Efficient and multiplexed tracking of single cells using whole-body PET/CT.

In vivo molecular imaging tools are crucially important for elucidating how cells move through complex biological systems, however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upwards of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a new tracking algorithm (PEPT-EM) to push the cellular detection threshold to below 4 Bq/cell, and a streamlined workflow to reliably label single cells with over 50 Bq/cell of 18F-fluorodeoxyglucose (FDG). To demonstrate the potential of method, we tracked the fate of over 70 melanoma cells after intracardiac injection and found they primarily arrested in the small capillaries of the pulmonary, musculoskeletal, and digestive organ systems. This study bolsters the evolving potential of PET in offering unmatched insights into the earliest phases of cell trafficking in physiological and pathological processes and in cell-based therapies.

Potential of Depth-of-Interaction-Based Detection Time Correction in Cherenkov Emitter Crystals for TOF-PET.

Cherenkov light can improve the timing resolution of Positron Emission Tomography (PET) radiation detectors, thanks to its prompt emission. Coincidence time resolutions (CTR) of ~30 ps were recently reported when using 3.2 mm-thick Cherenkov emitters. However, sufficient detection efficiency requires thicker crystals, causing the timing resolution to be degraded by the optical propagation inside the crystal. We report on depth-of-interaction (DOI) correction to mitigate the time-jitter due to the photon time spread in Cherenkov-based radiation detectors. We simulated the Cherenkov and scintillation light generation and propagation in 3 × 3 mm2 lead fluoride, lutetium oxyorthosilicate, bismuth germanate, thallium chloride, and thallium bromide. Crystal thicknesses varied from 9 to 18 mm with a 3-mm step. A DOI-based time correction showed a 2-to-2.5-fold reduction of the photon time spread across all materials and thicknesses. Results showed that highly refractive crystals, though producing more Cherenkov photons, were limited by an experimentally obtained high-cutoff wavelength and refractive index, restricting the propagation and extraction of Cherenkov photons mainly emitted at shorter wavelengths. Correcting the detection time using DOI information shows a high potential to mitigate the photon time spread. These simulations highlight the complexity of Cherenkov-based detectors and the competing factors in improving timing resolution.

The SNR of Positron Emission Data With Gaussian and Non-Gaussian Time-of-Flight Kernels, With Application to Prompt Photon Coincidence.

It is well known that measurement of the time-of-flight (TOF) increases the information provided by coincident events in positron emission tomography (PET). This information increase propagates through the reconstruction and improves the signal-to-noise ratio in the reconstructed images. Takehiro Tomitani has analytically computed the gain in variance in the reconstructed image, provided by a particular TOF resolution, for the center of a uniform disk and for a Gaussian TOF kernel. In this paper we extend this result, by computing the signal-to-noise ratio (SNR) contributed by individual coincidence events for two different tasks. One task is the detection of a hot spot in the center of a uniform cylinder. The second one is the same as that considered by Tomitani, i.e. the reconstruction of the central voxel in the image of a uniform cylinder. In addition, we extend the computation to non-Gaussian TOF kernels. It is found that a modification of the TOF-kernel changes the SNR for both tasks in almost exactly the same way. The proposed method can be used to compare TOF-systems with different and possibly event-dependent TOF-kernels, as encountered when prompt photons, such as Cherenkov photons are present, or when the detector is composed of different scintillators. The method is validated with simple 2D simulations and illustrated by applying it to PET detectors producing optical photons with event-dependent timing characteristics.

Preclinical Evaluation of 68Ga- and 177Lu-Labeled Integrin αvß6-Targeting Radiotheranostic Peptides.

The integrin αvß6, an epithelium-specific cell surface receptor, is overexpressed on numerous malignancies, including the highly lethal pancreatic ductal adenocarcinomas. Here, we developed and tested a novel αvß6-targeting peptide, DOTA-5G (1) radiolabeled with 68Ga, for PET/CT imaging and 177Lu for treatment. With the goal to develop a radiotheranostic, further modifications were made for increased circulation time, renal recycling, and tumor uptake, yielding DOTA-albumin-binding moiety-5G (2). Methods: Peptides 1 and 2 were synthesized on solid phase, and their affinity for αvß6 was assessed by enzyme-linked immunosorbent assay. The peptides were radiolabeled with 68Ga and 177Lu. In vitro cell binding, internalization, and efflux of 68Ga-1 and 177Lu-2 were evaluated in αvß6-positive BxPC-3 human pancreatic cancer cells. PET/CT imaging of 68Ga-1 and 68Ga-2 was performed on female nu/nu mice bearing subcutaneous BxPC-3 tumors. Biodistribution was performed for 68Ga-1 (1 and 2 h after injection), 68Ga-2 (2 and 4 h after injection), and 177Lu-1 and 177Lu-2 (1, 24, 48, and 72 h after injection). The 177Lu-2 biodistribution data were extrapolated for human dosimetry data estimates using OLINDA/EXM 1.1. Therapeutic efficacy of 177Lu-2 was evaluated in mice bearing BxPC-3 tumors. Results: Peptides 1 and 2 demonstrated high affinity (<55 nM) for αvß6 by enzyme-linked immunosorbent assay. 68Ga-1, 68Ga-2, 177Lu-1, and 177Lu-2 were synthesized in high radiochemical purity. Rapid in vitro binding and internalization of 68Ga-1 and 177Lu-2 were observed in BxPC-3 cells. PET/CT imaging and biodistribution studies demonstrated uptake in BxPC-3 tumors. Introduction of the albumin-binding moiety in 177Lu-2 resulted in a 5-fold increase in tumor uptake and retention over time. Based on the extended dosimetry data, the dose-limiting organ for 177Lu-2 is the kidney. Treatment with 177Lu-2 prolonged median survival by 1.5- to 2-fold versus controls. Conclusion: 68Ga-1 and 177Lu-2 demonstrated high affinity for the integrin αvß6 both in vitro and in vivo, were rapidly internalized into BxPC-3 cells, and were stable in mouse and human serum. Both radiotracers showed favorable pharmacokinetics in preclinical studies, with predominantly renal excretion and good tumor-to-normal-tissue ratios. Favorable human dosimetry data suggest the potential of 177Lu-2 as a treatment for pancreatic ductal adenocarcinoma.

The OpenGATE ecosystem for Monte Carlo simulation in medical physics.

This paper reviews the ecosystem of GATE, an open-source Monte Carlo toolkit for medical physics. Based on the shoulders of Geant4, the principal modules (geometry, physics, scorers) are described with brief descriptions of some key concepts (Volume, Actors, Digitizer). The main source code repositories are detailed together with the automated compilation and tests processes (Continuous Integration). We then described how the OpenGATE collaboration managed the collaborative development of about one hundred developers during almost 20 years. The impact of GATE on medical physics and cancer research is then summarized, and examples of a few key applications are given. Finally, future development perspectives are indicated.

The Impact of Injection Distance to Bifurcations on Yttrium-90 Distribution in Liver Cancer Radioembolization.

PURPOSE: To model the effect of the injection location on the distribution of yttrium-90 (90Y) microspheres in the liver during radioembolization using computational simulation and to determine the potential effects of radial movements of the catheter tip. MATERIALS AND METHODS: Numerical studies were conducted using images from a representative patient with hepatocellular carcinoma. The right hepatic artery (RHA) was segmented from contrast-enhanced cone-beam computed tomography scans. The blood flow was investigated in the trunk of the RHA using numerical simulations for 6 injection position scenarios at 2 sites located at a distance of approximately 5 and 20 mm upstream of the first bifurcation (RHA diameters of approximately 4.6 mm). The 90Y delivery to downstream vessels was calculated from the simulated hepatic artery hemodynamics. RESULTS: Varying the injection location along the RHA and across the vessel cross-section resulted in different simulated microsphere distributions in the downstream vascular bed. When the catheter tip was 5 mm upstream of the bifurcation, 90Y distribution in the downstream branches varied by as much as 53% with a 1.5-mm radial movement of the tip. However, the catheter radial movement had a weaker effect on the microsphere distribution when the injection plane was farther from the first bifurcation (20 mm), with a maximum delivery variation of 9% to a downstream branch. CONCLUSIONS: An injection location far from bifurcations is recommended to minimize the effect of radial movements of the catheter tip on the microsphere distribution.

Radioembolization Dosimetry with Total-Body 90Y PET.

Transarterial radioembolization (TARE) is a locoregional radiopharmaceutical therapy based on the delivery of radioactive 90Y microspheres to liver tumors. The importance of personalized dosimetry to make TARE safer and more effective has been demonstrated in recent clinical studies, stressing the need for quantification of the dose-response relationship to ultimately optimize the administered activity before treatment and image it after treatment. 90Y dosimetric studies are challenging because of the lack of accurate and precise methods but are best realized with PET combined with Monte Carlo simulations and other image modalities to calculate a segmental dose distribution. The aim of this study was to assess the suitability of imaging 90Y PET patients with the total-body PET/CT uEXPLORER and to investigate possible improvements in TARE 90Y PET-based dosimetry. The uEXPLORER is the first commercially available ultra-high-resolution (171 cps/kBq) total-body digital PET/CT device with a 194-cm axial PET field of view that enables the whole body to be scanned at a single bed position. Methods: Two PET/CT scanners were evaluated in this study: the Biograph mCT and the total-body uEXPLORER. Images of a National Electrical Manufacturers Association (NEMA) image-quality phantom and 2 patients were reconstructed using our standard clinical oncology protocol. A late portal phase contrast-enhanced CT scan was used to contour the liver segments and create corresponding volumes of interest. To calculate the absorbed dose, Monte Carlo simulations were performed using Geant4 Application for Tomographic Emission (GATE). The absorbed dose and dose-volume histograms were calculated for all 6 spheres (diameters ranging from 10 to 37 mm) of the NEMA phantom, the liver segments, and the entire liver. Differences between the phantom doses and an analytic ground truth were quantified through the root mean squared error. Results: The uEXPLORER showed a higher signal-to-noise ratio at 10- and 13-mm diameters, consistent with its high spatial resolution and system sensitivity. The total liver-absorbed dose showed excellent agreement between the uEXPLORER and the mCT for both patients, with differences lower than 0.2%. Larger differences of up to 60% were observed when comparing the liver segment doses. All dose-volume histograms were in good agreement, with narrower tails for the uEXPLORER in all segments, indicating lower image noise. Conclusion: This patient study is compelling for the use of total-body 90Y PET for liver dosimetry. The uEXPLORER scanner showed a better signal-to-noise ratio than mCT, especially in lower-count regions of interest, which is expected to improve dose quantification and tumor dosimetry.

The Accuracy of Cerenkov Photons Simulation in Geant4/Gate Depends on the Parameterization of Primary Electron Propagation.

Energetic electrons traveling in a dispersive medium can produce Cerenkov radiation. Cerenkov photons' prompt emission, combined with their predominantly forward emission direction with respect to the parent electron, makes them extremely promising to improve radiation detector timing resolution. Triggering gamma detections based on Cerenkov photons to achieve superior timing resolution is challenging due to the low number of photons produced per interaction. Monte Carlo simulations are fundamental to understanding their behavior and optimizing their pathway to detection. Therefore, accurately modeling the electron propagation and Cerenkov photons emission is crucial for reliable simulation results. In this work, we investigated the physics characteristics of the primary electrons (velocity, energy) and those of all emitted Cerenkov photons (spatial and timing distributions) generated by 511 keV photoelectric interactions in a bismuth germanate crystal using simulations with Geant4/GATE. Geant4 uses a stepwise particle tracking approach, and users can limit the electron velocity change per step. Without limiting it (default Geant4 settings), an electron mean step length of ~250 µm was obtained, providing only macroscopic modeling of electron transport, with all Cerenkov photons emitted in the forward direction with respect to the incident gamma direction. Limiting the electron velocity change per step reduced the electron mean step length (~0.200 µm), leading to a microscopic approach to its transport which more accurately modeled the electron physical properties in BGO at 511 keV. The electron and Cerenkov photons rapidly lost directionality, affecting Cerenkov photons' transport and, ultimately, their detection. Results suggested that a deep understanding of low energy physics is crucial to perform accurate optical Monte Carlo simulations and ultimately use them in TOF PET detectors.

Integration of polarization in the LUTDavis model for optical Monte Carlo simulation in radiation detectors.

OBJECTIVE: Cerenkov photons have distinctive features from scintillation photons. Among them is their polarization: their electric field is always perpendicular to the direction of propagation of light and parallel to the plane of incidence. Scintillation photons are instead considered unpolarized. APPROACH: This study aims at understanding and optimizing the reflectance of polarized Cerenkov photons for optical Monte Carlo simulation of scintillation detectors with Geant4/GATE. First, the Cerenkov emission spectrum and polarization were implemented in the previously developed look-up-table Davis model of crystal reflectance. Next, we modified Geant4/GATE source code to account for scintillation and Cerenkov photons LUTs simultaneously. Then, we performed optical Monte Carlo simulations in BGO using GATE to show the effect of Cerenkov features on the photons' momentum at the photodetector face, using two surface finishes, with and without reflector. MAIN RESULTS: In this work, we describe the new features added to the algorithm and GATE. We showed that Cerenkov characteristics affect their probability to be reflected/refracted and thus their travel path within a material. SIGNIFICANCE: We showed the importance of accounting for accurate Cerenkov photons reflectance while performing advanced optical Monte Carlo simulations.

Study of Cerenkov Light Emission in the Semiconductors TlBr and TlCl for TOF-PET.

Thallium bromide (TlBr) and thallium chloride (TlCl) are semiconductor materials with high transparency to visible light, high index of refraction, and high detection efficiency for gamma rays and annihilation photons. This manuscript reports on measurements of the light intensity and timing response of Cerenkov light emitted in one 3 mm × 3 mm × 5 mm slab of each of these materials operated in coincidence with a lutetium fine silicate (LFS) crystal with dimensions of 3 mm × 3 mm × 20 mm. A 22Na radioactive source was used. The measured average number of detected photons per event was 1.5 photons for TlBr and 2.8 photons for TlCl when these materials were coupled to a silicon photomultiplier. Simulation predicts these results with an overestimation of 12%. The best coincidence time resolution (CTR) for events in TlBr and TlCl were 329 ± 9 ps and 316 ± 9 ps, respectively, when events with 4 photons and >7 photons were selected. Simulation showed the CTR degraded from 120 ps to 405 ps in TlCl, and from 160 ps to 700 ps in TlBr when the first or second Cerenkov photon were selected. Results of this work show TlCl has a stronger Cerenkov light emission compared to TlBr and a greater potential to obtain the best timing measurements. Results also stress the importance of improving detection efficiency and transport of light to capture the first Cerenkov photon in timing measurements.

Optimization of scintillator-reflector optical interfaces for the LUT Davis model.

PURPOSE: Designing and optimizing scintillator-based gamma detector using Monte Carlo simulation is of great importance in nuclear medicine and high energy physics. In scintillation detectors, understanding the light transport in the scintillator and the light collection by the photodetector plays a crucial role in achieving high performance. Thus, accurately modeling them is critical. METHODS: In previous works, we developed a model to compute crystal reflectance from the crystal 3D surface measurement and store it in look-up tables to be used in the Monte Carlo simulation software GATE. The relative light output comparison showed excellent agreement between simulations and experiments for both polished and rough surfaces in several configurations, that is, without and with reflector. However, when comparing them at the irradiation depth closest to the photodetector face, rough crystals with a reflector overestimated the predicted light output. Investigating the cause of this overestimation, we optimized the LUT algorithm to improve the reflectance computation accuracy, especially for rough surfaces. However, optical Monte Carlo simulations carried out with these newly generated LUTs still overestimate the light output. Based on previous observations, one probable cause is the erroneous assumption of perfect couplings between the reflector and crystal and between the crystal and photodetector, which likely results in an important overestimation of the light output compared to experimental values. In practice, several factors could degrade it. Here, we investigated possible suboptimal optical experimental configurations that could lead to a degraded light collection when using Teflon or ESR reflectors coupled to the crystal with air or grease. We generated look-up tables with a mixture of air and grease and showed the effect of three possible sources of light loss: the presence of a small gap between the crystal and the reflector edges close to the photodetector face, the infiltration of grease in the crystal-reflector coupling, and the presence of inhomogeneities in the photodetector-crystal interface. RESULTS: The strongest effect is linked to the presence of a small gap of grease between the edges of the reflector material and the crystal (light loss of 10%-12% for 0.2 mm gap). The optical grease infiltrating the crystal-reflector air coupling decreases the light output, depending on the infiltration's extent and the amount of grease infiltrated. Five percent of air in the crystal-photodetector coupling can cause a light output decrease of 2% to 4%. The individual and combined effect of these advanced models can explain the discrepancy of the relative light output obtained with ESR in simulations and experiments. With Teflon, the study indicates that the light output loss strongly depends on the reflectance deterioration caused by grease absorption. CONCLUSIONS: Our results indicate that when studying scintillation detector performance with different finishes, performing simulations in ideal coupling conditions can lead to light output overestimation. To perform an accurate light output comparison and ultimately have a reliable detector performance estimation, all potential sources of practical limitations must be carefully considered. To broadly enable high-fidelity modeling, we developed an interface for users to compute their own LUTs, using their surface, scintillator, and reflector characteristics.

Realistic boundary conditions in SimVascular through inlet catheter modeling.

OBJECTIVE: This study aims at developing a pipeline that provides the capability to include the catheter effect in the computational fluid dynamics (CFD) simulations of the cardiovascular system and other human vascular flows carried out with the open-source software SimVascular. This tool is particularly useful for CFD simulation of interventional radiology procedures such as tumor embolization where estimation of a therapeutic agent distribution is of interest. RESULTS: A pipeline is developed that generates boundary condition files which can be used in SimVascular CFD simulations. The boundary condition files are modified such that they simulate the effect of catheter presence on the flow field downstream of the inlet. Using this pipeline, the catheter flow, velocity profile, radius, wall thickness, and deviation from the vessel center can be defined. Since our method relies on the manipulation of the boundary condition that is imposed on the inlet, it is sensitive to the mesh density. The finer the mesh is (especially around the catheter wall), the more accurate the velocity estimations are. In this study, we also utilized this pipeline to qualitatively investigate the effect of catheter presence on the flow field in a truncated right hepatic arterial tree of a liver cancer patient.

Technical Note: Standalone application to generate custom reflectance Look-Up Table for advanced optical Monte Carlo simulation in GATE/Geant4.

PURPOSE: The need for high-fidelity modeling of radiation detectors to perform reliable detector performance optimization using Monte Carlo simulations requires to accurately simulate the light transport in the scintillator and the light collection by the photodetector. In this work, we implement our well-validated crystal reflectance model computed from three-dimensional (3D) crystal surface measurement in a standalone open-source application to allow researchers to generate fully customized crystal reflectance look-up-tables (LUTs) to be used in optical Monte Carlo simulation. METHODS: The LUTDavisModel application can be installed in a few minutes on Windows, macOS, and Linux, using 26 MB of space. MATLAB Runtime is required and is automatically installed with the application. The core algorithm has been previously validated experimentally and implemented in GATE v8.0. The standalone is divided into five panels, each of which performing a specific task: generate LUTs from a combination of surface type, scintillator, and coupling medium available in the database (such as LSO or BGO) or custom; compute LUTs with the reflectors available and custom coupling thickness; create a mixture of coupling media to account for possible defects in the optical coupling; plot precomputed LUTs for visual comparison. Tooltips and errors/warnings facilitate the navigation. The reported computational times were obtained with an Intel Core i7 MacBook Pro. RESULTS: LUTs can be generated with computational time ranging from a few minutes to several hours depending on the selected surface, sampling, and computational power. A longer time is needed when using rough surfaces and thick coupling media (hundreds of µ m ) due to increased photon tracking. CONCLUSIONS: We developed a user-friendly standalone application to generate LUTs that can be used inside GATE Monte Carlo simulations. It can be easily downloaded, installed, and used. Future optimizations will expand the database, decrease the computational time through greater parallelization, and include the generation of LUTs to study Cerenkov photons transport.

Advanced Monte Carlo simulations of emission tomography imaging systems with GATE.

Built on top of the Geant4 toolkit, GATE is collaboratively developed for more than 15 years to design Monte Carlo simulations of nuclear-based imaging systems. It is, in particular, used by researchers and industrials to design, optimize, understand and create innovative emission tomography systems. In this paper, we reviewed the recent developments that have been proposed to simulate modern detectors and provide a comprehensive report on imaging systems that have been simulated and evaluated in GATE. Additionally, some methodological developments that are not specific for imaging but that can improve detector modeling and provide computation time gains, such as Variance Reduction Techniques and Artificial Intelligence integration, are described and discussed.

Multiscale Computational Fluid Dynamics Modeling for Personalized Liver Cancer Radioembolization Dosimetry.

Yttrium-90 (90Y) radioembolization is a minimally invasive procedure increasingly used for advanced liver cancer treatment. In this method, radioactive microspheres are injected into the hepatic arterial bloodstream to target, irradiate, and kill cancer cells. Accurate and precise treatment planning can lead to more efficient and safer treatment by delivering a higher radiation dose to the tumor while minimizing the exposure of the surrounding liver parenchyma. Treatment planning primarily relies on the estimated radiation dose delivered to tissue. However, current methods used to estimate the dose are based on simplified assumptions that make the dosimetry results unreliable. In this work, we present a computational model to predict the radiation dose from the 90Y activity in different liver segments to provide a more realistic and personalized dosimetry. Computational fluid dynamics (CFD) simulations were performed in a 3D hepatic arterial tree model segmented from cone-beam CT angiographic data obtained from a patient with hepatocellular carcinoma (HCC). The microsphere trajectories were predicted from the velocity field. 90Y dose distribution was then calculated from the volumetric distribution of the microspheres. Two injection locations were considered for the microsphere administration, a lobar and a selective injection. Results showed that 22% and 82% of the microspheres were delivered to the tumor, after each injection, respectively, and the combination of both injections ultimately delivered 49% of the total administered 90Y microspheres to the tumor. Results also illustrated the nonhomogeneous distribution of microspheres between liver segments, indicating the importance of developing patient-specific dosimetry methods for effective radioembolization treatment.

Current Status of Radiopharmaceutical Therapy.

In radiopharmaceutical therapy (RPT), a radionuclide is systemically or locally delivered with the goal of targeting and delivering radiation to cancer cells while minimizing radiation exposure to untargeted cells. Examples of current RPTs include thyroid ablation with the administration of 131I, treatment of liver cancer with 90Y microspheres, the treatment of bony metastases with 223Ra, and the treatment of neuroendocrine tumors with 177Lu-DOTATATE. New RPTs are being developed where radionuclides are incorporated into systemic targeted therapies. To assure that RPT is appropriately implemented, advances in targeting need to be matched with advances in quantitative imaging and dosimetry methods. Currently, radiopharmaceutical therapy is administered by intravenous or locoregional injection, and the treatment planning has typically been implemented like chemotherapy, where the activity administered is either fixed or based on a patient's body weight or body surface area. RPT pharmacokinetics are measurable by quantitative imaging and are known to vary across patients, both in tumors and normal tissues. Therefore, fixed or weight-based activity prescriptions are not currently optimized to deliver a cytotoxic dose to targets while remaining within the tolerance dose of organs at risk. Methods that provide dose estimates to individual patients rather than to reference geometries are needed to assess and adjust the injected RPT dose. Accurate doses to targets and organs at risk will benefit the individual patients and decrease uncertainties in clinical trials. Imaging can be used to measure activity distribution in vivo, and this information can be used to determine patient-specific treatment plans where the dose to the targets and organs at risk can be calculated. The development and adoption of imaging-based dosimetry methods is particularly beneficial in early clinical trials. In this work we discuss dosimetric accuracy needs in modern radiation oncology, uncertainties in the dosimetry in RPT, and best approaches for imaging and dosimetry of internal radionuclide therapy.

Overview of the First NRG Oncology-National Cancer Institute Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy.

In 2018, the National Cancer Institute and NRG Oncology partnered for the first time to host a joint workshop on systemic radiopharmaceutical therapy (RPT) to specifically address dosimetry issues and strategies for future clinical trials. The workshop focused on current dosimetric approaches for clinical trials, strategies under development that would optimize dose reporting, and future desired or optimized approaches for novel emerging radionuclides and carriers in development. In this article, we review the main approaches that are applied clinically to calculate the absorbed dose. These include absorbed doses calculated over a variety of spatial scales, including whole body, organ, suborgan, and voxel, the last 3 of which are achievable within the MIRD schema (S value) and can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This article will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biologic effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We also briefly discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation when merited by evidence collected during early-phase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.

Quantitative PET in the 2020s: a roadmap.

Positron emission tomography (PET) plays an increasingly important role in research and clinical applications, catalysed by remarkable technical advances and a growing appreciation of the need for reliable, sensitive biomarkers of human function in health and disease. Over the last 30 years, a large amount of the physics and engineering effort in PET has been motivated by the dominant clinical application during that period, oncology. This has led to important developments such as PET/CT, whole-body PET, 3D PET, accelerated statistical image reconstruction, and time-of-flight PET. Despite impressive improvements in image quality as a result of these advances, the emphasis on static, semi-quantitative 'hot spot' imaging for oncologic applications has meant that the capability of PET to quantify biologically relevant parameters based on tracer kinetics has not been fully exploited. More recent advances, such as PET/MR and total-body PET, have opened up the ability to address a vast range of new research questions, from which a future expansion of applications and radiotracers appears highly likely. Many of these new applications and tracers will, at least initially, require quantitative analyses that more fully exploit the exquisite sensitivity of PET and the tracer principle on which it is based. It is also expected that they will require more sophisticated quantitative analysis methods than those that are currently available. At the same time, artificial intelligence is revolutionizing data analysis and impacting the relationship between the statistical quality of the acquired data and the information we can extract from the data. In this roadmap, leaders of the key sub-disciplines of the field identify the challenges and opportunities to be addressed over the next ten years that will enable PET to realise its full quantitative potential, initially in research laboratories and, ultimately, in clinical practice.

Estimation of Yttrium-90 Distribution in Liver Radioembolization using Computational Fluid Dynamics and Deep Neural Networks.

Yttrium-90 (90Y) radioembolization is a liver cancer therapy based on 90Y microspheres injected into the hepatic artery. Current dosimetry methods used to estimate the absorbed dose in order to prescribe the 90Y activity to inject are not accurate, which can affect the treatment effectiveness. A new dosimetry based on the hemodynamics simulation of the hepatic arterial tree, CFDose, aimed at overcoming some of the limitations of the current methods. However, due to the expensive computational cost of computational fluid dynamics (CFD) simulations, this method needs to be accelerated before it can be used in real-time during treatment planning. In this paper, we introduce a convolutional neural network model trained with the CFD results of a patient with hepatocellular carcinoma to predict the 90Y distribution under different downstream vasculature resistance conditions. The model performance was evaluated using two metrics, the mean squared error and prediction accuracy. The prediction accuracy showed that the average difference between the actual and predicted data was less than 1%. The proposed model could estimate the 90Y distribution significantly faster than a CFD simulation.