Publications by authors named "Delphine L Chen"

48 Publications

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

Sci Rep 2021 Feb 12;11(1):3731. Epub 2021 Feb 12.

Department of Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Box 356410, Health Sciences Bldg. Room BB-442, Seattle, WA, 98195-6410, USA.

Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 (Zr) and yttrium-90 (Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUV by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R = 0.90). Serum AFP was significantly lower 30 days after RIT in Y-αGPC3 treated animals compared to those untreated (p = 0.01) or treated with non-radiolabeled αGPC3 (p = 0.02). Immuno-PET GTV measurements strongly correlated with tumor burden after RIT (R = 0.87), and GTV of animals treated with Y-αGPC3 was lower than in animals who did not receive treatment or were treated with non-radiolabeled αGPC3, although this only trended toward statistical significance. A theranostic platform utilizing GPC3 targeted Zr and Y effectively imaged, treated, and assessed response after radioimmunotherapy in a GPC3-expressing HCC xenograft model.
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http://dx.doi.org/10.1038/s41598-021-82172-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881163PMC
February 2021

Consensus Recommendations on the Use of F-FDG PET/CT in Lung Disease.

J Nucl Med 2020 12 18;61(12):1701-1707. Epub 2020 Sep 18.

Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

PET with F-FDG has been increasingly applied, predominantly in the research setting, to study drug effects and pulmonary biology and to monitor disease progression and treatment outcomes in lung diseases that interfere with gas exchange through alterations of the pulmonary parenchyma, airways, or vasculature. To date, however, there are no widely accepted standard acquisition protocols or imaging data analysis methods for pulmonary F-FDG PET/CT in these diseases, resulting in disparate approaches. Hence, comparison of data across the literature is challenging. To help harmonize the acquisition and analysis and promote reproducibility, we collated details of acquisition protocols and analysis methods from 7 PET centers. From this information and our discussions, we reached the consensus recommendations given here on patient preparation, choice of dynamic versus static imaging, image reconstruction, and image analysis reporting.
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http://dx.doi.org/10.2967/jnumed.120.244780DOI Listing
December 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

Radiologic Assessment of Groin Lymph Nodes in Pelvic Malignancies.

Int J Gynecol Cancer 2020 07 2;30(7):947-953. Epub 2020 Jun 2.

Department of Radiation Oncology, Washington University in Saint Louis, Saint Louis, Missouri, USA

Introduction: Metastatic involvement of groin nodes can alter radiation therapy planning for pelvic tumors. F-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) can identify nodal metastases; however, interpretation of PET/CT-positive nodes can be complicated by non-malignant processes. We evaluated quantitative metrics as methods to identify groin metastases in patients with pelvic tumors by comparison with standard subjective interpretive criteria, with pathology as the reference standard.

Methods: We retrospectively identified patients with vulvar, vaginal, or anal cancers who underwent F-FDG PET/CT before pathologic evaluation of groin nodes between 2007 and 2017. Because patho-radiologic correlation was not possible for every node, one index node identified on imaging was selected for each groin. For each index node, standardized uptake value measurements, total lesion glycolysis, metabolic tumor volume, CT-based volume, and short and long axes were measured. Multivariate logistic regression was used to identify metrics predictive for pathologically positive groins and generate a probabilistic model. Area under the receiver-operating characteristic curves (AUCs) for the model were compared with clinical interpretation from the diagnostic report via a Wald's χ test.

Results: Of 55 patients identified for analysis, 75 groins had pathologic evaluation resulting in 75 index groin nodes for analysis with 35 groins pathologically positive for malignancy. Logistic regression identified mean standardized-uptake-value (50% threshold) and short-axis length as the most predictive imaging metrics for metastatic nodal involvement. The probabilistic model performed better at predicting pathologic involvement compared with standard clinical interpretation on analysis (AUC 0.91, 95% CI 0.84 to 0.97 vs 0.80, 95% CI 0.71 to 0.89; p<0.01).

Discussion: Accuracy of F-FDG PET/CT for detecting groin nodal metastases in patients with pelvic tumors may be improved with the use of quantitative metrics. Improving prediction of nodal metastases can aid with appropriate selection of patients for pathologic node evaluation and guide radiation volumes and doses.
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http://dx.doi.org/10.1136/ijgc-2020-001363DOI Listing
July 2020

Promising Advances for Imaging Lung Macrophage Recruitment.

Authors:
Delphine L Chen

Am J Respir Crit Care Med 2020 01;201(1):11-13

Seattle Cancer Care AllianceUniversity of WashingtonSeattle, Washington.

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http://dx.doi.org/10.1164/rccm.201907-1455EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938155PMC
January 2020

Automated production of a sphingosine-1 phosphate receptor 1 (S1P1) PET radiopharmaceutical [C]CS1P1 for human use.

Appl Radiat Isot 2019 Oct 20;152:30-36. Epub 2019 Jun 20.

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

Automated synthesis of a radiopharmaceutical 3-((2-fluoro-4-(5-(2'-methyl-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl) (methyl-C)amino)propanoic acid ([C]CS1P1) for PET imaging sphingosine-1 phosphate receptor 1 (S1P1) was accomplished by a two-step-one-pot procedure in a Siemens CTI methylation automated module using TR-19 cyclotron. The synthesis of [C]CS1P1 was successfully validated under current Good Manufacturing Practices (cGMP) conditions, resulting in a consistent average radiochemical yield of ∼15%, molar activity of ∼3129 GBq/μmol (decay corrected to end of bombardment, EOB), and radiochemical purity > 95%. The radiopharmaceutical product meets all quality control criteria for human use for an Investigational New Drug (IND) application to permit human studies.
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http://dx.doi.org/10.1016/j.apradiso.2019.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708718PMC
October 2019

An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants.

JCI Insight 2019 04 16;5. Epub 2019 Apr 16.

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

Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell-mediated repair. In contrast, allogeneic lung transplants develop severe OB lesions and poorly regenerate club cells despite immunosuppression treatment. Lung allograft club cell ablation also triggers the recognition of alloantigens, and pulmonary restricted self-antigens reported associated with BOS development. However, CD8+ T cell depletion restores club cell reparative responses and prevents OB. In addition, ex-vivo analysis reveals a specific role for alloantigen-primed effector CD8+ T cells in preventing club cell proliferation and maintenance. Taken together, we demonstrate a vital role for club cells in maintaining lung transplant tolerance and propose a new model to identify the underlying mechanisms of OB.
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http://dx.doi.org/10.1172/jci.insight.124732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538316PMC
April 2019

PET Imaging of PARP Expression Using F-Olaparib.

Authors:
Delphine L Chen

J Nucl Med 2019 Apr 10;60(4):502-503. Epub 2019 Jan 10.

Divisions of Radiological Sciences and Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri

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http://dx.doi.org/10.2967/jnumed.118.219733DOI Listing
April 2019

Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates.

Org Biomol Chem 2018 12;16(47):9171-9184

Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, Missouri 63110, USA.

A series of seventeen hydroxyl-containing sphingosine 1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized. Their in vitro binding potencies were determined using [32P]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC50 values ranging from 3.9 to 15.4 nM and also displayed high selectivity for S1PR1 over other S1P receptor subtypes (IC50 > 1000 nM for S1PR2-5). The most potent compounds 10a, 17a, 17b, and 24 were subsequently radiolabeled with F-18 in high yields and purities. MicroPET studies in cynomolgus macaque showed that [18F]10a, [18F]17a, and [18F]17b but not [18F]24 crossed the blood brain barrier and had high initial brain uptake. Further validation of [18F]10a, [18F]17a, and [18F]17b in preclinical models of neuroinflammation is warranted to identify a suitable PET radioligand to quantify S1PR1 expression in vivo as a metric of an inflammatory response.
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http://dx.doi.org/10.1039/c8ob02609bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561338PMC
December 2018

Update 2018: 18F-FDG PET/CT and PET/MRI in Head and Neck Cancer.

Clin Nucl Med 2018 Dec;43(12):e439-e452

R.D.N. is a Nuclear Medicine Physician, Kaiser Permanente, Santa Clara, CA.

There are recent advances, namely, a standardized method for reporting therapy response (Hopkins criteria), a multicenter prospective cohort study with excellent negative predictive value of F-FDG PET/CT for N0 clinical neck, a phase III multicenter randomized controlled study establishing the value of a negative posttherapy F-FDG PET/CT for patient management, a phase II randomized controlled study demonstrating radiation dose reduction strategies for human papilloma virus-related disease, and Food and Drug Administration approval of nivolumab for treatment of recurrent head and neck squamous cell carcinoma.
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http://dx.doi.org/10.1097/RLU.0000000000002247DOI Listing
December 2018

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia on Somatostatin Receptor Imaging.

Am J Respir Crit Care Med 2018 11;198(9):1223-1225

1 Mallinckrodt Institute of Radiology and.

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http://dx.doi.org/10.1164/rccm.201711-2360IMDOI Listing
November 2018

Long-range function of secreted small nucleolar RNAs that direct 2'--methylation.

J Biol Chem 2018 08 6;293(34):13284-13296. Epub 2018 Jul 6.

From the Department of Medicine,

Small nucleolar RNAs (snoRNAs) are noncoding RNAs that guide chemical modifications of structural RNAs. Whereas snoRNAs primarily localize in the nucleolus, where their canonical function is to target nascent ribosomal RNAs for 2'--methylation, recent studies provide evidence that snoRNAs traffic out of the nucleus. Furthermore, RNA-Seq data indicate that extracellular vesicles released from cells contain snoRNAs. However, it is not known whether snoRNA secretion is regulated or whether secreted snoRNAs are functional. Here, we show that inflammation stimulates secretion of snoRNAs U32a (SNORD32a), U33 (SNORD33), U34 (SNORD34), and U35a (SNORD35a) from cultured macrophages, in mice, and in human subjects. Secreted snoRNAs co-fractionate with extracellular vesicles and are taken up by recipient cells. In a murine parabiosis model, we demonstrate that snoRNAs travel through the circulation to function in distant tissues. These findings support a previously unappreciated link between inflammation and snoRNA secretion in mice and humans and uncover a potential role for secreted snoRNAs in cell-cell communication.
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http://dx.doi.org/10.1074/jbc.RA118.003410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109910PMC
August 2018

The peroxisome proliferator-activated receptor agonist pioglitazone and 5-lipoxygenase inhibitor zileuton have no effect on lung inflammation in healthy volunteers by positron emission tomography in a single-blind placebo-controlled cohort study.

PLoS One 2018 7;13(2):e0191783. Epub 2018 Feb 7.

Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.

Background: Anti-inflammatory drug development efforts for lung disease have been hampered in part by the lack of noninvasive inflammation biomarkers and the limited ability of animal models to predict efficacy in humans. We used 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a human model of lung inflammation to assess whether pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, and zileuton, a 5-lipoxygenase inhibitor, reduce lung inflammation.

Methods: For this single center, single-blind, placebo-controlled cohort study, we enrolled healthy volunteers sequentially into the following treatment cohorts (N = 6 per cohort): pioglitazone plus placebo, zileuton plus placebo, or dual placebo prior to bronchoscopic endotoxin instillation. 18F-FDG uptake pre- and post-endotoxin was quantified as the Patlak graphical analysis-determined Ki (primary outcome measure). Secondary outcome measures included the mean standard uptake value (SUVmean), post-endotoxin bronchoalveolar lavage (BAL) cell counts and differentials and blood adiponectin and urinary leukotriene E4 (LTE4) levels, determined by enzyme-linked immunosorbent assay, to verify treatment compliance. One- or two-way analysis of variance assessed for differences among cohorts in the outcome measures (expressed as mean ± standard deviation).

Results: Ten females and eight males (29±6 years of age) completed all study procedures except for one volunteer who did not complete the post-endotoxin BAL. Ki and SUVmean increased in all cohorts after endotoxin instillation (Ki increased by 0.0021±0.0019, 0.0023±0.0017, and 0.0024±0.0020 and SUVmean by 0.47±0.14, 0.55±0.15, and 0.54±0.38 in placebo, pioglitazone, and zileuton cohorts, respectively, p<0.001) with no differences among treatment cohorts (p = 0.933). Adiponectin levels increased as expected with pioglitazone treatment but not urinary LTE4 levels as expected with zileuton treatment. BAL cell counts (p = 0.442) and neutrophil percentage (p = 0.773) were similar among the treatment cohorts.

Conclusions: Endotoxin-induced lung inflammation in humans is not responsive to pioglitazone or zileuton, highlighting the challenge in translating anti-inflammatory drug efficacy results from murine models to humans.

Trial Registration: ClinicalTrials.gov NCT01174056.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191783PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802889PMC
March 2018

Rare Variant of Intravascular Large B-Cell Lymphoma With Hemophagocytic Syndrome.

Clin Nucl Med 2018 Apr;43(4):e125-e126

Intravascular lymphoma (IVL) is a rare subtype of diffuse large B-cell lymphoma characterized by a clonal proliferation of lymphocytes restricted to the intravascular space. We present the case of a 60-year-old man with hemophagocytic syndrome secondary to IVL. F-FDG PET/CT demonstrated hepatosplenomegaly with marked diffuse hepatic, splenic, and bone marrow hypermetabolism. The case report illustrates the imaging findings of this uncommon variant of IVL.
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http://dx.doi.org/10.1097/RLU.0000000000001969DOI Listing
April 2018

False-Positive Heat-Damaged RBC Scan for Splenosis: Case of Retroperitoneal Extramedullary Hematopoiesis.

Clin Nucl Med 2018 Feb;43(2):139-140

Extramedullary hematopoiesis (EMH) is a well-known compensatory response to severe anemia, most commonly due to a chronic hemolytic anemia such as thalassemia or sickle cell disease. We present a case of a 72-year-old man with autoimmune hemolytic anemia refractory to steroids and splenectomy. An incidental retroperitoneal mass on CT was suggestive of ectopic splenic tissue. However, an alternative diagnosis of EMH was considered, given an atypical appearance on heat-damaged Tc-RBC scan, and was confirmed with biopsy. The case report illustrates the imaging characteristics of EMH, widely known to have increased activity on Tc-sulfur colloid scans.
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http://dx.doi.org/10.1097/RLU.0000000000001953DOI Listing
February 2018

Quantification of Lung PET Images: Challenges and Opportunities.

J Nucl Med 2017 02 12;58(2):201-207. Epub 2017 Jan 12.

Experimental Medicine Imaging, GlaxoSmithKline, Stevenage, United Kingdom.

Millions of people are affected by respiratory diseases, leading to a significant health burden globally. Because of the current insufficient knowledge of the underlying mechanisms that lead to the development and progression of respiratory diseases, treatment options remain limited. To overcome this limitation and understand the associated molecular changes, noninvasive imaging techniques such as PET and SPECT have been explored for biomarker development, with F-FDG PET imaging being the most studied. The quantification of pulmonary molecular imaging data remains challenging because of variations in tissue, air, blood, and water fractions within the lungs. The proportions of these components further differ depending on the lung disease. Therefore, different quantification approaches have been proposed to address these variabilities. However, no standardized approach has been developed to date. This article reviews the data evaluating F-FDG PET quantification approaches in lung diseases, focusing on methods to account for variations in lung components and the interpretation of the derived parameters. The diseases reviewed include acute respiratory distress syndrome, chronic obstructive pulmonary disease, and interstitial lung diseases such as idiopathic pulmonary fibrosis. Based on review of prior literature, ongoing research, and discussions among the authors, suggested considerations are presented to assist with the interpretation of the derived parameters from these approaches and the design of future studies.
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http://dx.doi.org/10.2967/jnumed.116.184796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288738PMC
February 2017

Response Assessment Criteria and Their Applications in Lymphoma: Part 2.

J Nucl Med 2017 Jan 22;58(1):13-22. Epub 2016 Nov 22.

Mount Sinai Hospital, New York, New York.

Interim and end-of-treatment PET/CT have become central to the evaluation of Hodgkin and non-Hodgkin lymphoma. This review article seeks to aid clinical decision making by providing an overview of available data on the diagnostic and prognostic value of PET/CT imaging for response assessment and pretransplant evaluation in lymphoma. The relative strengths and limitations of these techniques in various disease subtypes and clinical scenarios are explored, along with their current standards for reporting and latest developments. Particular attention is given to response-adapted therapy, which is emerging as a cornerstone of clinical management.
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http://dx.doi.org/10.2967/jnumed.116.184242DOI Listing
January 2017

PET of Poly (ADP-Ribose) Polymerase Activity in Cancer: Preclinical Assessment and First In-Human Studies.

Radiology 2017 Feb 14;282(2):453-463. Epub 2016 Nov 14.

From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).

Purpose To demonstrate that positron emission tomography (PET) with fluorine 18 (F) fluorthanatrace (FTT) depicts activated poly (adenosine diphosphate-ribose)polymerase (PARP) expression and is feasible for clinical trial evaluation. Materials and Methods All studies were conducted prospectively from February 2012 through July 2015 under protocols approved by the local animal studies committee and institutional review board. The area under the receiver operating characteristic curve (AUC, in g/mL· min) for F-FTT was assessed in normal mouse organs before and after treatment with olaparib (n = 14), a PARP inhibitor, or iniparib (n = 11), which has no PARP inhibitory activity. Murine biodistribution studies were performed to support human translational studies. Eight human subjects with cancer and eight healthy volunteers underwent imaging to verify the human radiation dosimetry of F-FTT. The Wilcoxon signed rank test was used to assess for differences among treatment groups for the mouse studies. Results In mice, olaparib, but not iniparib, significantly reduced the F-FTT AUC in the spine (median difference before and after treatment and interquartile range [IQR]: -17 g/mL· min and 10 g/mL · min, respectively [P = .0001], for olaparib and -3 g/mL · min and 13 g/mL · min [P = .70] for iniparib) and in nodes (median difference and interquartile range [IQR] before and after treatment: -23 g/mL · min and 13 g/mL · min [P = .0001] for olaparib; -9 g/mL · min and 17 g/mL · min [P = .05] for iniparib). The effective dose was estimated at 6.9 mSv for a 370-MBq F-FTT dose in humans. In humans, the organs with the highest uptake on images were the spleen and pancreas. Among five subjects with measurable tumors, increased F-FTT uptake was seen in one subject with pancreatic adenocarcinoma and another with liver cancer. Conclusion The results suggest that F-FTT uptake reflects PARP expression and that its radiation dosimetry profile is compatible with those of agents currently in clinical use. RSNA, 2016 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2016161929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283874PMC
February 2017

Imaging Pulmonary Inflammation.

J Nucl Med 2016 Nov 1;57(11):1764-1770. Epub 2016 Sep 1.

Washington University School of Medicine, St. Louis, Missouri

Lung inflammatory diseases contribute significantly to the socioeconomic burden of disease. Yet very few new, effective therapies for respiratory disease have been approved for use. A major contributing factor is the lack of biomarkers that can accurately quantify the lung inflammatory burden and can be used to understand the contribution of lung inflammation to loss in lung function. Molecular imaging approaches can detect and quantify the recruitment and activation of specific immune cells in lung inflammation. We review the clinical techniques used to image lung inflammation, provide an overview of clinical and emerging PET techniques for quantifying lung inflammation, and discuss potential clinical applications.
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http://dx.doi.org/10.2967/jnumed.115.157438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095507PMC
November 2016

PET imaging approaches for inflammatory lung diseases: Current concepts and future directions.

Eur J Radiol 2017 Jan 16;86:371-376. Epub 2016 Sep 16.

Clinical Research Imaging Centre, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Inflammatory lung disease is one of the most common clinical scenarios, and yet, it is often poorly understood. Inflammatory lung disorders, such as chronic obstructive pulmonary diseases, which are causing significant mortality and morbidity, have limited therapeutic options. Recently, new treatments have become available for pulmonary fibrosis. This review article will describe the new insights that are starting to be gained from positron emission tomography (PET) methods, by targeting molecular processes using dedicated radiotracers. Ultimately, this should aid in deriving better pathophysiological classification of these disorders, which will ultimately result in better evaluation of novel therapies.
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http://dx.doi.org/10.1016/j.ejrad.2016.09.014DOI Listing
January 2017

PET imaging of in vivo caspase-3/7 activity following myocardial ischemia-reperfusion injury with the radiolabeled isatin sulfonamide analogue [(18)F]WC-4-116.

Am J Nucl Med Mol Imaging 2016 24;6(2):110-9. Epub 2016 Apr 24.

Mallinckrodt Institute of Radiology, Washington University School of MedicineSt. Louis, MO 63110, USA; Department of Cell Biology & Physiology, Washington University School of MedicineSt. Louis, MO 63110, USA; Department of Biochemistry & Molecular Biophysics, Washington University School of MedicineSt. Louis, MO 63110, USA.

The utility of [(18)F]WC-4-116, a PET tracer for imaging caspase-3 activation, was evaluated in an animal model of myocardial apoptosis. [(18)F]WC-4-116 was injected into rats at 3 hours after a 30 min period of ischemia induced by temporary occlusion of the left anterior descending coronary artery in Sprague-Dawley rats. [(18)F]WC-4-116 uptake was quantified by 1) autoradiography, 2) microPET imaging studies, and 3) post-PET biodistribution studies. MicroPET imaging also assessed uptake of the non-caspase-3-targeted tracer [(18)F]ICMT-18 at 3 hours postischemia. Enzyme assays and Western blotting assessed caspase-3 activation in both at-risk and not-at-risk regions. Caspase-3 enzyme activity increased in the at-risk but not in the not-at-risk myocardium. Quantitative autoradiographic analysis of [(18)F]WC-4-116 demonstrated nearly 2-fold higher uptake in the ischemia-reperfusion (IR) versus sham animals. [(18)F]WC-4-116 microPET imaging studies demonstrated that the IR animals was similarly elevated in relation to sham. [(18)F]ICMT-18 uptake did not increase in at-risk myocardium despite evidence of caspase-3 activation. Biodistribution studies with [(18)F]WC-4-116 confirmed the microPET findings. These data indicate that the caspase-3-PET tracer [(18)F]WC-4-116 can noninvasively image in vivo caspase activity during myocardial apoptosis and may be useful for clinical imaging in humans.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858607PMC
May 2016

Response Assessment Criteria and Their Applications in Lymphoma: Part 1.

J Nucl Med 2016 06 28;57(6):928-35. Epub 2016 Apr 28.

Stanford University Medical Center, Stanford, California

The effectiveness of cancer therapy, both in individual patients and across populations, requires a systematic and reproducible method for evaluating response to treatment. Early efforts to meet this need resulted in the creation of numerous guidelines for quantifying posttherapy changes in disease extent, both anatomically and metabolically. Over the past few years, criteria for disease response classification have been developed for specific cancer histologies. To date, the spectrum of disease broadly referred to as lymphoma is perhaps the most common for which disease response classification is used. This review article provides an overview of the existing response assessment criteria for lymphoma and highlights their respective methodologies and validities. Concerns over the technical complexity and arbitrary thresholds of many of these criteria, which have impeded the long-standing endeavor of standardizing response assessment, are also discussed.
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http://dx.doi.org/10.2967/jnumed.115.166280DOI Listing
June 2016

Imaging pulmonary inducible nitric oxide synthase expression with PET.

J Nucl Med 2015 Jan 18;56(1):76-81. Epub 2014 Dec 18.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri

Unlabelled: Inducible nitric oxide synthase (iNOS) activity increases in acute and chronic inflammatory lung diseases. Imaging iNOS expression may be useful as an inflammation biomarker for monitoring lung disease activity. We developed a novel tracer for PET that binds to iNOS in vivo, (18)F-NOS. In this study, we tested whether (18)F-NOS could quantify iNOS expression from endotoxin-induced lung inflammation in healthy volunteers.

Methods: Healthy volunteers were screened to exclude cardiopulmonary disease. Qualifying volunteers underwent a baseline, 1-h dynamic (18)F-NOS PET/CT scan. Endotoxin (4 ng/kg) was then instilled bronchoscopically in the right middle lobe. (18)F-NOS imaging was performed again approximately 16 h after endotoxin instillation. Radiolabeled metabolites were determined from blood samples. Cells recovered by bronchoalveolar lavage (BAL) after imaging were stained immunohistochemically for iNOS. (18)F-NOS uptake was quantified as the distribution volume ratio (DVR) determined by Logan plot graphical analysis in volumes of interest placed over the area of endotoxin instillation and in an equivalent lung region on the left. The mean Hounsfield units (HUs) were also computed using the same volumes of interest to measure density changes.

Results: Seven healthy volunteers with normal pulmonary function completed the study with evaluable data. The DVR increased by approximately 30%, from a baseline mean of 0.42 ± 0.07 to 0.54 ± 0.12, and the mean HUs by 11% after endotoxin in 6 volunteers who had positive iNOS staining in BAL cells. The DVR did not change in the left lung after endotoxin. In 1 volunteer with low-level iNOS staining in BAL cells, the mean HUs increased by 7% without an increase in DVR. Metabolism was rapid, with approximately 50% of the parent compound at 5 min and 17% at 60 min after injection.

Conclusion: (18)F-NOS can be used to image iNOS activity in acute lung inflammation in humans and may be a useful PET tracer for imaging iNOS expression in inflammatory lung disease.
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http://dx.doi.org/10.2967/jnumed.114.146381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501590PMC
January 2015

Imaging caspase-3 activation as a marker of apoptosis-targeted treatment response in cancer.

Mol Imaging Biol 2015 Jun;17(3):384-93

Division of Radiological Sciences and Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO, 63110, USA,

Purpose: We tested whether positron emission tomography (PET) with the caspase-3-targeted isatin analog [(18)F]WC-4-116 could image caspase-3 activation in response to an apoptosis-inducing anticancer therapy.

Procedures: [(18)F]WC-4-116 uptake was determined in etoposide-treated EL4 cells. Biodistribution studies with [(18)F]WC-4-116 and [(18)F]ICMT-18, a non-caspase-3-targeted tracer, as well as [(18)F]WC-4-116 microPET imaging assessed responses in Colo205 tumor-bearing mice treated with death receptor 5 (DR5)-targeted agonist antibodies. Immunohistochemical staining and enzyme assays confirmed caspase-3 activation. Two-way analysis of variance or Student's t test assessed for treatment-related changes in tracer uptake.

Results: [(18)F]WC-4-116 increased 8 ± 2 fold in etoposide-treated cells. The [(18)F]WC-4-116 % ID/g also increased significantly in tumors with high caspase-3 enzyme activity (p < 0.05). [(18)F]ICMT-18 tumor uptake did not differ in tumors with high or low caspase-3 enzyme activity.

Conclusions: [(18)F]WC-4-116 uptake in vivo reflects increased caspase-3 activation and may be useful for detecting caspase-3-mediated apoptosis treatment responses in cancer.
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http://dx.doi.org/10.1007/s11307-014-0802-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874215PMC
June 2015

Multimodality molecular imaging of the lung.

Clin Transl Imaging 2014 Oct 16;2(5):391-401. Epub 2014 Oct 16.

Department of Radiology and Bioengineering and Physics, University of Washington Medical Center, Seattle, WA, USA.

Lung diseases cause significant morbidity and mortality and lead to high healthcare utilization. However, few lung disease-specific biomarkers are available to accurately monitor disease activity for the purposes of clinical management or drug development. Advances in cross-modal imaging technologies, such as combined positron emission tomography (PET) and magnetic resonance (MR) imaging scanners and PET or single-photon emission computed tomography (SPECT) combined with computed tomography (CT), may aid in the development of noninvasive, molecular-based biomarkers for lung disease. However, the lungs pose particular challenges in obtaining accurate quantification of imaging data due to the low density of the organ and breathing motion. This review covers the basic physics underlying PET, SPECT, CT, and MR lung imaging and presents technical considerations for multimodal imaging with regard to PET and SPECT quantification. It also includes a brief review of the current and potential clinical applications for these hybrid imaging technologies.
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http://dx.doi.org/10.1007/s40336-014-0084-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289702PMC
October 2014

Synthesis, [¹⁸F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography.

Bioorg Med Chem 2014 Mar 24;22(5):1700-7. Epub 2014 Jan 24.

Department of Radiology, School of Medicine, Washington University in Saint Louis, St. Louis, MO 63110, USA. Electronic address:

Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be (18)F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC50=6.3 nM). [(18)F]12 was synthesized under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET studies using [(18)F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [(18)F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [(18)F]12 in the tumor is specific to PARP-1 expression.
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http://dx.doi.org/10.1016/j.bmc.2014.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020173PMC
March 2014

FDG PET imaging in cystic fibrosis.

Semin Nucl Med 2013 Nov;43(6):412-9

Washington University School of Medicine, St. Louis, MO. Electronic address:

Cystic fibrosis (CF) is characterized by persistent neutrophilic lung inflammation that begins early in life and leads to an inexorable progressive loss of lung function over time, causing significant morbidity and mortality. Studies to date support the hypothesis that higher levels of lung inflammation lead to worsening lung dysfunction. However, measuring the extent and severity of lung inflammation in the CF lung is difficult as few lung-specific biomarkers of inflammation can quantify the regional and whole-lung inflammatory burden accurately and reproducibly. PET with (18)F-fluorodeoxyglucose ((18)F-FDG) has shown promise in measuring lung inflammation in both acute and chronic lung diseases. Several studies have now shown that (18)F-FDG uptake may be a useful measure of lung inflammation in CF. The whole-lung rate of (18)F-FDG uptake in stable CF, quantified by the Patlak graphical analysis, appears to correlate with more rapidly declining lung function. Acute exacerbation, on the contrary, leads to focally increased (18)F-FDG uptake, which decreases with antibiotic treatment. These small studies are the first attempts to characterize the patterns of (18)F-FDG uptake in CF and suggest a potential role for (18)F-FDG as a treatment modifiable biomarker of lung inflammation in CF.
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http://dx.doi.org/10.1053/j.semnuclmed.2013.06.002DOI Listing
November 2013

Radiolabeled isatin binding to caspase-3 activation induced by anti-Fas antibody.

Nucl Med Biol 2012 Jan 26;39(1):137-44. Epub 2011 Oct 26.

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

Introduction: Noninvasive imaging methods that can distinguish apoptosis from necrosis may be useful in furthering our understanding of diseases characterized by apoptotic dysregulation as well as aiding drug development targeting apoptotic pathways. We evaluated the ability of radiolabeled isatins to quantify caspase-3 activity induced by the activation of the extrinsic apoptotic pathway by the anti-Fas antibody in mice.

Methods: The behavior of three different radiolabeled isatins ([(18)F]WC-II-89, [(18)F]WC-IV-3 and [(11)C]WC-98) was characterized in mice with and without anti-Fas antibody treatment by microPET imaging and biodistribution studies. The activity of [(18)F]WC-II-89 was also compared with [(99m)Tc]mebrofenin. The effect of pan-caspase inhibition with quinolyl-valyl-O-methylaspartyl-[2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh) on [(18)F]WC-II-89 uptake was studied. Caspase-3 activity was confirmed by a fluorometric enzyme assay.

Results: All three tracers behaved similarly in microPET and biodistribution studies. Increased retention of all tracers was observed in the livers of treated animals and several other organs, all of which demonstrated increased caspase-3 enzyme activity; however, impaired hepatobiliary excretion made attribution of these findings to caspase-3 activity difficult. The isatin [(18)F]WC-II-89 was retained at statistically significantly higher levels in the organs after anti-Fas antibody treatment while [(99m)Tc]mebrofenin activity cleared, suggesting specific binding to activated caspase-3, but the magnitude of increased binding was still relatively low. Caspase inhibition with Q-VD-OPh partially blocked [(18)F]WC-II-89 retention but completely blocked caspase-3 enzyme activity in the liver.

Conclusions: The radiolabeled isatins appear to bind specifically to caspase-3 in vivo, but their sensitivity is limited. Further optimization is required for these tracers to be useful for clinical applications.
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http://dx.doi.org/10.1016/j.nucmedbio.2011.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253226PMC
January 2012

Synthesis and evaluation of 18F-labeled PPARγ antagonists.

Nucl Med Biol 2012 Jan 9;39(1):77-87. Epub 2011 Sep 9.

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

Introduction: Peroxisome proliferator-activated receptor gamma (PPARγ) transcriptionally modulates fat metabolism and also plays a role in pathological conditions such as cancer, neurodegenerative disease and inflammation. PPARγ imaging agents are potential tools for investigating these diseases.

Methods: Four analogs of GW9662, a PPARγ antagonist, with different fluorine-containing substituents at the para-position of the aniline ring were synthesized and evaluated using two different receptor binding assays for measuring PPARγ affinity. Micro-positron emission tomography (PET) imaging studies were performed in a transgenic mouse model having a heart-specific overexpression of PPARγ.

Results: All four analogs were found to have binding affinities that were comparable to or better than the reference antagonist, GW9662, using a scintillation proximity assay (SPA). However, only the chloro-based analogs (compounds 3 and 4) had activity in a whole-cell assay measuring activation of the PPARγ/retinoid X receptor complex. The microPET imaging studies in an MHC-PPARγ transgenic mouse model showed high uptake and PPARγ-specific binding for the irreversible antagonist [(18)F]3, whereas the corresponding reversible methoxy analog ([(18)F]5) displayed only nonspecific uptake in heart.

Conclusions: The results of this preliminary study show that the irreversible antagonist [(18)F]3 may represent a novel strategy for imaging PPARγ in vivo with PET.
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http://dx.doi.org/10.1016/j.nucmedbio.2011.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248633PMC
January 2012