the united states and japan, will be briefly summarized. this study differed significantly from all previous clinical trials in that the total amount of bpa administered was increased (900 mg/kg), and it was infused i.v. over 6 hours. this was based on experimental animal studies in glioma bearing rats demonstrating enhanced uptake of bpa by infiltrating tumor cells following a 6-hour infusion. the longer infusion time of the bpa was well tolerated by the 30 patients who were enrolled in this study. all were treated with 2 fields, and the average whole brain dose was 3.2–6.1 gy (weighted), and the minimum dose to the tumor ranged from 15.4 to 54.3 gy (w). there has been some disagreement among the swedish investigators regarding the evaluation of the results. based on incomplete survival data, the mest was reported as 14.2 months and the time to tumor progression was 5.8 months. however, more careful examination of the complete survival data revealed that the mest was 17.7 months compared to 15.5 months that has been reported for patients who received standard therapy of surgery, followed by radiotherapy (rt) and the drug temozolomide (tmz). furthermore, the frequency of adverse events was lower after bnct (14%) than after radiation therapy (rt) alone (21%) and both of these were lower than those seen following rt in combination with tmz. if this improved survival data, obtained using the higher dose of bpa and a 6-hour infusion time, can be confirmed by others, preferably in a randomized clinical trial, it could represent a significant step forward in bnct of brain tumors, especially if combined with a photon boost. clinical studies of bnct for extracranial tumors head and neck cancers the single most important clinical advance over the past 15 years has been the application of bnct to treat patients with recurrent tumors of the head and neck region who had failed all other therapy. these studies were first initiated by kato et al. in japan. and subsequently followed by several other japanese groups and by kankaanranta, joensuu, auterinen, koivunoro and their co-workers in finland. all of these studies employed bpa as the boron delivery agent, usually alone but occasionally in combination with bsh. a very heterogeneous group of patients with a variety of histopathologic types of tumors have been treated, the largest number of which had recurrent squamous cell carcinomas. kato et al. have reported on a series of 26 patients with far-advanced cancer for whom there were no further treatment options. either bpa + bsh or bpa alone were administered by a 1 or 2 h i.v. infusion, and this was followed by bnct using an epithermal beam. in this series, there were complete regressions in 12 cases, 10 partial regressions, and progression in 3 cases. the mst was 13.6 months, and the 6-year survival was 24%. significant treatment related complications ("adverse" events) included transient mucositis, alopecia and, rarely, brain necrosis and osteomyelitis. kankaanranta et al. have reported their results in a prospective phase i/ii study of 30 patients with inoperable, locally recurrent squamous cell carcinomas of the head and neck region. patients received either two or, in a few instances, one bnct treatment using bpa (400 mg/kg), administered i.v. over 2 hours, followed by neutron irradiation. of 29 evaluated patients, there were 13 complete and 9 partial remissions, with an overall response rate of 76%. the most common adverse event was oral mucositis, oral pain, and fatigue. based on the clinical results, it was concluded that bnct was effective for the treatment of inoperable, previously irradiated patients with head and neck cancer. some responses were durable but progression was common, usually at the site of the previously recurrent tumor. as previously indicated in the section on neutron sources, all clinical studies have ended in finland, for variety of reasons including economic difficulties of the two companies directly involved, vtt and boneca. however, clinical studies using an accelerator neutron source designed and fabricated by neutron therapeutics and installed at the helsinki university hospital should be fully functional by 2022. finally, a group in taiwan, led by ling-wei wang and his co-workers at the taipei veterans general hospital, have treated 17 patients with locally recurrent head and neck cancers at the tsing hua open-pool reactor (thor) of the national tsing hua university. two-year overall survival was 47% and two-year loco-regional control was 28%. further studies are in progress to further optimize their treatment regimen. melanoma and extramammary paget's disease other extracranial tumors that have been treated with bnct include malignant melanomas. the original studies were carried out in japan by the late yutaka mishima and his clinical team in the department of dermatology at kobe university using locally injected bpa and a thermal neutron beam. it is important to point out that it was mishima who first used bpa as a boron delivery agent, and this approach subsequently was extended to other types of tumors based on the experimental animal studies of coderre et al. at the brookhaven national laboratory. local control was achieved in almost all patients, and some were cured of their melanomas. patients with melanoma of the head and neck region, vulva, and extramammary paget's disease of the genital region have been treated by hiratsuka et al. with promising clinical results. the first clinical trial of bnct in argentina for the treatment of melanomas was performed in october 2003 and since then several patients with cutaneous melanomas have been treated as part of a phase ii clinical trial at the ra-6 nuclear reactor in bariloche. the neutron beam has a mixed thermal-hyperthermal neutron spectrum that can be used to treat superficial tumors. the in-hospital neutron irradiator (ihni) in beijing has been used to treat a small number of patients with cutaneous melanomas with a complete response of the primary lesion and no evidence of late radiation injury during a 24+-month follow-up period. colorectal cancer two patients with colon cancer, which had spread to the liver, have been treated by zonta and his co-workers at the university of pavia in italy. the first was treated in 2001 and the second in mid-2003. the patients received an i.v. infusion of bpa, followed by removal of the liver (hepatectomy), which was irradiated outside of the body (extracorporeal bnct) and then re-transplanted into the patient. the first patient did remarkably well and survived for over 4 years after treatment, but the second died within a month of cardiac complications. clearly, this is a very challenging approach for the treatment of hepatic metastases, and it is unlikely that it will ever be widely used. nevertheless, the good clinical results in the first patient established proof of principle. finally, yanagie and his colleagues at meiji pharmaceutical university in japan have treated several patients with recurrent rectal cancer using bnct. although no long-term results have been reported, there was evidence of short-term clinical responses. accelerators as neutron sources accelerators now are the primary source of epithermal neutrons for clinical bnct. the first papers relating to their possible use were published in the 1980s, and, as summarized by blue and yanch, this topic became an active area of research in the early 2000s. however, it was the fukushima nuclear disaster in japan in 2011 that gave impetus to their development for clinical use. accelerators also can be used to produce epithermal neutrons. today several accelerator-based neutron sources (abns) are commercially available or under development. most existing or planned systems use either the lithium-7 reaction, 7li(p,n)7be or the beryllium-9 reaction,9be(p,n)9be, to generate neutrons, though other nuclear reactions also have been considered. the lithium-7 reaction requires a proton accelerator with energies between 1.9 and 3.0 mev, while the beryllium-9 reaction typically uses accelerators with energies between 5 and 30 mev. aside from the lower proton energy that the lithium-7 reaction requires, its main benefit is the lower energy of the neutrons produced. this in turn allows the use of smaller moderators, “cleaner” neutron beams, and reduced neutron activation. benefits of the beryllium-9 reaction include simplified target design and disposal, long target lifetime, and lower required proton beam current. since the proton beams for bnct are quite powerful (~20-100 kw), the neutron generating target must incorporate cooling systems capable of removing the heat safely and reliably to protect the target from damage. in the case of the lithium-7, this requirement is especially important due to the low melting point and chemical volatility of the target material. liquid jets, micro-channels and rotating targets have been employed to solve this problem. several researchers have proposed the use of liquid lithium-7 targets in which the target material doubles as the coolant. in the case of beryllium-9, “thin” targets, in which the protons come to rest and deposit much of their energy in the cooling fluid, can be employed. target degradation due to beam exposure (“blistering”) is another problem to be solved, either by using layers of materials resistant to blistering or by spreading the protons over a large target area. since the nuclear reactions yield neutrons with energies ranging from < 100kev to tens of mev, a beam shaping assembly (bsa) must be used to moderate, filter, reflect and collimate the neutron beam to achieve the desired epithermal energy range, neutron beam size and direction. bsas are typically composed of a range of materials with desirable nuclear properties for each function. a well-designed bsa should maximize neutron yield per proton while minimizing fast neutron, thermal neutron and gamma contamination. it should also produce a sharply delimited and generally forward directed beam enabling flexible positioning of the patient relative to the aperture. one key challenge for an abns is the duration of treatment time: depending on the neutron beam intensity, treatments can take up to an hour or more. therefore, it is desirable to reduce the treatment time both for patient comfort during immobilization and to increase the number of patients that could be treated in a 24-hour period. increasing the neutron beam intensity for the same proton current by adjusting the bsa is often achieved at the cost of reduced beam quality (higher levels of unwanted fast neutrons or gamma rays in the beam or poor beam collimation). therefore, increasing the proton current delivered by abns bnct systems remains a key goal of technology development programs. the table below summarizes the existing or planned abns installations for clinical use (updated june, 2021). manufacturer product reaction accelerator type website host institution first clinical use status sumitomo heavy industries neucure 9be(p,n)9be cyclotron https://www.shi.co.jp/industrial/ en/product/medical/bnct/neucure.html particle radiation oncology research center, kyoto university, kumatori, japan 2012 retired from clinical use southern tohoku bcnt research center, southern tohoku general hospital, koriyama, fukushima, japan 2016 active clinical use (approved) kansai bnct research center, osaka medical and pharmaceutical university, takatsuki, osaka, japan 2020 active clinical use (approved) cancer intelligence care systems 7li(p,n)7be rfq https://www.cics.jp/page/english.html national cancer center, tsukiji, tokyo, japan 2019 active clinical use for treatment of superficial tumors edogawa hospital, edogawa, tokyo, japan n/a operational, but not in clinical use neutron therapeutics nubeam 7li(p,n)7be single-ended electrostatic http://www.neutrontherapeutics.com/ technology/ helsinki university hospital, helsinki, finland n/a operational, but not in clinical use shonan kamakura general hospital, kamakura, kanagawa, japan n/a under construction ihep d-bnct 9be(p,n)9be linac http://english.ihep.cas.cn/doc/3931.html institute of high energy physics, dongguan, guangdong, china n/a operational university of tsukuba ibnct 9be(p,n)9be linac university of tsukuba, tokai, ibaraki, japan n/a operational, but not in clinical use in addition, two other abnss are in planning or under construction: neuboron medtech, https://en.neuboron.com/products; and tae life sciences, https://taelifesciences.com/alphabeam-neutron-system/. several companies have announced plans to develop abns for bnct, including heron neutron medical (taiwan), https://www.digitimes.com/news/a20201221pd206.html, and fukushima sic applied engineering (japan), http://en.fukushima-sic.co.jp/. bnct accelerator research projects with hardware in place also exist at several research institutions in argentina, russia, japan, the united kingdom, and korea. clinical studies using accelerator neutron sources treatment of recurrent malignant gliomas the single greatest advance in moving bnct forward clinically has been the introduction of cyclotron-based neutron sources (c-bns) in japan. shin-ichi miyatake and shinji kawabata have led the way with the treatment of patients with recurrent glioblastomas (gbms). in their phase ii clinical trial, they used the sumitomo heavy industries accelerator at the osaka medical college, kansai bnct medical center to treat a total of 24 patients. these patients ranged in age from 20 to 75 years, and all previously had received standard treatment