John Sunderland

Kinetic Analysis of 3′-Deoxy-3′-18F-Fluorothymidine (18F-FLT) in Head and Neck Cancer Patients Before and Early After Initiation of Chemoradiation Therapy

The purpose of this study was to investigate the kinetic behavior of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) before and early after initiation of chemoradiation therapy in patients with squamous cell head and neck cancer. Methods: A total of 8 patients with head and neck cancer underwent 18F-FLT PET scans (7 patients at baseline and after 5 d [10 Gy] of radiation therapy given with concomitant chemotherapy and 1 patient only at baseline). Dynamic PET images were obtained with concurrent arterial or venous blood sampling. Kinetic parameters including the flux constant of 18F-FLT based on compartmental analysis (K-FLT), the Patlak influx constant (K-Patlak), and standardized uptake value (SUV) were calculated for the primary tumor and 18F-FLT–avid cervical lymph nodes for all scans. Results: Mean pretreatment values of uptake for the primary tumor and cervical nodes were 0.075 ± 0.006 min−1, 0.042 ± 0.004 min−1, and 3.4 ± 0.5 (mean ± SD) for K-FLT, K-Patlak, and SUV, respectively. After 10 Gy of radiation therapy, these values were 0.040 ± 0.01 min−1, 0.018 ± 0.016 min−1, and 1.8 ± 1.1 for K-FLT, K-Patlak, and SUV, respectively. For all lesions seen on pretherapy and midtherapy scans, the correlation was 0.90 between K-FLT and K-Patlak, 0.91 between K-FLT and SUV, and 0.99 between K-Patlak and SUV. Conclusion: The initial 18F-FLT uptake and change early after treatment in squamous head and neck tumors can be adequately characterized with SUV obtained at 45–60 min, which demonstrates excellent correlation with influx parameters obtained from compartmental and Patlak analyses.

Quantitative PET/CT Scanner Performance Characterization Based Upon the Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network Oncology Clinical Simulator Phantom

The Clinical Trials Network (CTN) of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) operates a PET/CT phantom imaging program using the CTN’s oncology clinical simulator phantom, designed to validate scanners at sites that wish to participate in oncology clinical trials. Since its inception in 2008, the CTN has collected 406 well-characterized phantom datasets from 237 scanners at 170 imaging sites covering the spectrum of commercially available PET/CT systems. The combined and collated phantom data describe a global profile of quantitative performance and variability of PET/CT data used in both clinical practice and clinical trials. Methods: Individual sites filled and imaged the CTN oncology PET phantom according to detailed instructions. Standard clinical reconstructions were requested and submitted. The phantom itself contains uniform regions suitable for scanner calibration assessment, lung fields, and 6 hot spheric lesions with diameters ranging from 7 to 20 mm at a 4:1 contrast ratio with primary background. The CTN Phantom Imaging Core evaluated the quality of the phantom fill and imaging and measured background standardized uptake values to assess scanner calibration and maximum standardized uptake values of all 6 lesions to review quantitative performance. Scanner make-and-model–specific measurements were pooled and then subdivided by reconstruction to create scanner-specific quantitative profiles. Results: Different makes and models of scanners predictably demonstrated different quantitative performance profiles including, in some cases, small calibration bias. Differences in site-specific reconstruction parameters increased the quantitative variability among similar scanners, with postreconstruction smoothing filters being the most influential parameter. Quantitative assessment of this intrascanner variability over this large collection of phantom data gives, for the first time, estimates of reconstruction variance introduced into trials from allowing trial sites to use their preferred reconstruction methodologies. Predictably, time-of-flight–enabled scanners exhibited less size-based partial-volume bias than non–time-of-flight scanners. Conclusion: The CTN scanner validation experience over the past 5 y has generated a rich, well-curated phantom dataset from which PET/CT make-and-model and reconstruction-dependent quantitative behaviors were characterized for the purposes of understanding and estimating scanner-based variances in clinical trials. These results should make it possible to identify and recommend make-and-model–specific reconstruction strategies to minimize measurement variability in cancer clinical trials.

Profiling Bortezomib Resistance Identifies Secondary Therapies in a Mouse Myeloma Model

Multiple myeloma is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. Although the first-to-market proteasome inhibitor bortezomib (Velcade) has been successfully used to treat patients with myeloma, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive (BzS) and bortezomib-resistant (BzR) cell lines created from the Bcl-XL/Myc double-transgenic mouse model of multiple myeloma. Notably, these BzR cell lines show cross-resistance to the next-generation proteasome inhibitors, MLN2238 and carfilzomib (Kyprolis) but not to other antimyeloma drugs. We further characterized the response to bortezomib using the Connectivity Map database, revealing a differential response between these cell lines to histone deacetylase (HDAC) inhibitors. Furthermore, in vivo experiments using the HDAC inhibitor panobinostat confirmed that the predicted responder showed increased sensitivity to HDAC inhibitors in the BzR line. These findings show that GEP may be used to document bortezomib resistance in myeloma cells and predict individual sensitivity to other drug classes. Finally, these data reveal complex heterogeneity within multiple myeloma and suggest that resistance to one drug class reprograms resistant clones for increased sensitivity to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy for patients with multiple myeloma. Mol Cancer Ther; 12(6); 1140–50. ©2013 AACR.

Summary of the UPICT Protocol for 18F-FDG PET/CT Imaging in Oncology Clinical Trials

The Uniform Protocols for Imaging in Clinical Trials (UPICT) 18F-FDG PET/CT protocol is intended to guide the performance of whole-body FDG PET/CT studies within the context of single- and multiple-center clinical trials of oncologic therapies by providing acceptable (minimum), target, and ideal standards for all phases of imaging. The aim is to minimize variability in intra- and intersubject, intra- and interplatform, interexamination, and interinstitutional primary or derived data. The goal of this condensed version of the much larger document is to make readers aware of the general content and subject area. The document has several main subjects: context of the imaging protocol within the clinical trial; site selection, qualification, and training; subject scheduling; subject preparation; imaging-related substance preparation and administration; imaging procedure; image postprocessing; image analysis; image interpretation; archiving and distribution of data; quality control; and imaging-associated risks and risk management.

GATE Simulations of Human and Small Animal PET for Determination of Scatter Fraction as a Function of Object Size

In 2D-mode positron emission tomography (PET), scatter is either compensated by approximate methods based on the existing emission data or ignored altogether as the magnitude of the scatter fraction (SF) is on the order of 10%-20%. In clinical PET studies, however, attenuation and sophisticated scatter correction methods are required along with CT or radionuclide transmission scans. With the growing interest in small animal imaging, these correction methods are being translated to small animal scanners, but there is little scientific information about the requirements associated with smaller size objects and scatter geometries. In this study, we focused on the magnitude of the scatter through a series of scatter fraction simulations. To determine the scatter as a function of object size, we performed Monte Carlo simulations using GATE (Geant4 application for emission tomography). Models of the ECAT HR+ PET scanner (included in the GATE package) and the Siemens Inveon small animal scanner (generated by the first author) were used. Simulations were performed for several digital phantoms including the NEMA, XCAT and MOBY phantoms over a wide range of sizes. Small animal NEMA-like phantoms indicated that for cylindrical objects less than 5 cm diameters (encompassing small rats and all mice), the scatter fraction was lower than 17.5% for the 350-650 keV and 20% for the 250-750 keV windows. Similar values were obtained for the MOBY phantoms for the respective sizes. On the other hand, the scatter fraction was more than 35% for even the smallest size human NEMA-like and XCAT phantoms. These results suggest that sophisticated scatter correction methods may not be required for the indicated sizes of mice and rats.

18 F-FDG-PET/CT imaging in an IL-6- and MYC-driven mouse model of human multiple myeloma affords objective evaluation of plasma cell tumor progression and therapeutic response to the proteasome inhibitor ixazomib

18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMycΔEμ gene insertion and the widely expressed H2-Ld-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage- and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma.

Evaluation of Attenuation and Scatter Correction Requirements as a Function of Object Size in Small Animal PET Imaging

In human emission tomography, an additional transmission scan (x-ray CT or external gamma-source) is often required to obtain accurate attenuation maps for attenuation correction (AC) and scatter correction (SC). These transmission-based correction methods have been translated to small animal imaging although the impact of photon interactions on the mouse/rat-reconstructed images is substantially less than that in human imaging. Considering the additional complexity in design and cost of these systems, the necessity of these correction methods is questionable for small animal emission tomography. In this study, we evaluate the requirement of these corrections for small animal positron emission tomography (PET) through Monte Carlo simulations of the Inveon PET scanner using various sizes of MOBY voxelized phantoms. The 3D sinogram data obtained from simulations were reconstructed in 6 different conditions: Accurate AC+SC, simple (water) AC+SC, accurate AC only, simple AC only, SC only and no correction (NC). Mean error% for 8 different ROIs and 6 different MOBY sizes were obtained against the accurate scatter and attenuation corrections (first on the list). In addition to simulations, real mouse data obtained from an Inveon PET scanner were analyzed using similar methods. Results from both simulation and real mouse data showed that attenuation correction based on solely emission data should be sufficient for imaging animals smaller than 4 cm diameter. For larger sizes, a scatter correction employing an additional transmission scan can also be included depending on the objective of the study.

Effect of Insulin and Dexamethasone on Fetal Assimilation of Maternal Glucose

The growing fetus depends upon transfer of glucose from maternal blood to fetal tissues. Insulin and glucocorticoid impact maternal glucose metabolism, but the effects of these hormones on fetal glucose assimilation in vivo are understudied. We thus used positron emission tomography imaging to determine the disposition of [(18)F]fluorodeoxyglucose (FDG) in rats on gestational d 20, quantifying the kinetic competition of maternal tissues and fetus for glucose. Three fasting maternal states were studied: after 2-d dexamethasone (DEX), during euglycemic hyperinsulinemic clamp insulin receiving (INS), and control (CON). In CON and DEX mothers, FDG accumulation in fetuses and placentae was substantial, rivaling that of maternal brain. By contrast, FDG accumulation was reduced in INS fetuses, placentae, and maternal brain by approximately 2-fold, despite no diminution in FDG extraction kinetics from maternal blood into these structures. The reduced FDG accumulation was due to more rapid clearance of FDG from the circulation in INS mothers, related to increased FDG avidity in INS select maternal tissues, including skeletal muscle, brown adipose tissue, and heart. DEX treatment of mothers reduced fetal weight by nearly 10%. Nonetheless, the accumulation of FDG into placentae and fetuses was similar in DEX and CON mothers. In our rat model, fetal growth restriction induced by DEX does not involve diminished glucose transport to the fetus. Maternal insulin action has little effect on the inherent avidity of the fetal-placental unit for glucose but increases glucose utilization by maternal tissues, thus indirectly reducing the glucose available to the fetus.

68Ga-DOTATOC Imaging of Neuroendocrine Tumors: A Systematic Review and Meta-Analysis

68Ga-DOTATOC, a somatostatin receptor–targeted ligand, has been used clinically in Europe over the past decade for imaging neuroendocrine tumors (NETs). It appears to be quite sensitive and effective for clinical management decision making. This metaanalysis summarizes the efficacy of 68Ga-DOTATOC for several distinct indications and is intended to support approval of this agent by the U.S. Food and Drug Administration. Methods: The major electronic medical databases were searched for relevant papers over the period from January 2001 to November 2015. Papers were selected for review in 3 categories: clinical trials that reported sensitivity and specificity, comparison studies with 111In-octreotide, and change of management studies. All the eligible papers underwent Quality Assessment of Diagnostic Accuracy Studies (QUADAS) assessment, which was useful in the final selection of papers for review. Results: The initial search yielded 468 papers. After detailed evaluation, 17 papers were finally selected. Five types of studies emerged: workup of patients with symptoms and biomarker findings suggestive of NET, but with negative conventional imaging (3 papers, yield was only 13%); sensitivity (12 papers; sensitivity, 92%) and specificity (7 papers; specificity, 82%); identification of site of unknown primary in patients with metastatic NET (4 papers, yield was 44%); impact on subsequent NET patient management (4 papers, change in management in 51%); and comparison with 111In-octreotide (2 papers, sensitivity of DOTATOC on a per-lesion basis was 100%, for 111In-octreotide it was 78.2%; specificity was not available). Safety was not explicitly addressed in any study, but there were no reports of adverse events. Conclusion: 68Ga-DOTATOC is useful for evaluating the presence and extent in disease for staging and restaging and for assisting in treatment decision making for patients with NET. It is also effective in locating the site of an unknown primary in NET patients who present with metastatic NET, but no known primary tumor. It also appears to be more accurate than 111In-octreotide. Although 68Ga-DOTATOC would seem to be useful in evaluating patients with suggestive symptoms and biomarker findings, it does not perform well in this setting and has low yield. Overall, it appears to be an excellent imaging agent to assess patients with known NET and frequently leads to a change in management.

Diagnostic Reference Levels of CT Radiation Dose in Whole-Body PET/CT

The role of CT in PET/CT imaging includes acquisition techniques for diagnostic, anatomic localization, and attenuation correction purposes. Diagnostic reference levels of the volumetric CT dose index (CTDIvol) are available for dedicated CT procedures on selected body regions, but similar reference levels for whole-body CT used in PET/CT examinations are limited. This work reports CTDIvol values from sites that conduct whole-body oncologic PET/CT examinations and participated in the scanner validation program of the Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network. Methods: From 2010 to 2014, a total of 154 sites submitted CT acquisition parameters used in their clinical 18F-FDG PET/CT oncology protocols. From these parameters, the CTDIvol was estimated using the ImPACT CTDI dosimetry tables. Histograms of CTDIvol values were created for each year, and descriptive statistics, including mean, median, and 75th percentile, were reported. Repeated-measures ANOVA was performed to determine whether significant differences occurred between reporting years. Results: A wide range of technical parameters was reported, most notably in tube current. Between 2010 and 2014, the median CTDIvol ranged from 4.9 to 6.2 mGy and the 75th percentile from 9.7 to 10.2 mGy. There was no significant change in CTDIvol between reporting years (repeated-measures ANOVA, P = 0.985). Conclusion: The 75th percentile CTDIvol reported in this work was 9.8 mGy averaged over all reporting years. These data provide a resource for establishing CTDIvol reference values specific to performing CT in PET/CT whole-body examinations. The wide ranges of CT acquisition parameters reported by sites suggest that CTDIvol reference levels may be beneficial for optimization of CT protocols.