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1.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
Objective
The objective was to update the 2001 systematic review conducted by the Institute For Clinical Evaluative Sciences (ICES) on the use of positron emission tomography (PET) in assessing myocardial viability. The update consisted of a review and analysis of the research evidence published since the 2001 ICES review to determine the effectiveness and cost-effectiveness of PET in detecting left ventricular (LV) viability and predicting patient outcomes after revascularization in comparison with other noninvasive techniques.
Background
Left Ventricular Viability
Heart failure is a complex syndrome that impairs the contractile ability of the heart to maintain adequate blood circulation, resulting in poor functional capacity and increased risk of morbidity and mortality. It is the leading cause of hospitalization in elderly Canadians. In more than two-thirds of cases, heart failure is secondary to coronary heart disease. It has been shown that dysfunctional myocardium resulting from coronary heart disease (CAD) may recover contractile function (i.e. considered viable). Dysfunctional but viable myocardium may have been stunned by a brief episode of ischemia, followed by restoration of perfusion, and may regain function spontaneously. It is believed that repetitive stunning results in hibernating myocardium that will only regain contractile function upon revascularization.
For people with CAD and severe LV dysfunction (left ventricular ejection fraction [LVEF] <35%) refractory to medical therapy, coronary artery bypass and heart transplantation are the only treatment options. The opportunity for a heart transplant is limited by scarcityof donor hearts. Coronary artery bypass in these patients is associated with high perioperative complications; however, there is evidence that revascularization in the presence of dysfunctional but viable myocardium is associated with survival benefits and lower rates of cardiac events. The assessment of left ventricular (LV) viability is, therefore, critical in deciding whether a patient with coronary artery disease and severe LV dysfunction should undergo revascularization, receive a heart transplant, or remain on medical therapy.
Assessment of Left Ventricular Viability
Techniques for assessing myocardial viability depend on the measurement of a specific characteristic of viable myocytes such as cell membrane integrity, preserved metabolism, mitochondria integrity, and preserved contractile reserve. In Ontario, single photon emission computed tomography (SPECT) using radioactive 201thallium is the most commonly used technique followed by dobutamine echocardiography. Newer techniques include SPECT using technetium tracers, cardiac magnetic resonance imaging, and PET, the subject of this review.
Positron Emission Tomography
PET is a nuclear imaging technique based on the metabolism of radioactive analogs of normal substrates such as glucose and water. The radiopharmaceutical used most frequently in myocardial viability assessment is F18 fluorodeoxyglucose (FDG), a glucose analog. The procedure involves the intravenous administration of FDG under controlled glycemic conditions, and imaging with a PET scanner. The images are reconstructed using computer software and analyzed visually or semi-quantitatively, often in conjunction with perfusion images. Dysfunctional but stunned myocardium is characterized by normal perfusion and normal FDG uptake; hibernating myocardium exhibits reduced perfusion and normal/enhanced FDG uptake (perfusion/metabolism mismatch), whereas scar tissue is characterized by reduction in both perfusion and FDG uptake (perfusion/metabolism match).
Review Strategy
The Medical Advisory Secretariat used a search strategy similar to that used in the 2001 ICES review to identify English language reports of health technology assessments and primary studies in selected databases, published from January 1, 2001 to April 20, 2005. Patients of interest were those with CAD and severe ventricular dysfunction being considered for revascularization that had undergone viability assessment using either PET and/or other noninvasive techniques. The outcomes of interest were diagnostic and predictive accuracy with respect to recovery of regional or global LV function, long-term survival and cardiac events, and quality of life. Other outcomes of interest were impact on treatment decision, adverse events, and cost-effectiveness ratios.
Of 456 citations, 8 systematic reviews/meta-analyses and 37 reports on primary studies met the selection criteria. The reports were categorized using the Medical Advisory Secretariat levels of evidence system, and the quality of the reports was assessed using the criteria of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) developed by the Centre for Dissemination of Research (National Health Service, United Kingdom). Analysis of sensitivity, specificity, predictive values and likelihood ratios were conducted for all data as well as stratified by mean left ventricular ejection fraction (LVEF). There were no randomized controlled trials. The included studies compared PET with one or more other noninvasive viability tests on the same group of patients or examined the long-term outcomes of PET viability assessments. The quality assessment showed that about 50% or more of the studies had selection bias, interpreted tests without blinding, excluded uninterpretable segments in the analysis, or did not have clearly stated selection criteria. Data from the above studies were integrated with data from the 2001 ICES review for analysis and interpretation.
Summary of Findings
The evidence was derived from populations with moderate to severe ischemic LV dysfunction with an overall quality that ranges from moderate to low.
PET appears to be a safe technique for assessing myocardial viability.
CAD patients with moderate to severe ischemic LV dysfunction and residual viable myocardium had significantly lower 2-year mortality rate (3.2%) and higher event-free survival rates (92% at 3 years) when treated with revascularization than those who were not revascularized but were treated medically (16% mortality at 2-years and 48% 3-year event-free survival).
A large meta-analysis and moderate quality studies of diagnostic accuracy consistently showed that compared to other noninvasive diagnostic tests such as thallium SPECT and echocardiography, FDG PET has:
Higher sensitivity (median 90%, range 71%–100%) and better negative likelihood ratio (median 0.16, range 0–0.38; ideal <0.1) for predicting regional myocardial function recovery after revascularization.
Specificity (median 73%, range 33%–91%) that is similar to other radionuclide imaging but lower than that of dobutamine echocardiography
Less useful positive likelihood ratio (median 3.1, range 1.4 –9.2; ideal>10) for predicting segmental function recovery.
Taking positive and negative likelihood ratios together suggests that FDG PET and dobutamine echocardiography may produce small but sometimes important changes in the probability of recovering regional wall motion after revascularization.
Given its higher sensitivity, PET is less likely to produce false positive results in myocardial viability. PET, therefore, has the potential to identify some patients who might benefit from revascularization, but who would not have been identified as suitable candidates for revascularization using thallium SPECT or dobutamine echocardiography.
PET appears to be superior to other nuclear imaging techniques including SPECT with 201thallium or technetium labelled tracers, although recent studies suggest that FDG SPECT may have comparable diagnostic accuracy as FDG PET for predicting regional and global LV function recovery.
No firm conclusion can be reached about the incremental value of PET over other noninvasive techniques for predicting global function improvement or long-term outcomes in the most important target population (patients with severe ischemic LV dysfunction) due to lack of direct comparison.
An Ontario-based economic analysis showed that in people with CAD and severe LV dysfunction and who were found to have no viable myocardium or indeterminate results by thallium SPECT, the use of PET as a follow-up assessment would likely result in lower cost and better 5-year survival compared to the use of thallium SPECT alone. The projected annual budget impact of adding PET under the above scenario was estimated to range from $1.5 million to $2.3 million.
Conclusion
In patients with severe LV dysfunction, that are deemed to have no viable myocardium or indeterminate results in assessments using other noninvasive tests, PET may have a role in further identifying patients who may benefit from revascularization. No firm conclusion can be drawn on the impact of PET viability assessment on long-term clinical outcomes in the most important target population (i.e. patients with severe LV dysfunction).
PMCID: PMC3385418  PMID: 23074467
2.  PET/MR: a paradigm shift 
Cancer Imaging  2013;13(1):36-52.
Abstract
More than a decade ago, multimodality imaging was introduced into clinical routine with the development of the positron emission tomography (PET)/computed tomography (CT) technique. Since then, PET/CT has been widely accepted in clinical imaging and has emerged as one of the main cancer imaging modalities. With the recent development of combined PET/magnetic resonance (MR) systems for clinical use, a promising new hybrid imaging modality is now becoming increasingly available. The combination of functional information delivered by PET with the morphologic and functional imaging of MR imaging (e.g., diffusion-weighted imaging, dynamic contrast-enhanced MR imaging and MR spectroscopy) offers exciting possibilities for clinical applications as well as basic research. However, the differences between CT and MR imaging are fundamental. This also leads to distinct differences between PET/CT and PET/MR not only regarding image interpretation but also concerning data acquisition, data processing and image reconstruction. This article provides an overview of the principal differences between PET/CT and PET/MR in terms of scanner design and technology, attenuation correction, speed, acquisition protocols, radiation exposure and safety aspects. PET/MR is expected to show advantages over PET/CT in clinical applications in which MR is known to be superior to CT due to its high intrinsic soft tissue contrast. However, as of now, only assumptions can be made about the future clinical role of PET/MR, as data about the performance of PET/MR in the clinical setting are still limited. The possible future clinical use of PET/MR in oncology, neurology and neurooncology, cardiology and imaging of inflammation is discussed.
doi:10.1102/1470-7330.2013.0005
PMCID: PMC3584300  PMID: 23446110
Positron emission tomography; magnetic resonance tomography; PET/MR; oncology; neurology; cardiology
3.  Ready for prime time? Dual tracer PET and SPECT imaging 
Dual isotope single photon emission computed tomography (SPECT) and dual tracer positron emission tomography (PET) imaging have great potential in clinical and molecular applications in the pediatric as well as the adult populations in many areas of brain, cardiac, and oncologic imaging as it allows the exploration of different physiological and molecular functions (e.g., perfusion, neurotransmission, metabolism, apoptosis, angiogenesis) under the same physiological and physical conditions. This is crucial when the physiological functions studied depend on each other (e.g., perfusion and metabolism) hence requiring simultaneous assessment under identical conditions, and can reduce greatly the quantitation errors associated with physical factors that can change between acquisitions (e.g., human subject or animal motion, change in the attenuation map as a function of time) as is detailed in this editorial. The clinical potential of simultaneous dual isotope SPECT, dual tracer PET and dual SPECT/PET imaging are explored and summarized. In this issue of AJNMMI (http://www.ajnmmi.us), Chapman et al. explore the feasibility of simultaneous and sequential SPECT/PET imaging and conclude that down-scatter and crosstalk from 511 keV photons preclude obtaining useful SPECT information in the presence of PET radiotracers. They report on an alternative strategy that consists of performing sequential SPECT and PET studies in hybrid microPET/SPECT/CT scanners, now widely available for molecular imaging. They validate their approach in a phantom consisting of a 96-well plate with variable 99mTc and 18F concentrations and illustrate the utility of such approaches in two sequential SPECT-PET/CT studies that include 99mTc-MAA/18F-NaF and 99mTc-Pentetate/18F-NaF. These approaches will need to be proven reproducible, accurate and robust to variations in the experimental conditions before they can be accepted by the molecular imaging community and be implemented in routine molecular microPET and microSPECT explorations. Although currently not accepted as standard procedures in the molecular imaging community, such approaches have the potential to open the way to new SPECT/PET explorations that allow studying molecular mechanisms and pathways in the living animal under similar physiological conditions. Although still premature for the clinical setting, these approaches can be extended to clinical research once proven accurate and precise in vivo in small and large animal models.
PMCID: PMC3484417  PMID: 23145358
Dualisotope; dual tracer; positron emission tomography (PET); single photon emission tomography (SPECT); quantitative imaging
4.  A systematic review of PET and PET/CT in oncology: A way to personalize cancer treatment in a cost-effective manner? 
Background
A number of diagnostic tests are required for the detection and management of cancer. Most imaging modalities such as computerized tomography (CT) are anatomical. However, positron emission tomography (PET) is a functional diagnostic imaging technique using compounds labelled with positron-emitting radioisotopes to measure cell metabolism. It has been a useful tool in studying soft tissues such as the brain, cardiovascular system, and cancer. The aim of this systematic review is to critically summarize the health economic evidence of oncologic PET in the literature.
Methods
Eight electronic databases were searched from 2005 until February 2010 to identify economic evaluation studies not included in previous Health Technology Assessment (HTA) reports. Only full health economic evaluations in English, French, or German were considered for inclusion. Economic evaluations were appraised using published quality criteria for assessing the quality of decision-analytic models. Given the variety of methods used in the health economic evaluations, the economic evidence has been summarized in qualitative form.
Results
From this new search, 14 publications were identified that met the inclusion criteria. All publications were decision-analytic models and evaluated PET using Fluorodeoxyglucose F18 (FDG-PET). Eight publications were cost-effectiveness analyses; six were cost-utility analyses. The studies were from Australia, Belgium, Canada, France, Italy, Taiwan, Japan, the Netherlands, the United Kingdom, and the United States. In the base case analyses of these studies, cost-effectiveness results ranged from dominated to dominant. The methodology of the economic evaluations was of varying quality. Cost-effectiveness was primarily influenced by the cost of PET, the specificity of PET, and the risk of malignancy.
Conclusions
Owing to improved care and less exposure to ineffective treatments, personalized medicine using PET may be cost-effective. However, the strongest evidence for the cost-effectiveness of PET is still in the staging of non-small cell lung cancer. Management decisions relating to the assessment of treatment response or radiotherapy treatment planning require further research to show the impact of PET on patient management and its cost-effectiveness. Because of the potential for increased patient throughput and the possible greater accuracy, the cost-effectiveness of PET/CT may be superior to that of PET. Only four studies of the cost-effectiveness of PET/CT were found in this review, and this is clearly an area for future research.
doi:10.1186/1472-6963-10-283
PMCID: PMC2959014  PMID: 20932288
5.  Functional Brain Imaging 
Executive Summary
Objective
The objective of this analysis is to review a spectrum of functional brain imaging technologies to identify whether there are any imaging modalities that are more effective than others for various brain pathology conditions. This evidence-based analysis reviews magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI) for the diagnosis or surgical management of the following conditions: Alzheimer’s disease (AD), brain tumours, epilepsy, multiple sclerosis (MS), and Parkinson’s disease (PD).
Clinical Need: Target Population and Condition
Alzheimer’s disease is a progressive, degenerative, neurologic condition characterized by cognitive impairment and memory loss. The Canadian Study on Health and Aging estimated that there will be 97,000 incident cases (about 60,000 women) of dementia (including AD) in Canada in 2006.
In Ontario, there will be an estimated 950 new cases and 580 deaths due to brain cancer in 2006. Treatments for brain tumours include surgery and radiation therapy. However, one of the limitations of radiation therapy is that it damages tissue though necrosis and scarring. Computed tomography (CT) and magnetic resonance imaging (MRI) may not distinguish between radiation effects and resistant tissue, creating a potential role for functional brain imaging.
Epilepsy is a chronic disorder that provokes repetitive seizures. In Ontario, the rate of epilepsy is estimated to be 5 cases per 1,000 people. Most people with epilepsy are effectively managed with drug therapy; but about 50% do not respond to drug therapy. Surgical resection of the seizure foci may be considered in these patients, and functional brain imaging may play a role in localizing the seizure foci.
Multiple sclerosis is a progressive, inflammatory, demyelinating disease of the central nervous system (CNS). The cause of MS is unknown; however, it is thought to be due to a combination of etiologies, including genetic and environmental components. The prevalence of MS in Canada is 240 cases per 100,000 people.
Parkinson’s disease is the most prevalent movement disorder; it affects an estimated 100,000 Canadians. Currently, the standard for measuring disease progression is through the use of scales, which are subjective measures of disease progression. Functional brain imaging may provide an objective measure of disease progression, differentiation between parkinsonian syndromes, and response to therapy.
The Technology Being Reviewed
Functional Brain Imaging
Functional brain imaging technologies measure blood flow and metabolism. The results of these tests are often used in conjunction with structural imaging (e.g., MRI or CT). Positron emission tomography and MRS identify abnormalities in brain tissues. The former measures abnormalities through uptake of radiotracers in the brain, while the latter measures chemical shifts in metabolite ratios to identify abnormalities. The potential role of functional MRI (fMRI) is to identify the areas of the brain responsible for language, sensory and motor function (sensorimotor cortex), rather than identifying abnormalities in tissues. Magnetoencephalography measures magnetic fields of the electric currents in the brain, identifying aberrant activity. Magnetoencephalography may have the potential to localize seizure foci and to identify the sensorimotor cortex, visual cortex and auditory cortex.
In terms of regulatory status, MEG and PET are licensed by Health Canada. Both MRS and fMRI use a MRI platform; thus, they do not have a separate licence from Health Canada. The radiotracers used in PET scanning are not licensed by Health Canada for general use but can be used through a Clinical Trials Application.
Review Strategy
The literature published up to September 2006 was searched in the following databases: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL, and International Network of Agencies for Health Technology Assessment (INAHTA). The database search was supplemented with a search of relevant Web sites and a review of the bibliographies of selected papers.
General inclusion criteria were applied to all conditions. Those criteria included the following:
Full reports of systematic reviews, randomized controlled trials (RCTs), cohort-control studies, prospective cohort studies (PCS’), and retrospective studies.
Sample sizes of at least 20 patients (≥ 10 with condition being reviewed).
English-language studies.
Human studies.
Any age.
Studying at least one of the following: fMRI, PET, MRS, or MEG.
Functional brain imaging modality must be compared with a clearly defined reference standard.
Must report at least one of the following outcomes: sensitivity, specificity, accuracy, positive predictive value (PPV), receiver operating characteristic curve, outcome measuring impact on diagnostic testing, treatment, patient health, or cost.
Summary of Findings
There is evidence to indicate that PET can accurately diagnose AD; however, at this time, there is no evidence to suggest that a diagnosis of AD with PET alters the clinical outcomes of patients.
The addition of MRS or O-(2-18F-Fluoroethyl)-L-Tyrosine (FET)-PET to gadolinium (Gd)-enhanced MRI for distinguishing malignant from benign tumours during primary diagnosis may provide a higher specificity than Gd-enhanced MRI alone. The clinical utility of additional imaging in patients to distinguish malignant from benign tumours is unclear, because patients with a suspected brain tumour will likely undergo a biopsy despite additional imaging results.
The addition of MRS, FET-PET, or MRI T2 to Gd-enhanced MRI for the differentiation of recurrence from radiation necrosis may provide a higher specificity than Gd-enhanced MRI alone. The clinical utility of additional imaging in patients with a suspected recurrence is in the monitoring of patients. Based on the evidence available, it is unclear if one of the imaging modalities (MRS, FET-PET, or MRI T2) offers significantly improved specificity over another.
There may be a role for fMRI in the identification of surgical candidates for tumour resection; however, this requires further research.
Based on the studies available, it is unclear if MEG has similar accuracy in localizing seizure foci to intracranial electroencephalogram (ICEEG). More high-quality research is needed to establish whether there is a difference in accuracy between MEG and ICEEG.
The results of the studies comparing PET to noninvasive electroencephalogram (EEG) did not demonstrate that PET was more accurate at localizing seizure foci; however, there may be some specific conditions, such as tuberous sclerosis, where PET may be more accurate than noninvasive EEG.
There may be some clinical utility for MEG or fMRI in presurgical functional mapping; however, this needs further investigation involving comparisons with other modalities. The clinical utility of MRS has yet to be established for patients with epilepsy.
Positron emission tomography has high sensitivity and specificity in the diagnosis of PD and the differential diagnosis of parkinsonian syndromes; however, it is unclear at this time if the addition of PET in the diagnosis of these conditions contributes to the treatment and clinical outcomes of patients.
There is limited clinical utility of functional brain imaging in the management of patients with MS at this time. Diagnosis of MS is established through clinical history, evoked potentials, and MRI. Magnetic resonance imaging can identify the multifocal white lesions and other structural characteristics of MS.
PMCID: PMC3379170  PMID: 23074493
6.  State of the Art in Cardiac Hybrid Technology: PET/MR 
Simultaneous PET/MRI is an emerging technique combining two powerful imaging modalities in a single device. The wide variety of available tracers for perfusion and metabolic studies and the high sensitivity of positron emission tomography (PET) combined with the high spatial resolution and soft tissue contrast of magnetic resonance imaging (MRI) in depicting cardiac morphology and function as well as MRI's absence of ionizing radiation makes PET/MRI very attractive to radiologists and clinicians. Nevertheless, PET/MR scientific and clinical promise is to be considered in the context of numerous technical challenges that hinder its use in the clinical setting. For example, in order for a PET system to work correctly within an MR field, major changes are required to the photon detection chain such as the elimination of photomultiplier tubes, etc. Another significant limitation of PET/MRI is the lack of an electron density map (as is the case with PET-CT) that can be readily obtained from MRI (the latter measures proton not electron density) and used to correct PET data for attenuation. Moreover, as with PET-CT, cardiac and respiratory motions cause image degradations that affect image quality and accuracy both in static and dynamic PET imaging. As a result, overcoming these (and other) technical limitations is a very active area of research both in academic institutions as well as industry. In this paper, we review recent literature on cardiac PET/MRI, present the state-of-the-art of this technology, and explore promising preclinical and clinical cardiac applications where PET/MRI could play a substantial role.
doi:10.1007/s12410-013-9213-5
PMCID: PMC3780420  PMID: 24073295
PET MRI; Hybrid PET/MRI; Cardiovascular disease; Coronary artery disease; Ischemia
7.  Competitive Advantage of PET/MRI 
European journal of radiology  2013;83(1):84-94.
Multimodality imaging has made great strides in the imaging evaluation of patients with a variety of diseases. Positron emission tomography/computed tomography (PET/CT) is now established as the imaging modality of choice in many clinical conditions, particularly in oncology. While the initial development of combined PET/magnetic resonance imaging (PET/MRI) was in the preclinical arena, hybrid PET/MR scanners are now available for clinical use. PET/MRI combines the unique features of MRI including excellent soft tissue contrast, diffusion-weighted imaging, dynamic contrast-enhanced imaging, fMRI and other specialized sequences as well as MR spectroscopy with the quantitative physiologic information that is provided by PET. Most evidence for the potential clinical utility of PET/MRI is based on studies performed with side-by-side comparison or software-fused MRI and PET images. Data on distinctive utility of hybrid PET/MRI are rapidly emerging. There are potential competitive advantages of PET/MRI over PET/CT. In general, PET/MRI may be preferred over PET/CT where the unique features of MRI provide more robust imaging evaluation in certain clinical settings. The exact role and potential utility of simultaneous data acquisition in specific research and clinical settings will need to be defined. It may be that simultaneous PET/MRI will be best suited for clinical situations that are disease-specific, organ-specific, related to diseases of the children or in those patients undergoing repeated imaging for whom cumulative radiation dose must be kept as low as reasonably achievable. PET/MRI also offers interesting opportunities for use of dual modality probes. Upon clear definition of clinical utility, other important and practical issues related to business operational model, clinical workflow and reimbursement will also be resolved.
doi:10.1016/j.ejrad.2013.05.028
PMCID: PMC3800216  PMID: 23791129
8.  Improvement of Attenuation Correction in Time-of-Flight PET/MR Imaging with a Positron-Emitting Source 
Quantitative PET imaging relies on accurate attenuation correction. Recently, there has been growing interest in combining state-of-the-art PET systems with MR imaging in a sequential or fully integrated setup. As CT becomes unavailable for these systems, an alternative approach to the CT-based reconstruction of attenuation coefficients (μ values) at 511 keV must be found. Deriving μ values directly from MR images is difficult because MR signals are related to the proton density and relaxation properties of tissue. Therefore, most research groups focus on segmentation or atlas registration techniques. Although studies have shown that these methods provide viable solutions in particular applications, some major drawbacks limit their use in whole-body PET/MR. Previously, we used an annulus-shaped PET transmission source inside the field of view of a PET scanner to measure attenuation coefficients at 511 keV. In this work, we describe the use of this method in studies of patients with the sequential time-of-flight (TOF) PET/MR scanner installed at the Icahn School of Medicine at Mount Sinai, New York, NY.
Methods
Five human PET/MR and CT datasets were acquired. The transmission-based attenuation correction method was compared with conventional CT-based attenuation correction and the 3-segment, MR-based attenuation correction available on the TOF PET/MR imaging scanner.
Results
The transmission-based method overcame most problems related to the MR-based technique, such as truncation artifacts of the arms, segmentation artifacts in the lungs, and imaging of cortical bone. Additionally, the TOF capabilities of the PET detectors allowed the simultaneous acquisition of transmission and emission data. Compared with the MR-based approach, the transmission-based method provided average improvements in PET quantification of 6.4%, 2.4%, and 18.7% in volumes of interest inside the lung, soft tissue, and bone tissue, respectively.
Conclusion
In conclusion, a transmission-based technique with an annulus-shaped transmission source will be more accurate than a conventional MR-based technique for measuring attenuation coefficients at 511 keV in future whole-body PET/MR studies.
doi:10.2967/jnumed.113.125989
PMCID: PMC4010111  PMID: 24434291
MR/PET; attenuation correction; transmission; TOF
9.  Bone formation rather than inflammation reflects Ankylosing Spondylitis activity on PET-CT: a pilot study 
Introduction
Positron Emission Tomography - Computer Tomography (PET-CT) is an interesting imaging technique to visualize Ankylosing Spondylitis (AS) activity using specific PET tracers. Previous studies have shown that the PET tracers [18F]FDG and [11C](R)PK11195 can target inflammation (synovitis) in rheumatoid arthritis (RA) and may therefore be useful in AS. Another interesting tracer for AS is [18F]Fluoride, which targets bone formation. In a pilot setting, the potential of PET-CT in imaging AS activity was tested using different tracers, with Magnetic Resonance Imaging (MRI) and conventional radiographs as reference.
Methods
In a stepwise approach different PET tracers were investigated. First, whole body [18F]FDG and [11C](R)PK11195 PET-CT scans were obtained of ten AS patients fulfilling the modified New York criteria. According to the BASDAI five of these patients had low and five had high disease activity. Secondly, an extra PET-CT scan using [18F]Fluoride was made of two additional AS patients with high disease activity. MRI scans of the total spine and sacroiliac joints were performed, and conventional radiographs of the total spine and sacroiliac joints were available for all patients. Scans and radiographs were visually scored by two observers blinded for clinical data.
Results
No increased [18F]FDG and [11C](R)PK11195 uptake was noticed on PET-CT scans of the first 10 patients. In contrast, MRI demonstrated a total of five bone edema lesions in three out of 10 patients. In the two additional AS patients scanned with [18F]Fluoride PET-CT, [18F]Fluoride depicted 17 regions with increased uptake in both vertebral column and sacroiliac joints. In contrast, [18F]FDG depicted only three lesions, with an uptake of five times lower compared to [18F]Fluoride, and again no [11C](R)PK11195 positive lesions were found. In these two patients, MRI detected nine lesions and six out of nine matched with the anatomical position of [18F]Fluoride uptake. Conventional radiographs showed structural bony changes in 11 out of 17 [18F]Fluoride PET positive lesions.
Conclusions
Our PET-CT data suggest that AS activity is reflected by bone activity (formation) rather than inflammation. The results also show the potential value of PET-CT for imaging AS activity using the bone tracer [18F]Fluoride. In contrast to active RA, inflammation tracers [18F]FDG and [11C](R)PK11195 appeared to be less useful for AS imaging.
doi:10.1186/ar3792
PMCID: PMC3446444  PMID: 22471910
10.  Methodology for Quantitative Rapid Multi-Tracer PET Tumor Characterizations 
Theranostics  2013;3(10):757-773.
Positron emission tomography (PET) can image a wide variety of functional and physiological parameters in vivo using different radiotracers. As more is learned about the molecular basis for disease and treatment, the potential value of molecular imaging for characterizing and monitoring disease status has increased. Characterizing multiple aspects of tumor physiology by imaging multiple PET tracers in a single patient provides additional complementary information, and there is a significant body of literature supporting the potential value of multi-tracer PET imaging in oncology. However, imaging multiple PET tracers in a single patient presents a number of challenges. A number of techniques are under development for rapidly imaging multiple PET tracers in a single scan, where signal-recovery processing algorithms are employed to recover various imaging endpoints for each tracer. Dynamic imaging is generally used with tracer injections staggered in time, and kinetic constraints are utilized to estimate each tracers' contribution to the multi-tracer imaging signal. This article summarizes past and ongoing work in multi-tracer PET tumor imaging, and then organizes and describes the main algorithmic approaches for achieving multi-tracer PET signal-recovery. While significant advances have been made, the complexity of the approach necessitates protocol design, optimization, and testing for each particular tracer combination and application. Rapid multi-tracer PET techniques have great potential for both research and clinical cancer imaging applications, and continued research in this area is warranted.
doi:10.7150/thno.5201
PMCID: PMC3840410  PMID: 24312149
PET tracers; Tumor Characterizations
11.  The future of hybrid imaging—part 3: PET/MR, small-animal imaging and beyond 
Insights into imaging  2011;2(3):235-246.
Since the 1990s, hybrid imaging by means of software and hardware image fusion alike allows the intrinsic combination of functional and anatomical image information. This review summarises in three parts the state of the art of dual-technique imaging with a focus on clinical applications. We will attempt to highlight selected areas of potential improvement of combined imaging technologies and new applications. In this third part, we discuss briefly the origins of combined positron emission tomography (PET)/magnetic resonance imaging (MRI). Unlike PET/computed tomography (CT), PET/MRI started out from developments in small-animal imaging technology, and, therefore, we add a section on advances in dual- and multi-modality imaging technology for small animals. Finally, we highlight a number of important aspects beyond technology that should be addressed for a sustained future of hybrid imaging. In short, we predict that, within 10 years, we may see all existing multi-modality imaging systems in clinical routine, including PET/MRI. Despite the current lack of clinical evidence, integrated PET/MRI may become particularly important and clinically useful in improved therapy planning for neurodegenerative diseases and subsequent response assessment, as well as in complementary loco-regional oncology imaging. Although desirable, other combinations of imaging systems, such as single-photon emission computed tomography (SPECT)/MRI may be anticipated, but will first need to go through the process of viable clinical prototyping. In the interim, a combination of PET and ultrasound may become available. As exciting as these new possible triple-technique—imaging systems sound, we need to be aware that they have to be technologically feasible, applicable in clinical routine and cost-effective.
doi:10.1007/s13244-011-0085-4
PMCID: PMC3270262  PMID: 22347950
Hybrid imaging; PET; MRI; PET/MR; Small-animal imaging
12.  The future of hybrid imaging—part 3: PET/MR, small-animal imaging and beyond 
Insights into Imaging  2011;2(3):235-246.
Since the 1990s, hybrid imaging by means of software and hardware image fusion alike allows the intrinsic combination of functional and anatomical image information. This review summarises in three parts the state of the art of dual-technique imaging with a focus on clinical applications. We will attempt to highlight selected areas of potential improvement of combined imaging technologies and new applications. In this third part, we discuss briefly the origins of combined positron emission tomography (PET)/magnetic resonance imaging (MRI). Unlike PET/computed tomography (CT), PET/MRI started out from developments in small-animal imaging technology, and, therefore, we add a section on advances in dual- and multi-modality imaging technology for small animals. Finally, we highlight a number of important aspects beyond technology that should be addressed for a sustained future of hybrid imaging. In short, we predict that, within 10 years, we may see all existing multi-modality imaging systems in clinical routine, including PET/MRI. Despite the current lack of clinical evidence, integrated PET/MRI may become particularly important and clinically useful in improved therapy planning for neurodegenerative diseases and subsequent response assessment, as well as in complementary loco-regional oncology imaging. Although desirable, other combinations of imaging systems, such as single-photon emission computed tomography (SPECT)/MRI may be anticipated, but will first need to go through the process of viable clinical prototyping. In the interim, a combination of PET and ultrasound may become available. As exciting as these new possible triple-technique—imaging systems sound, we need to be aware that they have to be technologically feasible, applicable in clinical routine and cost-effective.
doi:10.1007/s13244-011-0085-4
PMCID: PMC3270262  PMID: 22347950
Hybrid imaging; PET; MRI; PET/MR; Small-animal imaging
13.  Quantitative approaches of dynamic FDG-PET and PET/CT studies (dPET/CT) for the evaluation of oncological patients 
Cancer Imaging  2012;12(1):283-289.
Abstract
Objectives: The use of dynamic positron emission tomography/computed tomography (dPET/CT) studies with [18F]deoxyglucose (FDG) in oncological patients is limited and primarily confined to research protocols. A more widespread application is, however, desirable, and may help to assess small therapeutic effects early after therapy as well as to differentiate borderline differences between tumour and non-tumour lesions, e.g., lipomas versus low-grade liposarcomas. The aim is to present quantification approaches that can be used for the evaluation of dPET/CT series in combination with parametric imaging and to demonstrate the feasibility with regard to tumour diagnostics and therapy management. Methods: A 60-min data acquisition and short acquisition protocols (20-min dynamic series and a static image 60 min post injection) are discussed. A combination of a modified two-tissue compartment model and non-compartmental approaches from the chaos theory (fractal dimension of the time–activity curves) are presented. Fused PET/CT images as well as regression-based parametric images fused with CT or with PET/standardised uptake value images are demonstrated for the exact placement of volumes of interest. Results: The two-tissue compartmental method results in the calculation of 5 kinetic parameters, the fractional blood volume VB (known also as the distribution volume), and the transport rates k1 to k4. Furthermore, the influx according to Patlak can be calculated from the transport rates. The fractal dimension of the time–activity curves describes the heterogeneity of the tracer distribution. The use of the regression-based parametric images of FDG helps to visualise the transport/perfusion and the transport/phosphorylation-dependent FDG uptake, and adds a new dimension to the existing conventional PET or PET/CT images. Conclusions: More sophisticated quantification methods and dedicated software as well as high computational power and faster acquisition protocols can facilitate the assessment of dPET/CT, and may find use in clinical routine, in particular for the assessment of early therapeutic effects or new treatment protocols in combination with the new generation of PET/CT scanners.
doi:10.1102/1470-7330.2012.0033
PMCID: PMC3485644  PMID: 23033440
Dynamic PET; oncology; compartment modelling; non-compartment modelling; parametric imaging; feature extraction
14.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.
A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.
The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Objective
The objective of this analysis is to assess the effectiveness and safety of positron emission tomography (PET) imaging using F-18-fluorodeoxyglucose (FDG) for the assessment of myocardial viability. To evaluate the effectiveness of FDG PET viability imaging, the following outcomes are examined:
the diagnostic accuracy of FDG PET for predicting functional recovery;
the impact of PET viability imaging on prognosis (mortality and other patient outcomes); and
the contribution of PET viability imaging to treatment decision making and subsequent patient outcomes.
Clinical Need: Condition and Target Population
Left Ventricular Systolic Dysfunction and Heart Failure
Heart failure is a complex syndrome characterized by the heart’s inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality.
In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD)1 is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997.
Treatment Options
In general, there are three options for the treatment of heart failure: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure.
Myocardial Viability
Left ventricular dysfunction may be permanent if a myocardial scar is formed, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically:
dobutamine echocardiography (echo),
stress echo with contrast,
SPECT using either technetium or thallium,
cardiac magnetic resonance imaging (cardiac MRI), and
positron emission tomography (PET).
Dobutamine Echocardiography
Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 – 10 μg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability.
Stress Echocardiography with Contrast
Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium.
SPECT
SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (> 10% increase in tracer uptake) on the re-injection images.
The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (> 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%.
There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery.
Cardiac Positron Emission Tomography
Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG).
During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. This collision results in annihilation where the combined mass of the positron and electron is converted into energy in the form of two 511 keV gamma rays, which are then emitted in opposite directions (180 degrees) and captured by an external array of detector elements in the PET gantry. Computer software is then used to convert the radiation emission into images. The system is set up so that it only detects coincident gamma rays that arrive at the detectors within a predefined temporal window, while single photons arriving without a pair or outside the temporal window do not active the detector. This allows for increased spatial and contrast resolution.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of PET for detecting myocardial viability?
What is the prognostic value of PET viability imaging (mortality and other clinical outcomes)?
What is the contribution of PET viability imaging to treatment decision making?
What is the safety of PET viability imaging?
Literature Search
A literature search was performed on July 17, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 to July 16, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In addition, published systematic reviews and health technology assessments were reviewed for relevant studies published before 2004. Reference lists of included studies were also examined for any additional relevant studies not already identified. The quality of the body of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
English language full-reports
Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies
Patients with chronic, known CAD
PET imaging using FDG for the purpose of detecting viable myocardium
Criteria applying to diagnostic accuracy studies:
Assessment of functional recovery ≥3 months after revascularization
Raw data available to calculate sensitivity and specificity
Gold standard: prediction of global or regional functional recovery
Criteria applying to prognosis studies:
Mortality studies that compare revascularized patients with non-revascularized patients and patients with viable and non-viable myocardium
Exclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
PET perfusion imaging
< 20 patients
< 18 years of age
Patients with non-ischemic heart disease
Animal or phantom studies
Studies focusing on the technical aspects of PET
Studies conducted exclusively in patients with acute myocardial infarction (MI)
Duplicate publications
Criteria applying to diagnostic accuracy studies
Gold standard other than functional recovery (e.g., PET or cardiac MRI)
Assessment of functional recovery occurs before patients are revascularized
Outcomes of Interest
Diagnostic accuracy studies
Sensitivity and specificity
Positive and negative predictive values (PPV and NPV)
Positive and negative likelihood ratios
Diagnostic accuracy
Adverse events
Prognosis studies
Mortality rate
Functional status
Exercise capacity
Quality of Life
Influence on PET viability imaging on physician decision making
Statistical Methods
Pooled estimates of sensitivity and specificity were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance was defined by P values less than 0.05, where “false discovery rate” adjustments were made for multiple hypothesis testing. Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced. The area under the sROC curve was estimated by numerical integration with a cubic spline (default option). Finally, pooled estimates of mortality rates were calculated using weighted means.
Quality of Evidence
The quality of evidence assigned to individual diagnostic studies was determined using the QUADAS tool, a list of 14 questions that address internal and external validity, bias, and generalizibility of diagnostic accuracy studies. Each question is scored as “yes”, “no”, or “unclear”. The quality of the body of evidence was then assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
A total of 40 studies met the inclusion criteria and were included in this review: one health technology assessment, two systematic reviews, 22 observational diagnostic accuracy studies, and 16 prognosis studies. The available PET viability imaging literature addresses two questions: 1) what is the diagnostic accuracy of PET imaging for the assessment; and 2) what is the prognostic value of PET viability imaging. The diagnostic accuracy studies use regional or global functional recovery as the reference standard to determine the sensitivity and specificity of the technology. While regional functional recovery was most commonly used in the studies, global functional recovery is more important clinically. Due to differences in reporting and thresholds, however, it was not possible to pool global functional recovery.
Functional recovery, however, is a surrogate reference standard for viability and consequently, the diagnostic accuracy results may underestimate the specificity of PET viability imaging. For example, regional functional recovery may take up to a year after revascularization depending on whether it is stunned or hibernating tissue, while many of the studies looked at regional functional recovery 3 to 6 months after revascularization. In addition, viable tissue may not recover function after revascularization due to graft patency or re-stenosis. Both issues may lead to false positives and underestimate specificity. Given these limitations, the prognostic value of PET viability imaging provides the most direct and clinically useful information. This body of literature provides evidence on the comparative effectiveness of revascularization and medical therapy in patients with viable myocardium and patients without viable myocardium. In addition, the literature compares the impact of PET-guided treatment decision making with SPECT-guided or standard care treatment decision making on survival and cardiac events (including cardiac mortality, MI, hospital stays, unintended revascularization, etc).
The main findings from the diagnostic accuracy and prognosis evidence are:
Based on the available very low quality evidence, PET is a useful imaging modality for the detection of viable myocardium. The pooled estimates of sensitivity and specificity for the prediction of regional functional recovery as a surrogate for viable myocardium are 91.5% (95% CI, 88.2% – 94.9%) and 67.8% (95% CI, 55.8% – 79.7%), respectively.
Based the available very low quality of evidence, an indirect comparison of pooled estimates of sensitivity and specificity showed no statistically significant difference in the diagnostic accuracy of PET viability imaging for regional functional recovery using perfusion/metabolism mismatch with FDG PET plus either a PET or SPECT perfusion tracer compared with metabolism imaging with FDG PET alone.
FDG PET + PET perfusion metabolism mismatch: sensitivity, 89.9% (83.5% – 96.4%); specificity, 78.3% (66.3% – 90.2%);
FDG PET + SPECT perfusion metabolism mismatch: sensitivity, 87.2% (78.0% – 96.4%); specificity, 67.1% (48.3% – 85.9%);
FDG PET metabolism: sensitivity, 94.5% (91.0% – 98.0%); specificity, 66.8% (53.2% – 80.3%).
Given these findings, further higher quality studies are required to determine the comparative effectiveness and clinical utility of metabolism and perfusion/metabolism mismatch viability imaging with PET.
Based on very low quality of evidence, patients with viable myocardium who are revascularized have a lower mortality rate than those who are treated with medical therapy. Given the quality of evidence, however, this estimate of effect is uncertain so further higher quality studies in this area should be undertaken to determine the presence and magnitude of the effect.
While revascularization may reduce mortality in patients with viable myocardium, current moderate quality RCT evidence suggests that PET-guided treatment decisions do not result in statistically significant reductions in mortality compared with treatment decisions based on SPECT or standard care protocols. The PARR II trial by Beanlands et al. found a significant reduction in cardiac events (a composite outcome that includes cardiac deaths, MI, or hospital stay for cardiac cause) between the adherence to PET recommendations subgroup and the standard care group (hazard ratio, .62; 95% confidence intervals, 0.42 – 0.93; P = .019); however, this post-hoc sub-group analysis is hypothesis generating and higher quality studies are required to substantiate these findings.
The use of FDG PET plus SPECT to determine perfusion/metabolism mismatch to assess myocardial viability increases the radiation exposure compared with FDG PET imaging alone or FDG PET combined with PET perfusion imaging (total-body effective dose: FDG PET, 7 mSv; FDG PET plus PET perfusion tracer, 7.6 – 7.7 mSV; FDG PET plus SPECT perfusion tracer, 16 – 25 mSv). While the precise risk attributed to this increased exposure is unknown, there is increasing concern regarding lifetime multiple exposures to radiation-based imaging modalities, although the incremental lifetime risk for patients who are older or have a poor prognosis may not be as great as for healthy individuals.
PMCID: PMC3377573  PMID: 23074393
15.  Radiotherapy of high-grade gliomas: current standards and new concepts, innovations in imaging and radiotherapy, and new therapeutic approaches 
Chinese Journal of Cancer  2014;33(1):16-24.
The current standards in radiotherapy of high-grade gliomas (HGG) are based on anatomic imaging techniques, usually computed tomography (CT) scanning and magnetic resonance imaging (MRI). The guidelines vary depending on whether the HGG is a histological grade 3 anaplastic glioma (AG) or a grade 4 glioblastoma multiforme (GBM). For AG, T2-weighted MRI sequences plus the region of contrast enhancement in T1 are considered for the delineation of the gross tumor volume (GTV), and an isotropic expansion of 15 to 20 mm is recommended for the clinical target volume (CTV). For GBM, the Radiation Therapy Oncology Group favors a two-step technique, with an initial phase (CTV1) including any T2 hyperintensity area (edema) plus a 20 mm margin treated with up to 46 Gy in 23 fractions, followed by a reduction in CTV2 to the contrast enhancement region in T1 with an additional 25 mm margin. The European Organisation of Research and Treatment of Cancer recommends a single-phase technique with a unique GTV, which comprises the T1 contrast enhancement region plus a margin of 20 to 30 mm. A total dose of 60 Gy in 30 fractions is usually delivered for GBM, and a dose of 59.4 Gy in 33 fractions is typically given for AG. As more than 85% of HGGs recur in field, dose-escalation studies have shown that 70 to 75 Gy can be delivered in 6 weeks with relevant toxicities developing in < 10% of the patients. However, the only randomized dose-escalation trial, in which the boost dose was guided by conventional MRI, did not show any survival advantage of this treatment over the reference arm. HGGs are amongst the most infiltrative and heterogeneous tumors, and it was hypothesized that the most highly aggressive areas were missed; thus, better visualization of these high-risk regions for radiation boost could decrease the recurrence rate. Innovations in imaging and linear accelerators (LINAC) could help deliver the right doses of radiation to the right subvolumes according to the dose-painting concept. Advanced imaging techniques provide functional information on cellular density (diffusion MRI), angiogenesis (perfusion MRI), metabolic activity and cellular proliferation [positron emission tomography (PET) and magnetic resonance spectroscopy (MRS)]. All of these non-invasive techniques demonstrated good association between the images and histology, with up to 40% of HGGs functionally presenting a high activity within the non-contrast-enhanced areas in T1. New LINAC technologies, such as intensity-modulated and stereotactic radiotherapy, help to deliver a simultaneous integrated boost (SIB) > 60 Gy. Trials delivering a SIB into a biological GTV showed the feasibility of this treatment, but the final results, in terms of clinical benefits for HGG patients, are still pending. Many issues have been identified: the variety of MRI and PET machines (and amino-acid tracers), the heterogeneity of the protocols used for image acquisition and post-treatment, the geometric distortion and the unreliable algorithms for co-registration of brain anatomy with functional maps, and the semi-quiescent but highly invasive HGG cells. These issues could be solved by the homogenization of the protocols and software applications, the simultaneous acquisition of anatomic and functional images (PET-MRI machines), the combination of complementary imaging tools (perfusion and diffusion MRI), and the concomitant addition of some ad hoc targeted drugs against angiogenesis and invasiveness to chemoradiotherapy. The integration of these hybrid data will construct new synthetic metrics for fully individualized treatments.
doi:10.5732/cjc.013.10217
PMCID: PMC3905086  PMID: 24384237
Radiotherapy; advanced imaging; MRI; PET; high-grade gliomas
16.  FDG-PET/CT pitfalls in oncological head and neck imaging 
Insights into Imaging  2014;5(5):585-602.
Objectives
Positron emission tomography-computed tomography (PET/CT) with fluorine-18-fluorodeoxy-D-glucose (FDG) has evolved from a research modality to an invaluable tool in head and neck cancer imaging. However, interpretation of FDG PET/CT studies may be difficult due to the inherently complex anatomical landmarks, certain physiological variants and unusual patterns of high FDG uptake in the head and neck. The purpose of this article is to provide a comprehensive approach to key imaging features and interpretation pitfalls of FDG-PET/CT of the head and neck and how to avoid them.
Methods
We review the pathophysiological mechanisms leading to potentially false-positive and false-negative assessments, and we discuss the complementary use of high-resolution contrast-enhanced head and neck PET/CT (HR HN PET/CT) and additional cross-sectional imaging techniques, including ultrasound (US) and magnetic resonance imaging (MRI).
Results
The commonly encountered false-positive PET/CT interpretation pitfalls are due to high FDG uptake by physiological causes, benign thyroid nodules, unilateral cranial nerve palsy and increased FDG uptake due to inflammation, recent chemoradiotherapy and surgery. False-negative findings are caused by lesion vicinity to structures with high glucose metabolism, obscuration of FDG uptake by dental hardware, inadequate PET scanner resolution and inherent low FDG-avidity of some tumours.
Conclusions
The interpreting physician must be aware of these unusual patterns of FDG uptake, as well as limitations of PET/CT as a modality, in order to avoid overdiagnosis of benign conditions as malignancy, as well as missing out on actual pathology.
Teaching points
• Knowledge of key imaging features of physiological and non-physiological FDG uptake is essential for the interpretation of head and neck PET/CT studies.
• Precise anatomical evaluation and correlation with contrast-enhanced CT, US or MRI avoid PET/CT misinterpretation.
• Awareness of unusual FDG uptake patterns avoids overdiagnosis of benign conditions as malignancy.
doi:10.1007/s13244-014-0349-x
PMCID: PMC4195840  PMID: 25154759
Positron emission tomography-computed tomography (PET/CT); Pitfalls; Head and neck tumours
17.  MR-assisted PET Motion Correction for eurological Studies in an Integrated MR-PET Scanner 
Head motion is difficult to avoid in long PET studies, degrading the image quality and offsetting the benefit of using a high-resolution scanner. As a potential solution in an integrated MR-PET scanner, the simultaneously acquired MR data can be used for motion tracking. In this work, a novel data processing and rigid-body motion correction (MC) algorithm for the MR-compatible BrainPET prototype scanner is described and proof-of-principle phantom and human studies are presented.
Methods
To account for motion, the PET prompts and randoms coincidences as well as the sensitivity data are processed in the line or response (LOR) space according to the MR-derived motion estimates. After sinogram space rebinning, the corrected data are summed and the motion corrected PET volume is reconstructed from these sinograms and the attenuation and scatter sinograms in the reference position. The accuracy of the MC algorithm was first tested using a Hoffman phantom. Next, human volunteer studies were performed and motion estimates were obtained using two high temporal resolution MR-based motion tracking techniques.
Results
After accounting for the physical mismatch between the two scanners, perfectly co-registered MR and PET volumes are reproducibly obtained. The MR output gates inserted in to the PET list-mode allow the temporal correlation of the two data sets within 0.2 s. The Hoffman phantom volume reconstructed processing the PET data in the LOR space was similar to the one obtained processing the data using the standard methods and applying the MC in the image space, demonstrating the quantitative accuracy of the novel MC algorithm. In human volunteer studies, motion estimates were obtained from echo planar imaging and cloverleaf navigator sequences every 3 seconds and 20 ms, respectively. Substantially improved PET images with excellent delineation of specific brain structures were obtained after applying the MC using these MR-based estimates.
Conclusion
A novel MR-based MC algorithm was developed for the integrated MR-PET scanner. High temporal resolution MR-derived motion estimates (obtained while simultaneously acquiring anatomical or functional MR data) can be used for PET MC. An MR-based MC has the potential to improve PET as a quantitative method, increasing its reliability and reproducibility which could benefit a large number of neurological applications.
doi:10.2967/jnumed.110.079343
PMCID: PMC3125596  PMID: 21189415
PET; MRI; multimodality imaging; motion tracking; motion correction
18.  Quantitative, Simultaneous PET/MRI for Intratumoral Imaging with an MRI-Compatible PET Scanner 
Noninvasive methods are needed to explore the heterogeneous tumor microenvironment and its modulation by therapy. Hybrid PET/MRI systems are being developed for small-animal and clinical use. The advantage of these integrated systems depends on their ability to provide MR images that are spatially coincident with simultaneously acquired PET images, allowing combined functional MRI and PET studies of intratissue heterogeneity. Although much effort has been devoted to developing this new technology, the issue of quantitative and spatial fidelity of PET images from hybrid PET/MRI systems to the tissues imaged has received little attention. Here, we evaluated the ability of a first-generation, small-animal MRI-compatible PET scanner to accurately depict heterogeneous patterns of radiotracer uptake in tumors.
Methods
Quantitative imaging characteristics of the MRI-compatible PET (PET/MRI) scanner were evaluated with phantoms using calibration coefficients derived from a mouse-sized linearity phantom. PET performance was compared with a commercial small-animal PET system and autoradiography in tumor-bearing mice. Pixel and structure-based similarity metrics were used to evaluate image concordance among modalities. Feasibility of simultaneous PET/MRI functional imaging of tumors was explored by following 64Cu-labeled antibody uptake in relation to diffusion MRI using cooccurrence matrix analysis.
Results
The PET/MRI scanner showed stable and linear response. Activity concentration recovery values (measured and true activity concentration) calculated for 4-mm-diameter rods within linearity and uniform activity rod phantoms were near unity (0.97 ± 0.06 and 1.03 ± 0.03, respectively). Intratumoral uptake patterns for both 18F-FDG and a 64Cu-antibody acquired using the PET/MRI scanner and small-animal PET were highly correlated with autoradiography (r > 0.99) and with each other (r = 0.97 ± 0.01). On the basis of these data, we performed a preliminary study comparing diffusion MRI and radiolabeled antibody uptake patterns over time and visualized movement of antibodies from the vascular space into the tumor mass.
Conclusion
The MRI-compatible PET scanner provided tumor images that were quantitatively accurate and spatially concordant with autoradiography and the small-animal PET examination. Cooccurrence matrix approaches enabled effective analysis of multimodal image sets. These observations confirm the ability of the current simultaneous PET/MRI system to provide accurate observations of intratumoral function and serve as a benchmark for future evaluations of hybrid instrumentation.
doi:10.2967/jnumed.111.099861
PMCID: PMC3552656  PMID: 22661534
PET/MRI; multimodal imaging; tumor heterogeneity; quantitative molecular imaging; preclinical
19.  The impact of 18 F-FET PET-CT on target definition in image-guided stereotactic radiotherapy in patients with skull base lesions 
Cancer Imaging  2014;14(1):25.
Background
18 F-fluoro-ethyl-tyrosine PET is gaining more indications in the field of oncology. We investigated the potentials of usage of FET-PET/CT in addition to MRI for definition of gross tumor volume (GTV) in stereotactic radiotherapy of lesions of skull base.
Methods
We included in a prospective setting 21 cases. An MRI was performed, completed by FET PET/CT. Different GTV’s were defined based on respective imaging tools: 1. GTVMRI, 2. GTV MRI /CT, 3. GTV composit (1 + 2), and GTVPET = GTV Boost. Lesions could be visualised by MRI and FET-PET/CT in all patients.
Results
FET tracer enhancement was found in all cases. Skull base infiltration by these lesions was observed by MRI, CT (PET/CT) and FET-PET (PET/CT) in all patients. Totally, brain tissue infiltration was seen in 10 patients. While, in 7 (out 10) cases, MRI and CT (from PET/CT) were indicating brain infiltration, FET-PET could add additional information regarding infiltrative behaviour: in 3 (out 10) patients, infiltration of the brain was displayed merely in FET-PET. An enlargement of GTVMRI/CT due to the FET-PET driven information, which revealed GTVcomposite , was necessary in 7 cases,. This enlargement was significant by definition (> 10% of GTVMRI/CT). The mean PET-effect on GTV counted for 1 ± 4 cm3. The restricted boost fields were based mainly on the GTVPET volume. In mean, about 8.5 cm3 of GTVMRI/CT, which showed no FET uptake, were excluded from target volume. GTVboost driven by only-PET-activity, was in mean by 33% smaller than the initial large treatment field, GTVcomposite, for those cases received boost treatment. FET-PET lead to significant (>10%) changes in the initial treatment fields in 11/21 patients and showed additional tumour volume relevant for radiation planning in 6/21 cases, and led to a subsequent decrease of more than 10% of the initial volumes for the boost fields.
Conclusion
The implementation of FET PET into the planning procedures showed a benefit in terms of accurate definition of skull base lesions as targets for Image-guided stereotactic Radiotherapy. This has to be investigated prospectively in larger cohorts.
doi:10.1186/1470-7330-14-25
PMCID: PMC4331830  PMID: 25608761
FET-PET; Skull base; Image-guided; Stereotactic radiotherapy
20.  Dynamic whole body PET parametric imaging: I. Concept, acquisition protocol optimization and clinical application 
Physics in medicine and biology  2013;58(20):7391-7418.
Static whole body PET/CT, employing the standardized uptake value (SUV), is considered the standard clinical approach to diagnosis and treatment response monitoring for a wide range of oncologic malignancies. Alternative PET protocols involving dynamic acquisition of temporal images have been implemented in the research setting, allowing quantification of tracer dynamics, an important capability for tumor characterization and treatment response monitoring. Nonetheless, dynamic protocols have been confined to single bed-coverage limiting the axial field-of-view to ~15–20 cm, and have not been translated to the routine clinical context of whole-body PET imaging for the inspection of disseminated disease. Here, we pursue a transition to dynamic whole body PET parametric imaging, by presenting, within a unified framework, clinically feasible multi-bed dynamic PET acquisition protocols and parametric imaging methods. We investigate solutions to address the challenges of: (i) long acquisitions, (ii) small number of dynamic frames per bed, and (iii) non-invasive quantification of kinetics in the plasma. In the present study, a novel dynamic (4D) whole body PET acquisition protocol of ~45min total length is presented, composed of (i) an initial 6-min dynamic PET scan (24 frames) over the heart, followed by (ii) a sequence of multi-pass multi-bed PET scans (6 passes x 7 bed positions, each scanned for 45sec). Standard Patlak linear graphical analysis modeling was employed, coupled with image-derived plasma input function measurements. Ordinary least squares (OLS) Patlak estimation was used as the baseline regression method to quantify the physiological parameters of tracer uptake rate Ki and total blood distribution volume V on an individual voxel basis. Extensive Monte Carlo simulation studies, using a wide set of published kinetic FDG parameters and GATE and XCAT platforms, were conducted to optimize the acquisition protocol from a range of 10 different clinically acceptable sampling schedules examined. The framework was also applied to six FDG PET patient studies, demonstrating clinical feasibility. Both simulated and clinical results indicated enhanced contrast-to-noise ratios (CNRs) for Ki images in tumor regions with notable background FDG concentration, such as the liver, where SUV performed relatively poorly. Overall, the proposed framework enables enhanced quantification of physiological parameters across the whole-body. In addition, the total acquisition length can be reduced from 45min to ~35min and still achieve improved or equivalent CNR compared to SUV, provided the true Ki contrast is sufficiently high. In the follow-up companion paper, a set of advanced linear regression schemes is presented to particularly address the presence of noise, and attempt to achieve a better trade-off between the mean-squared error (MSE) and the CNR metrics, resulting in enhanced task-based imaging.
doi:10.1088/0031-9155/58/20/7391
PMCID: PMC3941007  PMID: 24080962
21.  The use of multi-gap resistive plate chambers for in-beam PET in proton and carbon ion therapy 
Journal of Radiation Research  2013;54(Suppl 1):i136-i142.
On-line verification of the delivered dose during proton and carbon ion radiotherapy is currently a very desirable goal for quality assurance of hadron therapy treatment plans. In-beam positron emission tomography (ibPET), which can provide an image of the β+ activity induced in the patient during irradiation, which in turn is correlated to the range of the ion beam, is one of the modalities for achieving this goal. Application to hadron therapy requires that the scanner geometry be modified from that which is used in nuclear medicine. In particular, PET detectors that allow a sub-nanosecond time-of-flight (TOF) registration of the collinear photons have been proposed. Inclusion of the TOF information in PET data leads to more effective PET sensitivity. Considering the challenges inherent in the ibPET technique, namely limited β+ activity and the effect of biological washout due to blood flow, TOF-PET technologies are very attractive. In this context, the TERA Foundation is investigating the use of resistive plate chambers (RPC) for an ibPET application because of their excellent timing properties and low cost. In this paper we present a novel compact multi-gap RPC (MRPC) module design and construction method, which considering the large number of modules that would be needed to practically implement a high-sensitivity RPC-PET scanner, could be advantageous. Moreover, we give an overview of the efficiency and timing measurements that have been obtained in the laboratory using such single-gap and multi-gap RPC modules.
doi:10.1093/jrr/rrt042
PMCID: PMC3700511  PMID: 23824118
in-beam PET; resistive plate chambers; on-line dosimetry; hadron therapy; quality assurance
22.  Single-scan dual-tracer FLT+FDG PET tumor characterization 
Physics in medicine and biology  2013;58(3):429-449.
Rapid multi-tracer PET aims to image two or more tracers in a single scan, simultaneously characterizing multiple aspects of physiology and function without the need for repeat imaging visits. Using dynamic imaging with staggered injections, constraints on the kinetic behavior of each tracer are applied to recover individual-tracer measures from the multi-tracer PET signal. The ability to rapidly and reliably image both 18F-fluorodeoxyglucose (FDG) and 18F-fluorothymidine (FLT) would provide complementary measures of tumor metabolism and proliferative activity, with important applications in guiding oncologic treatment decisions and assessing response. However, this tracer combination presents one of the most challenging dual-tracer signal-separation problems—both tracers have the same radioactive half-life, and the injection delay is short relative to the half-life and tracer kinetics. This work investigates techniques for single-scan dual-tracer FLT+FDG PET tumor imaging, characterizing the performance of recovering static and dynamic imaging measures for each tracer from dual-tracer datasets. Simulation studies were performed to characterize dual-tracer signal-separation performance for imaging protocols with both injection orders and injection delays of 10–60 min. Better performance was observed when FLT was administered first, and longer delays before administration of FDG provided more robust signal-separation and recovery of the single-tracer imaging measures. An injection delay of 30 min led to good recovery (R > 0.96) of static image values (e.g. SUV), Knet, and K1 as compared to values from separate, single-tracer time-activity curves. Recovery of higher order rate parameters (k2, k3) was less robust, indicating that information regarding these parameters was harder to recover in the presence of statistical noise and dual-tracer effects. Performance of the dual-tracer FLT(0 min)+FDG(32 min) technique was further evaluated using PET/CT imaging studies in five patients with primary brain tumors where the data from separate scans of each tracer were combined to synthesize dual-tracer scans with known single-tracer components; results demonstrated similar dual-tracer signal recovery performance. We conclude that rapid dual-tracer FLT+FDG tumor imaging is feasible and can provide quantitative tumor imaging measures comparable to those from conventional separate-scan imaging.
doi:10.1088/0031-9155/58/3/429
PMCID: PMC3553659  PMID: 23296314
23.  Does the Novel Integrated PET/MRI Offer the Same Diagnostic Performance as PET/CT for Oncological Indications? 
PLoS ONE  2014;9(3):e90844.
Background
We compared PET/MRI with PET/CT in terms of lesion detection and quantitative measurement to verify the feasibility of the novel integrated imaging modality for oncological applications.
Methodology/Principal Findings
In total, 285 patients referred to our PET/CT center for oncological indications voluntarily participated in this same-day PET/CT and PET/MRI comparative study. PET/CT images were acquired and reconstructed following routine protocols, and then PET/MRI was performed at a mean time interval of 28±11 min (range 15–45 min). PET/MRI covered the body trunk with a sequence combination of transverse T1WI 3D-volumetric interpolated breath-hold, T2WI turbo spin echo with fat saturation, diffusion-weighted imaging with double b values (50 and 800 s/mm2), and simultaneous PET acquisition over 45 min/5 bed positions. The maximum standardized uptake value (SUVmax) was assessed by manually drawn regions of interest over fluorodeoxyglucose-positive lesions. Among 285 cases, 57 showed no abnormalities, and 368 lesions (278 malignant, 68 benign and 22 undetermined) were detected in 228 patients. When stand-alone modalities were evaluated, PET revealed 31 and 12 lesions missed by CT and MRI, respectively, and CT and MRI revealed 38 and 61 more lesions, respectively, than PET. Compared to CT, MRI detected 40 more lesions and missed 8. In the integrated mode, PET/CT correctly detected 6 lesions misdiagnosed by PET/MRI, but was false-negative in 30 cases that were detected by PET/MRI. The overall diagnosis did not differ between integrated PET/MRI and PET/CT. SUVmax for lesions were slightly higher from PET/MRI than PET/CT but correlated well (ρ = 0.85–0.91).
Conclusions/Significance
The novel integrated PET/MRI performed comparatively to PET/CT in lesion detection and quantitative measurements. PET from either scanner modality offered almost the same information despite differences in hardware. Further study is needed to explore features of integrated PET/MRI not addressed in this study.
doi:10.1371/journal.pone.0090844
PMCID: PMC3946212  PMID: 24603857
24.  Predictive and prognostic value of FDG-PET 
Cancer Imaging  2008;8(1):70-80.
Abstract
The predictive and prognostic value of fluorodeoxyglucose (FDG)-positron emission tomography (PET) in non-small-cell lung carcinoma, colorectal carcinoma and lymphoma is discussed. The degree of FDG uptake is of prognostic value at initial presentation, after induction treatment prior to resection and in the case of relapse of non-small cell lung cancer (NSCLC). In locally advanced and advanced stages of NSCLC, FDG-PET has been shown to be predictive for clinical outcome at an early stage of treatment. In colorectal carcinoma, limited studies are available on the prognostic value of FDG-PET, however, the technique appears to have great potential in monitoring the success of local ablative therapies soon after intervention and in the prediction and evaluation of response to radiotherapy, systemic therapy, and combinations thereof. The prognostic value of end-of treatment FDG-PET for FDG-avid lymphomas has been established, and the next step is to define how to use this information to optimize patient outcome. In Hodgkin's lymphoma, FDG-PET has a high negative predictive value, however, histological confirmation of positive findings should be sought where possible. For non-Hodgkin's lymphoma, the opposite applies. The newly published standardized guidelines for interpretation formulates specific criteria for visual interpretation and for defining PET positivity in the liver, spleen, lung, bone marrow and small residual lesions. The introduction of these guidelines should reduce variability among studies. Interim PET offers a reliable method for early prediction of long-term remission, however it should only be performed in prospective randomized controlled trials. Many of the diagnostic and management questions considered in this review are relevant to other tumour types. Further research in this field is of great importance, since it may lead to a change in the therapeutic concept of cancer. The preliminary findings call for systematic inclusion of FDG-PET in therapeutic trials to adequately position FDG-PET in treatment time lines.
doi:10.1102/1470-7330.2008.0010
PMCID: PMC2324370  PMID: 18390390
FDG-PET; prediction; prognosis; response monitoring; therapy monitoring; SUV; non-small-cell lung cancer; colorectal cancer; lymphoma
25.  Advances in multimodality molecular imaging 
Multimodality molecular imaging using high resolution positron emission tomography (PET) combined with other modalities is now playing a pivotal role in basic and clinical research. The introduction of combined PET/CT systems in clinical setting has revolutionized the practice of diagnostic imaging. The complementarity between the intrinsically aligned anatomic (CT) and functional or metabolic (PET) information provided in a “one-stop shop” and the possibility to use CT images for attenuation correction of the PET data has been the driving force behind the success of this technology. On the other hand, combining PET with Magnetic Resonance Imaging (MRI) in a single gantry is technically more challenging owing to the strong magnetic fields. Nevertheless, significant progress has been made resulting in the design of few preclinical PET systems and one human prototype dedicated for simultaneous PET/MR brain imaging. This paper discusses recent advances in PET instrumentation and the advantages and challenges of multimodality imaging systems. Future opportunities and the challenges facing the adoption of multimodality imaging instrumentation will also be addressed.
doi:10.4103/0971-6203.54844
PMCID: PMC2807675  PMID: 20098557
Instrumentation; multimodality imaging; PET; PET/CT; PET/MR

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