Predictors of changes in preoperative tumor stage between dynamic computed tomography and gadoxetate disodium-enhanced magnetic resonance imaging for hepatocellular carcinoma.

BACKGROUND/PURPOSE: Gadoxetate disodium-enhanced magnetic resonance imaging (EOB-MRI) has a higher diagnostic accuracy for hepatocellular carcinoma (HCC) than computed tomography (CT). However, indications for performing EOB-MRI after dynamic CT are not well defined. Therefore, we investigated the clinical factors associated with changes in the preoperative tumor stage between dynamic CT and EOB-MRI. METHODS: A prospective cohort was conducted from January 2014 to December 2017. 156 adult patients with clinical suspicion of HCC before liver resection were enrolled and we retrospectively reviewed the images. The tumor staging was evaluated by dynamic CT and then EOB-MRI subsequently according to the TNM staging system. The changes in tumor stage between two modalities were identified, and the associated clinical factors were analyzed. RESULTS: A total of 99 patients were analyzed after excluding 57 patients. 20 patients (20.2%) had changes in tumor stage between dynamic CT and EOB-MRI. The change occurred only in early stage (T1 and T2 lesions) based on dynamic CT initially. Furthermore, in univariate and multivariate analyses, albumin-bilirubin (ALBI) grade 2 and log alpha-fetoprotein (AFP) levels were associated with changes in tumor staging by EOB-MRI than those without (50% vs. 9.9%, p < 0.001 and 2.04 ± 1.35 vs. 1.40 ± 1.16, p = 0.038, respectively). Patients with changes in tumor stage also exhibited higher 1-year recurrence rate and shorter recurrence-free survival. CONCLUSION: Changes in preoperative tumor stage between dynamic CT and EOB-MRI were associated with CT-defined early stage, ALBI grades, higher log AFP levels, and early recurrence.

Cell-Free Virus-Host Chimera DNA From Hepatitis B Virus Integration Sites as a Circulating Biomarker of Hepatocellular Cancer.

BACKGROUND AND AIMS: Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to implement salvage therapies appropriately. This study examined the feasibility of virus-host chimera DNA (vh-DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting. APPROACH AND RESULTS: HBV integration in 50 patients with HBV-related HCC was determined by the Hybridization capture-based next-generation sequencing (NGS) platform. For individual HCC, the vh-DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV-related HCC. Tumor-specific ddPCR was developed to measure the corresponding vh-DNA copy number in baseline plasma from each patient immediately before surgery. vh-DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh-DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh-DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh-DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh-DNA, whereas 18.2% were from de novo HCC. CONCLUSIONS: vh-DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV-related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.

The occurrence of primary hepatic adenoma in deceased donor renal transplant recipient.

MAIN FINDINGS: We reported a case of new-onset, multi-focal hepatic adenoma in an 18 year-old man with no classic risk factors occurring forty months after a renal transplant from a cadaver donor. Histopathology of the adenoma was examined and genotype and phenotype were also analyzed. Histopathologic examination of the adenoma showed no malignancy. Genotype and phenotype analysis revealed no HNF1α or ß-catenin gene mutations and no inflammatory infiltration. The patient was well and disease-free postoperatively. CASE HYPOTHESIS: Hepatic adenoma occurs mostly in those taking oral contraceptives or androgenic-anabolic steroids or in those with hereditary diseases. Hepatic adenoma in a renal transplant recipient is rare and has only been reported in one case with glycogen storage disease type Ia. Immunosuppressive treatment might have contributed to the development of the neoplasm. PROMISING FUTURE IMPLICATIONS: Although malignant change occurs most often in ß-catenin gene mutation hepatic adenoma, surgical resection of the adenoma in a patient under immunosuppressive therapy should be considered in order to avoid the possibility of malignant transformation or hemorrhagic rupture.

Multifunctional Structure-Modified Quaternary Compounds Co9Se8-CuSe2-WSe2 Mixed with MWCNT as a Counter Electrode Material for Dye-Sensitized Solar Cells.

In this study, a trimetallic selenide material with a hollow spherical structure (Co9Se8-CuSe2-WSe2) was synthesized through two consecutive solvothermal reactions. The synergistic effect between the quaternary elements, the benefits of the selenization of metals, and the unique morphology led to the prominent electrocatalytic ability of Co9Se8-CuSe2-WSe2 hollow spheres. Co9Se8-CuSe2-WSe2 hollow spheres were then mixed with oxygen plasma-treated multiwalled carbon nanotubes (MWCNT) as counter electrode (CE) material for dye-sensitized solar cells (DSSCs), achieving a photoelectric conversion efficiency (η) of 9.23% under one sun condition (AM 1.5G, 100 mW cm-2), surpassing the 8.08% of devices with platinum counter electrodes (PtCEs). For indoor conditions, a T5 light source was applied to the DSSCs with Co9Se8-CuSe2-WSe2 + MWCNT CE, and the efficiency increased to 14.14% under 3600 lx irradiance. Finally, Co9Se8-CuSe2-WSe2 + MWCNT CE demonstrated good stability with 92.23% retention after 1000 cycles of cyclic voltammetry, exceeding the 82.49% of PtCE. Therefore, Co9Se8-CuSe2-WSe2 + MWCNT shows potential as a substitute for platinum as CE material for DSSCs.

Paradoxical overexpression of MBNL2 in hepatocellular carcinoma inhibits tumor growth and invasion.

Pre-mRNA alternative splicing is an essential step in the process of gene expression. It provides cells with the opportunity to create various protein isoforms. Disruptions of alternative splicing are associated with various diseases, including cancer. The muscleblind-like (MBNL) protein is a splicing regulatory protein. Overexpression of MBNL proteins in embryonic stem cells promotes differentiated cell-like alternative splicing patterns. We examined the expression level of MBNL2 in 143 resected HCCs using immunohistochemistry. MBNL2 was overexpressed in 51 (35.7%) HCCs. The overexpression of MBNL2 correlated with smaller tumor size (≤ 3 cm, P = 0.0108) and low tumor stage (Stage I, P = 0.0026), indicating that MBNL2 expression was lost in the late stage of HCC development. Furthermore, patients with MBNL2-positive HCCs had a borderline better 5-year overall survival (P = 0.0579). In non-cancerous liver parenchyma, MBNL2 was stained on the Canals of Hering and hepatocytes newly derived from hepatic progenitor cells. The overexpression of MBNL2 in Hep-J5 cells suppressed proliferation, tumorsphere formation, migration, and in vitro invasion, and also reduced in vivo tumor growth in NOD/SCID mice. In contrast, MBNL2 depletion with RNA interference in Huh7 cells increased in vitro migration and invasion, but did not enhance tumor growth. These results indicate that MBNL2 is a tumor suppressor in hepatocarcinogenesis.

Changes in backscattered ultrasonic envelope statistics as a function of thrombus age: an in vitro study.

It is necessary to determine the age of thrombi in planning clinical treatment for thrombolysis. Ultrasound imaging can potentially be used to evaluate thrombus age in real time. The backscattered signals from thrombi may contain useful information regarding their age. On the basis of the randomness of ultrasound backscattering, this study explored changes in backscattered US statistics as a function of thrombus age. Porcine blood samples were used for the in vitro induction of fresh thrombi (day 0) with hematocrits ranging from 0%-40% and aged thrombi (days 0-8) with a hematocrit of 40%. Each thrombus was imaged using a pulse-echo ultrasound scanner equipped with a 7.5-MHz linear array transducer to acquire raw backscattered signals for B-mode and Nakagami imaging, by which the backscattered statistics were visualized. Hematoxylin and eosin staining and scanning electron microscopy were used to observe the histology of fresh and aged thrombi. The results indicated that a decrease in the number of red blood cells in the thrombus caused by the aging effect was observed in the in vitro model, indicating that the proposed model could simulate the structural changes in the thrombus during aging. Compared with fresh thrombi with various hematocrits, the aged thrombi exhibited a trend toward more substantial decreases in the Nakagami parameter with increasing thrombus age (the Nakagami parameter decreased from 1.1 to 0.6 as thrombus age increased from day 0 to day 8), indicating that thrombus aging causes the backscattered statistics to follow a pre-Rayleigh distribution to a high degree. This finding may be applied to the determination of thrombus age using conventional ultrasound imaging in the future.

Window-modulated compounding Nakagami imaging for ultrasound tissue characterization.

Ultrasound Nakagami parametric imaging is a useful tool for tissue characterization. Previous literature has suggested using a square with side lengths corresponding to 3 times the transducer pulse length as the minimum window for constructing the Nakagami image. This criterion does not produce sufficiently smooth images for the Nakagami image to characterize homogeneous tissues. To improve image smoothness, we proposed window-modulated compounding (WMC) Nakagami imaging based on summing and averaging the Nakagami images formed using sliding windows with varying window side lengths from 1 to N times the transducer pulse length in 1 pulse length step. Simulations (the number densities of scatterers: 2-16 scatterers/mm(2)) and experiments on fully developed speckle phantoms (the scatterer diameters: 20-106 µm) were conducted to suggest an appropriate number of frames N and to evaluate the image smoothness and resolution by analyzing the full width at half maximum (FWHM) of the parameter distribution and the widths of the image autocorrelation function (ACF), respectively. In vivo ultrasound measurements on rat livers without and with cirrhosis were performed to validate the practical performance of the WMC Nakagami image in tissue characterization. The simulation results showed that using a range of N from 7 to 10 as the number of frames for image compounding reduces the estimation error to less than 5%. Based on this criterion, the Nakagami parameter obtained from the WMC Nakagami image increased from 0.45 to 0.95 after increasing the number densities of scatterers from 2 to 16 scatterers/mm(2). The FWHM of the parameter distribution (bins=40) was 13.5±1.4 for the Nakagami image and 9.1±1.43 for the WMC Nakagami image, respectively (p-value<.05). The widths of the ACF for the Nakagami and WMC Nakagami images were 454±5.36 and 458±4.33, respectively (p-value>.05). In the phantom experiments, we also found that the FWHM of the parameter distribution for the WMC Nakagami image was smaller than that of the conventional Nakagami image (p-value<.05), and there was no significant difference of the ACF width between the Nakagami and WMC Nakagami images (p-value>.05). In the animal experiments, the Nakagami parameters obtained from the WMC Nakagami image for normal and cirrhotic rat livers were 0.62±0.08 and 0.92±0.07, respectively (p-value<.05). The results demonstrated that the WMC technique significantly improved the image smoothness of Nakagami imaging without resolution degradation, giving Nakagami model-based imaging the ability to visualize scatterer properties with enhanced image quality.

Early detection of liver fibrosis in rats using 3-D ultrasound Nakagami imaging: a feasibility evaluation.

We investigated the feasibility of using 3-D ultrasound Nakagami imaging to detect the early stages of liver fibrosis in rats. Fibrosis was induced in livers of rats (n = 60) by intraperitoneal injection of 0.5% dimethylnitrosamine (DMN). Group 1 was the control group, and rats in groups 2-6 received DMN injections for 1-5 weeks, respectively. Each rat was sacrificed to perform 3-D ultrasound scanning of the liver in vitro using a single-element transducer of 6.5 MHz. The 3-D raw data acquired at a sampling rate of 50 MHz were used to construct 3-D Nakagami images. The liver specimen was further used for histologic analysis with hematoxylin and eosin and Masson staining to score the degree of liver fibrosis. The results indicate that the Metavir scores of the hematoxylin and eosin-stained sections in Groups 1-4 were 0 (defined as early liver fibrosis in this study), and those in groups 5 and 6 ranged from 1 to 2 and 2 to 3, respectively. To quantify the degree of early liver fibrosis, the histologic sections with Masson stain were analyzed to calculate the number of fiber-related blue pixels. The number of blue pixels increased from (2.36 ± 0.79) × 10(4) (group 1) to (7.68 ± 2.62) × 10(4) (group 4) after DMN injections for 3 weeks, indicating that early stages of liver fibrosis were successfully induced in rats. The Nakagami parameter increased from 0.36 ± 0.02 (group 1) to 0.55 ± 0.03 (group 4), with increasing numbers of blue pixels in the Masson-stained sections (p-value < 0.05, t-test). We concluded that 3-D Nakagami imaging has potential in the early detection of liver fibrosis in rats and may serve as an image-based pathologic model to visually track fibrosis formation and growth.

Relationship between ultrasound backscattered statistics and the concentration of fatty droplets in livers: an animal study.

Ultrasound grayscale B-mode imaging is the most frequently used modality for examining fatty liver. Different concentrations and arrangements of fatty droplets in the liver may produce different statistical distributions of ultrasound backscatter signals, which may be treated as a useful clue for assessing the stage of fatty liver. To verify this point, we investigate the relationship between changes in backscattered statistics and the concentration of fatty droplets in the liver. Fatty liver was induced in rats fed a methionine-choline-deficient diet. Livers were excised from rats for in vitro ultrasound scanning using a single-element transducer. The envelopes of the acquired raw ultrasound signals were used for the analysis of the backscattered statistics by ultrasound Nakagami parametric imaging, which has been shown as a reliable tool to model the statistical distribution of ultrasound backscatter signals. Histological analyses and the measurements of triglyceride and cholesterol in the rat liver were conducted for comparison with the Nakagami parameter. Results show that the ultrasound Nakagami parameter has an excellent correlation with the concentration of fatty droplets, demonstrating that ultrasound backscatter statistics depend on the degree of fatty liver in rats.

The Occurrence of Primary Hepatic Adenoma in Deceased Donor Renal Transplant Recipient

Main findings: We reported a case of new-onset, multi-focal hepatic adenoma in an 18 year-old man with no classic risk factors occurring forty months after a renal transplant from a cadaver donor. Histopathology of the adenoma was examined and genotype and phenotype were also analyzed. Histopathologic examination of the adenoma showed no malignancy. Genotype and phenotype analysis revealed no HNF1α or β-catenin gene mutations and no inflammatory infiltration. The patient was well and disease-free postoperatively. Case hypothesis: Hepatic adenoma occurs mostly in those taking oral contraceptives or androgenic-anabolic steroids or in those with hereditary diseases. Hepatic adenoma in a renal transplant recipient is rare and has only been reported in one case with glycogen storage disease type Ia. Immunosuppressive treatment might have contributed to the development of the neoplasm. Promising future implications: Although malignant change occurs most often in β-catenin gene mutation hepatic adenoma, surgical resection of the adenoma in a patient under immunosuppressive therapy should be considered in order to avoid the possibility of malignant transformation or hemorrhagic rupture. .

Use of nakagami statistics and empirical mode decomposition for ultrasound tissue characterization by a nonfocused transducer.

The Nakagami parameter associated with the Nakagami distribution estimated from ultrasonic backscattered signals reflects the scatterer concentration in a tissue. A nonfocused transducer does not allow tissue characterization based on the Nakagami parameter. This paper proposes a new method called the noise-assisted Nakagami parameter based on empirical mode decomposition of noisy backscattered echoes to allow quantification of the scatterer concentration based on data obtained using a nonfocused transducer. To explore the practical feasibility of the proposed method, the current study performed experiments on phantoms and measurements on rat livers in vitro with and without fibrosis induction. The results show that using a nonfocused transducer makes it possible to use the noise-assisted Nakagami parameter to classify phantoms with different scatterer concentrations and different stages of liver fibrosis in rats more accurately than when using techniques based on the echo intensity and the conventional Nakagami parameter. However, the conventional Nakagami parameter and the noise-assisted Nakagami parameter have different meanings: the former represents the statistics of signals backscattered from unresolvable scatterers, whereas the latter is associated with stronger resolvable scatterers or local inhomogeneity caused by scatterer aggregation.