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Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine

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A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Biophysics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 50715

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Special Issue Editors

Prof. Dr. Ignacio Porras

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Guest Editor

Departamento de Física Atómica, Molecular y Nuclear, Universidad de Granada, Granada, Spain
Interests: Boron Neutron Capture Therapy (BNCT); medical physics; experimental nuclear physics

Dr. Silva Bortolussi

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Guest Editor

1. Department of Physics, University of Pavia, Pavia, Italy
2. National Institute of Nuclear Physics (INFN), Pavia, Italy
Interests: Boron Neutron Capture Therapy (BNCT); computational dosimetry; neutron beam design; boron measurements; radiobiological measurements; treatment planning
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Prof. Dr. Yuan-Hao Liu

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Guest Editor

Department of Nuclear Science and Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China
Interests: Boron Neutron Capture Therapy (BNCT); medical physics; radiation detection and measurement; accelerator neutron source

Special Issue Information

Dear Colleagues,

We are facing a new era for Boron Neutron Capture Therapy (BNCT). Considering the very promising results obtained in clinical trials performed using research reactors to treat tumors of very bad prognosis and the current projects applying in-hospital accelerator-based neutron sources for tumor therapy, we expect that the number of BNCT clinical trials will expand worldwide. BNCT is a paradigm of interdisciplinary research, as it consists in the production of nuclear reactions selectively into tumor cells.

The aim of this Special Issue is to illustrate this interdisciplinary research, with a focus on the transition from nuclear physics to biomedicine. Topics of interest for this Special Issue include, but are not limited to, the production of neutron beams for BNCT, experimental dosimetry—including real-time dosimetry—computational dosimetry, radiobiological models and treatment planning, boron quantification and imaging, new BNCT applications, and radiation protection issues.

This Special Issue welcomes the submission of original research and review manuscripts focusing on any of these topics, including papers on methods that have made contributions to the development of this field. Both basic and clinical research papers are welcome and are expected to contribute to a global interdisciplinary vision of BNCT.

Prof. Dr. Ignacio Porras
Dr. Silva Bortolussi
Prof. Dr. Yuan-Hao Liu
Guest Editors

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Keywords

Boron Neutron Capture Therapy (BNCT)
neutron beam design and evaluation
neutron sources based on accelerators and compact machines
neutron and gamma experimental dosimetry
computational dosimetry
radiobiological models
treatment planning
boron determination and imaging

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Published Papers (12 papers)

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Editorial

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2 pages, 186 KiB

Open AccessEditorial

Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine

by Silva Bortolussi, Yuan-Hao Liu and Ignacio Porras

Biology 2021, 10(5), 370; https://doi.org/10.3390/biology10050370 - 26 Apr 2021

Cited by 8 | Viewed by 2819

Abstract

Boron Neutron Capture Therapy (BNCT) is a binary radiation treatment exploiting a nuclear reaction occurring in tumor cells [...] Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

Research

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12 pages, 5040 KiB

Open AccessArticle

Extracellular Release of HMGB1 as an Early Potential Biomarker for the Therapeutic Response in a Xenograft Model of Boron Neutron Capture Therapy

by Shoji Imamichi, Lichao Chen, Tasuku Ito, Ying Tong, Takae Onodera, Yuka Sasaki, Satoshi Nakamura, PierLuigi Mauri, Yu Sanada, Hiroshi Igaki, Yasufumi Murakami, Minoru Suzuki, Jun Itami, Shinichiro Masunaga and Mitsuko Masutani

Biology 2022, 11(3), 420; https://doi.org/10.3390/biology11030420 - 10 Mar 2022

Cited by 11 | Viewed by 3113 | Correction

Abstract

Boron neutron capture therapy (BNCT) is a non-invasive therapeutic technique for treating malignant tumors, however, methods to evaluate its therapeutic efficacy and adverse reactions are lacking. High mobility group box 1 (HMGB1) is an inflammatory molecule released during cell death. Therefore, we aimed to investigate HMGB1 as a biomarker for BNCT response, by examining the early responses of tumor cells to ¹⁰B-boronophenylalanine (BPA)-based BNCT in the Kyoto University Nuclear Reactor. Extracellular HMGB1 release was significantly increased in human squamous carcinoma SAS and melanoma A375 cells 24 h after neutron irradiation but not after γ-irradiation. At 3 days post-BPA-based BNCT irradiation in a SAS xenograft mouse model, plasma HMGB1 levels were higher than those in the non-irradiation control, and HMGB1 was detected in both nuclei and cytoplasm in tumor cells. Additionally, increased plasma HMGB1 levels post-BNCT irradiation were detected even when tumors decreased in size. Collectively, these results indicate that the extracellular HMGB1 release occurs at an early stage and is persistent when tumors are reduced in size; therefore, it is a potential biomarker for evaluating the therapeutic response during BNCT. Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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10 pages, 1224 KiB

Open AccessArticle

Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation for BNCT in a Rat Melanoma Model

by Sachie Kusaka, Yuri Morizane, Yugo Tokumaru, Shingo Tamaki, Indah Rosidah Maemunah, Yoko Akiyama, Fuminobu Sato and Isao Murata

Biology 2022, 11(3), 397; https://doi.org/10.3390/biology11030397 - 3 Mar 2022

Cited by 8 | Viewed by 3030

Abstract

Recently, exploitation of cerebrospinal fluid (CSF) circulation has become increasingly recognized as a feasible strategy to solve the challenges involved in drug delivery for treating brain tumors. Boron neutron capture therapy (BNCT) also faces challenges associated with the development of an efficient delivery system for boron, especially to brain tumors. Our laboratory has been developing a system for boron delivery to brain cells using CSF, which we call the “boron CSF administration method”. In our previous study, we found that boron was efficiently delivered to the brain cells of normal rats in the form of small amounts of L-p-boronophenylalanine (BPA) using the CSF administration method. In the study described here, we carried out experiments with brain tumor model rats to demonstrate the usefulness of the CSF administration method for BNCT. We first investigated the boron concentration of the brain cells every 60 min after BPA administration into the lateral ventricle of normal rats. Second, we measured and compared the boron concentration in the melanoma model rats after administering boron via either the CSF administration method or the intravenous (IV) administration method, with estimation of the T/N ratio. Our results revealed that boron injected by the CSF administration method was excreted quickly from normal cells, resulting in a high T/N ratio compared to that of IV administration. In addition, the CSF administration method resulted in high boron accumulation in tumor cells. In conclusion, we found that using our developed CSF administration method results in more selective delivery of boron to the brain tumor compared with the IV administration method. Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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20 pages, 13732 KiB

Open AccessArticle

In Vivo Accelerator-Based Boron Neutron Capture Therapy for Spontaneous Tumors in Large Animals: Case Series

by Vladimir Kanygin, Aleksandr Kichigin, Alexander Zaboronok, Anna Kasatova, Elena Petrova, Alphiya Tsygankova, Evgenii Zavjalov, Bryan J. Mathis and Sergey Taskaev

Biology 2022, 11(1), 138; https://doi.org/10.3390/biology11010138 - 14 Jan 2022

Cited by 14 | Viewed by 5136

Abstract

(1) Background: accelerator-based neutron sources are a new frontier for BNCT but many technical issues remain. We aimed to study such issues and results in larger-animal BNCT (cats and dogs) with naturally occurring, malignant tumors in different locations as an intermediate step in translating current research into clinical practice. (2) Methods: 10 pet cats and dogs with incurable, malignant tumors that had no treatment alternatives were included in this study. A tandem accelerator with vacuum insulation was used as a neutron source. As a boron-containing agent, ¹⁰B-enriched sodium borocaptate (BSH) was used at a dose of 100 mg/kg. Animal condition as well as tumor progression/regression were monitored. (3) Results: regression of tumors in response to treatment, improvements in the overall clinical picture, and an increase in the estimated duration and quality of life were observed. Treatment-related toxicity was mild and reversible. (4) Conclusions: our study contributes to preparations for human BNCT clinical trials and suggests utility for veterinary oncology. Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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16 pages, 2411 KiB

Open AccessArticle

Dose-Dependent Suppression of Human Glioblastoma Xenograft Growth by Accelerator-Based Boron Neutron Capture Therapy with Simultaneous Use of Two Boron-Containing Compounds

by Vladimir Kanygin, Ivan Razumov, Alexander Zaboronok, Evgenii Zavjalov, Aleksandr Kichigin, Olga Solovieva, Alphiya Tsygankova, Tatiana Guselnikova, Dmitrii Kasatov, Tatiana Sycheva, Bryan J. Mathis and Sergey Taskaev

Biology 2021, 10(11), 1124; https://doi.org/10.3390/biology10111124 - 2 Nov 2021

Cited by 9 | Viewed by 3117

Abstract

(1) Background: Developments in accelerator-based neutron sources moved boron neutron capture therapy (BNCT) to the next phase, where new neutron radiation parameters had to be studied for the treatment of cancers, including brain tumors. We aimed to further improve accelerator-BNCT efficacy by optimizing dosimetry control, beam parameters, and combinations of boronophenylalanine (BPA) and sodium borocaptate (BSH) administration in U87MG xenograft-bearing immunodeficient mice with two different tumor locations. (2) Methods: The study included two sets of experiments. In Experiment #1, BPA only and single or double irradiation in higher doses were used, while, in Experiment #2, BPA and BSH combinations and single or double irradiation with dosage adjustment were analyzed. Mice without treatment or irradiation after BPA or BPA+BSH injection were used as controls. (3) Results: Irradiation parameter adjustment and BPA and BSH combination led to 80–83% tumor-growth inhibition index scores, irradiation:BNCT ratios of 1:2, and increases in animal life expectancy from 9 to 107 days. (4) Conclusions: Adjustments in dosimetry control, calculation of irradiation doses, and combined use of two ¹⁰B compounds allowed for BNCT optimization that will be useful in the development of clinical-trial protocols for accelerator-based BNCT. Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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14 pages, 13416 KiB

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The Measurement of the Neutron Yield of the ⁷Li(p,n)⁷Be Reaction in Lithium Targets

by Marina Bikchurina, Timofey Bykov, Dmitrii Kasatov, Iaroslav Kolesnikov, Aleksandr Makarov, Ivan Shchudlo, Evgeniia Sokolova and Sergey Taskaev

Biology 2021, 10(9), 824; https://doi.org/10.3390/biology10090824 - 24 Aug 2021

Cited by 17 | Viewed by 3431

Abstract

A compact accelerator-based neutron source has been proposed and created at the Budker Institute of Nuclear Physics in Novosibirsk, Russia. An original design tandem accelerator is used to provide a proton beam. The neutron flux is generated as a result of the ⁷Li(p,n)⁷Be threshold reaction using the solid lithium target. A beam shaping assembly is applied to convert this flux into a beam of epithermal neutrons with characteristics suitable for BNCT. The BNCT technique is being tested in in vitro and in vivo studies, and dosimetry methods are being developed. Currently, the BNCT technique has entered into clinical practice in the world: after successful clinical trials, two clinics in Japan began treating patients, and four more BNCT clinics are ready to start operating. The neutron source proposed at the Budker Institute of Nuclear Physics served as a prototype for a facility created for a clinic in Xiamen (China). It is planned to equip the National Medical Research Center of Oncology (Moscow, Russia) and National Oncological Hadron Therapy Center (Pavia, Italy) with the same neutron sources. Due to the impending use of an accelerator neutron source for treating patients, the validation of the neutron yield of the ⁷Li(p,n)⁷Be reaction in lithium metal targets is required. The theoretical neutron yield has not been evaluated experimentally so far. Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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11 pages, 1943 KiB

Open AccessArticle

Neutron Source Based on Vacuum Insulated Tandem Accelerator and Lithium Target

by Sergey Taskaev, Evgenii Berendeev, Marina Bikchurina, Timofey Bykov, Dmitrii Kasatov, Iaroslav Kolesnikov, Alexey Koshkarev, Aleksandr Makarov, Georgii Ostreinov, Vyacheslav Porosev, Sergey Savinov, Ivan Shchudlo, Evgeniia Sokolova, Igor Sorokin, Tatiana Sycheva and Gleb Verkhovod

Biology 2021, 10(5), 350; https://doi.org/10.3390/biology10050350 - 21 Apr 2021

Cited by 53 | Viewed by 4473

Abstract

A compact accelerator-based neutron source has been proposed and created at the Budker Institute of Nuclear Physics in Novosibirsk, Russia. An original design tandem accelerator is used to provide a proton beam. The proton beam energy can be varied within a range of 0.6–2.3 MeV, keeping a high-energy stability of 0.1%. The beam current can also be varied in a wide range (from 0.3 mA to 10 mA) with high current stability (0.4%). In the device, neutron flux is generated as a result of the ⁷Li(p,n)⁷Be threshold reaction. A beam-shaping assembly is applied to convert this flux into a beam of epithermal neutrons with characteristics suitable for BNCT. A lot of scientific research has been carried out at the facility, including the study of blistering and its effect on the neutron yield. The BNCT technique is being tested in in vitro and in vivo studies, and the methods of dosimetry are being developed. It is planned to certify the neutron source next year and conduct clinical trials on it. The neutron source served as a prototype for a facility created for a clinic in Xiamen (China). Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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16 pages, 3713 KiB

Open AccessArticle

Salvage Boron Neutron Capture Therapy for Malignant Brain Tumor Patients in Compliance with Emergency and Compassionate Use: Evaluation of 34 Cases in Taiwan

by Yi-Wei Chen, Yi-Yen Lee, Chun-Fu Lin, Po-Shen Pan, Jen-Kun Chen, Chun-Wei Wang, Shih-Ming Hsu, Yu-Cheng Kuo, Tien-Li Lan, Sanford P. C. Hsu, Muh-Lii Liang, Robert Hsin-Hung Chen, Feng-Chi Chang, Chih-Chun Wu, Shih-Chieh Lin, Hsiang-Kuang Liang, Jia-Cheng Lee, Shih-Kuan Chen, Hong-Ming Liu, Jinn-Jer Peir, Ko-Han Lin, Wen-Sheng Huang, Kuan-Hsuan Chen, Yu-Mei Kang, Shueh-Chun Liou, Chun-Chieh Wang, Ping-Ching Pai, Chih-Wei Li, Daniel Quah Song Chiek, Tai-Tong Wong, Shih-Hwa Chiou, Yee Chao, Hiroki Tanaka, Fong-In Chou and Koji Ono Show full author list Hide full author list

Biology 2021, 10(4), 334; https://doi.org/10.3390/biology10040334 - 15 Apr 2021

Cited by 53 | Viewed by 6959

Abstract

Although boron neutron capture therapy (BNCT) is a promising treatment option for malignant brain tumors, the optimal BNCT parameters for patients with immediately life-threatening, end-stage brain tumors remain unclear. We performed BNCT on 34 patients with life-threatening, end-stage brain tumors and analyzed the relationship between survival outcomes and BNCT parameters. Before BNCT, MRI and ¹⁸F-BPA-PET analyses were conducted to identify the tumor location/distribution and the tumor-to-normal tissue uptake ratio (T/N ratio) of ¹⁸F-BPA. No severe adverse events were observed (grade ≥ 3). The objective response rate and disease control rate were 50.0% and 85.3%, respectively. The mean overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) times were 7.25, 7.80, and 4.18 months, respectively. Remarkably, the mean OS, CSS, and RFS of patients who achieved a complete response were 17.66, 22.5, and 7.50 months, respectively. Kaplan–Meier analysis identified the optimal BNCT parameters and tumor characteristics of these patients, including a T/N ratio ≥ 4, tumor volume < 20 mL, mean tumor dose ≥ 25 Gy-E, MIB-1 ≤ 40, and a lower recursive partitioning analysis (RPA) class. In conclusion, for malignant brain tumor patients who have exhausted all available treatment options and who are in an immediately life-threatening condition, BNCT may be considered as a therapeutic approach to prolong survival. Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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17 pages, 1670 KiB

Open AccessArticle

A Novel Approach to Design and Evaluate BNCT Neutron Beams Combining Physical, Radiobiological, and Dosimetric Figures of Merit

by Ian Postuma, Sara González, Maria S Herrera, Lucas Provenzano, Michele Ferrarini, Chiara Magni, Nicoletta Protti, Setareh Fatemi, Valerio Vercesi, Giuseppe Battistoni, Umberto Anselmi Tamburini, Yuan Hao Liu, Leena Kankaanranta, Hanna Koivunoro, Saverio Altieri and Silva Bortolussi

Biology 2021, 10(3), 174; https://doi.org/10.3390/biology10030174 - 26 Feb 2021

Cited by 20 | Viewed by 4928

Abstract

(1) Background:The quality of neutron beams for Boron Neutron Capture Therapy (BNCT) is currently defined by its physical characteristics in air. Recommendations exist to define whether a designed beam is useful for clinical treatment. This work presents a new way to evaluate neutron beams based on their clinical performance and on their safety, employing radiobiological quantities. (2) Methods: The case study is a neutron beam for deep-seated tumors from a 5 MeV proton beam coupled to a beryllium target. Physical Figures of Merit were used to design five beams; however, they did not allow a clear ranking of their quality in terms of therapeutic potential. The latter was then evaluated based on in-phantom dose distributions and on the calculation of the Uncomplicated Tumor Control Probability (UTCP). The safety of the beams was also evaluated calculating the in-patient out-of-beam dosimetry. (3) Results: All the beams ensured a UTCP comparable to the one of a clinical beam in phantom; the safety criterion allowed to choose the best candidate. When this was tested in the treatment planning of a real patient treated in Finland, the UTCP was still comparable to the one of the clinical beam. (4) Conclusions: Even when standard physical recommendations are not met, radiobiological and dosimetric criteria demonstrate to be a valid tool to select an effective and safe beam for patient treatment. Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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16 pages, 1963 KiB

Open AccessArticle

The Therapeutic Effects of Dodecaborate Containing Boronophenylalanine for Boron Neutron Capture Therapy in a Rat Brain Tumor Model

by Yusuke Fukuo, Yoshihide Hattori, Shinji Kawabata, Hideki Kashiwagi, Takuya Kanemitsu, Koji Takeuchi, Gen Futamura, Ryo Hiramatsu, Tsubasa Watanabe, Naonori Hu, Takushi Takata, Hiroki Tanaka, Minoru Suzuki, Shin-Ichi Miyatake, Mitsunori Kirihata and Masahiko Wanibuchi

Biology 2020, 9(12), 437; https://doi.org/10.3390/biology9120437 - 1 Dec 2020

Cited by 20 | Viewed by 4688

Abstract

Background: The development of effective boron compounds is a major area of research in the study of boron neutron capture therapy (BNCT). We created a novel boron compound, boronophenylalanine–amide alkyl dodecaborate (BADB), for application in BNCT and focused on elucidating how it affected a rat brain tumor model. Methods: The boron concentration of F98 rat glioma cells following exposure to boronophenylalanine (BPA) (which is currently being utilized clinically) and BADB was evaluated, and the biodistributions in F98 glioma-bearing rats were assessed. In neutron irradiation studies, the in vitro cytotoxicity of each boron compound and the in vivo corresponding therapeutic effect were evaluated in terms of survival time. Results: The survival fractions of the groups irradiated with BPA and BADB were not significantly different. BADB administered for 6 h after the termination of convection-enhanced delivery ensured the highest boron concentration in the tumor (45.8 μg B/g). The median survival time in the BADB in combination with BPA group showed a more significant prolongation of survival than that of the BPA group. Conclusion: BADB is a novel boron compound for BNCT that triggers a prolonged survival effect in patients receiving BNCT. Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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14 pages, 3420 KiB

Open AccessEditor’s ChoiceArticle

Clinical Veterinary Boron Neutron Capture Therapy (BNCT) Studies in Dogs with Head and Neck Cancer: Bridging the Gap between Translational and Clinical Studies

by Amanda E. Schwint, Andrea Monti Hughes, Marcela A. Garabalino, Gustavo A. Santa Cruz, Sara J. González, Juan Longhino, Lucas Provenzano, Paulina Oña, Monica Rao, María de los Ángeles Cantarelli, Andrea Leiras, María Silvina Olivera, Verónica A. Trivillin, Paula Alessandrini, Fabricio Brollo, Esteban Boggio, Hernan Costa, Romina Ventimiglia, Sergio Binia, Emiliano C. C. Pozzi, Susana I. Nievas and Iara S. Santa Cruz Show full author list Hide full author list

Biology 2020, 9(10), 327; https://doi.org/10.3390/biology9100327 - 7 Oct 2020

Cited by 20 | Viewed by 4720

Abstract

Translational Boron Neutron Capture Therapy (BNCT) studies performed by our group and clinical BNCT studies worldwide have shown the therapeutic efficacy of BNCT for head and neck cancer. The present BNCT studies in veterinary patients with head and neck cancer were performed to optimize the therapeutic efficacy of BNCT, contribute towards exploring the role of BNCT in veterinary medicine, put in place technical aspects for an upcoming clinical trial of BNCT for head and neck cancer at the RA-6 Nuclear Reactor, and assess the feasibility of employing the existing B2 beam to treat large, deep-seated tumors. Five dogs with head and neck cancer with no other therapeutic option were treated with two applications of BNCT mediated by boronophenyl-alanine (BPA) separated by 3–5 weeks. Two to three portals per BNCT application were used to achieve a potentially therapeutic dose over the tumor without exceeding normal tissue tolerance. Clinical and Computed Tomography results evidenced partial tumor control in all cases, with slight-moderate mucositis, excellent life quality, and prolongation in the survival time estimated at recruitment. These exploratory studies show the potential value of BNCT in veterinary medicine and contribute towards initiating a clinical BNCT trial for head and neck cancer at the RA-6 clinical facility. Full article

(This article belongs to the Special Issue Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine)

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