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1.  Combined SPECT and Multidetector CT for Prostate Cancer Evaluations 
111In-capromab pendetide is an imaging probe for noninvasive detection of prostate cancer dissemination, and can be difficult to interpret because of low photon statistics resulting in noisy images with limited anatomical precision. We examined if a 16-slice multidetector computed tomography (MDCT) combined with single photon emission computed tomography (SPECT) could increase the impact on the clinical management and improve confidence in SPECT image interpretations in comparison to a relatively low-mA (limited resolution) CT. 17 scans were reviewed from a SPECT combined with low-mA CT scanner; 21 scans were reviewed from a SPECT combined with 16-slice MDCT scanner. Reports of the clinical interpretations from the imaging studies, additional examinations performed by referring physicians as a follow-up to the imaging results, and long-term clinical and laboratory follow-ups were used to define confidence of the SPECT/CT readings and impact of the readings on the patient management. The impact was defined as: the occurrence of the 111In-capromab pendetide interpretation resulted in additional imaging studies or biopsies. MDCT improved the quality and confidence in the characterization of small lymph nodes with or without uptake of 111In-capromab pendetide. The increased confidence with MDCT in SPECT/CT readings was evident in all cases reviewed in this study, and the impact on the clinical management was higher (8 out of 21) using SPECT/MDCT than the impact using SPECT combined with low-mA CT (2 out of 17). The dual-modality SPECT/CT provides a quantifiable benefit when MDCT is used instead of low-mA CT, particularly for prostate cancer evaluations using 111In-capromab pendetide.
PMCID: PMC3260786  PMID: 22267999
prostate cancer; capromab pendetide; SPECT/CT; MDCT; prostate specific membrane antigen (PSMA)
2.  In vivo Tumor Grading of Prostate Cancer using Quantitative 111In-Capromab Pendetide SPECT/CT 
We have developed an in vivo antibody uptake quantification method using 111In-capromab pendetide single photon emission computed tomography combined with computed tomography (SPECT/CT) technology. Our goal is to evaluate this noninvasive antibody quantification method for potential prostate tumor grading.
Methods
Our phantom experiments focused on the robustness of an advanced iterative reconstruction algorithm that involves corrections for photon attenuation, scatter, and geometric blurring caused by radionuclide collimators. The conversion factors between image values and tracer concentrations (in Bq/ml) were calculated from uniform phantom filled with aqueous solution of 111InCl3 using the same acquisition protocol and reconstruction parameters as for patient studies. In addition, the spatial resolution of the reconstructed images was measured from a point source phantom. The measured spatial resolution was modeled into a point spread function (PSF), and the PSF was implemented in a deconvolution-based partial volume error (PVE) correction algorithm. The recovery capability to correctly estimate true tracer concentration values was tested using prostate-like and bladder-like lesion phantoms fitted in the modified NEMA/IEC body phantom. Patients with biopsy-proven prostate cancer (n=10) who underwent prostatectomy were prospectively enrolled in the preoperative SPECT/CT studies at the San Francisco VA Medical Center. The CT portion of SPECT/CT was used for CT-based attenuation map generation as well as an anatomical localization tool for clinical interpretation. Pathologic Gleason grades were compared with in vivo “antibody uptake value” (AUV) normalized by injected dose, effective half-life, and injection-scan time difference. AUVs were calculated in each lobe of prostate gland with cylindrical volumes of interest (VOIs) having dimensions of 1.5 cm both in diameter and height.
Results
Reconstructed SPECT images further corrected by the deconvolution-based PVE correction could recover true tracer concentrations in volumes as small as 7.77 ml up to 90% in phantom measurements. From patient studies, there was a statistically significant correlation (ρ = 0.71, P = 0.033) between higher AUVs (from either left or right lobe) and higher components of pathologic Gleason scores.
Conclusion
Our results strongly indicate noninvasive prostate tumor grading potential using quantitative 111In-capromab pendetide SPECT/CT for prostate cancer evaluation.
doi:10.2967/jnumed.109.067108
PMCID: PMC2821016  PMID: 20008977
prostate cancer; capromab pendetide; SPECT; SPECT/CT; quantification; tracer quantification; quantitative SPECT; prostate specific membrane antigen (PSMA)
3.  Multi-Detector Computed Tomography Angiography for Coronary Artery Disease 
Executive Summary
Purpose
Computed tomography (CT) scanning continues to be an important modality for the diagnosis of injury and disease, most notably for indications of the head and abdomen. (1) According to a recent report published by the Canadian Institutes of Health Information, (1) there were about 10.3 scanners per million people in Canada as of January 2004. Ontario had the fewest number of CT scanners per million compared to the other provinces (8 CT scanners per million). The wait time for CT in Ontario of 5 weeks approaches the Canadian median of 6 weeks.
This health technology and policy appraisal systematically reviews the published literature on multidetector CT (MDCT) angiography as a diagnostic tool for the newest indication for CT, coronary artery disease (CAD), and will apply the results of the review to current health care practices in Ontario. This review does not evaluate MDCT to detect coronary calcification without contrast medium for CAD screening purposes.
The Technology
Compared with conventional CT scanning, MDCT can provide smaller pieces of information and can cover a larger area faster. (2) Advancing MDCT technology (8, 16, 32, 64 slice systems) is capable of producing more images in less time. For general CT scanning, this faster capability can reduce the time that patients must stay still during the procedure, thereby reducing potential movement artefact. However, the additional clinical utility of images obtained from faster scanners compared to the images obtained from conventional CT scanners for current CT indications (i.e., non-moving body parts) is not known.
There are suggestions that the new fast scanners can reduce wait times for general CT. MDCT angiography that utilizes a contrast medium, has been proposed as a minimally invasive replacement to coronary angiography to detect coronary artery disease. MDCT may take between 15 to 45 minutes; coronary angiography may take up to 1 hour.
Although 16-slice and 32-slice CT scanners have been available for a few years, 64-slice CT scanners were released only at the end of 2004.
Review Strategy
There are many proven, evidence-based indications for conventional CT. It is not clear how MDCT will add to the clinical utility and management of patients for established CT indications. Therefore, because cardiac imaging, specifically MDCT angiography, is a new indication for CT, this literature review focused on the safety, effectiveness, and cost-effectiveness of MDCT angiography compared with coronary angiography in the diagnosis and management of people with CAD.
This review asked the following questions:
Is the most recent MDCT angiography effective in the imaging of the coronary arteries compared with conventional angiography to correctly diagnose of significant (> 50% lumen reduction) CAD?
What is the utility of MDCT angiography in the management and treatment of patients with CAD?
How does MDCT angiography in the management and treatment of patients with CAD affect longterm outcomes?
The published literature from January 2003 to January 31, 2005 was searched for articles that focused on the detection of coronary artery disease using 16-slice CT or faster, compared with coronary angiography. The search yielded 138 articles; however, 125 were excluded because they did not meet the inclusion criteria (comparison with coronary angiography, diagnostic accuracy measures calculated, and a sample size of 20 or more). As screening for CAD is not advised, studies that utilized MDCT for this purpose or studies that utilized MDCT without contrast media were also excluded. Overall, 13 studies were included in this review.
Summary of Findings
The published literature focused on 16-slice CT angiography for the detection of CAD. Two abstracts that were presented at the 2005 European Congress of Radiology meeting in Vienna compared 64-slice CT angiography with coronary angiography.
The 13 studies focussing on 16-slice CT angiography were stratified into 2 groups: Group 1 included 9 studies that focused on the detection of CAD in symptomatic patients, and Group 2 included 4 studies that examined the use of 16-slice CT angiography to detect disease progression after cardiac interventions. The 2 abstracts on 64-slice CT angiography were presented separately, but were not critically appraised due to the lack of information provided in the abstracts.
16-Slice Computed Tomography Angiography
The STARD initiative to evaluate the reporting quality of studies that focus on diagnostic tests was used. Overall the studies were relatively small (fewer than 100 people), and only about one-half recruited consecutive patients. Most studies reported inclusion criteria, but 5 did not report exclusion criteria. In these 5, the patients were highly selected; therefore, how representative they are of the general population of people with suspicion if CAD or those with disease progression after cardiac intervention is questionable. In most studies, patients were either already taking, or were given, β-blockers to reduce their heart rates to improve image quality sufficiently. Only 6 of the 13 studies reported interobserver reliability quantitatively. The studies typically assessed the quality of the images obtained from 16-slice CT angiography, excluded those of poor quality, and compared the rest with the gold standard, coronary angiography. This practice necessarily inflated the diagnostic accuracy measures. Only 3 studies reported confidence intervals around their measures.
Evaluation of the studies in Group 1 reported variable sensitivity, from just over 60% to 96%, but a more stable specificity, at more than 95%. The false positive rate ranged from 5% to 8%, but the false negative rate was at best under 10% and at worst about 30%. This means that up to one-third of patients who have disease may be missed. These patients may therefore progress to a more severe level of disease and require more invasive procedures. The calculated positive and negative likelihood ratios across the studies suggested that 16-slice CT angiography may be useful to detect disease, but it is not useful to rule out disease. The prevalence of disease, measured by conventional coronoary angiography, was from 50% to 80% across the studies in this review. Overall, 16-slice CT angiography may be useful, but there is no conclusive evidence to suggest that it is equivalent to or better than coronary angiography to detect CAD in symptomatic patients.
In the 4 studies in Group 2, sensitivity and specificity were both reported at more than 95% (except for 1 that reported sensitivity of about 80%). The positive and negative likelihood ratios suggested that the test might be useful to detect disease progression in patients who had cardiac interventions. However, 2 of the 4 studies recruited patients who had been asymptomatic since their intervention. As many of the patients studied were not symptomatic, the relevance of performing MDCT angiography in the patient population may be in question.
64-Slice Computed Tomography Angiography
An analysis from the interim results based on 2 abstracts revealed that 64-slice CT angiography was insufficient compared to coronary angiography and may not be better than 16-slice CT angiography to detect CAD.
Conclusions
Cardiac imaging is a relatively new indication for CT. A systematic review of the literature was performed from 2003 to January 2005 to determine the effectiveness of MDCT angiography (16-slice and 64-slice) compared to coronary angiography to detect CAD. At the time of this report, there was no published literature on 64-slice CT for any indications.
Based on this review, the Medical Advisory Secretariat concluded that there is insufficient evidence to suggest that 16-slice or 64-slice CT angiography is equal to or better than coronary angiography to diagnose CAD in people with symptoms or to detect disease progression in patients who had previous cardiac interventions. An analysis of the evidence suggested that in investigating suspicion of CAD, a substantial number of patients would be missed. This means that these people would not be appropriately treated. These patients might progress to more severe disease and possibly more adverse events. Overall, the clinical utility of MDCT in patient management and long-term outcomes is unknown.
Based on the current evidence, it is unlikely that CT angiography will replace coronary angiography completely, but will probably be used adjunctively with other cardiac diagnostic tests until more definitive evidence is published.
If multi-slice CT scanners are used for coronary angiography in Ontario, access to the current compliment of CT scanners will necessarily increase wait times for general CT scanning. It is unlikely that these newer-generation scanners will improve patient throughput, despite the claim that they are faster.
Screening for CAD in asymptomatic patients and who have no history of ischemic heart disease using any modality is not advised, based on the World Health Organization criteria for screening. Therefore, this review did not examine the use of multi-slice CT for this purpose.
PMCID: PMC3382628  PMID: 23074474
4.  PROSTATE SPECIFIC MEMBRANE ANTIGEN-BASED IMAGING 
Urologic oncology  2012;31(2):144-154.
SUMMARY
Prostate cancer (PC) is the most common non-cutaneous malignancy affecting men in North America. Despite significant efforts, conventional imaging of PC does not contribute to patient management as much as imaging performed for other common cancers. Given the lack of specificity in conventional imaging techniques, one possible solution is to screen for PC specific antigenic targets and generate agents able to specifically bind. Prostate specific membrane antigen (PSMA) is over-expressed in PC tissue, with low levels of expression in the small intestine, renal tubular cells and salivary gland. The first clinical agent for targeting PSMA was 111In-capromab, involving an antibody recognizing the internal domain of PSMA. The second- and third-generation humanized PSMA binding antibodies have the potential to overcome some of the limitations inherent to capromab pendetide i.e. inability to bind to live PC cells. One example is the humanized monoclonal antibody J591 (Hu mAb J591) that was developed primarily for therapeutic purposes but also has interesting imaging characteristics including the identification of bone metastases in PC.
The major disadvantage of use of mAb for imaging is slow target recognition and background clearance in an appropriate timeframe for diagnostic imaging. Urea-based compounds such as small molecule inhibitors may also present promising agents for PC imaging with SPECT and PET. Two such small-molecule inhibitors targeting PSMA, MIP-1072 and MIP-1095, have exhibited high affinity for PSMA. The uptake of 123I-MIP-1072 and 123I-MIP-1095 in PC xenografts have imaged successfully with favorable properties amenable to human trials. While advances in conventional imaging will continue, Ab and small molecule imaging exemplified by PSMA targeting have the greatest potential to improve diagnostic sensitivity and specificity.
doi:10.1016/j.urolonc.2012.04.016
PMCID: PMC3461099  PMID: 22658884
Prostate specific membrane antigen; prostate cancer; molecular imaging; monoclonal antibody; single-photon emission computed tomography; positron emission tomography
5.  Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. 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 for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series 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
Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Pease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:
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
The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:
The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7
Objective
The objective of the analysis is to determine the diagnostic accuracy of single photon emission tomography (SPECT) in the diagnosis of coronary artery disease (CAD) compared to the reference standard of coronary angiography (CA). The analysis is primarily meant to allow for indirect comparisons between non-invasive strategies for the diagnosis of CAD, using CA as a reference standard.
SPECT
Cardiac SPECT, or myocardial perfusion scintigraphy (MPS), is a widely used nuclear, non-invasive image acquisition technique for investigating ischemic heart disease. SPECT is currently appropriate for all aspects of detecting and managing ischemic heart disease including diagnosis, risk assessment/stratification, assessment of myocardial viability, and the evaluation of left ventricular function. Myocardial perfusion scintigraphy was originally developed as a two-dimensional planar imaging technique, but SPECT acquisition has since become the clinical standard in current practice. Cardiac SPECT for the diagnosis of CAD uses an intravenously administered radiopharmaceutical tracer to evaluate regional coronary blood flow usually at rest and after stress. The radioactive tracers thallium (201Tl) or technetium-99m (99mTc), or both, may be used to visualize the SPECT acquisition. Exercise or a pharmacologic agent is used to achieve stress. After the administration of the tracer, its distribution within the myocardium (which is dependent on myocardial blood flow) is imaged using a gamma camera. In SPECT imaging, the gamma camera rotates around the patients for 10 to 20 minutes so that multiple two-dimensional projections are acquired from various angles. The raw data are then processed using computational algorithms to obtain three-dimensional tomographic images.
Since its inception, SPECT has evolved and its techniques/applications have become increasingly more complex and numerous. Accordingly, new techniques such as attenuation correction and ECG gating have been developed to correct for attenuation due to motion or soft-tissue artifact and to improve overall image clarity.
Research Questions
What is the diagnostic accuracy of SPECT for the diagnosis of CAD compared to the reference standard of CA?
Is SPECT cost-effective compared to other non-invasive cardiac imaging modalities for the diagnosis of CAD?
What are the major safety concerns with SPECT when used for the diagnosis of CAD?
Methods
A preliminary literature search was performed across OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for all systematic reviews/meta-analysis published between January 1, 2004 and August 22, 2009. A comprehensive systematic review was identified from this search and used as a basis for an updated search.
A second comprehensive literature search was then performed on October 30, 2009 across the same databases for studies published between January 1, 2002 and October 30, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also hand-searched for any additional studies.
Systematic reviews, meta-analyses, controlled clinical trials, and observational studies
Minimum sample size of 20 patients who completed coronary angiography
Use of CA as a reference standard for the diagnosis of CAD
Data available to calculate true positives (TP), false positives (FP), false negatives (FN) and true negatives (TN)
Accuracy data reported by patient not by segment
English language
Non-systematic reviews, case reports
Grey literature and abstracts
Trials using planar imaging only
Trials conducted in patients with non-ischemic heart disease
Studies done exclusively in special populations (e.g., patients with left branch bundle block, diabetics, minority populations) unless insufficient data available
Summary of Findings
Eighty-four observational studies, one non-randomized, single arm controlled clinical trial, and one poorly reported trial that appeared to be a randomized controlled trial (RCT) met the inclusion criteria for this review. All studies assessed the diagnostic accuracy of myocardial perfusion SPECT for the diagnosis of CAD using CA as a reference standard. Based on the results of these studies the following conclusions were made:
According to very low quality evidence, the addition of attenuation correction to traditional or ECG-gated SPECT greatly improves the specificity of SPECT for the diagnosis of CAD although this improvement is not statistically significant. A trend towards improvement of specificity was also observed with the addition of ECG gating to traditional SPECT.
According to very low quality evidence, neither the choice of stress agent (exercise or pharmacologic) nor the choice of radioactive tracer (technetium vs. thallium) significantly affect the diagnostic accuracy of SPECT for the diagnosis of CAD although a trend towards accuracy improvement was observed with the use of pharmacologic stress over exercise stress and technetium over thallium.
Considerably heterogeneity was observed both within and between trials. This heterogeneity may explain why some of the differences observed between accuracy estimates for various subgroups were not statistically significant.
More complex analytic techniques such as meta-regression may help to better understand which study characteristics significantly influence the diagnostic accuracy of SPECT.
PMCID: PMC3377554  PMID: 23074411
6.  Multidetector Computed Tomography for Coronary Artery Disease Screening in Asymptomatic Populations 
Executive Summary
Objective
This evidence-based health technology assessment systematically reviewed the published literature on multidetector computed tomography (MDCT) angiography (with contrast) as a diagnostic tool for coronary artery disease (CAD), and applied the results of the assessment to health care practices in Ontario.
Clinical Need
Coronary artery disease is the leading cause of death in the western world. Occlusion of coronary arteries reduces coronary blood flow and oxygen delivery to the myocardium (heart muscle). The rupture of an unstable atherosclerotic plaque may result in myocardial infarction. If left untreated, CAD can result in heart failure and, subsequently, death. According to the Heart and Stroke Foundation of Canada, 54% of all cardiovascular deaths are due to CAD. Patient characteristics (e.g., age, sex, and genetics), underlying clinical conditions that predispose to cardiac conditions (e.g., diabetes, hypertension, and elevated cholesterol), lifestyle characteristics, (e.g., obesity, smoking, and physical inactivity), and, more recently, determinants of health (e.g., socioeconomic status) may predict the risk of getting CAD.
In 2004/2005, The Ontario government funded approximately 15,400 percutaneous (through the skin) coronary interventions and 7,840 coronary bypass procedures for the treatment of CAD. These numbers are expected to reach 22,355 for percutaneous coronary interventions and 12,323 for coronary bypass procedures in 2006/2007. It was noted that more than one-half of all first coronary events occur in people without symptoms of CAD. In Ontario in 2000/2001, $457.9 million (Cdn) was spent on invasive ($237.4 million) and noninvasive ($220.5 million) cardiac services. The use of noninvasive cardiac tests, in particular, is rising rapidly.
The Technology
Computed tomography (CT) is a medical imaging method employing tomography where digital geometry processing is used to generate a 3-dimensional image of the internals of an object from a large series of 2-dimensional X-ray images taken around a single axis of rotation. Multidetector computed tomography is performed for noninvasive imaging of the coronary arteries. Computer software quantifies the amount of calcium within the coronary arteries and calculates a coronary artery calcium score.
Compared with conventional CT scanning, MDCT can provide smaller pieces of information and cover a larger area faster. Advanced MDCT technology (that is, 8-, 16-, 32-, and 64-slice systems) can produce more images in less time. For general CT scanning, this faster capability can reduce the length of time people are required to be still during the procedure and thereby reduce potential movement artifact. However, the additional clinical utility of images obtained from faster scanners compared with the images obtained from conventional CT scanners for current CT indications (i.e., nonmoving body parts) is unknown.
Review Strategy
The Medical Advisory Secretariat completed a computer-aided search limited to English-language studies in humans from 1998 to 2007 in multiple medical literature databases, including MEDLINE, EMBASE, The Cochrane Library, and INAHTA/CRD. Case reports, letters, editorials, nonsystematic reviews, and comments were excluded. Additional studies that met the inclusion and exclusion criteria were obtained from reference lists of included studies. Inclusion and exclusion criteria were applied to the results according to the criteria listed below.
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review.
Summary of Findings and Conclusions
Screening the asymptomatic population for CAD using MDCT does not meet World Health Organization criteria for screening; hence, it is not justifiable. Coronary artery calcification measured by MDCT is a good predictor of future cardiovascular events. However, MDCT exhibits only moderately high sensitivity and specificity for detection of CAD in an asymptomatic population. If population-based screening were implemented, a high rate of false positives would result in increased downstream costs and interventions. Additionally, some cases of CAD would be missed, as they may not be developed, or not yet have progressed to detectable levels. There is no evidence for the impact of screening on patient management. Cardiovascular risk factors are positively associated with the presence of coronary artery calcification and cardiovascular events; however, risk factor stratification to identify high-risk asymptomatic individuals is unclear given the current evidence-base.
Safety of MDCT screening is also an issue because of the introduction of increased radiation doses for the initial screening scan and possible follow-up interventions.
No large randomized controlled trials of MDCT screening have been published, which indicates an important area of future research.
Lastly, the policy implications for MDCT screening for CAD in the asymptomatic population are significant. There is no evidence on the long-term implications of screening, and the potential impact on the resources of the health care system is considerable.
PMCID: PMC3377586  PMID: 23074503
7.  Diagnostic and therapeutic impact of SPECT/CT in patients with unspecific pain of the hand and wrist 
EJNMMI Research  2012;2:53.
Background
Unspecific pain of the hand/wrist is a diagnostic challenge. Radiographs and planar bone scan are useful diagnostic tools in patients with unspecific wrist pain. Both modalities are deficient, either by not presenting metabolic disorders or due to inadequate anatomical resolution. Single photon emission computed tomography/computed tomography (SPECT/CT) claims to fuse both features.
Methods
Fifty-one patients with persisting wrist pain were referred for evaluation by SPECT/CT. All patients received X-ray and early-phase/late-phase SPECT/CT imaging. SPECT/CT results were compared with X-ray alone and X-ray combined with planar bone scan. The therapeutic impact was evaluated in consensus with the referring hand surgeon.
Results
A total of 48 lesions were detected on plain radiographs, 117 on planar bone scan, and 142 on SPECT/CT. SPECT/CT detected significantly more lesions than the other imaging modalities. In 30 out of 51 patients (61%), a positive concordance between the clinical diagnosis and SPECT/CT findings was found. In 19 out of 51 patients (37%), SPECT/CT findings had significant impact on consecutive therapy.
Conclusions
SPECT/CT showed higher lesion detection rates compared to standard X-rays and planar bone scan. Significant impact on patient management could be demonstrated. SPECT/CT might be added to the workup of such a specific patient population when standard imaging fails to detect the patient's main pathology.
doi:10.1186/2191-219X-2-53
PMCID: PMC3506557  PMID: 23021154
SPECT/CT; Therapeutic impact; Multimodality imaging; Hand and wrist pain
8.  Limited value of 99mTc depreotide single photon emission CT compared with CT for the evaluation of pulmonary lesions 
The British Journal of Radiology  2012;85(1015):e307-e313.
Objectives
A contrast-enhanced multidetector CT (MDCT) scan is the first choice examination when evaluating patients with suspected lung cancer. However, while the clinical focus is on CT, research focus is on molecular biological methods whereby radiolabelled pharmaceuticals are injected into participants and target malignant lung tumours. We examined whether a contrast-enhanced MDCT scan supplied with an additional non-contrast enhanced high-resolution CT scan, or a newer but more expensive 99mTc depreotide single photon emission CT (SPECT) scan, was the better first-choice examination for the work-up of pulmonary lesions. Furthermore, we examined whether a 99mTc depreotide SPECT scan was an appropriate second-choice examination for patients with indeterminate lesions.
Methods
140 participants were included in the analysis. CT images were given a malignancy potential rating of 1, 2 or 3 with higher rating being indicative of disease. 99mTc depreotide SPECT images were graded either positive or negative. Histopathology and CT follow-up were used as reference standard. Sensitivity, specificity and diagnostic accuracy were calculated.
Results
Overall sensitivity, specificity and diagnostic accuracy of CT were 97%, 30% and 84%, respectively. Overall sensitivity, specificity and diagnostic accuracy of 99mTc depreotide SPECT were 94%, 58% and 76%, respectively. For indeterminate lesions sensitivity, specificity and diagnostic accuracy of 99mTc depreotide SPECT were 71%, 68% and 69%, respectively.
Conclusion
Both CT and 99mTc depreotide SPECT made valuable contributions to the evaluation of pulmonary lesions. 99mTc depreotide SPECT results were not superior to CT results and did not contribute further to the diagnostic work-up. Regarding indeterminate lesions, 99mTc depreotide SPECT sensitivity was too low.
doi:10.1259/bjr/10438644
PMCID: PMC3474046  PMID: 22745210
9.  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
10.  SPECT/CT and pulmonary embolism 
Acute pulmonary embolism (PE) is diagnosed either by ventilation/perfusion (V/P) scintigraphy or pulmonary CT angiography (CTPA). In recent years both techniques have improved. Many nuclear medicine centres have adopted the single photon emission CT (SPECT) technique as opposed to the planar technique for diagnosing PE. SPECT has been shown to have fewer indeterminate results and a higher diagnostic value. The latest improvement is the combination of a low-dose CT scan with a V/P SPECT scan in a hybrid tomograph. In a study comparing CTPA, planar scintigraphy and SPECT alone, SPECT/CT had the best diagnostic accuracy for PE. In addition, recent developments in the CTPA technique have made it possible to image the pulmonary arteries of the lungs in one breath-hold. This development is based on the change from a single-detector to multidetector CT technology with an increase in volume coverage per rotation and faster rotation. Furthermore, the dual energy CT technique is a promising modality that can provide functional imaging in combination with anatomical information. Newer high-end CT scanners and SPECT systems are able to visualize smaller subsegmental emboli. However, consensus is lacking regarding the clinical impact and treatment. In the present review, SPECT and SPECT in combination with low-dose CT, CTPA and dual energy CT are discussed in the context of diagnosing PE.
doi:10.1007/s00259-013-2614-5
PMCID: PMC4003400  PMID: 24213621
SPECT; SPECT/CT; Pulmonary CT angiography; Lung scintigraphy; Pulmonary embolism; Overview; Diagnostic test
11.  Post-radioembolization yttrium-90 PET/CT - part 1: diagnostic reporting 
EJNMMI Research  2013;3:56.
Background
Yttrium-90 (90Y) positron emission tomography with integrated computed tomography (PET/CT) represents a technological leap from 90Y bremsstrahlung single-photon emission computed tomography with integrated computed tomography (SPECT/CT) by coincidence imaging of low abundance internal pair production. Encouraged by favorable early experiences, we implemented post-radioembolization 90Y PET/CT as an adjunct to 90Y bremsstrahlung SPECT/CT in diagnostic reporting.
Methods
This is a retrospective review of all paired 90Y PET/CT and 90Y bremsstrahlung SPECT/CT scans over a 1-year period. We compared image resolution, ability to confirm technical success, detection of non-target activity, and providing conclusive information about 90Y activity within targeted tumor vascular thrombosis. 90Y resin microspheres were used. 90Y PET/CT was performed on a conventional time-of-flight lutetium-yttrium-oxyorthosilicate scanner with minor modifications to acquisition and reconstruction parameters. Specific findings on 90Y PET/CT were corroborated by 90Y bremsstrahlung SPECT/CT, 99mTc macroaggregated albumin SPECT/CT, follow-up diagnostic imaging or review of clinical records.
Results
Diagnostic reporting recommendations were developed from our collective experience across 44 paired scans. Emphasis on the continuity of care improved overall diagnostic accuracy and reporting confidence of the operator. With proper technique, the presence of background noise did not pose a problem for diagnostic reporting. A counter-intuitive but effective technique of detecting non-target activity is proposed, based on the pattern of activity and its relation to underlying anatomy, instead of its visual intensity. In a sub-analysis of 23 patients with a median follow-up of 5.4 months, 90Y PET/CT consistently outperformed 90Y bremsstrahlung SPECT/CT in all aspects of qualitative analysis, including assessment for non-target activity and tumor vascular thrombosis. Parts of viscera closely adjacent to the liver remain challenging for non-target activity detection, compounded by a tendency for mis-registration.
Conclusions
Adherence to proper diagnostic reporting technique and emphasis on continuity of care are vital to the clinical utility of post-radioembolization 90Y PET/CT. 90Y PET/CT is superior to 90Y bremsstrahlung SPECT/CT for the assessment of target and non-target activity.
doi:10.1186/2191-219X-3-56
PMCID: PMC3726297  PMID: 23883566
Yttrium-90 radioembolization; Selective internal radiation therapy; Yttrium-90 PET/CT; Bremsstrahlung SPECT/CT; Diagnostic reporting; Non-target activity
12.  Single Resting hsTnT Level Predicts Abnormal Myocardial Stress Test in Acute Chest Pain Patients With Normal Initial Standard Troponin 
JACC. Cardiovascular imaging  2013;6(1):72-82.
OBJECTIVES
The goal of this study was to determine the ability of a single, resting high-sensitivity troponin T (hsTnT) measurement to predict abnormal myocardial perfusion imaging (MPI) in patients presenting with acute chest pain to the emergency department (ED).
BACKGROUND
HsTnT assays precisely detect very low levels of troponin T, which may be a surrogate for the presence and extent of myocardial ischemia.
METHODS
We included all patients from the ROMICAT I (Rule Out Myocardial Infarction Using Computer Assisted Tomography) trial, an observational cohort study, who underwent both single-photon emission computed tomography (SPECT)-MPI stress testing and 64-slice computed tomography angiography (CTA) and in whom hsTnT measurements were available. We assessed the discriminatory value of hsTnT for abnormal SPECT-MPI and the association of reversible myocardial ischemia by SPECT-MPI and the extent of coronary atherosclerosis by CTA to hsTnT levels.
RESULTS
Of the 138 patients (mean age 54 ± 11 years, 46% male), 19 (13.7%) had abnormal SPECT-MPI. Median hsTnT levels were significantly different between patients with normal and abnormal SPECT-MPI (9.41 pg/ml [interquartile range (IQR): 5.73 to 19.20 pg/ml] vs. 4.89 pg/ml [IQR: 2.34 to 7.68 pg/ml], p = 0.001). Sensitivity of 80% and 90% to detect abnormal SPECT-MPI was reached at hsTnT levels as low as 5.73 and 4.26 pg/ml, respectively. Corresponding specificity was 62% and 46%, and negative predictive value was 96% and 96%, respectively. HsTnT levels had good discriminatory ability for prediction of abnormal SPECT-MPI (area under the curve: 0.739, 95% confidence interval: 0.609 to 0.868). Both reversible myocardial ischemia and the extent of coronary atherosclerosis (combined model r2 = 0.19 with partial of r2 = 0.12 and r2 = 0.05, respectively) independently and incrementally predicted the measured hsTnT levels.
CONCLUSIONS
In patients with acute chest pain, myocardial perfusion abnormalities and coronary artery disease are predicted by resting hsTnT levels. Prospective evaluations are warranted to confirm whether resting hsTnT could serve as a powerful triage tool in chest pain patients in the ED before diagnostic testing and improve the effectiveness of patient management.
doi:10.1016/j.jcmg.2012.08.014
PMCID: PMC3734805  PMID: 23328564
coronary computed tomographic angiography; high-sensitivity troponin T; myocardial perfusion imaging; single-photon emission computed tomography
13.  Automatic and manual image fusion of 111In-pentetreotide SPECT and diagnostic CT in neuroendocrine tumor imaging – An evaluation 
In the clinical diagnosis of neuroendocrine tumors (NET), the results of examinations, such as high-resolution computed tomography (CT) and single photon computerized tomography (SPECT), have conventionally been interpreted separately. The aim of the present study was to evaluate Hermes Multimodality™ 5.0 H Image Fusion software-based automatic and manual image fusion of SPECT and CT for the localization of NET lesions. Out of 34 NET patients who were examined by means of somatostatin receptor scintigraphy (SRS) with 111In- pentetreotide along with SPECT, 22 patients had a CT examination of the abdomen, which was used in the fusion analysis. SPECT and CT data were fused using software with a registration algorithm based on normalized mutual information. The criteria for acceptable fusion were established at a maximum cranial or caudal dislocation of 25 mm between the images and at a reasonable consensus (in order of less than 1 cm) between outline of the reference organs. The automatic fusion was acceptable in 13 of the 22 examinations, whereas 9 fusions were not. However all the 22 examinations were acceptable at the manual fusion. The result of automatic fusion was better when the slice thickness of 5 mm was applied at CT examination, when the number of slices was below 100 in CT data and when both examinations included uptakes of pathological lesions. Retrospective manual image fusion of SPECT and CT is a relatively inexpensive but reliable method to be used in NET imaging. Automatic image fusion with specified software of SPECT and CT acts better when the number of CT slices is reduced to the SPECT volume and when corresponding pathological lesions appear at both SPECT and CT examinations.
doi:10.4103/0971-6203.71766
PMCID: PMC2990117  PMID: 21170187
Computed tomography; image fusion; neuroendocrine tumors; single photon emission computed tomography; somatostatin receptor scintigraphy
14.  Transitioning from 16-slice to 64-slice multidetector computed tomography for the assessment of coronary artery disease: Are we really making progress? 
BACKGROUND:
Multidetector computed tomography (MDCT) has demonstrated promise in the noninvasive evaluation of coronary artery disease.
OBJECTIVE:
To systematically review the literature regarding the improved diagnostic accuracy of 64-slice MDCT.
METHODS:
An EMBASE, OVID, PubMed and Cochrane Library database search was performed using the key words ‘computed tomography’ matched with the terms ‘coronary artery’ or ‘coronary angiography’ to identify English-language articles examining MDCT cardiac imaging. Studies that compared 16-slice or 64-slice MDCT with catheter-based coronary angiography for the detection of coronary artery disease in non-revascularized, poststent and post-coronary artery bypass graft patients were included. Data were pooled to obtain a weighted sensitivity, specificity and diagnostic accuracy for MDCT. Negative and positive predictive values, and likelihood ratios were calculated based on sensitivity and specificity.
RESULTS:
Currently, 15 studies involving 1008 patients have examined the efficacy of 64-slice MDCT in the assessment of coronary artery stenosis (more than 50% luminal narrowing). In these studies, 64-slice MDCT has demonstrated a sensitivity (89%), specificity (96%) and diagnostic accuracy (95%) similar to that of 16-slice MDCT. However, 64-slice MDCT was able to assess 5% more coronary artery segments than 16-slice MDCT. In revascularized patients, MDCT can accurately assess both bypass graft occlusion and stenosis. The 64-slice MDCT is also capable of adequately detecting in-stent restenosis. Improvements in spatial and temporal resolution with 64-slice technology have decreased the occurrence of high attenuation and motion artefacts that plagued the previous generation of MDCT scanners.
CONCLUSION:
MDCT offers an accurate assessment of the coronary arteries, stented arteries and bypass grafts. The improved accuracy and safety of MDCT may reduce the need for catheter-based coronary angiography.
PMCID: PMC2780905  PMID: 19746244
Angiography; Bypass; Computed tomography; Coronary disease; Restenosis
15.  Magnetic Resonance Imaging (MRI) 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 noninvasive 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.
A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
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 cost-effectiveness of cardiovascular magnetic resonance imaging (cardiac MRI) for the assessment of myocardial viability. To evaluate the effectiveness of cardiac MRI viability imaging, the following outcomes were examined: the diagnostic accuracy in predicting functional recovery and the impact of cardiac MRI viability imaging on prognosis (mortality and other 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, in some cases, 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, due to the formation of myocardial scar, 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 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.
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.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of cardiac MRI for detecting myocardial viability?
What is the impact of cardiac MRI viability imaging on prognosis (mortality and other clinical outcomes)?
How does cardiac MRI compare with cardiac PET imaging for the assessment of myocardial viability?
What is the contribution of cardiac MRI viability imaging to treatment decision making?
Is cardiac MRI cost-effective compared with other cardiac imaging modalities for the assessment of myocardial viability?
Literature Search
A literature search was performed on October 9, 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, 2005 until October 9, 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 2005. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language full-reports
Published between January 1, 2005 and October 9, 2009
Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies
Patients with chronic, known coronary artery disease (CAD)
Used contrast-enhanced MRI
Assessment of functional recovery ≥ 3 months after revascularization
Exclusion Criteria
< 20 patients
< 18 years of age
Patients with non-ischemic heart disease
Studies conducted exclusively in patients with acute myocardial infarction (MI)
Studies where TP, TN, FP, FN cannot be determined
Outcomes of Interest
Sensitivity
Specificity
Positive predictive value (PPV)
Negative Predictive value (NPV)
Positive likelihood ratio
Negative likelihood ratio
Diagnostic accuracy
Mortality rate (for prognostic studies)
Adverse events
Summary of Findings
Based on the available very low quality evidence, MRI 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 84.5% (95% CI: 77.5% – 91.6%) and 71.0% (95% CI: 68.8% – 79.2%), respectively.
Subgroup analysis demonstrated a statistically significant difference in the sensitivity of MRI to assess myocardial viability for studies using ≤25% hyperenhancement as a viability threshold versus studies using ≤50% hyperenhancement as their viability threshold [78.7 (95% CI: 69.1% - 88.2%) and 96.2 (95% CI: 91.8 – 100.6); p=0.0044 respectively]. Marked differences in specificity were observed [73.6 (95% CI: 62.6% - 84.6%) and 47.2 (95% CI: 22.2 – 72.3); p=0.2384 respectively]; however, these findings were not statistically significant.
There were no statistically significant differences between the sensitivities or specificities for any other subgroups including mean preoperative LVEF, imaging method for function recovery assessment, and length of follow-up.
There was no evidence available to determine whether patients with viable myocardium who are revascularized have a lower mortality rate than those who are treated with medical therapy.
PMCID: PMC3426228  PMID: 23074392
16.  Evaluation of coronary atheroma by 64-slice multidetector computed tomography: Comparison with intravascular ultrasound and angiography 
The Canadian Journal of Cardiology  2009;25(11):641-647.
BACKGROUND:
Recent improvements in multidetector computed tomography (MDCT) with 64-slice scanners have allowed acquisition of a coronary study in 5 s to 6 s, with good temporal and spatial resolution. Previous studies have reported an underestimation of plaque burden by MDCT. Whether shorter scan times can allow correct assessment of plaque volume requires comparison with intravascular ultrasound (IVUS).
METHODS:
Patients (n=30) scheduled for coronary angiography also underwent MDCT and IVUS examinations within 96 h. MDCT examination was performed with a 64-slice scanner. Nitroglycerin was administered before all imaging procedures. MDCT, quantitative coronary angiography (QCA) and IVUS analyses were performed by observers blinded to other results. Plaque volumes were determined by MDCT and IVUS in one vessel, and maximum percentage diameter stenosis was identified in each coronary segment by MDCT and QCA.
RESULTS:
The mean (± SD) plaque volume was determined to be 179.1±78.9 mm3 by MDCT and 176.1±87.9 mm3 by IVUS. There was a strong positive correlation for plaque volume between MDCT and IVUS (r=0.84, P<0.0001). Percentage diameter stenosis assessed by MDCT and QCA also correlated well (r=0.88 per patient and r=0.87 per vessel, P<0.0001 for both). The maximum percentage diameter stenosis per vessel was 38.1±30.2% with MDCT and 34.1±27.6% with QCA. The sensitivity and specificity of MDCT in detecting stenoses above 50% per vessel were 100% and 91.0%, respectively.
CONCLUSIONS:
Plaque volumes measured by 64-slice MDCT and IVUS correlate well, without systematic underestimation. The sensitivity and specificity of MDCT to detect stenoses greater than 50% by QCA are excellent with the administration of nitroglycerin before imaging.
PMCID: PMC2776562  PMID: 19898696
Angiography; Atherosclerosis; Coronary disease; Tomography; Ultrasonics
17.  Investigation of dynamic SPECT measurements of the arterial input function in human subjects using simulation, phantom and human studies 
Physics in Medicine and Biology  2011;57(2):375-393.
Computer simulations, a phantom study and a human study were performed to determine whether a slowly rotating single-photon computed emission tomography (SPECT) system could provide accurate arterial input functions for quantification of myocardial perfusion imaging using kinetic models. The errors induced by data inconsistency associated with imaging with slow camera rotation during tracer injection were evaluated with an approach called SPECT/P (dynamic SPECT from positron emission tomography (PET)) and SPECT/D (dynamic SPECT from database of SPECT phantom projections). SPECT/P simulated SPECT-like dynamic projections using reprojections of reconstructed dynamic 94Tc-methoxyisobutylisonitrile (94Tc-MIBI) PET images acquired in three human subjects (1 min infusion). This approach was used to evaluate the accuracy of estimating myocardial wash-in rate parameters K1 for rotation speeds providing 180° of projection data every 27 or 54 s. Blood input and myocardium tissue time-activity curves (TACs) were estimated using spatiotemporal splines. These were fit to a one-compartment perfusion model to obtain wash-in rate parameters K1. For the second method (SPECT/D), an anthropomorphic cardiac torso phantom was used to create real SPECT dynamic projection data of a tracer distribution derived from 94Tc-MIBI PET scans in the blood pool, myocardium, liver and background. This method introduced attenuation, collimation and scatter into the modeling of dynamic SPECT projections. Both approaches were used to evaluate the accuracy of estimating myocardial wash-in parameters for rotation speeds providing 180° of projection data every 27 and 54 s. Dynamic cardiac SPECT was also performed in a human subject at rest using a hybrid SPECT/CT scanner. Dynamic measurements of 99mTc-tetrofosmin in the myocardium were obtained using an infusion time of 2 min. Blood input, myocardium tissue and liver TACs were estimated using the same spatiotemporal splines. The spatiotemporal maximum-likelihood expectation-maximization (4D ML-EM) reconstructions gave more accurate reconstructions than did standard frame-by-frame static 3D ML-EM reconstructions. The SPECT/P results showed that 4D ML-EM reconstruction gave higher and more accurate estimates of K1 than did 3D ML-EM, yielding anywhere from a 44% underestimation to 24% overestimation for the three patients. The SPECT/D results showed that 4D ML-EM reconstruction gave an overestimation of 28% and 3D ML-EM gave an underestimation of 1% for K1. For the patient study the 4D ML-EM reconstruction provided continuous images as a function of time of the concentration in both ventricular cavities and myocardium during the 2 min infusion. It is demonstrated that a 2 min infusion with a two-headed SPECT system rotating 180° every 54 s can produce measurements of blood pool and myocardial TACs, though the SPECT simulation studies showed that one must sample at least every 30 s to capture a 1 min infusion input function.
doi:10.1088/0031-9155/57/2/375
PMCID: PMC3325151  PMID: 22170801
18.  Comparison of single photon emission computed tomography-computed tomography, computed tomography, single photon emission computed tomography and planar scintigraphy for characterization of isolated skull lesions seen on bone scintigraphy in cancer patients 
Purpose:
The purpose of this study is to evaluate the added value of single photon emission computed tomography-computed tomography (SPECT-CT) over planar scintigraphy, SPECT and CT alone for characterization of isolated skull lesions in bone scintigraphy (BS) in cancer patients.
Materials and Methods:
A total of 32 cancer patients (age: 39.5 ± 21.9; male: female - 1:1) with 36 isolated skull lesions on planar BS, underwent SPECT-CT of skull. Planar BS, SPECT, CT and SPECT-CT images were evaluated in separate sessions to minimize recall bias. A scoring scale of 1-5 was used, where 1 is definitely metastatic, 2 is probably metastatic, 3 is indeterminate, 4 is probably benign and 5 is definitely benign. With receiver operating characteristic analysis area under the curves (AUC) was calculated for each modality. For calculation of sensitivity, specificity and predictive values a Score ≤3 was taken as metastatic. Clinical/imaging follow-up and/or histopathology were taken as reference standard.
Results:
Of 36 skull lesions 11 lesions each were on frontal, parietal and occipital bone while three lesions were in the temporal bone. Of these 36 lesions, 16 were indeterminate (Score-3) on planar and SPECT, five on CT and none on SPECT-CT. The AUC was largest for SPECT-CT followed by CT, SPECT and planar scintigraphy, respectively. Planar scintigraphy was inferior to SPECT-CT (P = 0.006) and CT (P = 0.012) but not SPECT (P = 0.975). SPECT was also inferior to SPECT-CT (P = 0.007) and CT (P = 0.015). Although no significant difference was found between SPECT-CT and CT (P = 0.469), the former was more specific (100% vs. 94%).
Conclusion:
SPECT-CT is better than planar scintigraphy and SPECT alone for correctly characterizing isolated skull lesions on BS in cancer patients. It is more specific than CT, but provides no significant advantage over CT alone for this purpose.
doi:10.4103/0972-3919.125766
PMCID: PMC3928746  PMID: 24591778
Bone scintigraphy; computed tomography; metastasis; single photon emission computed tomography; skull; single photon emission computed tomography-computed tomography
19.  Meta-analysis of the literature on diagnostic accuracy of SPECT in parkinsonian syndromes 
BMC Neurology  2007;7:27.
Background
Parkinson's disease (PD) is the second most common neurodegenerative disorder. One of the most widely used techniques to diagnose PD is a Single Photon Emission Computer Tomography (SPECT) scan to visualise the integrity of the dopaminergic pathways in the brain. Despite this there remains some discussion on the value of SPECT in the differential diagnosis of PD. We did a meta-analysis of all the existing literature on the diagnostic accuracy of both pre- and post-synaptic SPECT imaging in the differential diagnosis of PD.
Methods
Relevant studies were searched in Medline, EMBASE and Cochrane databases with back-searching of their reference lists. We limited our analysis to studies with a clinically relevant methodology: i.e. when they assessed the ability of the SPECT to provide 1. diagnosis of PD in an early phase vs. normalcy; 2 diagnostic differentiation between PD and essential tremor (ET); 3. distinguishing between PD and vascular parkinsonism (VP); 4. delineation of PD from atypical parkinsonian syndromes (APS). Gold standard was, dependent on the study type, clinical examination at initial visit or follow-up, and/or response to dopaminergic agents.
Results
The search gave 185 hits, of which we deemed 32 suitable for our analysis. From these we recalculated the diagnostic odds ratio of SPECT for the clinical questions above. The pooled odds ratio (with 95%CI) for presynaptic SPECT scan's ability to distinguish between early PD and normalcy was 60 (13 – 277). For the ability to differentiate between PD and ET this ratio was 210 (79–562). The ratio for presynaptic SPECT's ability to delineate PD from VP was 105 (32 – 348). The mean odds ratio for the presynaptic SPECT scans to differentiate between PD and the two APS was 2 (1 – 4), and for the postsynaptic SPECT imaging this was 19 (9–36).
Conclusion
SPECT with presynaptic radiotracers is relatively accurate to differentiate patients with PD in an early phase from normalcy, patients with PD from those with ET, and PD from VP.
The accuracy of SPECT with both presynaptic and postsynaptic tracers to differentiate between PD and APS is relatively low.
doi:10.1186/1471-2377-7-27
PMCID: PMC2064928  PMID: 17764571
20.  Breath-hold CT attenuation correction for quantitative cardiac SPECT 
EJNMMI Research  2012;2:33.
Background
Attenuation correction of a single photon emission computed tomography (SPECT) image is possible using computed tomography (CT)-based attenuation maps with hybrid SPECT/CT. CT attenuation maps acquired during breath holding can be misaligned with SPECT, generating artifacts in the reconstructed images. The purpose of this study was to investigate the effects of respiratory phase during breath-hold CT acquisition on attenuation correction of cardiac SPECT imaging.
Methods
A series of 201Tl-emission and 99mTc-based transmission computed tomography (TCT) scans was carried out along with CT-attenuation scans on 11 young normal volunteers using a hybrid SPECT/CT scanner. The CT scans were performed at three respiratory phases: end-inspiration (INS), end-expiration (EXP), and the midpoint (MID) between these phases. Using alignment parameters between attenuation maps and SPECT images without attenuation or scatter corrections, quantitative SPECT images were reconstructed, including corrections for attenuation and scatter. Regional radioactivity concentrations normalized by the subjects’ weights were compared between CT- and TCT-based attenuation correction techniques.
Results
SPECT images with CT attenuation maps at the EXP phase showed significant differences in regional weight-normalized radioactivity concentrations relative to the images using the other attenuation maps (p < 0.05), as well as systematic positive bias errors, compared to TCT-based images for all myocardial segments, 5.7% ± 2.7% (1.9% to 10.0%). No significant differences in regional weight-normalized radioactivity concentrations were observed between images with CT attenuation maps at MID and INS phases or between these and the TCT-based images, but regional tendencies were found: for anterior to anterolateral segment, positive bias of 5.0% ± 2.2% (1.3% to 8.1%) and 5.6% ± 1.9% (2.6% to 8.5%) and for inferior to inferoseptal segment, negative bias of −5.3% ± 2.6% (−9.1% to −1.7%) and −4.6% ± 2.5% (−8.8% to −1.5%) for the MID and INS phases, respectively.
Conclusions
Use of breath-hold CT attenuation maps at INS and MID phases for attenuation and scatter corrections demonstrated accurate quantitative images that would prove beneficial in cardiac SPECT/CT studies.
doi:10.1186/2191-219X-2-33
PMCID: PMC3444955  PMID: 22726667
21.  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
22.  Can DCE-MRI Explain the Heterogeneity in Radiopeptide Uptake Imaged by SPECT in a Pancreatic Neuroendocrine Tumor Model? 
PLoS ONE  2013;8(10):e77076.
Although efficient delivery and distribution of treatment agents over the whole tumor is essential for successful tumor treatment, the distribution of most of these agents cannot be visualized. However, with single-photon emission computed tomography (SPECT), both delivery and uptake of radiolabeled peptides can be visualized in a neuroendocrine tumor model overexpressing somatostatin receptors. A heterogeneous peptide uptake is often observed in these tumors. We hypothesized that peptide distribution in the tumor is spatially related to tumor perfusion, vessel density and permeability, as imaged and quantified by DCE-MRI in a neuroendocrine tumor model. Four subcutaneous CA20948 tumor-bearing Lewis rats were injected with the somatostatin-analog 111In-DTPA-Octreotide (50 MBq). SPECT-CT and MRI scans were acquired and MRI was spatially registered to SPECT-CT. DCE-MRI was analyzed using semi-quantitative and quantitative methods. Correlation between SPECT and DCE-MRI was investigated with 1) Spearman’s rank correlation coefficient; 2) SPECT uptake values grouped into deciles with corresponding median DCE-MRI parametric values and vice versa; and 3) linear regression analysis for median parameter values in combined datasets. In all tumors, areas with low peptide uptake correlated with low perfusion/density/ /permeability for all DCE-MRI-derived parameters. Combining all datasets, highest linear regression was found between peptide uptake and semi-quantitative parameters (R2>0.7). The average correlation coefficient between SPECT and DCE-MRI-derived parameters ranged from 0.52-0.56 (p<0.05) for parameters primarily associated with exchange between blood and extracellular extravascular space. For these parameters a linear relation with peptide uptake was observed. In conclusion, the ‘exchange-related’ DCE-MRI-derived parameters seemed to predict peptide uptake better than the ‘contrast amount- related’ parameters. Consequently, fast and efficient diffusion through the vessel wall into tissue is an important factor for peptide delivery. DCE-MRI helps to elucidate the relation between vascular characteristics, peptide delivery and treatment efficacy, and may form a basis to predict targeting efficiency.
doi:10.1371/journal.pone.0077076
PMCID: PMC3792933  PMID: 24116203
23.  Noise correlation in PET, CT, SPECT and PET/CT data evaluated using autocorrelation function: a phantom study on data, reconstructed using FBP and OSEM 
Background
Positron Emission Tomography (PET), Computed Tomography (CT), PET/CT and Single Photon Emission Tomography (SPECT) are non-invasive imaging tools used for creating two dimensional (2D) cross section images of three dimensional (3D) objects. PET and SPECT have the potential of providing functional or biochemical information by measuring distribution and kinetics of radiolabelled molecules, whereas CT visualizes X-ray density in tissues in the body. PET/CT provides fused images representing both functional and anatomical information with better precision in localization than PET alone.
Images generated by these types of techniques are generally noisy, thereby impairing the imaging potential and affecting the precision in quantitative values derived from the images. It is crucial to explore and understand the properties of noise in these imaging techniques. Here we used autocorrelation function (ACF) specifically to describe noise correlation and its non-isotropic behaviour in experimentally generated images of PET, CT, PET/CT and SPECT.
Methods
Experiments were performed using phantoms with different shapes. In PET and PET/CT studies, data were acquired in 2D acquisition mode and reconstructed by both analytical filter back projection (FBP) and iterative, ordered subsets expectation maximisation (OSEM) methods. In the PET/CT studies, different magnitudes of X-ray dose in the transmission were employed by using different mA settings for the X-ray tube. In the CT studies, data were acquired using different slice thickness with and without applied dose reduction function and the images were reconstructed by FBP. SPECT studies were performed in 2D, reconstructed using FBP and OSEM, using post 3D filtering. ACF images were generated from the primary images, and profiles across the ACF images were used to describe the noise correlation in different directions. The variance of noise across the images was visualised as images and with profiles across these images.
Results
The most important finding was that the pattern of noise correlation is rotation symmetric or isotropic, independent of object shape in PET and PET/CT images reconstructed using the iterative method. This is, however, not the case in FBP images when the shape of phantom is not circular. Also CT images reconstructed using FBP show the same non-isotropic pattern independent of slice thickness and utilization of care dose function. SPECT images show an isotropic correlation of the noise independent of object shape or applied reconstruction algorithm. Noise in PET/CT images was identical independent of the applied X-ray dose in the transmission part (CT), indicating that the noise from transmission with the applied doses does not propagate into the PET images showing that the noise from the emission part is dominant. The results indicate that in human studies it is possible to utilize a low dose in transmission part while maintaining the noise behaviour and the quality of the images.
Conclusion
The combined effect of noise correlation for asymmetric objects and a varying noise variance across the image field significantly complicates the interpretation of the images when statistical methods are used, such as with statistical estimates of precision in average values, use of statistical parametric mapping methods and principal component analysis. Hence it is recommended that iterative reconstruction methods are used for such applications. However, it is possible to calculate the noise analytically in images reconstructed by FBP, while it is not possible to do the same calculation in images reconstructed by iterative methods. Therefore for performing statistical methods of analysis which depend on knowing the noise, FBP would be preferred.
doi:10.1186/1471-2342-5-5
PMCID: PMC1208889  PMID: 16122383
24.  Clinical Utility of SPECT Neuroimaging in the Diagnosis and Treatment of Traumatic Brain Injury: A Systematic Review 
PLoS ONE  2014;9(3):e91088.
Purpose
This systematic review evaluated the clinical utility of single photon emission computed tomography (SPECT) in traumatic brain injury (TBI).
Methods
After defining a PICO Statement (Population, Intervention, Comparison and Outcome Statement), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria were applied to identify 1600 articles. After screening, 374 articles were eligible for review. Inclusion for review was focus on SPECT in the setting of mild, moderate, or severe TBI with cerebral lobar specificity of SPECT findings. Other inclusion criteria were comparison modalities in the same subjects and articles in English. Foreign language articles, SPECT studies that did not include comparison modalities, and case reports were not included for review.
Results
We identified 19 longitudinal and 52 cross-sectional studies meeting inclusion criteria. Three longitudinal studies examined diagnostic predictive value. The first showed positive predictive value increases from initial SPECT scan shortly after trauma to one year follow up scans, from 59% to 95%. Subsequent work replicated these results in a larger cohort. Longitudinal and cross sectional studies demonstrated SPECT lesion localization not detected by CT or MRI. The most commonly abnormal regions revealed by SPECT in cross-sectional studies were frontal (94%) and temporal (77%) lobes. SPECT was found to outperform both CT and MRI in both acute and chronic imaging of TBI, particularly mild TBI. It was also found to have a near 100% negative predictive value.
Conclusions
This review demonstrates Level IIA evidence (at least one non-randomized controlled trial) for the value of SPECT in TBI. Given its advantages over CT and MRI in the detection of mild TBI in numerous studies of adequate quality, and given its excellent negative predictive value, it may be an important second test in settings where CT or MRI are negative after a closed head injury with post-injury neurological or psychiatric symptoms.
doi:10.1371/journal.pone.0091088
PMCID: PMC3960124  PMID: 24646878
25.  Improved diagnosis and prognosis using Decisions Informed by Combining Entities (DICE): results from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) 
Objectives
To introduce an algorithmic approach to improve the interpretation of myocardial perfusion images in women with suspected myocardial ischemia.
Background
Gated single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) approaches have relatively poor diagnostic and prognostic value in women with suspected myocardial ischemia. Here we introduce an approach: Decisions Informed by Combining Entities (DICE) that forms a mathematical model utilizing MPI and cardiac dimensions generated by one modality to predict the perfusion status of another modality. The effect of the model is to systematically incorporate cardiac metrics that influence the interpretation of perfusion images, leading to greater consistency in designation of myocardial perfusion status between studies.
Methods
Women (n=213), with suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two modalities: gated SPECT (n=207) and MR imaging (n=203). To determine perfusion status, MR data were evaluated qualitatively and semi-quantitatively while SPECT data were evaluated using conventional clinical criteria. These perfusion status readings were designated “Original”. Four regression models were generated to model perfusion status obtained with one modality [e.g., semi-quantitative magnetic resonance imaging (MRI)] against another modality (e.g., SPECT) and a threshold applied (DICE modeling) to designate perfusion status as normal or low. The DICE models included perfusion status, left ventricular (LV) chamber volumes and myocardial wall thickness. Women were followed for 40±16 months for the development of first major adverse cardiovascular event (MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for congestive heart failure). Original and DICE perfusion status were compared in their ability to detect high-grade coronary artery disease (CAD) and for prediction of MACE.
Results
Adverse events occurred in 25 (12%) women and CAD was present in 34 (16%). In receiver-operator characteristic (ROC) analysis for CAD detection, the average area under the curve (AUC) for DICE vs. Original status was 0.77±0.03 vs. 0.70±0.03, P<0.01. Similarly, in Kaplan-Meier survival analysis the average log-rank statistic was higher for DICE vs. the Original readings (10.6±5.2 vs. 3.0±0.6, P<0.05).
Conclusions
While two data sets are required to generate the DICE models no knowledge of follow-up results is needed. DICE modeling improved diagnostic and prognostic value vs. the Original interpretation of the myocardial perfusion status.
doi:10.3978/j.issn.2223-3652.2013.10.07
PMCID: PMC3878119  PMID: 24400205
Modeling; prognosis; diagnosis; perfusion; imaging; women

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