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February 2022.


Newsletter #12


On this day

71 years ago the first BNCT treatment took place at Brookhaven National Laboratory. In words of Prof. W. Sweet: “It makes fascinating reading, decades later, to see what facts relevant to biological studies needed to be known if one were to embark on such studies” (Sweet, 1997). If you want to know about the origin of BNCT, you can re-visit our post from last year, related to the 70th anniversary
On this first edition of 2022, you will read about a research project for glioma. This year looks very promising in terms of BNCT events! The Young Researchers BNCT meeting, the upcoming IAEA Technical Meeting and a proposal from the Communication Task Force (CTF) to host webinars are announced. 
At the Communication Task Force (CTF) we continue working in preparing very interesting info to share with you. As usual, we invite you to read more content on our websitefacebookinstagram, linkedin and twitter. Take a look to the videos and interviews at our youtube channel.  You can also write to news@isnct.net.

Now... let's read these exciting news!

BNCT Research Projects for Glioma

By Natsuko Kondo.

My main biological research project for BNCT is working to aim to overcome glioblastoma (GBM). As you know, GBM is the most lethal tumor with a median overall survival of 14 months and is resistant to chemo-radiation therapy and immuno-therapy. In addition, GBM is so invasive and infiltrative tumor into the normal brain that it is impossible to control it with other particle radiation therapy using focused ion beams. BNCT has prolonged the survival time of malignant glioma patients [1]. However, recurrences have occurred locally or remotely as cerebrospinal fluid dissemination (CSFD) after BNCT and complete cure is still not achieved [2].
One reason may come from endogenous property of glioma. For example, we found that small cell subtype of IDH1R132H mutation-negative glioblastoma more frequently developed CSFD after BNCT [2]. Another reason may come from incomplete uptake of p-boronophenylalanine (BPA) with heterogeneous distribution of BPA in the tumor [3].
Recent studies have shown that glioma stem cells (GSCs), a small subpopulation of tumor cells, are responsible for tumor resistance to radiation and chemotherapy, and the stemness, quiescence and therapy resistance are maintained by GSC niches in the tumor microenvironment [4, 5]. However, BPA uptake in GSCs has been unknown. Therefore, we investigated whether BPA is taken up by GSCs using mass cytometry (Cytof) and a mouse orthotopic tumor model. In brief, we established two glioma stem like cells from two GBM patients (GSLCs) and induced differentiated cells (DCs) with fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO2 incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA+ or CD98+ cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2–15 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2+ or Nestin+ GSLCs were BPA+, whereas only 36.9% of glial fibrillary acidic protein (GFAP)+ DCs were BPA+. Therefore, GSLCs may take up BPA and could be targeted by BNCT [6]. Then why does the recurrence occur although GSLCs can be eliminated with BPA-BNCT? Cell-cell interactions between residual tumors and tumor microenvironment maybe the key. Peri-hypoxic niches, one of the GSC niches, can dedifferentiate glioma differentiated cells into GSCs [7], and this may contribute to the resistance to BNCT. Now we are investigating these cell-cell interactions in vitro and in vivo.  
To protect normal brain tissue is also an important issue because most glioma cases are re-irradiations in BNCT. Radiation brain necrosis (RN) is a late adverse event that often occurs after BNCT and Bevacizumab (anti-Vascular Endothelial Growth Factor antibody) is shown to avoid the progression of RN after BNCT [8]. However, once bevacizumab is discontinued, the RN can occur [9]. Other treatment strategy should also be studied. We developed a mouse RN model using proton beams, in which the restricted area in right hemisphere of mouse brain is irradiated [10]. Recently, lipid mediators, lysophospholipids are shown to be involved in pathogenesis of cerebral or cardiac infarction [11]. We are investigating the relationship of these lipid mediators and RN pathogenesis with the RN mouse model.          
In conclusion, we edge toward efforts to achieve a complete cure with BNCT for glioma.

Natsuko Kondo MD, PhD
Particle Radiation Oncology Research Center
Institute for Integrated Radiation and Nuclear Science, Kyoto university
Member of the ISNCT's Board of Councilors 

References
[1] Miyatake SI, Wanibuchi M, Hu N, Ono K. Boron neutron capture therapy for malignant brain tumors. J Neurooncol. 2020;149:1-11.
[2] Kondo N, Barth RF, Miyatake SI, Kawabata S, Suzuki M, Ono K, Lehman NL. Cerebrospinal fluid dissemination of high-grade gliomas following boron neutron capture therapy occurs more frequently in the small cell subtype of IDH1R132H mutation-negative glioblastoma. J Neurooncol. 2017;133:107-118.
[3] Yokoyama K, Miyatake S, Kajimoto Y, Kawabata S, Doi A, Yoshida T, Okabe M, Kirihata M, Ono K, Kuroiwa T. Analysis of boron distribution in vivo for boron neutron capture therapy using two different boron compounds by secondary ion mass spectrometry. Radiat Res. 2007;167:102-9.
[4] Kreso A, Dick J.E. Evolution of the Cancer Stem Cell Model. Cell. Stem Cell. 2014; 14; 275–291.
[5] Gulaia V, Kumeiko V, Shved N, Cicinskas E, Rybtsov S, Ruzov A, Kagansky A. Molecular Mechanisms Governing the Stem Cell’s Fate in Brain Cancer: Factors of Stemness and Quiescence. Front. Cell Neurosci.2018; 12; 388.
[6] Kondo N, Hikida M, Nakada M, Sakurai Y, Hirata E, Takeno S, Suzuki M. Glioma Stem-Like Cells Can Be Targeted in Boron Neutron Capture Therapy with Boronophenylalanine. Cancers. 2020; 12(10); 3040.
[7] Aderetti D.A, Hira V.V.V, Molenaar R.J, van Noorden C.J.F. The hypoxic peri-arteriolar glioma stem cell niche, an integrated concept of five types of niches in human glioblastoma. Biochim. Biophys. Acta Rev. Cancer 2018; 1869; 346–354
[8] Furuse M, Kawabata S, Wanibuchi M, Shiba H, Takeuchi K, Kondo N, Tanaka H, Sakurai Y, Suzuki M, Ono K, Miyatake SI. Boron neutron capture therapy and add-on bevacizumab in patients with recurrent malignant glioma. Jpn J Clin Oncol. 2022: hyac004. 
[9] Zhuang H, Shi Siyu, Yuan Z, Chang JY. Bevacizumab treatment for radiation brain necrosis: mechanism, efficacy and issues. Molecular Cancer. 2019; 18:21
[10] Kondo N, Sakurai Y, Takata T, Takai N, Nakagawa Y, Tanaka H, Watanabe T, Kume K, Toho T, Miyatake S, Suzuki M, Masunaga S, Ono K. Localized radiation necrosis model in mouse brain using proton ion beams. Appl Radiat Isot. 2015;106:242-6.
[11] Shao Y, Nanayakkara G, Cheng J, Cueto R, Yang WY, Park JY, Wang H, Yang X. Lysophospholipids and their receptors serve as conditional DAMPs and DAMP receptors in tissue oxidative and inflammatory injury. Antioxid. Redox Signal 2018; 28: 973-986.

NOTE: While you read, these references are being included in our repository.

Registration for 11-YBNCT is now available

by Sergey Taskaev & Alexandr Makarov.

We are pleased to announce that we have launched the website of the 11th Young Researchers Boron Neutron Capture Therapy Meeting (11-YBNCT) . For the convenience of BNCT community members, we have also created a conference page on our ISNCT.net website. To participate in the conference, it is enough to register. Online participation is completely free for everybody. We also invite everyone, especially young scientists, to submit their abstracts by April 1, 2022. A feature of our conference is an agreement with the journal Cells to make a Special Issue. 

The conference will be held from 11 to 13 July, 2022 in Novosibirsk, Russia at the Academpark with the support of Budker Institute, Institute of Chemical BiologyRussian Science Foundation and Novosibirsk University. The format and venue will be similar to the 1st RuBNCT Conference we hosted in 2019 and featured in Newsletter #1. We really hope that most of the participants will be able to come in person and visit our VITA facility. Most likely, most of you have never been to Siberia and are unlikely to ever be here again. Therefore, do not miss this great opportunity to see the world in all its diversity!

IAEA Technical Meeting 2022

by Chiara Magni.

From 14 to 18 March 2022, IAEA’s Headquarters in Vienna, Austria, will host the Technical Meeting on Best Practices in Boron Neutron Capture Therapy. The event is expected to be hybrid, with virtual participation possible via Cisco Webex. 

The event aims to discuss best practices in BNCT in light of the most recent developments in the field. After this meeting the TECDOC drafted as the output from the Technical Meeting held in July 2020 is expected to be finalized.

The agenda will be structured around presentations from experts, contributed presentations electronically provided ahead of the meeting, break-out sessions to discuss specific sections of the TECDOC draft. 

The technical and discussion sessions will focus on: 

• Prerequisites for neutron beam parameters; 
• Neutron sources for BNCT treatment facilities; 
• Beam design considerations; 
• Irradiation (patient treatment) facility design; 
• Physical dosimetry of BNCT: determination of beam parameters; 
• Organization, operation and management of a BNCT treatment facility; 
• Boron compounds; 
• Radiobiology; 
• Boron concentration determination and imaging; 
• Prescribing and treatment planning for BNCT; 
• Dose reporting in BNCT; 
• Clinical trial design and procedures for BNCT; and 
• Regulatory aspects. 

The event is addressed to: staff from hospitals interested in establishing a Boron Neutron Capture Therapy clinical facility, specialists involved in the planning or executing a project in the field; scientists performing research and patient treatments for and with BNCT. 

IAEA’s Member States are invited to designate one or more participants to represent the government. The participation of women is strongly encouraged. 

It is possible to apply for a limited financial support offered by IAEA, for participants (normally one per country) relevantly contributing to the event. The request should be made at the time of designating the attendants using the dedicated form.

DESIGNATIONS DEADLINE: 22 February 2022

Designations should be submitted to the IAEA through the competent national authority (Ministry of Foreign Affairs, Permanent Mission to the IAEA or National Atomic Energy Authority) before the 22 February. Completed and authorized Participation Forms should be sent by mail to official.mail@iaea.org or by fax to +43126007. Copies should be emailed to the Scientific Secretary of the event, Mr Ian Swainson (i.swainson@iaea.org) and to the Administrative Secretary, Mr Rubén Gómez Zaragoza (r.gomez-zaragoza@iaea.org). 

Once received the official designations, the Scientific Secretariat will directly contact the participants regarding further arrangements.

Participants are encouraged to give presentations on the work of their respective institutions regarding the topics of the above list. Participants wishing to present a contribution at the event are requested to submit an abstract of their work. The abstract (A4 page format, max. 1 page and 700 words) will be reviewed as part of the selection process. The abstract should be sent electronically to Mr Ian Swainson, the Scientific Secretary, not later than 22 February 2022. Apart from live talks, a SharePoint will be available to upload contributions of accepted abstracts.

Governments are allowed to appoint observers to assist and advise the designated participants, informing IAEA with names and contact details of any such observers before the date. 

The venue will be the Vienna International Centre (VIC). Participants must make their own travel and accommodation arrangements.

For general information on the VIC and other practical details: https://www.iaea.org/events/guide-to-the-vic.

Webinars BNCT CTF

by Andrea Monti Hughes.

From the Communication Task Force, and now that we gained experience in the organization of virtual meetings, we would like to suggest to the ISNCT community to start with monthly webinars in 2022. We think they are important to stay in touch and updated with the latest advances on BNCT and, why not, other topics that could be useful to improve BNCT or broaden our knowledge :).
The idea is to organize 45-minute webinars: 30 minutes exposition + 15 minutes discussion. We will have to stick to the time because participants will be from all over the World! The proposed time for the webinars is 10 UTC. You could also suggest and invite speakers! Let's think together!
Thank you so much for your feedback!
In this sense, we invite you to complete this form.
If you organize these type of events in your group, you can contact us to tell about your experience and we will publish your article at the newsletter.

That's all for now!
We hope you enjoyed this communication.

 
Any news to share? Please contact us and we will announce it in this newsletter. You can also write us to news@isnct.net and will publish your achievement. 

Have you published a new paper? Congratulations! You can upload the citation here and we will include it in our repository, in order to make it visible to our community.

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