwata, K.
  • Journal Title: J Cereb Blood Flow Metab Volume: 34 Issue: 3 Pages: 389-396
  • DOI: 10.1038/jcbfm.2013.220
  • Peer Reviewed
• [Journal Article] グリオーマの診断と治療に有効な放射線診断学の進歩 (2014)
  • Author(s): 成相直
  • Journal Title: 脳神経外科ジャーナル Volume: 23 Pages: 559-568
  • Peer Reviewed
• [Journal Article] A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1-4 vs >/= 5 tumors. (2013)
  • Author(s): Yamamoto M
  • Journal Title: J Neurosurg. Volume: online Issue: 6 Pages: 1258-68
  • DOI: 10.3171/2013.3.jns121900
  • Peer Reviewed
• [Journal Article] Delayed complications in patients surviving at least 3 years after stereotactic radiosurgery for brain metastases. (2013)
  • Author(s): Yamamoto M
  • Journal Title: International Journal of Radiation Oncology, Biology, Physics. Volume: 85 Issue: 1 Pages: 53-60
  • DOI: 10.1016/j.ijrobp.2012.04.018
  • Peer Reviewed
• [Journal Article] PET molecular imaging to investigate the higher brain dysfunction in patients with neurotrauma. (2013)
  • Author(s): Nariai T
  • Journal Title: Acta Neurochir Supple Volume: in press
  • Peer Reviewed
• [Journal Article] Direct comparison of radiation dosimetry of six PET tracers using human whole-body imaging and murine biodistribution studies. (2013)
  • Author(s): Sakata M
  • Journal Title: Ann Nucl Med Volume: 27 Issue: 3 Pages: 285-96
  • DOI: 10.1007/s12149-013-0685-9
  • Peer Reviewed
• [Journal Article] Longitudinal observation of ^<11>C-4DST uptake in turpentine-induced inflammatory tissue. (2013)
  • Author(s): Toyohara, J., Sakata, M., Oda, K., Ishii, K. and Ishiwata, K.
  • Journal Title: Nucl. Med. Biol. Volume: 40 Issue: 2 Pages: 240-244
  • DOI: 10.1016/j.nucmedbio.2012.10.008
  • Peer Reviewed
• [Journal Article] Increased Adenosine A1 Receptor Levels in Hemianopia Patients After Cerebral Injury: An Application of PET Using 11C-8-Dicyclopropylmethyl-1-Methyl-3-Propylxanthine. (2012)
  • Author(s): Suzuki Y
  • Journal Title: Clinical Nuclear Medicine Volume: 37 Issue: 12 Pages: 1146-51
  • DOI: 10.1097/rlu.0b013e31826392a7
  • Peer Reviewed
• [Journal Article] Long-term follow-up of surgically treated juvenile patients with moyamoya disease. (2012)
  • Author(s): Mukawa M
  • Journal Title: J Neurosurg Pediatr Volume: 10 Issue: 5 Pages: 451-6
  • DOI: 10.3171/2012.8.peds11539
  • Peer Reviewed
• [Journal Article] The effects of professional oral health care on patients in the subacute stage of emergent neurosurgical disorders. (2012)
  • Author(s): Mori C
  • Journal Title: Spec Care Dentist. Volume: 32 Issue: 6 Pages: 259-64
  • DOI: 10.1111/j.1754-4505.2012.00278.x
  • Peer Reviewed
• [Journal Article] Comparison of the kinetics of pulmonary oxygen uptake and middle cerebral artery blood flow velocity during cycling exercise (2012)
  • Author(s): Hiura, M,, Kinoshita, N., Izumi, S., Nariai, T., et al.
  • Journal Title: Advances in experimental medicine and biology Volume: 737 Pages: 25-31
  • DOI: 10.1007/978-1-4614-1566-4_4
  • ISBN: 9781461415657, 9781461415664
  • Peer Reviewed
• [Journal Article] Neural mechanism of language switch (2012)
  • Author(s): Hosoda, C., Hanakawa, T. Nariai, T, et al.
  • Journal Title: J Neuroling Volume: 25 Issue: 1 Pages: 44-61
  • DOI: 10.1016/j.jneuroling.2011.08.007
  • Peer Reviewed
• [Journal Article] Optical analysis of developmental changes in synaptic potentiation in the neonatal rat corticostriatal projection (2012)
  • Author(s): Mullah, S.H.-E.-R., et al
  • Journal Title: Neuroscience Volume: 201 Pages: 338-348
  • DOI: 10.1016/j.neuroscience.2011.11.023
  • Peer Reviewed
• [Journal Article] Evaluation of 4'-[methyl-^<11>C]thiothymidine (^<11>C-4DST) in a rodent tumor and inflammation model. (2012)
  • Author(s): Toyohara, J., Elsinga, P. H., Ishiwata, K., Sijbesma, J. W. A. Dierckx, R. A. J. 0. and van Waarde, A.
  • Journal Title: J. Nucl. Med. Volume: 53 Issue: 3 Pages: 488-494
  • DOI: 10.2967/jnumed.111.098426
  • Peer Reviewed
• [Journal Article] Whole-body distribution and brain tumor imaging with ^<11>C-4DST : a pilot study (2011)
  • Author(s): Toyohara J, et al
  • Journal Title: The Journal of Nuclear Medicine Volume: 52 Issue: 8 Pages: 1322-1325
  • DOI: 10.2967/jnumed.111.088435
  • Peer Reviewed
• [Journal Article] the status of Tsukuba BNCT trial : BPA-based boron neutron capture therapy combined with X-ray irradiation (2011)
  • Author(s): Yamamoto T, Nakai K, Nariai T, Kumada H, Okumura T, Mizumoto M, Tsuboi K, Zaboronok A, Ishikawa E, Aiyama H, Endo K, Takada T, Yoshida F, Shibata Y, Matsumura A
  • Journal Title: Appl Radiat Isot Volume: 69 Issue: 12 Pages: 1817-1818
  • DOI: 10.1016/j.apradiso.2011.02.013
  • Peer Reviewed
• [Journal Article] A clinical trial protocol for second line treatment of malignant brain tumors with BNCT at University of Tsukuba (2011)
  • Author(s): Aiyama H, Nakai K, Yamamoto T, Nariai T, Kumada H, Ishikawa E, Isobe T, Endo K, Takada T, Yoshida F, Shibata Y, Matsumura A
  • Journal Title: Appl Radiat Isot Volume: 69 Issue: 12 Pages: 1819-1822
  • DOI: 10.1016/j.apradiso.2011.04.031
  • Peer Reviewed
• [Journal Article] Arterial spin labeling and dynamic susceptibility contrast CBF MRI in postischemic hyperperfusion, hypercapnia, and after mannitol injection (2011)
  • Author(s): Tanaka Y, et al.
  • Journal Title: Journal of cerebral blood flow and metabolism Volume: 31 Issue: 6 Pages: 1403-11
  • DOI: 10.1038/jcbfm.2010.228
  • Peer Reviewed
• [Journal Article] Memory deficit due to brain injury : unique PET findings and dream (2011)
  • Author(s): Nishida M, Nariai T, et al.
  • Journal Title: BMJ Case reports Volume: (e-pub)
  • Peer Reviewed
• [Presentation] 悪性脳腫瘍に対するPET代謝イメージガイド定位放射線治療の臨床的有用性に関する解析. (2014)
  • Author(s): 成相直、山本昌昭、百瀬俊也、川邊拓也、稲次基希、田中洋次、前原健寿、石井賢二、石渡喜一
  • Organizer: 日本脳神経外科学会 第73回学術総会
  • Place of Presentation: 新高輪プリンスホテル（東京都港区）
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] Roles of Methionine PET in Gamma Knife Radiosurgery for Malignant Glioma (2014)
  • Author(s): Nariai T, Yamamoto M, Momose T, Inaji M, Tanaka Y, Kawabe T, Nagatomo Y, Barfod B, Ishiwata K, Ishii K.
  • Organizer: 17th Leksell GK Society Meeting
  • Place of Presentation: New York (USA)
  • Year and Date: 2014-05-11 – 2014-05-15
• [Presentation] Methionine-PET、4DST-PETを用いた悪性脳腫瘍診断・治療成績の検討 (2014)
  • Author(s): 稲次基希、成相直、林志保里、田中洋次、織田圭一、坂田宗之、豊原潤、石井賢二、石渡喜一、前原健寿
  • Organizer: 第37回日本脳神経CI学会,
  • Place of Presentation: 大宮ソニックシティー（埼玉県さいたま市）
  • Year and Date: 2014-02-28 – 2014-03-01
• [Presentation] 11C-4DST PETのGlioma悪性度診断における有用性と妥当性の検証 (2013)
  • Author(s): 21.稲次基希、成相直、林志保里、田中洋次、織田圭一、坂田宗之、石渡喜一、豊原潤、石井賢二、前原健寿
  • Organizer: 第53回日本核医学会学術総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2013-11-08 – 2013-11-10
• [Presentation] Improved treatment of malignant glioma with clinical use of a newly developed PET molecular imaging probe 4DST to measure DNS synthesis rate. 2013 Annual Meeting of Congress of Neurosurgeons (2013)
  • Author(s): 11.Nariai T, Inaji M, Hayashi S, Tanaka Y, Maehara T, Ishiwata K, Toyohara J
  • Organizer: 2013 Annual Meeting of Congress of Neurosurgeons.
  • Place of Presentation: San Francisco,（USA）
  • Year and Date: 2013-10-19 – 2013-10-23
• [Presentation] 合同シンポジウム：｢分子イメージング｣脳腫瘍に対するPET分子イメージングの開発と臨床応用 (2013)
  • Author(s): 成相直
  • Organizer: 第１４回日本分子脳神経外科学会および第７２回日本脳神経外科学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2013-10-18
  • Invited
• [Presentation] PET multi-tracerによるGlioma診断・治療の有用性 (2013)
  • Author(s): 17.稲次基希、成相直、田中洋次、林志保里、坂田宗之、織田圭一、石渡喜一、豊原潤、石井賢二、前原健寿
  • Organizer: 日本脳神経外科学会 第72回学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2013-10-16 – 2013-10-18
• [Presentation] Clinical benefit of PET Metabolic Image for the second Gamma Knife radiosurgery against focally recurred metastatic brain tumor after the initial treatment (2013)
  • Author(s): Nariai, T., Inaji, M., Momose, T., Kawabe, T., Tanaka, Y., Maehara, T., Ishii, K., Ishiwata, K., Sato, Y. and Yamamoto, M.
  • Organizer: 11th International Stereotactic Radiosurgery Society Congress
  • Place of Presentation: Toronto（Canada）
  • Year and Date: 2013-06-16 – 2013-06-20
• [Presentation] Validation of MRI T1/T2 mismatch method for accurate differentiation between radiation injury and recurrence of metastatic brain tumor after gamma knife radiosurgery. –Comparison with methionine PET – (2013)
  • Author(s): Inaji, M., Yamamoto, M., Nariai, T., Tanaka, Y., Urakawa, Y., Ishiwata, K., Ishii, K. and Maehara, T.
  • Organizer: 11th International Stereotactic Radiosurgery Society Congress
  • Place of Presentation: Toronto,（Canada）
  • Year and Date: 2013-06-16 – 2013-06-20
• [Presentation] シンポジウム。グリオーマ研究の最先端。グリオーマの診断と治療に有用な放射線診断学の進歩 (2013)
  • Author(s): 成相直
  • Organizer: 第33回日本脳神経外科コングレス総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2013-05-12
  • Invited
• [Presentation] 悪性脳腫瘍の集学的治療におけるPETの臨床利用 －現状と未来－ (2013)
  • Author(s): 成相直
  • Organizer: 第４０回新潟核医学懇話会
  • Place of Presentation: ANAクラウンプラザホテル新潟（新潟県新潟市）
  • Year and Date: 2013-04-20
  • Invited
• [Presentation] Current status of clinical PET imaging for malignant brain tumor (2013)
  • Author(s): Nariai T
  • Organizer: The 42nd Annual Meeting of The Japanese Society of Neuroradiology.
  • Place of Presentation: 小倉
  • Invited
• [Presentation] Use of GKRS for local control of malignant glioma detected with Methionine PET (2012)
  • Author(s): Nariai T, et al.
  • Organizer: 10th Biennial Congress and Exhibition of the International Stereotactic Radiosurgery Society
  • Place of Presentation: Paris, France
  • Year and Date: 2012-05-08
• [Presentation] Surgical Treatment of Juvenile Patients with Moyamoya Disease Based on Clinical Use of Hemodynamic Measurement. (2012)
  • Author(s): Nariai T
  • Organizer: 80th AANS Annual Meeting
  • Place of Presentation: Miami, USA
• [Presentation] Clinical use of PET amino acid imaging in boron neutron capture therapy for malignant brain tumor. (2012)
  • Author(s): Nariai T
  • Organizer: 15th ICNCT
  • Place of Presentation: Tskuba
• [Presentation] 形態画像と機能画像の融合による手術支援－核医学画像の役割－ (2012)
  • Author(s): 成相直
  • Organizer: 第３２回日本脳神経外科コングレス総会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] Clinical use of PET imaging for the treatment of malignant brain tumor (2011)
  • Author(s): Nariai T
  • Organizer: Seminar at National Institute of Health
  • Place of Presentation: Bethesda, USA
  • Year and Date: 2011-10-04
• [Presentation] Importance of detection and treating glioma without contrast enhancement using PET imaging as guide (2011)
  • Author(s): Nariai T, et al.
  • Organizer: 79th Annual Scientific Meeting of the American Association of Neurological Surgeons
  • Place of Presentation: Denver, USA
• [Presentation] Kinetic modeling of [11C] 4DST PET imaging DNA synthesis rate. Initial clinical trials in brain tumors (2011)
  • Author(s): Sakata M, Toyohara J, Nariai T, et al.
  • Organizer: 25th International Symposium on Cerebral Blood Flow, Metabolism, and Function & 10th International Conference on Quantification of Brain Function with PET 2011
  • Place of Presentation: Barcelona, Spain
• [Presentation] DNA synthesis imaging of non-small-cell lung cancer using a new PET tracer [11C] 4DST (2011)
  • Author(s): Minamimoto R, et al.
  • Organizer: SNM 2011 Annual Meeting
  • Place of Presentation: San Antonio, USA
• [Presentation] Initial clinical trials of carbon-11-labeled 4DST in brain tumors (2011)
  • Author(s): Toyohara J, Nariai T, et al.
  • Organizer: SNM 2011 Annual Meeting
  • Place of Presentation: San Antonio, USA
• [Presentation] Clinical use of molecular imaging for the treatment of malignant brain tumor (2011)
  • Author(s): Nariai T, et al.
  • Organizer: Annual Meeting of the Congress of Neurological Surgeons
  • Place of Presentation: Washington D. C., USA
• [Presentation] Initial clinical trials of carbon-11-labeled 4DST for malignant brain tumors as a PET molecular imaging probe to measure DNA synthesis Rate (2011)
  • Author(s): Nariai T, et al.
  • Organizer: 16th Annual Scientific Meeting & Education Day of the Society for Neuro-Oncology
  • Place of Presentation: Orange County, USA
• [Presentation] Clinical use of 4DST as a new PET molecular imaging probe to measure DNA synthesis of brain tumor.
  • Author(s): Nariai T
  • Organizer: The 4th International Symposium of Brain Tumor Pathology.
  • Place of Presentation: Nagoya
• [Presentation] Chronic Ischemia and Cerebrovascular Reserve
  • Author(s): Nariai T
  • Organizer: ISMRM2013
  • Place of Presentation: Salt Lake City, USA
  • Invited
• [Presentation] 悪性脳腫瘍の治療におけるPETイメージングの臨床的有用性。
  • Author(s): 成相直
  • Organizer: 第２８回BFIC
  • Place of Presentation: 神戸
  • Invited
• [Presentation] 脳血管障害の臨床と研究におけるPETの役割
  • Author(s): 成相直
  • Organizer: Stroke2013
  • Place of Presentation: 東京
  • Invited
• [Presentation] 脳循環代謝の定量計測によってわかること－脳神経外科疾患患者の計測から－
  • Author(s): 成相直
  • Organizer: 第１８回Hyogo Fire Side Talk。
  • Place of Presentation: 西宮
  • Invited
• [Presentation] 分子イメージングによる悪性脳腫瘍病態の画像化と治療への応用
  • Author(s): 成相直
  • Organizer: 第１９回多摩脳腫瘍研究会
  • Place of Presentation: 三鷹
  • Invited
• [Book] Use of (11)C-4DST-PET for Imaging Human Brain Tumors. (2014)
  • Author(s): Nariai, T Inaji, M Sakata, M Toyohara, J.
  • Total Pages: 8
  • Publisher: Springer
• [Book] Use of (11)C-4DST-PET for Imaging Human Brain Tumors. In: Hayat M, editor. Tumors of the central nervous system. (2013)
  • Author(s): Nariai T
  • Publisher: Springer-Verlag
• [Book] Analysis and Imaging - PET. In: Sauerwein W, Wittig A, Moss R, Nakagawa Y, editors. Neutron Capture Therapy. (2012)
  • Author(s): Nariai T
  • Publisher: Springer-Verlag