Quantification of Boron Compound Concentration for BNCT Using Positron Emission Tomography

Boron neutron capture therapy requires a 2 mM 10B concentration in the tumor. The well-known BNCT patient treatment method using boronophenylalanine (BPA) as a boron-carrying agent utilizes [18F]fluoroBPA ([18F]FBPA) as an agent to qualify for treatment. Precisely, [ 18F]FBPA must have at least a 3:1 tumor to background tissue ratio to qualify the patient for BNCT treatment. Normal, hyperplasia, and cancer thyroids capture iodine and several other large ions, including BF4 −, through a sodium-iodine symporter (NIS) expressed on the cell surface in normal conditions. In cancer, NIS is also expressed within the thyroid cell and is not functional. Methods: To visualize the thyroids and NIS, we have used a [18F]NaBF4 positron emission tomography (PET) tracer. It was injected into the tail veins of rats. The [18F]NaBF4 PET tracer was produced from NaBF4 by the isotopic exchange of natural 19F with radioactive 18F. Rats were subject to hyperplasia and tumor-inducing treatment. The NIS in thyroids was visualized by immunofluorescence staining. The boron concentration was calculated from Standard Uptake Values (SUV) in the PET/CT images and from the production data. Results: 41 MBq, 0.64 pmol of [18F]NaBF4 PET tracer that contained 0.351 mM, 53 nmol of NaBF4 was injected into the tail vein. After 17 min, the peak activity in the thyroid reached 2.3 MBq/mL (9 SUVmax). The natB concentration in the thyroid with hyperplasia reached 381 nM. Conclusions: Such an incorporation would require an additional 110 mg/kg dose of [ 10B]NaBF4 to reach the necessary 2 mM 10B concentration in the tumor. For future BNCT treatments of thyroid cancer, contrary to the 131I used now, there is no post-treatment radioactive decay, the patient can be immediately discharged from hospital, and there is no six-month moratorium for pregnancy. This method can be used for BNCT treatment compounds of the type R-BFn, where 1 <= n <= 3, labeled with 18F relatively easily, as in our example. A patient may undergo injection of a mixture of nonradioactive R-BFn to reach the necessary 10B concentration for BNCT treatment in the tumor together, with [18F]R-BFn for boron mapping.Spanish RTI2018-098117-B-C21 projec

Accurate,robust and harmonized implementation of morpho-functional imaging in treatment planning for personalized radiotherapy

In this work we present a methodology able to use harmonized PET/CT imaging in dose painting by number (DPBN) approach by means of a robust and accurate treatment planning system. Image processing and treatment planning were performed by using a Matlab-based platform, called CARMEN, in which a full Monte Carlo simulation is included. Linear programming formulation was developed for a voxel-by-voxel robust optimization and a specific direct aperture optimization was designed for an efficient adaptive radiotherapy implementation. DPBN approach with our methodology was tested to reduce the uncertainties associated with both, the absolute value and the relative value of the information in the functional image. For the same H&N case, a single robust treatment was planned for dose prescription maps corresponding to standardized uptake value distributions from two different image reconstruction protocols: One to fulfill EARL accreditation for harmonization of [18F]FDG PET/CT image, and the other one to use the highest available spatial resolution. Also, a robust treatment was planned to fulfill dose prescription maps corresponding to both approaches, the dose painting by contour based on volumes and our voxel-by-voxel DPBN. Adaptive planning was also carried out to check the suitability of our proposal. Different plans showed robustness to cover a range of scenarios for implementation of harmonizing strategies by using the highest available resolution. Also, robustness associated to discretization level of dose prescription according to the use of contours or numbers was achieved. All plans showed excellent quality index histogram and quality factors below 2%. Efficient solution for adaptive radiotherapy based directly on changes in functional image was obtained. We proved that by using voxel-by-voxel DPBN approach it is possible to overcome typical drawbacks linked to PET/CT images, providing to the clinical specialist confidence enough for routinely implementation of functional imaging for personalized radiotherapy.Junta de Andalucía (FISEVI, reference project CTS 2482)European Regional Development Fund (FEDER

Theranostics in Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) has the potential to specifically destroy tumor cells without damaging the tissues infiltrated by the tumor. BNCT is a binary treatment method based on the combination of two agents that have no effect when applied individually: B-10 and thermal neutrons. Exclusively, the combination of both produces an effect, whose extent depends on the amount of B-10 in the tumor but also on the organs at risk. It is not yet possible to determine the B-10 concentration in a specific tissue using non-invasive methods. At present, it is only possible to measure the B-10 concentration in blood and to estimate the boron concentration in tissues based on the assumption that there is a fixed uptake of B-10 from the blood into tissues. On this imprecise assumption, BNCT can hardly be developed further. A therapeutic approach, combining the boron carrier for therapeutic purposes with an imaging tool, might allow us to determine the B-10 concentration in a specific tissue using a non-invasive method. This review provides an overview of the current clinical protocols and preclinical experiments and results on how innovative drug development for boron delivery systems can also incorporate concurrent imaging. The last section focuses on the importance of proteomics for further optimization of BNCT, a highly precise and personalized therapeutic approach

Theranostics in Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) has the potential to specifically destroy tumor cells without damaging the tissues infiltrated by the tumor. BNCT is a binary treatment method based on the combination of two agents that have no effect when applied individually: 10B and thermal neutrons. Exclusively, the combination of both produces an effect, whose extent depends on the amount of 10B in the tumor but also on the organs at risk. It is not yet possible to determine the 10B concentration in a specific tissue using non-invasive methods. At present, it is only possible to measure the 10B concentration in blood and to estimate the boron concentration in tissues based on the assumption that there is a fixed uptake of 10B from the blood into tissues. On this imprecise assumption, BNCT can hardly be developed further. A therapeutic approach, combining the boron carrier for therapeutic purposes with an imaging tool, might allow us to determine the 10B concentration in a specific tissue using a non-invasive method. This review provides an overview of the current clinical protocols and preclinical experiments and results on how innovative drug development for boron delivery systems can also incorporate concurrent imaging. The last section focuses on the importance of proteomics for further optimization of BNCT, a highly precise and personalized therapeutic approach

Theranostics in Boron neutron capture therapy

Boron neutron capture therapy (BNCT) has the potential to specifically destroy tumor cells without damaging the tissues infiltrated by the tumor. BNCT is a binary treatment method based on the combination of two agents that have no effect when applied individually:B and thermal neutrons. Exclusively, the combination of both produces an effect, whose extent depends on the amount ofB in the tumor but also on the organs at risk. It is not yet possible to determine theB concentration in a specific tissue using non-invasive methods. At present, it is only possible to measure theB concentration in blood and to estimate the boron concentration in tissues based on the assumption that there is a fixed uptake ofB from the blood into tissues. On this imprecise assumption, BNCT can hardly be developed further. A therapeutic approach, combining the boron carrier for therapeutic purposes with an imaging tool, might allow us to determine theB concentration in a specific tissue using a non-invasive method. This review provides an overview of the current clinical protocols and preclinical experiments and results on how innovative drug development for boron delivery systems can also incorporate concurrent imaging. The last section focuses on the importance of proteomics for further optimization of BNCT, a highly precise and personalized therapeutic approach.E.H.-H. and M.K. gratefully acknowledge support from the DFG (HE 1376/38-1); L.S. received funding from GEFLUC Grenoble Dauphiné Savoie

Research facilities and highlights at the Centro Nacional de Aceleradores (CNA)

The Centro Nacional de Aceleradores is a user-oriented accelerator facility in Seville, Spain. Its main facilities are a 3 MV tandem accelerator, an 18 MeV proton Cyclotron, a tandetron used for AMS, a compact accelerator used for radiocarbon measurements, a 60Co irradiator and a PET/CT scanner. The technical specifications and research applications of these facilities are described. A neutron beam line associated to a charged pulsed beam in the tandem allows for time of flight measurements which determine the neutron energy. The use of an adequate stripper gas in the AMS tandetron permits to measure heavy radionuclides with very low detection levels, allowing to perform environmental studies using these radionuclides as tracers. The use of the microbeam in the tandem accelerator allows to apply the ion beam-induced current technique to investigate the spectroscopic properties and radiation hardness of different semiconductor detectors.European Union, H2020-847594, H2020-654002, H2020-847552, H2020-847594Ministry of Science RTI2018-098117-B-C21, RTC-2017-6369-3, EQC2018-004193-P, EQC2018-004095-P, EQC2018-004166- P, PGC2018-094546-B-I00Junta de Andalucía FEDER US-1261006, US-1263369, P18-RT-190

Predicting the risk of death or vasospasm in a patient with a subarachnoid hemorrhage

La invención describe un método para predecir o pronosticar el riesgo de muerte o vasoespasmo en un paciente con hemorragia subaracnoidea que comprende los siguientes pasos: realizar una evaluación clínica del paciente según las escalas Hunt- Hess y WFNS

Nuevos compuestos, afines a las placas β-amiloideas, para el manejo potencial de la enfermedad de Alzheimer

et al.Los nuevos compuestos son candidatos potenciales para ser empleados en el diagnóstico temprano, como sondas para la visualización de las placas seniles constituidas por depósitos de proteína -amiloide (A), así como para el tratamiento de la Enfermedad de Alzheimer (EA), ya que inhiben el proceso de plegamiento anómalo de proteínas. La EA es un trastorno neurodegenerativo que conlleva a la pérdida de las capacidades cognitivas y de memoria y se evidencia fundamentalmente en la tercera edad. Cuba es un país con un 18,3 % de sus habitantes que supera los 60 años y para el año 2020 se convertirá en el país de la región con mayor proporción de adultos mayores. La prevalencia de la EA es de 150 000 personas y esta cifra alcanzará para el 2040 el 2.7 % de la población cubana adulta mayor. (J.J. Libre Anales de la Academia de Ciencias de Cuba; 2011 2(2):1-18). La aparición de las placas seniles ocurre 20 años antes de que aparezcan los síntomas de la EA. Por esto, resulta de gran valor disponer de un medio de diagnóstico precoz e in vivo que permita visualizarlas con el propósito de implementar una terapia temprana que puede retardar el inicio de la manifestación de la EA. Así, en el Centro de Neurociencias de Cuba (CNEURO) se sintetizaron nuevos compuestos derivados del naftaleno, mediante métodos de síntesis convencionales. Estos compuestos son marcados con diferentes nucleidos (99mTc, 131I, 11C y 18F) y pueden ser utilizados como sondas para la visualización de A fibrilos, mediante tomografía por emisión de positrones (PET) y tomografía computarizada de emisión de fotón simple (SPECT). Se comprobó, in vivo, que los radiofármacos con 131I, 11C y 18F, son capaces de atravesar la barrera hematoencefálica (BHE) en animales sanos y transgénicos (tipo EA), siendo su captación y tiempo de retención mayor en el caso de los animales transgénicos. Por otra parte, los estudios in silico de los compuestos evidenciaron que interactúan con los aminoácidos de la A, responsables de la agregación proteica, desestabilizando su conformación , por lo que pueden modular el proceso de plegamiento anómalo de proteínas. Esto se comprobó en los estudios in vitro, en donde los compuestos modularon la cinética del proceso de fibrilogénesis de proteínas modelos, lo cual fue monitoreado por técnicas espectroscópicas y microscópicas. También, los compuestos presentaron actividad citoprotectora en cultivos de células granulares de cerebelo expuestos a estímulos citotóxicos, lo cual se evidenció por los ensayos de viabilidad celular y apoptosis realizados. Los resultados obtenidos avalan las posibilidades de que los compuestos sean empleados como radiofármacos para el diagnóstico de la EA. Algunos de los compuestos resultan versátiles a ser marcados con distintos radionucleidos lo que permite su adaptabilidad al equipamiento disponible en el servicio de medicina nuclear. Los resultados en la modulación de la fibrilogénesis como agentes terapéuticos para la EA, sustentan futuros estudios encaminados hacia la evaluación preclínica de estos compuestos Los compuestos y sus procedimientos de síntesis son novedosos. Los resultados de este trabajo forman parte de tres patentes, dos aprobadas por la Oficina Cubana de la Propiedad Industrial (OCPI) y de ellas, una aprobada por la Oficina Europea y de Sudáfrica, y la tercera solicitada ante la OCPI. También aparecen publicados en tres artículos nacionales y tres internacionales. El trabajo ha sido expuesto en forma de cartel o presentación oral, en varios eventos internacionales y ha contribuido a la formación de nuevos profesionales.Peer reviewe

The promotion of publishing company`s products in international market

Bakalaura darbā autors analizē izdevniecības uzņēmuma produktu virzīšanas iespējas starptautiskajā tirgū. Darba mērķis, ir pamatojoties uz teorijā un analīzē gūtajām atziņām par produktu virzīšanas tirgū metodēm, analizējot Latvijas lielāko nacionālo izdevniecību „Žurnāls Santa” un Eiropas lielākās izdevniecības, analizējot starptautisko izdevniecības produktu tirgu, un produktu konkurētspēju starptautiskajā tirgū, noteikt, ka izdevniecībai SIA „Žurnāls Santa” ir konkurētspējīgi produkti, kurus ir iespējams virzīt starptautiskajā tirgū. Bakalaura darbs sastāv no ievada, trim nodaļām, secinājumu un priekšlikumu daļas, kā arī pielikumiem. Darbs sastāv no 80 lappusēm, tabulām un 3 pielikumiem. Atslēgvārdi: izdevniecības produktu virzīšana tirgū, tirgus struktūras analīze, starptautiskais tirgus, konkurentu analīze.Author of the bachelor analyze opportunities of the publishing company product promotion in international market. The goal of bachelor is based on the theoretical part and analysis about product promotion methods in the market, by analysis of Latvia`s largest publishing companies "Žurnāls Santa" and Europes largest publishing companies, analysis of the international market for printed output and product competitiveness in the international market, provide that the publishing company "Žurnāls Santa" has competitive products, which can be promoted in international market. Bachelor consists of introduction, three chapters, par of conclusions and suggestions, and attachments. Bachelor consists of 80 pages, tables and three attachments. Keywords: product promotion, market structure analysis, international market, competitor analysis

Rapid and simplified synthesis of [18F]MISO and its use in subarachnoidal hemorrhage PET imaging

Resumen del póster presentado al "Annual Congress of the European Association of Nuclear Medicine" celebrado en Gothenburg (Suecia) del 18 al 22 de octubre de 2014.-- et al.[Aim]: Difered cerebral damage secondary to the vasospasm due to subarachnoidal hemorrhage is an important cause of morbi‐mortality. We propose the use of the PET tracer 1‐[18F]Fluoro‐3‐(2‐nitro‐imidazol‐1‐yl)‐propan‐2‐ol ([18F]MISO) to visualize the hypoxia caused by vasospasm. On the other hand [18F]MISO synthesis process can be optimized, avoiding HPLC purification, with solid phase extraction cartridges (SPE). [Matherial and methods]: [18F]MISO was obtained by nucleophilic substitution of 1‐(2´‐Nitro‐1´‐imidazolyl)‐2‐O‐tetrahydropyranyl‐3‐O‐toluenesulfonyl‐propanediol (NITTP) precursor with 18F‐, following Tang et al. method. We adapted our TracerLab FXFN module reducing some synthesis steps. 18F‐ was obtained from a 18/9 MeV Cyclone Cyclotron. Azeotropic distillation was reduced to 5 minutes. Fluorination of precursor took 5 minutes. Hydrolysis with HCl 1M of the protective groups and later neutralization with 1N NaOH was about 6 minutes. The solution was purified passing through three Sep‐Paks cartridges; Alumina‐SCX‐C18 connected in series. Final product was eluted in hydro‐alcoholic mixture (90/10). The completed synthesis was carried out in 21 minutes. Radiochemical purity of [18F]MISO (higher than 95%) was determined by analytical HPLC, and pH tested before injection to the animals. Two Wistar rats were used to obtain [18F]MISO PET images. 100‐200uL of blood obtained from the tail vein were injected in the Cisterna magna to cause the hemorrhage at one animal. The control animal was injected with saline, with the same procedure. Two days after the hemorrhage [18F]MISO PET/CT studies were carried out at a Mosaic MicroPET (Philips) and Bioscan nanoCT scanner to study the hemorrhage‐induced hypoxia. 100MBq of [18F]MISO were injected to each animal at the dorsal tail vein. After three hours of incorporation, PET images were adquired. CT scan followed the PET study. Images of both studies could be overlaid, because the animals remained anesthetized and immobilized during all process. [Results]: and discussion The synthesis steps were optimized; azeotropic distillation was completed in 5 minutes and we avoided HPLC purification using the SPE instead. Total synthesis time was reduced to 21 minutes with high radiochemical yield, up to 45% without decay correction. [18F]MISO PET Images will be available at poster.Peer Reviewe