Correlative dynamic contrast MRI and microscopic assessments of tumor vascularity in RIP‐tag2 transgenic mice

The purpose of this study was to define the feasibility of dynamic contrast‐enhanced magnetic resonance imaging (MRI) to estimate the vascular density and leakiness of spontaneous islet cell tumors in RIP‐Tag2 transgenic mice. Dynamic T₁‐weighted spoiled gradient echo (SPGR) imaging at 2.0 T was performed in 17 RIP‐Tag2 mice using a prototype blood pool macromolecular contrast medium (MMCM), albumin‐(Gd‐DTPA)₃₅. Kinetic analysis of the dynamic enhancement responses based on a two‐compartment model was used to estimate fractional plasma volume (fPV) and the coefficient of endothelial permeability (K^PS) for each tumor. The MRI estimate of fPV was correlated on a tumor‐by‐tumor basis with corresponding microscopic measurements of vascular density. The fPV assays by MMCM‐enhanced imaging ranged from 2.4%–14.1% of tissue volume. Individual tumor fPV values correlated significantly (r = 0.79, P < 0.001) with the corresponding microscopic estimates of vascularity consisting of the combined area densities of lectin‐perfused microvessels plus erythrocyte‐stained blood lakes. A biotinylated derivative of the albumin‐based MMCM confirmed extravasation of the contrast agent from some tumor blood vessels and accumulation in 25% of blood lakes. The K^PS values ranged from 0 (no detectable leak) to 0.356 mL/min/100 cm³. Dynamic MMCM‐enhanced MRI is feasible in RIP‐Tag2 pancreatic tumors, yielding estimates of vascular permeability and microscopically validated measurements of vascular richness. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Evaluation of right ventricular function with multidetector computed tomography: comparison with magnetic resonance imaging and analysis of inter- and intraobserver variability

This study was performed to prospectively compare multidetector computed tomography (MDCT) with 16 simultaneous sections and magnetic resonance imaging (MRI) for the assessment of global right ventricular function in 50 patients. MDCT using a semiautomatic analysis tool showed good correlation with MRI for end-diastolic volume (EDV, r = 0.83, p < 0.001), end-systolic volume (ESV, r = 0.86, p < 0.001) and stroke volume (SV, r = 0.74, p < 0.001), but only a moderate correlation for the ejection fraction (EF, r = 0.67, p < 0.001). Bland Altman analysis revealed a slight, but insignificant overestimation of EDV (4.0 ml, p = 0.08) and ESV (2.4 ml, p = 0.07), and underestimation of EF (0.1%, p = 0.92) with MDCT compared with MRI. All limits of agreement between both modalities (EF: ±15.7%, EDV: ±31.0 ml, ESV: ±18.0 ml) were in a moderate but acceptable range. Interobserver variability of MDCT was not significantly different from that of MRI. For MDCT software, the post-processing time was significantly longer (19.6 ± 5.8 min) than for MRI (11.8 ± 2.6 min, p < 0.001). Accurate assessment of right ventricular volumes by 16-detector CT is feasible but still rather time-consuming.     

Contrast-enhanced cardiac MRI before coronary artery bypass surgery: impact of myocardial scar extent on bypass flow

The aim of the study was to relate the extent of myocardial late gadolinium enhancement (LGE) in cardiac MRI to intraoperative graft flow in patients undergoing coronary artery bypass graft (CABG) surgery. Thirty-three CAD patients underwent LGE MRI before surgery using an inversion-recovery GRE sequence (turboFLASH). Intraoperative graft flow in Doppler ultrasonography was compared with the scar extent in each coronary vessel territory. One hundred and fourteen grafts were established supplying 86 of the 99 vessel territories. A significant negative correlation was found between scar extent and graft flow (r = −0.4, p < 0.0001). Flow in grafts to territories with no or small subendocardial scar was significantly higher than in grafts to territories with broad nontransmural or transmural scar (75 ± 39 vs. 38 ± 26 cc min⁻¹; p < 0.0001). In summary, the extent of myocardial scar as defined by contrast-enhanced MRI predicts coronary bypass graft flow. Beyond the probability of functional recovery, preoperative MRI might add value to surgery planning by predicting midterm bypass graft patency.     

99mTc-sestamibi kinetics predict myocardial viability in a perfused rat heart model

Introduction ^99mTc-sestamibi has been proposed as a viability imaging agent. The purposes of this study were: (1) to determine the relationship between myocardial viability and ^99mTc-sestamibi kinetics using perfused rat heart models across a full spectrum of viability, (2) to do so under conditions where myocardial flow was controlled and held constant, and (3) to do so using multiple quantitative methods to assess myocardial viability. Methods Twenty-three isolated rat hearts were perfused retrogradely with a modified Krebs-Henseleit (KH) solution. Four groups were studied: controls (C, n = 6), stunned (S, n = 6), ischemic-reperfused (IR, n = 6), and calcium injured (CAL, n = 5). Following a 20-min baseline and subsequent treatment phase, ^99mTc-sestamibi was infused over 60 min (uptake) followed by 60 min clearance. Treatment phases consisted of 20 min no flow for S, 60 min no flow followed by 60 min reflow for IR, and 10 min infusion of KH solution without calcium followed by 20 min infusion of KH solution with 2 times normal calcium for CAL hearts. Creatine kinase (CK) assay, triphenyltetrazolium chloride (TTC) staining, and transmission electron microscopic (TEM) analysis were used to determine tissue viability. Results Myocardial peak ^99mTc-sestamibi uptake (%id) was significantly decreased in IR (4.11 ± 0.22 SEM; p < 0.05) and CAL (1.07 ± 0.13; p < 0.05), but not in S (4.88 ± 0.17) as compared with C (5.99 ± 0.50). One hour fractional retention was 79.3 ± 1.9% for C, 80.3 ± 1.3% for S (p = n.s.), 79.1 ± 1.8% for IR (p = n.s.), and 14.9 ± 4.3% for CAL (p < 0.05 compared to all other groups). ^99mTc-sestamibi absolute retention (%id) 1 h after the end of tracer administration was significantly decreased in IR (3.26 ± 0.23) and CAL (0.15 ± 0.02) as compared with both S (3.92 ± 0.16) and C (4.52 ± 0.32) (p < 0.05). CK increased significantly from baseline in the IR and CAL hearts. TTC determined percent viability was 100 ± 0% for C, 98.3 ± 1.1% for S, 82.8 ± 2.6% for IR, and 0.0 ± 0% for CAL. TEM analysis supported these findings. End tracer activity was significantly correlated with TTC determined percentage viable myocardium (r = 0.93, p < 0.05) and CK leak (r = −0.90, p < 0.05). Conclusion ^99mTc-sestamibi myocardial activity is significantly reduced in areas of nonviability after 1 h of tracer uptake and 1 h of tracer clearance. There is a linear correlation between myocardial viability, as determined by three independent methods, and tracer activity. This work was supported by the American Heart Association, the Anne and Henry Zarrow Foundation, and the William K. Warren Medical Research Foundation.     

<Superscript>18</Superscript>F-FDG PET analysis of schwannoma: increase of SUVmax in the delayed scan is correlated with elevated VEGF/VPF expression in the tumors

Objective  In order to clarify the increased 2-deoxy-2-fluoro-¹⁸F-d-glucopyranose (¹⁸F-FDG) accumulation in schwannoma by positron emission tomography (PET) analysis, immunohistochemical analysis for the factors involved in glucose transportation and vascular formation was performed. Materials and methods  Twenty-six patients with schwannoma (13 men and 13 women) with ages ranging from 27 to 75 years, who received whole body ¹⁸F-FDG PET scan, were enrolled for the present study. The retention index (RI) was calculated by dividing the increase in the standardized uptake value (SUVmax) at the delayed scan by the SUVmax in the early scan. SUVmax and RI were compared with the histologic variables, including the expression of glucose transporters 1 and 3, hexokinase II, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), and microvascular density shown by CD31 immunohistochemistry. Results  Mean SUVmax values in the early and delayed scans were 2.64 ± 1.47 and 2.71 ± 1.57 (mean ± SD), respectively. RI was −2.5 ± 21 (percentage). SUVmax showed a positive correlation with the tumor size (tumor size <5 cm, 2.06 ± 0.72; >5 cm, 3.95 ± 1.89; p < 0.05) and the microvascular density (negative density, 2.16 ± 1.12; positive density, 3.56 ± 1.67; p < 0.05). RI correlated with VEGF/VPF expression in the tumors (negative expression, −11 ± 6.1; positive expression, 13 ± 8.1; p < 0.05). Other factors showed no correlation with SUVmax or RI. Conclusions  Microvascular density and vascular permeability of the tumor are suggested to affect the enhanced ¹⁸F-FDG accumulation in schwannoma.     

Permeability to macromolecular contrast media quantified by dynamic MRI correlates with tumor tissue assays of vascular endothelial growth factor (VEGF)

Purpose

To correlate dynamic MRI assays of macromolecular endothelial permeability with microscopic area–density measurements of vascular endothelial growth factor (VEGF) in tumors.

Methods and material

This study compared tumor xenografts from two different human cancer cell lines, MDA-MB-231 tumors (n = 5), and MDA-MB-435 (n = 8), reported to express respectively higher and lower levels of VEGF. Dynamic MRI was enhanced by a prototype macromolecular contrast medium (MMCM), albumin-(Gd-DTPA)35. Quantitative estimates of tumor microvascular permeability (K^PS; μl/min × 100 cm³), obtained using a two-compartment kinetic model, were correlated with immunohistochemical measurements of VEGF in each tumor.

Results

Mean K^PS was 2.4 times greater in MDA-MB-231 tumors (K^PS = 58 ± 30.9 μl/min × 100 cm³) than in MDA-MB-435 tumors (K^PS = 24 ± 8.4 μl/min × 100 cm³) (p < 0.05). Correspondingly, the area–density of VEGF in MDA-MB-231 tumors was 2.6 times greater (27.3 ± 2.2%, p < 0.05) than in MDA-MB-435 cancers (10.5 ± 0.5%, p < 0.05). Considering all tumors without regard to cell type, a significant positive correlation (r = 0.67, p < 0.05) was observed between MRI-estimated endothelial permeability and VEGF immunoreactivity.

Conclusion

Correlation of MRI assays of endothelial permeability to a MMCM and VEGF immunoreactivity of tumors support the hypothesis that VEGF is a major contributor to increased macromolecular permeability in cancers. When applied clinically, the MMCM-enhanced MRI approach could help to optimize the appropriate application of VEGF-inhibiting therapy on an individual patient basis.     

Glucosamine sulfate effect on the degenerated patellar cartilage: preliminary findings by pharmacokinetic magnetic resonance modeling

Normal and degenerated cartilages have different magnetic resonance (MR) capillary permeability (K^trans) and interstitial interchangeable volume (v_e). Our hypothesis was that glucosamine sulfate treatment modifies these neovascularity abnormalities in osteoarthritis. Sixteen patients with patella degeneration, randomly distributed into glucosamine or control groups, underwent two 1.5-Tesla dynamic contrast-enhanced MR imaging studies (treatment initiation and after 6 months). The pain visual analog scale (VAS) and American Knee Society (AKS) score were used. A two-compartment pharmacokinetic model was used. Percentages of variations (postreatment-pretreatment/pretreatment) were compared (t-test for independent data). In the glucosamine group, pain and functional outcomes statistically improved (VAS: 7.3 ± 1.1 to 3.6 ± 1.3, p < 0.001; AKS: 18.6 ± 6.9 to 42.9 ± 2.7, p < 0.01). Glucosamine significantly increased K^trans at 6 months (−54.4 ± 21.2% vs 126.7 ± 56.9%, p < 0.001, control vs glucosamine). In conclusion, glucosamine sulfate decreases pain while improving functional outcome in patients with cartilage degeneration. Glucosamine sulfate increases K^trans, allowing its proposal as a surrogate imaging biomarker after 6 months of treatment.     

Comparison of MRI (including SS SE-EPI and SPIO-enhanced MRI) and FDG-PET/CT for the detection of colorectal liver metastases

Fluoro-18-deoxyglucose positron emission tomography computed tomography (FDG-PET/CT) and magnetic resonance imaging (MRI), including unenhanced single-shot spin-echo echo planar imaging (SS SE-EPI) and small paramagnetic iron oxide (SPIO) enhancement, were compared prospectively for detecting colorectal liver metastases. Twenty-four consecutive patients suspected for metastases underwent MRI and FDG-PET/CT. Fourteen patients (58%) had previously received chemotherapy, including seven patients whose chemotherapy was still continuing to within 1 month of the PET/CT study. The mean interval between PET/CT and MRI was 10.2 ± 5.2 days. Histopathology (n = 18) or follow-up imaging (n = 6) were used as reference. Seventy-seven metastases were detected. In nine patients, MRI and PET/CT gave concordant results. Sensitivities for unenhanced SS SE-EPI, MRI without SS SE-EPI and FDG-PET/CT were, respectively, 100% (p = 9 × 10⁻¹⁰ vs PET, p = 8 × 10⁻³ vs MRI without SS SE-EPI), 90% (p = 2 × 10⁻⁷ vs PET) and 60%. PET/CT sensitivity dropped significantly with decreasing size, from 100% in lesions larger than 20 mm (identical to MRI), over 54% in lesions between 10 and 20 mm (p = 3 × 10⁵ versus unenhanced SS SE-EPI), to 32% in lesions under 10 mm (p = 6 × 10⁻⁵ versus unenhanced SS SE-EPI). Positive predictive value of PET was 100% (identical to MRI). MRI, particularly unenhanced SS SE-EPI, has good sensitivity and positive predictive value for detecting liver metastases from colorectal carcinoma. Its sensitivity is better than that of FDG-PET/CT, especially for small lesions.     

Comprehensive assessment of the severity and mechanism of aortic regurgitation using multidetector CT and MR

Recent studies have suggested that both cardiac magnetic resonance (MR) and multidetector computed tomography (MDCT) can quantify aortic regurgitation (AR) by planimetry of the anatomical regurgitant orifice (ARO). However, this measurement was not compared with quantitative assessment of AR such as the effective regurgitant orifice (ERO) by proximal isosurface area (PISA) transthoracic echocardiography (TTE) or phase contrast MR. In 42 patients (34 men, age 54 ± 11 years) we compared planimetered ARO by MDCT and MR with ERO and regurgitant volume by PISA TTE and phase contrast MR. ARO by MDCT (r = 0.87, p < 0.001) and MR (r = 0.81, p < 0.001) correlated highly with ERO by TTE. However, ARO by MDCT (27 ± 15 mm², p < 0.001), but not by MR (23 ± 13 mm², p = 0.58), were larger than PISA ERO (22 ± 11 mm²). ARO by MDCT (r = 0.78, p < 0.001; r = 0.85, p < 0.001) and MR (r = 0.85, p < 0.001; r = 0.87 p < 0.001) correlated well with regurgitant volume by PISA and phase contrast MR. Both MDCT (к = 0.80, p < 0.001) and MR (к = 0.84, p < 0.001) demonstrated excellent agreement in correctly assessing the mechanisms of AR, i.e. aortic root dilatation (type I), cusp prolapse (type II) and restrictive cusp motion (type III), using surgical inspection as a reference. Measurement of ARO by both MDCT and MR allows accurate quantitative assessment of AR. Both techniques can also accurately determine the mechanism of AR.     

Assessment of coronary flow reserve by sestamibi imaging in patients with typical chest pain and normal coronary arteries

Purpose We assessed coronary flow reserve (CFR) by sestamibi imaging in patients with typical chest pain, positive exercise stress test and normal coronary vessels. Methods Thirty-five patients with typical chest pain and normal angiogram and 12 control subjects with atypical chest pain underwent dipyridamole/rest ^99mTc-sestamibi imaging. Myocardial blood flow (MBF) was estimated by measuring first transit counts in the pulmonary artery and myocardial counts from SPECT images. Estimated CFR was expressed as the ratio of stress to rest MBF. Rest MBF and CFR were corrected for rate–pressure product (RPP) and expressed as normalised MBF (MBF_n) and normalised CFR (CFR_n). Coronary vascular resistances (CVR) were calculated as the ratio between mean arterial pressure and estimated MBF. Results At rest, estimated MBF and MBF_n were lower in controls than in patients (0.98 ± 0.4 vs 1.30 ± 0.3 counts/pixel/s and 1.14 ± 0.5 vs 1.64 ± 0.6 counts/pixel/s, respectively, both p < 0.02). Stress MBF was not different between controls and patients (2.34 ± 0.8 vs 2.01 ± 0.7 counts/pixel/s, p=NS). Estimated CFR was 2.40 ± 0.3 in controls and 1.54 ± 0.3 in patients (p < 0.0001). After correction for the RPP, CFR_n was still higher in controls than in patients (2.1 ± 0.5 vs 1.29 ± 0.5, p < 0.0001). At baseline, CVR values were lower (p < 0.01) in patients than in controls. Dipyridamole-induced changes in CVR were greater (p < 0.0001) in controls (−63%) than in patients (−35%). In the overall study population, a significant correlation between dipyridamole-induced changes in CVR and CFR was observed (r = −0.88, p < 0.0001). Conclusion SPECT might represent a useful non-invasive method for assessing coronary vascular function in patients with angina and a normal coronary angiogram.     

Myocardial pre-synaptic sympathetic function correlates with glucose uptake in the failing human heart

Purpose We have previously shown that the myocardium of patients with heart failure (HF) is insulin resistant. Chronic β-adrenergic stimulation has been implicated in insulin resistance in cultured cardiomyocytes in vitro, where sustained noradrenaline stimulation inhibited insulin-modulated glucose uptake. As the failing heart is characterized by increased sympathetic drive, we hypothesized that there is a correlation between pre-synaptic sympathetic function and insulin sensitivity in the myocardium of patients with HF. Methods Eight patients (aged 67 ± 7 years) with coronary artery disease and left ventricular dysfunction (ejection fraction 44 ± 10%) underwent function and viability assessment with cardiovascular magnetic resonance. Myocardial glucose utilization (MGU) was measured using positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (FDG). Pre-synaptic noradrenaline re-uptake was measured by calculating [¹¹C]meta-hydroxy-ephedrine (HED) volume of distribution (V _d) with PET. Two groups of healthy volunteers served as controls for the FDG (n = 8, aged 52 ± 4 years, p < 0.01 vs patients) and HED (n = 8, aged 40 ± 6 years, p < 0.01 vs patients) data. Results MGU in patients was reduced in both normal remote (0.44 ± 0.14 μmol·min⁻¹·g⁻¹) and dysfunctional (0.49 ± 0.14 μmol·min⁻¹·g⁻¹) segments compared with controls (0.61 ± 0.7 μmol·min⁻¹·g⁻¹; p < 0.001 vs both). HED V _d was reduced in dysfunctional segments of patients (38.9 ± 21.2 ml·g⁻¹) compared with normal segments (52.2 ± 19.6 ml·g⁻¹) and compared with controls (62.7 ± 11.3 ml·g⁻¹). In patients, regional MGU was correlated with HED V _d. Conclusion The results of this study provide novel evidence of a correlation between cardiac sympathetic function and insulin sensitivity, which may represent one of the mechanisms contributing to insulin resistance in failing human hearts.     

High-resolution myocardial perfusion imaging at 3 T: comparison to 1.5 T in healthy volunteers

The purpose of this study was to evaluate high-resolution (HR) myocardial first-pass perfusion in healthy volunteers at 3 T compared to a typical clinical imaging protocol at 1.5 T, with respect to overall image quality and the presence of subendocardial dark rim artifacts. Myocardial first-pass rest perfusion studies were performed at both field strengths using a T1-weighted saturation-recovery segmented k-space gradient-echo sequence combined with parallel imaging (Gd-DTPA 0.05 mmol/kg). Twenty-six healthy volunteers underwent (1) a HR perfusion scan at 3 T(pixel size 3.78 mm²) and (2) a standard perfusion approach at 1.5 T(pixel size 9.86 mm²). The contrast enhancement ratio (CER) and overall image quality (4-point grading scale: 4: excellent; 1: non-diagnostic) were assessed, and a semiquantitative analysis of dark rim artifacts was performed for all studies. CER was slightly higher (1.31 ± 0.32 vs. 1.14 ± 0.34; p<0.01), overall image quality was significantly improved (3.03 ± 0.43 vs. 2.37 ± 0.39; p<0.01), and the number of dark rim artifacts (139 ± 2.09 vs. 243 ± 2.33; p<0.01) was significantly reduced for HR perfusion imaging at 3 T compared to the standard approach at 1.5 T. HR myocardial rest perfusion at 3 T is superior to the typical clinical perfusion protocol performed at 1.5 T with respect to the overall image quality and presence of subendocardial dark rim artifacts.     

Gastrointestinal 18F-FDG accumulation on PET without a corresponding CT abnormality is not an early indicator of cancer development

Focal gastrointestinal 2-deoxy-2-[¹⁸F]-fluoro-D-glucose (FDG) uptake can frequently be found on FDG-PET/CT even in patients without known gastrointestinal malignancy. The aim of this study was to evaluate whether increased gastrointestinal FDG uptake without CT correlate is an early indicator of patients developing gastrointestinal malignancies. A total of 1,006 patients without esophagogastric or anorectal malignancies underwent FDG-PET/CT. The esophagogastric junction, the stomach and the anorectum were evaluated for increased FDG uptake. Patients without elevated uptake were assigned to group A, patients with elevated uptake were allocated to group B. The SUVmax values of both groups were tested for significant differences using the U test. A follow-up of longer than 1 year (mean 853 ± 414 days) served as gold standard. A total of 460 patients had to be excluded based on insufficient follow-up data. For the remaining 546 patients the mean SUVmax was as follows: (a) esophagogastric junction, group A 3.1 ± 0.66, group B 4.0 ± 1.11, p < 0.01; (b) stomach, group A 2.8 ± 0.77, group B 4.1 ± 1.33, p < 0.01; (c) rectal ampulla, group A 2.8 ± 0.83, group B 3.9 ± 1.49, p < 0.01; (d) anal canal, group A 2.7 ± 0.55, group B 3.9 ± 1.59, p < 0.01. Only one patient developed gastric cancer. In the case of an unremarkable CT, elevated esophagogastric or anorectal FDG uptake does not predict cancer development and does not have to be investigated further.     

Optimization of b value in diffusion-weighted MRI for the differential diagnosis of benign and malignant vertebral fractures

Objective The objective was to explore the optimal b value in diffusion-weighted imaging (DWI) of MRI for differential diagnosis of benign and malignant vertebral fractures. Materials and Methods Thirty-four consecutive patients with vertebral compression fractures underwent sagittal diffusion-weighted imaging (DWI) with different b values. The group included 14 patients with 18 benign vertebral fractures due to osteoporosis and/or trauma and 20 patients with 27 malignant vertebral fractures due to malignancy. The quality of the images was analyzed qualitatively on a three-point scale and quantitatively by measurement of the signal-to-noise ratio (SNR). Apparent diffusion coefficient (ADC) values were also calculated. Results Smaller b values correlated with better DW image quality. We found significant differences in the qualitative points values among the DW images with different b values (F = 302.18, p < 0.001). The mean SNR of the images ranged from 21.75 ± 3.64 at a b value of 0 s/mm² to 5.31 ± 3.17 at a b value of 800 s/mm². The SNR of DWI with a b value of 300 s/mm² (18.62 ± 2.47) was significantly different from that with other b values (p < 0.01). The mean combined ADC values of malignant fractures were significantly lower than those of benign ones on DWI with a b value of 300 s/mm² (t = 9.097, p < 0.01). Four cases of benign vertebral fractures were misdiagnosed as being malignant when b values of 0 s/mm² and 100 s/mm² were used. Conclusions When DWI with multiple b values is used to differentiate benign from malignant vertebral compression fractures, b values within the range of around 300 s/mm² are recommended, taking into account both SNR and diffusion weighting of water molecules.     

Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi

Purpose The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with ^99mTc-sestamibi. Methods Doxorubicin-sensitive (143B-luc⁺) and resistant (MNNG/HOS-luc⁺) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a ^99mTc-sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of ^99mTc-sestamibi washout half-life (t _1/2), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio. Results A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t _1/2 of ^99mTc-sestamibi was significantly shorter (p < 0.05) in drug-resistant MNNG/HOS-luc⁺ tumours (t _1/2 = 87.3 ± 15.7 min) than in drug-sensitive 143B-luc⁺ tumours (t _1/2 = 161.0 ± 47.4 min) and decreased significantly with PSC833 (t _1/2 = 173.0 ± 24.5 min, p < 0.05). No significant effects of PSC833 were observed in 143B-luc⁺ tumours. The T/NT ratio was significantly lower (p < 0.05) in MNNG/HOS-luc⁺ tumours than in 143B-luc⁺ tumours at early (1.55 ± 0.22 vs 2.14 ± 0.36) and delayed times (1.12 ± 0.11 vs 1.62 ± 0.33). PSC833 had no significant effects on the T/NT ratios of either tumour. Conclusion The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of ^99mTc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma.     

Infarct size in primary angioplasty without on-site cardiac surgical backup versus transferal to a tertiary center: a single photon emission computed tomography study

Background  Primary percutaneous coronary intervention (PCI) performed in large community hospitals without cardiac surgery back-up facilities (off-site) reduces door-to-balloon time compared with emergency transferal to tertiary interventional centers (on-site). The present study was performed to explore whether off-site PCI for acute myocardial infarction results in reduced infarct size. Methods and results  One hundred twenty-eight patients with acute ST-segment elevation myocardial infarction were randomly assigned to undergo primary PCI at the off-site center (n = 68) or to transferal to an on-site center (n = 60). Three days after PCI, ^99mTc-sestamibi SPECT was performed to estimate infarct size. Off-site PCI significantly reduced door-to-balloon time compared with on-site PCI (94 ± 54 versus 125 ± 59 min, respectively, p < 0.01), although symptoms-to-treatment time was only insignificantly reduced (257 ± 211 versus 286 ± 146 min, respectively, p = 0.39). Infarct size was comparable between treatment centers (16 ± 15 versus 14 ± 12%, respectively p = 0.35). Multivariate analysis revealed that TIMI 0/1 flow grade at initial coronary angiography (OR 3.125, 95% CI 1.17–8.33, p = 0.023), anterior wall localization of the myocardial infarction (OR 3.44, 95% CI 1.38–8.55, p < 0.01), and development of pathological Q-waves (OR 5.07, 95% CI 2.10–12.25, p < 0.01) were independent predictors of an infarct size > 12%. Conclusions  Off-site PCI reduces door-to-balloon time compared with transferal to a remote on-site interventional center but does not reduce infarct size. Instead, pre-PCI TIMI 0/1 flow, anterior wall infarct localization, and development of Q-waves are more important predictors of infarct size.     

Magnetic resonance imaging assays for dimethyl sulfoxide effect on cancer vasculature

OBJECTIVES: To evaluate the potential of quantitative assays of vascular characteristics based on dynamic contrast-enhanced magnetic resonance imaging (MRI) using a macromolecular contrast medium (MMCM) to search for and measure effects of dimethyl sulfoxide (DMSO) on cancer vasculature with microscopic correlations. MATERIAL AND METHODS: Saline-treated control (n = 8) and DMSO-treated (n = 7) human breast cancer xenografts (MDA-MB-435) in rats were imaged dynamically by MMCM-enhanced MRI using albumin-(Gd-DTPA)27-(biotin)11 (molecular weight approximately 90 kDa), before and after a 1-week, 3-dose treatment course. After the posttreatment MRI examinations, tumors were perfused with lectin and fixative and subsequently stained with RECA-1 and streptavidin for quantitative fluorescent microscopy. Quantitative MRI estimates of cancer microvessel permeability (KPS; microL/min.100 cm3) and fractional plasma volume (fPV; %) were based on a 2-compartment kinetic model. Fluorescent microscopy yielded estimates of MMCM extravasation and vascular density that were compared to the MRI results. RESULTS: DMSO decreased cancer vascular endothelial permeability significantly (P < 0.05) from tumor KPSday0 = 19.3 +/- 8.8 microL/min.100 cm3 to KPSday7 = 0 microL/min.100 cm3). K values in the saline-treated tumors did not change significantly. The amount of extravasated albumin-Gd-(DTPA)27-(biotin)11, as assayed by a fluorescently labeled streptavidin stain that strongly binds to the biotin tag on the MMCM, was significantly (P < 0.05) lower in the DMSO-treated cancers than in the control cancers (57.7% +/- 5.5% vs. 34.2% +/- 4.9%). Tumor vascular richness as reflected by the MRI-assayed fPV and by the RECA-1 and lectin-stained microscopy did not change significantly with DMSO or saline treatment. CONCLUSION: Reductions in cancer microvascular leakiness induced by a 7-day course of DMSO could be detected and measured by dynamic MMCM-enhanced MRI and were confirmed by microscopic measurements of the leaked macromolecular agents in the same cancers. Results support the robustness of an MMCM-enhanced MRI approach to the characterization of cancers and providing first evidence for an in vivo effect of DMSO on cancer blood vessels.     

Diffusion-weighted imaging and proton MR spectroscopy in the characterization of acute disseminated encephalomyelitis

Introduction Acute disseminated encephalomyelitis (ADEM) is usually a monophasic illness characterized by multiple lesions involving gray and white matter. Quantitative MR techniques were used to characterize and stage these lesions. Methods Eight patients (seven males and one female; mean age 19 years, range 5 to 36 years) were studied using conventional MRI (T2- and T1-weighted and FLAIR sequences), diffusion-weighted imaging (DWI) and proton magnetic resonance spectroscopy (MRS). Apparent diffusion coefficient (ADC) values and MRS ratios were calculated for the lesion and for normal-appearing white matter (NAWM). Three patients were imaged in the acute stage (within 7 days of the onset of neurological symptoms) and five in the subacute stage (after 7 days from the onset of symptoms). Results ADC values in NAWM were in the range 0.7–1.24×10⁻³ mm/s² (mean 0.937 ± 0.17 mm/s²). ADC values of ADEM lesions in the acute stage were in the range 0.37–0.68×10⁻³ mm/s² (mean 0.56 ± 0.16 mm/s²) and 1.01–1.31×10⁻³ mm/s² (mean 1.24 ± 0.13 mm/s²) in the subacute stage. MRS ratios were obtained for all patients. NAA/Cho ratios were in the range 1.1–3.5 (mean 1.93 ± 0.86) in the NAWM. NAA/Cho ratios within ADEM lesions in the acute stage were in the range 0.63–1.48 (mean 1.18 ± 0.48) and 0.29–0.84 (mean 0.49 ± 0.22) in the subacute stage. The ADC values, NAA/Cho and Cho/Cr ratios were significantly different between lesions in the acute and subacute stages (P < 0.001, P < 0.027, P < 0.047, respectively). ADC values were significantly different between lesions in the acute (P < 0.009) and subacute stages (P < 0.005) with NAWM. In addition, NAA/Cho and Cho/Cr ratios were significantly different between lesions in the subacute stage and NAWM (P < 0.006, P < 0.007, respectively). Conclusion ADEM lesions were characterized in the acute stage by restricted diffusion and in the subacute stage by free diffusion and a decrease in NAA/Cho ratios. Restricted diffusion and progressive decrease in NAA/Cho ratios may help in staging the disease.     

Indium-111 oxine labelling affects the cellular integrity of haematopoietic progenitor cells

Purpose Cell-based therapy by transplantation of progenitor cells has emerged as a promising development for organ repair, but non-invasive imaging approaches are required to monitor the fate of transplanted cells. Radioactive labelling with ¹¹¹In-oxine has been used in preclinical trials. This study aimed to validate ¹¹¹In-oxine labelling and subsequent in vivo and ex vivo detection of haematopoietic progenitor cells. Methods Murine haematopoietic progenitor cells (10⁶, FDCPmix) were labelled with 0.1 MBq (low dose) or 1.0 MBq (high dose) ¹¹¹In-oxine and compared with unlabelled controls. Cellular retention of ¹¹¹In, viability and proliferation were determined up to 48 h after labelling. Labelled cells were injected into the cavity of the left or right cardiac ventricle in mice. Scintigraphic images were acquired 24 h later. Organ samples were harvested to determine the tissue-specific activity. Results Labelling efficiency was 75 ± 14%. Cellular retention of incorporated ¹¹¹In after 48 h was 18 ± 4%. Percentage viability after 48 h was 90 ± 1% (control), 58 ± 7% (low dose) and 48 ± 8% (high dose) (p<0.0001). Numbers of viable cells after 48 h (normalised to 0 h) were 249 ± 51% (control), 42 ± 8% (low dose) and 32 ± 5% (high dose) (p<0.0001). Cells accumulated in the spleen (86.6 ± 27.0% ID/g), bone marrow (59.1 ± 16.1% ID/g) and liver (30.3 ± 9.5% ID/g) after left ventricular injection, whereas most of the cells were detected in the lungs (42.4 ± 21.8% ID/g) after right ventricular injection. Conclusion Radiolabelling of haematopoietic progenitor cells with ¹¹¹In-oxine is feasible, with high labelling efficiency but restricted stability. The integrity of labelled cells is significantly affected, with substantially reduced viability and proliferation and limited migration after systemic transfusion.     

Abdominal visceral fat accumulation is associated with the results of <Superscript>123</Superscript>I-metaiodobenzylguanidine myocardial scintigraphy in type 2 diabetic patients

Purpose We tested the hypothesis that increased abdominal visceral accumulation (VFA) is associated with insulin resistance and cardiovascular autonomic dysfunction in type 2 diabetic patients not receiving insulin treatment. Methods The fat distribution was evaluated by measuring the VFA by abdominal computed tomography at the umbilical level. The study group consisted of 24 type 2 diabetic patients with high VFA (≥100 cm², age 60 ± 8 years, high VFA group). The control group consisted of 19 age-matched type 2 diabetic patients with normal VFA (<100 cm², age 60 ± 7 years, normal VFA group). Cardiovascular autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations, and cardiac ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy. Results Early and delayed ¹²³I-MIBG myocardial uptake values were lower (p < 0.005 and p < 0.0001, respectively) and the percent washout rate of ¹²³I-MIBG was higher (p < 0.0005) in the high VFA group than in the normal VFA group. The fasting plasma insulin concentrations (p < 0.005) and the homeostasis model assessment (HOMA) index values (p < 0.0005) were higher in the high VFA group than in normal VFA group. Multiple regression analysis revealed that the level of VFA was independently predicted by the HOMA index values and the myocardial uptake of ¹²³I-MIBG during the delayed phase. Conclusion Our results demonstrate that the level of VFA is associated with depressed cardiovascular autonomic function and insulin resistance in patients with type 2 diabetes mellitus.