Challenges in Pharmacokinetic Modelling of [18F]fluoro-PEG-folate PET/CT Imaging in Epithelial Ovarian Cancer Patients.

PURPOSE: To describe the pharmacokinetic properties of the [18F]fluoro-polyethylene glycol(PEG)-folate radiotracer in PET/CT imaging of patients with advanced stage epithelial ovarian cancer (EOC). PROCEDURES: In five patients with advanced EOC (FIGO stage IIIB/IIIC, Fédération Internationale de Gynécologie et d'Obstétrique), a 90-min dynamic PET acquisition of the pelvis was performed directly after i.v. administration of 185 MBq [18F]fluoro-PEG6-folate. Arterial blood samples collected at nineteen timepoints were used to determine the plasma input function. A static volume of interest (VOI) for included tumor lesions was drawn manually on the PET images. Modelling was performed using PMOD software. Three different models (a 1-tissue compartment model (1T2k) and two 2-tissue compartment models, irreversible (2T3k) and reversible (2T4k)) were compared in goodness of fit with the time activity curves by means of the Akaike information criterion. RESULTS: The pharmacokinetic analysis in the pelvic area has proven to be much more challenging than expected. Only four out of 22 tumor lesions in five patients were considered suitable to perform modelling on. The remaining tumor lesions were inapt due to either low tracer uptake, small size, proximity to other [18F]fluoro-PEG6-folate -avid structures and/or displacement by abdominal organ motion in the dynamic scan. Data from the four analyzed tumor lesions suggest that the irreversible 2T3k may best describe the pharmacokinetics. All 22 lesions were immunohistochemically stained positive for the folate receptor alpha (FRα) after resection. CONCLUSION: Performing pharmacokinetic analysis in the abdominal pelvic region is very challenging. This brief article describes the challenges and pitfalls in pharmacokinetic analysis of a tracer with high physiological accumulation in the intestines, in case of lesions of limited size in the abdominal pelvic area.

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.

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.

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 .

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.

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.

Effect of intramyocardial bone marrow-derived mononuclear cell injection on cardiac sympathetic innervation in patients with chronic myocardial ischemia.

Intramyocardial bone marrow cell injection has been associated with improvements in myocardial perfusion and left ventricular function. The current substudy of a randomized, placebo-controlled, double-blinded study, investigated the effect of intramyocardial bone marrow cell injection on myocardial sympathetic innervation in patients with chronic myocardial ischemia. In a total of 16 patients (64 ± 8 years, 13 men), early and late iodine-123 metaiodobenzylguanidine (MIBG) imaging was performed before and 3 months after intramyocardial bone marrow cell injection. No improvements were observed in global early H/M ratio (P = 0.40), late H/M ratio (P = 0.43) and cardiac washout rate (P = 0.98). However, late 123-I MIBG SPECT defect score showed a trend to improvement in the bone marrow cell group (from 31.0 ± 7.1 to 28.1 ± 14.9) as compared to the placebo group (from 33.6 ± 8.5 to 34.5 ± 9.8, P = 0.055 between groups). This trend was mainly driven by a substantial improvement in three bone marrow cell-treated patients, which all had diabetes and severe MIBG defects. In these patients, the extent and severity of MIBG defects improved substantially independent of myocardial perfusion and cell injection sites. The present study does not demonstrate improvements in global cardiac sympathetic nerve innervation after intramyocardial bone marrow cell injection in patients with chronic myocardial ischemia. However, regional analysis of sympathetic nerve innervation reveals improvements in three diabetic patients independent of myocardial perfusion, suggestive of a therapeutic effect on diabetic cardiac sympathetic dysinnervation.

Intramyocardial injection of autologous bone marrow-derived ex vivo expanded mesenchymal stem cells in acute myocardial infarction patients is feasible and safe up to 5 years of follow-up.

In experimental studies, mesenchymal stem cell (MSC) transplantation in acute myocardial infarction (AMI) models has been associated with enhanced neovascularization and myogenesis. Clinical data however, are scarce. Therefore, the present study evaluates the safety and feasibility of intramyocardial MSC injection in nine patients, shortly after AMI during short-term and 5-year follow-up. Periprocedural safety analysis demonstrated one transient ischemic attack. No other adverse events related to MSC treatment were observed during 5-year follow-up. Clinical events were compared to a nonrandomized control group comprising 45 matched controls. A 5-year event-free survival after MSC-treatment was comparable to controls (89 vs. 91 %, P = 0.87). Echocardiographic imaging for evaluation of left ventricular function demonstrated improvements up to 5 years after MSC treatment. These findings were not significantly different when compared to controls. The present safety and feasibility study suggest that intramyocardial injection of MSC in patients shortly after AMI is feasible and safe up to 5-year follow-up.

Intramyocardial injection of bone marrow mononuclear cells in chronic myocardial ischemia patients after previous placebo injection improves myocardial perfusion and anginal symptoms: an intra-patient comparison.

BACKGROUND: We recently demonstrated in a randomized, double-blind, placebo-controlled trial that intramyocardial bone marrow cell (BMC) injection is associated with improvements in myocardial perfusion and anginal symptoms in chronic myocardial ischemia patients. In the present study the results of the crossover phase of this trial, in which patients previously treated with placebo received autologous BMC injections are reported. This allows a unique intra-patient comparison on the effect of BMC versus placebo injection with elimination of patient-related confounding factors. METHODS: In 16 patients (14 male, 64 ± 10 years), who previously received intramyocardial placebo injections in the setting of a randomized trial, 100 × 10(6) BMC were injected using the NOGA-system. Canadian Cardiovascular Society angina score and quality of life were evaluated at baseline, 3 and 6 months. Tc-99m single photon emission computed tomography and magnetic resonance imaging were performed at baseline and 3 months to assess myocardial perfusion and left ventricular (LV) function. RESULTS: Canadian Cardiovascular Society score and quality of life improved significantly after BMC injection as compared to placebo (P = 0.01 and P = 0.02, respectively). Single photon emission computed tomography revealed a significant greater improvement (P = 0.03) in summed stress score after BMC injection as compared to placebo. LV end-systolic volume significantly decreased after BMC injection but not after placebo injection. LV end-diastolic volume and LV ejection fraction did not change. CONCLUSION: Intramyocardial BMC injection in patients with chronic myocardial ischemia who previously received intramyocardial placebo treatment resulted in significant improvement in angina symptoms and myocardial perfusion. These results confirm the outcome of our previously reported randomized trial.

Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial.

CONTEXT: Previous studies have suggested that bone marrow cell injection may improve myocardial perfusion and left ventricular (LV) function in patients with chronic myocardial ischemia. OBJECTIVE: To investigate the effect of intramyocardial bone marrow cell injection on myocardial perfusion and LV function in patients with chronic myocardial ischemia. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, placebo-controlled trial at a Netherlands university hospital, May 1, 2005-March 3, 2008 (6-month follow-up ended September 2008) of 50 patients with chronic myocardial ischemia (mean age [SD], 64 [8] years; 43 men). INCLUSION CRITERIA: severe angina pectoris despite optimal medical therapy and myocardial ischemia. All patients were ineligible for conventional revascularization. INTERVENTIONS: Intramyocardial injection of 100 x 10(6) autologous bone marrow-derived mononuclear cells or placebo solution. MAIN OUTCOME MEASURES: Primarily, the summed stress score, a 17-segment score for stress myocardial perfusion assessed by Tc-99m tetrofosmin single-photon emission computed tomography (SPECT). Secondary included LV ejection fraction (LVEF), Canadian Cardiovascular Society (CCS) class, and Seattle Angina Questionnaire quality-of-life score (mean difference >5% considered clinically significant). RESULTS: After 3-month follow-up, the summed stress score (mean [SD]) improved from 23.5 (4.7) to 20.1 (4.6) (P < .001) in the bone marrow cell group, compared with a decrease from 24.8 (5.5) to 23.7 (5.4) (P = .004) in the placebo group. In the bone marrow cell-treated patients who underwent magnetic resonance imaging (MRI), a 3% absolute increase in LVEF was observed at 3 months (95% CI, 0.5% to 4.7%; n = 18), but the placebo group showed no improvement. CCS angina score improved significantly in the bone marrow cell group (6-month absolute difference, -0.79; 95% CI, -1.10 to -0.48; P < .001) compared with no significant improvement in the placebo group. Quality-of-life score increased from 56% (9%) to 64% (12%) at 3 months and 69% (12%) at 6 months in bone marrow cell-treated patients, compared with a smaller increase in the placebo group from 57% (11%) to 61% (14%) to 64% (17%). The improvements in CCS class and quality of life score were significantly greater in bone marrow cell-treated patients than in placebo-treated patients (P = .03 and P = .04, respectively). CONCLUSIONS: In this short-term study of patients with chronic myocardial ischemia refractory to medical treatment, intramyocardial bone marrow cell injection resulted in a statistically significant but modest improvement in myocardial perfusion compared with placebo. Further studies are required to assess long-term results and efficacy for mortality and morbidity. TRIAL REGISTRATIONS: trialregister.nl Identifier: NTR400 and isrctn.org Identifier: ISRCTN58194927.

Prevalence and predictors of an abnormal stress myocardial perfusion study in asymptomatic patients with type 2 diabetes mellitus.

PURPOSE: The purpose of this study was to evaluate the prevalence of an abnormal stress myocardial perfusion study in a cohort of truly asymptomatic patients with type 2 diabetes mellitus using myocardial perfusion imaging by means of single photon emission computed tomography (SPECT). Secondly, we determined which clinical characteristics may predict an abnormal stress myocardial perfusion study in this population. METHODS: A total of 120 asymptomatic patients (mean age 53+/-10 years) with type 2 diabetes mellitus and one or more risk factors for coronary artery disease were prospectively recruited from an outpatient diabetes clinic. All patients underwent myocardial perfusion imaging by means of adenosine (99m)Tc sestamibi SPECT. Images were evaluated for the presence of perfusion abnormalities as well as other nonperfusion abnormalities that may indicate extensive ischaemia, including left ventricular dysfunction (defined as a left ventricular ejection fraction <45%), transient ischaemic dilatation and adenosine-induced ST segment depression. Multivariable analysis was performed using a backward selection strategy to identify potential predictors for an abnormal stress myocardial perfusion study. Finally, all patients were followed up for 12 months to determine the occurrence of cardiovascular events: (1) cardiac death, (2) nonfatal myocardial infarction, (3) unstable angina requiring hospitalization, (4) revascularization, or (5) stroke. RESULTS: Of the 120 patients, 40 (33%) had an abnormal stress study, including myocardial perfusion abnormalities in 30 patients (25%). In 10 patients (8%), indicators of extensive (possibly balanced ischaemia) were observed in the absence of abnormal perfusion. The multivariable analysis identified current smoking, duration of diabetes and the cholesterol/high-density lipoprotein (HDL) ratio as independent predictors of an abnormal stress study. During a follow-up period of 12 months six patients (5%) had a cardiovascular event. CONCLUSION: The current study revealed a high prevalence of abnormal stress myocardial perfusion studies in patients with type 2 diabetes mellitus despite the absence of symptoms. In contrast to earlier studies, current smoking, duration of diabetes and the cholesterol/HDL ratio were identified as independent predictors of an abnormal study.

Different manifestations of coronary artery disease by stress SPECT myocardial perfusion imaging, coronary calcium scoring, and multislice CT coronary angiography in asymptomatic patients with type 2 diabetes mellitus.

BACKGROUND: We sought to assess prospectively the evidence for silent coronary artery disease (CAD) in asymptomatic patients with type 2 diabetes mellitus by stress single-photon emission computed tomography (SPECT) myocardial perfusion imaging, coronary artery calcium (CAC) scoring, and multislice computed tomographic (MSCT) coronary angiography. METHODS: One hundred asymptomatic patients (aged 30 to 72 years) with type 2 diabetes mellitus and one or more risk factors for CAD were prospectively recruited from an outpatient diabetes clinic. All patients underwent adenosine technetium-99m sestamibi SPECT imaging, CAC scoring, and 64-slice MSCT coronary angiography. RESULTS: Twenty-three patients (23%) had abnormal stress SPECT imaging, consistent with inducible myocardial ischemia, whereas 60 patients (60%) had positive CAC scoring (18 patients [18%] with significant CAC >401), and 70 patients (70%) had abnormal MSCT coronary angiography (24 patients [24%] with significant, >or=50% stenosis). Of 77 patients with normal SPECT, 44 had a positive CAC score (10 patients [13%] >401), and 54 showed CAD on MSCT angiography (16 patients [21%] with >or=50% stenosis). Of 23 patients with an abnormal SPECT, 16 patients had a positive CAC score (8 patients [35%] >401), and 16 patients had CAD on MSCT angiography (8 patients [35%] with >or=50% stenosis). Overall, 17 patients (17%) had more than 2 significantly abnormal diagnostic test results, and 5 patients had three tests with significantly abnormal results. CONCLUSIONS: In this cohort of asymptomatic patients with type 2 diabetes mellitus, different modalities visualized different aspects of silent coronary atherosclerosis. Anatomic evidence of coronary atherosclerosis (CAC and MSCT) occurred more frequently than functional evidence (stress SPECT). However, clinically significant manifestations of CAD were observed in about one-quarter to one-fifth of patients by each modality, either separately or combined. The relative prognostic value of each modality needs to be determined by a follow-up of this cohort.