malignancies at other sites in the body. malignant gliomas are highly infiltrative of normal brain, histologically diverse, heterogeneous in their genomic profile and therefore it is very difficult to kill all of them. gadolinium neutron capture therapy (gd nct) there also has been some interest in the possible use of gadolinium-157 (157gd) as a capture agent for nct for the following reasons: first, and foremost, has been its very high neutron capture cross section of 254,000 barns. second, gadolinium compounds, such as gd-dtpa (gadopentetate dimeglumine magnevist®), have been used routinely as contrast agents for magnetic resonance imaging (mri) of brain tumors and have shown high uptake by brain tumor cells in tissue culture (in vitro). third, gamma rays and internal conversion and auger electrons are products of the 157gd(n,γ)158gd capture reaction (157gd + nth (0.025ev) → → 158gd + γ + 7.94 mev). though the gamma rays have longer pathlengths, orders of magnitude greater depths of penetration compared with alpha particles, the other radiation products (internal conversion and auger electrons) have pathlengths of about one cell diameter and can directly damage dna. therefore, it would be highly advantageous for the production of dna damage if the 157gd were localized within the cell nucleus. however, the possibility of incorporating gadolinium into biologically active molecules is very limited and only a small number of potential delivery agents for gd nct have been evaluated. relatively few studies with gd have been carried out in experimental animals compared to the large number with boron containing compounds (table 1), which have been synthesized and evaluated in experimental animals (in vivo). although in vitro activity has been demonstrated using the gd-containing mri contrast agent magnevist® as the gd delivery agent, there are very few studies demonstrating the efficacy of gd nct in experimental animal tumor models, and, as evidenced by a lack of citations in the literature, gd nct has not, as of 2019, been used clinically in humans. neutron sources clinical studies using nuclear reactors as neutron sources until 2014, neutron sources for nct were limited to nuclear reactors. reactor-derived neutrons are classified according to their energies as thermal (en < 0.5 ev), epithermal (0.5 ev < en < 10 kev), or fast (en >10 kev). thermal neutrons are the most important for bnct since they usually initiate the 10b(n,α)7li capture reaction. however, because they have a limited depth of penetration, epithermal neutrons, which lose energy and fall into the thermal range as they penetrate tissues, are not used for clinical therapy other than for skin tumors such as melanoma. a number of nuclear reactors with very good neutron beam quality have been developed and used clinically. these include: kyoto university research reactor institute (kurri) in kumatori, japan; the massachusetts institute of technology research reactor (mitr); the fir1 (triga mk ii) research reactor at vtt technical research centre, espoo, finland; the ra-6 cnea reactor in bariloche, argentina; the high flux reactor (hfr) at petten in the netherlands; and tsing hua open-pool reactor (thor) at the national tsing hua university, hsinchu, taiwan. jrr-4 at japan atomic energy agency, tokai, japan a compact in-hospital neutron irradiator (ihni) in a free-standing facility in beijing, china. as of may 2021, only the reactors in argentina, china, and taiwan are still being used clinically. it is anticipated that, beginning some time in 2022, clinical studies in finland will utilize an accelerator neutron source designed and fabricated in the united states by neutron therapeutics, danvers, massachusetts. clinical studies of bnct for brain tumors early studies in the us and japan it was not until the 1950s that the first clinical trials were initiated by farr at the brookhaven national laboratory (bnl) in new york and by sweet and brownell at the massachusetts general hospital (mgh) using the massachusetts institute of technology (mit) nuclear reactor (mitr) and several different low molecular weight boron compounds as the boron delivery agent. however, the results of these studies were disappointing, and no further clinical trials were carried out in the united states until the 1990s. following a two-year fulbright fellowship in sweet's laboratory at the mgh, clinical studies were initiated by hiroshi hatanaka in japan in 1967. he used a low-energy thermal neutron beam, which had low tissue penetrating properties, and sodium borocaptate (bsh) as the boron delivery agent, which had been evaluated as a boron delivery agent by albert soloway at the mgh. in hatanaka's procedure, as much as possible of the tumor was surgically resected ("debulking"), and at some time thereafter, bsh was administered by a slow infusion, usually intra-arterially, but later intravenously. twelve to 14 hours later, bnct was carried out at one or another of several different nuclear reactors using low-energy thermal neutron beams. the poor tissue-penetrating properties of the thermal neutron beams necessitated reflecting the skin and raising a bone flap in order to directly irradiate the exposed brain, a procedure first used by sweet and his collaborators. approximately 200+ patients were treated by hatanaka, and subsequently by his associate, nakagawa. due to the heterogeneity of the patient population, in terms of the microscopic diagnosis of the tumor and its grade, size, and the ability of the patients to carry out normal daily activities (karnofsky performance status), it was not possible to come up with definitive conclusions about therapeutic efficacy. however, the survival data were no worse than those obtained by standard therapy at the time, and there were several patients who were long-term survivors, and most probably they were cured of their brain tumors. further clinical studies in the united states and japan bnct of patients with brain tumors was resumed in the united states in the mid-1990s by chanana, diaz, and coderre and their co-workers at the brookhaven national laboratory using the brookhaven medical research reactor (bmrr) and at harvard/massachusetts institute of technology (mit) using the mit research reactor (mitr). for the first time, bpa was used as the boron delivery agent, and patients were irradiated with a collimated beam of higher energy epithermal neutrons, which had greater tissue-penetrating properties than thermal neutrons. a research group headed up by zamenhof at the beth israel deaconess medical center/harvard medical school and mit was the first to use an epithermal neutron beam for clinical trials. initially patients with cutaneous melanomas were treated and this was expanded to include patients with brain tumors, specifically melanoma metastatic to the brain and primary glioblastomas (gbms). included in the research team were otto harling at mit and the radiation oncologist paul busse at the beth israel deaconess medical center in boston. a total of 22 patients were treated by the harvard-mit research group. five patients with cutaneous melanomas were also treated using an epithermal neutron beam at the mit research reactor (mitr-ii) and subsequently patients with brain tumors were treated using a redesigned beam at the mit reactor that possessed far superior characteristics to the original mitr-ii beam and bpa as the capture agent. the clinical outcome of the cases treated at harvard-mit has been summarized by busse. although the treatment was well tolerated, there were no significant differences in the mean survival times (msts)of patients that had received bnct compared to those who received conventional external beam x-irradiation. shin-ichi miyatake and shinji kawabata at osaka medical college in japan have carried out extensive clinical studies employing bpa (500 mg/kg) either alone or in combination with bsh (100 mg/kg), infused intravenously (i.v.) over 2 h, followed by neutron irradiation at kyoto university research reactor institute (kurri). the mean survival time (mst) of 10 patients with high grade gliomas in the first of their trials was 15.6 months, with one long-term survivor (>5 years). based on experimental animal data, which showed that bnct in combination with x-irradiation produced enhanced survival compared to bnct alone, miyatake and kawabata combined bnct, as described above, with an x-ray boost. a total dose of 20 to 30 gy was administered, divided into 2 gy daily fractions. the mst of this group of patients was 23.5 months and no significant toxicity was observed, other than hair loss (alopecia). however, a significant subset of these patients, a high proportion of which had small cell variant glioblastomas, developed cerebrospinal fluid dissemination of their tumors. miyatake and his co-workers also have treated a cohort of 44 patients with recurrent high grade meningiomas (hgm) that were refractory to all other therapeutic approaches. the clinical regimen consisted of intravenous administration of boronophenylalanine two hours before neutron irradiation at the kyoto university research reactor institute in kumatori, japan. effectiveness was determined using radiographic evidence of tumor shrinkage, overall survival (os) after initial diagnosis, os after bnct, and radiographic patterns associated with treatment failure. the median os after bnct was 29.6 months and 98.4 months after diagnosis. better responses were seen in patients with lower grade tumors. in 35 of 36 patients, there was tumor shrinkage, and the median progression-free survival (pfs) was 13.7 months. there was good local control of the patients' tumors, as evidenced by the fact that only 22.2% of them experienced local recurrence of their tumors. from these results, it was concluded that bnct was effective in locally controlling tumor growth, shrinking tumors, and improving survival with acceptable safety in patients with therapeutically refractory hgms. in another japanese trial, carried out by yamamoto et al., bpa and bsh were infused over 1 h, followed by bnct at the japan research reactor (jrr)-4 reactor. patients subsequently received an x-ray boost after completion of bnct. the overall median survival time (mest) was 27.1 months, and the 1 year and 2-year survival rates were 87.5 and 62.5%, respectively. based on the reports of miyatake, kawabata, and yamamoto, combining bnct with an x-ray boost can produce a significant therapeutic gain. however, further studies are needed to optimize this combined therapy alone or in combination with other approaches including chemo- and immunotherapy, and to evaluate it using a larger patient population. table 2. past bnct clinical trials using an epithermal neutron beams for bnct of patients with gliomas* reactor facility*no. of patients & duration of trialdelivery agentmedian survival time (months)reference no. bmrr, u.s.a53 (1994–1999)bpa 250–330 mg/kg12.8 mitr, mit, u.s.a.20 (1996–1999)bpa 250 or 350 mg/kg11.1 kurri, japan40 (1998–2008)bpa 500 mg/kg23.5 (primary + x-ray) jrr4, japan15 (1998–2007)bpa 250 mg/kg + bsh 5 g10.8 (recurrent), 27.1 (+ x-ray) r2-0, studsvik medical ab, sweden30 (2001–2007)bpa 900 mg/kg17.7 (primary) fir1, finland50 (1999–2012)bpa 290–400 mg/kg11.0 – 21.9 (primary), 7.0 (recurrent) hfr, netherlands26 (1997–2002)bsh 100 mg/kg10.4 – 13.2 * a more comprehensive compilation of data relating to bnct clinical trials can be found in radiation oncology 7:146–167, 2012 clinical studies in finland the technological and physical aspects of the finnish bnct program have been described in considerable detail by savolainen et al. a team of clinicians led by heikki joensuu and leena kankaanranta and nuclear engineers led by iro auterinen and hanna koivunoro at the helsinki university central hospital and vtt technical research center of finland have treated approximately 200+ patients with recurrent malignant gliomas (glioblastomas) and head and neck cancer who had undergone standard therapy, recurred, and subsequently received bnct at the time of their recurrence using bpa as the boron delivery agent. the median time to progression in patients with gliomas was 3 months, and the overall mest was 7 months. it is difficult to compare these results with other reported results in patients with recurrent malignant gliomas, but they are a starting point for future studies using bnct as salvage therapy in patients with recurrent tumors. due to a variety of reasons, including financial, no further studies have been carried out at this facility, which has been decommissioned. however, a new facility for bnct treatment has been installed using an accelerator designed and fabricated by neutron therapeutics. this accelerator was specifically designed to be used in a hospital, and the bnct treatment and clinical studies will be carried out there after dosimetric studies have been completed in 2021. both finnish and foreign patients are expected to be treated at the facility. clinical studies in sweden to conclude this section on treating brain tumors with bnct using reactor neutron sources, a clinical trial that was carried out by stenstam, sköld, capala and their co-workers in studsvik, sweden, using an epithermal neutron beam produced by the studsvik nuclear reactor, which had greater tissue penetration properties than the thermal beams originally used in