Background: Proton and ion therapy have gained significant importance in radiation therapy cancer treatment due to their favorable dose distribution and tissue-sparing properties. In conventional gamma radiation therapy some methods of in vivo dose verification are possible with current medical devices. Proton and ion therapy dose verification is limited, mainly using PET for particle range. Prompt gamma methods offer low spatial resolution. This study presents initial results for in-vivo dose verification with PET imaging of F-18 during proton therapy. Although the activity concentration of F-18 generated by typical clinical doses (several Gy )is low, PET imaging performed approximately one hour post-irradiation yields sufficient image quality to derive dose-volume histograms (DVH), enabling spatial dose verification. Purpose: To verify the applied dose in proton therapy in vivo using Positron Emission Tomography with millimetric precision. Materials and Methods: We simulated proton treatment in a brain phantom using Gate and RayStation platforms to assess the production of several positron emitting isotopes. We focused on the production of fluorine-18 (F-18), given its low positron energy, which enables accurate reproduction of the dose distribution. To evaluate the detectability of the anticipated low activity concentrations (on the order of a few Bq/mL) following a 3 Gy proton irradiation, we tested three PET systems: two preclinical scanners based on LYSO detectors and one clinical scanner based on BGO crystals. Finally, we have analyzed the dose-volume histograms for simulated and measured dose and activity distributions and compared them with the planned ones. Results: F-18 PET imaging in proton therapy correlates with delivered dose within 5% error and matches the planned dose fall-off edge within 1 mm, enabling accurate and precise in vivo dose verification. Conclusion: The dose verification in proton therapy using F-18 Positron Emission Tomography allows higher precision of dose than other positron emitters like C-11, N-12 or O-15. ### Competing Interest Statement The method described in the manuscript of dose verification using β+ isotopes in proton and He-4 radiation therapy is patent pending (EP25382365). Marcin Balcerzyk, Marta Freire and Antonio Gonzalez are inventors in this patent. ### Funding Statement The publication was funded in part by Fundacion Vital Fundazioa. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Objective. To diagnose if a patient has subarachnoid hemorrhage (SAH) and predict if he/she will develop angiographic vasospasm/delayed cerebral ischemia (DCI) or will die using only admission cranial computed tomography (CT) and World Federation of Neurological Surgeons (WFNS) or Hunt-Hess clinical grades. Methods: We developed a semiautomatic method of quantification of SAH volume, surface, sphericity, fractal dimension, and other parameters by retrospectively analyzing admission CT scans of 127 SAH patients. A multivariable model to predict the development of vasospasm/DCI and death was fitted by combining CT and admission neurological grade with derived data. It was also developed and then validated with bootstrapping and with a separate group of patients. Results: The diagnosis of SAH can be given by surface to volume ratio AUC 0.98 (95% CI 0.95-1) , hemorrhage volume 0.92 (95% CI 0.85-0.99), sphericity 0.87 (95% CI 0.73-1) and surface area 0.75 (95% CI 0.56-0.94). For vasospasm/DCI prediction AUC of biomarker panel was 0.731 (95%CI 0.626-0.836) which was significantly different from random (p<0.001) while Hunt-Hess gave 0.653 (95%CI 0.535-0.772). We established one individual image derived predictor of death by the surface to volume ratio of the 60-80 HU volume of interest for blood at the level of AUC (Area under the curve) of 0.777 (95% CI 0.667 - 0.886), while a biomarker panel gave the value of AUC of 0.857 (95%CI 0.769-0.944). These two biomarkers allow the correct prediction of the death of nine of ten patients with 36% and 59% probability, respectively. Conclusions: The model allows rapid, objective, and quantitative assessment of the risk of vasospasm/DCI and death in SAH patients. Both assessments, being fully automatic, can be easily introduced to CT scanner reconstruction software. ### Competing Interest Statement Juan Jose Egea-Guerrero and Marcin Balcerzyk are inventors of the patent EPO EP3664027A1 and USPTO patent US11344260B2 to the described biomarker panel method. Marcin Balcerzyk is an owner of a company CT Provision SLU located in Spain. R. Loch Macdonald discloses receiving consulting fees from CSL Behring, LLC, Acasti Pharma and Idorsia Pharmaceuticals. Gabriel Cepeda-Carrion, Angel Parrado-Gallego, Zaida Ruiz de Azua Lopez, Angel Vilches-Arenas, Javier Rodriguez-Santero, Enrique de Vega-Rios, Manuel Quintana-Diaz, Julene Argaluza-Escudero, Soledad Perez-Sanchez report no disclosures. The study is not industry sponsored. The patients for this study were recruited thanks to a grant from Consejeria de Igualdad, Salud y Politicas Sociales de Andalucia, Spain (PI-0136-2012). ### Funding Statement 1. The study is not industry sponsored. The patients for this study were recruited thanks to a grant from Consejeria de Igualdad, Salud y Politicas Sociales de Andalucia, Spain (PI-0136-2012). 2. The study was partially funded by the project CI19-00068 from CaixaImpulse program of La Caixa Foundation (Barcelona, Spain). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research project was overseen and approved by Hospital Universitario Virgen del Rocio in Seville, Spain hospital ethics committee (Cod. CEI2012PI/228). Informed consent was obtained from all patients participating in the study or from their close relatives. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Intracranial hemorrhage is a serious medical problem that requires rapid and often intensive medical care. Identifying the location and type of any hemorrhage present is a critical step in the treatment of the patient. Detection of, and diagnosis of, a hemorrhage that requires an urgent procedure is a difficult and time-consuming process for human experts. In this paper, we propose methods based on EfficientDet’s deep-learning technology that can be applied to the diagnosis of hemorrhages at a patient level and which could, thus, become a decision-support system. Our proposal is two-fold. On the one hand, the proposed technique classifies slices of computed tomography scans for the presence of hemorrhage or its lack of, and evaluates whether the patient is positive in terms of hemorrhage, and achieving, in this regard, 92.7% accuracy and 0.978 ROC AUC. On the other hand, our methodology provides visual explanations of the chosen classification using the Grad-CAM methodology.

The purpose of this work is to present useful recommendations for the use of [18F]FDG-PET/CT imaging in radiotherapy planning and monitoring under different versions of EARL accreditation for harmonization of PET devices. A proof-of-concept experiment designed on an anthropomorphic phantom was carried out to establish the most suitable interpolation methods of the PET images in the different steps of the planning procedure. Based on PET/CT images obtained by using these optimal interpolations for the old EARL accreditation (EARL1) and for the new one (EARL2), the treatment plannings of representative actual clinical cases were calculated, and the clinical implications of the resulting differences were analyzed. As expected, EARL2 provided smaller volumes with higher resolution than EARL1. The increase in the size of the reconstructed volumes with EARL1 accreditation caused high doses in the organs at risk and in the regions adjacent to the target volumes. EARL2 accreditation allowed an improvement in the accuracy of the PET imaging precision, allowing more personalized radiotherapy. This work provides recommendations for those centers that intend to benefit from the new accreditation, EARL2, and can help build confidence of those that must continue working under the EARL1 accreditation.

Sugars are a versatile tool for targeting malignant cells and have been extensively used for drug delivery and imaging techniques. Their prototype, fluorodeoxyglucose ([18F]FDG), is currently used for positron emission tomography. Boron neutron capture therapy (BNCT) is a cancer treatment that relies on irradiation with thermal neutrons of cancer cells previously loaded with [10B]-containing compounds. The recent introduction of accelerators as a neutron source for clinical use prompts the planning of delivery compounds enriched with boron able to be traced in real time. This work describes the first synthesis of a new class of sugar derivatives conjugated to a trifluoroborate moiety as potential theranostic agents. Stability and cytotoxicity studies are reported for all compounds, together with [18F] radiolabeling optimization and in vivo preliminary positron emission tomography (PET) experiments on a selected compound.

Boron Neutron Capture Therapy (BNCT) is a promising binary disease-targeted therapy, as neutrons preferentially kill cells labeled with boron (10B), which makes it a precision medicine treatment modality that provides a therapeutic effect exclusively on patient-specific tumor spread. Contrary to what is usual in radiotherapy, BNCT proposes cell-tailored treatment planning rather than to the tumor mass. The success of BNCT depends mainly on the sufficient spatial biodistribution of 10B located around or within neoplastic cells to produce a high-dose gradient between the tumor and healthy tissue. However, it is not yet possible to precisely determine the concentration of 10B in a specific tissue in real-time using non-invasive methods. Critical issues remain to be resolved if BNCT is to become a valuable, minimally invasive, and efficient treatment. In addition, functional imaging technologies, such as PET, can be applied to determine biological information that can be used for the combined-modality radiotherapy protocol for each specific patient. Regardless, not only imaging methods but also proteomics and gene expression methods will facilitate BNCT becoming a modality of personalized medicine. This work provides an overview of the fundamental principles, recent advances, and future directions of BNCT as cell-targeted cancer therapy for personalized radiation treatment.

The synthesis of uniform neodymium-doped lanthanum trifluoride nanoparticles with lenticular shape and a mean diameter around 45 nm by using a homogeneous precipitation method is reported. The luminescent properties of the synthesized samples in terms of their emission spectra and emission lifetime are analyzed as a function of the Nd content to find the optimum phosphor and its suitability for luminescent imaging in the second biological window. The X-ray attenuation properties of the optimum phosphor are evaluated to investigate their additional ability as contrast agent for X-ray computed tomography. Finally, the colloidal stability of the obtained nanoparticles in physiological medium and their cytotoxicity are also analyzed to assess their aptness for in vivo bioimaging applications. (c) 2021 SECV. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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.

The success of boron neutron capture therapy(BNCT) mainly depends on sufficient spatial bio-distribution of boron(10B) localized around or within the neoplastic cells to produce a high dose gradient between the tumor and healthy tissue. Contrary to what is usual in radiotherapy, BNCT proposes treatment planning directed at the cell instead of the tumor mass. However, it is not yet possible to precisely determine the concentration of 10B in a specific tissue in real-time using non-invasive methods. Some critical issues still need to be resolved if BNCT is to become valuable, minimally invasive, and efficient cancer treatment. This review article provides an overview of fundamental principles, the recent advances, and future directions of BNCT as cellular targeted cancer therapy. The main emphasis is on topics related to biological dosimetry, methods for as-sessment of boron concentration, mechanisms of action of BNCT, and its physical bases for clinical implementation.

Background: 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.

Uniform Nd3+-doped LuVO4 nanophosphors have been synthesized for the first time in literature by using a poliol-based method at 120 °C from Nd3+ and vanadate precursors. After optimizing the Nd doping level, these phosphors present intense luminescence in the near-infrared biological windows. The X-ray attenuation capacity of the optimum nanophosphor has been found to be higher than that of a commercial X-ray computed tomography contrast agent. After surface coating with polyacrylic acid, such nanoparticles present high colloidal stability in physiological pH medium and high cell viability. Because of these properties, the developed Nd3+-doped LuVO4 nanoparticles have potential applications as a bimodal probe for NIR luminescent bioimaging and X-ray computed tomography.

We describe a wet chemical method for the synthesis of uniform and well-dispersed dysprosium vanadate (DyVO4) and holmium vanadate (HoVO4) nanoparticles with an almost spherical shape and a mean size of ∼60 nm and their functionalization with poly(acrylic acid). The transverse magnetic relaxivity of both systems at 9.4 T is analyzed on the basis of magnetic susceptibility and magnetization measurements in order to evaluate their potential for application as high-field MRI contrast agents. In addition, the X-ray attenuation properties of these systems are also studied to determine their capabilities as computed tomography contrast agent. Finally, the colloidal stability under physiological pH conditions and the cytotoxicity of the functionalized NPs are also addressed to assess their suitability for bioimaging applications.

The combination of different bioimaging techniques, mainly in the field of oncology, allows circumventing the defects associated with the individual imaging modalities, thus providing a more reliable diagnosis. The development of multimodal endogenous probes that are simultaneously suitable for various imaging modalities, such as magnetic resonance imaging (MRI), X-ray computed tomography (CT) and luminescent imaging (LI) is, therefore, highly recommended. Such probes should operate in the conditions imposed by the newest imaging equipment, such as MRI operating at high magnetic fields and dual-energy CT. They should show, as well, high photoluminescence emission intensity for their use in optical imaging and present good biocompatibility. In this context, we have designed a single nanoprobe, based on a core-shell architecture, composed of a luminescent Eu3+:Ba0.3Lu0.7F2.7 core surrounded by an external HoF3 shell that confers the probe with very high magnetic transverse relaxivity at high field. An intermediate, optically inert Ba0.3Lu0.7F2.7 layer was interposed between the core and the shell to hinder Eu3+-Ho3+ cross-relaxation and avoid luminescence quenching. The presence of Ba and Lu, with different K-edges, allows for good X-ray attenuation at high and low voltages. The core-shell nanoparticles synthesized are good potential candidates as trimodal bioprobes for MRI at high field, dual-energy CT and luminescent imaging.

Resumen del trabajo presentado en NanoSpain Conference, celebrada en Barcelona (Espana), del 28 al 31 de mayo de 2019

Bi3+ codoping has been proposed in this work with a twofold objective, namely, enhancing the luminescence emission of Eu3+:LaF3 nanoparticles (NPs) and increasing their X-ray attenuation capacity, with the purpose of obtaining a bimodal bioprobe for luminescence bioimaging and X-ray computed tomography. The synthesis method, reported here for the first time for LaF3 particles, allowed obtaining uniform, nonaggregated NPs using a homogeneous precipitation in polyol medium at room temperature in just 2 h. The simplicity of the synthesis method allows the large-scale production of NPs. LaF3 NPs with different Eu3+ contents were first synthesized to find the critical Eu3+ concentration, producing the highest emission intensity. This concentration was subsequently used to fabricate Bi3+-Eu3+-codoped LaF3 NPs using the same method. The emission intensity of the codoped NPs increased in more than one order of magnitude, thanks to the possibility of excitation through the Bi3+. Eu3+ energy-transfer band. The luminescence properties of the codoped NPs were analyzed in detail to find the mechanism responsible for the emission enhancement. Finally, it was demonstrated that the high atomic number of Bi3+, higher than that of lanthanides, was an added value of the material because it increased its X-ray attenuation capacity. In summary, the LaF3 NPs codoped with Eu3+ and Bi3+ presented in this work are promising candidates as a bimodal bioprobe for luminescence bioimaging and X-ray computed tomography.

A one-pot simple procedure for the synthesis of uniform, ellipsoidal Eu3+-doped sodium lanthanum tungstate and molybdate (NaLa(XO4)2, X  = W, Mo) nanophosphors, functionalized with carboxylate groups, is described. The method is based on a homogeneous precipitation process at 120 °C from appropriate Na+, Ln3+ and tungstate or molybdate precursors dissolved in ethylene glycol/water mixtures containing polyacrylic acid. A comparative study of the luminescent properties of both luminescent materials as a function of the Eu3+ doping level has been performed to find the optimum nanophosphor, whose efficiency as X-ray computed tomography contrast agent is also evaluated and compared with that of a commercial probe. Finally, the cell viability and colloidal stability in physiological pH medium of the optimum samples have also been studied to assess their suitability for biomedical applications.

BACKGROUND:Alzheimer's disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice.METHODS:Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice.RESULTS:The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aβ-peptide, mainly through π-π interactions. According to a dynamic simulation study the ligand-Aβ peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aβ plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model.CONCLUSION:The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aβ senile plaques.