Publications by authors named "Richard Laforest"

91 Publications

Deep learning-based T1-enhanced selection of linear attenuation coefficients (DL-TESLA) for PET/MR attenuation correction in dementia neuroimaging.

Magn Reson Med 2021 Feb 8. Epub 2021 Feb 8.

Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.

Purpose: The accuracy of existing PET/MR attenuation correction (AC) has been limited by a lack of correlation between MR signal and tissue electron density. Based on our finding that longitudinal relaxation rate, or R , is associated with CT Hounsfield unit in bone and soft tissues in the brain, we propose a deep learning T -enhanced selection of linear attenuation coefficients (DL-TESLA) method to incorporate quantitative R for PET/MR AC and evaluate its accuracy and longitudinal test-retest repeatability in brain PET/MR imaging.

Methods: DL-TESLA uses a 3D residual UNet (ResUNet) for pseudo-CT (pCT) estimation. With a total of 174 participants, we compared PET AC accuracy of DL-TESLA to 3 other methods adopting similar 3D ResUNet structures but using UTE , or Dixon, or T -MPRAGE as input. With images from 23 additional participants repeatedly scanned, the test-retest differences and within-subject coefficient of variation of standardized uptake value ratios (SUVR) were compared between PET images reconstructed using either DL-TESLA or CT for AC.

Results: DL-TESLA had (1) significantly lower mean absolute error in pCT, (2) the highest Dice coefficients in both bone and air, (3) significantly lower PET relative absolute error in whole brain and various brain regions, (4) the highest percentage of voxels with a PET relative error within both ±3% and ±5%, (5) similar to CT test-retest differences in SUVRs from the cerebrum and mean cortical (MC) region, and (6) similar to CT within-subject coefficient of variation in cerebrum and MC.

Conclusion: DL-TESLA demonstrates excellent PET/MR AC accuracy and test-retest repeatability.
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http://dx.doi.org/10.1002/mrm.28689DOI Listing
February 2021

Heterogeneity in insulin-stimulated glucose uptake among different muscle groups in healthy lean people and people with obesity.

Diabetologia 2021 Jan 29. Epub 2021 Jan 29.

Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA.

Aims/hypothesis: It has been proposed that muscle fibre type composition and perfusion are key determinants of insulin-stimulated muscle glucose uptake, and alterations in muscle fibre type composition and perfusion contribute to muscle, and consequently whole-body, insulin resistance in people with obesity. The goal of the study was to evaluate the relationships among muscle fibre type composition, perfusion and insulin-stimulated glucose uptake rates in healthy, lean people and people with obesity.

Methods: We measured insulin-stimulated whole-body glucose disposal and glucose uptake and perfusion rates in five major muscle groups (erector spinae, obliques, rectus abdominis, hamstrings, quadriceps) in 15 healthy lean people and 37 people with obesity by using the hyperinsulinaemic-euglycaemic clamp procedure in conjunction with [H]glucose tracer infusion (to assess whole-body glucose disposal) and positron emission tomography after injections of [O]HO (to assess muscle perfusion) and [F]fluorodeoxyglucose (to assess muscle glucose uptake). A biopsy from the vastus lateralis was obtained to assess fibre type composition.

Results: We found: (1) a twofold difference in glucose uptake rates among muscles in both the lean and obese groups (rectus abdominis: 67 [51, 78] and 32 [21, 55] μmol kg min in the lean and obese groups, respectively; erector spinae: 134 [103, 160] and 66 [24, 129] μmol kg min, respectively; median [IQR]) that was unrelated to perfusion or fibre type composition (assessed in the vastus only); (2) the impairment in insulin action in the obese compared with the lean group was not different among muscle groups; and (3) insulin-stimulated whole-body glucose disposal expressed per kg fat-free mass was linearly related with muscle glucose uptake rate (r = 0.65, p < 0.05).

Conclusions/interpretation: Obesity-associated insulin resistance is generalised across all major muscles, and is not caused by alterations in muscle fibre type composition or perfusion. In addition, insulin-stimulated whole-body glucose disposal relative to fat-free mass provides a reliable index of muscle glucose uptake rate.
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http://dx.doi.org/10.1007/s00125-021-05383-wDOI Listing
January 2021

CC Chemokine Receptor 2-Targeting Copper Nanoparticles for Positron Emission Tomography-Guided Delivery of Gemcitabine for Pancreatic Ductal Adenocarcinoma.

ACS Nano 2021 01 6;15(1):1186-1198. Epub 2021 Jan 6.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with dire prognosis due to aggressive biology, lack of effective tools for diagnosis at an early stage, and limited treatment options. Detection of PDAC using conventional radiographic imaging is limited by the dense, hypovascular stromal component and relatively scarce neoplastic cells within the tumor microenvironment (TME). The CC motif chemokine 2 (CCL2) and its cognate receptor CCR2 (CCL2/CCR2) axis are critical in fostering and maintaining this kind of TME by recruiting immunosuppressive myeloid cells such as the tumor-associated macrophages, thereby presenting an opportunity to exploit this axis for both diagnostic and therapeutic purposes. We engineered CCR2-targeting ultrasmall copper nanoparticles (Cu@CuO) as nanovehicles not only for targeted positron emission tomography imaging by intrinsic radiolabeling with Cu but also for loading and delivery of the chemotherapy drug gemcitabine to PDAC. This Cu-radiolabeled nanovehicle allowed sensitive and accurate detection of PDAC malignancy in autochthonous genetically engineered mouse models. The ultrasmall Cu@CuO showed efficient renal clearance, favorable pharmacokinetics, and minimal toxicity. Systemic administration of gemcitabine-loaded Cu@CuO effectively suppressed the progression of PDAC tumors in a syngeneic xenograft mouse model and prolonged survival. These CCR2-targeted ultrasmall nanoparticles offer a promising image-guided therapeutic agent and show great potential for translation.
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http://dx.doi.org/10.1021/acsnano.0c08185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846978PMC
January 2021

PIDSC Remote Viewing Guidelines Document.

J Nucl Med Technol 2020 Dec 30. Epub 2020 Dec 30.

Icahn School of Medicine at Mount Sinai.

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http://dx.doi.org/10.2967/jnmt.120.261890DOI Listing
December 2020

A LIST-MODE OSEM-BASED ATTENUATION AND SCATTER COMPENSATION METHOD FOR SPECT.

Proc IEEE Int Symp Biomed Imaging 2020 Apr 22;2020:646-650. Epub 2020 May 22.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.

Reliable attenuation and scatter compensation (ASC) is a pre-requisite for quantification and beneficial for visual interpretation tasks in SPECT. In this paper, we develop a reconstruction method that uses the entire SPECT emission data, i.e. data in both the photopeak and scatter windows, acquired in list-mode format and including the energy attribute of the detected photon, to perform ASC. We implemented a GPU-based version of this method using an ordered subsets expectation maximization (OSEM) algorithm. The method was objectively evaluated using realistic simulation studies on the task of estimating uptake in the striatal regions of the brain in a 2-D dopamine transporter (DaT)-scan SPECT study. We observed that inclusion of data from the scatter window and using list-mode data yielded improved quantification compared to using data only from the photopeak window or using binned data. These results motivate further development of list-mode-based ASC methods that include scatter-window data for SPECT.
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http://dx.doi.org/10.1109/isbi45749.2020.9098333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561042PMC
April 2020

Co-Clinical Imaging Resource Program (CIRP): Bridging the Translational Divide to Advance Precision Medicine.

Tomography 2020 Sep;6(3):273-287

Department of Radiology, Perelman School of Medicine, University of Pennsylvania.

The National Institutes of Health's (National Cancer Institute) precision medicine initiative emphasizes the biological and molecular bases for cancer prevention and treatment. Importantly, it addresses the need for consistency in preclinical and clinical research. To overcome the translational gap in cancer treatment and prevention, the cancer research community has been transitioning toward using animal models that more fatefully recapitulate human tumor biology. There is a growing need to develop best practices in translational research, including imaging research, to better inform therapeutic choices and decision-making. Therefore, the National Cancer Institute has recently launched the Co-Clinical Imaging Research Resource Program (CIRP). Its overarching mission is to advance the practice of precision medicine by establishing consensus-based best practices for co-clinical imaging research by developing optimized state-of-the-art translational quantitative imaging methodologies to enable disease detection, risk stratification, and assessment/prediction of response to therapy. In this communication, we discuss our involvement in the CIRP, detailing key considerations including animal model selection, co-clinical study design, need for standardization of co-clinical instruments, and harmonization of preclinical and clinical quantitative imaging pipelines. An underlying emphasis in the program is to develop best practices toward reproducible, repeatable, and precise quantitative imaging biomarkers for use in translational cancer imaging and therapy. We will conclude with our thoughts on informatics needs to enable collaborative and open science research to advance precision medicine.
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http://dx.doi.org/10.18383/j.tom.2020.00023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442091PMC
September 2020

Chemokine Receptor 2-targeted Molecular Imaging in Pulmonary Fibrosis. A Clinical Trial.

Am J Respir Crit Care Med 2021 01;203(1):78-89

Department of Radiology.

Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis. To phenotype patients with IPF for potential targeted therapy, we developed Cu-DOTA-ECL1i, a radiotracer to noninvasively track CCR2 monocytes and macrophages using positron emission tomography (PET). CCR2 cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR2 cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and RNA hybridization and then correlated with parallel quantitation of lung uptake by Cu-DOTA-ECL1i PET. Mouse models established that increased Cu-DOTA-ECL1i PET uptake in the lung correlates with CCR2 cell infiltration associated with fibrosis ( = 72). As therapeutic models, the inhibition of fibrosis by IL-1β blockade ( = 19) or antifibrotic pirfenidone ( = 18) reduced CCR2 macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR2 cells concentrated in perifibrotic regions and correlated with radiotracer localization ( = 21). Human imaging revealed little lung uptake in healthy volunteers ( = 7), whereas subjects with IPF ( = 4) exhibited intensive signals in fibrotic zones. These findings support a role for imaging CCR2 cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.Clinical trial registered with www.clinicaltrials.gov (NCT03492762).
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http://dx.doi.org/10.1164/rccm.202004-1132OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781144PMC
January 2021

Obesity Is Associated With Increased Basal and Postprandial β-Cell Insulin Secretion Even in the Absence of Insulin Resistance.

Diabetes 2020 10 10;69(10):2112-2119. Epub 2020 Jul 10.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO

We tested the hypothesis that obesity, independent of insulin resistance, is associated with increased insulin secretion. We compared insulin kinetics before and after glucose ingestion in lean healthy people and people with obesity who were matched on multiorgan insulin sensitivity (inhibition of adipose tissue lipolysis and glucose production and stimulation of muscle glucose uptake) as assessed by using a two-stage hyperinsulinemic-euglycemic pancreatic clamp procedure in conjunction with glucose and palmitate tracer infusions and positron emission tomography. We also evaluated the effect of diet-induced weight loss on insulin secretion in people with obesity who did not improve insulin sensitivity despite marked (∼20%) weight loss. Basal and postprandial insulin secretion rates were >50% greater in people with obesity than lean people even though insulin sensitivity was not different between groups. Weight loss in people with obesity decreased insulin secretion by 35% even though insulin sensitivity did not change. These results demonstrate that increased insulin secretion in people with obesity is associated with excess adiposity itself and is not simply a compensatory response to insulin resistance. These findings have important implications regarding the pathogenesis of diabetes because hyperinsulinemia causes insulin resistance and insulin hypersecretion is an independent risk factor for developing diabetes.
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http://dx.doi.org/10.2337/db20-0377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506835PMC
October 2020

CCR2 Positron Emission Tomography for the Assessment of Abdominal Aortic Aneurysm Inflammation and Rupture Prediction.

Circ Cardiovasc Imaging 2020 03 13;13(3):e009889. Epub 2020 Mar 13.

Department of Radiology (L.D., D.S., H.L., G.S.H., X.Z., R.L., J.Z., R.J.G., Y.L.), Washington University, St. Louis, MO.

Background: The monocyte chemoattractant protein-1/CCR2 (chemokine receptor 2) axis plays an important role in abdominal aortic aneurysm (AAA) pathogenesis, with effects on disease progression and anatomic stability. We assessed the expression of CCR2 in a rodent model and human tissues, using a targeted positron emission tomography radiotracer (Cu-DOTA-ECL1i).

Methods: AAAs were generated in Sprague-Dawley rats by exposing the infrarenal, intraluminal aorta to PPE (porcine pancreatic elastase) under pressure to induce aneurysmal degeneration. Heat-inactivated PPE was used to generate a sham operative control. Rat AAA rupture was stimulated by the administration of β-aminopropionitrile, a lysyl oxidase inhibitor. Biodistribution was performed in wild-type rats at 1 hour post tail vein injection of Cu-DOTA-ECL1i. Dynamic positron emission tomography/computed tomography imaging was performed in rats to determine the in vivo distribution of radiotracer.

Results: Biodistribution showed fast renal clearance. The localization of radiotracer uptake in AAA was verified with high-resolution computed tomography. At day 7 post-AAA induction, the radiotracer uptake (standardized uptake value [SUV]=0.91±0.25) was approximately twice that of sham-controls (SUV=0.47±0.10; <0.01). At 14 days post-AAA induction, radiotracer uptake by either group did not significantly change (AAA SUV=0.86±0.17 and sham-control SUV=0.46±0.10), independent of variations in aortic diameter. Competitive CCR2 receptor blocking significantly decreased AAA uptake (SUV=0.42±0.09). Tracer uptake in AAAs that subsequently ruptured (SUV=1.31±0.14; <0.005) demonstrated uptake nearly twice that of nonruptured AAAs (SUV=0.73±0.11). Histopathologic characterization of rat and human AAA tissues obtained from surgery revealed increased expression of CCR2 that was co-localized with CD68 macrophages. Ex vivo autoradiography demonstrated specific binding of Cu-DOTA-ECL1i to CCR2 in both rat and human aortic tissues.

Conclusions: CCR2 positron emission tomography is a promising new biomarker for the noninvasive assessment of AAA inflammation that may aid in associated rupture prediction.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.009889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101060PMC
March 2020

Bone material analogues for PET/MRI phantoms.

Med Phys 2020 Jun 13;47(5):2161-2170. Epub 2020 Mar 13.

Department of Radiology and Biomedical Imaging, University of California - San Francisco, San Francisco, CA, 94143, USA.

Purpose: To develop bone material analogues that can be used in construction of phantoms for simultaneous PET/MRI systems.

Methods: Plaster was used as the basis for the bone material analogues tested in this study. It was mixed with varying concentrations of an iodinated CT contrast, a gadolinium-based MR contrast agent, and copper sulfate to modulate the attenuation properties and MRI properties (T1 and T2*). Attenuation was measured with CT and Ge transmission scans, and MRI properties were measured with quantitative ultrashort echo time pulse sequences. A proof-of-concept skull was created by plaster casting.

Results: Undoped plaster has a 511 keV attenuation coefficient (~0.14 cm ) similar to cortical bone (0.10-0.15 cm ), but slightly longer T1 (~500 ms) and T2* (~1.2 ms) MR parameters compared to bone (T1 ~ 300 ms, T2* ~ 0.4 ms). Doping with the iodinated agent resulted in increased attenuation with minimal perturbation to the MR parameters. Doping with a gadolinium chelate greatly reduced T1 and T2*, resulting in extremely short T1 values when the target T2* values were reached, while the attenuation coefficient was unchanged. Doping with copper sulfate was more selective for T2* shortening and achieved comparable T1 and T2* values to bone (after 1 week of drying), while the attenuation coefficient was unchanged.

Conclusions: Plaster doped with copper sulfate is a promising bone material analogue for a PET/MRI phantom, mimicking the MR properties (T1 and T2*) and 511 keV attenuation coefficient of human cortical bone.
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http://dx.doi.org/10.1002/mp.14079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901472PMC
June 2020

Cu-ATSM Positron Emission Tomography/Magnetic Resonance Imaging of Hypoxia in Human Atherosclerosis.

Circ Cardiovasc Imaging 2020 01 8;13(1):e009791. Epub 2020 Jan 8.

Mallinckrodt Institute of Radiology (X.N., R.L., J.Z., T.F.V., N.B., J.X., R.L., R.J.G., P.K.W), Washington University School of Medicine, St Louis, MO.

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http://dx.doi.org/10.1161/CIRCIMAGING.119.009791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328725PMC
January 2020

Fluselenamyl: Evaluation of radiation dosimetry in mice and pharmacokinetics in brains of non-human primate.

Nucl Med Biol 2020 Mar - Apr;82-83:33-40. Epub 2019 Oct 22.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States of America; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States of America; Department of Biomedical Engineering, School of Engineering & Applied Science, Washington University, St. Louis 63105, United States of America. Electronic address:

Introduction: To allow quantitative assessment of therapeutic efficacy for therapeutic interventions (either approved or undergoing FDA approvals) for either inhibiting or reducing development of Aβ pathophysiology in vivo, F-labelled tracers, such as Florbetapir, Florbetaben, and Flutemetamol have been approved. Previously, we have reported on development and preclinical validation of F-Fluselenamyl, comprising traits of translatable Aβ imaging agents. Herein, we report the dosimetry data for F-Fluselenamyl to provide radiation dose deposited within organs and determine effective dose (ED) for human studies, while also evaluating its pharmacokinetics in the nonhuman primate brains.

Methods: To evaluate safety profiles of F-Fluselenamyl for enabling its deployment as a PET imaging agent for monitoring Aβ pathophysiology in vivo, we estimated the human radiation dosimetry extrapolated from rodent biodistribution data obtained by standard method of organ dissection. Animal biodistribution studies were performed in FVB/NCR mice (20 males, 20 females), following tail-vein injection of the tracer. Following euthanasia of mice, organs were harvested, counted, radiation dose to each organ and whole body was determined using the standard MIRD methodology. For evaluation of pharmacokinetics in non-human primates, following intravenous injection of the tracer, dynamic PET scan of rhesus monkey brains were performed, and co-registered with MR for anatomical reference. Parametric images of tracer transport rate constant and distribution volume relative to cerebellum were generated using a simplified reference tissue model and a spatially-constraint linear regression algorithm.

Results: The critical organ in humans has been determined to be the gall bladder with a gender average radiation absorbed dose of 0.079 mGy/MBq with an effective dose of 0.017 mSv/MBq and 0.020 mSv/MBq, in males and females, respectively. Therefore, these data provide preliminary projections on human dosimetry derived from rodent estimates, thereby defining safe imaging conditions for further validations in human subjects. Additionally, the tracer penetrated the non-human primate brain and excreted to background levels at later-time points thus pointing to the potential for high signal/noise ratios during noninvasive imaging. Tissue time activity curves (TACs) also show fast initial uptake with maximum projection of activity at 2-6 min post administration followed by clearance of activity at later time-points from cortex, cerebellum, and white matter of nonhuman primate brain. Parametric images confirmed that the F-Fluselenamyl has relative high transport rate constant at striatum, thalamus, and cortex.

Conclusions: The data obtained from radiation dosimetry studies in mice indicate that F-Fluselenamyl can be safely used for further evaluation in humans. Additionally, F-Fluselenamyl demonstrated ability to traverse the blood brain barrier (BBB) and indicated high initial influx, followed by clearance to background levels in non-human primate brains. Combined information indicates that F-Fluselenamyl would be a potential candidate for detecting amyloid plaques in the living human brain.
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http://dx.doi.org/10.1016/j.nucmedbio.2019.10.004DOI Listing
October 2019

Myocardial glucose and fatty acid metabolism is altered and associated with lower cardiac function in young adults with Barth syndrome.

J Nucl Cardiol 2019 Nov 8. Epub 2019 Nov 8.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Background: Barth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function.

Methods/results: Young adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of O-water and 1-C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 μmol·g·min, P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g·min, P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS.

Conclusions: Myocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS. Clinical Trials #: NCT01625663.
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http://dx.doi.org/10.1007/s12350-019-01933-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205570PMC
November 2019

Folate Receptor α-Targeted Zr-M9346A Immuno-PET for Image-Guided Intervention with Mirvetuximab Soravtansine in Triple-Negative Breast Cancer.

Mol Pharm 2019 09 16;16(9):3996-4006. Epub 2019 Aug 16.

ImmunoGen, Inc. , Waltham , Massachusetts 02451 , United States.

Folate receptor α (FRα) is a well-studied tumor biomarker highly expressed in many epithelial tumors such as breast, ovarian, and lung cancers. Mirvetuximab soravtansine (IMGN853) is the antibody-drug conjugate of FRα-binding humanized monoclonal antibody M9346A and cytotoxic maytansinoid drug DM4. IMGN853 is currently being evaluated in multiple clinical trials, in which the immunohistochemical evaluation of an archival tumor or biopsy specimen is used for patient screening. However, limited tissue collection may lead to inaccurate diagnosis due to tumor heterogeneity. Herein, we developed a zirconium-89 (Zr)-radiolabeled M9346A (Zr-M9346A) as an immuno-positron emission tomography (immuno-PET) radiotracer to evaluate FRα expression in triple-negative breast cancer (TNBC) patients, providing a novel means to guide intervention with therapeutic IMGN853. In this study, we verified the binding specificity and immunoreactivity of Zr-M9346A by in vitro studies in FRα cells (HeLa) and FRα cells (OVCAR-3). In vivo PET/computed tomography (PET/CT) imaging in HeLa xenografts and TNBC patient-derived xenograft (PDX) mouse models with various levels of FRα expression demonstrated its targeting specificity and sensitivity. Following PET imaging, the treatment efficiencies of IMGN853, pemetrexed, IMGN853 + pemetrexed, paclitaxel, and saline were assessed in FRα and FRα TNBC PDX models. The correlation between Zr-M9346A tumor uptake and treatment response using IMGN853 in FRα TNBC PDX model suggested the potential of Zr-M9346A PET as a noninvasive tool to prescreen patients based on the in vivo PET imaging for IMGN853-targeted treatment.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00653DOI Listing
September 2019

Repeatability of Quantitative Brown Adipose Tissue Imaging Metrics on Positron Emission Tomography with F-Fluorodeoxyglucose in Humans.

Cell Metab 2019 07 20;30(1):212-224.e4. Epub 2019 Jun 20.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Brown adipose tissue (BAT) is a promising target for anti-obesity interventions. This prospective test-retest study assessed the repeatability of several important quantitative BAT metrics. After cold activation, 24 subjects underwent positron emission tomography (PET)/computed tomography (CT) and PET/magnetic resonance imaging (MRI), utilizing F-fluorodeoxyglucose. Repeat imaging occurred within 14 days per an identical protocol. BAT volumes were strongly correlated between sessions for PET/CT (intraclass correlation coefficient [ICC], 0.85) and PET/MRI (ICC, 0.82). BAT maximum lean-body-mass-adjusted standardized uptake values (SUL) were also strongly correlated between sessions for both PET/CT (ICC, 0.74) and PET/MRI (ICC, 0.83). Much longitudinal variability in BAT metrics was likely due to biological factors intrinsic to BAT, whole-body metabolic fluctuations, or temporal differences in cold-activation efficacy, rather than imaging factors. Future studies utilizing these imaging metrics to track the response BAT to interventions should incorporate this variation into sample-size considerations and response criteria.
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http://dx.doi.org/10.1016/j.cmet.2019.05.019DOI Listing
July 2019

Acute Rodent Tolerability, Toxicity, and Radiation Dosimetry Estimates of the S1P1-Specific Radioligand [C]CS1P1.

Mol Imaging Biol 2020 04;22(2):285-292

Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Purpose: In preclinical studies with rodent models of inflammatory diseases, [C]CS1P1 has been identified as a promising imaging agent targeting sphingosine-1-phosphate receptor 1 (S1P1) in the central nervous system and other tissues. In preparation for USA Food and Drug Administration (FDA) approval of [C]CS1P1 for human use, an acute biodistribution study in mice and an acute tolerability and toxicity evaluation in rats were conducted.

Procedures: Acute organ biodistribution and excretion data was obtained using male and female Swiss Webster mice intravenously (IV) injected with 4.8-10 MBq of [C]CS1P1. The organ residence times for each harvested organ were calculated using the animal biodistribution data, and were entered in the program OLINDA/EXM for C-11 to obtain human radiation dosimetry estimates. Acute tolerability and toxicity studies were conducted in male and female Sprague Dawley rats. Rats were administered an IV bolus of either the vehicle control or 0.3 mg/kg CS1P1. Blood samples were collected and a gross post-mortem examination was conducted at day 2 or day 15 post-injection.

Results: The extrapolated human radiation dose estimates revealed that the highest organ dose was received by the liver with 24.05 μGy/MBq in males and 32.70 μGy/MBq in females. The effective dose (ED) estimates of [C]CS1P1 were calculated at 3.5 μSv/MBq in males and 5.9 μSv/MBq in females. The acute tolerability and toxicity study identified 0.3 mg/kg as a no observable adverse effect level (NOAEL) dose, which is a ~ 300-fold dose multiple of the human equivalent dose of the mass to be injected for positron emission tomography (PET) imaging studies in humans as a no-observable-effect limit.

Conclusions: The toxicity study in rats suggested that injection dose of radiotracer [C]CS1P1 with mass amount < 10 μg is safe for performing a human PET study. The dosimetry data supported an injection of 0.74 GBq (20 mCi) dose for human studies would be acceptable.
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http://dx.doi.org/10.1007/s11307-019-01380-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893109PMC
April 2020

68Ga-Galmydar: A PET imaging tracer for noninvasive detection of Doxorubicin-induced cardiotoxicity.

PLoS One 2019 23;14(5):e0215579. Epub 2019 May 23.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States of America.

Background: Cancer patients undergoing Doxorubicin (DOX) treatment are susceptible to acute and chronic cardiac anomalies, including aberrant arrhythmias, ventricular dysfunction, and heart failure. To stratify patients at high risk for DOX -related heart failure (CHF), diagnostic techniques have been sought. While echocardiography is used for monitoring LVEF and LV volumes due to its wide-availability and cost-efficiency, it may not identify early stages of the initiation of DOX-induced systolic heart failure. To address these limitations, PET tracers could also provide noninvasive assessment of early and reversible metabolic changes of the myocardium.

Objective: Herein, we report a preliminary investigation of 68Ga-Galmydar potential to monitor Dox-induced cardiomyopathy in vivo, ex vivo, and in cellulo employing both nuclear- and optical imaging.

Methods And Results: To assess 68Ga-Galmydar ability for monitoring DOX-induced cardiomyopathy, microPET imaging was performed 5 d post treatment of rats either with a single dose of DOX (15 mg/kg) or vehicle as a control (saline) and images were co-registered for anatomical reference using CT. Following tail-vein injection of the radiotracer in rats at 60 min, micro-PET/CT static scan (10 min acquisition), 68Ga-Galmydar demonstrated 1.91-fold lower uptake in hearts of DOX-treated (standard uptake value; SUV: 0.92, n = 3) rats compared with their vehicle treated (SUV: 1.76, n = 3) control counterparts. For correlation of PET imaging data, post-imaging quantitative biodistribution studies were also performed, wherein excised organs were counted for γ activity, and normalized to injected dose. The post imaging pharmacokinetic data also demonstrated heart uptake values of 2.0 fold lower for DOX treated rats(%ID/g; DOX: 0.44 ± 0.1, n = 3) compared to their vehicle-treated controls (%ID/g; Control: 0.89 ± 0.03, n = 3, p = 0.04). Employing the fluorescent traits of Galmydar, live cell fluorescence imaging indicated a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2 cells following DOX-treatment, while indicating dose-dependent and time-dependent uptake profiles. Following depolarization of electronegative transmembrane gradients at the mitochondrial membrane, the uptake of the probe was decreased in H9c2 cells, and the uptake profiles were found to be identical, using both fluorescence and radiotracer bioassays. Finally, the decreased uptake of the metalloprobe in H9c2 cells also correlated with caspase-3 expression resulting from DOX-induced cardiotoxicity and cell death.

Conclusions: 68Ga-Galmydar could provide a noninvasive assessment of DOX-related and likely reversible metabolic changes at earliest stages. Further studies with other chemotherapeutics (potentially capable of inducing cardiomyopathy) are underway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215579PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532866PMC
January 2020

Cavitation dose painting for focused ultrasound-induced blood-brain barrier disruption.

Sci Rep 2019 02 26;9(1):2840. Epub 2019 Feb 26.

Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, 63130, USA.

Focused ultrasound combined with microbubble for blood-brain barrier disruption (FUS-BBBD) is a promising technique for noninvasive and localized brain drug delivery. This study demonstrates that passive cavitation imaging (PCI) is capable of predicting the location and concentration of nanoclusters delivered by FUS-BBBD. During FUS-BBBD treatment of mice, the acoustic emissions from FUS-activated microbubbles were passively detected by an ultrasound imaging system and processed offline using a frequency-domain PCI algorithm. After the FUS treatment, radiolabeled gold nanoclusters, Cu-AuNCs, were intravenously injected into the mice and imaged by positron emission tomography/computed tomography (PET/CT). The centers of the stable cavitation dose (SCD) maps obtained by PCI and the corresponding centers of the Cu-AuNCs concentration maps obtained by PET coincided within 0.3 ± 0.4 mm and 1.6 ± 1.1 mm in the transverse and axial directions of the FUS beam, respectively. The SCD maps were found to be linearly correlated with the Cu-AuNCs concentration maps on a pixel-by-pixel level. These findings suggest that SCD maps can spatially "paint" the delivered nanocluster concentration, a technique that we named as cavitation dose painting. This PCI-based cavitation dose painting technique in combination with FUS-BBBD opens new horizons in spatially targeted and modulated brain drug delivery.
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http://dx.doi.org/10.1038/s41598-019-39090-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391404PMC
February 2019

Validation of post-treatment PET-based dosimetry software for hepatic radioembolization of Yttrium-90 microspheres.

Med Phys 2019 May 12;46(5):2394-2402. Epub 2019 Mar 12.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Purpose: Yttrium-90 ( Y) microsphere radioembolization enables selective internal radiotherapy for hepatic malignancies. Currently, there is no standard postdelivery imaging and dosimetry of the microsphere distribution to verify treatment. Recent studies have reported utilizing the small positron yield of Y (32 ppm) with positron emission tomography (PET) to perform treatment verification and dosimetry analysis. In this study, we validated a commercial dosimetry software, MIM SurePlan™ LiverY90 (MIM Software Inc., Cleveland, OH), for clinical use.

Methods: A MATLAB-based algorithm for Y PET-based dosimetry was developed in-house and validated for the purpose of commissioning the commercial software. The algorithm is based on voxel S values and dosimetry formalism reported in MIRD Pamphlet 17. We validated the in-house algorithm to establish it as the ground truth by comparing results from a digital point phantom and a digital uniform cylinder to manual calculations. Once we validated our in-house MATLAB-based algorithm, we used it to perform acceptance testing and commissioning of the commercial dosimetry software, MIM SurePlan, which uses the same dosimetry formalism. A 0.4 cm/5% gamma test was performed on PET-derived dose maps from each algorithm of uniform digital and nonuniform physical phantoms filled with Y chloride solution. Average dose (D ) and minimum dose to 70% (D ) of a given volume of interest (VOI) were compared for the digital phantom, the physical phantom, and five patient cases (27 tumor VOIs), representing different clinical scenarios.

Results: The gamma-pass rates were 97.26% and 97.66% for the digital and physical phantoms, respectively. The differences between D and D were 0.076% and 0.10% for the digital phantom, respectively, and <5.2% for various VOIs in the physical phantom. In the clinical cases, 96.3% of the VOIs had a difference <5% for D , and 88.9% of the VOIs had a difference <5% for D .

Conclusions: Dose calculation results from MIM SurePlan were found to be in good agreement with our in-house algorithm. This indicates that MIM SurePlan performs as it should and, hence, can be deemed accepted and commissioned for clinical use for post-implant PET-based dosimetry of Y radioembolization.
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http://dx.doi.org/10.1002/mp.13444DOI Listing
May 2019

Measurement Repeatability of F-FDG PET/CT Versus F-FDG PET/MRI in Solid Tumors of the Pelvis.

J Nucl Med 2019 08 7;60(8):1080-1086. Epub 2019 Feb 7.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.

Knowledge of the within-subject variability of F-FDG PET/MRI measurements is necessary for proper interpretation of quantitative PET or MRI metrics in the context of therapeutic efficacy assessments with integrated PET/MRI scanners. The goal of this study was to determine the test-retest repeatability of these metrics on PET/MRI, with comparison to similar metrics acquired by PET/CT. This prospective study enrolled subjects with pathology-proven pelvic malignancies. Baseline imaging consisted of PET/CT immediately followed by PET/MRI, using a single 370-MBq F-FDG dose. Repeat imaging was performed within 7 d using an identical imaging protocol, with no oncologic therapy between sessions. PET imaging on both scanners consisted of a list-mode acquisition at a single pelvic station. The MRI consisted of 2-point Dixon imaging for attenuation correction, standard sequences for anatomic correlation, and diffusion-weighted imaging. PET data were statically reconstructed using various frame durations and minimizing uptake time differences between sessions. SUV metrics were extracted for both PET/CT and PET/MRI in each imaging session. Apparent diffusion coefficient (ADC) metrics were extracted for both PET/MRI sessions. The study cohort consisted of 14 subjects (13 female, 1 male) with various pelvic cancers (11 cervical, 2 rectal, 1 endometrial). For SUV, the within-subject coefficient of variation (wCV) appeared higher for PET/CT (8.5%-12.8%) than PET/MRI (6.6%-8.7%) across all PET reconstructions, though with no significant repeatability differences (all values ≥ 0.08) between modalities. For lean body mass-adjusted SUV, the wCVs appeared similar for PET/CT (9.9%-11.5%) and PET/MRI (9.2%-11.3%) across all PET reconstructions, again with no significant repeatability differences (all values ≥ 0.14) between modalities. For PET/MRI, the wCV for ADC of 3.5% appeared lower than the wCVs for SUV (6.6%-8.7%) and SUL (9.2%-11.3%), though without significant repeatability differences (all values ≥ 0.23). For solid tumors of the pelvis, the repeatability of the evaluated SUV and ADC metrics on F-FDG PET/MRI is both acceptably high and similar to previously published values for F-FDG PET/CT and MRI, supporting the use of F-FDG PET/MRI for quantitative oncologic treatment response assessments.
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http://dx.doi.org/10.2967/jnumed.118.218735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681694PMC
August 2019

Reply to 'Is Cherenkov luminescence bright enough for photodynamic therapy?'

Nat Nanotechnol 2018 05;13(5):354-355

Department of Radiology, Washington University School of Medicine, St Louis, MO, USA.

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http://dx.doi.org/10.1038/s41565-018-0143-xDOI Listing
May 2018

Multi institutional quantitative phantom study of yttrium-90 PET in PET/MRI: the MR-QUEST study.

EJNMMI Phys 2018 Apr 4;5(1). Epub 2018 Apr 4.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, Campus Box 8225, St. Louis, MO, 63110, USA.

Background: Yttrium-90 (Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to treat hepatic malignancies. Though this therapy involves careful pre-treatment planning and imaging, little is known about the precise location of the microspheres once they are administered. Recently, there has been growing interest post-radioembolization imaging using positron-emission tomography (PET) for quantitative dosimetry and identifying lesions that may benefit from additional salvage therapy. In this study, we aim to measure the inter-center variability of Y PET measurements as measured on PET/MRI in preparation for a multi-institutional prospective phase I/II clinical trial. Eight institutions participated in this study and followed a standardized phantom filling and imaging protocol. The NEMA NU2-2012 body phantom was filled with 3 GBq of Y chloride solution. The phantom was imaged for 30 min in listmode on a Siemens Biograph mMR non-TOF PET/MRI scanner at five time points across 10 days (0.3-3.0 GBq). Raw PET data were sent to a central site for image reconstruction and data analysis. Images were reconstructed with optimal parameters determined from a previous study. Volumes of interest (VOIs) matching the known sphere diameters were drawn on the vendor-provided attenuation map and propagated to the PET images. Recovery coefficients (RCs) and coefficient of variation of the RCs (COV) were calculated from these VOIs for each sphere size and activity level.

Results: Mean RCs ranged from 14.5 to 75.4%, with the lowest mean RC coming from the smallest sphere (10 mm) on the last day of imaging (0.16 MBq/ml) and the highest mean RC coming from the largest sphere (37 mm) on the first day of imaging (2.16 MBq/ml). The smaller spheres tended to exhibit higher COVs. In contrast, the larger spheres tended to exhibit lower COVs. COVs from the 37 mm sphere were < 25.3% in all scans. For scans with ≥ 0.60 MBq/ml, COVs were ≤ 25% in spheres ≥ 22 mm. However, for all other spheres sizes and activity levels, COVs were usually > 25%.

Conclusions: Post-radioembolization dosimetry of lesions or other VOIs ≥ 22 mm in diameter can be consistently obtained (< 25% variability) at a multi-institutional level using PET/MRI for any clinically significant activity for Y radioembolization.
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http://dx.doi.org/10.1186/s40658-018-0206-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882483PMC
April 2018

Cardiac Positron Emission Tomography-Magnetic Resonance Imaging: Current Status and Future Directions.

J Thorac Imaging 2018 May;33(3):139-146

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO.

Simultaneous acquisition positron emission tomography-magnetic resonance imaging (PET-MRI) has the ability to combine anatomic information derived from cardiac MRI with quantitative capabilities of cardiac PET and MRI and the promise of molecular imaging by specific PET tracers. This combination of cardiac PET and MRI delivers a robust and comprehensive clinical examination. It has the potential to assess various cardiovascular conditions, including assessment of myocardial ischemia, infarction, and function, as well as specific characterization of inflammatory and infiltrative heart diseases such as cardiac sarcoid and amyloid. It also offers fascinating possibilities in imaging other cardiovascular-related disease states, such as tumor imaging and vascular imaging. In this review, we begin with a general overview of the potentials of PET-MRI in cardiovascular imaging, followed by a discussion of the technical challenges unique to cardiovascular PET-MRI. We then discuss PET-MRI in various cardiovascular disease imaging applications. Potential limitations of PET-MRI and future directions are also considered.
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http://dx.doi.org/10.1097/RTI.0000000000000327DOI Listing
May 2018

Ga[Ga]-Galmydar: Biodistribution and radiation dosimetry studies in rodents.

Nucl Med Biol 2018 04 1;59:29-35. Epub 2017 Dec 1.

ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, United States; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States; Department of Biomedical Engineering, School of Engineering & Applied Science, Washington University, St. Louis 63105, United States. Electronic address:

Introduction: Ga[Ga]-Galmydar is an avid transport substrate of ABCB1 (P-Glycoprotein; 170kDa plasma membrane protein), breast cancer resistance protein (BCRP; ABCG2; 72kDa), penetrates human epidermal carcinoma (KB3-1), breast cancer (MCF7), embryonic kidney (HEK 293) tumor cells and rat cardiomyoblasts, and localizes within the mitochondria of tumor and myocardium cells. Ga[Ga]-Galmydar excretes from blood pool quickly, and shows stable retention within rat myocardium in vivo for extended periods, therefore, the agent shows potential to enable myocardial perfusion imaging. The PET tracer also demonstrates ability to probe viability of the blood brain barrier (BBB) in WT mice compared with their mdr1a/1b (dKO) and mdr1a/1b/ABCG2 (t-KO) counterparts. Herein, we report dosimetry data for Ga[Ga]-Galmydar in mice, and extrapolate that information to determine effective dose (ED) for human studies.

Methods: To further assess safety profiles of Ga[Ga]-Galmydar for enabling its deployment as a PET imaging probe for biomedical imaging in vivo, we estimated human radiation dosimetry extrapolated from mice biodistribution data. To accomplish this objective, Ga[Ga]-Galmydar was injected intravenously into tails, mice were euthanized, organs harvested (5min, 15min, 30min, 60min, 120min), counted, radiation doses to each organ, and whole body were also determined.

Results: The effective dose (ED) have been found to be 0.021mGy/MBq in males and 0.023mGy/MBq in females. The highest radiation dose was estimated to the kidneys with a value of 0.17mGy/MBq for males and 0.19mGy/MBq for females with contribution from activity in the urine prior to excretion. The critical organ in humans has been determined to be the gall bladder. These data provide preliminary projections on human dosimetry derived from rodent estimates thus providing platform for further validation of dosimetry analysis in human subjects.

Conclusions: Combined data obtained from radiation dosimetry studies in mice indicate that Ga[Ga]-Galmydar would be safe for further evaluation of dosimetry toxicity and myocardial perfusion PET imaging in humans.
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http://dx.doi.org/10.1016/j.nucmedbio.2017.11.008DOI Listing
April 2018

Evaluation of [Zr]trastuzumab-PET/CT in differentiating HER2-positive from HER2-negative breast cancer.

Breast Cancer Res Treat 2018 Jun 13;169(3):523-530. Epub 2018 Feb 13.

Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.

Purpose: To evaluate whether tumor uptake of [Zr]trastuzumab can distinguish HER2-positive from HER2-negative breast cancer.

Methods: Women with HER2-positive (n = 34) and HER2-negative (n = 16) breast cancer underwent PET/CT 5 ± 2 days following [Zr]trastuzumab administration. HER2 status was determined based on immunohistochemistry and/or fluorescence in situ hybridization of primary or metastatic/recurrent tumor. Tumor [Zr]trastuzumab uptake was assessed qualitatively and semiquantitatively as maximum standardized uptake value (SUV), and correlated with HER2 status. Additionally, intrapatient heterogeneity of [Zr]trastuzumab uptake was evaluated.

Results: On a per-patient basis, [Zr]trastuzumab-PET/CT was positive in 30/34 (88.2%) HER2-positive and negative in 15/16 (93.7%) HER2-negative patients. Considering all lesions, the SUV was not significantly different in patients with HER2-positive versus HER2-negative disease (p = 0.06). The same was true of when only hepatic lesions were evaluated (p = 0.42). However, after excluding hepatic lesions, tumor SUV was significantly higher in HER2-positive compared to HER2-negative patients (p = 0.003). A cutoff SUV of 3.2, determined by ROC analysis, demonstrated positive-predictive value of 83.3% (95% CI 65.3%, 94.4%), sensitivity of 75.8% (57.7%, 88.9%), negative-predictive value of 50% (24.7%, 75.3%), and specificity of 61.5% (95% 31.6%, 86.1%) for differentiating HER2-positive from HER2-negative lesions. There was intrapatient heterogeneity of [Zr]trastuzumab uptake in 20% of patients with multiple lesions.

Conclusions: [Zr]trastuzumab has the potential to characterize the HER2 status of the complete tumor burden in patients with breast cancer, thus obviating repeat or multiple tissue sampling to assess intrapatient heterogeneity of HER2 status.
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http://dx.doi.org/10.1007/s10549-018-4696-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955803PMC
June 2018

Medical imaging data in the digital innovation age.

Med Phys 2018 Apr 1;45(4):e40-e52. Epub 2018 Mar 1.

Department of Imaging Physics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

As we reflect on decades of exponential advancements in electronic innovation, we can see the field of medical imaging eclipsed by a new digital landscape - one that is inexpensive, fast, and powerful. This new paradigm presents new opportunities to innovate in both research and clinical settings. In this article, we review the current role of data: the common perceptions around its valuation and the infrastructure currently in place for data-driven innovation. Looking forward, we consider what has already been achieved using modern data capacities, the opportunities we have for further expansion in this area, and the obstacles we will need to transcend.
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http://dx.doi.org/10.1002/mp.12794DOI Listing
April 2018

Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent.

Oncotarget 2017 Nov 1;8(61):104303-104314. Epub 2017 Nov 1.

Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.

High levels of expression of glycoprotein non-metastatic B (gpNMB) in triple negative breast cancer (TNBC) and its association with metastasis and recurrence make it an attractive target for therapy with the antibody drug conjugate, glembatumumab vedotin (CDX-011). This report describes the development of a companion PET-based diagnostic imaging agent using Zr-labeled glembatumumab ([Zr]DFO-CR011) to potentially aid in the selection of patients most likely to respond to targeted treatment with CDX-011. [Zr]DFO-CR011 was characterized for its pharmacologic properties in TNBC cell lines. Preclinical studies determined that [Zr]DFO-CR011 binds specifically to gpNMB with high affinity (Kd = 25 ± 5 nM), immunoreactivity of 2.2-fold less than the native CR011, and its cellular uptake correlates with gpNMB expression (r = 0.95). In PET studies at the optimal imaging timepoint of 7 days p.i., the [Zr]DFO-CR011 tumor uptake in gpNMB-expressing MDA-MB-468 xenografts had a mean SUV of 2.9, while significantly lower in gpNMB-negative MDA-MB-231 tumors with a mean SUV of 1.9. [Zr]DFO-CR011 was also evaluated in patient-derived xenograft models of TNBC, where tumor uptake had a positive correlation with total gpNMB protein expression via ELISA (r = 0.79), despite the heterogeneity of gpNMB expression within the same group of PDX mice. Lastly, the radiation dosimetry calculated from biodistribution studies in MDA-MB-468 xenografts determined the effective dose for human use would be 0.54 mSv/MBq. Overall, these studies demonstrate that [Zr]DFO-CR011 is a potential companion diagnostic imaging agent for CDX-011 which targets gpNMB, an emerging biomarker for TNBC.
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http://dx.doi.org/10.18632/oncotarget.22228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732808PMC
November 2017

First-in-Man Evaluation of I-PGN650: A PET Tracer for Detecting Phosphatidylserine as a Biomarker of the Solid Tumor Microenvironment.

Mol Imaging 2017 Jan-Dec;16:1536012117733349

2 Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.

Purpose: PGN650 is a F(ab') antibody fragment that targets phosphatidylserine (PS), a marker normally absent that becomes exposed on tumor cells and tumor vasculature in response to oxidative stress and increases in response to therapy. PGN650 was labeled with I to create a positron emission tomography (PET) agent as an in vivo biomarker for tumor microenvironment and response to therapy. In this phase 0 study, we evaluated the pharmacokinetics, safety, radiation dosimetry, and tumor targeting of this tracer in a cohort of patients with cancer.

Methods: Eleven patients with known solid tumors received approximately 140 MBq (3.8 mCi) I-PGN650 intravenously and underwent positron emission tomography-computed tomography (PET/CT) approximately 1 hour, 3 hours, and either 24 hours or 48 hours later to establish tracer kinetics for the purpose of calculating radiation dosimetry (from integration of the organ time-activity curves and OLINDA/EXM using the adult male and female models).

Results: Known tumor foci demonstrated mildly increased uptake, with the highest activity at the latest imaging time. There were no unexpected adverse events. The liver was the organ receiving the highest radiation dose (0.77 mGy/MBq); the effective dose was 0.41 mSv/MBq.

Conclusion: Although I-PGN650 is safe for human PET imaging, the tumor targeting with this agent in patients was less than previously observed in animal studies.
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http://dx.doi.org/10.1177/1536012117733349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648081PMC
July 2018

Cardiac Applications of PET/MR Imaging.

Magn Reson Imaging Clin N Am 2017 May 27;25(2):325-333. Epub 2017 Feb 27.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, MO 63108, USA. Electronic address:

Simultaneous acquisition PET/MR imaging combines the anatomic capabilities of cardiac MR imaging with quantitative capabilities of both PET and MR imaging. Cardiac PET/MR imaging has the potential not only to assess cardiac tumors but also to provide thorough assessment of myocardial ischemia, infarction, and function and specific characterization of cardiomyopathies, such as cardiac sarcoid. In this article, the authors start with a discussion of the technical challenges specific to cardiovascular PET/MR imaging followed by a discussion of the use of PET/MR imaging in various cardiovascular conditions.
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http://dx.doi.org/10.1016/j.mric.2016.12.007DOI Listing
May 2017