Dr. Franc has over 15 years of experience in clinical nuclear medicine with particular expertise in PET-CT. He publishes and lectures predominantly on applications and innovations of PET-CT. As a clinical leader, Dr. Franc has developed programs for the early adoption and implementation of nuclear-based imaging and therapeutic technologies including combined positron emission tomography (PET) and computed tomography (CT) (combined PET-CT) and combined single photon emission computed tomography and CT (SPECT-CT) for quantitative oncologic and cardiac applications. Dr. Franc has experience in all aspects of PET radiopharmaceutical development, spanning the design of molecules, synthesis of radioligands, and use in animal and human imaging. He also has expertise in quantitative image analysis, development of novel post-processing image reconstruction methods, and the application of artificial intelligence in human diagnostics. Along with radiochemistry and radiopharmacy colleagues at the UCSF Cyclotron Facility, Dr. Franc has implemented new radiopharmaceuticals in pre-clinical and clinical research PET imaging as well as for clinical PET with applications in cancer, infectious disease (HIV), and autoimmune disease (RA).
In addition to translational science and clinical research, Dr. Franc has established himself in the area of health policy. His research, publications, and lectures in health policy focus on improving value of healthcare through decrease in variability and implementation of precision health techniques into the clinic.
- Nuclear Medicine
Clinical Professor, Radiology - Rad/Nuclear Medicine
Medical Education:University of Southern California Keck School of Medicine Registrar (2000) CA
Board Certification: Nuclear Medicine, American Board of Nuclear Medicine (2003)
Residency:Stanford University Nuclear Medicine Residency (2003) CA
Internship:Stanford University General Surgery Residency (2001) CA
Fungal endocarditis resembling primary cardiac malignancy in a patient with B-cell ALL with culture confirmation.
Radiology case reports
2020; 15 (2): 117–19
Fungal endocarditis is a rare subtype of infective endocarditis that often presents with nonspecific symptoms in patients with complex medical histories, making diagnosis challenging. Patients with a history of ALL may present with congestive heart failure, chemo-induced cardiomyopathy, acute coronary syndrome, cardiac lymphomatous metastasis, or infections. We present the case of a patient with a history of ALL who presented with acute coronary syndrome and imaging concerning for primary cardiac lymphoma, when in fact the patient ended up suffering from culture proven fungal endocarditis.
View details for DOI 10.1016/j.radcr.2019.10.022
View details for PubMedID 31768196
- Using diagnosis codes in claims data to identify cohorts of breast cancer patients following initial treatment. The breast journal 2020
Identifying tests related to breast cancer care in claims data.
The breast journal
To develop a method for calculating rates of testing for breast cancer recurrence in patients who have already undergone initial treatment for breast cancer, we calculated rates in a cohort of Medicare breast cancer patients and an age-matched noncancer cohort. We first used only tests with claims including diagnosis codes indicating invasive breast cancer and then used all tests regardless of diagnosis code. For each method, we calculated testing rates in the breast cancer cohort above the background rate in the noncancer population. The two methods provided similar estimates of testing prevalence and frequency, with exception of prevalence of CT.
View details for DOI 10.1111/tbj.13691
View details for PubMedID 31736191
Prospective Evaluation in an Academic Center of 18F-DCFPyL PET/CT in Biochemically Recurrent Prostate Cancer: A Focus on Localizing Disease and Changes in Management.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
18F-DCFPyL is a promising PET radiopharmaceutical targeting prostate specific membrane antigen (PSMA). We present our experience in this single academic center prospective study evaluating the positivity rate of 18F-DCFPyL PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC). Methods: We prospectively enrolled 72 men (52-91 years old, mean±SD: 71.5±7.2) with BCR after primary definitive treatment with prostatectomy (n = 42) or radiotherapy (n = 30). The presence of lesions compatible with PC was evaluated by two independent readers. Fifty-nine patients had concurrent scans with at least one other conventional scan: bone scan (24), CT (21), MR (20), 18F-Fluciclovine PET/CT (18) and/or 18F-NaF PET (14). Findings from 18F-DCFPyL PET/CT were compared with those from other modalities. Impact on patient management based on 18F-DCFPyL PET/CT was recorded from clinical chart review. Results: 18F-DCFPyL PET/CT had an overall positivity rate of 85%, which increased with higher prostate specific antigen (PSA) levels (ng/mL): 50% (PSA<0.5), 69% (0.5≤PSA<1), 100% (1≤PSA<2), 91% (2≤PSA<5) and 96% (PSA≥5), respectively. 18F-DCFPyL PET detected more lesions than conventional imaging. For anatomic imaging, 20/41 (49%) CT/MRI had congruent findings with 18F-DCFPyL, while 18F-DCFPyL PET was positive in 17/41 (41%) cases with negative CT/MRI. For bone imaging, 26/38 (68%) bone scan/18F-NaF PET were congruent with 18F-DCFPyL PET, while 18F-DCFPyL PET localized bone lesions in 8/38 (21%) patients with negative bone scan/18F-NaF PET. In 8/18 (44%) patients, 18F-Fluciclovine PET had located the same lesions as the 18F-DCFPyL PET, while 5/18 (28%) patients with negative 18F-Fluciclovine had positive 18F-DCFPyL PET findings and 1/18 (6%) patient with negative 18F-DCFPyL had uptake in the prostate bed on 18F-Fluciclovine PET. In the remaining 4/18 (22%) patients, 18F-DCFPyL and 18F-Fluciclovine scans showed different lesions. Lastly, 43/72 (60%) patients had treatment changes after 18F-DCFPyL PET and, most noticeably, 17 of these patients (24% total) had lesion localization only on 18F-DCFPyL PET, despite negative conventional imaging. Conclusion: 18F-DCFPyL PET/CT is a promising diagnostic tool in the work-up of biochemically recurrent prostate cancer given the high positivity rate as compared to FDA-approved currently available imaging modalities and its impact on clinical management in 60% of patients.
View details for DOI 10.2967/jnumed.119.231654
View details for PubMedID 31628216
Prospective Evaluation of F-18-DCFPyL PET/CT and Conventional Imaging in Patients with Biochemically Recurrent Prostate Cancer
SOC NUCLEAR MEDICINE INC. 2019
View details for Web of Science ID 000473116801016
Prospective evaluation of F-18- DCFPyL in Patients with Biochemically Recurrent Prostate Cancer: Positivity Rate and Correlation with PSA levels
SOC NUCLEAR MEDICINE INC. 2019
View details for Web of Science ID 000473116801610
Prospective Comparison of F-18-DCFPyL PET/CT with F-18-NaF PET/CT for Detection of Skeletal Metastases in Biochemically Recurrent Prostate Cancer
SOC NUCLEAR MEDICINE INC. 2019
View details for Web of Science ID 000473116801621
Performance Comparison of Individual and Ensemble CNN Models for the Classification of Brain 18F-FDG-PET Scans.
Journal of digital imaging
The high-background glucose metabolism of normal gray matter on [18F]-fluoro-2-D-deoxyglucose (FDG) positron emission tomography (PET) of the brain results in a low signal-to-background ratio, potentially increasing the possibility of missing important findings in patients with intracranial malignancies. To explore the strategy of using a deep learning classifier to aid in distinguishing normal versus abnormal findings on PET brain images, this study evaluated the performance of a two-dimensional convolutional neural network (2D-CNN) to classify FDG PET brain scans as normal (N) or abnormal (A).Two hundred eighty-nine brain FDG-PET scans (N; n = 150, A; n = 139) resulting in a total of 68,260 images were included. Nine individual 2D-CNN models with three different window settings for axial, coronal, and sagittal axes were trained and validated. The performance of these individual and ensemble models was evaluated and compared using a test dataset. Odds ratio, Akaike's information criterion (AIC), and area under curve (AUC) on receiver-operative-characteristic curve, accuracy, and standard deviation (SD) were calculated.An optimal window setting to classify normal and abnormal scans was different for each axis of the individual models. An ensembled model using different axes with an optimized window setting (window-triad) showed better performance than ensembled models using the same axis and different windows settings (axis-triad). Increase in odds ratio and decrease in SD were observed in both axis-triad and window-triad models compared with individual models, whereas improvements of AUC and AIC were seen in window-triad models. An overall model averaging the probabilities of all individual models showed the best accuracy of 82.0%.Data ensemble using different window settings and axes was effective to improve 2D-CNN performance parameters for the classification of brain FDG-PET scans. If prospectively validated with a larger cohort of patients, similar models could provide decision support in a clinical setting.
View details for DOI 10.1007/s10278-019-00289-x
View details for PubMedID 31659587
PET/CT Imaging of Human TNFα Using [89Zr]Certolizumab Pegol in a Transgenic Preclinical Model of Rheumatoid Arthritis.
Molecular imaging and biology
Tumor necrosis factor alpha (TNFα) drives inflammation and bone degradation in patients with rheumatoid arthritis (RA). Some RA patients experience a rapid clinical response to TNFα inhibitors such as certolizumab pegol (CZP) while other patients show limited to no response. Current methods for imaging RA have limited sensitivity and do not assist in the selection of patients most likely to respond to immune-mediated therapy. Herein, we developed a novel positron emission tomography (PET) radiotracer for immuno-PET imaging of TNFα in transgenic human TNFα-expressing mice.CZP was modified with p-isothiocyanatobenzyl-deferoxamine (DFO) and radiolabeled with Zr-89. The biological activity of [89Zr]DFO-CZP was evaluated by HPLC and binding assay using human recombinant TNFα (hTNFα). The feasibility of specific immuno-PET imaging of human TNFα was assessed in a transgenic mouse model of RA that expresses human TNFα. This model resembles the progression of RA in humans by maintaining lower levels of circulating hTNFα and exhibits chronic arthritis in the forepaw and hind paw joints. The dosimetry of [89Zr]DFO-CZP in humans was estimated using microPET/CT imaging in Sprague Dawley rats.[89Zr]DFO-CZP was isolated with radiolabeling yields of 85 ± 6 % (n = 5) and specific activities ranging from 74 to 185 MBq/mg (n = 5). Following size exclusion purification, the radiochemical purity of [89Zr]DFO-CZP was greater than 97 %. [89Zr]DFO-CZP retained high immunoreactivity with more than 95 % of the radioactivity shifted into higher molecular weight complexes. Images showed increasing uptake of the tracer in forepaw and hind paw joints with disease progression. No uptake was observed in the model previously administered with an excess amount of unmodified CZP and in normal control mice, demonstrating in vivo specific uptake of [89Zr]DFO-CZP.The feasibility of immuno-PET imaging of human TNFα with [89Zr]DFO-CZP has been demonstrated in a preclinical model of RA.
View details for DOI 10.1007/s11307-019-01363-0
View details for PubMedID 31065895
Initial experience of dedicated breast PET imaging of ER+ breast cancers using [F-18]fluoroestradiol.
NPJ breast cancer
2019; 5: 12
Dedicated breast positron emission tomography (dbPET) is an emerging technology with high sensitivity and spatial resolution that enables detection of sub-centimeter lesions and depiction of intratumoral heterogeneity. In this study, we report our initial experience with dbPET using [F-18]fluoroestradiol (FES) in assessing ER+ primary breast cancers. Six patients with >90% ER+ and HER2- breast cancers were imaged with dbPET and breast MRI. Two patients had ILC, three had IDC, and one had an unknown primary tumor. One ILC patient was treated with letrozole, and another patient with IDC was treated with neoadjuvant chemotherapy without endocrine treatment. In this small cohort, we observed FES uptake in ER+ primary breast tumors with specificity to ER demonstrated in a case with tamoxifen blockade. FES uptake in ILC had a diffused pattern compared to the distinct circumscribed pattern in IDC. In evaluating treatment response, the reduction of SUVmax was observed with residual disease in an ILC patient treated with letrozole, and an IDC patient treated with chemotherapy. Future study is critical to understand the change in FES SUVmax after endocrine therapy and to consider other tracer uptake metrics with SUVmax to describe ER-rich breast cancer. Limitations include variations of FES uptake in different ER+ breast cancer diseases and exclusion of posterior tissues and axillary regions. However, FES-dbPET has a high potential for clinical utility, especially in measuring response to neoadjuvant endocrine treatment. Further development to improve the field of view and studies with a larger cohort of ER+ breast cancer patients are warranted.
View details for DOI 10.1038/s41523-019-0107-9
View details for PubMedID 31016232
View details for PubMedCentralID PMC6467896
A Deep Learning Model to Predict a Diagnosis of Alzheimer Disease by Using 18F-FDG PET of the Brain.
2019; 290 (2): 456–64
Purpose To develop and validate a deep learning algorithm that predicts the final diagnosis of Alzheimer disease (AD), mild cognitive impairment, or neither at fluorine 18 (18F) fluorodeoxyglucose (FDG) PET of the brain and compare its performance to that of radiologic readers. Materials and Methods Prospective 18F-FDG PET brain images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (2109 imaging studies from 2005 to 2017, 1002 patients) and retrospective independent test set (40 imaging studies from 2006 to 2016, 40 patients) were collected. Final clinical diagnosis at follow-up was recorded. Convolutional neural network of InceptionV3 architecture was trained on 90% of ADNI data set and tested on the remaining 10%, as well as the independent test set, with performance compared to radiologic readers. Model was analyzed with sensitivity, specificity, receiver operating characteristic (ROC), saliency map, and t-distributed stochastic neighbor embedding. Results The algorithm achieved area under the ROC curve of 0.98 (95% confidence interval: 0.94, 1.00) when evaluated on predicting the final clinical diagnosis of AD in the independent test set (82% specificity at 100% sensitivity), an average of 75.8 months prior to the final diagnosis, which in ROC space outperformed reader performance (57% [four of seven] sensitivity, 91% [30 of 33] specificity; P < .05). Saliency map demonstrated attention to known areas of interest but with focus on the entire brain. Conclusion By using fluorine 18 fluorodeoxyglucose PET of the brain, a deep learning algorithm developed for early prediction of Alzheimer disease achieved 82% specificity at 100% sensitivity, an average of 75.8 months prior to the final diagnosis. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Larvie in this issue.
View details for DOI 10.1148/radiol.2018180958
View details for PubMedID 30398430
View details for PubMedCentralID PMC6358051
Large Scale Semi-Automated Labeling of Routine Free-Text Clinical Records for Deep Learning.
Journal of digital imaging
2019; 32 (1): 30–37
Breast cancer is a leading cause of cancer death among women in the USA. Screening mammography is effective in reducing mortality, but has a high rate of unnecessary recalls and biopsies. While deep learning can be applied to mammography, large-scale labeled datasets, which are difficult to obtain, are required. We aim to remove many barriers of dataset development by automatically harvesting data from existing clinical records using a hybrid framework combining traditional NLP and IBM Watson. An expert reviewer manually annotated 3521 breast pathology reports with one of four outcomes: left positive, right positive, bilateral positive, negative. Traditional NLP techniques using seven different machine learning classifiers were compared to IBM Watson's automated natural language classifier. Techniques were evaluated using precision, recall, and F-measure. Logistic regression outperformed all other traditional machine learning classifiers and was used for subsequent comparisons. Both traditional NLP and Watson's NLC performed well for cases under 1024 characters with weighted average F-measures above 0.96 across all classes. Performance of traditional NLP was lower for cases over 1024 characters with an F-measure of 0.83. We demonstrate a hybrid framework using traditional NLP techniques combined with IBM Watson to annotate over 10,000 breast pathology reports for development of a large-scale database to be used for deep learning in mammography. Our work shows that traditional NLP and IBM Watson perform extremely well for cases under 1024 characters and can accelerate the rate of data annotation.
View details for DOI 10.1007/s10278-018-0105-8
View details for PubMedID 30128778
View details for PubMedCentralID PMC6382632
Translational Radiomics: Defining the Strategy Pipeline and Considerations for Application-Part 2: From Clinical Implementation to Enterprise
JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY
2018; 15 (3): 543–49
Enterprise imaging has channeled various technological innovations to the field of clinical radiology, ranging from advanced imaging equipment and postacquisition iterative reconstruction tools to image analysis and computer-aided detection tools. More recently, the advancement in the field of quantitative image analysis coupled with machine learning-based data analytics, classification, and integration has ushered in the era of radiomics, a paradigm shift that holds tremendous potential in clinical decision support as well as drug discovery. However, there are important issues to consider to incorporate radiomics into a clinically applicable system and a commercially viable solution. In this two-part series, we offer insights into the development of the translational pipeline for radiomics from methodology to clinical implementation (Part 1) and from that point to enterprise development (Part 2). In Part 2 of this two-part series, we study the components of the strategy pipeline, from clinical implementation to building enterprise solutions.
View details for PubMedID 29366598
Translational Radiomics: Defining the Strategy Pipeline and Considerations for Application-Part 1: From Methodology to Clinical Implementation
JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY
2018; 15 (3): 538–42
Enterprise imaging has channeled various technological innovations to the field of clinical radiology, ranging from advanced imaging equipment and postacquisition iterative reconstruction tools to image analysis and computer-aided detection tools. More recently, the advancements in the field of quantitative image analysis coupled with machine learning-based data analytics, classification, and integration have ushered us into the era of radiomics, which has tremendous potential in clinical decision support as well as drug discovery. There are important issues to consider to incorporate radiomics as a clinically applicable system and a commercially viable solution. In this two-part series, we offer insights into the development of the translational pipeline for radiomics from methodology to clinical implementation (Part 1) and from that to enterprise development (Part 2).
View details for PubMedID 29366600
Delayed Fluorodeoxyglucose Positron Emission Tomography Imaging in the Differentiation of Tumor Recurrence and Radiation Necrosis in Pediatric Central Nervous System Tumors: Case Report and Review of the Literature.
2018; 10 (9): e3364
Malignant central nervous system (CNS) tumors are often treated with radiation therapy, after which clinical and radiographic sequelae can lead to difficulties differentiating tumor recurrence from treatment effect. Magnetic resonance imaging (MRI) is often unable to distinguish between these two entities. The improved ability to delineate concerning foci could lead to earlier tumor detection with quicker access to new therapies and/or clinical trials; conversely, it could alleviate patient concerns in the case of radiation necrosis as the etiology. The utility of positron emission tomography with computed tomography (PET/CT) imaging with fluorodeoxyglucose (FDG) has been explored in CNS tumors in the past, as this imaging modality is widely used in oncologic practices. As there are concerns with false positive imaging in the case of cells with a high metabolic uptake due to causes other than malignancy (i.e. infection, inflammation), delayed FDG PET imaging has been proposed as a mechanism to reduce this confusion. Delayed FDG PET imaging has been explored in several adult and pediatric malignancies, including adult CNS tumors, though there are no current publications applying its use in pediatric CNS tumors. We present two cases of pediatric CNS tumors, where delayed FDG PET imaging helped in the early diagnosis of a recurrence through a distinguishing tumor from the treatment effect.
View details for DOI 10.7759/cureus.3364
View details for PubMedID 30510874
View details for PubMedCentralID PMC6257469
Geographic Variation in Postoperative Imaging for Low-Risk Breast Cancer.
Journal of the National Comprehensive Cancer Network : JNCCN
2018; 16 (7): 829–37
Background: The objective of this study was to examine the presence and magnitude of US geographic variation in use rates of both recommended and high-cost imaging in young patients with early-stage breast cancer during the 18 month period after surgical treatment of their primary tumor. Methods: Using the Truven Health MarketScan Commercial Database, a descriptive analysis was conducted of geographic variation in annual rates of dedicated breast imaging and high-cost body imaging of 36,045 women aged 18 to 64 years treated with surgery for invasive unilateral breast cancer between 2010 and 2012. Multivariate hierarchical analysis examined the relationship between likelihood of imaging and patient characteristics, with metropolitan statistical area (MSA) serving as a random effect. Patient characteristics included age group, BRCA1/2 carrier status, family history of breast cancer, combination of breast surgery type and radiation therapy, drug therapy, and payer type. All MSAs in the United States were included, with areas outside MSAs within a given state aggregated into a single area for analytic purposes. Results: Descriptive analysis of rates of imaging use and intensity within MSA regions revealed wide geographic variation, irrespective of treatment cohort or age group. Increased probability of recommended postoperative dedicated breast imaging was primarily associated with age and treatment including both surgery and radiation therapy, followed by MSA region (odds ratio, 1.42). Increased probability of PET use-a high-cost imaging modality for which postoperative routine use is not recommended in the absence of specific clinical findings-was primarily associated with surgery type followed by MSA region (odds ratio, 1.82). Conclusions: In patients with breast cancer treated for low-risk disease, geography has effects on the rates of posttreatment imaging, suggesting that some patients are not receiving beneficial dedicated breast imaging, and high-cost nonbreast imaging may not be targeted to those groups most likely to benefit.
View details for DOI 10.6004/jnccn.2018.7024
View details for PubMedID 30006425
Exploration of PET and MRI radiomic features for decoding breast cancer phenotypes and prognosis.
NPJ breast cancer
2018; 4: 24
Radiomics is an emerging technology for imaging biomarker discovery and disease-specific personalized treatment management. This paper aims to determine the benefit of using multi-modality radiomics data from PET and MR images in the characterization breast cancer phenotype and prognosis. Eighty-four features were extracted from PET and MR images of 113 breast cancer patients. Unsupervised clustering based on PET and MRI radiomic features created three subgroups. These derived subgroups were statistically significantly associated with tumor grade (p = 2.0 × 10-6), tumor overall stage (p = 0.037), breast cancer subtypes (p = 0.0085), and disease recurrence status (p = 0.0053). The PET-derived first-order statistics and gray level co-occurrence matrix (GLCM) textural features were discriminative of breast cancer tumor grade, which was confirmed by the results of L2-regularization logistic regression (with repeated nested cross-validation) with an estimated area under the receiver operating characteristic curve (AUC) of 0.76 (95% confidence interval (CI) = [0.62, 0.83]). The results of ElasticNet logistic regression indicated that PET and MR radiomics distinguished recurrence-free survival, with a mean AUC of 0.75 (95% CI = [0.62, 0.88]) and 0.68 (95% CI = [0.58, 0.81]) for 1 and 2 years, respectively. The MRI-derived GLCM inverse difference moment normalized (IDMN) and the PET-derived GLCM cluster prominence were among the key features in the predictive models for recurrence-free survival. In conclusion, radiomic features from PET and MR images could be helpful in deciphering breast cancer phenotypes and may have potential as imaging biomarkers for prediction of breast cancer recurrence-free survival.
View details for DOI 10.1038/s41523-018-0078-2
View details for PubMedID 30131973
View details for PubMedCentralID PMC6095872
Contextualizing Oncologic Imaging Utilization Through End-of-Life Spending Patterns
JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY
2017; 14 (10): 1269–78
The aim of this study was to assess the effect of spending patterns during the final year of life on high-cost imaging utilization in the final 3 months of life.An academic comprehensive cancer center's radiology, cancer registry, and claims records were matched to identify decedents with dates of death from April 2013 through June 2014. Spending patterns in the final year of life were identified using group-based trajectory modeling. Descriptive analysis of CT, MRI, and PET utilization across trajectories was conducted. Multivariate logistic regressions modeled the likelihood of imaging utilization in the final 3 months of life, and a sensitivity analysis assessed the impact of spending trajectories on model fit.Six spending trajectories were identified. Membership in the late rising trajectory was the strongest predictor of high-cost imaging in the final 3 months of life (odds ratio, 11.61; P = .000), followed by diagnosis 12 to 6 months premortem (odds ratio, 7.49; P = .000). The likelihood of imaging the final 3 months of life was no different between high persistent and low persistent trajectory patients, despite the heterogeneity between the two patient groups. Sensitivity analysis indicated that spending trajectory improved the prediction of imaging in the final 3 months of life to a greater extent than temporal proximity to death at the time of diagnosis, which may serve as a proxy for severity and/or complexity.Clinical measures of severity and patients' utilization histories should be considered by hospital administrators in estimations of aggregate and individual oncologic imaging utilization. This analytic approach may aid in evaluating participation in advanced payment models.
View details for DOI 10.1016/j.jacr.2017.06.004
View details for Web of Science ID 000412625400007
View details for PubMedID 28709782
In Vivo PET Imaging of the Activated Immune Environment in a Small Animal Model of Inflammatory Arthritis
2017; 16: 1536012117712638
Evolving immune-mediated therapeutic strategies for rheumatoid arthritis (RA) may benefit from an improved understanding of the complex role that T-cell activation plays in RA. This study assessed the potential of fluorine-18-labeled 9-β-d-arabinofuranosylguanine ([18F]F-AraG) positron emission tomography (PET) imaging to report immune activation in vivo in an adjuvant-induced arthritis (AIA) small animal model.Using positron emission tomography-computed tomography imaging, uptake of [18F]F-AraG in the paws of mice affected by arthritis at 6 (acute) and 20 (chronic) days following AIA induction in a single paw was assessed and compared to uptake in contralateral control paws. Fractions of T cells and B cells demonstrating markers of activation at the 2 time points were determined by flow cytometry.Differential uptake of [18F]F-AraG was demonstrated on imaging of the affected joint when compared to control at both acute and chronic time points with corresponding changes in markers of T-cell activation observed on flow cytometry.[18F]F-AraG may serve as an imaging biomarker of T-cell activation in inflammatory arthritis. Further development of this technique is warranted and could offer a tool to explore the temporal link between activated T cells and RA as well as to monitor immune-mediated therapies for RA in clinical trials.
View details for DOI 10.1177/1536012117712638
View details for Web of Science ID 000403887800001
View details for PubMedID 28625080
View details for PubMedCentralID PMC5480631
A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant.
2017; 77 (11): 2893-2902
A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893-902. ©2017 AACR.
View details for DOI 10.1158/0008-5472.CAN-16-2953
View details for PubMedID 28572504
Contextualizing the use of oncologic imaging within treatment phases: imaging trends and modality preferences, 2000-2014
2017; 24 (2): E99–E105
In the present study, we retrospectively evaluated the use of tomographic imaging in adult cancer patients to clarify how recent growth plateaus in the use of tomographic imaging in the United States might have affected oncologic imaging during the same period.At a U.S. academic cancer centre, 12,059 patients with dates of death from January 2000 through December 2014 were identified. Imaging was restricted to brain and body computed tomography (ct), brain and body magnetic resonance (mr), and body positron-emission tomography (pet) with and without superimposed ct. Trends during the staging (1 year after diagnosis), monitoring (18-6 months before death), and end-of-life (final 6 months before death) phases were analyzed.Comparing the 2005-2009 with the 2010-2014 period, mean intensity of pet imaging increased 21% during staging (p = 0.0000) and 27% during end of life (p = 0.0019). In the monitoring phase, mean intensity for ct brain, ct body, and mr body imaging decreased by 26% (p = 0.0133), 11% (p = 0.0118), and 26% (p = 0.0008), respectively. Aggregate mean intensity of imaging increased in the 13%-27% range every 3 months from 18 months before death to death, reaching 1.43 images in the final 3 months of life. Patients diagnosed in the final 18 months of life had an average of 1 additional image during both the 3 months after diagnosis (p = 0.0000) and the final 3 months before death (p = 0.0000).Imaging increased as temporal proximity to death decreased, and patients diagnosed near death received more staging imaging, suggesting that imaging guidelines should consider imaging intensity within the context of treatment phase. Despite the development, by multiple organizations, of appropriateness criteria to reduce imaging utilization, aggregate per-patient imaging showed insignificant changes. Simultaneous fluctuations in the intensity of imaging by modality suggest recent changes in the modalities preferred by providers.
View details for DOI 10.3747/co.24.3216
View details for Web of Science ID 000401830000004
View details for PubMedID 28490932
View details for PubMedCentralID PMC5407885
- Dedicated Breast Positron Emission Tomography for the Evaluation of Early Response to Neoadjuvant Chemotherapy in Breast Cancer. Clinical breast cancer 2017; 17 (3): e155–e159
Imaging Bone-Cartilage Interactions in Osteoarthritis Using [F-18]-NaF PET-MRI
2016; 15: 1–12
Simultaneous positron emission tomography-magnetic resonance imaging (PET-MRI) is an emerging technology providing both anatomical and functional images without increasing the scan time. Compared to the traditional PET/computed tomography imaging, it also exposes the patient to significantly less radiation and provides better anatomical images as MRI provides superior soft tissue characterization. Using PET-MRI, we aim to study interactions between cartilage composition and bone function simultaneously, in knee osteoarthritis (OA).In this article, bone turnover and remodeling was studied using [18F]-sodium fluoride (NaF) PET data. Quantitative MR-derived T1ρ relaxation times characterized the biochemical cartilage degeneration. Sixteen participants with early signs of OA of the knee received intravenous injections of [18F]-NaF at the onset of PET-MR image acquisition. Regions of interest were identified, and kinetic analysis of dynamic PET data provided the rate of uptake ( Ki) and the normalized uptake (standardized uptake value) of [18F]-NaF in the bone. Morphological MR images and quantitative voxel-based T1ρ maps of cartilage were obtained using an atlas-based registration technique to segment cartilage automatically. Voxel-by-voxel statistical parameter mapping was used to investigate the relationship between bone and cartilage.Increases in cartilage T1ρ, indicating degenerative changes, were associated with increased turnover in the adjoining bone but reduced turnover in the nonadjoining compartments. Associations between pain and increased bone uptake were seen in the absence of morphological lesions in cartilage, but the relationship was reversed in the presence of incident cartilage lesions.This study shows significant cartilage and bone interactions in OA of the knee joint using simultaneous [18F]-NaF PET-MR, the first in human study. These observations highlight the complex biomechanical and biochemical interactions in the whole knee joint in OA, which potentially could help assess therapeutic targets in treating OA.
View details for DOI 10.1177/1536012116683597
View details for Web of Science ID 000394789100001
View details for PubMedID 28654417
View details for PubMedCentralID PMC5470142
ACR Practice Parameter for the Performance of Therapy With Unsealed Radiopharmaceutical Sources
CLINICAL NUCLEAR MEDICINE
2016; 41 (2): 106–17
This practice parameter is intended to guide appropriately trained and licensed physicians performing therapy with unsealed radiopharmaceutical sources. Such therapy requires close cooperation and communication between the physicians who are responsible for the clinical management of the patient and those who administer radiopharmaceutical therapy and manage the attendant side effects. Adherence to this practice parameter should help to maximize the efficacious use of these procedures, maintain safe conditions, and ensure compliance with applicable regulations. The goal of therapy with unsealed radiopharmaceutical sources is to provide either cure or effective palliation of disease while minimizing untoward side effects and complications.
View details for DOI 10.1097/RLU.0000000000001036
View details for Web of Science ID 000368629600017
View details for PubMedID 26646993
- Overall and disease-free survival outcomes of patients receiving intensity-modulated radiation therapy (IMRT) with PET-CT-based planning for cancers of the head and neck JOURNAL OF RADIOTHERAPY IN PRACTICE 2015; 14 (3): 285–95
Detection of Recurrent Non-Hodgkin Lymphoma on In-111 Capromab Pendetide Imaging
CLINICAL NUCLEAR MEDICINE
2015; 40 (7): 585–88
A 73-year-old man presented with a rising prostate-specific antigen (PSA) level 5 years following brachytherapy for prostate cancer. In-111 capromab pendetide (ProstaScint) whole-body planar imaging revealed abnormal uptake in the right knee, localizing to a mass in the popliteal fossa on SPECT/CT. MRI showed a mass encasing the popliteal artery and vein, subsequently found to be non-Hodgkin lymphoma on biopsy. Response of the mass to chemotherapy was documented on ¹⁸F-FDG PET/CT. Elevated In-111 capromab pendetide uptake in soft tissue can be important but unrelated to prostate cancer, as demonstrated in this case.
View details for DOI 10.1097/RLU.0000000000000782
View details for Web of Science ID 000356375000013
View details for PubMedID 25899589
Detection and localization of carcinoma within the prostate using high resolution transrectal gamma imaging (TRGI) of monoclonal antibody directed at prostate specific membrane antigen (PSMA)-Proof of concept and initial imaging results
EUROPEAN JOURNAL OF RADIOLOGY
2013; 82 (11): 1877–84
Molecular imaging methods may identify primary prostate cancer foci and potentially guide biopsy and optimal management approaches. In this exploratory study, safety and first human imaging experience of a novel solid state endocavity transrectal gamma-imaging (TRGI) device was evaluated.Twelve patients received 5 ± 0.5 mCi In-111 capromab pendetide (ProstaScint) intravenously and the prostate of each was imaged 4 days later transrectally using an endoluminal cadmium zinc telluride (CZT)-based compact gamma camera (ProxiScan™, Hybridyne Imaging Technologies, Inc.). Immediate and 5-7-day post imaging safety assessments were performed. In those patients with a prostate cancer diagnosis (N=10), single photon emission computed tomography (SPECT-CT) and magnetic resonance imaging (MRI) of the pelvis were also acquired. Images were reviewed and sites of suspected cancer were localized by prostate quadrant by consensus of two nuclear medicine physicians. Pathology from TRUS biopsy, or surgical pathology following prostatectomy (N=3) when available, served as the gold standard.There were no serious adverse events associated with TRGI. No focal signal was detected in patients without a diagnosis of prostate cancer (N=2). Of 40 quadrants evaluated in the cancer cohort (N=10), 22 contained malignancy. In 8 of these 10 patients, the most focal site of uptake on TRGI corresponded to a prostatic quadrant with biopsy-proven malignancy. In 6 cancer-containing quadrants, TRGI was positive where SPECT-CT was negative; MRI showed a detectable abnormality in only 1 of these 6 quadrants. Qualitative image review of the planar TRGI images for prostate cancer localization was severely limited in some cases by scatter artifact within the vicinity of the prostate gland arising from physiologic urine and blood pool activity from nearby structures.TRGI is a safe imaging method that can potentially detect radiopharmaceutical uptake of primary prostate cancer and facilitate prostatic quadrant - localization of cancer. Further investigation of this technology is warranted.
View details for DOI 10.1016/j.ejrad.2013.07.025
View details for Web of Science ID 000325484600026
View details for PubMedID 23993140
Preclinical SPECT and SPECT/CT.
Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer
2013; 187: 193–220
The molecular processes underlying carcinogenesis and malignant spread are the foundation of future drug development for the treatment of cancer. Understanding these processes requires study of the interaction of complex biologic systems in a way that spatially and temporally recapitulates that seen in humans. Likewise, once an anticancer agent is developed, its intended antitumor action and its unintended side-effects must be studied in a rigorous and reproducible manner prior to its introduction into the clinic, a process that can benefit from methods that elucidate specific molecular processes and that can be performed serially. Recent advances in small-animal models of cancer, radiochemistry of single photon emitting radionuclides, single photon emission tomography systems, and image reconstruction techniques have set the stage for an ever-increasing use of SPECT and SPECT/CT in preclinical oncology-related applications. Several of these advances as well as several specific applications in oncology are highlighted and areas needing further improvement are identified.
View details for DOI 10.1007/978-3-642-10853-2_6
View details for PubMedID 23179882
Improved techniques to localize foci of carcinoma within the prostate using high-resolution transrectal gamma imaging (TRGI) of monoclonal antibody directed at prostate specific membrane antigen (PSMA).
AMER SOC CLINICAL ONCOLOGY. 2012
View details for Web of Science ID 000318009803664
Clinical Utility of SPECT-(Low-Dose)CT Versus SPECT Alone in Patients Presenting for Bone Scintigraphy
CLINICAL NUCLEAR MEDICINE
2012; 37 (1): 26–34
This prospective study evaluated the contribution of single-photon emission computed tomography (SPECT)-(low-dose)CT (SPECT-ldCT) over SPECT alone in all-comers referred for bone scintigraphy for any indication.In this prospective study, imaging was performed on 100 consecutive patients who presented for bone scintigraphy using a combined SPECT-ldCT single-gantry system (Brightview XCT, Philips Medical Systems Inc., Cleveland, OH). SPECT images were reconstructed with (AC) and without (NAC) attenuation and scatter correction. SPECT (NAC), SPECT-ldCT (NAC), and SPECT-ldCT (AC) were reviewed independently and in a blinded manner. Reader interpretation of images was compared with the final clinical diagnosis.Subjects were referred for oncologic (28%) and nononcologic (72%) indications. Attenuation correction significantly improved perceived image quality (P = 0.012), but did not significantly alter diagnostic confidence (P = 0.96). Availability of ldCT data during interpretation of the SPECT images yielded a significant increase in the level of diagnostic confidence (P < 0.001). When the ldCT data were available, 18 of 200 bone SPECT reads recommended additional diagnostic CT imaging, compared with 70 when ldCT data were unavailable at the time of reading (P < 0.001). The sensitivity, specificity, and accuracy of SPECT-ldCT (with or without attenuation and scatter correction) in the diagnosis of osseous processes were 90.9%, 85.9%, and 87.0%, respectively, and these values did not differ significantly from those obtained with SPECT alone.Bone SPECT-ldCT provides interpreting physicians a significantly greater level of diagnostic confidence and reduces additional diagnostic imaging studies, but the overall diagnostic accuracy of SPECT-ldCT was not affected when compared with SPECT alone, suggesting that SPECT-ldCT should be used on a patient-by-patient basis.
View details for DOI 10.1097/RLU.0b013e3182392bd0
View details for Web of Science ID 000298146300013
View details for PubMedID 22157024
Thyroid and Hepatic Function After High-Dose I-131-Metaiodobenzylguanidine (I-131-MIBG) Therapy for Neuroblastoma
PEDIATRIC BLOOD & CANCER
2011; 56 (2): 191–201
(131) I-Metaiodobenzylguanidine ((131) I-MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and (131) I-MIBG is concentrated in the liver after (131) I-MIBG therapy. The aim of our study was to analyze the effects of (131) I-MIBG therapy on thyroid and liver function.Pre- and post-therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with (131) I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg, number of treatments, time from treatment to follow-up, sex, and patient age was examined.In patients who presented with Grade 0 or 1 thyroid toxicity at baseline, 12 ± 4% experienced onset of or worsening to Grade 2 hypothyroidism and one patient developed Grade 2 hyperthyroidism by 2 years after (131) I-MIBG therapy. At 2 years post-(131) I-MIBG therapy, 76 ± 4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23 ± 5% experienced onset of or worsening to Grade 3 or 4 liver toxicity. Liver toxicity was usually transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies.The prophylactic regimen of potassium iodide and potassium perchlorate with (131) I-MIBG therapy resulted in a low rate of significant hypothyroidism. Liver abnormalities following (131) I-MIBG therapy were primarily reversible and did not result in late toxicity. (131) I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction.
View details for DOI 10.1002/pbc.22767
View details for Web of Science ID 000286017500005
View details for PubMedID 20830775
View details for PubMedCentralID PMC3006009
Patient-Specific Method of Generating Parametric Maps of Patlak K(i) without Blood Sampling or Metabolite Correction: A Feasibility Study.
International journal of molecular imaging
2011; 2011: 185083
Currently, kinetic analyses using dynamic positron emission tomography (PET) experience very limited use despite their potential for improving quantitative accuracy in several clinical and research applications. For targeted volume applications, such as radiation treatment planning, treatment monitoring, and cerebral metabolic studies, the key to implementation of these methods is the determination of an arterial input function, which can include time-consuming analysis of blood samples for metabolite correction. Targeted kinetic applications would become practical for the clinic if blood sampling and metabolite correction could be avoided. To this end, we developed a novel method (Patlak-P) of generating parametric maps that is identical to Patlak K(i) (within a global scalar multiple) but does not require the determination of the arterial input function or metabolite correction. In this initial study, we show that Patlak-P (a) mimics Patlak K(i) images in terms of visual assessment and target-to-background (TB) ratios of regions of elevated uptake, (b) has higher visual contrast and (generally) better image quality than SUV, and (c) may have an important role in improving radiotherapy planning, therapy monitoring, and neurometabolism studies.
View details for DOI 10.1155/2011/185083
View details for PubMedID 21912742
View details for PubMedCentralID PMC3168784
Biodistributions of Lu-177- and In-111-Labeled 7E11 Antibodies to Prostate-Specific Membrane Antigen in Xenograft Model of Prostate Cancer and Potential Use of In-111-7E11 as a Pre-therapeutic Agent for Lu-177-7E11 Radioimmunotherapy
MOLECULAR IMAGING AND BIOLOGY
2009; 11 (3): 159–66
Prostate-specific membrane antigen is a transmembrane glycoprotein highly expressed in many prostate cancers and can be targeted with radiolabeled antibodies for diagnosis and treatment of this disease. To serve as a radioimmunotherapeutic agent, a kinetically inert conjugate is desired to maximize tumor uptake and tumor radiation dose with minimal nonspecific exposure to bone marrow and other major organs.In this study, we assessed the pharmacokinetics and biodistribution of the 7E11 monoclonal antibody (MAb) radiolabeled with the lutetium-177 ((177)Lu)-tetraazacyclododecanetetraacetic acid conjugate system ((177)Lu-7E11) versus those of the 7E11 MAb radiolabeled with the indium-111 ((111)In)/glycyl-tyrosyl-(N,-diethylenetriaminepentaacetic acid)/lysine hydrochloride conjugate system ((111)In-7E11, also known as ProstaScint) to determine the feasibility of using (111)In-7E11 as a pre-therapeutic agent for (177)Lu-7E11 radioimmunotherapy. Pharmacokinetic and biodistribution studies of (177)Lu-7E11 in lymph node cancer of the prostate (LNCaP) xenograft mice were performed at 2, 8, 12, 24, 72, and 168 h after radiopharmaceutical administration. For (111)In-7E11, pharmacokinetic and biodistribution studies were performed at 8, 24, and 72 h. Parallel studies of (177)Lu-7E11 in non-tumor-bearing mice at 8, 24, and 72 h post-injection served as controls. Gamma scintigraphy was performed, followed by autoradiography and tissue counting, to demonstrate and quantify the distributions of radioconjugated MAb in the tumor and normal tissues.Both (177)Lu- and (111)In-7E11 conjugates demonstrated an early blood pool phase in which uptake was dominated by the blood, lung, spleen and liver, followed by uptake and retention of the radiolabeled antibody in the tumor which was most prominent at 24 h. Total accumulation of radioconjugated MAb in tumor at 24 h was greater in the case of (177)Lu-7E11 in comparison to that of (111)In-7E11. Continued accumulation in tumor was observed for the entire time course studied for both (177)Lu-7E11 and (111)In-7E11. The liver was the only major organ demonstrating a significant difference in accumulation between the two conjugates. In conclusion, pharmacokinetic and biodistribution studies of (177)Lu-7E11 in LNCaP xenograft mouse models support its potential application as a radioimmunotherapeutic agent targeting prostate cancer, and the distribution and tumor uptake of (111)In-7E11 appear to be similar to those of (177)Lu-7E11, supporting its use as a pre-therapeutic tool to assess the potential accumulation of (177)Lu-7E11 radioimmunotherapeutic at sites of prostate cancer. However, the different accumulation patterns of the (111)In and (177)Lu immunoconjugates in liver will likely prevent the use of (111)In-7E11 as a true dosimetry tool for (177)Lu-7E11 radioimmunotherapy.
View details for DOI 10.1007/s11307-008-0185-9
View details for Web of Science ID 000265686900003
View details for PubMedID 19034582
View details for PubMedCentralID PMC2841328
Iodine-131-Metaiodobenzylguanidine Double Infusion With Autologous Stem-Cell Rescue for Neuroblastoma: A New Approaches to Neuroblastoma Therapy Phase I Study
JOURNAL OF CLINICAL ONCOLOGY
2009; 27 (7): 1020–25
Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) provides targeted radiotherapy with more than 30% response rate in refractory neuroblastoma, but activity infused is limited by radiation safety and hematologic toxicity. The goal was to determine the maximum-tolerated dose of (131)I-MIBG in two consecutive infusions at a 2-week interval, supported by autologous stem-cell rescue (ASCR) 2 weeks after the second dose.The (131)I-MIBG dose was escalated using a 3 + 3 phase I trial design, with levels calculated by cumulative red marrow radiation index (RMI) from both infusions. Using dosimetry, the second infusion was adjusted to achieve the target RMI, except at level 4, where the second infusion was capped at 21 mCi/kg.Twenty-one patients were enrolled onto the study at levels 1 to 4, with 18 patients assessable for toxicity and 20 patients assessable for response. Cumulative (131)I-MIBG given to achieve the target RMI ranged from 22 to 50 mCi/kg, with cumulative RMI of 3.2 to 8.92 Gy. No patient had a dose-limiting toxicity. Reversible grade 3 nonhematologic toxicity occurred in six patients at level 4, establishing the recommended cumulative dose as 36 mCi/kg. The median time to absolute neutrophil count more than 500/microL after ASCR was 13 days (4 to 27 days) and to platelet independence was 17 days (6 to 47 days). Responses included two partial responses, eight mixed responses, three stable disease, and seven progressive disease. Responses by semiquantitative MIBG score occurred in eight patients, soft tissue responses occurred in five of 11 patients, but bone marrow responses occurred in only two of 13 patients.The lack of toxicity with this approach allowed dramatic dose intensification of (131)I-MIBG, with minimal toxicity and promising activity.
View details for DOI 10.1200/JCO.2007.15.7628
View details for Web of Science ID 000266193500005
View details for PubMedID 19171714
View details for PubMedCentralID PMC2738616
Identification of MCAM/CD146 as the Target Antigen of a Human Monoclonal Antibody that Recognizes Both Epithelioid and Sarcomatoid Types of Mesothelioma
2009; 69 (4): 1570–77
The prognosis for patients diagnosed with mesothelioma is generally poor, and currently available treatments are usually ineffective. Therapies that specifically target tumor cells hold much promise for the treatment of cancers that are resistant to current approaches. We have previously selected phage antibody display libraries on mesothelioma cell lines to identify a panel of internalizing human single chain (scFv) antibodies that target mesothelioma-associated, clinically represented cell surface antigens and further exploited the internalizing function of these scFvs to specifically deliver lethal doses of liposome-encapsulated small molecule drugs to both epithelioid and sarcomatous subtypes of mesothelioma cells. Here, we report the identification of MCAM/MUC18/CD146 as the surface antigen bound by one of the mesothelioma-targeting scFvs using a novel cloning strategy based on yeast surface human proteome display. Immunohistochemical analysis of mesothelioma tissue microarrays confirmed that MCAM is widely expressed by both epithelioid and sarcomatous types of mesothelioma tumor cells in situ but not by normal mesothelial cells. In addition, quantum dot-labeled anti-MCAM scFv targets primary meosthelioma cells in tumor fragment spheroids cultured ex vivo. As the first step in evaluating the therapeutic potential of MCAM-targeting antibodies, we performed single-photon emission computed tomography studies using the anti-MCAM scFv and found that it recognizes mesothelioma organotypic xenografts in vivo. The combination of phage antibody library selection on tumor cells and rapid target antigen identification by screening the yeast surface-displayed human proteome could be a powerful method for mapping the targetable tumor cell surface epitope space.
View details for DOI 10.1158/0008-5472.CAN-08-1363
View details for Web of Science ID 000263399100042
View details for PubMedID 19221091
View details for PubMedCentralID PMC2752656
CAN POSITRON EMISSION TOMOGRAPHY (PET) OR PET/COMPUTED TOMOGRAPHY (CT) ACQUIRED IN A NONTREATMENT POSITION BE ACCURATELY REGISTERED TO A HEAD-AND-NECK RADIOTHERAPY PLANNING CT?
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2009; 73 (2): 578–84
To quantify the uncertainties associated with incorporating diagnostic positron emission tomography/CT (PET/CT) and PET into the radiotherapy treatment-planning process using different image registration tools, including automated and manual rigid body registration methods, as well as deformable image registration.The PET/CTs and treatment-planning CTs from 12 patients were used to evaluate image registration accuracy. The PET/CTs also were used without the contemporaneously acquired CTs to evaluate the registration accuracy of stand-alone PET. Registration accuracy for relevant normal structures was quantified using an overlap index and differences in the center of mass (COM) positions. For tumor volumes, the registration accuracy was measured using COM positions only.Registration accuracy was better with PET/CT than with PET alone. The COM displacements ranged from 3.2 +/- 0.6 mm (mean +/- 95% confidence interval, for brain) to 8.4 +/- 2.6 mm (spinal cord) for registration with PET/CT data, compared with 4.8 +/- 1.7 mm (brain) and 9.9 +/- 3.1 mm (spinal cord) with PET alone. Deformable registration improved accuracy, with minimum and maximum errors of 1.1 +/- 0.8 mm (brain) and 5.4 +/- 1.4 mm (mandible), respectively.It is possible to incorporate PET and/or PET/CT acquired in diagnostic positions into the treatment-planning process through the use of advanced image registration algorithms, but precautions must be taken, particularly when delineating tumor volumes in the neck. Acquisition of PET/CT in the treatment-planning position would be the ideal method to minimize registration errors.
View details for DOI 10.1016/j.ijrobp.2008.09.041
View details for Web of Science ID 000262543800036
View details for PubMedID 19084350
Development of an optimized activatable MMP-14 targeted SPECT imaging probe
BIOORGANIC & MEDICINAL CHEMISTRY
2009; 17 (2): 653-659
Matrix metalloproteinase-14 (MT1-MMP or MMP-14) is a membrane-associated protease implicated in a variety of tissue remodeling processes and a molecular hallmark of select metastatic cancers. The ability to detect MMP-14 in vivo would be useful in studying its role in pathologic processes and may potentially serve as a guide for the development of targeted molecular therapies. Four MMP-14 specific probes containing a positively charged cell penetrating peptide (CPP) d-arginine octamer (r(8)) linked with a MMP-14 peptide substrate and attenuating sequences with glutamate (8e, 4e) or glutamate-glycine (4eg and 4egg) repeating units were modeled using an AMBER force field method. The probe with 4egg attenuating sequence exhibited the highest CPP/attenuator interaction, predicting minimized cellular uptake until cleaved. The in vitro MMP-14-mediated cleavage studies using the human recombinant MMP-14 catalytic domain revealed an enhanced cleavage rate that directly correlated with the linearity of the embedded peptide substrate sequence. Successful cleavage and uptake of a technetium-99m labeled version of the optimal probe was demonstrated in MMP-14 transfected human breast cancer cells. Two-fold reduction of cellular uptake was found in the presence of a broad spectrum MMP inhibitor. The combination of computational chemistry, parallel synthesis and biochemical screening, therefore, shows promise as a set of tools for developing new radiolabeled probes that are sensitive to protease activity.
View details for DOI 10.1016/j.bmc.2008.11.078
View details for Web of Science ID 000262708300027
View details for PubMedID 19109023
View details for PubMedCentralID PMC2639212
Diagnostic value of PET/CT for the staging and restaging of pediatric tumors
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
2009; 36 (1): 23-36
The objective of this retrospective study was to compare the diagnostic value of 2-[(18)F]fluoro-2-deoxy-D: -glucose positron emission tomography ((18)F-FDG PET)/CT versus (18)F-FDG PET and CT alone for staging and restaging of pediatric solid tumors.Forty-three children and adolescents (19 females and 24 males; mean age, 15.2 years; age range, 6-20 years) with osteosarcoma (n = 1), squamous cell carcinoma (n = 1), synovial sarcoma (n = 2), germ cell tumor (n = 2), neuroblastoma (n = 2), desmoid tumor (n = 2), melanoma (n = 3), rhabdomyosarcoma (n = 5), Hodgkin's lymphoma (n = 7), non-Hodgkin-lymphoma (n = 9), and Ewing's sarcoma (n = 9) who had undergone (18)F-FDG PET/CT imaging for primary staging or follow-up of metastases were included in this study. The presence, location, and size of primary tumors was determined separately for PET/CT, PET, and CT by two experienced reviewers. The diagnosis of the primary tumor was confirmed by histopathology. The presence or absence of metastases was confirmed by histopathology (n = 62) or clinical and imaging follow-up (n = 238).The sensitivities for the detection of solid primary tumors using integrated (18)F-FDG PET/CT (95%), (18)F-FDG PET alone (73%), and CT alone (93%) were not significantly different (p > 0.05). Seventeen patients showed a total of 153 distant metastases. Integrated PET/CT had a significantly higher sensitivity for the detection of these metastases (91%) than PET alone (37%; p < 0.05), but not CT alone (83%; p > 0.05). When lesions with a diameter of less than 0.5 cm were excluded, PET/CT (89%) showed a significantly higher specificity compared to PET (45%; p < 0.05) and CT (55%; p < 0.05). In a sub-analysis of pulmonary metastases, the values for sensitivity and specificity were 90%, 14%, 82% and 63%, 78%, 65%, respectively, for integrated PET/CT, stand-alone PET, and stand-alone CT. For the detection of regional lymph node metastases, (18)F-FDG PET/CT, (18)F-FDG PET alone, and CT alone were diagnostically correct in 83%, 61%, and 42%. A sub-analysis focusing on the ability of PET/CT, PET, and CT to detect osseous metastases showed no statistically significant difference between the three imaging modalities (p > 0.05).Our study showed a significantly increased sensitivity of PET/CT over that of PET for the detection of distant metastases but not over that of CT alone. However, the specificity of PET/CT for the characterization of pulmonary metastases with a diameter > 0.5 cm and lymph node metastases with a diameter of <1 cm was significantly increased over that of CT alone.
View details for DOI 10.1007/s00259-008-0911-1
View details for Web of Science ID 000261422600004
View details for PubMedID 18719909
Multiple Scalp Lesions in a Patient with Keratitis, Ichthyosis and Deafness Syndrome Mimicking Metastatic Squamous Cell Carcinoma on 18F-FDG PET/CT.
Radiology case reports
2009; 4 (2): 218-?
We report the case of a 17-year-old girl with keratitis, ichthyosis, and deafness (KID) syndrome. As a complication of her KID syndrome she developed squamous cell carcinoma at the left index finger. Additional clinical features were multiple soft tissue lesions over the scalp mimicking metastatic disease on 18F-FDG PET/CT. To our knowledge, this is the first case report about the uptake pattern of KID syndrome associated skin lesions on whole body PET/CT with 18F-FDG.
View details for DOI 10.2484/rcr.v4i2.218
View details for PubMedID 27307799
Role of IV Iodinated Contrast Material in F-18-FDG PET/CT of Liver Metastases
AMERICAN JOURNAL OF ROENTGENOLOGY
2008; 191 (5): 1436–39
The purpose of our study was to investigate the role of IV iodinated contrast material in the evaluation of hepatic metastases at (18)F-FDG PET/CT.We retrospectively identified 39 patients (25 men and 14 women) with suspected isolated hepatic metastases from colorectal cancer who underwent FDG PET/CT. The CT protocol included acquisition of unenhanced and multiphase contrast-enhanced CT images through the liver. At two separate sittings, four readers (two radiologists and two nuclear medicine physicians) noted and characterized all hepatic lesions in consensus, first based on PET and unenhanced CT images and later based on PET and contrast-enhanced CT images. The nature of detected lesions was established by histopathologic or clinicoradiologic correlation.A total of 178 hepatic lesions were identified, consisting of 137 metastases and 41 benign lesions. Using lesion-based analyses with Obuchowski's method for paired observations, 172 of 178 lesions (97%) were detected at PET/contrast-enhanced CT compared with only 135 of 178 (76%) at PET/unenhanced CT (p = 0.0004). Specifically, 114 of 137 (83%) hepatic metastases were detected on PET/contrast-enhanced CT compared with 92 of 137 (67%) on PET/unenhanced CT (p = 0.012). One hundred thirty-one of 178 lesions (73%) were accurately characterized at PET/contrast-enhanced CT compared with 101 of 178 (57%) at PET/unenhanced CT (p = 0.004).IV iodinated contrast material administration improves the detection of hepatic metastases and the characterization of focal hepatic lesions at PET/CT.
View details for DOI 10.2214/AJR.07.3750
View details for Web of Science ID 000260246700024
View details for PubMedID 18941082
Small-Animal SPECT and SPECT/CT: Important Tools for Preclinical Investigation
JOURNAL OF NUCLEAR MEDICINE
2008; 49 (10): 1651–63
The need to study dynamic biologic processes in intact small-animal models of disease has stimulated the development of high-resolution nuclear imaging methods. These methods are capable of clarifying molecular interactions important in the onset and progression of disease, assessing the biologic relevance of drug candidates and potential imaging agents, and monitoring therapeutic effectiveness of pharmaceuticals serially within a single-model system. Single-photon-emitting radionuclides have many advantages in these applications, and SPECT can provide 3-dimensional spatial distributions of gamma- (and x-) ray-emitting radionuclide imaging agents or therapeutics. Furthermore, combining SPECT with CT in a SPECT/CT system can assist in defining the anatomic context of biochemical processes and improve the quantitative accuracy of the SPECT data. Over the past decade, dedicated small-animal SPECT and SPECT/CT systems have been developed in academia and industry. Although significant progress in this arena has been realized through system development and biologic application, further innovation continues to address challenges in camera sensitivity, spatial resolution, and image reconstruction and quantification. The innumerable applications of small-animal SPECT and SPECT/CT in drug development, cardiology, neurology, and oncology are stimulating further investment in education, research, and development of these dedicated small-animal imaging modalities.
View details for DOI 10.2967/jnumed.108.055442
View details for Web of Science ID 000260229900044
View details for PubMedID 18794275
Assessment of the sources of error affecting the quantitative accuracy of SPECT imaging in small animals
PHYSICS IN MEDICINE AND BIOLOGY
2008; 53 (9): 2233–52
Small animal SPECT imaging systems have multiple potential applications in biomedical research. Whereas SPECT data are commonly interpreted qualitatively in a clinical setting, the ability to accurately quantify measurements will increase the utility of the SPECT data for laboratory measurements involving small animals. In this work, we assess the effect of photon attenuation, scatter and partial volume errors on the quantitative accuracy of small animal SPECT measurements, first with Monte Carlo simulation and then confirmed with experimental measurements. The simulations modeled the imaging geometry of a commercially available small animal SPECT system. We simulated the imaging of a radioactive source within a cylinder of water, and reconstructed the projection data using iterative reconstruction algorithms. The size of the source and the size of the surrounding cylinder were varied to evaluate the effects of photon attenuation and scatter on quantitative accuracy. We found that photon attenuation can reduce the measured concentration of radioactivity in a volume of interest in the center of a rat-sized cylinder of water by up to 50% when imaging with iodine-125, and up to 25% when imaging with technetium-99m. When imaging with iodine-125, the scatter-to-primary ratio can reach up to approximately 30%, and can cause overestimation of the radioactivity concentration when reconstructing data with attenuation correction. We varied the size of the source to evaluate partial volume errors, which we found to be a strong function of the size of the volume of interest and the spatial resolution. These errors can result in large (>50%) changes in the measured amount of radioactivity. The simulation results were compared with and found to agree with experimental measurements. The inclusion of attenuation correction in the reconstruction algorithm improved quantitative accuracy. We also found that an improvement of the spatial resolution through the use of resolution recovery techniques (i.e. modeling the finite collimator spatial resolution in iterative reconstruction algorithms) can significantly reduce the partial volume errors.
View details for DOI 10.1088/0031-9155/53/9/002
View details for Web of Science ID 000255120100003
View details for PubMedID 18401059
View details for PubMedCentralID PMC2871254
Correcting tumour SUV for enhanced bone marrow uptake: retrospective F-18-FDG PET/CT studies
NUCLEAR MEDICINE COMMUNICATIONS
2008; 29 (4): 359-366
The concentration of F-FDG in the bone marrow is usually low. One common cause of high uptake is due to bone marrow stimulating drugs administered in conjunction with chemotherapy or radiation therapy. It has been hypothesized that the sequestration of F-FDG to the bone marrow may reduce the standardized uptake value (SUV) of a tumour. We tested this hypothesis by quantifying total F-FDG uptake in the bone marrow of patients with visibly enhanced bone marrow uptake and computing its effect on tumour SUV.Total F-FDG in bone marrow was measured in two groups of PET/CT studies: one (n=19) with visibly enhanced bone marrow, the other (n=5), a baseline group with 'normal' levels of uptake. To measure the F-FDG in bone marrow, the entire skeleton in the CT was segmented from surrounding tissue, and the resulting volume applied to the PET image. Using kinetic analysis we show that the predicted correction factor to tumour SUV is given by (1-q0/Q)/(1-q/Q), where Q is the injected dose, and q and q0 are enhanced and baseline bone marrow uptake (MBq).The enhanced bone marrow uptake averaged 8.9+/-3.2% of injected dose (15.2% max) vs. 4.2+/-0.4% (4.6% max) at baseline. This resulted in a predicted artificial decrease in tumour SUV of up to 11.5% (4.9+/-4.3%, on average).Enhanced bone marrow uptake is predicted to reduce tumour SUVs by as much as 11.5% in our patient group and is a potential confounding factor in using SUV for monitoring tumour response to therapy.
View details for Web of Science ID 000254261300010
View details for PubMedID 18317301
Nuclear medicine in the assessment of differentiated thyroid cancer
2008; 63 (4): 453–63
Despite modern multi-modality treatment, 10-30% of patients treated for differentiated thyroid cancer (DTC) ultimately develop local recurrence or metastatic disease. These malignancies are frequently slow-growing and secondary surgical resection is often undertaken along with radioactive iodine treatment. Correlation of radiological imaging with nuclear medicine studies is essential for individualized treatment planning, and to optimize this management. Radiologists should be familiar with the interpretation of various nuclear medicine studies used to image differentiated thyroid neoplasms.
View details for DOI 10.1016/j.crad.2007.08.002
View details for Web of Science ID 000254516900015
View details for PubMedID 18325367
Nanoprobes for medical diagnosis: Current status of nanotechnology in molecular imaging
2008; 4 (1): 17–29
View details for Web of Science ID 000254019100002
In vivo imaging of mucosal CD4(+) T cells using single photon emission computed tomography in a murine model of colitis
JOURNAL OF IMMUNOLOGICAL METHODS
2008; 329 (1-2): 21–30
Immune responses that occur in the context of human infectious and inflammatory diseases are usually studied by sampling cells from peripheral blood, from biopsies, or by end-point harvests at necropsy. These approaches are likely to yield information that is incomplete and/or non-representative. Here, we report the development and validation of a non-invasive method to localize and to quantitate the disposition of specific subpopulations of cells in vivo. In a murine model of dextran sulfate sodium (DSS)-induced colitis, CD4+ T cells were visualized in the colon by single photon emission computed tomography (SPECT-CT) after injection of monoclonal, non-depleting, indium-111 (111In) labeled anti-CD4+ antibodies. The SPECT-CT colon uptake ratio (CUR) was found to correlate (p<0.01) with the number of total CD4+ T cells and with standard measures of pathology (colon length, cell counts, and histopathologic evidence of apoptosis, edema, and cellular infiltrates) as assessed by direct examination of diseased colon. Each of these parameters, including the SPECT-CT signal uptake, increased as a function of DSS dose (p<0.05). We conclude that CT-SPECT imaging using an 111In-labeled anti-CD4+ antibody is reflective of traditional parameters of pathology in this experimental model of murine colitis. This approach should be readily applicable to the imaging of discrete cell subpopulations in non-human primates and in humans, thus augmenting our understanding of infectious diseases and inflammation in vivo.
View details for DOI 10.1016/j.jim.2007.09.008
View details for Web of Science ID 000253124100003
View details for PubMedID 17964595
View details for PubMedCentralID PMC2683264
- Positron emission tomography, positron emission tomography-computed tomography, and molecular imaging of the breast cancer patient SEMINARS IN ROENTGENOLOGY 2007; 42 (4): 265–79
Anterior layering of excreted F-18-FDG in the bladder on PET/CT: Frequency and cause
AMERICAN JOURNAL OF ROENTGENOLOGY
2007; 189 (2): W96–W99
The objective of our study was to determine the frequency and cause of anterior layering of excreted 18F-FDG in the bladder on PET/CT.Anterior layering of excreted FDG in the bladder is commonly seen on PET/CT scans obtained with i.v. iodinated contrast material and is due to displacement of FDG by excreted iodinated contrast material; this phenomenon may unmask FDG-avid bladder disease.
View details for DOI 10.2214/AJR.07.2175
View details for Web of Science ID 000248624400045
View details for PubMedID 17646448
- An automatic method to delineate 18F-FDG PET tumor volumes for radiation treatment planning AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2007: 2397–98
Calciphylaxis and bone scintigraphy: case report with histological confirmation and review of the literature
ANNALS OF NUCLEAR MEDICINE
2007; 21 (4): 235–38
We present a patient with a history of end-stage renal disease, who developed skin lesions in the bilateral calves a month after the initiation of hemodialysis. The lesions were biopsied, and the histological findings were consistent with a diagnosis of calciphylaxis. The patient had a baseline pretreatment bone scan that showed extensive systemic disease. The patient died 20 days after the imaging study. A review of the literature on bone scans and calciphylaxis is presented.
View details for DOI 10.1007/s12149-007-0013-3
View details for Web of Science ID 000248096500007
View details for PubMedID 17581723
Partial-volume correction in PET: Validation of an iterative postreconstruction method with phantom and patient data
JOURNAL OF NUCLEAR MEDICINE
2007; 48 (5): 802–10
Partial-volume errors (PVEs) in PET can cause incorrect estimation of radiopharmaceutical uptake in small tumors. An iterative postreconstruction method was evaluated that corrects for PVEs without a priori knowledge of tumor size or background.Volumes of interest (VOIs) were drawn on uncorrected PET images. PVE-corrected images were produced using an iterative 3-dimensional deconvolution algorithm and a local point spread function. The VOIs were projected on the corrected image to estimate the PVE-corrected mean activity concentration. These corrected mean values were compared with uncorrected maximum and mean values. Simulated data were generated as a first test of the correction algorithm. Phantom measurements were made using (18)F-FDG-filled spheres in a scattering medium. Clinical validation used 154 surrogate tumors from 9 patients. The surrogate tumors were blood-pool images of the descending aorta as well as mesenteric and iliac arteries and veins. Surrogate tumors ranged in diameter from 5 to 25 mm. Analysis used (18)F-FDG and (11)C-CO datasets (both dynamic and static). Values representing "truth" were derived from imaging the blood pool in large structures (e.g., the left ventricle, left atrium, or sections of the aorta) where PVEs were negligible. Surrogate tumor sizes were measured from contrast CT.The PVE-correction technique, when applied to the mean value in spheric phantoms, yielded recovery coefficients of 87% for an 8-mm-diameter sphere and between 100% and 103% for spheres between 13 and 29 mm. For the human studies, PVE-corrected data recovered a large fraction of the true activity concentration (86% +/- 7% for an 8-mm-diameter tumor and 98% +/- 8% for tumors between 10 and 24 mm). For tumors smaller than 18 mm, the PVE-corrected mean values were less biased (P<0.05) than the uncorrected maximum or mean values.Iterative postreconstruction PVE correction generated more accurate uptake measurements in subcentimeter tumors for both phantoms and patients than the uncorrected values. The method eliminates the requirement for segmenting anatomic data and estimating tumor metabolic size or tumor background level. This technique applies a PVE correction to the mean voxel value within a VOI, yielding a more accurate estimate of uptake than the maximum voxel value.
View details for DOI 10.2967/jnumed.106.035576
View details for Web of Science ID 000246326100027
View details for PubMedID 17475970
Interpretation, accuracy and management implications of FDG PET/CT in cutaneous malignant melanoma
NUCLEAR MEDICINE COMMUNICATIONS
2007; 28 (4): 273–80
To investigate the accuracy of different interpretative approaches and to evaluate the management implications of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in cutaneous malignant melanoma.We retrospectively identified 60 consecutive patients who underwent 76 PET/CT scans for cutaneous malignant melanoma. PET/CT reports were classified as positive, negative, or equivocal for regional and distant disease. Scan indication (staging, restaging, surveillance, or therapeutic monitoring), tumour stage, presence or absence of regional or distant disease, and post-scan management changes were determined by review of all available medical records. Maximum standardized uptake values (SUV(max)) of all findings were noted. Diagnostic accuracy of PET/CT was compared using either a high or low threshold interpretation (i.e. subtle, but indeterminate findings coded negative or positive, respectively). The frequency of management changes was compared between patient subgroups (stratified by tumour stage or indication).Using a high threshold interpretative approach, the overall accuracy of PET/CT for disease was 72.4% (55/76), which was significantly (P<0.05) greater than the accuracy of 53.9% (41/76) seen when using a low threshold approach. Per scan accuracy by staging site was 92.1% (70/76) for regional and 76.3% (58/76) for distant disease. PET/CT changed management in 21 of 76 studies (27.6%). When stratified by stage and indication, management changes occurred in all patient subgroups, except for stage I patients (0 of 5).When interpreted with a high threshold approach, PET/CT demonstrates high accuracy for the diagnosis of both regional and distant disease in cutaneous malignant melanoma and frequently changes management in patients with stage II-IV disease referred for a variety of indications.
View details for DOI 10.1097/MNM.0b013e3280708ecf
View details for Web of Science ID 000245373900008
View details for PubMedID 17325590
Rodent brain imaging with SPECT/CT
2007; 34 (4): 1217–20
We evaluated methods of imaging rat models of stroke in vivo using a single photon emission computed tomography (SPECT) system dedicated to small animal imaging (X-SPECT, Gamma Medica-Ideas, Northridge, CA). An animal model of ischemic stroke was developed for in vivo SPECT/CT imaging using the middle cerebral artery occlusion (MCAO) technique. The presence of cerebral ischemia was verified in ex vivo studies using triphenyltetrazolium chloride (TTC) staining. In vivo radionuclide imaging of cerebral blood flow was performed in rats following MCAO using dynamic planar imaging of 99mTc-exametazime with parallel hole collimation. This was followed immediately by in vivo radionuclide imaging of cerebral blood flow with 99mTc-exametazime in the same animals using 1-mm pinhole SPECT. Correlated computed tomography imaging was performed to localize radiopharmaceutical uptake. The animals were allowed to recover and ex vivo autoradiography was performed with separate administration of 99mTc-exametazime. Time activity curve of 99mTc-exametazime showed that the radiopharmaceutical uptake could be maintained for over 9 min. The activity would be expected to be relatively stable for a much longer period, although the data were only obtained for 9 min. TTC staining revealed sizable infarcts by visual observation of inexistence of TTC stain in infracted tissues of MCAO rat brains. In vivo SPECT imaging showed cerebral blood flow deficit in the MCAO model, and the in vivo imaging result was confirmed with ex vivo autoradiography. We have demonstrated a capability of imaging regions of cerebral blood flow deficit in MCAO rat brains in vivo using a pinhole SPECT dedicated to small animal imaging.
View details for DOI 10.1118/1.2710950
View details for Web of Science ID 000245842500010
View details for PubMedID 17500453
- Case 110: Nonossifying fibroma. Radiology 2007; 243 (1): 288–92
Telomeric transgenes are silenced in adult mouse tissues and embryo fibroblasts but are expressed in embryonic stem cells
2007; 25 (12): 3085–92
In addition to their role in protecting the ends of chromosomes, telomeres also influence the expression of adjacent genes, a process called telomere-position effect. We previously reported that the neo and HSV-tk transgenes located adjacent to telomeres in mouse embryonic stem cells are initially expressed at low levels and then become gradually silenced upon passage in culture through a process involving DNA methylation. We also reported extensive DNA methylation in these telomeric transgenes in three different tissues isolated from mice generated from one of these embryonic stem cell clones. In the present study, we demonstrate that embryo fibroblasts isolated from two different mouse strains show extensive DNA methylation and silencing of the telomeric transgenes. Consistent with this observation, we also demonstrate little or no detectable expression of the HSV-tk telomeric transgene in somatic tissues using whole body imaging. In contrast, both telomeric transgenes are expressed at low levels and have little DNA methylation in embryonic stem cell lines isolated from these same mouse strains. Our results demonstrate that telomere-position effect in mammalian cells can be observed either as a low level of expression in embryonic stem cells in the preimplantation embryo or as complete silencing and DNA methylation in differentiated cells and somatic tissues. This pattern of expression of the telomeric transgenes demonstrates that subtelomeric regions, like much of the genome, are epigenetically reprogrammed in the preimplantation embryo, a process that has been proposed to be important in early embryonic development. Disclosure of potential conflicts of interest is found at the end of this article.
View details for DOI 10.1634/stemcells.2007-0478
View details for Web of Science ID 000251707200013
View details for PubMedID 17823235
Evaluation of semi-quantitative scoring system for metaiodobenzylguanidine (mIBG) scans in patients with relapsed neuroblastoma
PEDIATRIC BLOOD & CANCER
2006; 47 (7): 865–74
The purpose of this study was to determine the accuracy of two semi-quantitative scoring systems to assess response to (131)I-metaiodobenzylguanidine (mIBG) therapy in recurrent neuroblastoma.Diagnostic mIBG scan pairs (n = 57) were collected for patients who underwent (131)I-mIBG therapy for relapsed neuroblastoma. Two scoring systems were designated: Method 1, which divided the body into nine segments to view osteomedullary lesions with an additional tenth segment to assess soft tissue involvement; and Method 2, which divided the body into seven segments without a corresponding compartment for soft tissue involvement. Four nuclear medicine physicians independently assigned extension and intensity scores utilizing both methods, and separately recorded their impression of whether the post-therapy scan had improved, not changed, or worsened. Inter- and intra-observer concordance and correlation with overall response and progression-free survival (PFS) were performed.Method 1 produced the highest inter-observer concordance and was used to calculate the relative extension scores (post-therapy score divided by pre-therapy score), which correlated significantly with overall response. Patients who achieved complete response (CR) or partial response (PR) (n = 21) had lower relative extension scores, compared to those without response (P < 0.001). The readers' overall impression associated highly (P < 0.001) with the relative extension scores though results were less quantitative. Concordance was higher if initial scores were >5. Relative extension score did not predict PFS.Semi-quantitative scoring of mIBG scans provides a more reliable method of assessing response in patients with relapsed neuroblastoma than qualitative impression. The reproducibility and high inter-observer concordance makes mIBG score an important component of overall response criteria in patients with recurrent neuroblastoma.
View details for DOI 10.1002/pbc.20777
View details for Web of Science ID 000241803700002
View details for PubMedID 16444675
Tumor fluoro-2-deoxy-D-glucose avidity on positron emission tomographic scan predicts mortality in patients with early-stage pure and mixed bronchioloalveolar carcinoma
MOSBY, INC. 2006: 1189–95
Bronchioloalveolar carcinoma is a clinically heterogeneous subtype of non-small cell lung carcinoma that frequently has low 2-[18F]fluoro-D-glucose (FDG) uptake on positron emission tomographic scanning. We investigated whether tumor FDG avidity was associated with worse survival among patients with completely resected node-negative pure and mixed bronchioloalveolar carcinoma.We performed a cohort study of 36 patients who had completely resected pure and mixed bronchioloalveolar carcinoma between 1998 and 2004, who had no hilar or mediastinal lymph node metastases, and who had undergone a preoperative positron emission tomographic scan. Tumor FDG avidity was defined as a standardized uptake value of 2.5 or greater. Survival analysis was performed with a proportional hazards model.Of 36 patients studied, 26 patients (72%) were alive and 10 patients (28%) were dead after a median follow-up of 31 months (interquartile range 17-41 months). Seventeen patients (47%) had FDG-avid tumors, and 19 patients (53%) had non-avid tumors. Three-year survival was 49% in the FDG-avid group and 95% in the non-avid group (P = .005). FDG avidity had a hazard ratio of death of 8.6 (95% confidence interval 1.4-244.7, P = .02) after adjusting for tumor size, the presence of multifocal bronchioloalveolar carcinoma, and the presence of histologically mixed bronchioloalveolar carcinoma.Preoperative tumor FDG standardized uptake value of 2.5 or greater on positron emission tomography is a powerful predictor of long-term mortality in patients with lymph node-negative pure and mixed bronchioloalveolar carcinoma who undergo complete surgical resection. Patients with a high level of FDG uptake (standardized uptake value > or = 2.5) may benefit from adjuvant chemotherapy or more frequent clinical follow-up.
View details for DOI 10.1016/j.jtcvs.2006.06.033
View details for Web of Science ID 000241497500028
View details for PubMedID 17059942
Progress in SPECT/CT imaging of prostate cancer
TECHNOLOGY IN CANCER RESEARCH & TREATMENT
2006; 5 (4): 329–36
Prostate cancer is the most common type of cancer (other than skin cancer) among men in the United States. Although prostate cancer is one of the few cancers that grow so slowly that it may never threaten the lives of some patients, it can be lethal once metastasized. Indium-111 capromab pendetide (ProstaScint, Cytogen Corporation, Princeton, NJ) imaging is indicated for staging and recurrence detection of the disease, and is particularly useful to determine whether or not the disease has spread to distant metastatic sites. However, the interpretation of 111In-capromab pendetide is challenging without correlated structural information mostly because the radiopharmaceutical demonstrates nonspecific uptake in the normal vasculature, bowel, bone marrow, and the prostate gland. We developed an improved method of imaging and localizing 111In-Capromab pendetide using a SPECT/CT imaging system. The specific goals included: i) development and application of a novel iterative SPECT reconstruction algorithm that utilizes a priori information from coregistered CT; and ii) assessment of clinical impact of adding SPECT/CT for prostate cancer imaging with capromab pendetide utilizing the standard and novel reconstruction techniques. Patient imaging studies with capromab pendetide were performed from 1999 to 2004 using two different SPECT/CT scanners, a prototype SPECT/CT system and a commercial SPECT/CT system (Discovery VH, GE Healthcare, Waukesha, WI). SPECT projection data from both systems were reconstructed using an experimental iterative algorithm that compensates for both photon attenuation and collimator blurring. In addition, the data obtained from the commercial system were reconstructed with attenuation correction using an OSEM reconstruction supplied by the camera manufacturer for routine clinical interpretation. For 12 sets of patient data, SPECT images reconstructed using the experimental algorithm were interpreted separately and compared with interpretation of images obtained using the standard reconstruction technique. The experimental reconstruction algorithm improved spatial resolution, reduced streak artifacts, and yielded a better correlation with anatomic details of CT in comparison to conventional reconstruction methods (e.g., filtered back-projection or OSEM with attenuation correction only). Images produced with the experimental algorithm produced a subjective improvement in the confidence of interpretation for 11 of 12 studies. There were also changes in interpretations for 4 of 12 studies although the changes were not sufficient to alter prognosis or the patient treatment plan.
View details for DOI 10.1177/153303460600500404
View details for Web of Science ID 000240089900005
View details for PubMedID 16866563
Intracellular cargo delivery by an octaarginine transporter adapted to target prostate cancer cells through cell surface protease activation
2006; 17 (3): 787-796
Delivery of therapeutics and imaging agents to target tissues requires localization and activation strategies with molecular specificity. Cell-associated proteases can be used for these purposes in a number of pathologic conditions, and their enzymatic activities can be exploited for activation strategies. Here, molecules based on the d-arginine octamer (r8) protein-transduction domain (PTD, also referred to as molecular transporters) have been adapted for selective uptake into cells only after proteolytic cleavage of a PTD-attenuating sequence by the prostate-specific antigen (PSA), an extracellular protease associated with the surface and microenvironment of certain prostate cancer cells. Convergent syntheses of these activatable PTDs (APTDs) are described, and the most effective r8 PTD-attenuating sequence is identified. The conjugates are shown to be stable in serum, cleaved by PSA, and taken up into Jurkat (human T cells) and PC3M prostate cancer cell lines only after cleavage by PSA. These APTD peptide-based molecules may facilitate targeted delivery of therapeutics or imaging agents to PSA-expressing prostate cancers.
View details for DOI 10.1021/bc0503216
View details for PubMedID 16704219
Lymphatic drainage patterns of head and neck cutaneous melanoma observed on lymphoscintigraphy and sentinel lymph node biopsy
WILEY. 2006: 249–55
The purpose of this study was to evaluate lymphatic drainage patterns of head and neck cutaneous melanoma observed on preoperative lymphoscintigraphy and sentinel lymph node biopsy (SLNB) and determine discordancy from clinically predicted lymphatic drainage patterns.We conducted a retrospective chart review of 114 patients with head and neck cutaneous melanomas evaluated with preoperative lymphoscintigraphy and SLNB from January 2001 through July 2004.At least one sentinel lymph node (SLN) was identified in 97% of cases. On preoperative lymphoscintigraphy, an SLN was identified in an area not clinically predicted in 49 cases (43%). The most common sites of discordancy were in areas not typically dissected in standard neck dissections, such as the postauricular region, or in areas of more distant drainage than described previously, such as the inferior or posterior neck. Their percentages of discordant cases were 51%, 27%, and 22%, respectively. The sites of regional recurrence occurred in two cases not predicted on preoperative lymphoscintigraphy and in two cases of failed SLNB.On the basis of preoperative lymphoscintigraphy and the results of SLNB, head and neck cutaneous melanomas do have expected lymphatic drainage patterns despite perceived discordancy with previously clinically predicted drainage patterns that are based on standard neck dissection specimens. These "discordant" sites can still harbor melanoma, and all sites predicted on preoperative lymphoscintigraphy still need to be explored. The four cases of recurrences underscore the importance of close follow-up for all patients regardless of the SLNB result.
View details for DOI 10.1002/hed.20328
View details for Web of Science ID 000235599600009
View details for PubMedID 16470744
Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: A new approaches to neuroblastoma therapy consortium study
AMER SOC CLINICAL ONCOLOGY. 2006: 500–506
To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine ((131)I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma.Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. (131)I-MIBG was administered on day -21, CEM was administered on days -7 to -4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. (131)I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR).The MTD for patients with normal GFR (> or = 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils > or = 500/microL of 10 days and median time for platelets > or = 20,000/microL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 +/- 0.10 and 0.58 +/- 0.10, respectively.131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.
View details for DOI 10.1200/JCO.2005.03.6400
View details for Web of Science ID 000234776300028
View details for PubMedID 16421427
Rodent Brain Imaging with SPECT and CT
IEEE. 2006: 3526-+
View details for Web of Science ID 000288875603130
FDG PET imaging in the evaluation of post-transplant lymphoproliferative disorder following renal transplantation
NUCLEAR MEDICINE COMMUNICATIONS
2005; 26 (12): 1107–11
To assess the usefulness of fluorodeoxyglucose positron emission tomography (FDG PET) in the evaluation of post-transplant lymphoproliferative disorder (PTLD) following renal transplantation.Staging FDG PET examinations were reviewed in five patients with biopsy proven post-renal allograft PTLD and compared with conventional imaging. Follow-up PET examinations of three patients at various points during their therapy for PTLD were also reviewed and compared with clinical outcome.PET imaging identified all disease sites seen at cross-sectional imaging, clarified sites of uncertain significance and detected additional disease in two out of five patients. Early follow-up imaging impacted PTLD management in two of three patients.In this limited series FDG PET was an effective imaging modality in the staging and follow-up of PTLD.
View details for DOI 10.1097/00006231-200512000-00010
View details for Web of Science ID 000233546000010
View details for PubMedID 16264358
The role of a positron- and high-energy gamma photon probe in intraoperative localization of recurrent melanoma
CLINICAL NUCLEAR MEDICINE
2005; 30 (12): 787-791
This preliminary study retrospectively evaluated the ability of intraoperative localization of recurrent melanoma using F-18 fluorodeoxyglucose (FDG) and a probe sensitive to both high-energy gamma rays and positrons to enable complete tumor resection and improved patient outcome.Three hours before surgery for resection of recurrent melanoma, 5 patients (mean age, 52 +/- 22 years) with a history of local surgery, radiation therapy, and/or large habitus received 14.6 +/- 3.2 mCi of F-18 FDG. Intraoperative tumor localization was performed with a radiation probe (PET-Probe; IntraMedical Imaging LLC, Los Angeles, CA). Intraoperative tumor tissue activities, background tissue activities, pathology results, and patient follow up (clinical/imaging) were recorded.Eight of the 19 surgical specimens were identified by the probe as having increased FDG uptake when compared with the surrounding tissues before resection. All 8 specimens contained melanoma. Of the 11 specimens that were not identified using the probe, one contained melanoma, yielding a sensitivity of 89% (8 of 9) and a specificity of 100% (10 of 10). In 3 of the 5 cases, the probe allowed the identification of nonvisualized and nonpalpable tumor foci that were later confirmed pathologic. At an average follow up of 210 days (range, 30-515 days), 2 of 5 patients had no evidence of recurrent melanoma by clinical or radiographic evaluations.In the setting of recurrent melanoma, there appear to be potential benefits to intraoperative detection with FDG and a positron-detecting probe, particularly in cases with challenging or altered anatomy.
View details for Web of Science ID 000233455500003
View details for PubMedID 16319633
- Improved prostate cancer imaging with SPECT/CT and MRI/MRSI IEEE TRANSACTIONS ON NUCLEAR SCIENCE 2005; 52 (5): 1316–20
Correction of photon attenuation and collimator response for a body-contouring SPECT/CT imaging system
JOURNAL OF NUCLEAR MEDICINE
2005; 46 (5): 868–77
(111)In-Capromab pendetide imaging is indicated for postprostatectomy patients at risk for residual or recurrent disease. However, this study is complicated by relatively long times for tumor uptake and background washout that require imaging to be performed several days after radiopharmaceutical administration. In addition, (111)In-capromab pendetide demonstrates uptake in normal structures that produce images that are interpreted best using correlation with anatomic imaging. Finally, the visual quality of radionuclide imaging can be improved with corrections for photon attenuation and for the geometric response of the radionuclide collimator. Therefore, we have evaluated the advantages of using a commercially available dual-modality SPECT/CT system. In this article, we evaluate a novel iterative reconstruction algorithm using the SPECT/CT data obtained from phantoms and (111)In-capromab pendetide patient studies.Phantom data acquired with the dual-head SPECT camera were reconstructed using both filtered backprojection (FBP) and an iterative maximum-likelihood expectation maximization (MLEM) algorithm incorporating corrections for (a) attenuation coefficient at the effective energy of the radionuclide (either (99m)Tc or (111)In) and (b) collimator response based on experimentally measured depth-dependent spatial resolution of the camera. The collimator response model used the coregistered CT image to estimate the source-target distances produced by the patient-contouring logic of the SPECT camera. Spatial resolution was measured using SPECT images of 2 line sources and uniformity from a uniform cylindric tank. Clinical (111)In-capromab pendetide SPECT/CT data were acquired according to the radiopharmaceutical manufacturer's protocol. Region-of-interest (ROI) analysis of a transverse slice at the level of the sacral base produced mean, median, maximum, and minimum counts per pixel for bone marrow and surrounding soft-tissue ROIs. Ratios of the mean capromab pendetide uptake within marrow to uptake within soft tissue were compared for images reconstructed with FBP versus that obtained from the MLEM method with photon attenuation and collimator response corrections.The source-target distances reconstructed from the patient-specific CT image agreed well with the corresponding values recorded manually from the camera display unit. This information was incorporated into the iterative reconstruction algorithms and improved the quality of SPECT images from phantoms and patients versus SPECT images reconstructed without the depth-dependent collimator response model. Qualitatively, SPECT images reconstructed with corrections for photon attenuation and collimator response showed less background activity and improved target contrast compared with those images reconstructed with FBP. The target-to-background ratio (marrow uptake-to-soft-tissue uptake) was significantly better using MLEM reconstruction than with FBP when mean uptake values were measured.A priori anatomic data can be used to enhance the quality of the SPECT image when reconstructed using iterative techniques (e.g., MLEM) that use the CT data to produce a patient-specific attenuation map and a collimator response model based on the body contour produced during the SPECT acquisition.
View details for Web of Science ID 000228952400029
View details for PubMedID 15872362
Pericardial lymph node involvement in lymphoma as identified on PET
CLINICAL NUCLEAR MEDICINE
2004; 29 (11): 741-742
View details for PubMedID 15483497
Apoptosis in a rodent model of cranial suture fusion: In situ imaging and gene expression analysis
PLASTIC AND RECONSTRUCTIVE SURGERY
2004; 113 (7): 2037-2047
Craniosynostosis, the premature fusion of cranial sutures, is one of the most common craniofacial anomalies, with a reported incidence of up to one in 2500 live births. Despite its prevalence, the cause of craniosynostosis remains unknown. Previously, apoptosis has been postulated to be a contributing factor in the pathogenesis of craniosynostosis, although the role of programmed cell death in cranial sutures is poorly understood. To address this problem, the authors used an established rodent model of posterior-frontal suture fusion and sagittal suture patency to globally examine apoptosis in cranial sutures. Apoptosis was evaluated by systemically coinjecting Sprague-Dawley rats with both fluorescent and technetium-99m-labeled annexin V at time points before, during, and after the period of predicted posterior-frontal suture fusion to determine the magnitude and time course of overall apoptotic activity in both fusing and patent sutures. Using these novel in situ imaging techniques, the authors observed a significant increase in the overall levels of apoptosis in both the posterior-frontal and sagittal suture complexes during the period of predicted posterior-frontal suture fusion. To further explore this increase in apoptotic activity, they used microarray technology to study apoptosis-related genes within the suture complex. Interestingly, there was activation of distinct apoptotic pathways in the posterior-frontal and sagittal sutures during the period of predicted posterior-frontal suture fusion. Whereas increased transcription of genes associated with the mitochondria-mediated apoptotic pathway occurred in the posterior-frontal suture during fusion, activation of genes associated with the death receptor-mediated apoptotic pathway predominated in the patent sagittal suture during the same time period. These data suggest that although overall apoptotic activity in rat patent and fusing sutures is similar, the pathways mediating apoptosis within each suture are distinct.
View details for DOI 10.1097/01.prs.000012118201199.c1
View details for PubMedID 15253194
Potential role for antiangiogenic proteins in the myocardial infarction repair process
JOURNAL OF SURGICAL RESEARCH
2004; 116 (1): 156–64
Although angiogenic proteins have been identified as positive modulators of myocardial revascularization following acute myocardial infarction, little if anything is known regarding the role that antiangiogenic proteins have in myocardial revascularization. We explored the temporospatial distribution of endothelial-monocyte activating polypeptide (EMAP) II to determine whether antiangiogenic proteins have a role in the repair of myocardial tissue following infarction.A rat model of myocardial infarction was utilized to examine EMAP II distribution (in situ hybridization) and protein expression (Western analysis) over a 6-week period.At baseline, EMAP II protein and mRNA are minimally expressed with transcription products localizing predominately to the perivascular stroma region in the normal rat myocardium. Six hours following myocardial infarction, EMAP II changes its distribution from the perivascular stroma to an invading inflammatory cell population. This is associated with a 2-fold (P < 0.0009) increase in EMAP II protein and its transcription primarily localized to the infarct region. EMAP II protein expression remains elevated throughout the weeks following the infarction with transcription limited to the infarct region and a notable decrease in EMAP II transcription products noted in the viable vasculature surrounding the infarct zone. Six weeks following myocardial infarction, EMAP II protein is elevated above control, changes its location of transcription from the inflammatory cell population to that of the fibroblasts located in the relative avascular scar tissue, and has resumed its perivascular stromal distribution in the viable periinfarct tissue.Thus, the temporospatial distribution of this antiangiogenic protein suggests that negative vascular modulators may have a function in the revascularization process following acute myocardial infarction.
View details for DOI 10.1016/j.jss.2003.06.001
View details for Web of Science ID 000188368900022
View details for PubMedID 14732363
Breaching biological barriers: protein translocation domains as tools for molecular imaging and therapy.
2003; 2 (4): 313-323
The lipid bilayer of a cell presents a significant barrier for the delivery of many molecular imaging reagents into cells at target sites in the body. Protein translocation domains (PTDs) are peptides that breach this barrier. Conjugation of PTDs to imaging agents can be utilized to facilitate the delivery of these agents through the cell wall, and in some cases, into the cell nucleus, and have potential for in vitro and in vivo applications. PTD imaging conjugates have included small molecules, peptides, proteins, DNA, metal chelates, and magnetic nanoparticles. The full potential of the use of PTDs in novel in vivo molecular probes is currently under investigation. Cells have been labeled in culture using magnetic nanoparticles derivatized with a PTD and monitored in vivo to assess trafficking patterns relative to cells expressing a target antigen. In vivo imaging of PTD-mediated gene transfer to cells of the skin has been demonstrated in living animals. Here we review several natural and synthetic PTDs that have evolved in the quest for easier translocation across biological barriers and the application of these peptide domains to in vivo delivery of imaging agents.
View details for PubMedID 14717330
Oral administration of F-18FDG to evaluate a single pulmonary nodule by positron emission tomography in a patient with poor intravenous access
CLINICAL NUCLEAR MEDICINE
2003; 28 (7): 541-544
F-18 fluorodeoxyglucose (FDG) is typically administered intravenously for positron emission tomography. The authors present a case of oral administration of FDG for evaluation of a pulmonary nodule and review the limited literature on this subject. Oral administration of FDG is a useful alternative to intravenous administration in patients with difficult intravenous access when the alimentary tract is not involved in the clinical diagnosis.
View details for Web of Science ID 000183782800001
View details for PubMedID 12819404
Low uptake of Tc-99m tetrofosmin in lung cancer - A case report
CLINICAL NUCLEAR MEDICINE
2002; 27 (10): 698-700
Technetium-99m tetrofosmin has been used as a tumor-imaging agent in cases of lung cancer. The authors present a case showing a lung tumor that concentrated Tl-201 distinctly more than Tc-99m tetrofosmin during a dual-isotope cardiac examination. A brief review of the literature is provided and possible explanations for this difference in tracer uptake are discussed.
View details for DOI 10.1097/01.RLU.0000027801.86894.5D
View details for PubMedID 12352109