Exploring the applicability of a lesion segmentation method on [18F]fluorothymidine PET/CT images in diffuse large B-cell lymphoma.

BACKGROUND AND PURPOSE: The determination of the total metabolic tumour volume based on [18F]fluorothymidine ([18F]FLT) PET/CT images in diffuse large B-cell lymphoma has a potential clinical value for detecting early relapse in this type of heterogeneous lymphoproliferative tumours. Tumour segmentation is a key step in this process. For this purpose, our objective was to determine a segmentation threshold of [18F]FLT PET/CT images, based on a reference tissue uptake, on a cohort of patients with diffuse large B-cell lymphoma (DLBCL) that have been scanned at different stages of the treatment. METHODS: We enrolled 23 adult patients with DLBCL confirmed in II-IV stages without nervous system compromise. All patients were scanned using [18F]FLT PET/CT at the time of diagnosis (baseline PET), interim PET (iPET), and at the end of treatment (fPET). The administered activity was 1.8-2.6 MBq/kg body weight, performed 60-70 min after injection and without use of contrast-enhanced CT. First, we assessed the [18F]FLT uptake stability in liver and bone marrow along the patient follow-up. For the lesion segmentation, three threshold values were assessed. RESULTS: Both, liver, and bone marrow can be indistinctly taken as reference tissue. The SUV threshold for a voxel to be considered as belonging to a lesion is expressed in terms of a percentage relative to the patient's uptake in the reference tissue. Found thresholds were: for liver, 62%, 33%, 27%; and for bone marrow, 35%, 21% and 22%, for baseline, iPET and fPET stages, respectively. The relative threshold throughout the treatment has a decreasing tendency along the stages. CONCLUSION: Based on the results obtained with [18F]FLT PET/CT during staging and follow-up in patients with DLBCL, reference values were obtained for each stage referring to liver and bone marrow uptake that could be used in clinical practice oncology.

Estudio preclínico en primate no-humano con [18F]Fluorotimidina. dosimetría y biodistribución / [18F]Fluorothymidine preclinical study in non-human primate. Dosimetry and biodistribution

Resumen En el linfoma Hodgkin, la tomografía por emisión de positrones (PET-TC) forma parte de los nuevos algoritmos diagnósticos y de valoración de respuesta al tratamiento como método eficaz para evaluar supervivencia y pronóstico de la enfermedad, ya sea a través del PET-TC interino con 2-[18F]fluoro- 2-desoxi-D-glucosa, ([18F]FDG), como también del PET-TC al final de la terapéutica. Sin embargo, la [18F]FDG presenta una baja especificidad en linfoma no Hodgkin de grandes células B. Ante la aprobación en nuestro país del radiotrazador 3´-desoxi-3´-[18F]fluorotimidina, [18F]FLT, indicador de proliferación celular de fase S, éste resultaría un prometedor radiofármaco de uso diagnóstico frente a [18F]FDG. Por lo tanto, el objetivo de este estudio fue valorar la utilización de [18F]FLT mediante un modelo animal en primates no humanos Sapajus cay. Se obtuvieron imágenes de cuerpo entero para evaluar la biodistribución y realizar un cálculo dosimétrico en la médula ósea, dado que este es un órgano crítico por la permanencia del radiofármaco. Para órganos de inte rés, se trazaron curvas de actividad en función del tiempo y se calculó la actividad acumulada normalizada. La dosis media absorbida en la médula ósea se determinó aplicando el esquema conocido como Medical Internal Radiation Dosimetry (MIRD). La dosis media obtenida en el modelo animal por unidad de actividad administrada fue de 8.7 μGy/MBq. Este resultado se extrapoló a un modelo humano adulto resultando en 32 μGy/MBq, de lo que se desprende que PET-TC con [18F]FLT es una herramienta segura para uso diagnóstico y de seguimiento en pacientes con enfermedad oncológica linfoproliferativa u otros tumores sólidos.

Abstract Positron emission tomography-computed tomography (PET-CT) is part of the new diagnostic and therapeutic algorithms for Hodgkin lymphoma. PET-CT is a valuable tool for the assessment of treatment response and prognosis, both by means of interim PET-CT with 2-[ 18F]fluoro-2-deoxy-D-glucose ([18F]FDG) as well as end of treatment (EOT) PET-CT. Given the low specificity of [ 18F]FDG for the diffuse large B cell lymphoma (DLBCL), there is an emerging need for a more specific radiopharmaceutical agent. The recent approval of the radiotracer 3´-deoxy-[18F]-3´-flourothymidine ([18F]FLT), a phase-S mitosis cell proliferation marker, for clinical application in our country, shows as a promising radiopharmaceutical for diagnostic use with incremental value over [18F]FDG. In this study, non-human primates (Sapajus cay) were studied. PET-CT study was performed after the injection of [18F]FLT. Whole-body images were obtained to evaluate the biodistribution and to calculate the dosimetry of bone marrow, as this is a critic organ to this radiotracer. Time-activity curves were traced, normalized activity uptake of the organs of interest were calculated, and mean absorbed dose was also calculated using the established Medical Internal Radiation Dosimetry (MIRD) scheme. The mean dose obtained in the animal model per unit of activity administered was 8.7 μGy/MBq. This result was extrapolated to an adult human model resulting in 32 μGy/MBq, thereby suggesting that [18F]FLT is a secure diagnostic tool to be used on the tracing of patients with DLBCL.

[18F-fluorothymidine preclinical study in non-human primate. Dosimetry and biodistribution]. / Estudio preclínico en primate no-humano con 18F-fluorotimidina. Dosimetría y biodistribución.

Positron emission tomography-computed tomography (PET-CT) is part of the new diagnostic and therapeutic algorithms for Hodgkin lymphoma. PET-CT is a valuable tool for the assessment of treatment response and prognosis, both by means of interim PET-CT with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) as well as end of treatment (EOT) PET-CT. Given the low specificity of [18F]FDG for the diffuse large B cell lymphoma (DLBCL), there is an emerging need for a more specific radiopharmaceutical agent. The recent approval of the radiotracer 3'-deoxy-[18F]-3'-flourothymidine ([18F]FLT), a phase-S mitosis cell proliferation marker, for clinical application in our country, shows as a promising radiopharmaceutical for diagnostic use with incremental value over [18F]FDG. In this study, non-human primates (Sapajus cay) were studied. PET-CT study was performed after the injection of [18F]FLT. Whole-body images were obtained to evaluate the biodistribution and to calculate the dosimetry of bone marrow, as this is a critic organ to this radiotracer. Time-activity curves were traced, normalized activity uptake of the organs of interest were calculated, and mean absorbed dose was also calculated using the established Medical Internal Radiation Dosimetry (MIRD) scheme. The mean dose obtained in the animal model per unit of activity administered was 8.7 uGy/MBq. This result was extrapolated to an adult human model resulting in 32 uGy/MBq, thereby suggesting that [18F]FLT is a secure diagnostic tool to be used on the tracing of patients with DLBCL.

En el linfoma Hodgkin, la tomografía por emisión de positrones (PET-TC) forma parte de los nuevos algoritmos diagnósticos y de valoración de respuesta al tratamiento como método eficaz para evaluar supervivencia y pronóstico de la enfermedad, ya sea a través del PET-TC interino con 2-[18F]fluoro-2-desoxi-D-glucosa, ([18F]FDG), como también del PET-TC al final de la terapéutica. Sin embargo, la [18F]FDG presenta una baja especificidad en linfoma no Hodgkin de grandes células B. Ante la aprobación en nuestro país del radiotrazador 3'-desoxi-3'-[18F]fluorotimidina, [18F]FLT, indicador de proliferación celular de fase S, éste resultaría un prometedor radiofármaco de uso diagnóstico frente a [18F]FDG. Por lo tanto, el objetivo de este estudio fue valorar la utilización de [18F]FLT mediante un modelo animal en primates no humanos Sapajus cay. Se obtuvieron imágenes de cuerpo entero para evaluar la biodistribución y realizar un cálculo dosimétrico en la médula ósea, dado que este es un órgano crítico por la permanencia del radiofármaco. Para órganos de interés, se trazaron curvas de actividad en función del tiempo y se calculó la actividad acumulada normalizada. La dosis media absorbida en la médula ósea se determinó aplicando el esquema conocido como Medical Internal Radiation Dosimetry (MIRD). La dosis media obtenida en el modelo animal por unidad de actividad administrada fue de 8.7 uGy/MBq. Este resultado se extrapoló a un modelo humano adulto resultando en 32 uGy/MBq, de lo que se desprende que PET-TC con [18F]FLT es una herramienta segura para uso diagnóstico y de seguimiento en pacientes con enfermedad oncológica linfoproliferativa u otros tumores sólidos.

Present status of Accelerator-Based BNCT.

AIM: This work aims at giving an updated report of the worldwide status of Accelerator-Based BNCT (AB-BNCT). BACKGROUND: There is a generalized perception that the availability of accelerators installed in hospitals, as neutron sources, may be crucial for the advancement of BNCT. Accordingly, in recent years a significant effort has started to develop such machines. MATERIALS AND METHODS: A variety of possible charged-particle induced nuclear reactions and the characteristics of the resulting neutron spectra are discussed along with the worldwide activity in suitable accelerator development. RESULTS: Endothermic (7)Li(p,n)(7)Be and (9)Be(p,n)(9)B and exothermic (9)Be(d,n)(10)B are compared. In addition to having much better thermo-mechanical properties than Li, Be as a target leads to stable products. This is a significant advantage for a hospital-based facility. (9)Be(p,n)(9)B needs at least 4-5 MeV bombarding energy to have a sufficient yield, while (9)Be(d,n)(10)B can be utilized at about 1.4 MeV, implying the smallest possible accelerator. This reaction operating with a thin target can produce a sufficiently soft spectrum to be viable for AB-BNCT. The machines considered are electrostatic single ended or tandem accelerators or radiofrequency quadrupoles plus drift tube Linacs. CONCLUSIONS: (7)Li(p,n)(7)Be provides one of the best solutions for the production of epithermal neutron beams for deep-seated tumors. However, a Li-based target poses significant technological challenges. Hence, Be has been considered as an alternative target, both in combination with (p,n) and (d,n) reactions. (9)Be(d,n)(10)B at 1.4 MeV, with a thin target has been shown to be a realistic option for the treatment of deep-seated lesions.

Induction and persistence of large γH2AX foci by high linear energy transfer radiation in DNA-dependent protein kinase-deficient cells.

PURPOSE: To evaluate the cell response to DNA double-strand breaks induced by low and high linear energy transfer (LET) radiations when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an essential protein of the nonhomologous end-joining repair pathway, lacks kinase activity. METHODS AND MATERIALS: CHO10B2, a Chinese hamster ovary cell line, and its derived radiosensitive mutant cell line, irs-20, lacking DNA-PKcs activity, were evaluated after 0 to 3 Gy of γ-rays, plateau and Bragg peak protons, and lithium beams by clonogenic assay, and as a measurement of double-strand breaks, phosphorylated H2AX (γH2AX) foci number and size were quantified by immunocytofluorescence. RESULTS: Irs-20 exhibited greater radiosensitivity and a higher amount of γH2AX foci than CHO10B2 at 6 hours after irradiation for all types of radiations. Remarkably, CHO10B2 and irs-20 maintained their difference in radiosensitivity after high-LET radiation. Six hours after low-LET radiations, irs-20 did not reach basal levels of γH2AX at high doses, whereas CHO10B2 recovered basal levels for all doses. After high-LET radiation, only CHO10B2 exhibited a reduction in γH2AX foci, but it never reached basal levels. Persistent foci in irs-20 confirmed a repair deficiency. Interestingly, after 30 minutes of high-LET radiation both cell lines exhibited large foci (size>0.9 µm2) related to the damage nature, whereas at 6 hours irs-20 showed a higher amount of large foci than CHO10B2, with a 7-fold increase at 3 Gy, that could also be associated to radiosensitivity. CONCLUSIONS: We demonstrated, for the first time, an association between deficient DNA-PKcs activity and not only high levels of H2AX phosphorylation but also persistence and size increase of γH2AX foci after high-LET irradiation.

Induction and rejoining of DNA double strand breaks assessed by H2AX phosphorylation in melanoma cells irradiated with proton and lithium beams.

PURPOSE: The aim of this study was to evaluate the induction and rejoining of DNA double strand breaks (DSBs) in melanoma cells exposed to low and high linear energy transfer (LET) radiation. METHODS AND MATERIALS: DSBs and survival were determined as a function of dose in melanoma cells (B16-F0) irradiated with monoenergetic proton and lithium beams and with a gamma source. Survival curves were obtained by clonogenic assay and fitted to the linear-quadratic model. DSBs were evaluated by the detection of phosphorylated histone H2AX (gammaH2AX) foci at 30 min and 6 h post-irradiation. RESULTS: Survival curves showed the increasing effectiveness of radiation as a function of LET. gammaH2AX labeling showed an increase in the number of foci vs. dose for all the radiations evaluated. A decrease in the number of foci was found at 6 h post-irradiation for low LET radiation, revealing the repair capacity of DSBs. An increase in the size of gammaH2AX foci in cells irradiated with lithium beams was found, as compared with gamma and proton irradiations, which could be attributed to the clusters of DSBs induced by high LET radiation. Foci size increased at 6 h post-irradiation for lithium and proton irradiations in relation with persistent DSBs, showing a correlation with surviving fraction. CONCLUSIONS: Our results showed the response of B16-F0 cells to charged particle beams evaluated by the detection of gammaH2AX foci. We conclude that gammaH2AX foci size is an accurate parameter to correlate the rejoining of DSBs induced by different LET radiations and radiosensitivity.