Simplified image-based dosimetry using planar images and patient-specific S-values.

BACKGROUND: Single time point measurement approach and hybrid dosimetry were proposed to simplify the dosimetry process. It is anticipated that utilizing patient-specific S-value would enable more accurate dosimetry assessment based on imaging compared to using the conventional MIRD S-values. PURPOSE: We performed planar image-based dosimetry scaled with a single SPECT image for the entire treatment cycle using patient-specific S-values (PSS dosimetry) of organs. PSS dosimetry could further simplify the dosimetry procedure compared with a conventional 2D planar/3D SPECT hybrid dosimetry, as PSS dosimetry requires only one SPECT/CT image for the treatment of the entire cycle, whereas the conventional hybrid dosimetry requires a SPECT/CT image for each treatment cycle. METHODS: 177Lu-DOTATATE SPECT/CT and planar image datasets acquired from Seoul National University Hospital (SNUH, Seoul, Republic of Korea) were utilized for the evaluation. Images were acquired 4, 24, 48, and 120 h after patients' intravenous injection of 177Lu-DOTATATE. Dose estimations based on a Monte Carlo (MC) simulation using the Geant4 Application for Emission Tomography (GATE) (v.8.2) were considered as the reference. Planar image-based dosimetry scaled with a single SPECT image was performed using the patient-specific S-value (PSS). Briefly, the CT image was considered as the patient's anatomical reference and PSSs were quantified using the multiple voxel S-value (VSV) method. Then, PSS dosimetry was performed by obtaining activity information from sequential planar images and a scaling factor derived from a single SPECT/planar image pair. Hybrid dosimetry using sequential planar images and a single SPECT image was performed for comparison. The absorbed doses of the kidneys, bone marrow (BM) in the lumbar spine, liver, and spleen calculated using the PSS and hybrid dosimetries were compared with the reference MC results. RESULTS: The mean differences (MDs) of the self-absorption S-values between S-value of OLINDA/EXM and PSS for the kidneys, liver, and spleen were -0.04%, -2.39%, and -2.62%, respectively. However, the differences in the self-absorption S-values were significantly higher for the BM (84.99%) and the remainder of the body (ROB) (280.84%). The absorbed doses estimated by the PSS and hybrid dosimetries showed relatively high errors compared with MC simulation result, regardless of the organ. In contrast, the PSS and hybrid dosimetries produced similar dose estimates. For the entire cycles of the treatment, the MDs of absorbed doses between PSS and hybrid dosimetries were -3.31%, -6.04%, 3.37%, and -2.17% for the kidneys, BM, liver, and spleen, respectively. Through a correlation analysis and the Wilcoxon signed-rank test, we concluded that there was no significant difference between the results obtained by the two dosimetry methods. CONCLUSIONS: As the PSS was derived using CT images with actual anatomical information and organ-specific volume of interest (VOI), PSS dosimetry provided reliable results. PSS dosimetry was robust in estimating the absorbed dose for the later treatment cycles. Therefore, PSS dosimetry outperformed hybrid dosimetry in terms of dose estimation for a greater number of treatment cycles.

Mapping Korean National Health Insurance Claim Codes for Laboratory Test to SNOMED CT.

The aim of this study was to map Korean national health insurance claims codes for laboratory tests to SNOMED CT. The mapping source codes were 4,111 claims codes for laboratory test and mapping target codes were the International Edition of SNOMED CT released on July 31, 2020. We used rule-based automated and manual mapping methods. The mapping results were validated by two experts. Out of 4,111 codes, 90.5% were mapped to the concepts of procedure hierarchy in SNOMED CT. Of them, 51.4% of the codes were exactly mapped to SNOMED CT concepts, and 34.8% of the codes were mapped to SNOMED CT concepts as one-to-one mapping.

Voxel-Based Internal Dosimetry for 177Lu-Labeled Radiopharmaceutical Therapy Using Deep Residual Learning.

Purpose: In this study, we propose a deep learning (DL)-based voxel-based dosimetry method in which dose maps acquired using the multiple voxel S-value (VSV) approach were used for residual learning. Methods: Twenty-two SPECT/CT datasets from seven patients who underwent 177Lu-DOTATATE treatment were used in this study. The dose maps generated from Monte Carlo (MC) simulations were used as the reference approach and target images for network training. The multiple VSV approach was used for residual learning and compared with dose maps generated from deep learning. The conventional 3D U-Net network was modified for residual learning. The absorbed doses in the organs were calculated as the mass-weighted average of the volume of interest (VOI). Results: The DL approach provided a slightly more accurate estimation than the multiple-VSV approach, but the results were not statistically significant. The single-VSV approach yielded a relatively inaccurate estimation. No significant difference was noted between the multiple VSV and DL approach on the dose maps. However, this difference was prominent in the error maps. The multiple VSV and DL approach showed a similar correlation. In contrast, the multiple VSV approach underestimated doses in the low-dose range, but it accounted for the underestimation when the DL approach was applied. Conclusion: Dose estimation using the deep learning-based approach was approximately equal to that in the MC simulation. Accordingly, the proposed deep learning network is useful for accurate and fast dosimetry after radiation therapy using 177Lu-labeled radiopharmaceuticals.

Immunofluorescent distribution of SIRT1, SIRT2, SIRT6 protein in the skin of SKH1 mouse after ultraviolet B irradiation for 10 Weeks / Distribución inmunofluorescente de la proteína SIRT1, SIRT2, SIRT6 en la piel del ratón SKH1 después de la irradiación ultravioleta B durante 10 semanas

SUMMARY: The skin, located on the outermost part of the body, is always exposed to external stimuli such as sunlight. The exposure of skin to ultraviolet B (UVB) radiation from sunlight is known to be a major environmental factor in inducing photoaging. After exposure to UVB, an increase in reactive oxygen species can affect the expression and activity of many critical proteins depending on the duration and dose of the UVB radiation. Mammalian sirtuins (SIRTs), which are nicotinamide dinucleotide-dependent protein deacetylases, are well known for playing a role in cellular longevity. However, little is known about SIRT protein alterations in keratinocytes upon UVB irradiation according to SIRT subtypes. Therefore, in this study, the distribution of non-mitochondrial SIRT1, SIRT2, and SIRT6 proteins was investigated by immunofluorescence (IF) staining of the skin of SKH-1 mice (n=12) after UVB irradiation for 10 weeks. After UVB irradiation for 10 weeks, the IF of both SIRT1 and SIRT6 was significantly increased in the UVB-irradiated mice group (UG), but the difference in SIRT2 IF was not statistically significant between the control group (CG) and the UG. The translocation of both SIRT1 and SIRT6 IF from the nucleus to the cytoplasm of keratinocytes was observed in the upper epidermis of the UG, whereas SIRT2 IF was localized in the cytoplasm of keratinocytes in the epidermis in both the CG and the UG. The translocation of SIRT1 and SIRT6 IF from the nucleus to the cytoplasm of keratinocytes may account for the physiologically protective action of keratinocytes against UVB irradiation. However, the exact role of SIRT1 and SIRT6 translocation in keratinocytes, where SIRT1 and SIRT6 shuttle from the nucleus to the cytoplasm, is not well known. Therefore, further studies are needed to understand the molecular mechanisms of SIRT1 and SIRT6 translocation in keratinocytes upon UVB irradiation.

La piel, situada en la parte más externa del cuerpo, está siempre expuesta a estímulos externos como la luz solar. Se sabe que la exposición de la piel a la radiación ultravioleta B (UVB) de la luz solar es un factor ambiental importante en la inducción del fotoenvejecimiento. Después de la exposición a los rayos UVB, un aumento en las especies reactivas de oxígeno puede afectar la expresión y la actividad de muchas proteínas críticas según la duración y la dosis de la radiación UVB. Las sirtuinas de mamíferos (SIRT), que son proteínas desacetilasas dependientes de dinucleótidos de nicotinamida, son bien conocidas por desempeñar un papel en la longevidad celular. Sin embargo, se sabe poco sobre las alteraciones de la proteína SIRT en los queratinocitos tras la irradiación UVB según los subtipos de SIRT. Por lo tanto, en este estudio, se investigó la distribución de las proteínas SIRT1, SIRT2 y SIRT6 no mitocondriales mediante tinción de inmunofluorescencia (IF) de la piel de ratones SKH-1 (n = 12), después de la irradiación con UVB durante 10 semanas. Posterior a la irradiación, el IF de SIRT1 y SIRT6 aumentaron significativamente en el grupo de ratones irradiados con UVB (UG), pero la diferencia en SIRT2 IF no fue estadísticamente significativa entre el grupo control (CG) y el UG. La translocación de SIRT1 y SIRT6 IF desde el núcleo al citoplasma de los queratinocitos se observó en la epidermis superior de la UG, mientras que SIRT2 IF se localizó en el citoplasma de los queratinocitos en la epidermis, tanto en el GC, como en la UG. La translocación de SIRT1 y SIRT6 IF del núcleo al citoplasma de los queratinocitos puede explicar la acción protectora fisiológica de estos contra la radiación UVB. Sin embargo, el papel exacto de la translocación de SIRT1 y SIRT6 en los queratinocitos, donde SIRT1 y SIRT6 se trasladan desde el núcleo al citoplasma, no se conoce bien. Por lo tanto, se necesitan más estudios para comprender los mecanismos moleculares de la translocación SIRT1 y SIRT6 en los queratinocitos tras la irradiación UVB.

Investigation of Electronic Signal Processing Chains for a Prototype TOF-PET System With 100-ps Coincidence Time Resolution.

We have evaluated CTR performance of four different mixed-signal front-end electronic readout configurations with the goal to achieve 100 picoseconds (ps) coincidence time resolution (CTR). The proposed TOF-PET detector elements are based on two 3 × 3 × 10 mm3 "fast LGSO" crystal segments, side-coupled to linear arrays of 3 × 3 mm2 silicon photomultipliers (SiPMs), to form a total crystal length of 20 mm. We studied multiple configurations and components for the front-end readout: 1) high speed radio frequency (RF) amplifiers; 2) an ASIC-based discriminator; 3) combination of RF amplifier, balun transformer, and discriminator ASIC; and 4) combination of balun transformer, and discriminator ASIC. Using two 3 × 3 × 10 mm3 fast LGSO crystals side coupled to a linear array of three SiPMs, coincidence data were experimentally acquired for each readout configuration in combination with a low jitter field programmable gate array (FPGA)-based time to digital converter (TDC). After evaluating timing performance of the three readout schemes, the best CTR value of 99.4 ± 1.9 ps FWHM was achieved for configuration (3), which is more than 20 ps better than the results achieved using configurations (1) and (2).

Comparison of voxel S-value methods for personalized voxel-based dosimetry of 177 Lu-DOTATATE.

PURPOSE: Voxel-based dosimetry is potentially accurate than organ-based dosimetry because it considers the anatomical variations in each individual and the heterogeneous radioactivity distribution in each organ. Here, voxel-based dosimetry for 177 Lu-DOTATATE therapy was performed using single and multiple voxel S-value (VSV) methods and compared with Monte Carlo simulations. To verify these methods, we adopted sequential 177 Lu-DOTATATE single-photon emission computed tomography and X-ray computed tomography (SPECT/CT) dataset acquired from Sunway Medical Centre using the major vendor's SPECT/CT scanner (Siemens Symbia Intevo). METHODS: The administered activity of 177 Lu-DOTATATE was 7.99 ± 0.36 GBq. SPECT/CT images were acquired 0.5, 4, 24, and 48 h after injection in Sunway Medical Centre. For the multiple VSV method, VSV kernels of 177 Lu in media with various densities were generated by Geant4 Application for Emission Tomography (GATE) simulation first. The second step involved the convolution of the time-integrated activity map with each kernel to produce medium-specific dose maps. Third, each medium-specific dose map was masked using binary medium masks, which were generated from CT-based density maps. Finally, all masked dose maps were summed to generate the final dose map. VSV methods with four different VSV sets (1, 4, 10, and 20 VSVs) were compared. Voxel-wise density correction for the single VSV method was also performed. The absorbed doses in the kidneys, bone marrow, and tumors were analyzed, and the relative errors between the VSV and Monte Carlo simulation approaches were estimated. Organ-based dosimetry using Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) was also compared. RESULTS: The accuracy of the multiple VSV approach increased with the number of dose kernels. The average dose estimation errors of a single VSV with density correction and 20 VSVs were less than 6% in most cases, although organ-based dosimetry using OLINDA/EXM yielded an error of up to 123%. The advantages of the single VSV method with density correction and the 20 VSVs over organ-based dosimetry were most evident in bone marrow and bone-metastatic tumors with heterogeneous medium properties. CONCLUSION: The single VSV method with density correction and multiple VSV method with 20 dose kernels enabled fast and accurate radiation dose estimation. Accordingly, voxel-based dosimetry methods can be useful for managing administration activity and for investigating tumor dose responses to further increase the therapeutic efficacy of 177 Lu-DOTATATE.

Study of optical reflectors for a 100ps coincidence time resolution TOF-PET detector design.

Positron Emission Tomography (PET) reconstructed image signal-to-noise ratio (SNR) can be improved by including the 511 keV photon pair coincidence time-of-flight (TOF) information. The degree of SNR improvement from this TOF capability depends on the coincidence time resolution (CTR) of the PET system, which is essentially the variation in photon arrival time differences over all coincident photon pairs detected for a point positron source placed at the system center. The CTR is determined by several factors including the intrinsic properties of the scintillation crystals and photodetectors, crystal-to-photodetector coupling configurations, reflective materials, and the electronic readout configuration scheme. The goal of the present work is to build a novel TOF-PET system with 100 picoseconds (ps) CTR, which provides an additional factor of 1.5-2.0 improvement in reconstructed image SNR compared to state-of-the-art TOF-PET systems which achieve 225-400 ps CTR. A critical parameter to understand is the optical reflector's influence on scintillation light collection and transit time variations to the photodetector. To study the effects of the reflector covering the scintillation crystal element on CTR, we have tested the performance of four different reflector materials: Enhanced Specular Reflector (ESR) -coupled with air or optical grease to the scintillator; Teflon tape; BaSO4paint alone or mixed with epoxy; and TiO2paint. For the experimental set-up, we made use of 3 × 3 × 10 mm3fast-LGSO:Ce scintillation crystal elements coupled to an array of silicon photomultipliers (SiPMs) using a novel 'side-readout' configuration that has proven to have lower variations in scintillation light collection efficiency and transit time to the photodetector.Results: show CTR values of 102.0 ± 0.8, 100.2 ± 1.2, 97.3 ± 1.8 and 95.0 ± 1.0 ps full-width-half-maximum (FWHM) with non-calibrated energy resolutions of 10.2 ± 1.8, 9.9 ± 1.2, 7.9 ± 1.2, and 8.6 ± 1.7% FWHM for the Teflon, ESR (without grease), BaSO4(without epoxy) and TiO2paint treatments, respectively.

Efficacy of voxel-based dosimetry map for predicting response to trans-arterial radioembolization therapy for hepatocellular carcinoma: a pilot study.

OBJECTIVE: Typical clinical dosimetry models for trans-arterial radioembolization (TARE) assume uniform dose distribution in each tissue compartment. We performed simple voxel-based dosimetry using post-treatment 90Y PET following TARE with 90Y-resin microspheres and investigated its prognostic value in a pilot cohort. METHOD: Ten patients with 14 hepatocellular carcinoma lesions who underwent TARE with 90Y-resin microspheres were retrospectively included. The partition model-based expected target tumor dose (TDp) was calculated using a pretreatment 99mTc-macroaggregated albumin scan. From post-treatment 90Y-microsphere PET and voxel-wise S-value kernels, voxel-based dose maps were produced and the absorbed dose of each lesion (TDv) was calculated. Heterogeneity of intratumoral absorbed doses was assessed using the SD and coefficient of variation of voxel doses. The response of each lesion was determined based on contrast-enhanced MRI or CT, or both. Lesion responses were classified as local control success or failure. Prognostic values of dosimetry parameters and clinicopathological factors were evaluated in terms of progression-free survival (PFS) of each lesion. RESULTS: TDv was significantly different between local control success and failure groups, whereas tumor size, TDp and intratumoral dose heterogeneity were not. Univariate survival analysis identified serum aspartate transaminase level ≥40 IU/L, tumor size ≥66 mm and TDv <81 Gy as significant prognostic factors for PFS. However, only TDv was an independent predictive factor in the multivariate analysis (P = 0.022). There was a significant correlation between TDv and PFS (P = 0.009; r = 0.669). CONCLUSIONS: In TARE, voxel-based dose index TDv can be estimated on post-treatment 90Y PET using a simple method. TDv was a more effective prognostic factor for TARE than TDp and clinicopathologic factors in this pilot study. Further studies are warranted on the role of voxel-based dose and dose distribution in TARE.

High-resolution time-of-flight PET detector with 100 ps coincidence time resolution using a side-coupled phoswich configuration.

Photon time-of-flight (TOF) capability in positron emission tomography (PET) enables reconstructed image signal-to-noise ratio (SNR) improvement. With the coincidence time resolution (CTR) of 100 picosecond (ps), a five-fold SNR improvement can be achieved with a 40 cm diameter imaging subject, relative to a system without TOF capability. This 100 ps CTR can be achieved for aclinically relevantdetector design (crystal element length ≥20 mm with reasonably high crystal packing fraction) using a side-readout PET detector configuration that enables 511 keV photon interaction depth-independent light collection efficiency and lower variance in scintillation photon transit time to the silicon photomultiplier (SiPM). In this study, we propose a new concept of TOF-PET detector to achieve high (<2 mm) resolution, using a 'side-coupled phoswich' configuration, where two crystals with different decay times (τd) are coupled in a side-readout configuration to a common row of photosensors. The proposed design was validated and optimized with GATE Monte Carlo simulation studies to determine an efficient detector design. Based on the simulation results, a proof-of-concept side-coupled phoswich detector design was developed comprising two LSO crystals with the size of 1.9 × 1.9 × 10 mm3with decay times of 34.39 and 43.07 ns, respectively. The phoswich crystals were side-coupled to the same three 4 × 4 mm2SiPMs and detector performances were evaluated. As a result of the experimental evaluation, the side-coupled phoswich configuration achieved CTR of 107 ± 3 ps, energy resolution of 10.5% ± 1.21% at 511 keV and >95% accuracy in identifying interactions in the two adjacent 1.9 × 1.9 × 10 mm3crystal elements using the time-over-threshold technique. Based on our results, we can achieve excellent spatial and energy resolution in addition to ∼100 ps CTR with this novel detector design.

Scalable electronic readout design for a 100 ps coincidence time resolution TOF-PET system.

We have developed a scalable detector readout design for a 100 ps coincidence time resolution (CTR) time of flight (TOF) positron emission tomography (PET) detector technology. The basic scintillation detectors studied in this paper are based on 2 × 4 arrays of 3 × 3 × 10 mm3'fast-LGSO:Ce' scintillation crystals side-coupled to 6 × 4 arrays of 3 × 3 mm2silicon photomultipliers (SiPMs). We employed a novel mixed-signal front-end electronic configuration and a low timing jitter Field Programming Gate Array-based time to digital converter for data acquisition. Using a22Na point source, >10 000 coincidence events were experimentally acquired for several SiPM bias voltages, leading edge time-pickoff thresholds, and timing channels. CTR of 102.03 ± 1.9 ps full-width-at-half-maximum (FWHM) was achieved using single 3 × 3 × 10 mm3'fast-LGSO' crystal elements, wrapped in Teflon tape and side coupled to a linear array of 3 SiPMs. In addition, the measured average CTR was 113.4 ± 0.7 ps for the side-coupled 2 × 4 crystal array. The readout architecture presented in this work is designed to be scalable to large area module detectors with a goal to create the first TOF-PET system with 100 ps FWHM CTR.

Simultaneous quantitative analysis of 3H and 14C radionuclides in aqueous samples via artificial neural network with a liquid scintillation counter.

Liquid scintillation counters are common instruments used in the measurement of pure beta-emitting radionuclides, and while they represent a conventional radiometric technique, they are still competitive for their potential to measure multiple radionuclides simultaneously. In this work, we propose an algorithm based on an artificial neural network (ANN) for the simultaneous analysis of the beta-ray spectra of 3H and 14C in dual beta-labeled samples using a liquid scintillation counter. We achieved percentage deviations below 5.0% using the proposed algorithm in 16 out of 18 cases, with RMSDs below 1.5% in 17 out of 18 cases. The trained ANN also produced activity ratios with high accuracy even while having to deal with highly fluctuating spectra. Results demonstrate that the rapid predictions with a short measurement time from our proposed ANN method are compatible with the calculated ones from previous studies that were obtained with long measurement times.

[18F]CB251 PET/MR imaging probe targeting translocator protein (TSPO) independent of its Polymorphism in a Neuroinflammation Model.

The 18 kDa translocator protein (TSPO) has been proposed as a biomarker for the detection of neuroinflammation. Although various PET probes targeting TSPO have been developed, a highly selective probe for detecting TSPO is still needed because single nucleotide polymorphisms in the human TSPO gene greatly affect the binding affinity of TSPO ligands. Here, we describe the visualization of neuroinflammation with a multimodality imaging system using our recently developed TSPO-targeting radionuclide PET probe [18F]CB251, which is less affected by TSPO polymorphisms. Methods: To test the selectivity of [18F]CB251 for TSPO polymorphisms, 293FT cells expressing polymorphic TSPO were generated by introducing the coding sequences of wild-type (WT) and mutant (Alanine → Threonine at 147th Amino Acid; A147T) forms. Competitive inhibition assay was conducted with [3H]PK11195 and various TSPO ligands using membrane proteins isolated from 293FT cells expressing TSPO WT or mutant-A147T, representing high-affinity binder (HAB) or low-affinity binder (LAB), respectively. IC50 values of each ligand to [3H]PK11195 in HAB or LAB were measured and the ratio of IC50 values of each ligand to [3H]PK11195 in HAB to LAB was calculated, indicating the sensitivity of TSPO polymorphism. Cellular uptake of [18F]CB251 was measured with different TSPO polymorphisms, and phantom studies of [18F]CB251-PET using 293FT cells were performed. To test TSPO-specific cellular uptake of [18F]CB251, TSPO expression was regulated with pCMV-TSPO (or shTSPO)/eGFP vector. Intracranial lipopolysaccharide (LPS) treatment was used to induce regional inflammation in the mouse brain. Gadolinium (Gd)-DOTA MRI was used to monitor the disruption of the blood-brain barrier (BBB) and infiltration by immune cells. Infiltration of peripheral immune cells across the BBB, which exacerbates neuroinflammation to produce higher levels of neurotoxicity, was also monitored with bioluminescence imaging (BLI). Peripheral immune cells isolated from luciferase-expressing transgenic mice were transferred to syngeneic inflamed mice. Neuroinflammation was monitored with [18F]CB251-PET/MR and BLI. To evaluate the effects of anti-inflammatory agents on intracranial inflammation, an inflammatory cytokine inhibitor, 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid methyl ester (CDDO-Me) was administered in intracranial LPS challenged mice. Results: The ratio of IC50 values of [18F]CB251 in HAB to LAB indicated similar binding affinity to WT and mutant TSPO and was less affected by TSPO polymorphisms. [18F]CB251 was specific for TSPO, and its cellular uptake reflected the amount of TSPO. Higher [18F]CB251 uptake was also observed in activated immune cells. Simultaneous [18F]CB251-PET/MRI showed that [18F]CB251 radioactivity was co-registered with the MR signals in the same region of the brain of LPS-injected mice. Luciferase-expressing peripheral immune cells were located at the site of LPS-injected right striatum. Quantitative evaluation of the anti-inflammatory effect of CDDO-Me on neuroinflammation was successfully monitored with TSPO-targeting [18F]CB251-PET/MR and BLI. Conclusion: Our results indicate that [18F]CB251-PET has great potential for detecting neuroinflammation with higher TSPO selectivity regardless of polymorphisms. Our multimodal imaging system, [18F]CB251-PET/MRI, tested for evaluating the efficacy of anti-inflammatory agents in preclinical studies, might be an effective method to assess the severity and therapeutic response of neuroinflammation.

Recovery of inter-detector and inter-crystal scattering in brain PET based on LSO and GAGG crystals.

Gadolinium aluminum gallium garnet (GAGG) is a promising scintillator crystal for positron emission tomography (PET) detectors owing to its advantages of energy resolution, light yield, and absence of intrinsic radiation. However, a large portion of the incident photons undergoes Compton scattering within GAGG crystal because of its low stopping power compared to that of lutetium-based crystals such as Lu2SiO5 (LSO). Inter-detector scattering (IDS) and inter-crystal scattering (ICS) result in loss of sensitivity and image quality of PET, respectively. We performed a Monte Carlo simulation study to evaluate IDS recovery in our currently developing brain-dedicated PET, and extended the idea to ICS recovery. We also compared the impact of the recoveries on LSO- and GAGG-based PET scanners. We measured the sensitivity and spatial resolution of the brain PET, and analyzed the image quality using a lesion phantom, a hot-rod phantom, and a 2D Hoffman phantom with applying IDS or ICS recovery. IDS recovery increased the PET sensitivity and improved the noise level of the reconstructed images. ICS recovery enhanced the spatial resolution and the contrast of the images was improved. As the occurrence rates of IDS and ICS were higher in GAGG than in LSO, the overall impact of IDS or ICS recovery was significant in GAGG. In conclusion, we showed that the proportional method would be suitable for IDS and ICS recoveries of PET, and emphasized the importance of ICS and IDS recoveries for PET using crystals with low stopping power.

Preclinical Voxel-Based Dosimetry in Theranostics: a Review.

Due to the increasing use of preclinical targeted radionuclide therapy (TRT) studies for the development of novel theranostic agents, several studies have been performed to accurately estimate absorbed doses to mice at the voxel level using reference mouse phantoms and Monte Carlo (MC) simulations. Accurate dosimetry is important in preclinical theranostics to interpret radiobiological dose-response relationships and to translate results for clinical use. Direct MC (DMC) simulation is believed to produce more realistic voxel-level dose distribution with high precision because tissue heterogeneities and nonuniform source distributions in patients or animals are considered. Although MC simulation is considered to be an accurate method for voxel-based absorbed dose calculations, it is time-consuming, computationally demanding, and often impractical in daily practice. In this review, we focus on the current status of voxel-based dosimetry methods applied in preclinical theranostics and discuss the need for accurate and fast voxel-based dosimetry methods for pretherapy absorbed dose calculations to optimize the dose computation time in preclinical TRT.

Cost implications of adverse drug event-related emergency department visits - a multicenter study in South Korea.

Background: Adverse drug reactions (ADRs) increase health-care resource utilization, including that for emergency department (ED) visits. However, cost analyses of ADRs resulting in ED visits are scarce. Therefore, we aimed to estimate the direct medical costs before and after ADR occurrence and analyzed the cost-driving factors.Methods: The ADR cases were identified by a retrospective review of medical records of patients who visited the ED of three tertiary hospitals in South Korea from July to December 2014. The direct medical cost was estimated by the difference in costs six months before and after the ED visit. A generalized linear model was used to identify the ADR-associated cost-driving factors.Results: The mean cost per ADR increased by 26.1% (±SD = 4.3) during the six-month follow-up compared with that during the six months before the ED visit (p < 0.05). Preventable ADRs accounted for approximately 19.9% of the cost increase among all ADR cases. The regression analysis revealed that 'ADR-related hospitalization' was a significant (p < 0.05) factor leading to an increase in the direct medical costs.Conclusion: Drug-related ED visits increase the burden on health insurance systems and patients' out-of-pocket costs, mostly due to the hospitalization costs.

Deep-dose: a voxel dose estimation method using deep convolutional neural network for personalized internal dosimetry.

Personalized dosimetry with high accuracy is crucial owing to the growing interests in personalized medicine. The direct Monte Carlo simulation is considered as a state-of-art voxel-based dosimetry technique; however, it incurs an excessive computational cost and time. To overcome the limitations of the direct Monte Carlo approach, we propose using a deep convolutional neural network (CNN) for the voxel dose prediction. PET and CT image patches were used as inputs for the CNN with the given ground truth from direct Monte Carlo. The predicted voxel dose rate maps from the CNN were compared with the ground truth and dose rate maps generated voxel S-value (VSV) kernel convolution method, which is one of the common voxel-based dosimetry techniques. The CNN-based dose rate map agreed well with the ground truth with voxel dose rate errors of 2.54% ± 2.09%. The VSV kernel approach showed a voxel error of 9.97% ± 1.79%. In the whole-body dosimetry study, the average organ absorbed dose errors were 1.07%, 9.43%, and 34.22% for the CNN, VSV, and OLINDA/EXM dosimetry software, respectively. The proposed CNN-based dosimetry method showed improvements compared to the conventional dosimetry approaches and showed results comparable with that of the direct Monte Carlo simulation with significantly lower calculation time.

Preclinical voxel-based dosimetry through GATE Monte Carlo simulation using PET/CT imaging of mice.

Internal dosimetry is of critical importance to obtain an accurate absorbed dose-response relationship during preclinical molecular imaging and targeted radionuclide therapy (TRT). Conventionally, absorbed dose calculations have been performed using organ-level dosimetry based on the Medical Internal Radiation Dose (MIRD) schema. However, recent research has focused on developing more accurate voxel-level calculation methods. Geant4 application for emission tomography (GATE) Monte Carlo (MC) is a simulation toolkit gaining attention in voxel-based dosimetry. In this study, we used PET/CT images of real mice to estimate the absorbed doses in sensitive organs at voxel-level to evaluate the suitability of GATE MC simulation for preclinical dosimetry. Thirteen normal C57BL/6 mice (male, body weight: 27.71 ± 4.25 g) were used to acquire dynamic positron emission tomography/computed tomography (PET/CT) images after IV injection of 18F-FDG. GATE MC toolkit was applied to estimate the absorbed doses in various organs of mice at voxel-level using CT and PET images as voxelized phantom and voxelized source, respectively. In addition, mean absorbed dose at organ-level was calculated using MIRD schema for comparison purposes. The differences in the respective absorbed doses (mGy MBq-1) between GATE MC and MIRD schema for brain, heart wall, liver, lungs, stomach wall, spleen, kidneys, and bladder wall were 1.36, 12.3, -22.4, -11.2, -16.9, -2.87, -4.29, and 3.71%, respectively. Considering that the PET/CT data of real mice were used for GATE simulation, the absorbed doses estimated in this study are mouse-specific. Therefore, the GATE-based Monte Carlo is likely to allow for more accurate internal dosimetry calculations. This method can be used in TRT for personalized dosimetry because it considers patient-specific heterogeneous tissue compositions and activity distributions.

Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis.

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. SIGNIFICANCE: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.

Discovery and Validation of Salivary Extracellular RNA Biomarkers for Noninvasive Detection of Gastric Cancer.

BACKGROUND: Biomarkers are needed for noninvasive early detection of gastric cancer (GC). We investigated salivary extracellular RNA (exRNA) biomarkers as potential clinical evaluation tools for GC. METHODS: Unstimulated whole saliva samples were prospectively collected from 294 individuals (163 GC and 131 non-GC patients) who underwent endoscopic evaluation at the Samsung Medical Center in Korea. Salivary transcriptomes of 63 GC and 31 non-GC patients were profiled, and mRNA biomarker candidates were verified with reverse transcription quantitative real-time PCR (RT-qPCR). In parallel, microRNA (miRNA) biomarkers were profiled and verified with saliva samples from 10 GC and 10 non-GC patients. Candidate biomarkers were validated with RT-qPCR in an independent cohort of 100/100 saliva samples from GC and non-GC patients. Validated individual markers were configured into a best performance panel. RESULTS: We identified 30 mRNA and 15 miRNA candidates whose expression pattern associated with the presence of GC. Among them, 12 mRNA and 6 miRNA candidates were verified with the discovery cohort by RT-qPCR and further validated with the independent cohort (n = 200). The configured biomarker panel consisted of 3 mRNAs (SPINK7, PPL, and SEMA4B) and 2 miRNAs (MIR140-5p and MIR301a), which were all significantly down-regulated in the GC group, and yielded an area under the ROC curve (AUC) of 0.81 (95% CI, 0.72-0.89). When combined with demographic factors, the AUC of the biomarker panel reached 0.87 (95% CI, 0.80-0.93). CONCLUSIONS: We have discovered and validated a panel of salivary exRNA biomarkers with credible clinical performance for the detection of GC. Our study demonstrates the potential utility of salivary exRNA biomarkers in screening and risk assessment for GC.

Systematic study on factors influencing the performance of interdetector scatter recovery in small-animal PET.

PURPOSE: Interdetector scatter (IDS) is a triple coincidence caused by the Compton scatter of an annihilation photon from one detector block to another which frequently occurs in small-animal positron emission tomography (PET). By finding the true lines-of-response (LORs) of annihilation photon pairs among three possible LORs in IDS events, we can utilize these recovered events to improve the sensitivity of PET systems. IDS recovery should be accurate to yield reliable images with relatively short scan times. We systemically investigated physical factors affecting IDS recovery performance, focusing on the reconstructed image quality of small-animal PET. We evaluated sensitivity increase, recovery accuracy, and image quality by applying different combinations of energy window, recovery scheme, and scanner properties. METHODS: We used GATE Monte Carlo simulation to acquire coincidence events from a NEMA NU 4-2008 image quality phantom using small-animal PET scanner with axial field of view of 55 mm and diameter of 64 mm. We first defined energy window criteria to obtain valid IDS events. Their role was to assign triple coincidences as IDS events and to restrict the number of LOR candidates to two. We tested three different energy windows around 511 keV. Second, we applied four different recovery schemes (maximum energy, Compton kinematics, neural network, and proportional) to assigned IDS events. To measure the effects of scanner properties, energy resolutions of 0-20% and one to four depth-of-interaction (DOI) layers were simulated. For every combination of the factors, we measured sensitivity increase and recovery accuracy. We also analyzed the reconstructed images for each IDS recovery method in terms of mean pixel intensity, noise, signal-to-noise ratio (SNR), contrast, and recovery coefficients. RESULTS: Sensitivity increase depended on the energy window and energy resolution. The maximum increase in sensitivity was 33% when energy window of [250, 750] keV was applied. Higher energy resolution yielded larger sensitivity increase, especially for narrow windows. Recovery accuracy was affected by all the factors tested in this study. Accuracy increased with narrower energy window, and a neural network scheme was the most accurate. The better energy resolution and DOI capability improved accuracy by providing precise measurement of energies and interaction positions. In image quality analysis, noise and SNR were highly dependent on the sensitivity increase and energy window. When the same energy window was applied, SNR, contrast, and recovery coefficients were higher with higher accuracy of the scheme. Meanwhile, the proportional scheme yielded the best image quality among the schemes and reduced 20% of scan time to achieve the same SNR as that of double coincidence images. CONCLUSIONS: As a fundamental research for real implementation of IDS recovery, we conducted a simulation study to evaluate the factors affecting sensitivity increase, recovery accuracy, and image quality. Sensitivity increase was dependent on the energy window and energy resolution, while the recovery accuracy was affected by energy window, recovery scheme, energy resolution, and DOI capability. In image quality analysis, sensitivity increase and recovery accuracy dominantly affected the noise and quantitative accuracy, respectively. Among the recovery schemes, the proportional scheme obtained the best image quality.