Nuclear Theranostics in Taiwan / 대한핵의학회잡지

Boron neutron capture therapy and Y-90 radioembolization are emerging therapeutic methods for uncontrolled brain cancers and hepatic cancers, respectively. These advanced radiation therapies are heavily relied on theranostic nuclear medicine imaging before the therapy for the eligibility of patients and the prescribed-dose simulation, as well as the post-therapy scanning for assessing the treatment efficacy. In Taiwan, the Taipei Veterans General Hospital is the only institute performing the BNCT and also the leading institute performing Y-90 radioembolization. In this article, we present our single institute experiences and associated theranostic nuclear medicine approaches for these therapies.

Boron neutron capture therapy in cancer: past, present and future

Undifferentiated thyroid cancer (UTC) is a very aggressive tumor with no effective treatment, since it lacks iodine uptake and does not respond to radio or chemotherapy. The prognosis of these patients is bad, due to the rapid growth of the tumor and the early development of metastasis. Boron neutron capture therapy (BNCT) is based on the selective uptake of certain boron non-radioactive compounds by a tumor, and the subsequent irradiation of the area with an appropriate neutron beam. 10B is then activated to 11B, which will immediately decay releasing alpha particles and 7Li, of high linear energy transfer (LET) and limited reach. Clinical trials are being performed in patients with glioblastoma multiforme and melanoma. We have explored its possible application to UTC. Our results demonstrated that a cell line of human UTC has a selective uptake of borophenylalanine (BPA) both in vitro and after transplantation to nude mice. Treatment of mice by BNCT led to a complete control of growth and cure of 100 percent of the animals. Moreover dogs with spontaneous UTC also have a selective uptake of BPA. At the present we are studying the biodistribution of BPA in patients with UTC before its application in humans.

O câncer indiferenciado de tiróide (CIT) é um tumor muito agressivo sem tratamento efetivo, uma vez que não capta iodo e não responde à radio ou quimioterapia. O prognóstico desses pacientes é ruim, devido ao rápido crescimento do tumor e surgimento precoce de metástases. A terapia por captura de nêutrons de boro (TCNB) é baseada na captação seletiva de certos compostos de boro não-radioativos pelo tumor, e à subsequente irradiação da área com um feixe de nêutrons apropriado. O 10B é então ativado para 11B, cujo decaimento imediato libera partículas alfa e 7Li, de alta transferência linear de energia (TLE) e alcance limitado. Ensaios clínicos estão sendo conduzidos em pacientes com glioblastoma multiforme e melanoma, e nós estamos explorando sua possível aplicação no CIT. Nossos resultados demonstram que uma linhagem celular do CIT humano mostra captação seletiva de borofenilalanina (BPA) tanto in vitro como após transplante em camundongos "nude". O tratamento de camundongos com TCNB leva a um controle completo do crescimento tumoral e à cura em 100 por cento dos animais. Além disso, cães com CIT espontâneo também apresentam captação seletiva de BPA. No momento, estamos estudando a biodistribuição de BPA em pacientes com CIT, antes de sua aplicação em humanos.

Monte Carlo calculation for the development of a BNCT neutron source (1eV – 10 KeV) using MCNP code

Different materials have been studies in order to produce the epithermal neutron beam between 1eV - 10 KeV, which extensively used to irradiate patients with brain tumors such as (GBM). For this purpose we have studied three different neutrons moderators (H2O, D2O and BeO) and their combinations, four reflectors (Al2O3, C, Bi, and Pb) and two filters (Cd and Bi). Results of calculation show, That the best obtained assembly configuration correspond to the combination of the three moderators H2O, BeO and D2O jointly to Al2O3 reflector and two filter Cd +Bi optimize the spectrum of the epithermal neutron at 72 percent, and minimize the thermal neutron to 4 percent and thus it can be used to treat the deep brain tumor. Our calculations have been performed by means of the Monte Carlo N- particle code MCNP 5C.

Histopathological changes of testes and eyes by neutron irradiation with boron compounds in mice

This study was performed to investigate the biological effects of boron neutron capture therapy (BNCT) on the testes and eyes in mice using HANARO Nuclear Reactor, Korea Atomic Energy Research Institute. BNCT relies on the high capacity of (10)B in capturing thermal neutrons. Sodium borocaptate (BSH, 75 ppm, iv) and boronophenylalanine (BPA, 750 ppm, ip) have been used as the boron delivery agents. Mice were irradiated with neutron (flux: 1.036739E +09, Fluence 9.600200E+12) by lying flat pose for 30 (10 Gy) or 100 min (33 Gy) with or without boron carrier treatment. In 45 days of irradiation, histopathological changes of the testes and eyes were examined. Thirty-three Gy neutron irradiation for 100 min induced testicular atrophy in which some of seminiferous tubules showed complete depletion of spermatogenic germ cells. Lens epithelial cells and lens fiber were swollen and showed granular changes in an exposure time dependent manner. However, boron carrier treatment had no significant effect on the lesions. These results suggest that the examination of histopathological changes of lens and testis can be used as "biological dosimeters" for gauging radiation responses and the HANARO Nuclear Reactor has sufficient capacities for the BNCT.

Tratamiento del cáncer por captura neutrónica de boro: su aplicación al carcinoma indiferenciado de tiroides / Boron neutron capture therapy applied to undifferentiated thyroid carcinoma

El cáncer indiferenciado de tiroides es un tumor muy agresivo, de muy mal pronóstico y sin tratamiento efectivo. La terapia por captura neutrónica de boro (BNCT) podría ser una alternativa para el tratamiento de esta enfermedad. Se basa en la captación selectiva de boro por el tumor y su activación por un haz de neutrones. El boro activado libera un núcleo de litio-7 y una partícula alfa, las cuales tienen una alta transmisión linear de energía (linear energy transfer, LET) y un alcance de 5-9 µm, destruyendo el tumor. En estudios previos hemos mostrado que la línea celular humana de cáncer indiferenciado de tiroides (ARO) tiene una captación selectiva de borofenilalanina (10BPA) tanto in vitro como después de ser implantada en ratones NIH nude. También demostramos en estos animales inyectados con BPA e irradiados con un haz de neutrones térmicos, un 100% de control sobre el crecimiento tumoral y un 50% de cura histológica. En trabajos posteriores mostramos que la porfirina 10BOPP tetrakis-carborane carboxylate ester de 2,4-bis-(a,b-dihydroxyethyl)-deutero-porphyrin IX) cuando es inyectada 5-7 días antes que el BPA se obtiene una concentración tumoral de boro de aproximadamente el doble que el BPA solo (45-38 ppm vs. 20 ppm). La posterior irradiación con neutrones mostró un 100% de remisión completa en animales con tumores cuyo volumen pre-tratamiento era de 50 mm3 o menor. Los perros padecen CIT espontáneo, con un comportamiento biológico similar al humano, y una captación selectiva de BPA, abriendo la posibilidad de su tratamiento por BNCT

Undifferentiated thyroid carcinoma (UTC) is an aggressive tumor with a poor prognosis due to the lack of an effective treatment. Boron neutron capture therapy (BNCT) is based on the selective uptake of boron by the tumor and its activation by a neutron beam, releasing lithium-7 and an alpha particle that will kill the tumor cells by their high linear energy transfer (LET). In previous studies we have shown a selective uptake of borophenylalanine (10BPA) in a human UTC cell line (ARO) and in NIH nude mice implanted with this cell line. When these animals were injected with BPA and irradiated with an appropriated neutron beam, we observed a 100% of tumor growth control and a 50 % of histological cure when the initial tumor volume was 50 mm3 or less. Further studies with BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(a, b-dihydroxyethyl)-deutero-porphyrin IX) showed that when this porphyrin was injected 5-7 days before BPA, and the animals were sacrificed 60 min after the i.p. injection of BPA, a significant increase in boron uptake by the tumor was found (45-38 ppm with both compounds vs. 20 ppm with BPA alone). The application of BNCT using the combination of boron compounds showed a 100% of complete remission in tumors with initial volumes under 50 mm3. Dogs suffer spontaneous UTC, with a similar biological behavior to the human tumor, and a selective uptake of BPA. These results open the possibility of applying BNCT to UTC

Neutron source design for boron neutron capture synovectomy

Se diseñó una fuente de neutrones para la Sinovectomía por Captura de Neutrones en Boro. La fuente utiliza una fuente isotópica de 239PuBe que se inserta en el centro de contenedor cilindrico con un arreglo heterogéneo de dos moderadores. Los moderadores estudiados son agua ligera/agua pesada, grafito/agua pesada, lucita/agua pesada y polietileno/agua pesada. La fluencia total y la de los neutrones térmicos producidas se emplearon para seleccionar el mejor embalaje. Así, el espectro que produce una fuente de 239PuBe dentro del moderador con polietileno/agua pesada se utilizó como término fuente para calcular los espectros de neutrones dentro de un modelo de rodilla. La composición elemental utilizada para modelar el saco y el líquido sinovial fue la del agua, la del tejido sanguíneo y la de este último con dos concentraciones de boro. Encontramos que cuando la composición elemental del saco sinovial se asume igual a la del tejido sanguíneo con 0.278 por ciento en peso de boro el kerma debido a los neutrones es 7351 veces mayor al que se obtiene cuando la composición del saco sinovial es la del agua.

Dosimetry of the Low Fluence Fast Neutron Beams for Boron Neutron Capture Therapy / 대한방사선종양학회지

PURPOSE: For the research of Boron Neutron Capture Therapy (BNCT), fast neutrons generated from the MC-50 cyclotron with maximum energy of 34.4 MeV in Korea Cancer Center Hospital were moderated by 70 cm paraffin and then the dose characteristics were investigated. Using these results, we hope to establish the protocol about dose measurement of epi-thermal neutron, to make a basis of dose characteristic of epi-thermal neutron emitted from nuclear reactor, and to find feasibility about accelerator-based BNCT. METHOD AND MATERIALS: For measuring the absorbed dose and dose distribution of fast neutron beams, we used Unidos 10005 (PTW, Germany) electrometer and IC-17 (Far West, USA), IC-18, EIC-1 ion chambers manufactured by A-150 plastic and used IC-17M ion chamber manufactured by magnesium for gamma dose. There chambers were flushed with tissue equivalent gas and argon gas and then the flow rate was 5 cc per minute. Using Monte Carlo N-Particle (MCNP) code, transport program in mixed field with neutron, photon, electron, two dimensional dose and energy fluence distribution was calculated and there results were compared with measured results. RESULTS: The absorbed dose of fast neutron beams was 6.47x10-3 cGy per 1 MU at the 4 cm depth of the water phantom, which is assumed to be effective depth for BNCT. The magnitude of gamma contamination intermingled with fast neutron beams was 65.2+/-0.9% at the same depth. In the dose distribution according to the depth of water, the neutron dose decreased linearly and the gamma dose decreased exponentially as the depth was deepened. The factor expressed energy level, D20/D10, of the total dose was 0.718. CONCLUSION: Through the direct measurement using the two ion chambers, which is made different wall materials, and computer calculation of isodose distribution using MCNP simulation method, we have found the dose characteristics of low fluence fast neutron beams. If the power supply and the target material, which generate high voltage and current, will be developed and gamma contamination was reduced by lead or bismuth, we think, it may be possible to accelerator-based BNCT.

Considerações sobre a terapia de captura de nêutrons pelo Boro / Considerations on Boron neutron capture therapy

Este artigo descreve a técnica de radioterapia chamada Boron Neutron Capture Therapy (BNCT), isto é, Terapia de Captura de Nêutrons por Boro. Serão abordados conceitos básicos em BNCT, em particular como esta técnica tem sido usada na tentativa de combater glioblastoma multiforme. Uma breve revisão histórica dos estudos clínicos feitos nas décadas de 50 e 60 será apresentada, incluindo resultados recentes do Laboratório Nacional de Brookhaven - BNL e do Instituto Tecnológico de Massachusetts - MIT. A experiência japonesa na área será comentada. Atualmente, novas ensaios clínicos no MIT e BNL foram iniciados, tentando obter a cura para o glioblastoma multiforme e melanoma intracranial periférico. Dados radiobiológicos e protocolos clínicos usados na Fase I do MIT serão apresentados. Considerações de como BNCT poderá ser aplicado no Brasil serão traçadas. O artigo aponta para a possibilidade de utilização da braquiterapia via Cf-252 acoplada à técnica de terapia de captura de nêutrons – NCT como uma alternativa simples e barata de implementação de BNCT no país.

Avaliaçäo da dose em braquiterapia acoplada à terapia por captura de nêutron por boro / Dosage evaluation in brachytherapy coupled to boron capturing therapy

Este trabalho descreve uma nova técnica radioterapêutica baseada no acoplamento de dois métodos distintos: a braquiterapia, proporcionada pela emissäo de nêutrons e raios gama de fontes mistas discretas colocadas em regiSes intracavitárias do paciente, e a captura neutrônica por boro (BNCT). Com o objetivo de estudar a "performance" do tratamento acoplado, avaliaçöes computacionais säo propostas para quantificar as doses absorvidas. Análises de possíveis fontes geradoras de nêutrons, a saber: fontes mistas discretas, reatores nucleares, aceleradores lineares tipo LINAC e dispositivos de nêutrons frios, säo apresentadas com o intuito de verificar a viabilidade técnica de instalaçäo e uso da terapia de nêutrons em hospitais.

Determinaçäo colorimétrica de boro em amostras biológicas para controle de terapia por captura neutrônica e10 boro (BNCT) / A calorimetric determination of boron in biologiacal sanple for boron neutron capture theraphy (BNTC)

A terapia por captura neutrônica e10 Boro (BNCT) tem apresentado melhores prognósticos para o tratamento de gliomas e glioblastomas com grau III e IV, do que outras modalidades de terapia. Durante o tratamento é necessário conhecer os níveis de Na210B12H11SH em vários compartimentos do organismo e para tanto, foi padronizado o método de determinaçäo colorimétrica de boro utilizando curcumine. Este se mostrou simples, reprodutível e com sensibilidade adequada para este controle.