Glypican-3 targeted positron emission tomography detects sub-centimeter tumors in a xenograft model of hepatocellular carcinoma.

BACKGROUND: Early intrahepatic recurrence is common after surgical resection of hepatocellular carcinoma (HCC) and leads to increased morbidity and mortality. Insensitive and nonspecific diagnostic imaging contributes to EIR and results in missed treatment opportunities. In addition, novel modalities are needed to identify targets amenable for targeted molecular therapy. In this study, we evaluated a zirconium-89 radiolabeled glypican-3 (GPC3) targeting antibody conjugate (89Zr-αGPC3) for use in positron emission tomography (PET) for detection of small, GPC3+ HCC in an orthotopic murine model. Athymic nu/J mice received hepG2, a GPC3+ human HCC cell line, into the hepatic subcapsular space. Tumor-bearing mice were imaged by PET/computerized tomography (CT) 4 days after tail vein injection of 89Zr-αGPC3. Livers were then excised for the tumors to be identified, measured, bisected, and then serially sectioned at 500 µm increments. Sensitivity and specificity of PET/CT for 89Zr-αGPC3-avid tumors were assessed using tumor confirmation on histologic sections as the gold standard. RESULTS: In tumor-bearing mice, 89Zr-αGPC3 avidly accumulated in the tumor within four hours of injection with ongoing accumulation over time. There was minimal off-target deposition and rapid bloodstream clearance. Thirty-eight of 43 animals had an identifiable tumor on histologic analysis. 89Zr-αGPC3 immuno-PET detected all 38 histologically confirmed tumors with a sensitivity of 100%, with the smallest tumor detected measuring 330 µm in diameter. Tumor-to-liver ratios of 89Zr-αGPC3 uptake were high, creating excellent spatial resolution for ease of tumor detection on PET/CT. Two of five tumors that were observed on PET/CT were not identified on histologic analysis, yielding a specificity of 60%. CONCLUSIONS: 89Zr-αGPC3 avidly accumulated in GPC3+ tumors with minimal off-target sequestration. 89Zr-αGPC3 immuno-PET yielded a sensitivity of 100% and detected sub-millimeter tumors. This technology may improve diagnostic sensitivity of small HCC and select GPC3+ tumors for targeted therapy. Human trials are warranted to assess its impact.

An Online Repository for Pre-Clinical Imaging Protocols (PIPs).

Providing method descriptions that are more detailed than currently available in typical peer reviewed journals has been identified as an actionable area for improvement. In the biochemical and cell biology space, this need has been met through the creation of new journals focused on detailed protocols and materials sourcing. However, this format is not well suited for capturing instrument validation, detailed imaging protocols, and extensive statistical analysis. Furthermore, the need for additional information must be counterbalanced by the additional time burden placed upon researchers who may be already overtasked. To address these competing issues, this white paper describes protocol templates for positron emission tomography (PET), X-ray computed tomography (CT), and magnetic resonance imaging (MRI) that can be leveraged by the broad community of quantitative imaging experts to write and self-publish protocols in protocols.io. Similar to the Structured Transparent Accessible Reproducible (STAR) or Journal of Visualized Experiments (JoVE) articles, authors are encouraged to publish peer reviewed papers and then to submit more detailed experimental protocols using this template to the online resource. Such protocols should be easy to use, readily accessible, readily searchable, considered open access, enable community feedback, editable, and citable by the author.

Glypican-3 targeted delivery of 89Zr and 90Y as a theranostic radionuclide platform for hepatocellular carcinoma.

Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 (89Zr) and yttrium-90 (90Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with 89Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with 90Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUVmax by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R2 = 0.90). Serum AFP was significantly lower 30 days after RIT in 90Y-αGPC3 treated animals compared to those untreated (p = 0.01) or treated with non-radiolabeled αGPC3 (p = 0.02). Immuno-PET GTV measurements strongly correlated with tumor burden after RIT (R2 = 0.87), and GTV of animals treated with 90Y-αGPC3 was lower than in animals who did not receive treatment or were treated with non-radiolabeled αGPC3, although this only trended toward statistical significance. A theranostic platform utilizing GPC3 targeted 89Zr and 90Y effectively imaged, treated, and assessed response after radioimmunotherapy in a GPC3-expressing HCC xenograft model.

Small animal PET: a review of what we have done and where we are going.

Small animal research is an essential tool in studying both pharmaceutical biodistribution and disease progression over time. Furthermore, through the rapid development ofin vivoimaging technology over the last few decades, small animal imaging (also referred to as preclinical imaging) has become a mainstay for all fields of biologic research and a center point for most preclinical cancer research. Preclinical imaging modalities include optical, MRI and MRS, microCT, small animal PET, ultrasound, and photoacoustic, each with their individual strengths. The strong points of small animal PET are its translatability to the clinic; its quantitative imaging capabilities; its whole-body imaging ability to dynamically trace functional/biochemical processes; its ability to provide useful images with only nano- to pico- molar concentrations of administered compounds; and its ability to study animals serially over time. This review paper gives an overview of the development and evolution of small animal PET imaging. It provides an overview of detector designs; system configurations; multimodality PET imaging systems; image reconstruction and analysis tools; and an overview of research and commercially available small animal PET systems. It concludes with a look toward developing technologies/methodologies that will further enhance the impact of small animal PET imaging on medical research in the future.

Individual and social factors affecting the ability of American crows to solve and master a string pulling task.

Crows and other birds in the family Corvidae regularly share information to learn the identity and whereabouts of dangerous predators, but can they use social learning to solve a novel task for a food reward? Here we examined the factors affecting the ability of 27 wild-caught American crows to solve a common string-pulling task in a laboratory setting. We split crows into two groups; one group was given the task after repeatedly observing a conspecific model the solution, the other solved in the absence of conspecific models. We recorded the crows' estimated age, sex, size, body condition, level of nervousness, and brain volume using DICOM images from a CT scan. Although none of these variables were statistically significant, crows without a conspecific model and large brain volumes consistently mastered the task in the minimum number of days, whereas those with conspecific models and smaller brain volumes required varying and sometimes a substantial number of days to master the task. We found indirect evidence that body condition might also be important for motivating crows to solve the task. Crows with conspecific models were no more likely to initially solve the task than those working the puzzle without social information, but those that mastered the task usually copied the method most frequently demonstrated by their knowledgeable neighbors. These findings suggest that brain volume and possibly body condition may be factors in learning new tasks, and that crows can use social learning to refine their ability to obtain a novel food source, although they must initially learn to access it themselves.

Development and testing of SPECT/CT lung phantoms made from expanding polyurethane foam.

PURPOSE: Currently, single-photon emission computed tomography (SPECT)/computed tomography (CT) lung phantoms are commonly constructed using polystyrene beads and interstitial radioactive water. However, this approach often results in a phantom with a density (typically -640 HU) that is considerably higher than that of healthy lung (-750 to -850 HU) or diseased lung (-900 to -950 HU). Furthermore, the polystyrene and water phantoms are often quite heterogeneous in both density and activity concentration, especially when reused. This work is devoted to examining methods for creating a more realistic lung phantom for quantitative SPECT/CT using 99m Tc-laced expanding polyurethane foam (EPF). METHODS: Numerous aspects of EPF utilization were studied, including stoichiometric mixing to control final foam density and the effect of water during growth. We also tested several ways of molding the foam lung phantoms. The most successful method utilized a three-part silicone mold that allowed for creation of a two-lobe phantom, with a different density and activity concentration in each lobe. RESULTS: The final phantom design allows for a more anatomically accurate geometry as well as customizable density and activity concentration in the different lobes of the lung. We demonstrated final lung phantom densities between -760 and -690 HU in the "healthy" phantom and -930 to -890 HU in the "unhealthy" phantom tissue. On average, we achieved 15% activity concentration nonuniformity and 12% density nonuniformity within a given lobe. CONCLUSIONS: Final EPF lung phantoms closely matched the densities of both health and diseased lung tissue and had sufficient uniformities in both density and activity concentration for most nuclear medicine applications. Management of component moisture content is critical for phantom reproducibility.

Depth of Interaction Calibration and Capabilities in 2×2 Discrete Crystal Arrays and Digital Silicon Photomultipliers.

Digital silicon photomultiplers (dSiPMs) have potential in the advancement of PET detectors. Their advantages include decreased dark counts through selective microcell activation, fast timing, and flexibility configuring event triggering and collection. Further improvements in PET image resolution are possible when photon depth of interaction (DOI) is available, as this reduces parallax error caused by mispositioning events at the peripheral field of view. These improvements are desirable in smaller ring diameter PET systems, such as whole body PET/MRI. In this study we quantify the DOI capabilities of a unique crystal array design (termed dual light sharing arrays or DLSA) that takes advantage of the 2-by-2-pixel die readout logic of a PDPC dSiPM (Philips Digital Photon Counting 3200) device by Philips Medical Systems. The DLSA is comprised of a 2×2 array of 4×4×22 mm3 LYSO crystals; inter-crystal surfaces were optically coupled in part with high-index optical adhesive and optically isolated in complimentary parts with mirror-film reflector such that light sharing was depth-dependent and different along two axes. The DLSA was mounted to one die of a PDPC and its depth-dependent response to 511-keV gamma rays was calibrated using a coincidence-collimated beam from both side and entrance surfaces. Entrance surface DOI calibration was performed through an iterative application of maximum likelihood calculations based on the signal ratio in crystals adjacent to the crystal of interaction. Results showed timing resolutions of 350-370 ps and energy resolutions of 10-12% while achieving a DOI position estimation of 6-7 mm FWHM. Significant improvements in depth estimation error were found when using maximum likelihood estimation and 3-4 depth bins. Furthermore, similar calibration results were obtained for both side-surface and entrance-surface illumination methods, which suggest that PET system calibrations may be easily performed using a monoenergetic flood source with entrance surface illumination.