Phase 1 Lymfactin® Study: 24-month Efficacy and Safety Results of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema.

BACKGROUND: Lymphedema is a common problem after breast cancer treatment. Lymfactin® is a prolymphangiogenic growth factor vector inducing the expression of human vascular endothelial growth factor C (VEGF-C). It promotes growth and repair of lymphatic vessels. METHODS: Lymfactin® was combined with microvascular lymph node transfer surgery (VLNT) to study the safety and efficacy of the treatment in breast cancer-related upper limb lymphedema (BCRL) patients. This is a continuation study with a 3 year efficacy and 5 year safety follow-up. RESULTS: Fifteen patients were recruited in the study between June 2016 and February 2018. Three patients received a lower dose (1 × 1010 viral particles (vp)), and 12 patients received a higher dose (1 × 1011 vp) of Lymfactin®, respectively. In the higher dose group, the reduction of excess arm volume was on average 46% after the 12 month follow-up, and the transport index was improved in 7/12 patients. At baseline, removal of the compression garment for 7 days resulted in significant arm swelling (105.7±161.0 ml, p=0.0253). However, at 12 months, there was less and not significant swelling after removal of the garment (84.4±143.0 ml, p=0.0682). Lymphedema Quality of Life Inventory (LQOLI or LyQLI) questionnaire showed significant and sustained improvement of quality of life. CONCLUSIONS: During 24 months' of follow-up, the results indicate that Lymfactin® is well tolerated. The most promising findings were a 46% reduction in excess arm volume and a nonsignificant volume increase after garment removal at 12 months, suggesting that there is potential for the reduction of lymphedema.

Long-term Results of Microvascular Lymph Node Transfer: Correlation of Preoperative Factors and Operation Outcome.

Our objective was to analyze whether a correlation could be observed between preoperative factors and microvascular lymph node transfer outcome after long-term follow-up. METHODS: We included 67 patients in this retrospective case series. The incidence of cellulitis, the difference of arm circumference, the use of the compression garments both preoperatively and postoperatively, and subjective symptoms, such as pain, were analyzed. Volumetry and lymphoscintigraphy results were also analyzed in a subgroup of patients. We correlated preoperative factors with postoperative results. RESULTS: After 70 ± 17 months of follow-up, 42% of the patients were able to discontinue the use of compression garments. The subjective pain symptoms were reduced in 75% of the patients. The incidence of cellulitis was reduced from preoperative 0.20 ± 0.55/y to postoperative 0.02 ± 0.08/y. As a novel finding, the patients with preoperative cellulitis were more likely to continue the use of the compression garments. CONCLUSIONS: The surgery is beneficial to most studied lymphedema patients, although it is not the cure for all patients. The incidence of cellulitis was reduced, and further, the presence of preoperative cellulitis seems to affect the outcome of the operation.

Combined Surgical Treatment for Chronic Upper Extremity Lymphedema Patients: Simultaneous Lymph Node Transfer and Liposuction.

BACKGROUND: Upper limb lymphedema is a common problem after axillary lymph node dissection. Lymphatic drainage can be improved by microvascular lymph node transfer, whereas liposuction can be used to reduce arm volume and excess of adipose tissue. We present the results of chronic lymphedema patients who have undergone lymph node transfer and liposuction simultaneously in 1 operation and compare the results with patients who have undergone lymph node transfer without liposuction. METHODS: During May 2007 to February 2015, 20 postmastectomy patients and 1 Hodgkin's lymphoma patient presenting with chronic nonpitting lymphedema (age between 37 and 74 years, average 56.7 years) were operated using the combined technique and 27 postmastectomy patients presenting with early-stage lymphedema (age between 31 and 68 years, average age 50.2 years) were operated using only the lymph node transfer. Compression therapy was started immediately after the operation and the patients used compression 24 h/d at least 6 months postoperatively. Changes in clinical parameters (number of erysipelas infections, pain), arm volume, transport indexes calculated form lymphoscintigraphy images, and daily usage of compression garments were compared preoperatively and postoperatively and between groups (combined technique vs lymph node transfer). The study was a retrospective observational study. RESULTS: In the combined technique group, the average arm volume excess decreased postoperatively 87.7%, and in 7 of 10 patients, the edema volume did not increase even without compression. Seventeen of 21 patients were able to reduce the use of compression garment. Lymphoscintigraphy results were improved in 12 of 15 patients and the improvement was significantly greater in the combined technique group than in the lymph node transfer group (P = 0.01). The number of erysipelas infections was decreased in 7 of 10 patients and the decrease was significantly greater in the combined technique group than in the lymph node transfer group (P = 0.02). In the lymph node transfer group, the average excess volume decreased postoperatively 27.5%. Fourteen of 27 patients were able to reduce the use of compression garments. Lymphoscintigraphy results were improved in 8 of 19 patients, and the number of erysipelas infections was decreased in 1 of 3 patients. CONCLUSIONS: Liposuction can safely be performed with lymph node transfer in 1 operation to achieve optimal results in patients with chronic lymphedema. The combined technique provides immediate volume reduction and further regenerative effects on the lymphatic circulation. The significantly greater reduction in lymphoscintigraphy values and erysipelas infections suggests that the combined technique might be better for late-stage lymphedema patients than lymph node transfer alone.

Diagnostic Value of Transluminal Attenuation Gradient for the Presence of Ischemia as Defined by Fractional Flow Reserve and Quantitative Positron Emission Tomography.

OBJECTIVES: The aim of this study was to investigate the incremental diagnostic value of transluminal attenuation gradient (TAG), TAG with corrected contrast opacification (TAG-CCO), and transluminal diameter gradient (TDG) over coronary computed tomography angiography (CTA)-derived diameter stenosis alone for the identification of ischemia as defined by both the invasive reference standard fractional flow reserve (FFR) and the noninvasive reference standard quantitative positron emission tomography (PET). BACKGROUND: In addition to anatomic information obtained by coronary CTA, several functional CT parameters have been proposed to identify hemodynamically significant lesions more accurately, such as TAG, TAG-CCO, and more recently TDG. However, clinical validation studies have reported conflicting results, and a recent study has suggested that TAG may be affected by changes in vessel diameter. METHODS: Patients with suspected coronary artery disease underwent coronary CTA and [15O]H2O PET followed by invasive coronary angiography with FFR of all major coronary arteries. TAG, TAG-CCO, and TDG were assessed, and the incremental diagnostic value of these parameters over coronary CTA-derived diameter stenosis alone for ischemia as defined by PET (hyperemic myocardial blood flow ≤2.30 ml/min/g) and FFR (≤0.80) was determined. RESULTS: A total of 557 (91.9%) coronary arteries of 201 patients were included for analysis. TAG, TAG-CCO, and TDG did not discriminate between vessels with or without ischemia as defined by either PET or FFR. Furthermore, these parameters did not have incremental diagnostic accuracy over coronary CTA alone for the presence of ischemia as defined by PET and FFR. There was a significant correlation between TDG and TAG (r = 0.47; p < 0.001) and between TDG and TAG-CCO (r = 0.37; p < 0.001). CONCLUSIONS: TAG, TAG-CCO, and TDG do not provide incremental diagnostic value over coronary CTA alone for the presence of ischemia as defined by [15O]H2O PET and/or FFR. The lack of diagnostic value of contrast enhancement-based flow estimations appears related to coronary luminal dimension variability.

Diagnostic value of longitudinal flow gradient for the presence of haemodynamically significant coronary artery disease.

Aims: The longitudinal myocardial blood flow (MBF) gradient derived from positron emission tomography (PET) has been proposed as an emerging non-invasive index of haemodynamically significant coronary artery disease (CAD). This study aimed to investigate the diagnostic value of longitudinal MBF gradient for the presence of haemodynamically significant CAD. Methods and results: A total of 204 patients (603 vessels) with suspected CAD underwent [15O]H2O PET followed by invasive coronary angiography with fractional flow reserve (FFR) of all major coronary arteries. Longitudinal base-to-apex MBF gradients were assessed by two methods, using MBF in apical and mid (Method 1) or in apical and basal (Method 2) myocardial segments to calculate the gradient. The hyperaemic longitudinal MBF gradient was only weakly correlated with FFR (Method 1: r = 0.12, P = 0.02; Method 2: r = 0.22, P < 0.001). The hyperaemic longitudinal MBF gradient (by both methods), had lower diagnostic value when compared with hyperaemic MBF for the presence of haemodynamically significant CAD, defined as an FFR ≤ 0.80. No significant correlations between longitudinal MBF gradients and FFR were noted in proximal lesions, whereas longitudinal MBF gradients and FFR were significantly correlated in non-proximal lesions (r = 0.57, P < 0.001). Conclusion: PET measured longitudinal flow parameters had lower diagnostic value when compared with hyperaemic MBF for the presence of haemodynamically significant CAD. Since lesion location was found to affect the correlation of PET measured longitudinal flow parameters and FFR, presence of a longitudinal flow gradient may be partly caused by normalization to a relatively normal perfused areas.

Impact of individualized segmentation on diagnostic performance of quantitative positron emission tomography for haemodynamically significant coronary artery disease.

AIMS: Despite high variability in coronary anatomy, quantitative positron emission tomography (PET) perfusion in coronary territories is traditionally calculated according to the American Heart Association (AHA) 17-segments model. This study aimed to assess the impact of individualized segmentation of myocardial segments on the diagnostic accuracy of hyperaemic myocardial blood flow (MBF) values for haemodynamically significant coronary artery disease (CAD). METHODS AND RESULTS: Patients with suspected CAD (n = 204) underwent coronary computed tomography angiography (CCTA) and [15O]H2O PET followed by invasive coronary angiography with fractional flow reserve assessment of all major coronary arteries. Hyperaemic MBF per vascular territory was calculated using both standard segmentation according to the AHA model and individualized segmentation, in which CCTA was used to assign coronary arteries to PET perfusion territories. In 122 (59.8%) patients, one or more segments were redistributed after individualized segmentation. No differences in mean MBF values were seen between segmentation methods, except for a minor difference in hyperaemic MBF in the LCX territory (P = 0.001). These minor changes resulted in discordant PET-defined haemodynamically significant CAD between the two methods in only 5 (0.8%) vessels. The diagnostic value for detecting haemodynamically significant CAD did not differ between individualized and standard segmentation, with area under the curves of 0.79 and 0.78, respectively (P = 0.34). CONCLUSIONS: Individualized segmentation using CCTA-derived coronary anatomy led to redistribution of standard myocardial segments in 60% of patients. However, this had little impact on [15O]H2O PET MBF values and diagnostic value for detecting haemodynamically significant CAD did not change. Therefore, clinical impact of individualized segmentation seems limited.

Impact of Revascularization on Absolute Myocardial Blood Flow as Assessed by Serial [15O]H2O Positron Emission Tomography Imaging: A Comparison With Fractional Flow Reserve.

BACKGROUND: The main goal of coronary revascularization is to restore myocardial perfusion in case of ischemia, causing coronary artery disease. Yet, little is known on the effect of revascularization on absolute myocardial blood flow (MBF). Therefore, the present prospective study assesses the impact of coronary revascularization on absolute MBF as measured by [15O]H2O positron emission tomography and fractional flow reserve (FFR) in patients with stable coronary artery disease. METHODS AND RESULTS: Fifty-three patients (87% men, mean age 58.7±9.0 years) with suspected coronary artery disease were included prospectively. All patients underwent serial [15O]H2O positron emission tomography perfusion imaging at baseline and after revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery. FFR was routinely measured at baseline and directly post-PCI. After revascularization, regional rest and stress MBF improved from 0.77±0.16 to 0.86±0.25 mL/min/g and from 1.57±0.59 to 2.48±0.91 mL/min/g, respectively, yielding an increase in coronary flow reserve from 2.02±0.69 to 2.94±0.94 (P<0.01 for all). Mean FFR at baseline improved post-PCI from 0.61±0.17 to 0.89±0.08 (P<0.01). After PCI, an increase in FFR paralleled improvement in absolute myocardial perfusion as reflected by stress MBF and coronary flow reserve (r = 0.74 and r = 0.71, respectively, P<0.01 for both). PCI demonstrated a greater improvement of regional stress MBF as compared with coronary artery bypass graft surgery (1.14±1.11 versus 0.66±0.69 mL/min/g, respectively, P=0.02). However, patients undergoing bypass grafting had a more advanced stage of coronary artery disease and more incomplete revascularizations. CONCLUSION: Successful coronary revascularization has a significant and positive impact on absolute myocardial perfusion as assessed by serial quantitative [15O]H2O positron emission tomography. Notably, improvement of FFR after PCI was directly related to the increase in hyperemic MBF.

Frequency and angiographic characteristics of coronary microvascular dysfunction in stable angina: a hybrid imaging study.

AIMS: Coronary microvascular dysfunction (CMD) can cause angina in the absence of obstructive coronary artery disease (CAD). We studied the frequency and angiographic characteristics of CMD in symptomatic patients with suspected stable CAD and identified CMD as diffusely abnormal coronary vasodilator capacity by positron emission tomography (PET) perfusion imaging. METHODS AND RESULTS: We recruited prospectively 189 patients with intermediate pre-test probability of CAD who underwent coronary computed tomography angiography and quantitative 15O-water PET perfusion imaging followed by invasive coronary angiography, and assessment of fractional flow reserve when feasible. Prevalence of obstructive epicardial CAD was 37%. Absolute myocardial blood flow was diffusely reduced (<2.4 mL/g/min) within the left ventricle during adenosine stress in 32 (17%) patients. In 15 (8%) patients, this was explained by three-vessel obstructive CAD, whereas the remaining 17 (9%) were diagnosed with CMD. Of these, 2 (1% of all patients) had no coronary atherosclerosis, 5 (3% of all patients) had non-obstructive atherosclerosis, and in 10 (5% of all patients) CMD co-existed with obstructive CAD. Atypical angina or non-anginal chest pain (53%) was the most common presentation. Older age and male sex were associated with CMD, but other risk factors of CAD were equally common in patients with or without CMD. CONCLUSION: Coronary microvascular dysfunction exists in 9% of symptomatic stable patients with suspected CAD. However, the prevalence of microvascular dysfunction without any coronary atherosclerosis is low (1%) in this population.

Comparison of Coronary CT Angiography, SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve.

Importance: At present, the choice of noninvasive testing for a diagnosis of significant coronary artery disease (CAD) is ambiguous, but nuclear myocardial perfusion imaging with single-photon emission tomography (SPECT) or positron emission tomography (PET) and coronary computed tomography angiography (CCTA) is predominantly used for this purpose. However, to date, prospective head-to-head studies are lacking regarding the diagnostic accuracy of these imaging modalities. Furthermore, the combination of anatomical and functional assessments configuring a hybrid approach may yield improved accuracy. Objectives: To establish the diagnostic accuracy of CCTA, SPECT, and PET and explore the incremental value of hybrid imaging compared with fractional flow reserve. Design, Setting, and Participants: A prospective clinical study involving 208 patients with suspected CAD who underwent CCTA, technetium 99m/tetrofosmin-labeled SPECT, and [15O]H2O PET with examination of all coronary arteries by fractional flow reserve was performed from January 23, 2012, to October 25, 2014. Scans were interpreted by core laboratories on an intention-to-diagnose basis. Hybrid images were generated in case of abnormal noninvasive anatomical or functional test results. Main Outcomes and Measures: Hemodynamically significant stenosis in at least 1 coronary artery as indicated by a fractional flow reserve of 0.80 or less and relative diagnostic accuracy of SPECT, PET, and CCTA in detecting hemodynamically significant CAD. Results: Of the 208 patients in the study (76 women and 132 men; mean [SD] age, 58 [9] years), 92 (44.2%) had significant CAD (fractional flow reserve ≤0.80). Sensitivity was 90% (95% CI, 82%-95%) for CCTA, 57% (95% CI, 46%-67%) for SPECT, and 87% (95% CI, 78%-93%) for PET, whereas specificity was 60% (95% CI, 51%-69%) for CCTA, 94% (95% CI, 88%-98%) for SPECT, and 84% (95% CI, 75%-89%) for PET. Single-photon emission tomography was found to be noninferior to PET in terms of specificity (P < .001) but not in terms of sensitivity (P > .99) using the predefined absolute margin of 10%. Diagnostic accuracy was highest for PET (85%; 95% CI, 80%-90%) compared with that of CCTA (74%; 95% CI, 67%-79%; P = .003) and SPECT (77%; 95% CI, 71%-83%; P = .02). Diagnostic accuracy was not enhanced by either hybrid SPECT and CCTA (76%; 95% CI, 70%-82%; P = .75) or by PET and CCTA (84%; 95% CI, 79%-89%; P = .82), but resulted in an increase in specificity (P = .004) at the cost of a decrease in sensitivity (P = .001). Conclusions and Relevance: This controlled clinical head-to-head comparative study revealed PET to exhibit the highest accuracy for diagnosis of myocardial ischemia. Furthermore, a combined anatomical and functional assessment does not add incremental diagnostic value but guides clinical decision-making in an unsalutary fashion.

Prognostic Value of Coronary CT Angiography With Selective PET Perfusion Imaging in Coronary Artery Disease.

OBJECTIVES: The purpose of this study was to evaluate the prognostic value of sequential hybrid imaging strategy in which positron emission tomography (PET) perfusion imaging is performed selectively in patients with suspected obstructive coronary artery disease (CAD) on coronary computed tomography angiography (CTA). BACKGROUND: Coronary CTA is an accurate diagnostic test for excluding obstructive CAD. However, the positive predictive value is suboptimal. METHODS: We investigated 864 consecutive symptomatic patients with intermediate probability of CAD who adhered to the sequential imaging approach. PET myocardial perfusion imaging using 15O-labeled water during adenosine stress was performed when suspected obstructive stenosis was present on coronary CTA. The major adverse events (AEs) including all-cause mortality, myocardial infarction (MI), and unstable angina pectoris (UAP) were recorded. RESULTS: During a median follow-up of 3.6 years, 16 deaths, 10 MIs, and 5 UAPs occurred. Obstructive CAD was excluded by coronary CTA in 462 (53%) patients who had significantly lower annual AE rate than did patients with suspected obstructive stenosis on coronary CTA (0.4% vs. 1.5%; p = 0.003). The latter underwent PET study, on which 195 (49%) had normal and 207 had abnormal perfusion. The annual rate of AEs was 5 times higher in those with abnormal perfusion than with normal perfusion (2.5% vs. 0.5%; p = 0.004). Patients with normal perfusion had AE rate comparable to patients without obstructive CAD on coronary CTA (p = 0.77). CONCLUSIONS: In patients with suspected CAD obstructive disease can be excluded in 53% of patients by coronary CTA, and these patients have good outcome. About one-half (49%) of the remaining patients have normal perfusion and event rate comparable to patients without obstructive CAD on coronary CTA while patients with ischemia have clearly worse outcome. Sequential approach utilizing anatomical imaging by coronary CTA followed by selective functional perfusion imaging is a feasible strategy to diagnose and risk-stratify patients with suspected CAD.

Visual versus automated analysis of [I-123]FP-CIT SPECT scans in parkinsonism.

The clinical evaluation of dopamine transporter (DAT) SPECT scans typically relies on visual analysis in combination with an automated semi-quantitative method. The interpretation of the results may be difficult in cases that show disagreement between the two methods on the borderline of abnormality. The frequency and clinical characteristics of such cases are unclear. Automated semi-quantitative analyses and independent visual analyses by two experienced nuclear medicine physicians and four inexperienced raters were performed for 120 patients with clinically uncertain parkinsonism scanned with brain [I-123]FP-CIT SPECT. Agreement was evaluated with kappa statistics. The clinical characteristics of patients who had discrepant findings between the two analysis methods were investigated. The expert raters outperformed nonexperts in terms of agreement between visual and automated analyses (κ = 0.66, 0.72 vs. 0.23-0.54) and between raters (κ = 0.81 vs. 0.44-0.63). Twelve patients showed discrepant findings between the visual and automated analyses. These patients were older compared to other patients (p = 0.023), had 17.6 % lower mean striatal tracer binding compared to normal scans (p = 0.003) and 62.7 % higher compared to abnormal scans (p < 0.001). After a minimum of 4.5 years of clinical follow-up, none of these patients developed neurodegenerative parkinsonism. Clinical DAT SPECT scans show discrepancies between visual and automated analyses in 10 % of cases. The patients with discrepant findings are older, show normal to slightly abnormal tracer binding, and importantly, do not develop neurodegenerative parkinsonism syndromes. Visual analyses by experienced raters are reliable, but the diagnostic accuracy in discrepant cases can be improved by an automated method.

Multicentre multi-device hybrid imaging study of coronary artery disease: results from the EValuation of INtegrated Cardiac Imaging for the Detection and Characterization of Ischaemic Heart Disease (EVINCI) hybrid imaging population.

AIMS: Hybrid imaging provides a non-invasive assessment of coronary anatomy and myocardial perfusion. We sought to evaluate the added clinical value of hybrid imaging in a multi-centre multi-vendor setting. METHODS AND RESULTS: Fourteen centres enrolled 252 patients with stable angina and intermediate (20-90%) pre-test likelihood of coronary artery disease (CAD) who underwent myocardial perfusion scintigraphy (MPS), CT coronary angiography (CTCA), and quantitative coronary angiography (QCA) with fractional flow reserve (FFR). Hybrid MPS/CTCA images were obtained by 3D image fusion. Blinded core-lab analyses were performed for CTCA, MPS, QCA and hybrid datasets. Hemodynamically significant CAD was ruled-in non-invasively in the presence of a matched finding (myocardial perfusion defect co-localized with stenosed coronary artery) and ruled-out with normal findings (both CTCA and MPS normal). Overall prevalence of significant CAD on QCA (>70% stenosis or 30-70% with FFR≤0.80) was 37%. Of 1004 pathological myocardial segments on MPS, 246 (25%) were reclassified from their standard coronary distribution to another territory by hybrid imaging. In this respect, in 45/252 (18%) patients, hybrid imaging reassigned an entire perfusion defect to another coronary territory, changing the final diagnosis in 42% of the cases. Hybrid imaging allowed non-invasive CAD rule-out in 41%, and rule-in in 24% of patients, with a negative and positive predictive value of 88% and 87%, respectively. CONCLUSION: In patients at intermediate risk of CAD, hybrid imaging allows non-invasive co-localization of myocardial perfusion defects and subtending coronary arteries, impacting clinical decision-making in almost one every five subjects.

Detection of significant coronary artery disease by noninvasive anatomical and functional imaging.

BACKGROUND: The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD. METHODS AND RESULTS: A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If ≥1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve ≤0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88-0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69-0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65-0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001). CONCLUSIONS: In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979199.

C-11 acetate has excellent reproducibility for quantification of myocardial oxidative metabolism.

AIMS: C-11 acetate PET imaging allows quantification of myocardial oxidative metabolism. We sought to assess the reproducibility of such analysis with the Carimas software. METHODS AND RESULTS: The myocardial oxygen consumption rate was assessed via a kmono index--the clearance rate constant of a mono-exponential function fitted to a C-11 acetate clearance curve. Two observers of different experience levels--a novice and an expert--analysed 53 C-11 acetate PET studies--each study twice. These results were compared using Bland-Altman (BA) plots with the global kmono-s obtained earlier with a validated reference method. We also assessed intra- and interobserver reproducibility on global, regional, and segmental [17-segment model (AHA)] levels--a linear mixed model for the repeated measures was fitted to our data--using intraclass correlation coefficients (ICCs) and differences between repeats and the observers. Carimas kmono values were lower than the reference--by 10.7% in the novice and by 9.6% in the expert, and were in substantial agreement with it--R(2) values were 0.944 and 0.943 correspondingly; the coefficients of repeatability--1.96 SD of biases in BA plots--were 11.2% in both the observers. The intra- and interobserver ICCs were high on global and regional levels--above 0.99 in the novice and 0.96 in the expert. The intra- and interobserver differences were low on global and regional levels, the most pronounced being the left anterior descending artery (LAD) interobserver difference of 2.2%. CONCLUSION: The study showed extremely good reproducibility-both intra- and interobserver-for C-11 acetate PET analysis of myocardial oxidative metabolism.

Absolute flow or myocardial flow reserve for the detection of significant coronary artery disease?

OBJECTIVES: We compared the accuracy of quantified myocardial flow reserve and absolute stress myocardial blood flow (MBF) alone in the detection of coronary artery disease (CAD). BACKGROUND: Myocardial flow reserve, i.e. ratio of stress and rest flow, has been commonly used to detect CAD with many imaging modalities. However, it is not known whether absolute stress flow alone is sufficient for detection of significant CAD. METHODS: We enrolled 104 patients with moderate (30-70%) pre-test likelihood of CAD without previous myocardial infarction. MBF was measured by positron emission tomography and O-15-water at rest and during the adenosine stress in the regions of the left anterior descending, left circumflex, and right coronary artery. All the patients underwent invasive coronary angiography including the measurement of fractional flow reserve when appropriate. RESULTS: Quantified myocardial flow reserve (optimal cut-off value 2.5) detected significant coronary stenosis with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 81, 87, 66 and 94%, respectively. When compared with flow reserve, absolute MBF at stress (optimal cut-off value of 2.4 mL/min/g) was more accurate in detecting significant coronary stenosis [area under the curve (AUC) 0.94 vs. 0.90, P = 0.02] with sensitivity, specificity, PPV, and NPV of 95% (P = 0.03 vs. flow reserve), 90, 73, and 98%, respectively. An absolute increase of MBF from rest to stress by <1.5 mL/g/min had also similar accuracy in detecting CAD (AUC: 0.95). The results were comparable in patients who did and did not receive i.v. beta-blockers prior imaging. CONCLUSIONS: Absolute stress perfusion alone was superior to perfusion reserve in the detection of haemodynamically significant CAD and allows shorter imaging protocols with smaller radiation dose.

Lymphatic vessel function and lymphatic growth factor secretion after microvascular lymph node transfer in lymphedema patients.

BACKGROUND: Recent reports have shown that microvascular lymph node transfer may improve lymphatic drainage in lymphedema patients. Lymphatic anastomoses are expected to form spontaneously in response to lymphatic growth factor [vascular endothelial growth factor C (VEGF-C)] secreted by the transferred lymph nodes. METHODS: We have analyzed the results of 19 lymph node transfer patients operated on 2007-2012. Postoperat ive lymphatic function of the affected arm was evaluated using semiquantitative lymphoscintigraphy (transport index) and limb circumference measurements. To investigate the postoperative VEGF-C secretion, we examined axillary seroma fluid samples after different surgical operations, including lymph node transfer. RESULTS: The transport index was improved postoperatively in 7 of 19 patients. Ten of the 19 patients were able to reduce or even discontinue using compression garments. Arm circumferences were reduced in 12 of 19 patients. Six of the 7 patients with preoperative erysipelas infections have not had infectious episodes postoperatively during 15-67 months follow-up. Neuropathic pain was relieved in 5 of 5 patients. VEGF-C protein was detected in the axillary seroma fluid both after lymph node transfer and normal breast reconstruction. CONCLUSIONS: Reconstructing the lymphatic anatomy of the axilla with a lymph node flap may offer possibilities that other reconstructive options are lacking. However, we will need further reports and comparative studies about the clinical efficacy of this new promising technique. In addition to the transferred lymph nodes, lymphatic growth factor production may also be induced by other factors related to microvascular breast reconstruction.

Donor-site lymphatic function after microvascular lymph node transfer.

BACKGROUND: Lymphedema remains a challenging clinical problem that often lacks curative treatment options. Recent reports have shown that microvascular lymph node transfer from the groin area into axillas of lymphedematous patients may improve lymphatic drainage, but the effect on donor-site lymphatic flow has not been studied. These patients may be more prone to develop lymphedema at donor sites as well; therefore, the authors' aim was to evaluate postoperative donor-site lymphatic function. METHODS: The authors performed lymphatic groin flap transfer to the axilla in 13 lymphedema patients. In 10 patients, the lymph node transfer was performed simultaneously with lower abdominal breast reconstruction. Postoperative lymphatic vessel function of the donor site was evaluated by lymphoscintigraphy and limb circumference measurements. For semiquantitative evaluation of lymphatic drainage, a numerical transport index was used. RESULTS: In six of 10 patients, postoperative lymphoscintigraphy revealed minor changes in lymphatic flow of the donor-site limbs. The transport index was considered slightly abnormal in two of 10 patients. None of the 13 patients had changes in lower limb circumferences during the 8- to 56-month follow-up. CONCLUSIONS: Lymph node transfer can be easily combined with lower abdominal breast reconstruction, and the popularity of this technique is increasing rapidly. Even though none of our patients had developed symptoms of postoperative lymphedema, the results of the first lymphoscintigrams show that it is important to reduce the surgical trauma to the lymphatic flap donor site. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

F-18 fluorodeoxyglucose uptake and water-perfusable tissue fraction in assessment of myocardial viability.

OBJECTIVES: (15)O-water-perfusable tissue fraction (PTF) has been shown to be a potential index for assessing myocardial viability in PET, an alternative to (18)F-fluorodeoxyglucose (FDG). This study aimed to directly compare these two independent methods in assessing myocardial viability in patients with abnormal wall motion. METHODS: PET study was performed on 16 patients with previous myocardial infarction, before coronary artery bypass graft operation (CABG). The protocol included a (15)O-carbonmonoxide static, a (15)O-water dynamic and an (18)F-FDG dynamic scan, during the euglycemic hyperinsulinemic clamp. Echocardiography was performed at the time of PET and 5-12 months after the CABG, and the wall motion recovery was evaluated on segmental and global bases. Consistency between PTF and (18)F-FDG was evaluated visually and also in a quantitative manner. Predictive values for the wall motion recovery were also compared between the two approaches. RESULTS: The image quality of (18)F-FDG was superior to that of (15)O-water. The qualitative PTF showed significantly smaller defects than (18)F-FDG, and the quantitative PTF showed slightly greater values than (18)F-FDG in the infarcted region. The two methods were, however, consistent visually and also quantitatively. The predictive values of the wall motion recovery were almost equal between the two approaches. The absolute (18)F-FDG uptake was varied in normal segments, and predictive values for the wall motion recovery by the absolute (18)F-FDG was less (accuracy: 80 %) compared with those by the relative (18)F-FDG (accuracy: 87 %) and the quantitative PTF (accuracy: 89 %). CONCLUSION: Despite the small sample size, PTF appears to give consistent results with the (18)F-FDG approach, and might be an alternative viability assessment.

Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-INSIGHT Sub-Study with PET and MRI.

PURPOSE: Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. METHODS: Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 10(6) CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7-12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. RESULTS: In BMC-treated patients, there was a decrease in [(11)C]-HED defect size (-4.9 ± 4.0 vs. -1.6 ± 2.2%, p = 0.08) and an increase in [(18)F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. -0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (-4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m(2), p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (-0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. -5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). CONCLUSION: After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no consistently better outcome was observed in the BMC-treated group compared to placebo.