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1.  Factors predicting aggressiveness of non-hypervascular hepatic nodules detected on hepatobiliary phase of gadolinium ethoxybenzyl diethylene-triamine-pentaacetic-acid magnetic resonance imaging 
AIM: To establish a prognostic formula that distinguishes non-hypervascular hepatic nodules (NHNs) with higher aggressiveness from less hazardous one.
METHODS: Seventy-three NHNs were detected in gadolinium ethoxybenzyl diethylene-triamine-pentaacetic-acid magnetic resonance imaging (Gd-EOB-DTPA-MRI) study and confirmed to change 2 mm or more in size and/or to gain hypervascularity. All images were interpreted independently by an experienced, board-certified abdominal radiologist and hepatologist; both knew that the patients were at risk for hepatocellular carcinoma development but were blinded to the clinical information. A formula predicting NHN destiny was developed using a generalized estimating equation model with thirteen explanatory variables: age, gender, background liver diseases, Child-Pugh class, NHN diameter, T1-weighted imaging/T2-weighted imaging detectability, fat deposition, lower signal intensity in arterial phase, lower signal intensity in equilibrium phase, α-fetoprotein, des-γ-carboxy prothrombin, α-fetoprotein-L3, and coexistence of classical hepatocellular carcinoma. The accuracy of the formula was validated in bootstrap samples that were created by resampling of 1000 iterations.
RESULTS: During a median follow-up period of 504 d, 73 NHNs with a median diameter of 9 mm (interquartile range: 8-12 mm) grew or shrank by 68.5% (fifty nodules) or 20.5% (fifteen nodules), respectively, whereas hypervascularity developed in 38.4% (twenty eight nodules). In the fifteen shrank nodules, twelve nodules disappeared, while 11.0% (eight nodules) were stable in size but acquired vascularity. A generalized estimating equation analysis selected five explanatories from the thirteen variables as significant factors to predict NHN progression. The estimated regression coefficients were 0.36 for age, 6.51 for lower signal intensity in arterial phase, 8.70 or 6.03 for positivity of hepatitis B virus or hepatitis C virus, 9.37 for des-γ-carboxy prothrombin, and -4.05 for fat deposition. A formula incorporating the five coefficients revealed sensitivity, specificity, and accuracy of 88.0%, 86.7%, and 87.7% in the formulating cohort, whereas these of 87.2% ± 5.7%, 83.8% ± 13.6%, and 87.3% ± 4.5% in the bootstrap samples.
CONCLUSION: These data suggest that the formula helps Gd-EOB-DTPA-MRI detect a trend toward hepatocyte transformation by predicting NHN destiny.
PMCID: PMC4402305  PMID: 25914467
Hepatocellular carcinoma; Magnetic resonance imaging; Ethoxybenzyl moiety; Non-hypervascular hepatic nodule; Fate prediction
2.  The effect of echo-sampling strategy on the accuracy of out-of-phase and in-phase multi-echo gradient-echo magnetic resonance imaging hepatic fat fraction estimation 
To assess the effect of echo-sampling strategy on the accuracy of out-of-phase (OP) and in-phase (IP) multi-echo gradient-echo magnetic resonance imaging (MRI) hepatic fat fraction (FF) estimation, using MR spectroscopy (MRS) proton density FF (PDFF) as a reference standard.
Materials and Methods
In this IRB-approved, HIPAA-compliant prospective study, 84 subjects underwent proton MRS and non-T1-weighted gradient-echo imaging of the liver at 3T. Imaging data were collected at 16 nominally OP and IP echo times (TEs). MRI-FF was estimated while varying two echo-sampling parameters (number of consecutive echoes, starting echo number). For each combination of these parameters, MRI-FF estimation accuracy was assessed with slope, intercept, average bias and R2 from a linear regression of MRS-PDFF on MRI-FF. The relationship between accuracy metrics and echo-sampling parameters was assessed by Spearman rank correlation.
For FF calculations using 3-16 echoes and a starting echo number of 1, the intercept ranged from 0.0046 to 0.0124, slope from 0.941 to 0.96, average bias from 0.0034 to 0.0078, and R2 from 0.968 to 0.976. All four accuracy metrics were the best with the 3- and 4- echo calculations and worsened progressively with increasing number of echoes. For a given number of echoes, there was an overall trend toward decreasing accuracy as starting echo number increased. Spearman correlation coefficients between starting echo number and intercept, slope, average bias and R2 were 0.911, -.64, -.889 and -.954, respectively, indicating progressive loss of accuracy in each case.
Multi-echo OP and IP imaging provided high FF estimation accuracy. Accuracy was highest using the earliest 3 or 4 echoes. Incorporation of additional echoes or delaying the starting echo number progressively reduced accuracy.
PMCID: PMC3760998  PMID: 23720420
Fatty liver disease; hepatic steatosis; magnetic resonance; fat quantification; multiecho
3.  Safety Assessment of Liver-Targeted Hydrodynamic Gene Delivery in Dogs 
PLoS ONE  2014;9(9):e107203.
Evidence in support of safety of a gene delivery procedure is essential toward gene therapy. Previous studies using the hydrodynamics-based procedure primarily focus on gene delivery efficiency or gene function analysis in mice. The current study focuses on an assessment of the safety of computer-controlled and liver-targeted hydrodynamic gene delivery in dogs as the first step toward hydrodynamic gene therapy in clinic. We demonstrate that the impacts of the hydrodynamic procedure were limited in the injected region and the influences were transient. Histological examination and the hepatic microcirculation measurement using reflectance spectrophotometry reveal that the liver-specific impact of the procedure involves a transient expansion of the liver sinusoids. No systemic damage or toxicity was observed. Physiological parameters, including electrocardiogram, heart rate, blood pressure, oxygen saturation, and body temperature, remained in normal ranges during and after hydrodynamic injection. Body weight was also examined to assess the long-term effects of the procedure in animals who underwent 3 hydrodynamic injections in 6 weeks with 2-week time interval in between. Serum biochemistry analysis showed a transient increase in liver enzymes and a few cytokines upon injection. These results demonstrate that image-guided, liver-specific hydrodynamic gene delivery is safe.
PMCID: PMC4175463  PMID: 25251246
4.  Hemodynamics of a hydrodynamic injection 
The hemodynamics during a hydrodynamic injection were evaluated using cone beam computed tomography (CBCT) and fluoroscopic imaging. The impacts of hydrodynamic (5 seconds) and slow (60 seconds) injections into the tail veins of mice were compared using 9% body weight of a phase-contrast medium. Hydrodynamically injected solution traveled to the heart and drew back to the hepatic veins (HV), which led to liver expansion and a trace amount of spillover into the portal vein (PV). The liver volumes peaked at 165.6 ± 13.3% and 165.5 ± 11.9% of the original liver volumes in the hydrodynamic and slow injections, respectively. Judging by the intensity of the CBCT images at the PV, HV, right atrium, liver parenchyma (LP), and the inferior vena cava (IVC) distal to the HV conjunction, the slow injection resulted in the higher intensity at PV than at LP. In contrast, a significantly higher intensity was observed in LP after hydrodynamic injection in comparison with that of PV, suggesting that the liver took up the iodine from the blood flow. These results suggest that the enlargement speed of the liver, rather than the expanded volume, primarily determines the efficiency of hydrodynamic delivery to the liver.
PMCID: PMC4362352  PMID: 26015971
5.  In vivo characterization of the liver fat 1H MR spectrum 
NMR in biomedicine  2010;24(7):10.1002/nbm.1622.
A theoretical triglyceride model was developed for in vivo human liver fat 1H MRS characterization, using the number of double bonds (–CH=CH–), number of methylene-interrupted double bonds (–CH=CH–CH2–CH=CH–) and average fatty acid chain length. Five 3 T, single-voxel, stimulated echo acquisition mode spectra (STEAM) were acquired consecutively at progressively longer TEs in a fat–water emulsion phantom and in 121 human subjects with known or suspected nonalcoholic fatty liver disease. T2-corrected peak areas were calculated. Phantom data were used to validate the model. Human data were used in the model to determine the complete liver fat spectrum. In the fat–water emulsion phantom, the spectrum predicted by the model (based on known fatty acid chain distribution) agreed closely with spectroscopic measurement. In human subjects, areas of CH2 peaks at 2.1 and 1.3 ppm were linearly correlated (slope, 0.172; r = 0.991), as were the 0.9 ppm CH3 and 1.3 ppm CH2 peaks (slope, 0.125; r = 0.989). The 2.75 ppm CH2 peak represented 0.6% of the total fat signal in high-liver-fat subjects. These values predict that 8.6% ofm the total fat signal overlies the water peak. The triglyceride model can characterize human liver fat spectra. This allows more accurate determination of liver fat fraction from MRI and MRS.
PMCID: PMC3860876  PMID: 21834002
liver; 1H MRS; triglyceride; quantification; NAFLD; fat fraction
6.  Phase I study of miriplatin combined with transarterial chemotherapy using CDDP powder in patients with hepatocellular carcinoma 
BMC Gastroenterology  2012;12:127.
There is no standard therapeutic procedure for the hepatocellular carcinoma (HCC) in patients with poor hepatic reserve function. With the approval of newly developed chemotherapeutic agent of miriplatin, we have firstly conducted the phase I study of CDDP powder (DDP-H) and miriplatin combination therapy and reported its safety and efficacy for treating unresectable HCC in such cases. To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) for the combination of transarterial oily chemoembolization (TOCE) and transarterial chemotherapy (TAC) using miriplatin and DDP-H for treating unresectable hepatocellular carcinoma (HCC).
Transarterial chemotherapy using DDP-H was performed through the proper hepatic artery targeting the HCC nodules by increasing the dose of DDP-H (35–65 mg/m2) followed by targeting the HCC nodules by transarterial oily chemoembolization with miriplatin.
A total of nine patients were enrolled in this study and no DLT was observed with any dose of DDP-H in all cases in whom 80 mg (median, 18–120) miriplatin was administered. An anti-tumour efficacy rating for partial response was obtained in one patient, while a total of four patients (among eight evaluated) showed stable disease response, leading to 62.5% of disease control rate. The pharmacokinetic results showed no further increase in plasma platinum concentration following miriplatin administration.
Our results suggest that a combination of DDP-H and miriplatin can be safely administered up to their respective MTD for treating HCC.
Trial registration
This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR000003541).
PMCID: PMC3482551  PMID: 22994941
Miriplatin; Hepatocellular carcinoma; Cisplatin powder; Phase I clinical trial
7.  Heritability of Nonalcoholic Fatty Liver Disease 
Gastroenterology  2009;136(5):1585-1592.
Background & Aims
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The etiology is believed to be multi-factorial with a substantial genetic component; however, the heritability of NAFLD is undetermined. Therefore, a familial aggregation study was performed to test the hypothesis that NAFLD is highly heritable.
Overweight children with biopsy-proven NAFLD and overweight children without NAFLD served as probands. Family members were studied including magnetic resonance imaging to quantify liver fat fraction. Fatty liver was defined as a liver fat fraction ≥ 5%. Etiologies for fatty liver other than NAFLD were excluded. Narrow-sense heritability estimates for fatty liver (dichotomous) and fat fraction (continuous) were calculated using variance components analysis adjusted for covariate effects.
Fatty liver was present in 17% of siblings and 37% of parents of overweight children without NAFLD. Fatty liver was significantly more common in siblings (59%) and parents (78%) of children with NAFLD. Liver fat fraction was correlated with body mass index (BMI), although the correlation was significantly stronger for families of children with NAFLD than those without NAFLD. Adjusted for age, sex, race, and BMI, heritability of fatty liver was 1.000 and of liver fat fraction 0.386.
Family members of children with NAFLD should be considered at high risk for NAFLD. These data suggest that familial factors are a major determinant of whether an individual has NAFLD. Studies examining the complex relations between genes and environment in the development and progression of NAFLD are warranted.
PMCID: PMC3397140  PMID: 19208353
magnetic resonance; genetics; family; obesity; fatty liver
8.  Constraining the Initial Phase in Water-Fat Separation 
Magnetic resonance imaging  2010;29(2):216-221.
An algorithm is described for use in chemical shift based water-fat separation to constrain the phase of both species to be equal at an echo-time of zero. This constraint is physically reasonable since the initial phase should be a property of the excitation pulse and receiver coil only. The advantages of phase-constrained water-fat separation, namely improved noise performance and/or reduced data requirements (fewer echos), are demonstrated in simulations and experiments.
PMCID: PMC3053064  PMID: 21159457
Water-Fat Separation; Dixon; Chemical Shift; Phase
9.  Assessment of Liver Fat Quantification in the Presence of Iron 
Magnetic resonance imaging  2010;28(6):767-776.
This study assesses the stability of magnetic resonance (MR) liver fat measurements against changes in T2* due to the presence of iron, which is a confound for accurate quantification. The liver T2* was experimentally shortened by intravenous infusion of a super paramagnetic iron oxide (SPIO) contrast agent. Low flip angle multi-echo gradient echo sequences were performed before, during, and after infusion. The liver fat fraction (FF) was calculated in co-localized regions-of-interest using T2* models that assumed no decay, monoexponential decay and biexponential decay. Results show that, when T2* was neglected, there was a strong underestimation of the computed FF and with monoexponential decay there was a weak overestimation of FF. Curve-fitting using the biexponential decay was found to be problematic. The overestimation of FF may be due to remaining deficiencies in the model, although is unlikely to be important for clinical diagnosis of steatosis.
PMCID: PMC2924146  PMID: 20409663
10.  The Effect of PRESS and STEAM Sequences on Magnetic Resonance Spectroscopic Liver Fat Quantification 
To compare PRESS and STEAM MR spectroscopy for assessment of liver fat in human subjects.
Materials and Methods
Single-voxel (20×20×20 mm) PRESS and STEAM spectra were obtained at 1.5T in 49 human subjects with known or suspected fatty liver disease. PRESS and STEAM sequences were obtained with fixed TR (1500 ms) and different TE (5 PRESS spectra between TE 30–70 ms, 5 STEAM spectra between TE 20–60 ms). Spectra were quantified and T2 and T2-corrected peak area were calculated by different techniques. The values were compared for PRESS and STEAM.
Water T2 values from PRESS and STEAM were not significantly different (p =0.33). Fat peak T2s were 25–50% shorter on PRESS than on STEAM (p <0.02 for all comparisons) and there was no correlation between T2s of individual peaks. PRESS systematically overestimated the relative fat peak areas (by 7–263%) compared to STEAM (p <0.005 for all comparisons). The peak area given by PRESS was more dependent on the T2-correction technique than STEAM.
Measured liver fat depends on the MRS sequence used. Compared to STEAM, PRESS underestimates T2 values of fat, overestimates fat fraction, and provides a less consistent fat fraction estimate, probably due to J coupling effects.
PMCID: PMC2982807  PMID: 19557733
Liver Fat Quantification; Magnetic Resonance Spectroscopy; PRESS and STEAM; j-coupling
11.  Optimal Phased Array Combination for Spectroscopy 
Magnetic resonance imaging  2008;26(6):847-850.
A method is described for making a weighted linear combination of the spectra acquired by a phased array coil. Unlike most previous combination methods, no special reference points in the data are chosen to represent the coil weights. Instead all the data points are used, which results in more reliable estimation. The method uses singular value decomposition to identify the coils weights and extract the principal component of variation in the signal. Subsequent processing of the combined signal (e.g. Fourier transform, baseline correction, phasing) may proceed as per a single coil acquisition.
PMCID: PMC2868913  PMID: 18486392
Spectroscopy; SVD; Phased Array; Coils
12.  Relaxation Effects in the Quantification of Fat using Gradient Echo Imaging 
Magnetic resonance imaging  2008;26(3):347-359.
Quantification of fat has been investigated using images acquired from multiple gradient echos. The evolution of the signal with echo time and flip angle was measured in phantoms of known fat and water composition and in 21 research subjects with fatty liver. Data were compared to different models of the signal equation, in which each model makes different assumptions about the T1 and/or T2* relaxation effects. A range of T1, T2*, fat fraction and number of echos was investigated to cover situations of relevance to clinical imaging. Results indicate that quantification is most accurate at low flip angles (to minimize T1 effects) with a small number of echos (to minimize spectral broadening effects). At short echo times the spectral broadening effects manifest as a short apparent T2 for the fat component.
PMCID: PMC2386876  PMID: 18093781

Results 1-12 (12)