Publications by authors named "Mirwais Wardak"

19 Publications

  • Page 1 of 1

Method for selective ablation of undifferentiated human pluripotent stem cell populations for cell-based therapies.

JCI Insight 2021 Apr 8;6(7). Epub 2021 Apr 8.

Stanford Cardiovascular Institute.

Human pluripotent stem cells (PSCs), which are composed of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide an opportunity to advance cardiac cell therapy-based clinical trials. However, an important hurdle that must be overcome is the risk of teratoma formation after cell transplantation due to the proliferative capacity of residual undifferentiated PSCs in differentiation batches. To tackle this problem, we propose the use of a minimal noncardiotoxic doxorubicin dose as a purifying agent to selectively target rapidly proliferating stem cells for cell death, which will provide a purer population of terminally differentiated cardiomyocytes before cell transplantation. In this study, we determined an appropriate in vitro doxorubicin dose that (a) eliminates residual undifferentiated stem cells before cell injection to prevent teratoma formation after cell transplantation and (b) does not cause cardiotoxicity in ESC-derived cardiomyocytes (CMs) as demonstrated through contractility analysis, electrophysiology, topoisomerase activity assay, and quantification of reactive oxygen species generation. This study establishes a potentially novel method for tumorigenic-free cell therapy studies aimed at clinical applications of cardiac cell transplantation.
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http://dx.doi.org/10.1172/jci.insight.142000DOI Listing
April 2021

Sanjiv Sam Gambhir, MD, PhD (1962-2020).

J Nucl Cardiol 2021 Feb 1;28(1):30-33. Epub 2020 Nov 1.

Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.

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http://dx.doi.org/10.1007/s12350-020-02404-wDOI Listing
February 2021

Initial evaluation of (4S)-4-(3-[F]fluoropropyl)-L-glutamate (FSPG) PET/CT imaging in patients with head and neck cancer, colorectal cancer, or non-Hodgkin lymphoma.

EJNMMI Res 2020 Aug 28;10(1):100. Epub 2020 Aug 28.

Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.

Purpose: (4S)-4-(3-[F]Fluoropropyl)-L-glutamic acid ([F]FSPG) measures system x transporter activity and shows promise for oncologic imaging. We present data on tumor uptake of this radiopharmaceutical in human subjects with head and neck cancer (HNC), colorectal cancer (CRC), and non-Hodgkin lymphoma (NHL).

Methods: A total of 15 subjects with HNC (n = 5), CRC (n = 5), or NHL (n = 5) were recruited (mean age 66.2 years, range 44-87 years). 301.4 ± 28.1 MBq (8.1 ± 0.8 mCi) of [F]FSPG was given intravenously to each subject, and 3 PET/CT scans were obtained 0-2 h post-injection. All subjects also had a positive [F]FDG PET/CT scan within 1 month prior to the [F]FSPG PET scan. Semi-quantitative and visual comparisons of the [F]FSPG and [F]FDG scans were performed.

Results: [F]FSPG showed strong uptake in all but one HNC subject. The lack of surrounding brain uptake facilitated tumor delineation in the HNC patients. [F]FSPG also showed tumor uptake in all CRC subjects, but variable uptake in the NHL subjects. While the absolute [F]FDG SUV values were comparable or higher than [F]FSPG, the tumor-to-background SUV ratios were greater with [F]FSPG than [F]FDG.

Conclusions: [F]FSPG PET/CT showed promising results across 15 subjects with 3 different cancer types. Concordant visualization was mostly observed between [F]FSPG and [F]FDG PET/CT images, with some inter- and intra-individual uptake variability potentially reflecting differences in tumor biology. The tumor-to-background ratios were greater with [F]FSPG than [F]FDG in the cancer types evaluated. Future studies based on larger numbers of subjects and those with a wider array of primary and recurrent or metastatic tumors are planned to further evaluate the utility of this novel tracer.
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http://dx.doi.org/10.1186/s13550-020-00678-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455665PMC
August 2020

Clinical Evaluation of (4S)-4-(3-[F]Fluoropropyl)-L-glutamate (F-FSPG) for PET/CT Imaging in Patients with Newly Diagnosed and Recurrent Prostate Cancer.

Clin Cancer Res 2020 Oct 21;26(20):5380-5387. Epub 2020 Jul 21.

Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, California.

Purpose: (4S)-4-(3-[F]Fluoropropyl)--glutamic acid (F-FSPG) is a radiopharmaceutical for PET imaging of system x activity, which can be upregulated in prostate cancer. We present data on the first evaluation of patients with newly diagnosed or recurrent prostate cancer with this radiopharmaceutical.

Experimental Design: Ten patients with primary and 10 patients with recurrent prostate cancer were enrolled in this prospective multicenter study. After injection of 300 MBq of F-FSPG, three whole-body PET/CT scans were obtained. Visual analysis was compared with step-section histopathology when available as well as other imaging studies and clinical outcomes. Metabolic parameters were measured semiquantitatively. Expression levels of xCT and CD44 were evaluated by IHC for patients with available tissue samples.

Results: F-FSPG PET showed high tumor-to-background ratios with a relatively high tumor detection rate on a per-patient (89%) and per-lobe (87%) basis. The sensitivity was slightly higher with imaging at 105 minutes in comparison with 60 minutes. The maximum standardized uptake values (SUV) for cancer was significantly higher than both normal ( < 0.005) and benign pathology ( = 0.011), while there was no significant difference between normal and benign pathology ( = 0.120). In the setting of recurrence, agreement with standard imaging was demonstrated in 7 of 9 patients (78%) and 13 of 18 lesions (72%), and revealed true local recurrence in a discordant case. F-FSPG accumulation showed moderate correlation with CD44 expression.

Conclusions: F-FSPG is a promising tumor imaging agent for PET that seems to have favorable biodistribution and high cancer detection rate in patients with prostate cancer. Further studies are warranted to determine the diagnostic value for both initial staging and recurrence, and how it compares with other investigational radiotracers and conventional imaging modalities.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0644DOI Listing
October 2020

Synthesis and Characterization of 9-(4-[F]Fluoro-3-(hydroxymethyl)butyl)-2-(phenylthio)-6-oxopurine as a Novel PET Agent for Mutant Herpes Simplex Virus Type 1 Thymidine Kinase Reporter Gene Imaging.

Mol Imaging Biol 2020 10;22(5):1151-1160

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 318 Campus Drive, Room E150A, Stanford, CA, 94305, USA.

Purpose: [F]FHBG has been used as a positron emission tomography (PET) imaging tracer for the monitoring of herpes simplex virus type 1 thymidine kinase (HSV1-tk), a reporter gene for cell and gene therapy in humans. However, this tracer shows inadequate blood-brain barrier (BBB) penetration and, therefore, would be limited for accurate quantification of reporter gene expression in the brain. Here, we report the synthesis and evaluation of 9-(4-[F]fluoro-3-(hydroxymethyl)butyl)-2(phenylthio)-6-oxopurine ([F]FHBT) as a new PET tracer for imaging reporter gene expression of HSV1-tk and its mutant HSV1-sr39tk, with the aim of improved BBB penetration.

Procedures: [F]FHBT was prepared by using a tosylate precursor and [F]KF. The cellular uptake of [F]FHBT was performed in HSV1-sr39tk-positive (+) or HSV1-sr39tk-negative (-) MDA-MB-231 breast cancer cells. The specificity of [F]FHBT to assess HSV1-sr39tk expression was evaluated by in vitro blocking studies using 1 mM of ganciclovir (GCV). Penetration of [F]FHBT and [F]FHBG across the BBB was assessed by dynamic PET imaging studies in normal mice.

Results: The tosylate precursor reacted with [F]KF using Kryptofix2.2.2 followed by deprotection to give [F]FHBT in 10 % radiochemical yield (decay-corrected). The uptake of [F]FHBT in HSV1-sr39tk (+) cells was significantly higher than that of HSV1-sr39tk (-) cells. In the presence of GCV (1 mM), the uptake of [F]FHBT was significantly decreased, indicating that [F]FHBT serves as a selective substrate of HSV1-sr39TK. PET images and time-activity curves of [F]FHBT in the brain regions showed similar initial brain uptakes (~ 12.75 min) as [F]FHBG (P > 0.855). Slower washout of [F]FHBT was observed at the later time points (17.75 - 57.75 min, P > 0.207).

Conclusions: Although [F]FHBT showed no statistically significant improvement of BBB permeability compared with [F]FHBG, we have demonstrated that the 2-(phenylthio)-6-oxopurine backbone can serve as a novel scaffold for developing HSV1-tk/HSV1-sr39tk reporter gene imaging agents for additional research in the future.
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http://dx.doi.org/10.1007/s11307-020-01517-5DOI Listing
October 2020

Molecular Imaging of Infective Endocarditis With 6''-[F]Fluoromaltotriose Positron Emission Tomography-Computed Tomography.

Circulation 2020 May 26;141(21):1729-1731. Epub 2020 May 26.

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Bio-X Program (M.W., G.G., E.C., M.N., T.H., M.T.G., J.C.W., S.S.G.), Stanford University School of Medicine, CA.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043924DOI Listing
May 2020

Molecular Imaging of Inflammation in Ischemic Heart Disease.

Curr Cardiovasc Imaging Rep 2018 Jun 26;11(6). Epub 2018 Apr 26.

Department of Medicine, Division of Cardiovascular Medicine, Stanford University, 300 Pasteur Drive, Stanford University, CA 94305.

Purpose Of Review: . Despite the advent of medical and surgical therapy to prevent and treat atherosclerosis and its adverse clinical effects, ischemic heart disease remains a leading cause of morbidity and mortality. . This review focuses on new molecular imaging techniques to visualize immune cells to study their contribution to ischemic heart disease.

Recent Findings: A common technique applied to imaging inflammation in ischemic heart disease is targeting the up-regulation and trafficking of immune cells, which may contribute to the adverse consequences associated with atherosclerosis. In the past five years, advances in cell labeling for imaging with PET and MRI, have confirmed that inflammatory cells can be visualized in vivo and in greater abundance in unstable cardiovascular disease and in areas of ischemic damage. The major criticisms of these studies to date include their small sample size, lack of histological correlation, limited association with long-term outcomes, and bias toward macrophage imaging.

Summary: While much progress has been made in imaging inflammation in ischemic heart disease over the past five years, additional studies in larger cohorts with histological validation and outcome correlation are needed.
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http://dx.doi.org/10.1007/s12410-018-9452-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559744PMC
June 2018

Simultaneous phase-contrast MRI and PET for noninvasive quantification of cerebral blood flow and reactivity in healthy subjects and patients with cerebrovascular disease.

J Magn Reson Imaging 2020 01 1;51(1):183-194. Epub 2019 May 1.

Department of Radiology, Stanford University, Stanford, California, USA.

Background: H O-positron emission tomography (PET) is considered the reference standard for absolute cerebral blood flow (CBF). However, this technique requires an arterial input function measured through continuous sampling of arterial blood, which is invasive and has limitations with tracer delay and dispersion.

Purpose: To demonstrate a new noninvasive method to quantify absolute CBF with a PET/MRI hybrid scanner. This blood-free approach, called PC-PET, takes the spatial CBF distribution from a static H O-PET scan, and scales it to the whole-brain average CBF value measured by simultaneous phase-contrast MRI.

Study Type: Observational.

Subjects: Twelve healthy controls (HC) and 13 patients with Moyamoya disease (MM) as a model of chronic ischemic disease.

Field Strength/sequences: 3T/2D cardiac-gated phase-contrast MRI and H O-PET.

Assessment: PC-PET CBF values from whole brain (WB), gray matter (GM), and white matter (WM) in HCs were compared with literature values since 2000. CBF and cerebrovascular reactivity (CVR), which is defined as the percent CBF change between baseline and post-acetazolamide (vasodilator) scans, were measured by PC-PET in MM patients and HCs within cortical regions corresponding to major vascular territories. Statistical Tests: Linear, mixed effects models were created to compare CBF and CVR, respectively, between patients and controls, and between different degrees of stenosis.

Results: The mean CBF values in WB, GM, and WM in HC were 42 ± 7 ml/100 g/min, 50 ± 7 ml/100 g/min, and 23 ± 3 ml/100 g/min, respectively, which agree well with literature values. Compared with normal regions (57 ± 23%), patients showed significantly decreased CVR in areas with mild/moderate stenosis (47 ± 17%, P = 0.011) and in severe/occluded areas (40 ± 16%, P = 0.016). Data Conclusion: PC-PET identifies differences in cerebrovascular reactivity between healthy controls and cerebrovascular patients. PC-PET is suitable for CBF measurement when arterial blood sampling is not accessible, and warrants comparison to fully quantitative H O-PET in future studies.

Level Of Evidence: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019. J. Magn. Reson. Imaging 2020;51:183-194.
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http://dx.doi.org/10.1002/jmri.26773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212833PMC
January 2020

Ga-labeled exendin-4 to image cardiac repair after myocardial infarction: From lizard venom to laboratory and beyond.

Authors:
Mirwais Wardak

J Nucl Cardiol 2020 12 25;27(6):2398-2401. Epub 2019 Feb 25.

Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University School of Medicine, 318 Campus Drive, Stanford, CA, 94305, USA.

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http://dx.doi.org/10.1007/s12350-019-01641-yDOI Listing
December 2020

Identifying Hypoperfusion in Moyamoya Disease With Arterial Spin Labeling and an [O]-Water Positron Emission Tomography/Magnetic Resonance Imaging Normative Database.

Stroke 2019 02;50(2):373-380

From the Department of Radiology (A.P.F., J.G., Y.I., J.R., M.W., J.H.P., B.S., D.H., H.G., T.H., P.S., F.T.C., G.Z.), Stanford University, CA.

Background and Purpose- Noninvasive imaging of brain perfusion has the potential to elucidate pathophysiological mechanisms underlying Moyamoya disease and enable clinical imaging of cerebral blood flow (CBF) to select revascularization therapies for patients. We used hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) technology to characterize the distribution of hypoperfusion in Moyamoya disease and its relationship to vessel stenosis severity, through comparisons with a normative perfusion database of healthy controls. Methods- To image CBF, we acquired [O]-water PET as a reference and simultaneously acquired arterial spin labeling (ASL) MRI scans in 20 Moyamoya patients and 15 age-matched, healthy controls on a PET/MRI scanner. The ASL MRI scans included a standard single-delay ASL scan with postlabel delay of 2.0 s and a multidelay scan with 5 postlabel delays (0.7-3.0s) to estimate and account for arterial transit time in CBF quantification. The percent volume of hypoperfusion in patients (determined as the fifth percentile of CBF values in the healthy control database) was the outcome measure in a logistic regression model that included stenosis grade and location. Results- Logistic regression showed that anterior ( P<0.0001) and middle cerebral artery territory regions ( P=0.003) in Moyamoya patients were susceptible to hypoperfusion, whereas posterior regions were not. Cortical regions supplied by arteries with stenosis on MR angiography showed more hypoperfusion than normal arteries ( P=0.001), but the extent of hypoperfusion was not different between mild-moderate versus severe stenosis. Multidelay ASL did not perform differently from [O]-water PET in detecting perfusion abnormalities, but standard ASL overestimated the extent of hypoperfusion in patients ( P=0.003). Conclusions- This simultaneous PET/MRI study supports the use of multidelay ASL MRI in clinical evaluation of Moyamoya disease in settings where nuclear medicine imaging is not available and application of a normative perfusion database to automatically identify abnormal CBF in patients.
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http://dx.doi.org/10.1161/STROKEAHA.118.023426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161423PMC
February 2019

Reply: 6″-F-Fluoromaltotriose PET Evaluation in -Induced Myositis: Is There Uptake Saturation in Control?

J Nucl Med 2018 07 13;59(7):1166-1167. Epub 2018 Apr 13.

Stanford University School of Medicine 318 Campus Dr., Room E150 Stanford, CA 94305 E-mail:

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http://dx.doi.org/10.2967/jnumed.118.208736DOI Listing
July 2018

The Gift of Light: Using Multiplexed Optical Imaging to Probe Cardiac Metabolism in Health and Disease.

Circ Cardiovasc Imaging 2018 03;11(3):e007597

From the Department of Radiology (M.W.), Molecular Imaging Program at Stanford (MIPS) (M.W.), Division of Cardiovascular Medicine, Department of Medicine (P.K.N.), and Stanford Cardiovascular Institute (M.W., P.K.N.), Stanford University School of Medicine, CA; and Cardiology Section, Veterans Affairs Palo Alto Health Care Administration, CA (P.K.N.).

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http://dx.doi.org/10.1161/CIRCIMAGING.118.007597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005795PMC
March 2018

Specific Imaging of Bacterial Infection Using 6″-F-Fluoromaltotriose: A Second-Generation PET Tracer Targeting the Maltodextrin Transporter in Bacteria.

J Nucl Med 2017 10 10;58(10):1679-1684. Epub 2017 May 10.

Department of Radiology, Stanford University School of Medicine, Stanford, California

6″-F-fluoromaltotriose is a PET tracer that can potentially be used to image and localize most bacterial infections, much like F-FDG has been used to image and localize most cancers. However, unlike F-FDG, 6″-F-fluoromaltotriose is not taken up by inflammatory lesions and appears to be specific to bacterial infections by targeting the maltodextrin transporter that is expressed in gram-positive and gram-negative strains of bacteria. 6″-F-fluoromaltotriose was synthesized with high radiochemical purity and evaluated in several clinically relevant bacterial strains in cultures and in living mice. 6″-F-fluoromaltotriose was taken up in both gram-positive and gram-negative bacterial strains. 6″-F-fluoromaltotriose was also able to detect in a clinically relevant mouse model of wound infection. The utility of 6″-F-fluoromaltotriose to help monitor antibiotic therapies was also evaluated in rats. 6″-F-fluoromaltotriose is a promising new tracer that has significant diagnostic utility, with the potential to change the clinical management of patients with infectious diseases of bacterial origin.
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http://dx.doi.org/10.2967/jnumed.117.191452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632736PMC
October 2017

Automated movement correction for dynamic PET/CT images: evaluation with phantom and patient data.

PLoS One 2014 11;9(8):e103745. Epub 2014 Aug 11.

Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America; Biomathematics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.

Head movement during a dynamic brain PET/CT imaging results in mismatch between CT and dynamic PET images. It can cause artifacts in CT-based attenuation corrected PET images, thus affecting both the qualitative and quantitative aspects of the dynamic PET images and the derived parametric images. In this study, we developed an automated retrospective image-based movement correction (MC) procedure. The MC method first registered the CT image to each dynamic PET frames, then re-reconstructed the PET frames with CT-based attenuation correction, and finally re-aligned all the PET frames to the same position. We evaluated the MC method's performance on the Hoffman phantom and dynamic FDDNP and FDG PET/CT images of patients with neurodegenerative disease or with poor compliance. Dynamic FDDNP PET/CT images (65 min) were obtained from 12 patients and dynamic FDG PET/CT images (60 min) were obtained from 6 patients. Logan analysis with cerebellum as the reference region was used to generate regional distribution volume ratio (DVR) for FDDNP scan before and after MC. For FDG studies, the image derived input function was used to generate parametric image of FDG uptake constant (Ki) before and after MC. Phantom study showed high accuracy of registration between PET and CT and improved PET images after MC. In patient study, head movement was observed in all subjects, especially in late PET frames with an average displacement of 6.92 mm. The z-direction translation (average maximum = 5.32 mm) and x-axis rotation (average maximum = 5.19 degrees) occurred most frequently. Image artifacts were significantly diminished after MC. There were significant differences (P<0.05) in the FDDNP DVR and FDG Ki values in the parietal and temporal regions after MC. In conclusion, MC applied to dynamic brain FDDNP and FDG PET/CT scans could improve the qualitative and quantitative aspects of images of both tracers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103745PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128781PMC
April 2015

¹⁸F-FLT    and ¹⁸F-FDOPA PET kinetics in recurrent brain tumors.

Eur J Nucl Med Mol Imaging 2014 Jun 7;41(6):1199-209. Epub 2014 Mar 7.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA, 90095-6948, USA.

Purpose: In this study, kinetic parameters of the cellular proliferation tracer (18)F-3'-deoxy-3'-fluoro-L-thymidine (FLT) and the amino acid probe 3,4-dihydroxy-6-(18)F-fluoro-L-phenylalanine (FDOPA) were measured before and early after the start of therapy, and were used to predict the overall survival (OS) of patients with recurrent malignant glioma using multiple linear regression (MLR) analysis.

Methods: High-grade recurrent brain tumors in 21 patients (11 men and 10 women, age range 26 - 76 years) were investigated. Each patient had three dynamic PET studies with each probe: at baseline and after 2 and 6 weeks from the start of treatment. Treatment consisted of biweekly cycles of bevacizumab (an angiogenesis inhibitor) and irinotecan (a chemotherapeutic agent). For each study, about 3.5 mCi of FLT (or FDOPA) was administered intravenously and dynamic PET images were acquired for 1 h (or 35 min for FDOPA). A total of 126 PET scans were analyzed. A three-compartment, two-tissue model was applied to estimate tumor FLT and FDOPA kinetic rate constants using a metabolite- and partial volume-corrected input function. MLR analysis was used to model OS as a function of FLT and FDOPA kinetic parameters for each of the three studies as well as their relative changes between studies. An exhaustive search of MLR models using three or fewer predictor variables was performed to find the best models.

Results: Kinetic parameters from FLT were more predictive of OS than those from FDOPA. The three-predictor MLR model derived using information from both probes (adjusted R(2) = 0.83) fitted the OS data better than that derived using information from FDOPA alone (adjusted R(2) = 0.41), but was only marginally different from that derived using information from FLT alone (adjusted R(2) = 0.82). Standardized uptake values (either from FLT alone, FDOPA alone, or both together) gave inferior predictive results (best adjusted R(2) = 0.25).

Conclusion: For recurrent malignant glioma treated with bevacizumab and irinotecan, FLT kinetic parameters obtained early after the start of treatment (absolute values and their associated changes) can provide sufficient information to predict OS with reasonable confidence using MLR. The slight increase in accuracy for predicting OS with a combination of FLT and FDOPA PET information may not warrant the additional acquisition of FDOPA PET for therapy monitoring in patients with recurrent glioma.
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http://dx.doi.org/10.1007/s00259-013-2678-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008691PMC
June 2014

Automated VOI Analysis in FDDNP PET Using Structural Warping: Validation through Classification of Alzheimer's Disease Patients.

Int J Alzheimers Dis 2012 1;2012:512069. Epub 2012 Mar 1.

Department of Biomathematics, David Geffen School of Medicine at UCLA, Box 951766, Los Angeles, CA 90095, USA.

We evaluate an automated approach to the cortical surface mapping (CSM) method of VOI analysis in PET. Although CSM has been previously shown to be successful, the process can be long and tedious. Here, we present an approach that removes these difficulties through the use of 3D image warping to a common space. We test this automated method using studies of FDDNP PET in Alzheimer's disease and mild cognitive impairment. For each subject, VOIs were created, through CSM, to extract regional PET data. After warping to the common space, a single set of CSM-generated VOIs was used to extract PET data from all subjects. The data extracted using a single set of VOIs outperformed the manual approach in classifying AD patients from MCIs and controls. This suggests that this automated method can remove variance in measurements of PET data and can facilitate accurate, high-throughput image analysis.
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http://dx.doi.org/10.1155/2012/512069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310148PMC
August 2012

Discriminant analysis of ¹⁸F-fluorothymidine kinetic parameters to predict survival in patients with recurrent high-grade glioma.

Clin Cancer Res 2011 Oct 25;17(20):6553-62. Epub 2011 Aug 25.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Purpose: The primary objective of this study was to investigate whether changes in 3'-deoxy-3'-[¹⁸F]fluorothymidine (¹⁸F-FLT) kinetic parameters, taken early after the start of therapy, could predict overall survival (OS) and progression-free survival (PFS) in patients with recurrent malignant glioma undergoing treatment with bevacizumab and irinotecan.

Experimental Design: High-grade recurrent brain tumors were investigated in 18 patients (8 male and 10 female), ages 26 to 76 years. Each had 3 dynamic positron emission tomography (PET) studies as follows: at baseline and after 2 and 6 weeks from the start of treatment, ¹⁸F-FLT (2.0 MBq/kg) was injected intravenously, and dynamic PET images were acquired for 1 hour. Factor analysis generated factor images from which blood and tumor uptake curves were derived. A three-compartment, two-tissue model was applied to estimate tumor ¹⁸F-FLT kinetic rate constants using a metabolite- and partial volume-corrected input function. Different combinations of predictor variables were exhaustively searched in a discriminant function to accurately classify patients into their known OS and PFS groups. A leave-one-out cross-validation technique was used to assess the generalizability of the model predictions.

Results: In this study population, changes in single parameters such as standardized uptake value or influx rate constant did not accurately classify patients into their respective OS groups (<1 and ≥ 1 year; hit ratios ≤ 78%). However, changes in a set of ¹⁸F-FLT kinetic parameters could perfectly separate these two groups of patients (hit ratio = 100%) and were also able to correctly classify patients into their respective PFS groups (<100 and ≥ 100 days; hit ratio = 88%).

Conclusions: Discriminant analysis using changes in ¹⁸F-FLT kinetic parameters early during treatment seems to be a powerful method for evaluating the efficacy of therapeutic regimens.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-3290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833447PMC
October 2011

Movement correction method for human brain PET images: application to quantitative analysis of dynamic 18F-FDDNP scans.

J Nucl Med 2010 Feb 15;51(2):210-8. Epub 2010 Jan 15.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-6948, USA.

Unlabelled: Head movement during a PET scan (especially a dynamic scan) can affect both the qualitative and the quantitative aspects of an image, making it difficult to accurately interpret the results. The primary objective of this study was to develop a retrospective image-based movement correction (MC) method and evaluate its implementation on dynamic 2-(1-{6-[(2-(18)F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ((18)F-FDDNP) PET images of cognitively intact controls and patients with Alzheimer's disease (AD).

Methods: Dynamic (18)F-FDDNP PET images, used for in vivo imaging of beta-amyloid plaques and neurofibrillary tangles, were obtained from 12 AD patients and 9 age-matched controls. For each study, a transmission scan was first acquired for attenuation correction. An accurate retrospective MC method that corrected for transmission-emission and emission-emission misalignments was applied to all studies. No restriction was assumed for zero movement between the transmission scan and the first emission scan. Logan analysis, with the cerebellum as the reference region, was used to estimate various regional distribution volume ratio (DVR) values in the brain before and after MC. Discriminant analysis was used to build a predictive model for group membership, using data with and without MC.

Results: MC improved the image quality and quantitative values in (18)F-FDDNP PET images. In this subject population, no significant difference in DVR value was observed in the medial temporal (MTL) region of controls and patients with AD before MC. However, after MC, significant differences in DVR values in the frontal, parietal, posterior cingulate, MTL, lateral temporal (LTL), and global regions were seen between the 2 groups (P < 0.05). In controls and patients with AD, the variability of regional DVR values (as measured by the coefficient of variation) decreased on average by more than 18% after MC. Mean DVR separation between controls and patients with AD was higher in frontal, MTL, LTL, and global regions after MC. Group classification by discriminant analysis based on (18)F-FDDNP DVR values was markedly improved after MC.

Conclusion: The streamlined and easy-to-use MC method presented in this work significantly improves the image quality and the measured tracer kinetics of (18)F-FDDNP PET images. The proposed MC method has the potential to be applied to PET studies on patients having other disorders (e.g., Down syndrome and Parkinson's disease) and to brain PET scans with other molecular imaging probes.
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http://dx.doi.org/10.2967/jnumed.109.063701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929579PMC
February 2010

Quantitative analysis of [18F]FDDNP PET using subcortical white matter as reference region.

Eur J Nucl Med Mol Imaging 2010 Mar 31;37(3):575-88. Epub 2009 Oct 31.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Rm. B2-085E CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.

Purpose: Subcortical white matter is known to be relatively unaffected by amyloid deposition in Alzheimer's disease (AD). We investigated the use of subcortical white matter as a reference region to quantify [(18)F]FDDNP binding in the human brain.

Methods: Dynamic [(18)F]FDDNP PET studies were performed on 7 control subjects and 12 AD patients. Population efflux rate constants (k(')(2)) from subcortical white matter (centrum semiovale) and cerebellar cortex were derived by a simplified reference tissue modeling approach incorporating physiological constraints. Regional distribution volume ratio (DVR) estimates were derived using Logan and simplified reference tissue approaches, with either subcortical white matter or cerebellum as reference input. Discriminant analysis with cross-validation was performed to classify control subjects and AD patients.

Results: The population estimates of k(')(2) in subcortical white matter did not differ significantly between control subjects and AD patients but the variability of individual estimates of k(')(2) determined in white matter was lower than that in cerebellum. Logan DVR showed dependence on the efflux rate constant in white matter. The DVR estimates in the frontal, parietal, posterior cingulate, and temporal cortices were significantly higher in the AD group (p<0.01). Incorporating all these regional DVR estimates as predictor variables in discriminant analysis yielded accurate classification of control subjects and AD patients with high sensitivity and specificity, and the results agreed well with those using the cerebellum as the reference region.

Conclusion: Subcortical white matter can be used as a reference region for quantitative analysis of [(18)F]FDDNP with the Logan method which allows more accurate and less biased binding estimates, but a population efflux rate constant has to be determined a priori.
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http://dx.doi.org/10.1007/s00259-009-1293-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822232PMC
March 2010