[Show abstract][Hide abstract] ABSTRACT: Exactly assessing tumor response to different dose of chemotherapy would help to tailor therapy for individual patients. This study was to determine the feasibility of dynamic contrast-enhanced ultrasound (CEUS) in the evaluation of tumor vascular response to different dose cisplatin.
MCF-7 breast cancer bearing mice were treated with different dose of cisplatin in group B (1 mg/kg) and group C (3 mg/kg). A control group A was given with saline. Sequential CEUS was performed on days 0, 3 and 7 of the treatment, in which time-signal intensity curves were obtained from the intratumoral and depth-matched liver parenchyma. Peak enhancement (PE), area under the curve of wash-in (WiAUC), wash-in rate (WiR) and wash-in perfusion index (WiPI) were calculated from perfusion time-intensity curves and normalized with respect to the adjacent liver parenchyma. Histopathological analysis was conducted to evaluate tumor cell density and microvascular density (MVD).
Significant decreases in tumor normalized perfusion parameters were observed on day 3 in the high dose group and on day 7 in the low dose group. On day 7, nPE, nWiAUC, and nWiPI significantly decreased in group C and group B as compared with group A (P < 0.05), and further decreased in group C as compared with group B (P < 0.05). Significant decreases of tumor cell density and MVD were seen in treated group (group B and C) compared to control group (P < 0.05) and further decrease in group C compared to group B (P < 0.05).
Dynamic CEUS for quantification of tumor perfusion could be used to evaluate tumor vascular response to different dose of chemotherapy.
BMC Cancer 12/2015; 15(1):1170. DOI:10.1186/s12885-015-1170-8 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our aim was to evaluate the correlation between tumor vasculature detected by pre-surgical contrast-enhanced ultrasonography and the post-surgical prognosis of patients with hepatocellular carcinoma. One hundred ninety-five patients with hepatocellular carcinoma who had undergone curative resection and pre-operative contrast-enhanced ultrasonography were enrolled. Intra-tumoral microvessels were evaluated by immunohistochemical staining for anti-CD31 and anti-CD34. On the basis of the immunohistochemical staining and morphology patterns, tumors were divided into capillary-like and sinusoid-like microvessel subtypes. The rise time of tumors was shorter in the capillary-like microvessel subtype than in the sinusoid-like microvasculature subtype (p = 0.026). Intra-tumor microvascular density (p < 0.001, hazard ratio = 0.137) and rise time (p = 0.006, hazard ratio = 2.475) were independent factors corresponding to different microvasculature types. Microvascular density, vascular invasion and wash-in perfusion index were determined to be independent factors in recurrence-free survival and overall survival. In conclusion, contrast-enhanced ultrasonography may serve as a means of non-invasive assessment of tumor angiogenesis and may be associated with the survival of patients with hepatocellular carcinoma after resection.
Ultrasound in medicine & biology 08/2015; 41(10):2621-30. DOI:10.1016/j.ultrasmedbio.2015.06.004 · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nasopharyngeal carcinoma (NPC) has the highest metastasis rate among head and neck cancers with unclear mechanism. WNT5A belongs to the WNT family of cysteine-rich secreted glycoproteins. Our previous high-throughput gene expression profiling revealed that WNT5A was up-regulated in highly metastatic cells. In the present study, we first confirmed the elevated expression of WNT5A in metastatic NPC tissues at both the mRNA and protein levels. We then found that WNT5A promoted epithelial-mesenchymal transition (EMT) in NPC cells, induced the accumulation of CD24-CD44+ cells and side population, which are believed to be cancer stem cell characteristics. Moreover, WNT5A promoted the migration and invasion of NPC cells in vitro, while in vivo treatment with recombinant WNT5A promoted lung metastasis. Knocking down WNT5A diminished NPC tumorigenesis in vivo. When elevated expression of WNT5A coincided with the elevated expression of vimentin in the primary NPC, the patients had a poorer prognosis. Among major signaling pathways, protein kinase C (PKC) signaling was activated by WNT5A in NPC cells. A positive feedback loop between WNT5A and phospho-PKC to promote EMT was also revealed. Taken together, these data suggest that WNT5A is an important molecule in promoting stem cell characteristics in NPC, leading to tumorigenesis and metastasis.
[Show abstract][Hide abstract] ABSTRACT: There is a strong need for early assessment of tumor response to chemotherapy in order to avoid the adverse effects of unnecessary chemotherapy and to allow early transition to second-line therapy. The purpose of this study was to determine the feasibility of ultrasonic spectral analysis for the in vivo characterization of changes in tumor microstructure in the evaluation of tumor response to chemotherapy using diagnostic ultrasound.
Experiments were approved by the regional animal care committee. Twenty-four MCF-7 breast cancer bearing nude mice were treated with adriamycin or sterile saline administered by intraperitoneal injection. Ultrasonic radio-frequency (RF) data was collected using a clinically available ultrasound scanner (6-MHz linear transducer). Linear regression parameters (spectral slope and midband-fit) regarding the calibrated power spectra from the RF signals were tested to monitor tumor response to treatment. The section equivalent to the ultrasound imaging plane was stained with hematoxylin and eosin to allow for assessment of the density of tumor cell nuclei.
Treatment with adriamycin significantly reduced tumor growth in comparison with the control group (p = 0.003). Significant changes were observed in the ultrasonic parameters of the treated relative to the untreated tumors (p < 0.05). The spectral slope increased by 48.5%, from -10.66 +/- 2.96 to -5.49 +/- 2.69; the midband-fit increased by 12.8%, from -57.10 +/- 7.68 to -49.81 +/- 5.40. Treated tumors were associated with a significant decrease in the density of tumor cell nuclei as compared with control tumors (p < 0.001).
Ultrasonic spectral analysis can detect changes in tumor microstructure after chemotherapy, and this will be helpful in the early evaluation tumor response to chemotherapy.
BMC Cancer 06/2013; 13(1):302. DOI:10.1186/1471-2407-13-302 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Currently used morphologic criteria have limitations in assessing tumor response to chemotherapy because of the relatively slow tumor shrinkage as measured by conventional morphologic imaging. Functional imaging techniques show promising results in early assessment of tumor response to treatment. PURPOSE: To quantitatively detect changes in tumor perfusion during chemotherapy with contrast-enhanced ultrasound. MATERIAL AND METHODS: Twenty-three MCF-7 breast cancer bearing nude mice treated by either adriamycin (n 11) or sterile saline (n 12) were imaged before and after treatment with an ultrasound scanner after bolus injection of SonoVue. Regions of interest within the tumor were analyzed offline to determine perfusion parameters including peak enhancement (PE), area under the curve of wash-in (WiAUC), rise time (RT), wash-in rate (WiR), wash-in perfusion index (WiPI), and quality of fit (QOF). Hematoxylin and eosin was used to assess tumor cell density and immunohistochemical analysis was performed for evaluation of microvascular density (MVD). RESULTS: Treatment with adriamycin significantly reduced tumor growth in comparison to the control group (P < 0.001). There was no significant difference in perfusion parameters before treatment. Treatment with adriamycin resulted in a significant decrease in PE, WiAUC, WiR, and WiPI in comparison with control group (P < 0.01). The tumor cell density estimated by pathology slice was significantly lower in treated tumors than in control tumors after treatment (P < 0.001). Immunohistochemistry showed significant decreases of MVD in treated tumors as compared with control tumors (P < 0.001) after treatment. CONCLUSION: Quantitative contrast-enhanced ultrasound can detect the change of tumor perfusion after chemotherapy, which may enable early assess tumor response to chemotherapy.
[Show abstract][Hide abstract] ABSTRACT: There is a strong need to assess early tumor response to chemotherapy in order to avoid adverse effects from unnecessary chemotherapy and allow early transition to second-line therapy. This study was to quantify tumor perfusion changes with dynamic contrast-enhanced ultrasound (CEUS) in the evaluation of early tumor response to cytotoxic chemotherapy. Sixty nude mice bearing with MCF-7 breast cancer were administrated with either adriamycin or sterile saline. CEUS was performed on days 0, 2, 4 and 6 of the treatment, in which time-signal intensity (SI) curves were obtained from the intratumoral and depth-matched liver parenchyma. Four perfusion parameters including peak enhancement (PE), area under the curve of wash-in (WiAUC), wash-in rate (WiR) and wash-in perfusion index (WiPI) were calculated from perfusion curves and normalized with respect to perfusion of adjacent liver parenchyma. Histopathological analysis was conducted to evaluate tumor perfusion, tumor cell density, microvascular density (MVD) and proliferating cell density. Significant decreases of tumor normalized perfusion parameters (i.e., nPE, nWiAUC, nWiR and nWiPI) were noticed between adriamycin-treated and control groups (<0.01) 2 days after therapy. There were significant differences of tumor volumes between control and treated groups on day 6 (<0.001) while there were no significant differences in tumor volume on days 0, 2 and 4 (>0.05). Significant decreases of tumor perfusion, tumor cell density, MVD and proliferating cell density were seen in adrianycin-treated group 2 days after therapy when compared to control group (<0.001). Dynamic CEUS for quantification of tumor perfusion could be used for early detection of cancer response to cytotoxic chemotherapy prior to notable tumor shrinkage.
PLoS ONE 05/2013; 8(3):e58274. DOI:10.1371/journal.pone.0058274 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The purpose of the study was to detect tumor blood flow changes after chemotherapy with contrast-enhanced destruction-replenishment sonography.
Twenty-four MCF-7 breast cancer-bearing nude mice were included in this study. Animals received either adriamycin or sterile saline and underwent contrast-enhanced sonography before and after treatment using a destruction-replenishment technique. A monoexponential function, y = A(1 - e(-βt)), was used to fit the replenishment kinetics, where the plateau signal intensity A reflects the percent blood volume; the time constant β reflects the average speed of blood; and their product A*β reflects the nutrient blood flow. Tumor blood perfusion was compared to measurements of cell density and microvascular density.
Volumes of the treated tumors were significantly reduced after 7 days of adriamycin treatment compared with the control tumors (P < .001). Before adriamycin administration, there was no significant difference in blood perfusion between the treated and control groups (P > .05). Treatment with adriamycin resulted in a significant decrease in A, β, and A*β (P <.001) compared with the control tumors. The tumor cell density and microvascular density estimated by pathologic slices were significantly lower in the treated tumors than in the control tumors (P <.001).
Quantification of tumor blood flow using contrast-enhanced destruction-replenishment sonography shows the potential to evaluate tumor responses to chemotherapy.
Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 04/2013; 32(4):683-90. · 1.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: To explore the potential of quantitative analysis of contrast-enhanced ultrasonography (CEUS) in differentiating focal nodular hyperplasia (FNH) from hepatocellular carcinoma (HCC). Methods: 34 cases of FNH and 66 cases of HCC (all lesions <5 cm) were studied using CEUS to evaluate enhancement patterns and using analytic software Sonoliver (R) (Image-Arena (TM) v.4.0, TomTec Imaging Systems, Munich, Germany) to obtain quantitative features of CEUS in the region of interest. The quantitative features of maximum of intensity (IMAX), rise slope (RS), rise time (RT) and time to peak (TTP) were compared between the two groups and applied to further characterise both FNH and HCC with hypoenhancing patterns in the late phase on CEUS. Results: The sensitivity and specificity of CEUS for diagnosis of FNH were 67.6% and 93.9%, respectively. For quantitative analysis, IMAX and RS in FNHs were significantly higher than those in HCCs (p<0.05), while RT and TTP in FNHs were significantly shorter (p<0.05). Both the 11 FNHs and 62 HCCs with hypo-enhancing patterns in the late phase were further characterised with their quantitative features, and the sensitivity and specificity of IMAX for diagnosis of FNH were 90.9% and 43.5%, RS 81.8% and 80.6%, RT 90.9% and 71.0%, and TTP 90.9% and 71.0%, respectively. Conclusion: The quantitative features of CEUS in FNH and HCC were significantly different, and they could further differentiate FNH from HCC following conventional CEUS. Advances in knowledge: Our findings suggest that quantitative analysis of CEUS can improve the accuracy of differentiating FNH from HCC.
The British journal of radiology 02/2013; 86(1023). DOI:10.1259/bjr.20120536 · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Portal vein embolization (PVE) has become a standard preoperative procedure to promote hypertrophy of the future remnant liver to reduce postoperative liver failure. Whether PVE accelerates tumor growth is still controversial. We developed a left PVE procedure and investigated its effect on liver hypertrophy and tumor growth in a rabbit liver tumor model.
VX2 tumors were implanted in both the external left and right middle lobe (the bilateral group) or in the external left lobe only (the unilateral group) of rabbit liver. Both groups were further divided into a PVE or a sham/control group. Tumor volume and tumor growth rate as volume relative increase were determined by ultrasound. Liver volume-to-body weight index, an index for liver volume, was compared. Serum HGF was measured by ELISA.
In the bilateral PVE group, tumor volume and relative increase value in the nonembolized lobe were significantly (71% and 65%, respectively) greater than those in the control group at 5 d post-PVE. In the unilateral PVE group, liver volume-to-body weight index of the nonembolized lobes was significantly increased by 17%. Increase of serum HGF level after PVE was correlated well with both tumor growth and liver hypertrophy.
Left PVE promoted both the growth of implanted tumors and liver hypertrophy in the nonembolized liver, in which serum HGF might play an important role.
Journal of Surgical Research 04/2012; 178(1):255-63. DOI:10.1016/j.jss.2012.02.002 · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This paper introduces a new graph-based method for segmenting breast tumors in US images. BACKGROUND AND MOTIVATION: Segmentation for breast tumors in ultrasound (US) images is crucial for computer-aided diagnosis system, but it has always been a difficult task due to the defects inherent in the US images, such as speckles and low contrast.
The proposed segmentation algorithm constructed a graph using improved neighborhood models. In addition, taking advantages of local statistics, a new pair-wise region comparison predicate that was insensitive to noises was proposed to determine the mergence of any two of adjacent subregions.
Experimental results have shown that the proposed method could improve the segmentation accuracy by 1.5-5.6% in comparison with three often used segmentation methods, and should be capable of segmenting breast tumors in US images.
[Show abstract][Hide abstract] ABSTRACT: To quantify tumor blood flow by using contrast material-enhanced destruction-replenishment ultrasonography (US) to evaluate tumor response to different doses of an agent for antiangiogenic treatment in hepatoma-bearing mice, with histologic measurements of microvascular density (MVD) as the reference standard.
Experiments were approved by the regional animal care committee. Mice bearing subcutaneous H22 hepatoma were treated with different doses of thalidomide, 100 mg/kg in group B and 200 mg/kg in group C. Group A (control group) was treated with 0.5% carboxylmethylcellulose. Treatment groups and the control group included 10 mice each. Contrast-enhanced US was used to evaluate the percentage of nonenhanced area, and contrast-enhanced destruction-replenishment US was used to evaluate tumor blood flow. Tumor blood flow was compared with measurements of MVD. Comparisons were made by using one-way analysis of variance and the post hoc least significant difference test for multiple comparisons.
Contrast-enhanced gray-scale US showed significant increases in the percentage of nonenhanced area in group C (mean, 10.56% ± 7.25 [standard deviation]), as compared with groups A (mean, 2.40% ± 3.12; P = .004) and B (mean, 3.75% ± 5.55; P = .012). Contrast-enhanced destruction-replenishment US showed significant decreases of tumor blood flow in groups B and C, as compared with group A (P = .003 and P < .001, respectively), and the blood flow in group C was significantly lower than that of group B (P = .01). Immunohistochemical analysis revealed significant decreases of MVD in groups B and C, as compared with MVD in group A (P = .002 and P < .001, respectively); however, there was no significant difference in MVD between groups B and C (P = .21).
Quantification of tumor blood flow by using contrast-enhanced destruction-replenishment US shows the potential to guide drug dosage during antiangiogenic therapy.
[Show abstract][Hide abstract] ABSTRACT: To assess the validity of contrast-enhanced ultrasonic parametric perfusion imaging in the evaluation of antiangiogenic tumor treatment by using histology as the reference standard.
H22 hepatoma-bearing mice were treated with thalidomide or placebo by intraperitoneal injection. Contrast-enhanced ultrasound was performed on day 8 after bolus injection of SonoVue. Three different parametric perfusion images were calculated based on the following parameters: area under the curve (AUC), maximum intensity (IMAX) and perfusion index (PI). A score from 1 to 5 (1 = low, 5 = excellent) was used for analysis of parametric perfusion images by two independent readers. Immunohistochemical analysis was performed for evaluation of microvascular density (MVD).
Treatment with thalidomide resulted in a significant decrease in perfusion scores assigned to AUC, IMAX and PI parametric images as compared with control tumors (P < 0.001). Immunohistochemistry showed significant decreases of MVD in treated tumors as compared with control tumors (P = 0.002). MVD was positively correlated with the perfusion scores assigned to AUC parametric images (r = 0.568, P = 0.009), IMAX parametric images (r = 0.614, P = 0.004) and PI parametric images (r = 0.636, P = 0.003).
Contrast-enhanced ultrasonic parametric perfusion imaging provides a noninvasive tool to directly visualize tumor perfusion changes after antiangiogenic tumor treatment.
European journal of radiology 02/2011; 81(6):1360-5. DOI:10.1016/j.ejrad.2011.01.099 · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to quantify tumor blood perfusion with contrast-enhanced gray-scale ultrasound in the evaluation of tumor response to chemotherapy.
Mice bearing H22 hepatoma were treated with cisplatin or placebo by intraperitoneal injection. Contrast-enhanced gray-scale ultrasound was performed on day 8 after bolus injection of a lipid-based ultrasound contrast agent. Regions of interest within the tumor were analyzed offline to determine area under the curve, maximum intensity, perfusion index, mean transit time, time to peak, and quality of fit. Immediately after imaging, mice were euthanized, and tumor tissue was removed for fixation in 10% formalin solution. Microvascular density was measured after anti-CD34 staining.
The volume of treated tumors was significantly smaller than that of control tumors (p < 0.001). Treatment with cisplatin resulted in a significant decrease in perfusion index and maximum intensity compared with control tumors (p < 0.05). There were no significant differences between control and treated tumors (p > 0.05) with respect to area under the curve, mean transit time, and time to peak. The microvascular density of treated tumors was significantly lower than that of control tumors (p < 0.001).
Quantitative analysis of tumor blood perfusion with contrast-enhanced ultrasound can be used for noninvasive assessment of functional changes in tumors after chemotherapy.
American Journal of Roentgenology 01/2011; 196(1):W13-7. DOI:10.2214/AJR.10.4734 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate genes around the locus D4S2964 affected by loss of heterozygosity (LOH) and their clinical implications.
Four hundred and forty single nucleotide polymorphisms (SNPs) located at 49 genes around D4S2964 were selected from the National Center for Biotechnology Information website for the SNPs microarray fabrication. LOH of SNPs markers in 112 cases of hepatocellular carcinoma (HCC) tissues and paired adjacent liver tissues were investigated by the SNPs microarray. The correlation between allelic losses with clinicopathological features and overall survival was analyzed.
A fine map of LOH of SNPs in genes around D4S2964 was plotted. The average frequency of LOH in genes was 0.39. A correlation between cirrhosis and the FAL index (fractional allelic loss) was found (P = 0.0202). Larger tumor size was found to be significantly associated with LOH in genes ADP-ribosyltransferase 3 (ART3), nucleoporin 54 kDa (NUP54), scavenger receptor class B, member 2 (SCARB2) and coiled-coil domain containing 158 (CCDC158) (P = 0.043, P = 0.019, P = 0.001, P = 0.037, respectively). Kaplan-Meier analysis showed that patients with LOH in ARD1 homolog B (ARD1B) and septin 11 (SEPT11) had a significantly lower survival rate than those with retention (P = 0.021 and P = 0.004, respectively). A Cox regression model suggested that LOH in ARD1B and SEPT11, respectively, were predictors of the overall survival in HCC (P = 0.006 and P = 0.026, respectively).
LOH in genes around D4S2964 may play an important role in HCC development and progression. LOH in ARD1B and SEPT11 could serve as novel prognostic predictors in HCC patients.
World Journal of Gastroenterology 04/2010; 16(16):2046-54. DOI:10.3748/wjg.v16.i16.2046 · 2.37 Impact Factor