Adjuvant holmium-166 radioembolization after radiofrequency ablation in early-stage hepatocellular carcinoma patients: a dose-finding study (HORA EST HCC trial).

PURPOSE: The aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (166Ho-MS), when administered as adjuvant therapy after RFA of HCC 2-5 cm. The objective was to establish a treatment volume absorbed dose that results in an absorbed dose of ≥ 120 Gy on the hyperemic zone around the ablation necrosis (i.e., target volume). METHODS: In this multicenter, prospective dose-escalation study in BCLC early stage HCC patients with lesions 2-5 cm, RFA was followed by (super-)selective infusion of 166Ho-MS on day 5-10 after RFA. Dose distribution within the treatment volume was based on SPECT-CT. Cohorts of up to 10 patients were treated with an incremental dose (60 Gy, 90 Gy, 120 Gy) of 166Ho-MS to the treatment volume. The primary endpoint was to obtain a target volume dose of ≥ 120 Gy in 9/10 patients within a cohort. RESULTS: Twelve patients were treated (male 10; median age, 66.5 years (IQR, [64.3-71.7])) with a median tumor diameter of 2.7 cm (IQR, [2.1-4.0]). At a treatment volume absorbed dose of 90 Gy, the primary endpoint was met with a median absorbed target volume dose of 138 Gy (IQR, [127-145]). No local recurrences were found within 1-year follow-up. CONCLUSION: Adjuvant (super-)selective infusion of 166Ho-MS after RFA for the treatment of HCC can be administered safely at a dose of 90 Gy to the treatment volume while reaching a dose of ≥ 120 Gy to the target volume and may be a favorable adjuvant therapy for HCC lesions 2-5 cm. TRIAL REGISTRATION: Clinicaltrials.gov NCT03437382 . (registered: 19-02-2018).

Baseline and early digital [ 18 F]FDG PET/CT and multiparametric MRI contain promising features to predict response to neoadjuvant therapy in locally advanced rectal cancer patients: a pilot study.

OBJECTIVE: In this pilot study, we investigated the feasibility of response prediction using digital [ 18 F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial. METHODS: Rectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [ 18 F]FDG PET/CT before, 2 weeks into, and 6-8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P  ≤ 0.2, promising predictive features for response were selected. RESULTS: Nineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Δ maximum standardized uptake value, Δ peak standardized uptake value corrected for lean body mass), were promising features. CONCLUSION: Both multiparametric MRI and [ 18 F]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT.

Prostate-Specific Membrane Antigen Targeted Pet/CT Imaging in Patients with Colon, Gastric and Pancreatic Cancer.

Current imaging modalities frequently misjudge disease stage in colorectal, gastric and pancreatic cancer. As treatment decisions are dependent on disease stage, incorrect staging has serious consequences. Previous preclinical research and case reports indicate that prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging might provide a solution to some of these challenges. This prospective clinical study aims to assess the feasibility of [18F]DCFPyL PET/CT imaging to target and visualize primary colon, gastric and pancreatic cancer. In this prospective clinical trial, patients with colon, gastric and pancreatic cancer were included and underwent both [18F]DCFPyL and [18F]FDG PET/CT scans prior to surgical resection or (for gastric cancer) neoadjuvant therapy. Semiquantitative analysis of immunohistochemical PSMA staining was performed on the surgical resection specimens, and the results were correlated to imaging parameters. The results of this study demonstrate detection of the primary tumor by [18F]DCFPyL PET/CT in 7 out of 10 patients with colon, gastric and pancreatic cancer, with a mean tumor-to-blood pool ratio (TBR) of 3.3 and mean SUVmax of 3.6. However, due to the high surrounding uptake, visual distinction of these tumors was difficult, and the SUVmax and TBR on [18F]FDG PET/CT were significantly higher than on [18F]DCFPyL PET/CT. In addition, no correlation between PSMA expression in the resection specimen and SUVmax on [18F]DCFPyL PET/CT was found. In conclusion, the detection of several gastrointestinal cancers using [18F]DCFPyL PET/CT is feasible. However, low tumor expression and high uptake physiologically in organs/background hamper the clear distinction of the tumor. As a result, [18F]FDG PET/CT was superior in detecting colon, gastric and pancreatic cancers.

Reinducing Radioiodine-Sensitivity in Radioiodine-Refractory Thyroid Cancer Using Lenvatinib (RESET): Study Protocol for a Single-Center, Open Label Phase II Trial.

Background: Management of patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) is a challenge as I-131 therapy is deemed ineffective while standard-of-care systemic therapy with tyrosine kinase inhibitor (TKI) lenvatinib is associated with frequent toxicities leading to dose reductions and withdrawal. A potential new treatment approach is to use TKIs as redifferentiation agent to restore RAI uptake to an extent that I-131 therapy is warranted. Prior studies show that short-term treatment with other TKIs restores RAI uptake in 50-60% of radioiodine-refractory DTC patients, but this concept has not been investigated for lenvatinib. Furthermore, the optimal duration of treatment with TKIs for maximal redifferentiation has not been explored. Methods and Design: A total of 12 patients with RAI-refractory DTC with an indication for lenvatinib will undergo I-124 PET/CT to quantify RAI uptake. This process is repeated after 6 and 12 weeks post-initiating lenvatinib after which the prospective dose estimate to target lesions and organs at risk will be determined. Patients will subsequently stop lenvatinib and undergo I-131 treatment if it is deemed effective and safe by predefined norms. The I-124 PET/CT measurements after 6 and 12 weeks of the first six patients are compared and the optimal timepoint will be determined for the remaining patients. In all I-131 treated patients post-therapy SPECT/CT dosimetry verification will be performed. During follow-up, clinical response will be evaluated using serum thyroglobulin levels and F-18 FDG PET/CT imaging for 6 months. It is hypothesized that at least 40% of patients will show meaningful renewed RAI uptake after short-term lenvatinib treatment. Discussion: Shorter treatment duration of lenvatinib treatment is preferred because of frequent toxicity-related dose reductions and drug withdrawals in long-term lenvatinib treatment. Short-term treatment with lenvatinib with subsequent I-131 therapy poses a potential new management approach for these patients. Since treatment duration is reduced and I-131 therapy is more tolerable for most patients, this potentially leads to less toxicity and higher quality of life. Identifying RAI-refractory DTC patients who redifferentiate after lenvatinib therapy is therefore crucial. Trial Registration: ClinicalTrials.gov, NTC04858867.

Ventricular Arrhythmia Substrate Distribution and Its Relation to Sympathetic Innervation in Nonischemic Cardiomyopathy Patients.

BACKGROUND: Nonischemic cardiomyopathy patients referred for catheter ablation of ventricular arrhythmias (VAs) typically have either inferolateral (ILS) or anteroseptal (ASS) VA substrate locations, with poorer outcomes for ASS. Sympathetic denervation is an important determinant of arrhythmogenicity. Its relation to nonischemic fibrosis in general and to the different VA substrates is unknown. OBJECTIVES: This study sought to evaluate the association between VA substrates, myocardial fibrosis, and sympathetic denervation. METHODS: Thirty-five patients from the Leiden Nonischemic Cardiomyopathy Study, who underwent electroanatomic voltage mapping and iodine-123 metaiodobenzylguanidine imaging between 2011 and 2018 were included. Late gadolinium-enhanced cardiac magnetic resonance data were collected when available. The relation between global cardiac sympathetic innervation and area-weighted unipolar voltage (UV) as a surrogate for diffuse fibrosis was evaluated. For regional analysis, patients were categorized as ASS or ILS. The distribution of low UV, sympathetic denervation, and late gadolinium enhancement (LGE) scar were compared using the 17-segment model. RESULTS: Median area-weighted UV was 12.3 mV in patients with normal sympathetic innervation and 8.7 mV in patients with sympathetic denervation. Global sympathetic denervation correlated with diffuse myocardial fibrosis (R = 0.53; P = 0.02). ILS (n = 13) matched with low UV, sympathetic denervation, and LGE scar in all patients, whereas ASS (n = 11) matched with low UV in all patients, with LGE scar in 63% (P = 0.20), but with sympathetic denervation in only 27% of patients (P = 0.0002). CONCLUSIONS: Global cardiac sympathetic denervation is related to fibrosis in nonischemic cardiomyopathy patients with VA. The mismatch between regional fibrosis and preserved innervation for ASS may contribute to a VA substrate difficult to control by catheter ablation.

Value-assessment of computer-assisted navigation strategies during percutaneous needle placement.

PURPOSE: Navigational strategies create a scenario whereby percutaneous needle-based interventions of the liver can be guided using both pre-interventional 3D imaging datasets and dynamic interventional ultrasound (US). To score how such technologies impact the needle placement process, we performed kinematic analysis on different user groups. METHODS: Using a custom biopsy phantom, three consecutive exercises were performed by both novices and experts (n = 26). The exercise came in three options: (1) US-guidance, (2) US-guidance with pre-interventional image-registration (US + Reg) and (3) US-guidance with pre-interventional image-registration and needle-navigation (US + Reg + Nav). The traveled paths of the needle were digitized in 3D. Using custom software algorithms, kinematic metrics were extracted and related to dexterity, decision making indices to obtain overall performance scores (PS). RESULTS: Kinematic analysis helped quantifying the visual assessment of the needle trajectories. Compared to US-guidance, novices yielded most improvements using Reg (PSavg(US) = 0.43 vs. PSavg(US+Reg) = 0.57 vs. PSavg(US+Reg+Nav) = 0.51). Interestingly, the expert group yielded a reversed trend (PSavg(US) = 0.71 vs PSavg(US+Reg) = 0.58 vs PSavg(US+Reg+Nav) = 0.59). CONCLUSION: Digitizing the movement trajectory allowed us to objectively assess the impact of needle-navigation strategies on percutaneous procedures. In particular, our findings suggest that these advanced technologies have a positive impact on the kinematics derived performance of novices.

Mutation in the CCAL1 locus accounts for bidirectional process of human subchondral bone turnover and cartilage mineralization.

OBJECTIVES: To study the mechanism by which the readthrough mutation in TNFRSF11B, encoding osteoprotegerin (OPG) with additional 19 amino acids at its C-terminus (OPG-XL), causes the characteristic bidirectional phenotype of subchondral bone turnover accompanied by cartilage mineralization in chondrocalcinosis patients. METHODS: OPG-XL was studied by human induced pluripotent stem cells expressing OPG-XL and two isogenic CRISPR/Cas9-corrected controls in cartilage and bone organoids. Osteoclastogenesis was studied with monocytes from OPG-XL carriers and matched healthy controls followed by gene expression characterization. Dual energy X-ray absorptiometry scans and MRI analyses were used to characterize the phenotype of carriers and non-carriers of the mutation. RESULTS: Human OPG-XL carriers relative to sex- and age-matched controls showed, after an initial delay, large active osteoclasts with high number of nuclei. By employing hiPSCs expressing OPG-XL and isogenic CRISPR/Cas9-corrected controls to established cartilage and bone organoids, we demonstrated that expression of OPG-XL resulted in excessive fibrosis in cartilage and high mineralization in bone accompanied by marked downregulation of MGP, encoding matrix Gla protein, and upregulation of DIO2, encoding type 2 deiodinase, gene expression, respectively. CONCLUSIONS: The readthrough mutation at CCAL1 locus in TNFRSF11B identifies an unknown role for OPG-XL in subchondral bone turnover and cartilage mineralization in humans via DIO2 and MGP functions. Previously, OPG-XL was shown to affect binding between RANKL and heparan sulphate (HS) resulting in loss of immobilized OPG-XL. Therefore, effects may be triggered by deficiency in the immobilization of OPG-XL Since the characteristic bidirectional pathophysiology of articular cartilage calcification accompanied by low subchondral bone mineralization is also a hallmark of OA pathophysiology, our results are likely extrapolated to common arthropathies.

Nuclear medicine imaging methods of radiation-induced cardiotoxicity.

Breast cancer survival is significantly improved over the past decades due to major improvements in anti-tumor therapies and the implementation of regular screening, which leads to early detection of breast cancer. Therefore, it is of utmost importance to prevent patients from long-term side effects, including radiotherapy-induced cardiotoxicity. Radiotherapy may contribute to damage of myocardial structures on the cellular level, which eventually could result in various types of cardiovascular problems, including coronary artery disease and (non-)ischemic cardiomyopathy, leading to heart failure. These cardiac complications of radiotherapy are preceded by alterations in myocardial perfusion and blood flow. Therefore, early detection of these alterations is important to prevent the progression of these pathophysiological processes. Several radionuclide imaging techniques may contribute to the early detection of these changes. Single-Photon Emission Computed Tomography (SPECT) cameras can be used to create Multigated Acquisition scans in order to assess the left ventricular systolic and diastolic function. Furthermore, SPECT cameras are used for myocardial perfusion imaging with radiopharmaceuticals such as 99mTc-sestamibi and 99mTc-tetrofosmin. Accurate quantitative measurement of myocardial blood flow (MBF), can be performed by Positron Emission Tomography (PET), as the uptake of some of the tracers used for PET-based MBF measurement almost creates a linear relationship with MBF, resulting in very accurate blood flow quantification. Furthermore, there are PET and SPECT tracers that can assess inflammation and denervation of the cardiac sympathetic nervous system. Research over the past decades has mainly focused on the long-term development of left ventricular impairment and perfusion defects. Considering laterality of the breast cancer, some early studies have shown that women irradiated for left-sided breast cancer are more prone to cardiotoxic side effects than women irradiated for right-sided breast cancer. The left-sided radiation field in these trials, which predominantly used older radiotherapy techniques without heart-sparing techniques, included a larger volume of the heart and left ventricle, leading to increased unavoidable radiation exposure to the heart due to the close proximity of the radiation treatment volume. Although radiotherapy for breast cancer exposes the heart to incidental radiation, several improvements and technical developments over the last decades resulted in continuous reduction of radiation dose and volume exposure to the heart. In addition, radiotherapy reduces loco-regional tumor recurrences and death from breast cancer and improves survival. Therefore, in the majority of patients, the benefits of radiotherapy outweigh the potential very low risk of cardiovascular adverse events after radiotherapy. This review addresses existing nuclear imaging techniques, which can be used to evaluate (long-term) effects of radiotherapy-induced mechanical cardiac dysfunction and discusses the potential use of more novel nuclear imaging techniques, which are promising in the assessment of early signs of cardiac dysfunction in selected irradiated breast cancer patients.

Inter-observer agreement of vertebral fracture assessment with dual-energy x-ray absorptiometry equipment.

PURPOSE: To investigate the time and effort needed to perform vertebral morphometry, as well as inter-observer agreement for identification of vertebral fractures on vertebral fracture assessment (VFA) images. METHODS: Ninety-six images were retrospectively selected, and three radiographers independently performed semi-automatic 6-point morphometry. Fractures were identified and graded using the Genant classification. Time needed to annotate each image was recorded, and reader fatigue was assessed using a modified Simulator Sickness Questionnaire (SSQ). Inter-observer agreement was assessed per-patient and per-vertebra for detecting fractures of all grades (grades 1-3) and for grade 2 and 3 fractures using the kappa statistic. Variability in measured vertebral height was evaluated using the intraclass correlation coefficient (ICC). RESULTS: Per-patient agreement was 0.59 for grades 1-3 fracture detection, and 0.65 for grades 2-3 only. Agreement for per-vertebra fracture classification was 0.92. Vertebral height measurements had an ICC of 0.96. Time needed to annotate VFA images ranged between 91 and 540 s, with a mean annotation time of 259 s. Mean SSQ scores were significantly lower at the start of a reading session (1.29; 95% CI: 0.81-1.77) compared to the end of a session (3.25; 95% CI: 2.60-3.90; p < 0.001). CONCLUSION: Agreement for detection of patients with vertebral fractures was only moderate, and vertebral morphometry requires substantial time investment. This indicates that there is a potential benefit for automating VFA, both in improving inter-observer agreement and in decreasing reading time and burden on readers.

Experimental validation of absolute SPECT/CT quantification for response monitoring in patients with coronary artery disease.

BACKGROUND: Quantitative SPECT enables absolute quantification of uptake in perfusion defects. The aim of this experimental study is to assess quantitative accuracy and precision of a novel iterative reconstruction technique (Evolution; GE Healthcare) for the potential application of response monitoring using 99mTc-tetrofosmin SPECT/CT in patients with coronary artery disease (CAD). METHODS: Acquisitions of an anthropomorphic torso phantom with cardiac insert containing defects (with varying sizes), filled with 99mTc-pertechnetate, were performed on a SPECT/CT (Discovery 670 Pro, GE Healthcare). Subsequently, volumes of interest of the defects were manually drawn on CT to assess the recovery coefficient (RC). Bull's eye plots were composed to evaluate the uptake per segment. Finally, 99mTc-tetrofosmin SPECT/CT scans of 10 CAD patients were used to illustrate clinical application. RESULTS: The phantom study indicated that Evolution showed convergence after 7 iterations and 10 subsets. The average repeatability deviation of all configurations was 2.91% and 3.15% (%SD mean) for filtered (Butterworth) and unfiltered data, respectively. The accuracy after post-filtering was lower compared to the unfiltered data with a mean (SD) RC of 0.63 (0.05) and 0.70 (0.07), respectively (p < 0.05). More artificial defects were found on Bull's eye plots created with the unfiltered data compared to filtered data. Eight out of ten patients showed significant changes in uptake before and after treatment (p < 0.05). CONCLUSION: Quantification of 99mTc-tetrofosmin SPECT/CT seems feasible for CAD patients when 7 iterations (10 subsets), Butterworth post-filtering (cut off frequency 0.52 in cycles/cm, order of 5) and manual CT-delineation are applied. However, future prospective patient studies are required for clinical application.

Lifestyle-Intervention-Induced Reduction of Abdominal Fat Is Reflected by a Decreased Circulating Glycerol Level and an Increased HDL Diameter.

SCOPE: Abdominal obesity is one of the main modifiable risk factors of age-related cardiometabolic disease. Cardiometabolic disease risk and its associated high abdominal fat mass, cholesterol, and glucose concentrations can be reduced by a healthier lifestyle. Hence, the aim is to understand the relation between lifestyle-induced changes in body composition, and specifically abdominal fat, and accompanying changes in circulating metabolic biomarkers. METHODS AND RESULTS: Data from the Growing Old Together (GOTO) study was used, which is a single arm lifestyle intervention in which 164 older adults (mean age 63 years, BMI 23-35 kg/m2 ) changed their lifestyle during 13 weeks by 12.5% caloric restriction plus 12.5% increase in energy expenditure. It is shown here that levels of circulating metabolic biomarkers, even after adjustment for body mass index, specifically associate with abdominal fat mass. The applied lifestyle intervention mainly reduces abdominal fat mass (-2.6%, SD = 3.0) and this reduction, when adjusted for general weight loss, is highly associated with decreased circulating glycerol concentrations and increased HDL diameter. CONCLUSION: The lifestyle-induced reduction of abdominal fat mass is particularly associated, independent of body mass index or general weight loss, with decreased circulating glycerol concentrations and increased HDL diameter.

Limited clinical value of two consecutive post-transplant renal scintigraphy procedures.

OBJECTIVES: Duration of delayed graft function (DGF) and length of hospital stay (LOS) are outcomes of interest in an era that warrants increased efficacy of transplant care whereas renal allografts originate increasingly from marginal donors. While earlier studies investigate the predictive capability of a single renal scintigraphy, this study focuses on the value for both DGF duration and LOS of consecutively performed scintigraphies. METHODS: From 2011 to 2014, renal transplant recipients referred for a Tc-99m MAG3 renal scintigraphy were included in a single-center retrospective study. Primary endpoints were DGF duration and LOS. Both the first (≤ 3 days) and second scintigraphies (3-7 days after transplantation) were analyzed using a 4-grade qualitative scale and quantitative indices (TFS, cTER, MUC10, average upslope). RESULTS: We evaluated 200 first and 108 (54%) consecutively performed scintigraphies. The Kaplan-Meier curves for DGF duration and qualitative grading of the first and second scintigraphy showed significant differences between the grades (p < 0.01). The Kaplan-Meier curve for the delta grades between these procedures (lower, equal, or higher grade) did not show significant differences (p = 0.18). Multivariate analysis showed a significant association between the qualitative grades, from the first and second scintigraphy, and DGF duration, HR 1.8 (1.4-2.2, p < 0.01) and 2.8 (1.8-4.3, p < 0.01), respectively. CONCLUSIONS: Qualitative grades of single renal scintigraphies, performed within 7 days after transplantation, can be used to make a reliable image-guided decision on the need for dialysis and to predict LOS. A consecutive renal scintigraphy, however, did not show an additional value in the assessment of DGF. KEY POINTS: • Post-transplant renal scintigraphy procedures provide information to predict delayed graft function duration and length of hospital stay. • Performing two consecutive renal scintigraphy procedures within 1 week after transplantation does not strengthen the prediction of delayed graft function duration and length of hospital stay. • Single renal scintigraphy procedures can be used to provide clinicians and patients with a reliable indication of the need for dialysis after transplantation and the expected duration of hospitalization.

Experimental validation of absolute SPECT/CT quantification for response monitoring in breast cancer.

PURPOSE: Recent developments in iterative image reconstruction enable absolute quantification of SPECT/CT studies by incorporating compensation for collimator-detector response, attenuation, and scatter as well as resolution recovery into the reconstruction process (Evolution; Q.Metrix package; GE Healthcare, Little Chalfont, UK). The aim of this experimental study is to assess its quantitative accuracy for potential clinical 99m Tc-sestamibi (MIBI)-related SPECT/CT application in neoadjuvant chemotherapy response studies in breast cancer. METHODS: Two phantoms were filled with MIBI and acquired on a SPECT/CT gamma camera (Discovery 670 Pro; GE Healthcare), that is, a water cylinder and a NEMA body phantom containing six spheres that were filled with an activity concentration reflecting clinical MIBI uptake. Subsequently, volumes-of-interest (VOI) of each sphere were drawn (semi)automatically on SPECT using various isocontour methods or manually on CT. Finally, prone MIBI SPECT/CT scans were acquired 5 and 90 min p.i. in a locally advanced breast cancer patient. RESULTS: Activity concentration in the four largest spheres converged after nine iterations of evolution. Depending on the count statistics, the accuracy of the reconstructed activity concentration varied between -4.7 and -0.16% (VOI covering the entire phantom) and from 6.9% to 10% (8.8 cm ⌀ cylinder VOI placed in the center of the phantom). Recovery coefficients of SUVmax were 1.89 ± 0.18, 1.76 ± 0.17, 2.00 ± 0.38, 1.89 ± 0.35, and 0.90 ± 0.26 for spheres with 37, 28, 22, 17, and 13 mm ⌀, respectively. Recovery coefficients of SUVmean were 1.07 ± 0.06, 1.03 ± 0.09, 1.17 ± 0.21, 1.10 ± 0.20, and 0.52 ± 0.14 (42% isocontour); 1.10 ± 0.07, 1.02 ± 0.09, 1.13 ± 0.19, 1.06 ± 0.19, and 0.51 ± 0.13 (36% isocontour with local background correction); and 0.96, 1.09, 1.03, 1.03, and 0.29 (CT). Patient study results were concordant with the phantom validation. CONCLUSIONS: Absolute SPECT/CT quantification of breast studies using MIBI seems feasible (<17% deviation) when a 42% isocontour is used for delineation for tumors of at least 17 mm diameter. However, with tumor shrinkage, response evaluation should be handled with caution, especially when using SUVmax .

Long-term prognostic value of single-photon emission computed tomography myocardial perfusion imaging after primary PCI for STEMI.

Aims: The aim of this study was to determine the long-term prognostic value of infarct size and myocardial ischaemia on single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Methods and results: In total, 1092 STEMI patients who underwent primary PCI and SPECT MPI within 1-6 months were included (median follow-up time of 6.9 years). In the entire cohort, SPECT infarct size was independently associated with the composite of cardiac death or reinfarction [hazard ratio (HR) per 10% increase in summed rest score 1.33; 95% confidence interval (95% CI) 1.12-1.58; P = 0.001], whereas myocardial ischaemia was not (HR per 5% increase in summed difference score 1.18; 95% CI 0.94-1.48; P = 0.16). Addition of SPECT infarct size to a model including the clinical variables provided significant incremental prognostic value for the prediction of cardiac death or reinfarction (global χ2 13.8 vs. 24.2; P = 0.002), whereas addition of SPECT ischaemia did not add significantly (global χ2 24.2 vs. 25.6; P = 0.24). In the subgroup of patients with left ventricular ejection fraction (LVEF) ≤ 45%, SPECT infarct size was independently associated with cardiac death or reinfarction (HR 1.59; 95% CI 1.15-2.22; P = 0.006), whereas in patients with LVEF > 45%, only SPECT ischaemia was independently associated with cardiac death or reinfarction (HR 1.28; 95% CI 1.00-1.63; P = 0.050). Conclusion: In patients with first STEMI and primary PCI, SPECT infarct size was independently associated with cardiac death and/or reinfarction, whereas myocardial ischaemia was not. In patients with LVEF ≤ 45%, SPECT infarct size was independently associated with cardiac death or reinfarction, whereas myocardial ischaemia was not. Conversely, in patients with LVEF > 45%, only SPECT ischaemia was independently associated with cardiac death or reinfarction.

Relationship Between Coronary Contrast-Flow Quantitative Flow Ratio and Myocardial Ischemia Assessed by SPECT MPI.

PURPOSE: A new method has been developed to calculate fractional flow reserve (FFR) from invasive coronary angiography, the so-called "contrast-flow quantitative flow ratio (cQFR)". Recently, cQFR was compared to invasive FFR in intermediate coronary lesions showing an overall diagnostic accuracy of 85%. The purpose of this study was to investigate the relationship between cQFR and myocardial ischemia assessed by single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI). METHODS: Patients who underwent SPECT MPI and coronary angiography within 3 months were included. The cQFR computation was performed offline, using dedicated software. The cQFR computation was based on 3-dimensional quantitative coronary angiography (QCA) and computational fluid dynamics. The standard 17-segment model was used to determine the vascular territories. Myocardial ischemia was defined as a summed difference score ≥2 in a vascular territory. A cQFR of ≤0.80 was considered abnormal. RESULTS: Two hundred and twenty-four coronary arteries were analysed in 85 patients. Overall accuracy of cQFR to detect ischemia on SPECT MPI was 90%. In multivariable analysis, cQFR was independently associated with ischemia on SPECT MPI (OR per 0.01 decrease of cQFR: 1.10; 95% CI 1.04-1.18, p = 0.002), whereas clinical and QCA parameters were not. Furthermore, cQFR showed incremental value for the detection of ischemia compared to clinical and QCA parameters (global chi square 48.7 to 62.6; p <0.001). CONCLUSIONS: A good relationship between cQFR and SPECT MPI was found. cQFR was independently associated with ischemia on SPECT MPI and showed incremental value to detect ischemia compared to clinical and QCA parameters.

Comparison between a count-based and geometrical approach for the assessment of left ventricular dyssynchrony using myocardial perfusion scintigraphy.

OBJECTIVE: There are two distinct approaches for the assessment of left ventricular (LV) dyssynchrony by myocardial perfusion scintigraphy (MPS). The aim of this study was to compare the performance of the count-based and geometrical approach in clinical data using gated single photon emission computed tomography MPS. MATERIAL AND METHODS: Group 1 consisted of 113 patients (49 men, 64 women) with normal perfusion [summed rest score (SRS)≤3], normal LV ejection fraction (≥55%), and normal QRS duration (QRSd<120 ms). Group 2 consisted of 89 heart failure patients (79 men, 10 women) with no restriction for SRS, LV ejection fraction ≤35%, and QRSd ≥120 ms. All MPS parameters were obtained from the software Corridor4DM. Dyssynchrony parameters used were time to peak contraction, SD, and bandwidth (BW). RESULTS: SD and BW were estimated higher (difference group 1: SD 3.0±2.3 and BW 11.3±9.3, P-values <0.001; difference group 2: SD 2.4±4.3 and BW 1.3±17.0, P-value <0.001 and 0.479 respectively) using the count-based approach in comparison with the geometrical method. A significant and good correlation was found between these two methods (R=0.763, 0.902, 0.896 for time to peak contraction, SD, and BW respectively, P-values ≤0.001). SD and BW in both approaches were equally good parameters for differentiating heart failure patients (area under the curve: 0.995-0.998), although using different cut-off values. CONCLUSION: The count-based approach generally provides a wider phase distribution and subsequently greater SD and BW estimates compared with the geometrical algorithm. These differences result in clinically relevant deviations in normal and cut-off values that have to be recognized when evaluating patients.

Metabolic effects of a 13-weeks lifestyle intervention in older adults: The Growing Old Together Study.

For people in their 40s and 50s, lifestyle programs have been shown to improve metabolic health. For older adults, however, it is not clear whether these programs are equally healthy. In the Growing Old Together study, we applied a 13-weeks lifestyle program, with a target of 12.5% caloric restriction and 12.5% increase in energy expenditure through an increase in physical activity, in 164 older adults (mean age=63.2 years; BMI=23-35 kg/m2). Mean weight loss was 4.2% (SE=2.8%) of baseline weight, which is comparable to a previous study in younger adults. Fasting insulin levels, however, showed a much smaller decrease (0.30 mU/L (SE=3.21)) and a more heterogeneous response (range=2.0-29.6 mU/L). Many other parameters of metabolic health, such as blood pressure, and thyroid, glucose and lipid metabolism improved significantly. Many 1H-NMR metabolites changed in a direction previously associated with a low risk of type 2 diabetes and cardiovascular disease and partially independently of weight loss. In conclusion, 25% reduction in energy balance for 13 weeks induced a metabolic health benefit in older adults, monitored by traditional and novel metabolic markers.

Repeated Intramyocardial Bone Marrow Cell Injection in Previously Responding Patients With Refractory Angina Again Improves Myocardial Perfusion, Anginal Complaints, and Quality of Life.

BACKGROUND: Intramyocardial bone marrow cell injection is associated with improvements in myocardial perfusion and anginal symptoms in patients with refractory angina pectoris. This study evaluates the effect of repeated intramyocardial bone marrow cell injection in patients with residual or recurrent myocardial ischemia. METHODS AND RESULTS: Twenty-three patients (17 men; 69±9 years) who had improved myocardial perfusion after the first injection but had residual or recurrent angina and ischemia on single-photon emission computed tomographic myocardial perfusion imaging were included. Patients again received intramyocardial injection of 100×10(6) autologous bone marrow mononuclear cells, 4.6±2.5 years after their first injection. No periprocedural complications occurred. Myocardial perfusion assessed using single-photon emission computed tomographic myocardial perfusion imaging improved from a summed stress score of 27.3±5.8 at baseline to 24.5±4.4 at 3 months (P=0.002) and 25.4±4.9 at 12 months of follow-up (P=0.002). Perfusion improvement after 3 months was comparable with the effect of the first injection (P=0.379). Anginal complaints improved ≤12 months after cell injection in Canadian Cardiovascular Society score (mean change at 3, 6, and 12 months: 0.6±0.9%, 0.5±0.9%, and 0.6±0.9%, respectively; Pslope=0.007, first versus repeated; P=0.188) and in quality of life score as measured by Seattle Angina Questionnaire (mean change at 3, 6, and 12 months: 7±14%, 8±14%, and 7±15%, respectively; Pslope=0.020, first versus repeated; P=0.126). CONCLUSIONS: Repeated bone marrow cell injection in previously responding patients with refractory angina is associated with improvements in myocardial perfusion, anginal complaints, and quality of life score ≤12 months of follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR2664.

Changes in ischaemia as assessed with single-photon emission computed tomography myocardial perfusion imaging in high-risk patients with diabetes without cardiac symptoms: relation with coronary atherosclerosis on computed tomography coronary angiography.

AIMS: The study aims (i) to evaluate changes in myocardial ischaemia on single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) after 2 years in a cohort of high-risk patients with diabetes without cardiac symptoms or known coronary artery disease (CAD) and (ii) to assess the value of baseline computed tomography coronary angiography (CTA)-derived coronary atherosclerosis parameters to predict changes in myocardial ischaemia. METHODS AND RESULTS: The population consisted of 100 high-risk patients with diabetes without cardiac symptoms referred for cardiovascular risk stratification. All patients underwent coronary artery calcium (CAC) scoring, CTA, and SPECT MPI. After 2 years of follow-up, SPECT MPI was repeated to evaluate potential progression of ischaemia.In total, 20% of patients presented with ischaemia at baseline. Of these 20 patients, 7 (35%) still had ischaemia at follow-up, whereas 13 (65%) showed resolution and 4 (20%) showed progression of ischaemia at follow-up. Of the 80 patients without ischaemia at baseline, 65 (81%) had a normal MPI at follow-up and 15 patients (19%) presented with new ischaemia. There were no significant differences in the CAC score or the extent, severity, and composition of CAD on CTA between patients with and without ischaemia at baseline. Similarly, no differences could be demonstrated between patients with and without ischaemia at follow-up or between patients with and without progression of ischaemia. CONCLUSION: The rate of progression of ischaemia in high-risk patients with diabetes without cardiac symptoms is limited. Few patients presented with new ischaemia, whereas some patients showed resolution of ischaemia. Atherosclerosis parameters on CTA were not predictive of new-onset ischaemia or progression of ischaemia.

Predictors of response to intramyocardial bone marrow cell treatment in patients with refractory angina and chronic myocardial ischemia.

BACKGROUND: We previously showed that intramyocardial bone marrow cell (BMC) injection in patients with refractory angina and chronic myocardial ischemia improves myocardial perfusion, cardiac function and disease-related complaints. Treatment effect varied between patients, but the predictors of response remain to be identified. Therefore, the aim of the present study was to assess whether patient characteristics, procedural data and baseline measurements influence the response to intramyocardial BMC treatment in a large cohort of refractory angina patients. METHODS AND RESULTS: In 120 patients (64 ± 9 years, 88% men) with refractory angina, 97 ± 13 × 10(6) BMCs were injected intramyocardially in regions with stress-inducible ischemia as assessed by single photon emission computed tomography (SPECT). Canadian Cardiovascular Society angina (CCS) class, quality-of-life score, exercise testing, SPECT and magnetic resonance imaging were performed at baseline and at 3 months follow-up demonstrating significant improvements in CCS class, quality-of-life, exercise capacity, myocardial perfusion and left ventricular function (all variables P<0.001). Multivariate analysis was performed to evaluate the influence of patient characteristics, procedural data and baseline measurements on BMC treatment response. Based on the improvement of myocardial perfusion at stress, diabetes and a large number of ischemic segments at baseline were shown to be independently associated with a large response to BMC therapy. CONCLUSION: The present study demonstrates that diabetes and a large number of ischemic segments are predictors of a large response to intramyocardial BMC injection in refractory angina and chronic ischemia. Furthermore, the safety and efficacy results of previous trials are now confirmed in a larger study population.