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Purpose: Glypican-3 (GPC3)-targeted radioisotope immuno-positron emission tomography (immunoPET) may lead to earlier and more accurate diagnosis of hepatocellular carcinoma (HCC), thus facilitating curative treatment, decreasing early recurrence, and enhancing patient survival. We previously demonstrated reliable HCC detection using a zirconium-89-labeled murine anti-GPC3 antibody (89Zr-αGPC3M) for immunoPET. This study evaluated the efficacy of the humanized antibody successor (αGPC3H) to further clinical translation of a GPC3-based theranostic for HCC. Methods: In vitro αGPC3 binding to HepG2 cells was assessed by flow cytometry. In vivo 89Zr-αGPC3H and 89Zr-αGPC3M tumor uptake was evaluated by PET/CT and biodistribution studies in an orthotopic xenograft mouse model of HCC. Results: αGPC3H maintained binding to GPC3 in vitro and 89Zr-αGPC3H immunoPET identified liver tumors in vivo. PET/CT and biodistribution analyses demonstrated high 89Zr-αGPC3H tumor uptake and tumor-to-liver ratios, with no difference between groups. Conclusion: Humanized αGPC3 successfully targeted GPC3 in vitro and in vivo. 89Zr-αGPC3H immunoPET had comparable tumor detection to 89Zr-αGPC3M, with highly specific tumor uptake, making it a promising strategy to improve HCC detection.
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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.
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Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Imagen por Resonancia MagnéticaRESUMEN
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.
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We evaluated the 3D spatial, energy, and timing resolution of the Brain (or Breast)-Initiative Next-Generation (BING) PET detector. The BING detector is an array of 1-mm-thick slats of LYSO scintillator with lapped specular-reflective faces (15-mm by 52-mm) that are stacked together and oriented with their long-narrow edges normal to the imaging field of view. Interaction positions are determined from the signals of silicon-photomultiplier (SiPM) arrays placed on the entrance (top) and exit (bottom) faces. The SiPM arrays are offset to determine the slat of interaction (SOI) without requiring any optical light sharing between slats. Maximum likelihood 2D location within the SOI is determined using the sensor signals. Interaction time is determined with a modified first-optical-photon pickoff method. Performance of the BING detector was measured as a function of position using a sideways coincidence-collimated beam. Slats were accurately identified, with an effective tangential detector resolution of 1 mm. Average resolutions (and ranges) are: 0.96 mm (0.85 mm to 1.11 mm) for lateral (axial) detector resolution, 1.6 mm (1.0 mm to 2.1 mm) for depth resolution, 13.6% (12.7% to 16.0%) for energy resolution, and 317 ps (241 ps to 404 ps) for coincidence timing resolution. Initial spatial and timing resolution results demonstrated that the BING detector can be effective in a small field-of view (e.g., brain or breast) PET system.
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The HyPET project proposes a hybrid dedicated TOF-PET for prostate imaging, with pixelated detector blocks in the front layer and monolithic blocks in the back layer. In this work, four detector configurations have been experimentally evaluated for the rear detector layer. The detector configuration consists of LYSO monolithic blocks with the same size (25.4 mm × 25.4 mm) but different thicknesses (5, 7.5, 10, and 15 mm) coupled to the same SiPM array. Each detector configuration has been experimentally characterized in terms of time, energy and spatial resolution by scanning the crystal surface using a fan beam in steps of 0.25 mm. Regarding spatial resolution, the interaction position was estimated using a Neural Network technique. All resolutions except energy, which remains nearly constant at 17% for all cases, show better values for the 5 mm detector thickness. We have achieved spatial resolution values of FWHM of 1.02 ± 0.10, 1.19 ± 0.13, 1.53 ± 0.17, 2.33 ± 0.55 mm, for the 5, 7.5, 10, and 15 mm blocks, respectively. The detector time resolution obtained was 275 ± 26, 291 ± 21, 344 ± 48, and 433 ± 45 ps respectively, using the energy weighted average method for the time stamps.
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BACKGROUND: Patients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC. METHODS: Patients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [99mTc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout. RESULTS: Thirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69-12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59-0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65-0.88]) or shape feature classes (c-index 0.79 [0.66-0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59-0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R2 = 0.84-1.00), representing surrogates rather than independent predictors of pneumonitis risk. CONCLUSIONS: In patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.
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Purpose: We characterize the performance of a dualsided position-sensitive sparse sensor (DS-PS3) array detector for positron emission tomography (PET). The DS-PS3 detector is designed as a high performance, cost effective PET detector for organ-specific imaging systems (e.g., brain, breast, etc.). Methods: Two sparse 4-by-4 arrays of silicon photomultipliers (18.5% SiPM fill-factor) coupled through segmented light guide are used to readout a 15-by-15 array of 2-mm-pitch, 20-mm-long LSYO crystals. Uniform flood data were used for crystal identification, depth determination, and position-dependent energy resolution. Intrinsic-spatial and depth-of-interaction (DOI) resolutions were determined by stepping a collimated gamma-ray source over the front and side, respectively. Results: We measured an average intrinsic spatial resolution of 2.14 ± 0.07 mm full width at half maximum (FWHM). DOI FWHM resolution varied from 2.2 mm for crystals over sensors to 5.3 mm for crystals between sensors. Average DOI resolution was 3.6 ± 0.8 mm FHWM. Average energy resolution for the detector module was 16.6% with a range of 11.3% to 25.8%. Conclusions: We have demonstrated use of a dual-sided sparse sensor arrays to enable low-cost high-performance decoding of three-dimensional positioning within a PET detector using an 18.5% sensor fill-factor.
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Purpose: We sought to examine the prognostic value of fluorodeoxyglucose-positron emission tomography (PET) imaging during chemoradiation for unresectable non-small cell lung cancer for survival and hypothesized that tumor PET response is correlated with peripheral T-cell function. Methods and Materials: Forty-five patients with American Joint Committee on Cancer version 7 stage IIB-IIIB non-small cell lung cancer enrolled in a phase II trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). Fluorodeoxyglucose-PET was performed before treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactorial radiologic interpretation. PET responders received 60 Gy in 30 fractions, while nonresponders received concomitant boosts to 74 Gy in 30 fractions. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor sequencing, and plasma cytokine analysis were performed. Results: Median follow-up was 18.8 months, 1-year overall survival (OS) 82%, 1-year progression-free survival 53%, and 1-year locoregional control 88%. Higher midtreatment PET total lesion glycolysis was detrimental to OS (1 year 87% vs 63%, P < .001), progression-free survival (1 year 60% vs 26%, P = .044), and locoregional control (1 year 94% vs 65%, P = .012), even after adjustment for clinical/treatment factors. Twenty-nine of 45 patients (64%) were classified as PET responders based on a priori definition. Higher tumor programmed death-ligand 1 expression was correlated with response on PET (P = .017). Higher T-cell receptor richness and clone distribution slope were associated with improved OS (P = .018-0.035); clone distribution slope was correlated with PET response (P = .031). Conclusions: Midchemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral T-cell biomarkers.
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PURPOSE OF THE REPORT: We evaluated the reliability of 18F-FDG PET imaging biomarkers to classify early response status across observers, scanners, and reconstruction algorithms in support of biologically adaptive radiation therapy for locally advanced non-small cell lung cancer. PATIENTS AND METHODS: Thirty-one patients with unresectable locally advanced non-small cell lung cancer were prospectively enrolled on a phase 2 trial (NCT02773238) and underwent 18F-FDG PET on GE Discovery STE (DSTE) or GE Discovery MI (DMI) PET/CT systems at baseline and during the third week external beam radiation therapy regimens. All PET scans were reconstructed using OSEM; GE-DMI scans were also reconstructed with BSREM-TOF (block sequential regularized expectation maximization reconstruction algorithm incorporating time of flight). Primary tumors were contoured by 3 observers using semiautomatic gradient-based segmentation. SUVmax, SUVmean, SUVpeak, MTV (metabolic tumor volume), and total lesion glycolysis were correlated with midtherapy multidisciplinary clinical response assessment. Dice similarity of contours and response classification areas under the curve were evaluated across observers, scanners, and reconstruction algorithms. LASSO logistic regression models were trained on DSTE PET patient data and independently tested on DMI PET patient data. RESULTS: Interobserver variability of PET contours was low for both OSEM and BSREM-TOF reconstructions; intraobserver variability between reconstructions was slightly higher. ΔSUVpeak was the most robust response predictor across observers and image reconstructions. LASSO models consistently selected ΔSUVpeak and ΔMTV as response predictors. Response classification models achieved high cross-validated performance on the DSTE cohort and more variable testing performance on the DMI cohort. CONCLUSIONS: The variability FDG PET lesion contours and imaging biomarkers was relatively low across observers, scanners, and reconstructions. Objective midtreatment PET response assessment may lead to improved precision of biologically adaptive radiation therapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Biomarcadores , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia , Fluorodesoxiglucosa F18 , Humanos , Procesamiento de Imagen Asistido por Computador , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , Estudios Prospectivos , Radiofármacos , Reproducibilidad de los ResultadosRESUMEN
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.
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Carcinoma Hepatocelular/terapia , Sistemas de Liberación de Medicamentos/métodos , Glipicanos/inmunología , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Glipicanos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Ratones , Ratones Desnudos , Tomografía de Emisión de Positrones/métodos , Medicina de Precisión/métodos , Radioinmunoterapia , Radioisótopos/farmacología , Radiofármacos , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto , Radioisótopos de Itrio/farmacología , Circonio/farmacologíaRESUMEN
We investigated the sensitivity of regional tumor response prediction to variability in voxel clustering techniques, imaging features, and machine learning algorithms in 25 patients with locally advanced non-small cell lung cancer (LA-NSCLC) enrolled on the FLARE-RT clinical trial. Metabolic tumor volumes (MTV) from pre-chemoradiation (PETpre) and mid-chemoradiation fluorodeoxyglucose-positron emission tomography (FDG PET) images (PETmid) were subdivided into K-means or hierarchical voxel clusters by standardized uptake values (SUV) and 3D-positions. MTV cluster separability was evaluated by CH index, and morphologic changes were captured by Dice similarity and centroid Euclidean distance. PETpre conventional features included SUVmean, MTV/MTV cluster size, and mean radiation dose. PETpre radiomics consisted of 41 intensity histogram and 3D texture features (PET Oncology Radiomics Test Suite) extracted from MTV or MTV clusters. Machine learning models (multiple linear regression, support vector regression, logistic regression, support vector machines) of conventional features or radiomic features were constructed to predict PETmid response. Leave-one-out-cross-validated root-mean-squared-error (RMSE) for continuous response regression (ΔSUVmean) and area-under-receiver-operating-characteristic-curve (AUC) for binary response classification were calculated. K-means MTV 2-clusters (MTVhi, MTVlo) achieved maximum CH index separability (Friedman p < 0.001). Between PETpre and PETmid, MTV cluster pairs overlapped (Dice 0.70-0.87) and migrated 0.6-1.1 cm. PETmid ΔSUVmean response prediction was superior in MTV and MTVlo (RMSE = 0.17-0.21) compared to MTVhi (RMSE = 0.42-0.52, Friedman p < 0.001). PETmid ΔSUVmean response class prediction performance trended higher in MTVlo (AUC = 0.83-0.88) compared to MTVhi (AUC = 0.44-0.58, Friedman p = 0.052). Models were more sensitive to MTV/MTV cluster regions (Friedman p = 0.026) than feature sets/algorithms (Wilcoxon signed-rank p = 0.36). Top-ranked radiomic features included GLZSM-LZHGE (large-zone-high-SUV), GTSDM-CP (cluster-prominence), GTSDM-CS (cluster-shade) and NGTDM-CNT (contrast). Top-ranked features were consistent between MTVhi and MTVlo cluster pairs but varied between MTVhi-MTVlo clusters, reflecting distinct regional radiomic phenotypes. Variability in tumor voxel cluster response prediction can inform robust radiomic target definition for risk-adaptive chemoradiation in patients with LA-NSCLC. FLARE-RT trial: NCT02773238.
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Quimioradioterapia , Fluorodesoxiglucosa F18 , Procesamiento de Imagen Asistido por Computador , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/terapia , Tomografía de Emisión de Positrones , Adulto , Anciano , Algoritmos , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Estudios Longitudinales , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Curva ROC , Radiometría , Resultado del Tratamiento , Carga TumoralRESUMEN
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.
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Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Animales , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/veterinaria , Distribución TisularRESUMEN
Preclinical PET/CT is a well-established noninvasive imaging tool for studying disease development/progression and the development of novel radiotracers and pharmaceuticals for clinical applications. Despite this pivotal role, standardization of preclinical PET/CT protocols, including CT absorbed dose guidelines, is essentially nonexistent. This study (1) quantitatively assesses the variability of current preclinical PET/CT acquisition and reconstruction protocols routinely used across multiple centers and scanners; and (2) proposes acquisition and reconstruction PET/CT protocols for standardization of multicenter data, optimized for routine scanning in the preclinical PET/CT laboratory. Methods: Five different commercial preclinical PET/CT scanners in Europe and the United States were enrolled. Seven different PET/CT phantoms were used for evaluating biases on default/general scanner protocols, followed by developing standardized protocols. PET, CT, and absorbed dose biases were assessed. Results: Site default CT protocols were the following: greatest extracted Hounsfield units (HU) were 133 HU for water and -967 HU for air; significant differences in all tissue equivalent material (TEM) groups were measured. The average CT absorbed doses for mouse and rat were 72 mGy and 40 mGy, respectively. Standardized CT protocol were the following: greatest extracted HU were -77 HU for water and -990 HU for air; TEM precision improved with a reduction in variability for each tissue group. The average CT absorbed dose for mouse and rat decreased to 37 mGy and 24 mGy, respectively. Site default PET protocols were the following: uniformity was substandard in one scanner, recovery coefficients (RCs) were either over- or underestimated (maximum of 43%), standard uptake values (SUVs) were biased by a maximum of 44%. Standardized PET protocols were the following: scanner with substandard uniformity improved by 36%, RC variability decreased by 13% points, and SUV accuracy improved to 10%. Conclusion: Data revealed important quantitative biases in preclinical PET/CT and absorbed doses with default protocols. Standardized protocols showed improvements in measured PET/CT accuracy and precision with reduced CT absorbed dose across sites. Adhering to standardized protocols generates reproducible and consistent preclinical imaging datasets, thus augmenting translation of research findings to the clinic.
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Tomografía Computarizada por Tomografía de Emisión de Positrones/normas , Animales , Procesamiento de Imagen Asistido por Computador , Ratones , Fantasmas de Imagen , Control de Calidad , Dosis de Radiación , Ratas , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
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.
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Pulmón/diagnóstico por imagen , Fantasmas de Imagen , Poliuretanos , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/instrumentación , Reproducibilidad de los Resultados , AguaRESUMEN
PURPOSE: External-beam radiation is the single most effective therapy for localized lymphoma. However, toxicity limits its use for multifocal disease. We evaluated CD45 as a therapeutic target for an antibody-radionuclide conjugate (ARC) for the treatment of lymphoma based on its ubiquitous expression, infrequent antigen loss or blockade, and the ability to target minimal disease based on panhematopoietic expression. PATIENTS AND METHODS: We performed a phase I trial of escalating doses of single-agent CD45-targeted ARC based on per-patient dosimetry using the BC8 antibody labeled with iodine-131 (131I) followed by autologous stem cell support in adults with relapsed, refractory, or high-risk B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), or Hodgkin lymphoma. The primary objective was to estimate the maximum tolerated radiation absorbed dose. RESULTS: Sixteen patients were enrolled: 7 patients had B-NHL, 6 had Hodgkin lymphoma, and 3 had T-NHL. Median number of prior therapies was three (range: 2-12). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Nonhematologic toxicity was infrequent and manageable. Objective responses were seen across histologies. Fourteen patients had measurable disease at enrollment, 57% of whom achieved complete remission (CR), including all 3 with T-NHL. Three patients with B-NHL treated among the highest dose levels (26-32 Gy) remain in CR without subsequent therapy 35-41 months later. CONCLUSIONS: CD45-targeted ARC therapy is well-tolerated at doses up to at least 32 Gy to the liver. Objective responses and long-term remissions were observed in patients with relapsed/refractory lymphoma. These data validate continued evaluation of anti-CD45 ARCs in lymphoma.
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Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Hodgkin/terapia , Inmunoconjugados/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Antígenos Comunes de Leucocito/antagonistas & inhibidores , Linfoma no Hodgkin/terapia , Trasplante de Células Madre/métodos , Adulto , Anciano , Terapia Combinada , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/patología , Humanos , Antígenos Comunes de Leucocito/inmunología , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Radioinmunoterapia , Terapia Recuperativa , Tasa de Supervivencia , Adulto JovenRESUMEN
OBJECTIVE: The effect of functional lung avoidance planning on radiation dose-dependent changes in regional lung perfusion is unknown. We characterized dose-perfusion response on longitudinal perfusion single photon emission computed tomography (SPECT)/CT in two cohorts of lung cancer patients treated with and without functional lung avoidance techniques. METHODS: The study included 28 primary lung cancer patients: 20 from interventional (NCT02773238) (FLARE-RT) and eight from observational (NCT01982123) (LUNG-RT) clinical trials. FLARE-RT treatment plans included perfused lung dose constraints while LUNG-RT plans adhered to clinical standards. Pre- and 3 month post-treatment macro-aggregated albumin (MAA) SPECT/CT scans were rigidly co-registered to planning four-dimensional CT scans. Tumour-subtracted lung dose was converted to EQD2 and sorted into 5 Gy bins. Mean dose and percent change between pre/post-RT MAA-SPECT uptake (%ΔPERF), normalized to total tumour-subtracted lung uptake, were calculated in each binned dose region. Perfusion frequency histograms of pre/post-RT MAA-SPECT were analyzed. Dose-response data were parameterized by sigmoid logistic functions to estimate maximum perfusion increase (%ΔPERFmaxincrease), maximum perfusion decrease (%ΔPERFmaxdecrease), dose midpoint (Dmid), and dose-response slope (k). RESULTS: Differences in MAA perfusion frequency distribution shape between time points were observed in 11/20 (55%) FLARE-RT and 2/8 (25%) LUNG-RT patients (p < 0.05). FLARE-RT dose response was characterized by >10% perfusion increase in the 0-5 Gy dose bin for 8/20 patients (%ΔPERFmaxincrease = 10-40%), which was not observed in any LUNG-RT patients (p = 0.03). The dose midpoint Dmid at which relative perfusion declined by 50% trended higher in FLARE-RT compared to LUNG-RT cohorts (35 GyEQD2 vs 21 GyEQD2, p = 0.09), while the dose-response slope k was similar between FLARE-RT and LUNG-RT cohorts (3.1-3.2, p = 0.86). CONCLUSION: Functional lung avoidance planning may promote increased post-treatment perfusion in low dose regions for select patients, though inter-patient variability remains high in unbalanced cohorts. These preliminary findings form testable hypotheses that warrant subsequent validation in larger cohorts within randomized or case-matched control investigations. ADVANCES IN KNOWLEDGE: This novel preliminary study reports differences in dose-response relationships between patients receiving functional lung avoidance radiation therapy (FLARE-RT) and those receiving conventionally planned radiation therapy (LUNG-RT). Following further validation and testing of these effects in larger patient populations, individualized estimation of regional lung perfusion dose-response may help refine future risk-adaptive strategies to minimize lung function deficits and toxicity incidence.
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Neoplasias Pulmonares/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Neoplasias Pulmonares/radioterapia , Masculino , Persona de Mediana Edad , Imagen de Perfusión/métodos , Estudios Prospectivos , Planificación de la Radioterapia Asistida por Computador , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
PURPOSE: Prediction of spatially variant response to cancer therapies can inform risk-adaptive management within precision oncology. We developed the "Voxel Forecast" multiscale regression framework for predicting spatially variant tumor response to chemoradiotherapy on fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging. EXPERIMENTAL DESIGN: Twenty-five patients with locally advanced non-small cell lung cancer, enrolled on the FLARE-RT phase II trial (NCT02773238), underwent FDG PET/CT imaging prior to (PETpre) and during week 3 (PETmid) of concurrent chemoradiotherapy. Voxel Forecast was designed to predict tumor voxel standardized uptake value (SUV) on PETmid from baseline patient-level and voxel-level covariates using a custom generalized least squares (GLS) algorithm. Matérn covariance matrices were fit to patient- specific empirical variograms of distance-dependent intervoxel correlation. Regression coefficients from variogram-based weights and corresponding standard errors were estimated using the jackknife technique. The framework was validated using statistical simulations of known spatially variant tumor response. Mean absolute prediction errors (MAEs) of Voxel Forecast models were calculated under leave-one-patient-out cross-validation. RESULTS: Patient-level forecasts resulted in tumor voxel SUV MAE on PETmid of 1.5 g/mL while combined patient- and voxel-level forecasts achieved lower MAE of 1.0 g/mL (P < 0.0001). PETpre voxel SUV was the most important predictor of PETmid voxel SUV. Patients with a greater percentage of under-responding tumor voxels were classified as PETmid nonresponders (P = 0.030) with worse overall survival prognosis (P < 0.001). CONCLUSIONS: Voxel Forecast multiscale regression provides a statistical framework to predict voxel-wise response patterns during therapy. Voxel Forecast can be extended to predict spatially variant response on multimodal quantitative imaging and may eventually guide optimized spatial-temporal dose distributions for precision cancer therapy.
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Oncología Médica , Neoplasias/diagnóstico , Neoplasias/terapia , Medicina de Precisión , Análisis de Regresión , Anciano , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Oncología Médica/métodos , Persona de Mediana Edad , Modelos Teóricos , Imagen Molecular/métodos , Imagen Multimodal , Análisis Multivariante , Neoplasias/mortalidad , Medicina de Precisión/métodos , PronósticoRESUMEN
BACKGROUND AND PURPOSE: Computer-based analysis of Dopamine transporter imaging (DaTscan) can aid in image interpretation. In this study, we examined the distribution of putamen-to-caudate ratios (PCRs) obtained by using a clinically available semiquantification method. METHODS: Medical records of 32 patients (M:16) with a diagnosis of Parkinson's disease (PD) (n = 22) or Parkinson's plus syndromes (PPS) (n = 10) based on clinical follow-up, were retrospectively reviewed. Single photon emission tomography (SPECT) imaging was performed 4 hours after intravenous injection of 3-5 mCi [I-123]-ioflupane. Semiquantitative evaluation using DaTQUANT software was performed. Utility of PCR with a cutoff of .7 and .8 in the diagnosis of nigrostriatal degeneration was assessed. PD and PPS groups based on clinical assessment and caudate-to-background ratio (CBR) were assessed separately. RESULTS: Minimum PCR for both hemispheres was .74 ± .09 (Mean ± SD, range: .58-.89), with 65.63% patients (21/32) having PCR > .7. Mean PCR in mild nigrostriatal degeneration was .77 ± .08 (range: .62-.89) and in advanced nigrostriatal degeneration was .73 ± .09 (range: .58-.89). Mean PCR in PD group was .73 ± .09 (range: .58-.89) and in PPS group was .75 ± .10 (range: .61-.88). CONCLUSIONS: Although PCR can intrinsically be a useful indication of disease, this ratio obtained in our analysis by using one of the clinically available automatic semiquantitative methods has large variability and might not be a reliable numeric marker in interpretation of [I-123]ioflupane studies. This may be due to difficulty in separating caudate from putamen on SPECT images, as well as the nonuniform decreased Ioflupane uptake in both putamen and caudate.
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Núcleo Caudado/diagnóstico por imagen , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Trastornos Parkinsonianos/diagnóstico por imagen , Putamen/diagnóstico por imagen , Anciano , Núcleo Caudado/metabolismo , Femenino , Humanos , Radioisótopos de Yodo , Masculino , Persona de Mediana Edad , Neuroimagen , Trastornos Parkinsonianos/metabolismo , Putamen/metabolismo , Estudios Retrospectivos , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
Recognizing the different mechanisms and imaging appearance of extraskeletal Tc-99m methylene diphosphonate uptake enhances the diagnostic value of bone scan interpretation. In this article, we present a pictorial review of the different mechanisms of extraskeletal Tc-99m methylene diphosphonate uptake on bone scintigraphy including neoplastic, inflammatory, ischemic, traumatic, excretory, and iatrogenic. We also illustrate through case examples the added value of correlation with cross-sectional and single photon emission computed tomography and computed tomography imaging in localizing and characterizing challenging cases of extraskeletal uptake.