Shwu-Yuan Wei

Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil

BACKGROUND & AIMS Sorafenib plus metronomic tegafur/uracil therapy can induce tumor stabilization in advanced hepatocellular carcinoma (HCC) patients. This study evaluated the correlation of vascular response measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and the clinical outcome. METHODS DCE-MRI was performed in advanced HCC patients treated with sorafenib (800 mg/d) plus tegafur/uracil (250 mg/m(2)/d based on tegafur) at baseline and after 14 days of treatment. An operator-defined region of interest was placed in the most strongly enhanced area of the tumor to measure the pharmacokinetic parameter K(trans). Changes in K(trans) after treatment were correlated with the best tumor response and survival. RESULTS Thirty-one patients were evaluable. There were one partial response (PR), 18 stable disease (SD), and 12 progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Baseline K(trans) was higher in patients with PR or SD (median 1215.2 × 10(-3)/min, range 582.5-4555.3 × 10(-3)/min) than patients with PD (median 702.0 × 10(-3)/min, range 375.2-1938.0 × 10(-3)/min, p = 0.008). After 14 days of study treatment, the median K(trans) change was -47.1% (range -87.0 to -18.0%) in patients with PR or SD, and 9.6% (range -44.8 to +81%) in those with PD (p<0.001). A vascular response, defined by a 40% or greater decrease in K(trans) after 14 days of study treatment, correlated with longer progression-free survival (median 29.1 vs. 8.7 weeks, p = 0.033) and overall survival (median 53.0 vs. 14.9 weeks, p = 0.016). Percentage of K(trans) change after treatment is an independent predictor of tumor response, progression-free survival, and overall survival. CONCLUSIONS K(trans) measured by DCE-MRI correlated well with tumor response and survival in HCC patients who received sorafenib plus metronomic tegafur/uracil therapy.

Dynamic contrast-enhanced magnetic resonance imaging with Gd-EOB-DTPA for the evaluation of liver fibrosis in chronic hepatitis patients

AbstractObjectivesTo develop a non-invasive MRI method for evaluation of liver fibrosis, with histological analysis as the reference standard.MethodsThe study protocol was approved by the Institutional Review Board for Human Studies of our hospital, and written informed consent was obtained from all subjects. Seventy-nine subjects who received dynamic contrast-enhanced MRI (DCE-MRI) with Gd-EOB-DTPA were divided into three subgroups according to Metavir score: no fibrosis (n = 30), mild fibrosis (n = 34), and advanced fibrosis (n = 15). The DCE-MRI parameters were measured using two models: (1) dual-input single-compartment model for arterial blood flow (Fa), portal venous blood flow, total liver blood flow, arterial fraction (ART), distribution volume, and mean transit time; and (2) curve analysis model for Peak, Slope, and AUC. Statistical analysis was performed with Student’s t-test and the nonparametric Kruskal-Wallis test.ResultsSlope and AUC were two best perfusion parameters to predict the severity of liver fibrosis (>F2 vs. ≦F2). Four significantly different variables were found between non-fibrotic versus mild-fibrotic subgroups: Fa, ART, Slope, and AUC; the best predictor for mild fibrosis was Fa (AUROC:0.701).ConclusionsDCE-MRI with Gd-EOB-DTPA is a noninvasive imaging, by which multiple perfusion parameters can be measured to evaluate the severity of liver fibrosis. Key Points • Dynamic Gd-EOB-DTPA contrast-enhanced-MRI can help evaluate the severity of liver fibrosis.• Slope and AUC were two best perfusion parameters to predict severity.• Absolute arterial blood flow was the best predictor for mild fibrosis.

Bone marrow angiogenesis magnetic resonance imaging in patients with acute myeloid leukemia: peak enhancement ratio is an independent predictor for overall survival.

Emerging evidence suggests that progression of hematologic malignancies is associated with angiogenesis. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide global and functional imaging of tumor angiogenesis. In this study, we performed bone marrow DCE-MRI prospectively at diagnosis and after induction chemotherapy in 78 de novo acute myeloid leukemia (AML) patients and correlated it with treatment outcome. An algorithm to assess bone marrow angiogenesis by measuring the DCE-MRI time-intensity curve pixel by pixel was developed using 3 distinct parameters: peak enhancement ratio (Peak) to indicate tissue blood perfusion; amplitude (Amp) to reflect vascularity; and volume transfer constant (K trans) to indicate vascular permeability. The Peak and Amp decreased significantly at remission status after induction chemotherapy. Patients with higher Peak or Amp at diagnosis had shorter overall survival and disease-free survival than others. Cox multivariate analysis identified higher Peak value (hazard ratio, 9.181; 95% confidence interval, 1.740-48.437; P = .009) as an independent predictor for overall survival in addition to unfavorable karyotype and old age. Our findings provide evidence that increased bone marrow angiogenesis measured by DCE-MRI can predict adverse clinical outcome in AML patients. DCE-MRI may help to select high-risk phenotype AML patients for tailored antiangiogenic therapy and to monitor treatment response.

Correlation of bone marrow lipid water content with bone mineral density on the lumbar spine.

Study Design. Prospective study. Objectives. To assess the proton MR spectroscopy (1H MRS) of vertebral bone marrow and correlate the lipid water ratio (LWR) and spectral line width (LW) with bone mineral density (BMD) in female subjects. Summary of Background Data. The mechanism of bone marrow fat accumulation and bone mineral content is poorly understood. Proton MR spectroscopy was used to demonstrate the lipid and water spectra in the bone marrow. We try to assess the possible interaction between the bone marrow lipid content, aging, and BMD. Methods. Proton MRS and BMD of the lumbar spine were performed in 52 female subjects (mean age, 58 years; SD, 10 years). They were 13 premenopausal and 39 postmenopausal women. The BMD (g/cm2) was measured using dual energy radiograph absorptiometry at the lumbar spine. Single voxel 1H MRS was measured at L3 vertebral body by stimulated echo-acquisition mode (STEAM) sequence and demonstrated two major peaks (lipid and water). Comparisons of the differences between the two subgroups were made. Pearson’s correlation was also calculated to explore the association of 1H MRS measurements with age and BMD. Partial correlation was further conducted when controlling the variable such as age or BMD. Results. BMD and LWR had statistically significant difference between the pre- and postmenopausal subgroups (P < 0.001), while lipid LW had a borderline difference and water LW had no difference. LWR was positively correlated with age (r = 0.52 and P < 0.0001) and negatively correlated with BMD (r = −0.40 and P = 0.003) for all the subjects. Lipid LW was negatively correlated with age (r = −0.32 and P = 0.0197) and positively correlated with BMD (r = 0.67 and P < 0.0001). When controlling for BMD effect, only LWR is statistically correlated with age (partial r = 0.39, P = 0.0045), while only the lipid LW is statistically correlated with BMD when controlling for age (partial r = 0.63, P < 0.0001). None of the correlations between water LW and age or BMD was significant. In the subgroups, only the lipid LW is significantly correlated with BMD (r = 0.78, P = 0.0016 in premenopausal women; r = 0.62, P < 0.0001 in postmenopausal women). Conclusion. The LWR had a positive correlation with the age, while the lipid LW had a positive correlation with BMD, even after controlling the age factor. The bone marrow lipid water content and metabolism acted as important roles in the internal environment of bone and influenced bone mineralization.

Dynamic Contrast-enhanced MR Imaging Measurement of Vertebral Bone Marrow Perfusion May Be Indicator of Outcome of Acute Myeloid Leukemia Patients in Remission

PURPOSE To examine whether dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging measurement of bone marrow perfusion in acute myeloid leukemia (AML) patients in complete remission (CR) is associated with outcome and survival. MATERIALS AND METHODS After institutional review board approval and informed consent were obtained, from September 2004 to October 2007, 51 patients (29 women, 22 men; mean age, 43.5 years; range, 17-66 years) agreed to undergo DCE MR imaging to assess bone marrow perfusion, among 96 patients with newly diagnosed de novo AML who had received induction chemotherapy and achieved CR. Two semiquantitative parameters (peak and slope) and another three quantitative parameters (amplitude, K(ep) [efflux rate constant], and K(el) [elimination rate constant]) were calculated. Overall survival (OS) and relapse-free survival (RFS) were assessed with the Kaplan-Meier model, while differences between patient groups with high and low DCE MR imaging parameter values were assessed by using the two-sided log-rank test. RESULTS The median follow-up was 25.9 months. Univariate analysis results showed that high values of peak (≥0.42), slope (≥0.0235), amplitude (≥0.03), and K(ep) (≥0.0082) were associated with shorter OS (P = .004, 0.01, 0.034, and 0.026, respectively). Besides, a high value of K(ep) was also associated with shorter RFS (P = .008). When age, sex, and initial karyotype at diagnosis were included in multivariate Cox proportional hazards analysis, the results showed that only K(ep), but not other DCE MR imaging parameters, was an independent factor for OS (relative risk [RR], 30.305; P = .021) and RFS (RR, 6.477; P = .009). CONCLUSION Bone marrow perfusion measured with DCE MR imaging in AML patients in CR can be an indicator of outcome and survival. K(ep) measured with kinetic modeling was useful and significantly associated with RFS, while heuristic parameters (peak and slope) were not.

Doxorubicin-modified magnetic nanoparticles as a drug delivery system for magnetic resonance imaging-monitoring magnet-enhancing tumor chemotherapy

In this study, we developed functionalized superparamagnetic iron oxide (SPIO) nanoparticles consisting of a magnetic Fe3O4 core and a shell of aqueous stable polyethylene glycol (PEG) conjugated with doxorubicin (Dox) (SPIO-PEG-D) for tumor magnetic resonance imaging (MRI) enhancement and chemotherapy. The size of SPIO nanoparticles was ~10 nm, which was visualized by transmission electron microscope. The hysteresis curve, generated with vibrating-sample magnetometer, showed that SPIO-PEG-D was superparamagnetic with an insignificant hysteresis. The transverse relaxivity (r2) for SPIO-PEG-D was significantly higher than the longitudinal relaxivity (r1) (r2/r1 >10). The half-life of Dox in blood circulation was prolonged by conjugating Dox on the surface of SPIO with PEG to reduce its degradation. The in vitro experiment showed that SPIO-PEG-D could cause DNA crosslink more serious, resulting in a lower DNA expression and a higher cell apoptosis for HT-29 cancer cells. The Prussian blue staining study showed that the tumors treated with SPIO-PEG-D under a magnetic field had a much higher intratumoral iron density than the tumors treated with SPIO-PEG-D alone. The in vivo MRI study showed that the T2-weighted signal enhancement was stronger for the group under a magnetic field, indicating that it had a better accumulation of SPIO-PEG-D in tumor tissues. In the anticancer efficiency study for SPIO-PEG-D, the results showed that there was a significantly smaller tumor size for the group with a magnetic field than the group without. The in vivo experiments also showed that this drug delivery system combined with a local magnetic field could reduce the side effects of cardiotoxicity and hepatotoxicity. The results showed that the developed SPIO-PEG-D nanoparticles own a great potential for MRI-monitoring magnet-enhancing tumor chemotherapy.

Standardized uptake value and apparent diffusion coefficient of endometrial cancer evaluated with integrated whole-body PET/MR: Correlation with pathological prognostic factors

To evaluate the correlation between maximum standardized uptake value (SUVmax) and minimum apparent diffusion coefficient (ADCmin) of endometrial cancer derived from an integrated positron emission tomography / magnetic resonance (PET/MR) system and to determine their correlation with pathological prognostic factors.

Correlation between Pancreatic Microcirculation and Type 2 Diabetes in Patients with Coronary Artery Disease: Dynamic Contrast-enhanced MR Imaging

PURPOSE To evaluate pancreatic perfusion by using dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging with pharmacokinetic modeling in coronary artery disease (CAD) patients with and those without type 2 diabetes to determine which perfusion parameter alterations might be associated with type 2 diabetes. MATERIALS AND METHODS This prospective study was approved by the responsible institutional review board. Written informed consent was obtained from all patients. All patients studied had CAD documented at conventional angiography. DCE MR with a two-dimensional T1-weighted fast low-angle shot sequence in oblique axial planes was used to assess pancreatic microcirculation in patients with and those without type 2 diabetes (age +/- standard deviation, 60.8 years +/- 11.2 and 61.8 years +/- 11.2, respectively; 20 men and five women in each group). Microcirculatory quantitative parameters, including volume transfer constant (K(trans), in min(-1)), extravascular extracellular space volume per unit volume of tissue (v(e)), and plasma volume per unit volume of tissue (v(p)) were compared between groups by using independent-sample t tests. RESULTS Patients with diabetes had a significantly higher K(trans) (0.977 vs 0.696, P = .031) and a lower v(p) (0.057 vs 0.084, P = .005) compared with patients without diabetes. A borderline difference in v(e) was found between the diabetes and nondiabetes groups (0.141 vs 0.103, P = .05). Among the 25 patients with diabetes, those who had the condition for more than 10 years (n = 11) had significantly higher K(trans) and v(e) than did those who had diabetes for less than 10 years (n = 14) (1.145 vs 0.783 and 0.174 vs 0.108; P = .04 and .02, respectively). CONCLUSION DCE MR imaging demonstrated increased endothelial permeability and decreased plasma volume in the pancreas in CAD patients with type 2 diabetes; patients with a history of diabetes for more than 10 years showed further increase in endothelial permeability.

Clinical and histologic implications of delayed hepatobiliary enhancement on magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic Acid.

PurposeThe aim of this study was to evaluate the serial signal changes in hepatobiliary enhancement on gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid or gadoxetic acid (Gd-EOB-DTPA)–enhanced magnetic resonance imaging and its correlation with clinical parameters. MethodUnder institutional review board approval, Gd-EOB-DTPA-enhanced magnetic resonance imaging was performed in 77 subjects (21 healthy volunteers and 56 biopsy-proven chronic hepatitis patients), and the signal intensities of the liver and common hepatic ducts (CHD) were measured every 2 minutes up to 50 minutes postcontrast. The associations among hepatic and CHD signals, physiological and hematological variables, histological activity index, and Metavir scores were analyzed with Pearson correlation and multiple linear stepwise regressions. The predictive ability of contrast enhancement index (CEI) of the liver with histological activity index and fibrosis scores at different time points were studied using nonparametric receiver operating characteristic curves. ResultsAmong the clinical parameters, body weight and body mass index had the highest negative correlation with hepatobiliary enhancement between 2 and 50 minutes postcontrast (P < 0.001). Multiple regressions showed that creatinine level, body weight, and body mass index were independent predictors for both mean hepatic and CHD signal intensity (P < 0.05). Patients with more severe fibrosis or moderate necrosis tended to have lower CEIs than other patients were. The predictive ability of CEI for the best differentiation between no fibrosis and any fibrosis (F ≥ 1) was at 10 minutes postcontrast (area under the receiver operating characteristic curve, 0.797). ConclusionsDelayed hepatobiliary enhancement with Gd-EOB-DTPA could be possibly used for staging liver fibrosis. Contrast enhancement index of the liver at 10 minutes is useful for differentiating between no fibrosis and any degree of fibrosis in chronic hepatitis patients.

Correlation among DCE-MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma†

We investigated correlations among angiogenesis parameters of the lumbar vertebrae measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), microvessel density (MVD) in bone marrow (BM), and extramedullary disease (EMD) in patients with multiple myeloma (MM). Forty-nine MM patients were enrolled. Two semiquantitative parameters, Peak and Slope, were obtained from the DCE-MRI signal-intensity curve; three more quantitative parameters, Amp, Kep, and Kel, were generated from bicompartmental modeling. Apart from Kep, all parameters were found to correlate positively with MVD (r range, 0.323– 0.594; all P < 0.03). Multivariate analysis indicated that the only factors significantly associated with MVD were Amp and plasma cell percentage in BM. Comparing angiogenesis parameters for patients with EMD at the time of DCE-MRI versus those who did not showed a high Amp ( 0.08) as the only significant factor associated with EMD (odds 6.33; P 5 0.045). During follow-up (median, 76 months), 4 more patients developed EMD. Accumulative incidence for developing EMD over time was significantly higher for patients with high Amp than those with low Amp (P 5 0.0254). In conclusion, Amp correlated strongly with MVD in BM and also EMD in patients with MM. Amp measurement might be helpful for identifying MM patients at risk for EMD. Multiple myeloma (MM) is a malignant plasma cell proliferation typically found in bone marrow (BM) [1]. Although MM cells (MCs) depend on the BM microenvironment to provide the signals essential for their growth and survival [2], in a fraction of patients MCs acquire the ability to proliferate in sites outside the BM. Such occurrences appear as extramedullary disease (EMD), indicating that MCs have become independent of the BM microenvironment [1]. The exact mechanism underlying the development of EMD in MM patients is not clear. One hypothesis suggests an alteration in the interaction between MCs and the BM microenvironment [2,3]. Within the BM microenvironment, angiogenesis might play a major role in not only promoting the growth and survival of MCs but also the disease progression itself [2–4]. The interaction between MCs and BM endothelial cells upregulates a number of angiogenic cytokines, such as vascular endothelial growth factor or matrix metalloproteinases. Such cytokines further stimulate BM angiogenesis and myeloma progression [5,6], as well as possible extramedullary dissemination [4]. To date, dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) is one of the most widely used noninvasive methods of measuring the perfusion and permeability of a biological tissue in the body, such as vertebral BM [7]. In MM patients, the angiogenesis parameters generated from DCE-MRI of vertebral BM reportedly correlate strongly with histological grade of infiltration, osteolytic bone involvement, microvessel density (MVD), and serum markers of disease activity [8,9]. However, prior to our study no data were available on the correlation between degree of BM angiogenesis and the development of EMD in MM patients. We thus examined the correlation between angiogenesis parameters generated from DCEMRI of vertebral bodies, together with MVD in BM (obtained from the posterior iliac crest), with the manifestation of EMD in patients with MM. Between September 2004 and April 2006, a total of 49 patients with MM were enrolled. Of this group, 27 (55%) patients had newly diagnosed MM (NDMM), 6 patients (12%) were in a post-treatment plateau (PTRP), and 16 (33%) had progressive disease (PD). This study was approved by our institutional ethics committee, and written informed consent was obtained from all patients in accordance with the Declaration of Helsinki (ClinicalTrials.gov Identifier: NCT00166855). The salient clinical characteristics of the 49 patients at enrollment are listed in Table I. Notably, 19 of the 49 patients (39%) had EMD at the time of their DCE-MRI, among whom 7 patients (37%) had more than one manifestation of EMD. BM samples were obtained from the posterior iliac crest in all 49 patients at approximately the same time as DCE-MRI was performed (median 2 days; range, -3 to 7 days). The mean MVD [vessels/4003 high-power field (HPF)] was 16.7 (range 1.5–40.2), with significant differences being found for patients in different subgroups (P 5 0.006). Patients with NDMM had a mean MVD of 20.3 (95% confidence interval [CI: 15.3–25.2]), patients in the PTRP group had a mean MVD of 3.2 (95% CI: 1.4–5.0), and patients with PD had a mean MVD of 15.7 (95% CI: 9.9–21.5). The time-signal intensity (SI) curve shown in DCE-MRI correlated strongly with tissue MVD, where a high peak and steep slope were associated with high MVD (Fig. 1A,B). By contrast, a lower peak and gentler slope were associated with lower MVD (Fig. 1C,D). Moderate correlations were found between MVD and the two semiquantitative parameters Peak and Slope (r 5 0.540 and 0.502, respectively; both P < 0.001). Amp and Kel, but not Kep, were also moderately correlated with MVD (r 5 0.594 and 0.323, respectively; P < 0.001 and P 5 0.024, respectively). Other salient characteristics significantly correlated with MVD were beta2-microglobulin (r 5 0.305; P 5 0.035), C-reactive protein (r 5 0.348; P 5 0.018), and percentage of MCs in BM (r 5 0.637; P < 0.001). Further multiple linear regression analysis showed that only Amp (r5 45.7; 95% CI: 13.0–78.3; P5 0.007) and percentage of MCs in BM (r5 0.18; 95% CI: 0.06–0.29; P 5 0.003) were independently correlated with MVD. Table II shows the results of our comparison of salient features and angiogenesis parameters between patients with and without EMD at the time of their DCE-MRI. When compared with patients without EMD, patients with EMD displayed significantly greater infiltration of MCs in BM and higher levels of the angiogenesis parameter Amp. Further multivariate analysis using a multiple logistic regression model showed that Amp was the only significant factor associated with EMD (OR 6.33; P 5 0.045). The median follow-up period was 76