Deep learning generation of preclinical positron emission tomography (PET) images from low-count PET with task-based performance assessment.

BACKGROUND: Preclinical low-count positron emission tomography (LC-PET) imaging offers numerous advantages such as facilitating imaging logistics, enabling longitudinal studies of long- and short-lived isotopes as well as increasing scanner throughput. However, LC-PET is characterized by reduced photon-count levels resulting in low signal-to-noise ratio (SNR), segmentation difficulties, and quantification uncertainties. PURPOSE: We developed and evaluated a novel deep-learning (DL) architecture-Attention based Residual-Dilated Net (ARD-Net)-to generate standard-count PET (SC-PET) images from LC-PET images. The performance of the ARD-Net framework was evaluated for numerous low count realizations using fidelity-based qualitative metrics, task-based segmentation, and quantitative metrics. METHOD: Patient Derived tumor Xenograft (PDX) with tumors implanted in the mammary fat-pad were subjected to preclinical [18F]-Fluorodeoxyglucose (FDG)-PET/CT imaging. SC-PET images were derived from a 10 min static FDG-PET acquisition, 50 min post administration of FDG, and were resampled to generate four distinct LC-PET realizations corresponding to 10%, 5%, 1.6%, and 0.8% of SC-PET count-level. ARD-Net was trained and optimized using 48 preclinical FDG-PET datasets, while 16 datasets were utilized to assess performance. Further, the performance of ARD-Net was benchmarked against two leading DL-based methods (Residual UNet, RU-Net; and Dilated Network, D-Net) and non-DL methods (Non-Local Means, NLM; and Block Matching 3D Filtering, BM3D). The performance of the framework was evaluated using traditional fidelity-based image quality metrics such as Structural Similarity Index Metric (SSIM) and Normalized Root Mean Square Error (NRMSE), as well as human observer-based tumor segmentation performance (Dice Score and volume bias) and quantitative analysis of Standardized Uptake Value (SUV) measurements. Additionally, radiomics-derived features were utilized as a measure of quality assurance (QA) in comparison to true SC-PET. Finally, a performance ensemble score (EPS) was developed by integrating fidelity-based and task-based metrics. Concordance Correlation Coefficient (CCC) was utilized to determine concordance between measures. The non-parametric Friedman Test with Bonferroni correction was used to compare the performance of ARD-Net against benchmarked methods with significance at adjusted p-value ≤0.01. RESULTS: ARD-Net-generated SC-PET images exhibited significantly better (p ≤ 0.01 post Bonferroni correction) overall image fidelity scores in terms of SSIM and NRMSE at majority of photon-count levels compared to benchmarked DL and non-DL methods. In terms of task-based quantitative accuracy evaluated by SUVMean and SUVPeak, ARD-Net exhibited less than 5% median absolute bias for SUVMean compared to true SC-PET and lower degree of variability compared to benchmarked DL and non-DL based methods in generating SC-PET. Additionally, ARD-Net-generated SC-PET images displayed higher degree of concordance to SC-PET images in terms of radiomics features compared to non-DL and other DL approaches. Finally, the ensemble score suggested that ARD-Net exhibited significantly superior performance compared to benchmarked algorithms (p ≤ 0.01 post Bonferroni correction). CONCLUSION: ARD-Net provides a robust framework to generate SC-PET from LC-PET images. ARD-Net generated SC-PET images exhibited superior performance compared other DL and non-DL approaches in terms of image-fidelity based metrics, task-based segmentation metrics, and minimal bias in terms of task-based quantification performance for preclinical PET imaging.

18F-FDG PET in Myocardial Viability Assessment: A Practical and Time-Efficient Protocol.

We assessed image quality using a practical and time-efficient protocol for intravenous glucose loading and insulin injection before administration of 18F-FDG for PET myocardial viability evaluation in patients with ischemic cardiomyopathy (ICM), with and without type 2 diabetes mellitus. Methods: The metabolic preparation period (MPP) or optimal cardiac 18F-FDG uptake was determined from the time of intravenous infusion of 12.5 or 25 g of 50% dextrose to the time of 18F-FDG injection. Cardiac 18F-FDG image quality was evaluated according to a 5-point scoring system (from 5, excellent, to 1, nondiagnostic) by 2 independent observers. In cases of disagreement, consensus was achieved in a joint reading. Fifteen patients with ICM who underwent oral glucose loading and intravenous insulin administration served as a reference for MPP comparisons. Results: Fifty-nine consecutive patients (age, 63 ± 10 y; 48 men and 11 women) underwent rest 99mTc-tetrofosmin SPECT/CT and 18F-FDG PET/CT for the evaluation of myocardial viability. 18F-FDG image quality was scored as excellent in 42%, very good in 36%, good in 17%, fair in 3%, and nondiagnostic in 2%. When diabetic and nondiabetic patients were compared, the quality scores were excellent in 29% versus 76%, very good in 41% versus 18%, good in 24% versus 6%, fair in 4% versus 0%, and nondiagnostic in 2% versus 0%. The mean (±SD) quality score was 4.12 ± 0.95, and overall it was better in nondiabetic than in diabetic patients (4.71 ± 0.59 vs. 3.88 ± 0.96; P < 0.0001). Notably, the average MPP was significantly less with intravenous glucose loading than with oral glucose loading (51 ± 15 min vs. 132 ± 29 min; P < 0.0001), paralleled by higher insulin doses (6.3 ± 2.2 U vs. 2.0 ± 1.69 U; P < 0.001). Conclusion: Using a practical and time-efficient protocol for intravenous glucose loading and insulin administration before 18F-FDG injection reduces the MPP by 61% as compared with an oral glucose challenge and affords good-to-excellent image quality in 95% of ICM patients.

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

BACKGROUND: The monocyte chemoattractant protein-1/CCR2 (chemokine receptor 2) axis plays an important role in abdominal aortic aneurysm (AAA) pathogenesis, with effects on disease progression and anatomic stability. We assessed the expression of CCR2 in a rodent model and human tissues, using a targeted positron emission tomography radiotracer (64Cu-DOTA-ECL1i). METHODS: AAAs were generated in Sprague-Dawley rats by exposing the infrarenal, intraluminal aorta to PPE (porcine pancreatic elastase) under pressure to induce aneurysmal degeneration. Heat-inactivated PPE was used to generate a sham operative control. Rat AAA rupture was stimulated by the administration of ß-aminopropionitrile, a lysyl oxidase inhibitor. Biodistribution was performed in wild-type rats at 1 hour post tail vein injection of 64Cu-DOTA-ECL1i. Dynamic positron emission tomography/computed tomography imaging was performed in rats to determine the in vivo distribution of radiotracer. RESULTS: Biodistribution showed fast renal clearance. The localization of radiotracer uptake in AAA was verified with high-resolution computed tomography. At day 7 post-AAA induction, the radiotracer uptake (standardized uptake value [SUV]=0.91±0.25) was approximately twice that of sham-controls (SUV=0.47±0.10; P<0.01). At 14 days post-AAA induction, radiotracer uptake by either group did not significantly change (AAA SUV=0.86±0.17 and sham-control SUV=0.46±0.10), independent of variations in aortic diameter. Competitive CCR2 receptor blocking significantly decreased AAA uptake (SUV=0.42±0.09). Tracer uptake in AAAs that subsequently ruptured (SUV=1.31±0.14; P<0.005) demonstrated uptake nearly twice that of nonruptured AAAs (SUV=0.73±0.11). Histopathologic characterization of rat and human AAA tissues obtained from surgery revealed increased expression of CCR2 that was co-localized with CD68+ macrophages. Ex vivo autoradiography demonstrated specific binding of 64Cu-DOTA-ECL1i to CCR2 in both rat and human aortic tissues. CONCLUSIONS: CCR2 positron emission tomography is a promising new biomarker for the noninvasive assessment of AAA inflammation that may aid in associated rupture prediction.

Medical imaging data in the digital innovation age.

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

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

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

Assessment of cellular proliferation in tumors by PET using 18F-ISO-1.

UNLABELLED: This first study in humans was designed to evaluate the safety and dosimetry of a cellular proliferative marker, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-(18)F-fluoroethoxy)-5-methylbenzamide ((18)F-ISO-1), and evaluate the feasibility of imaging tumor proliferation by PET in patients with newly diagnosed malignant neoplasms. METHODS: Patients with biopsy-proven lymphoma, breast cancer, or head and neck cancer underwent (18)F-ISO-1 PET. Tumor (18)F-ISO-1 uptake was assessed semiquantitatively by maximum standardized uptake value, ratios of tumor to normal tissue and tumor to muscle, and relative distribution volume ratio. The PET results were correlated with tumor Ki-67 and mitotic index, from in vitro assays of the tumor tissue. The biodistribution of (18)F-ISO-1 and human dosimetry were evaluated. RESULTS: Thirty patients with primary breast cancer (n = 13), head and neck cancer (n = 10), and lymphoma (n = 7) were evaluated. In the entire group, tumor maximum standardized uptake value and tumor-to-muscle ratio correlated significantly with Ki-67 (τ = 0.27, P = 0.04, and τ = 0.38, P = 0.003, respectively), but no significant correlation was observed between Ki-67 and tumor-to-normal-tissue ratio (τ = 0.07, P = 0.56) or distribution volume ratio (τ = 0.26, P = 0.14). On the basis of whole-body PET data, the gallbladder is the dose-limiting organ, with an average radiation dose of 0.091 mGy/MBq. The whole-body and effective doses were 0.012 mGy/MBq and 0.016 mSv/MBq, respectively. No adverse effects of (18)F-ISO-1 were encountered. CONCLUSION: The presence of a significant correlation between (18)F-ISO-1 and Ki-67 makes this agent promising for evaluation of the proliferative status of solid tumors. The relatively small absorbed doses to normal organs allow for the safe administration of up to 550 MBq, which is sufficient for PET imaging in clinical trials.

Assessment of progesterone receptors in breast carcinoma by PET with 21-18F-fluoro-16α,17α-[(R)-(1'-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione.

UNLABELLED: This first-in-human study was designed to evaluate the safety and dosimetry of the progesterone analog 21-(18)F-fluoro-16α,17α-[(R)-(1'-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione ((18)F-FFNP), as well the feasibility of imaging tumor progesterone receptors (PRs) by PET in breast cancer. METHODS: Women with breast cancer underwent PET with (18)F-FFNP. Tumor (18)F-FFNP uptake was assessed semiquantitatively by determining maximum standardized uptake value and tumor-to-normal breast (T/N) activity ratio and by Logan graphical analysis. The PET results were correlated with estrogen receptor (ER) and PR status, assessed by in vitro assays of the tumor tissue. The biodistribution of (18)F-FFNP was measured in patients by whole-body PET, and human dosimetry was estimated. RESULTS: Twenty patients with 22 primary breast cancers (16 PR-positive [PR+] and 6 PR-negative [PR-]) were evaluated. Tumor maximum standardized uptake value was not significantly different in PR+ and PR- cancers (mean ± SD, 2.5 ± 0.9 vs. 2.0 ± 1.3, P = 0.386), but the T/N ratio was significantly greater in the PR+ cancers (2.6 ± 0.9 vs. 1.5 ± 0.3, P = 0.001). In addition, there was a significant correlation between distribution volume ratio and T/N ratio (r = 0.89; P = 0.001) but not between distribution volume ratio and either PR status or standardized uptake value, likely because of small sample size. On the basis of whole-body PET data in 12 patients, the gallbladder appeared to be the dose-limiting organ, with an average radiation dose of 0.113 mGy/MBq. The whole-body dose was 0.015 mGy/MBq, and the effective dose was 0.020 mSv/MBq. No adverse effects of (18)F-FFNP were encountered. CONCLUSION: (18)F-FFNP PET is a safe, noninvasive means for evaluating tumor PRs in vivo in patients with breast cancer. The relatively small absorbed doses to normal organs allow for the safe injection of up to 440 MBq of (18)F-FFNP.

Cascade removal and microPET imaging with 76Br.

PET imaging with non-standard nuclides has limitations due to the reduced spatial resolution from the positron range and from the concurrent emission of other gamma rays during the decay process. Particularly in high-resolution small animal PET imaging, these factors become detrimental for accurate quantitation of the activity concentrations from the reconstructed images. This paper presents an evaluation for imaging with such a nuclide, (76)Br, through imaging of specifically designed phantoms in a high-resolution small animal PET scanner. A model is presented for the calculation and removal of fortuitous cascade gamma ray coincidences based on estimation of the activity distribution and the attenuation correction file. In this evaluation, it is shown that 2 mm spatial resolution can be achieved with (76)Br while 1.7 mm was achieved with (18)F using a filtered back projection algorithm despite the much higher end-point energy of the positrons from (76)Br. A detailed evaluation of the point spread function for this nuclide was fitted by a double Gaussian function and explained the long tail from the high-energy positrons. These evaluations are crucial for accurate correction for partial volume effects and to provide accurate measurement of the activity concentrations in small animal PET imaging.

Performance evaluation of the microPET focus: a third-generation microPET scanner dedicated to animal imaging.

UNLABELLED: The microPET Focus is the latest generation microPET system dedicated to high-resolution animal imaging and incorporates several changes to enhance its performance. This study evaluated the basic performance of the scanner and compared it with the Primate (P4) and Rodent (R4) models. METHODS: The system consists of 168 lutetium oxyorthosilicate (LSO) detectors arranged in 4 contiguous rings, with a 25.8-cm diameter and a 7.6-cm axial length. Each detector consists of a 12 x 12 LSO crystal array of 1.51 x 1.51 x 10.00 mm3 elements. The scintillation light is transmitted to position-sensitive photomultiplier tubes via optical fiber bundles. The system was evaluated for its energy and spatial resolutions, sensitivity, and noise equivalent counting rate. Phantoms and animals of varying sizes were scanned to evaluate its imaging capability. RESULTS: The energy resolution averages 18.5% for the entire system. Reconstructed image resolution is 1.3-mm full width at half maximum (FWHM) at the center of field of view (CFOV) and remains under 2 mm FWHM within the central 5-cm-diameter FOV in all 3 dimensions. The absolute sensitivity of the system is 3.4% at the CFOV for an energy window of 250-750 keV and a timing window of 10 ns. The noise equivalent counting-rate performance reaches 645 kcps for a mouse-size phantom using 250- to 750-keV and 6-ns settings. Emission images of a micro-Derenzo phantom demonstrate the improvement in image resolution compared with previous models. Animal studies exhibit the capability of the system in studying disease models using mouse, rat, and nonhuman primates. CONCLUSION: The Focus has significantly improved performance over the previous models in all areas evaluated. This system represents the state-of-the-art scintillator-based animal PET scanner currently available and is expected to advance the potential of small animal PET.

In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM.

Tumor hypoxia is recognized as an important determinant of response to therapy. In this study we investigated the feasibility of clinical imaging with copper-60 diacetyl-bis( N(4)-methylthiosemicarbazone) ((60)Cu-ATSM) in patients with non-small-cell lung cancer (NSCLC) and also assessed whether pretreatment tumor uptake of (60)Cu-ATSM predicts tumor responsiveness to therapy. Nineteen patients with biopsy-proved NSCLC were studied by positron emission tomography (PET) with (60)Cu-ATSM before initiation of therapy. (60)Cu-ATSM uptake was evaluated semiquantitatively by determining the tumor-to-muscle activity ratio (T/M). All patients also underwent PET with fluorine-18 fluorodeoxyglucose (FDG) prior to institution of therapy. The PET results were correlated with follow-up evaluation (2-46 months). It was demonstrated that PET imaging with (60)Cu-ATSM in patients with NCSLC is feasible. The tumor of one patient had no discernible (60)Cu-ATSM uptake, whereas the tumor uptake in the remaining patients was variable, as expected. Response was evaluated in 14 patients; the mean T/M for (60)Cu-ATSM was significantly lower in responders (1.5+/-0.4) than in nonresponders (3.4+/-0.8) (P=0.002). However, the mean SUV for (60)Cu-ATSM was not significantly different in responders (2.8+/-1.1) and nonresponders (3.5+/-1.0) ( P=0.2). An arbitrarily selected T/M threshold of 3.0 discriminated those likely to respond to therapy: all eight responders had a T/M <3.0 and all six nonresponders had a T/M > or =3.0. Tumor SUV for FDG was not significantly different in responders and nonresponders (P=0.7) and did not correlate with (60)Cu-ATSM uptake (r=0.04; P=0.9). (60)Cu-ATSM-PET can be readily performed in patients with NSCLC and the tumor uptake of (60)Cu-ATSM reveals clinically unique information about tumor oxygenation that is predictive of tumor response to therapy.