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Establishment of Optimal Thermal Neutron Capture Therapy for 5 Types of Human Malignant Melanoma

Research Project

Project/Area Number 03557047
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Dermatology
Research InstitutionKobe University

Principal Investigator

MISHIMA Yutaka  Kobe Univ., School of Medicine, Honorary Professor, 医学部, 名誉教授 (10073743)

Co-Investigator(Kenkyū-buntansha) HIRATSUKA Junichi  Kawasaki Medical School, Instructor, 講師 (30192298)
ICHIHASHI Masamitsu  Kobe Univ., School of Medicine, Professor, 医学部, 教授 (00030867)
FUKUDA Hiroshi  Tohoku Univ., Res. Inst. for Tuberculosis and Cancer, Professor, 抗酸菌病研究所, 教授 (30125645)
YOSHINO Kazuo  Shinshu Univ., Faculty of Science, Research Associate, 理学部, 助手 (70143964)
KOBAYASHI Tooru  Kyoto Univ., Reactor Institute, Instructor, 原子炉実験所, 講師 (90089136)
Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1992: ¥5,000,000 (Direct Cost: ¥5,000,000)
KeywordsMelanoma / Neutron Capture Therapy / PET diagnosis / 黒色腫 / 悪性黒子型黒色腫
Research Abstract

In this project, 12 melanoma patients have been treated with our Boron Neutron Capture Therapy(BNCT). The results of treatment in the 12 cases, may be summarized as follows:
Sex:7 male, 5 female.
Age of patient on the day of neutron irradiation:50-85
Type of melanoma:6 ALM(acral lentiginous melanoma), 5 nodular, 1 lentigo maligna.
Lesion:8 primary 3 metastases, 1 primary accompanied with satellite metastases;
6 resulted in complete cure, 4 showed marked regression, 2 under observation
Locations of lesions:5 on the sole and 1 each in occiput, groin inguinal, scalp, face, thumb subungual, foot, and thigh.leg.foot.
Among three cases treated in the last 2 years, one is a female patient who had a lentigo maligna lesion spread over her face. Complete cure was obtained by single BNCT, and pigmented spots on her face are still fading gradually. The second case, having metastatic lesions in right and left lymph nodes of the inguinal region was cured by the use of heavy water, D_2O, which decreases the … More attenuation of the neutron beam and thus lets it reach the deep seated lesions more efficiently. The third case (ALM) is still under observation, although no symptoms of recurrence and no other troubles have been found as yet.
It is regrettable that the treatments of Superficially Spreading Melanoma and Malignant Blue Nevus could not be carried out in this project period because of technical trouble with the Musashi Institute of Technology Reactor. The treatments are expected to be done in the succeeding period.
^<18>F is fluorine isotope with a half-life of 109 minutes which decays with emission of positrons. L-^<10>B-p-Boronophenylalanine (L-^<10>BPA), which has been used in our BNCT, can be labeled with ^<18>F to form L-^<18>F-^<10>BPA. Performing positron emission tomography (PET) on a melanoma-bearing hamster after administration of L-^<18>F-^<10>BPA, we obtained a positron image which makes visible the distribution pattern of this melanoma seeking compound in the whole body of the hamster. The concentration of L-^<18>F-^<10>BPA in melanoma and its dynamics can be estimated with significant accuracy by analyzing PET images. This method has also been successfully applied to human patients and gives a promising new tool to the diagnosis of melanoma with which one can detect even deep-seated lesion for example those located in the brain or lymph nodes. Less

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (64 results)

All Other

All Publications (64 results)

  • [Publications] MISHIMA,Y.: "Treatment of metastatic melanoma of neutron capture therapy." Proc.of the 18th World Congress of Dermatology,June 12-18,1992,New York,The Parthenon Pub.Group Ltd.,Carnforth,U.K.,(in press),. (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 三嶋 豊: "悪性黒色腫とその前癌症-流動する治療概念-。" 日本皮膚科学会誌. 102. 1627-1634 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 三島 豊: "悪性黒色腫の特異的代謝活性による熱中性子捕捉療法。" 皮膚,Special Issue. 34. 11-17 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] ISHIWATA,K.: "A unique in vivo assessment of 4-[^<10>B]borono-L-phenylalanine in tumour tissues for boron neutron capture therapy of malignant melanomas using positron emission tomography and 4-borono-2-[^<18>F]fluoro-L-phenylalanine" Melanoma Research. 2. 171-179 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] SAKURAI,Y.: "Analysis of remodeling the KUP heavy water facility for biomedical uses(Shutter system for continuous use of the facility under 5MW operation)." Annu.Rep.Res.Reactor Inst.Kyoto Univ.24. 90-100 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 桜井 良憲: "BNCTにおける生体内深部での熱中性子線量率改善の計算及び実験による検討" 京都大学原子炉実験所第26回学術講演会論文集. 55-62 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 古林 徹: "医療照射を主目的にした重水熱中性子設備改造検討" 京都大学原子炉実験所第26回学術講演会論文集. 47-54 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 桜井 良憲: "熱中性子束測定における生体表面近傍での金線および金箔の自己庶蔽因子の検討。" 京都大学原子炉実験所第27回学術講演会論文集. 21-28 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 福田 寛: "中性子捕捉療法の現状(3)-ホウ素中性子捕捉治療の現状と問題点-" 臨床放射線. 37(13). 1643-1644 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] ICHIHASHI,M.: "In vitro radiobiological analysis of ^<10>B-L-BPA for BNCT of malignant melanoma:Correlation of determined ^<10>B-content and cell killing effect." Pigment Cell Research. Suppl.2. 193-198 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] HIRATSUKA,J.: "The relative biological effectiveness of ^<10>B-neutron capture therapy for early skin reaction in the hamster." Radiation Research. 128. 186-191 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 平塚 純一: "悪性黒色腫に対する熱中性子捕捉療法の治療効果比。" Japan Drug Delivery System学会誌. 7(6). 447-452 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] MISHIMA,Y.ed.: "The Pigment Cell:From Molecular to the Clinical Level," Munksgaard,Copenhagen, 312 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 三嶋 豊(編集企画): "皮膚科MOOK No.18,「悪性黒色腫」(編集企画:三嶋 豊)(悪性黒色腫の選択的熱中性子捕捉療法-ヒト症例の治療-)" 金原出版,東京, 234 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] MISHIMA,Y.: "“Neutron Capture Therapy",Proc.5th Int'l Symp.on Neutron Capture Therapy for Cancer,Sept.13-17,1992,Columbus(Barth,RF & Soloway,AH eds.)(in press)(Selective melanoma thermal neutron capture therapy for lymph node metastases.)" Plenum Publishing Co.,New York, (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] AIZAWA,O.: "“Neutron Capture Therapy",Proc.5th Int'l Symp.on Neutron Capture Therapy for Cancer,Sept.13-17,1992,Columbus(Barth,RF & Soloway,AH eds.)(Evaluation of neutron irradiation field for BNCT by using absorbed dose in a phantom.)" Plenum Publishing Co.,New York, (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] KAKIHANA,H.: "(Relation between structures of p-boronophenylalanine related compounds and their usefulness for boron neutron capture therapy.)" Plenum Publishing Co.,New York, (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] YOSHINO,K.: "(Capture of p-boronophenylalanine by melanin-related compounds:complex formation of p-boronophenylalanine with L-dopa.)ibid." Plenum Publishing Co.,New York, (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] YOSHINO,K.: "(Proposed mechanism of capture and release of p-boronophenylalanine through melanoma cells:chemical behaviour of p-boronophenyl-alanine fructose complex in L-dopa solution.)ibid." Plenum Publishing Co.,New York, (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] YOSHINO,K.: "(Determination of p-boronophenylalanine in biological tissues with high performance liquid chromatography.)ibid." Plenum Publishing Co.,New York, (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] YOSHINO,K.: "(Synthesis of o-and m-boronophenylalanine.)ibid." Plenum Publishing Co.,New York, (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mishima,Y., et al: "Treatment of metastatic melanoma of neutron capture therapy." Proc. 18th World Congress of Dermatology. June 12-18. (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mishima,Y.: "Malignant melanoma and its precanceroses:Newer therapeutic concepts." Jap.J.of Derm.102. 1627-1634 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mishima,Y.: "Selective thermal neutron capture therapy of malignant melanoma using its specific metabolic activities." Skin Research,Special issue. 34. 11-17 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ishiwata,K., et al: "A unique in vivo assessment of 4-[^<10>B]borono-L-phenylalanine in tumor tissues for boron neutron capture therapy of malignant melanomas using positron emission tomography and 4-borono-2-[^<18>F]fluoro-D, L-phenylalanine." Melanoma Research. 2. 171-179 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kobayashi,T., et al.: "Study on remodeling of the heavy water facility of the KUR mainly from the viewpoint of neutron capture therapy." 26th Scientific Meeting of KUR Progress Report:47-54,1992.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Sakurai,Y., et al.: "Improvement of thermal neutron fluency of the deeper part in tissue for BNCT:Simulation calculation and phantom experiment." 26th Scientific Meeting of KUR Progress Report:47-54,1992. 55-62 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ichihashi,M., et al: "In vitro radiobiological analysis of ^<10>B-L-BPA for BNCT of malignant melanoma:Correlation of determined ^<10>B-content and cell killing effect." Pigment Cell Research. Suppl.2. 193-198 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Hiratsuka,J., et al.: "The relative biological effectiveness of ^<10>B-neutron capture therapy for early skin reaction in the hamster." Radiation Research. 128. 186-191 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Hiratsuka,J., et al.: "Therapeutic gain factor of thermal neutron capture therapy of malignant melanoma" Drug Delivery System. 7. 447-452 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mishima,Y., et al.: "Selective thermal neutron capture therapy of malignant melanoma:Treatment of human cases." Dermatology Handbook"MOOK"No.18:Malignant Melanoma(Mishima,Y. ed.). 201-211 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mishima,Y., et al.: "Selective melanoma thermal neutron capture therapy for lymph node metastases." Neutron Capture Therapy(Proc. 5th Int'l Symp. on Neutron Capture Therapy for Cancer, Sept. 13-17, 1992, Columbus, Barth, RF & Soloway, AH eds.). Plenum,Pub. Corp., New York. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Aizawa,O.: "Evaluation of neutron irradiation field for BNCT by using absorbed dose in a phantom." Neutron Capture Therapy(Proc. 5th Int'l Symp. on Neutron Capture Therapy for Cancer, Sept. 13-17, 1992, Columbus, Barth, RF & Soloway, AH eds.). Plenum,Pub. Corp., New York. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] KAKIHANA,H., et al.: "Relation between structures of p-boronophenylalanine related compounds and their usefulness for boron neutron capture therapy." Neutron Capture Therapy(Proc. 5th Int'l Symp. on Neutron Capture Therapy for Cancer. Sept. 13-17, 1992, Columbus, Barth, RF & Soloway, AH eds.). Plenum,Pub. Corp., New York. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshino,K., et al.: "Capture of p-boronophenylalanine by melaninrelated compounds:complex formation of p-boronophenylalanine with L-dopa." Neutron Capture Therapy(Proc. 5th Int'l Symp. on Neutron Capture Therapy for Cancer, Sept. 13-17, 1992, Columbus, Barth, RF & Soloway, AH eds.). Plenum,Pub. Corp., New York. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshino,K., et al.: "Proposed mechanism of capture and release of p-boronophenylalanine through melanoma cells:chemical behavior of p-boronophenylalanine fructose complex in L-dopa solution." Neutron Capture Therapy(Proc. 5th Int'l Symp. on Neutron Capture Therapy for Cancer, Sept. 13-17, 1992, Columbus, Barth, RF & Soloway, AH eds.). Plenum,Pub. Corp., New York. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshino,K., et al.: "Determination of p-boronophenylalanine in biological tissues with high performance liquid chromatography." Neutron Capture Therapy(Proc. 5th Int'l Symp. on Neutron Capture Therapy for Cancer, Sept. 13-17, 1992, Columbus, Barth, RF & Soloway, AH eds.). Plenum,Pub. Corp., New York. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshino,K., et al.: "Synthesis of o-and m-boronophenylalanine." Neutron Capture Therapy(Proc. 5th Int'l Symp. on Neutron Capture Therapy for Cancer, Sept. 13-17, 1992, Columbus, Barth, RF & Soloway, AH eds.). Plenum,Pub. Corp., New York. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mishima,Y., et al.: Munksgaard Int. Publishers, Copenhagen. Pigment Cell:From Molecullar to the Clinical Level(Mishima,Y., ed.), 1-312 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mishima,Y.: "Treatment of metastatic melanoma of neutron capture therapy." Proc.of the 18th World Congress of Dermatology,June 12-18,1992,New York,The Parthenon Pub.Group Ltd.,Carnforth,U.K.,. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] 三嶋 豊: "悪性黒色腫とその前癌症ー流動する治療概念ー。" 日本皮膚科学会誌. 102. 1627-1634 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 三島 豊: "悪性黒色腫の特異的代謝活性による熱中性子捕捉療法。" 皮膚,Special Issue. 34. 11-17 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Ishiwata,K.: "A unique in vivo assessment of 4-[ ^<10>B]borono-L-phenylalanine in tumour tissues for boron neutron capture therapy of malignant melanomas using positron emission tomography and 4-borono-2-[ ^<18>F]fluoro-L-phenylalanine" Melanoma Research. 2. 171-179 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Ichihashi,M.: "In vitro radiobiological analysis of ^<10>B-L-BPA for BNCT of malignant melanoma:Correlation of determined ^<10>B-content and cell killing effect." Pigment Cell Research. Suppl.2. 193-198 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 桜井 良憲: "熱中性子束測定における生体表面近傍での金線および金箔の自己遮蔽因子の検討。" 京都大学原子炉実験所第27回学術講演会論文集. 21-28 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] 福田 寛: "中性子捕捉療法の現状(3)ーホウ素中性子捕捉治療の現状と問題点ー" 臨床放射線. 37(13). 1643-1644 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 平塚 純一: "悪性黒色腫に対する熱中性子捕捉療法の治療効果比。" Japan Drug Delivery System学会誌. 7(6). 447-452 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 三嶋 豊: "皮膚科MOOK「悪性黒色腫」(編集企画:三嶋豊)(悪性黒色腫の選択的熱中性子捕捉療法ーヒト症例の治療ー)" 金原出版,東京, 234 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Mishima,Y.: "“Neutron Capture Therapy",Proc.5th Int'I Symp.on Neutron Capture Therapy for Cancer,Sept.13-17,1992,Columbus(Barth,RF & Soloway,AH eds.)(Selecive melanoma thermal neutron capture therapy for lymph node metastases.)" Plenum Publishing Co.,New York, (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Aizawa,O.: "“Neutron Capture Therapy",Proc.5th Int'l Symp.on Neutron Capture Therapy for Cancer,Sept.13-17,1992,Columbus(Barth,RF & Soloway,AH eds.)(Evaluation of neutron irradiation field for BNCT by using absorbed dose in a phantom.)" PLenum Publishing Co.,New York, (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kakihana,H.: "(Relation between structures of p-boronophenylalanine related compounds and their usefulness for boron neutron capture therapy.)" Plenum Publising Co.,New York, (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yoshino,K.: "(Capture of p-boronophenylalanine by melanin-related compounds:complex formation of p-boronophenylalanine with L-dopa.)idid." Plenum Publising Co.,New York, (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yoshino,K.: "(Proposed mechanism of capture and release of p-boronophenylalanine through melanoma cells:chemical behaviour of p-boronophenylalanine fructose complex in L-dopa solution.)idid." Plenum Publishing Co.,New York, (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yosino,K.: "(Determination of p-boronophenylalanine in biological tissues with high performance liquid chromatography.)ibid." Plenum Publishing Co.,New York, (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yoshino,K.: "(Synthesis of o-and m-boronophenylalaniNE.)ibid." Plenum Publishing Co.,New York, (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Mishima,Y.: "A post melanosomal era: Control of melanogenesis and melanoma growth." Pigment Cell Research (The Pigment Cell: From the Molecular to the Clinical Level Mishima,Y.ed.). Suppl.2. 3-16 (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] 桜井 良憲: "BNCTにおける生体内深部での熱中性子線量率改善の計算及び実験による検討" 京都大学原子炉実験所第26回学術講演会論文集. 55-62 (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] 古林 徹: "医療照射を主目的にした重水熱中性子設備改造検討" 京都大学原子炉実験所第26回学術講演会論文集. 47-54 (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sakurai,Y.: "Analvsis of remodeling the KUR heavy water facility for biomedical uses (Shutter system for continuous use of the facility under 5 MW operation)" Annu.Rep.Res.Reactor Inst.Kyoto Univ.24. 90-100 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hiratsuka,J.: "The relative biological effectiveness of 10B-neutron capture therapy for early skin reaction in the hamster." Radiation Research. 128. 186-191 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Aizawa,O.: "Proc.of International Workshop on Macro and Microdosimetry and Treatment Planning for Neutron Capture Therapy,Oct.31-NoV.1,1991,Boston(A theoretical approach to whole-body macrodosimetry for BNCT)" (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kobayashi,T.: "ibid.(Technical aspects related to thermal neutron irradiation and its dose estimation for neutron capture therapy)" (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kobayashi,T.: "ibid.(Depth dose characteristics in tissue for parallel thermal neutron beam)" (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kobayashi,T.: "Proc.of World Congress on Medical Physics and Biomedical Engineering (8th IOMP),July,1991,Kyoto(A monitoring technique and dose estimation of thermal neutrons for neutron capture therapy)" (1992)

    • Related Report
      1991 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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