Quantitative Study of Liver Magnetic Resonance Spectroscopy Quality at 3T Using Body and Phased Array Coils with Physical Analysis and Clinical Evaluation

This study aims to investigate the quality difference of short echo time (TE) breathhold 1H magnetic resonance spectroscopy (MRS) of the liver at 3.0T using the body and phased array coils, respectively. In total, 20 pairs of single-voxel proton spectra of the liver were acquired at 3.0T using the phased array and body coils as receivers. Consecutive stacks of breathhold spectra were acquired using the point resolved spectroscopy (PRESS) technique at a short TE of 30 ms and a repetition time (TR) of 1500 ms. The first spectroscopy sequence was “copied” for the second acquisition to ensure identical voxel positioning. The MRS prescan adjustments of shimming and water suppression, signal-to noise ratio (SNR), and major liver quantitative information were compared between paired spectra. Theoretical calculation of the SNR and homogeneity of the region of interest (ROI, 2 cm×2 cm×2 cm) using different coils loaded with 3D liver electromagnetic model of real human body was implemented in the theoretical analysis. The theoretical analysis showed that, inside the ROI, the SNR of the phase array coil was 2.8387 times larger than that of body coil and the homogeneity of the phase array coil and body coil was 80.10% and 93.86%, respectively. The experimental results showed excellent correlations between the paired data (all r > 0.86). Compared with the body coil group, the phased array group had slightly worse shimming effect and better SNR (all P values < .01). The discrepancy of the line width because of the different coils was approximately 0.8 Hz (0.00625 ppm). No significant differences of the major liver quantitative information of Cho/Lip2 height, Cho/Lip2 area, and lipid content were observed (all P values >0.05). The theoretical analysis and clinical experiment showed that the phased array coil was superior to the body coil with respect to 3.0T breathhold hepatic proton MRS.     

Radiofrequency Ablation of Liver VX2 Tumor: Experimental Results with MR Diffusion-Weighted Imaging at 3.0T

Purpose

To evaluate the value of DWI in detecting the lesions of pre- and post-radiofrequency ablation (RFA) of the rabbit liver VX2 tumors.

Materials and Methods

Twenty-two New Zealand White rabbits were tested. The protocol was approved by the Committee on the Ethics of Animal Experiments. Twenty separate tumor fragments were implanted into the livers of 20 rabbits, the liver was exposed by performing midline laparotomy. 3.0T MR DWI (b = 0, 200, 400, 600, 800,1000 s/mm²) were performed 14–21 days after tumor implantation (mean, 17 days) in the 18 tumor-bearing animals. Then RFA was performed in the 18 tumor-bearing animals and in the two healthy animals. 3.0T MR DWI was performed 7–10 days after RFA (mean, 8 days). Pathology exam was performed immediately after the completion of post- RFA MR imaging. Analyzing the features of MRI and ADC values in the pre- and post- RFA lesions of the VX2 tumors, and histopathologic results were compared with imaging findings.

Results

The difference of ADC value between viable tumor and normal liver parenchyma was significant (P<.001). After RFA, when b = 200, 400, 600, 800, 1000 s/mm², the differences of ADC values of viable tumor, granulation tissue, necrosis, normal liver parenchyma were significant (P<.001). At the time the animals were sacrificed after RFA and MR imaging, histopathologic results of local viable tumors were found in 9 (50%) of the 18 treated tumors. Macroscopic viable tumors were found at the RFA sites in 3 (17%), all 3 macroscopic viable tumors were visualized at the periphery of the RFA areas.

Conclusions

3.0T MR DWI can be used to follow up the progress of the RFA lesion, it is useful in detecting different tissues after RFA, and it is valuable in the further clinical research.     

Liquid-Solid Phase-Inversion PLGA Implant for the Treatment of Residual Tumor Tissue after HIFU Ablation

BackgroundHIFU has been shown to be a more suitable alternative for the treatment of primary solid tumors and metastatic diseases than other focal heat ablation techniques due to its noninvasive and extracorporeal nature. However, similar to other focal heat ablation techniques, HIFU is still in need of refinements due to tumor recurrence.MethodsIn this work, we investigated the effectiveness of an adjunct treatment regimen using doxorubicin (DOX)-loaded, injectable, in situ-forming, and phase-inverting PLGA as the second line of defense after HIFU ablation to destroy detrimental residual tumors and to prevent tumor recurrence. All of the statistical analyses were performed using the Statistical Package for the Social Sciences 18.0(SPSS, Inc., Chicago, IL, USA), and p< 0.05 was considered statistically significant. All of the results are presented as the means ± STDEV (standard deviation). For multiple comparisons, ANOVA (differences in tumor volumes, growth rates, apoptosis, proliferation indexes, and Bcl-2 and Bax protein levels) was used when the data were normally distributed with homogenous variance, and rank sum tests were used otherwise. Once significant differences were detected, Student-t tests were used for comparisons between two groups.ResultsOur results revealed that DOX diffused beyond the ablated tissue regions and entered tumor cells that were not affected by the HIFU ablation. Our results also show that HIFU in concert with DOX-loaded PLGA led to a significantly higher rate of tumor cell apoptosis and a lower rate of tumor cell proliferation in the areas beyond the HIFU-ablated tissues and consequently caused significant tumor volume shrinkage (tumor volumes:0.26±0.1,1.09±0.76, and 1.42±0.9cm³ for treatment, sham, and no treatment control, respectively).ConclusionsFrom these results, we concluded that the intralesional injection of DOX-loaded PLGA after HIFU ablation is significantly more effective than HIFU alone for the treatment of solid tumors.     

An Ultrasound Image-Based Dynamic Fusion Modeling Method for Predicting the Quantitative Impact of In Vivo Liver Motion on Intraoperative HIFU Therapies: Investigations in a Porcine Model

Organ motion is a key component in the treatment of abdominal tumors by High Intensity Focused Ultrasound (HIFU), since it may influence the safety, efficacy and treatment time. Here we report the development in a porcine model of an Ultrasound (US) image-based dynamic fusion modeling method for predicting the effect of in vivo motion on intraoperative HIFU treatments performed in the liver in conjunction with surgery. A speckle tracking method was used on US images to quantify in vivo liver motions occurring intraoperatively during breathing and apnea. A fusion modeling of HIFU treatments was implemented by merging dynamic in vivo motion data in a numerical modeling of HIFU treatments. Two HIFU strategies were studied: a spherical focusing delivering 49 juxtapositions of 5-second HIFU exposures and a toroidal focusing using 1 single 40-second HIFU exposure. Liver motions during breathing were spatially homogenous and could be approximated to a rigid motion mainly encountered in the cranial-caudal direction (f = 0.20Hz, magnitude >13mm). Elastic liver motions due to cardiovascular activity, although negligible, were detectable near millimeter-wide sus-hepatic veins (f = 0.96Hz, magnitude <1mm). The fusion modeling quantified the deleterious effects of respiratory motions on the size and homogeneity of a standard “cigar-shaped” millimetric lesion usually predicted after a 5-second single spherical HIFU exposure in stationary tissues (Dice Similarity Coefficient: DSC<45%). This method assessed the ability to enlarge HIFU ablations during respiration, either by juxtaposing “cigar-shaped” lesions with spherical HIFU exposures, or by generating one large single lesion with toroidal HIFU exposures (DSC>75%). Fusion modeling predictions were preliminarily validated in vivo and showed the potential of using a long-duration toroidal HIFU exposure to accelerate the ablation process during breathing (from 0.5 to 6 cm³·min^-1). To improve HIFU treatment control, dynamic fusion modeling may be interesting for assessing numerically focusing strategies and motion compensation techniques in more realistic conditions.     

Noninvasive Assessment of Gene Transfer and Expression by In Vivo Functional and Morphologic Imaging in a Rabbit Tumor Model

Purpose

To evaluate the importance of morphology in quantifying expression after in vivo gene transfer and to compare gene expression after intra-arterial (IA) and intra-tumoral (IT) delivery of adenovirus expressing a SSTR2-based reporter gene in a large animal tumor model.

Materials and Methods

Tumor directed IA or IT delivery of adenovirus containing a human somatostatin receptor type 2A (Ad-CMV-HA-SSTR2A) gene chimera or control adenovirus (Ad-CMV-GFP) was performed in VX2 tumors growing in both rabbit thighs. Three days later, ¹¹¹In-octreotide was administered intravenously after CT imaging using a clinical scanner. ¹¹¹In-octreotide uptake in tumors was evaluated the following day using a clinical gamma-camera. Gene expression was normalized to tumor weight with and without necrosis. This procedure was repeated on nine additional rabbits to investigate longitudinal gene expression both 5 days and 2 weeks after adenovirus delivery. CT images were used to evaluate tumor morphology and excised tissue samples were analyzed to determine ¹¹¹In-octreotide biodistribution ex vivo.

Results

VX2 tumors infected with Ad-CMV-HA-SSTR2 had greater ¹¹¹In-octreotide uptake than with control virus (P<0.05). Intra-arterial and intra-tumoral routes resulted in similar levels of gene expression. Longitudinally, expression appeared to wane at 2 weeks versus 5 days after delivery. Areas of necrosis did not demonstrate significant uptake ex vivo. Morphology identified areas of necrosis on contrast enhanced CT and upon excluding necrosis, in vivo biodistribution analysis resulted in greater percent injected dose per gram (P<0.01) and corresponded better with ex vivo biodistribution(r = 0.72, P<0.01, Coefficient of the x-variable = .72) at 2 weeks than without excluding necrosis (P<0.01).

Conclusion

Tumor specificity and high transgene expression can be achieved in tumors via both tumor directed intra-arterial and intra-tumoral delivery in a large animal tumor model. Using clinical machines, morphologic imaging contributes to functional imaging for quantifying SSTR2-based reporter expression in vivo.     

Differences between Spinocerebellar Ataxias and Multiple System Atrophy-Cerebellar Type on Proton Magnetic Resonance Spectroscopy

Purpose

A broad spectrum of diseases can manifest cerebellar ataxia. In this study, we investigated whether proton magnetic resonance spectroscopy (MRS) may help differentiate spinocerebellar ataxias (SCA) from multiple systemic atrophy- cerebellar type (MSA-C).

Material and Methods

This prospective study recruited 156 patients with ataxia, including spinocerebellar ataxia (SCA) types 1, 2, 3, 6 and 17 (N = 94) and MSA-C (N = 62), and 44 healthy controls. Single voxel proton MRS in the cerebellar hemispheres and vermis were measured. The differences were evaluated using nonparametric statistic tests.

Results

When compared with healthy controls, the cerebellar and vermis NAA/Cr and NAA/Cho were lower in all patients(p<0.002). The Cho/Cr was lower in SCA2 and MSA-C (p<0.0005). The NAA/Cr and Cho/Cr were lower in MSA-C or SCA2 comparing with SCA3 or SCA6. The MRS features of SCA1 were in between (p<0.018). The cerebellar NAA/Cho was lower in SCA2 than SCA1, SCA3 or SCA6 (p<0.04). The cerebellar NAA/Cho in MSA-C was lower than SCA3 (p<0.0005). In the early stages of diseases (SARA score<10), significant lower NAA/Cr and NAA/Cho in SCA2, SCA3, SCA6 or MSA-C were observed comparing with healthy controls (p<0.017). The Cho/Cr was lower in MSA-C or SCA2 (p<0.0005). Patients with MSA-C and SCA2 had lower NAA/Cr and Cho/Cr than SCA3 or SCA6 (p<0.016).

Conclusion

By using MRS, significantly lower NAA/Cr, Cho/Cr and NAA/Cho in the cerebellar hemispheres and vermis were found in patients with ataxia (SCAs and MSA-C). Rapid neuronal degeneration and impairment of membrane activities were observed more often in patients with MSA-C than those with SCA, even in early stages. MRS could also help distinguish between SCA2 and other subtypes of SCAs. MRS ratios may be of use as biomarkers in early stages of disease and should be further assessed in a longitudinal study.     

Comparison of Ablation Zones among Different Tissues Using 2450-MHz Cooled-Shaft Microwave Antenna: Results in Ex Vivo Porcine Models

Background

For complete tumor ablation in different tissues, it is necessary to investigate the exact coagulation zone of microwave ablation in different tissues. The aim of this study was to compare the extent of microwave ablation zone in muscle, liver and adipose tissue in ex vivo porcine models and assess the shape of microwave coagulation zone among these tissues.

Materials and Methods

Microwave ablations were performed in ex vivo porcine muscle, liver and adipose tissue using 2450-MHz cooled-shaft microwave antenna. The content of water, fat and protein in these three tissues was determined. Two power increments (40 and 80 W) and five time increments (1, 3, 5, 7, and 10 minutes) were used in this study. Diameters and shapes of the ablation zones were assessed on gross specimens.

Results

The average percentages of water, fat and protein in these three tissues were significantly different (P < 0.001), respectively. The long-axis and short-axis diameters among these three tissues at each time-power combination were not significantly different (P > 0.05). The coagulation zones were all elliptical in muscle, liver and adipose tissue. When microwave ablation was performed in the tissue containing both muscle and adipose tissue, the coagulation zone was also elliptical. Regardless of the output power, the ellipticity index (EI) value of 1 minute treatment duration was higher than that of 10 minutes treatment duration (P < 0.05). Furthermore, the EI value did not decrease significantly when the treatment duration was more than 5 minutes (P > 0.05).

Conclusion

The extent of microwave ablation zones was not significantly different among completely different tissues. Microwave ablations with ≥ 5 minutes time duration can induce coagulation zones with clinical desirable shape. Future clinical studies are still required to determine the role of microwave ablation in different tissues.     

The liver X receptor agonist TO901317 protects mice against cisplatin-induced kidney injury

Liver X receptors are in the nuclear receptor superfamily and are contained in the regulation of lipid and cholesterol metabolism. Besides, liver X receptors are considered crucial regulators of the inflammatory response and innate immunity. The current study evaluates the in vivo effects that the synthetic liver X receptor agonist TO901317 protects against cisplatin-induced kidney injury in mice. Mice received cisplatin administration through a single intraperitoneal injection (20 mg/kg in saline). And then the mice were treated with the TO901317 by daily gavage (10 mg/kg/day) 12 h postcisplatin administration, and cisplatin nephrotoxicity was evaluated. At 72 h after cisplatin treatment, elevated plasma urea and creatinine levels (P < 0.05) were evidenced which indicates the renal dysfunction of the vehicle-treated mice, consistent with tubular necrosis, protein cast, dilation of renal tubules, and desquamation of epithelial cells in renal tubules. In contrast, the severity of renal dysfunction and histological damage was reduced in TO901317 treated mice (P < 0.05). In accordance, circulating tumor necrosis factor alpha levels, renal tumor necrosis factor alpha, p47^phox, gp91^phox, and protein expression levels and COX-2 mRNA, renal monocyte chemoattractant protein 1, VACAM-1 mRNA and intercellular adhesion molecule-1 contents, and renal prostaglandin E₂ amounts, were higher in samples from cisplatin-treated mice in comparison with controls (P < 0.05) but attenuated in the TO901317 treatment group (P < 0.05). Taken together, treatment with the liver X receptor agonist TO901317 ameliorated the inflammatory response and oxidative stress in cisplatin-induced kidney injury in mice.     

Hepatic Parenchymal Changes following Transcatheter Embolization and Chemoembolization in a Rabbit Tumor Model

Objective

To compare the effects of transcatheter arterial chemoembolization (TACE) with transcatheter arterial embolization (TAE) on liver function, hepatic damage, and hepatic fibrogenesis in a rabbit tumor model.

Materials and Methods

Thirty-nine New Zealand white rabbits implanted with VX2 tumors in the left liver lobes were randomly divided into three groups: TAE, TACE, and control group. In the TAE group (n = 15), polyvinyl alcohol particles (PVAs) were used for left hepatic artery embolization. In the TACE group (n = 15), the tumors were treated with left hepatic arterial infusions of a suspension of 10-hydroxycamptothecin and lipiodol, followed by embolization with PVAs. In the control group (n = 9), the animals received sham treatment with distilled water. Serum and liver samples were collected at 6 hours, 3 days and 7 days after treatment. Liver damage was measured using a liver function test and histological analyses. Liver fibrogenesis and hepatic stellate cell (HSC) activation were evaluated using Sirius Red and anti-alpha-smooth muscle actin (α-SMA) immunohistochemical stains.

Results

TACE caused liver injury with greater increases in serum alanine aminotransferase and aspartate aminotransferase levels on day 3 (P<0.05). Histological analyses revealed increased hepatic necrosis in adjacent non-tumorous liver tissue from day 3 compared to the TAE group (Suzuki score of 2.33±1.29 versus 1.13±1.18, P = 0.001). HSC activation and proliferation were significantly increased in the TACE group compared to the control group at 3 and 7 days after treatment (0.074±0.014 vs. 0.010±0.006, and 0.088±0.023 vs. 0.017±0.009, P<0.05). Sirius Red staining demonstrated a statistically significant increase in collagen deposition in the livers in the TACE group 7 days after embolization compared to the control group (0.118±0.012 vs. 0.060±0.017, P = 0.05).

Conclusion

The results of this animal study revealed that TACE induced prominent hepatocellular damage and hepatic fibrogenesis, which compromised liver function and may be responsible for chronic liver decompensation.     

Effective Strategy of the Combination of High-Intensity Focused Ultrasound and Transarterial Chemoembolization for Improving Outcome of Unresectable and Metastatic Hepatoblastoma: a Retrospective Cohort Study

The combination of high-intensity focused ultrasound (HIFU) and transarterial chemoembolization (TACE) has been experimentally performed in a variety of malignant tumors, and its validity has not yet been evaluated for hepatoblastoma (HB). We evaluated the disease-response rate, resection rate, and toxicity in children with unresectable or metastatic HB (stage III and stage IV HB) after sequential treatment with TACE plus HIFU in a controlled clinical trial. The 35 patients with unresectable or metastatic HB were nonrandomly assigned to HIFU ablation (n = 12) or C5V chemotherapy (n = 23). The rates of complete resection, tumor response, and treatment toxicity were evaluated for both regimens. Nine patients who received C5V and 10 patients who received TACE plus HIFU became operable (P = .02). The 3-year event-free survival and overall survival rates were 43.03% and 56.68% in the C5V group and 38.57% and 57.86% in the TACE plus HIFU group, respectively. Acute grade 3 or 4 adverse events, including neutropenia, thrombocytopenia, and anemia, were more frequent in patients treated with C5V therapy than in patients receiving TACE plus HIFU. HIFU ablation achieved a higher rate of complete resection and a lower rate of severe complications compared with C5V treatment in children with advanced HB (Chinese Clinical Trials Registry No. ChiCTR-PRCH-08000182).     

Intravoxel Incoherent Motion Diffusion Weighted MR Imaging for Monitoring the Instantly Therapeutic Efficacy of Radiofrequency Ablation in Rabbit VX2 Tumors without Evident Links between Conventional Perfusion Weighted Images

ObjectiveTo investigate the intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) as a potential valuable marker to monitor the therapy responses of VX2 to radiofrequency ablation (RF Ablation).MethodsThe institutional animal care and use committee approved this study. In 10 VX2 tumor–bearing rabbits, IVIM-DWI examinations were performed with a 3.0T imaging unit by using 16 b values from 0 to 800 sec/mm². The true diffusion coefficient (D), pseudodiffusion coefficient (D^*) and perfusion fraction (f) of tumors were compared between before and instantly after RF Ablation treatment. The differences of D, D^* and f and conventional perfusion parameters (from perfusion CT and dynamic enhanced magnetic resonance imaging, DCE-MRI) in the coagulation necrosis area, residual unablated area, untreated area, and normal control had been calculated by compared t- test. The correlation between f or D^* with perfusion weighted CT including blood flow, BF (milliliter per 100 mL/min), blood volume, BV (milliliter per 100 mL/min), and capillary permeability–surface area, PMB (as a fraction) or from DCE-MRI: transfer constant (K_trans), extra-vascular extra-cellular volume fraction (V_e) and reflux constant (K_ep) values had been analyzed by region-of-interest (ROI) methods to calculate Pearson’s correlation coefficients.ResultsIn the ablated necrosis areas, f and D^* significantly decreased and D significantly increased, compared with residual unblazed areas or untreated control groups and normal control groups (P < 0.001). The IVIM-DWI derived f parameters showed significant increases in the residual unablated tumor area. There was no significant correlations between f or D^* and conventional perfusion parameters.ConclusionsThe IVIM-DW derived f, D and D^* parameters have the potential to indicate therapy response immediately after RF Ablation treatment, while no significant correlations with classical tumor perfusion metrics were derived from DCE-MRI and perfusion-CT measurements.     

Dynamical Observation on Biological Progression of VX2 Liver Tumors to Identify the Optimal Time for Intervention in Animal Models

Purpose

Based on practice guideline of “management of hepatocellular carcinoma (HCC): update” published by American Association for the Study of Liver Diseases (AASLD) and “Barcelona Clinic Liver Cancer staging system (BCLC),” this study investigated how to enroll the optimal VX2 liver tumor model for HCC researches by dynamically observing the biological progression of the tumor.

Materials

Thirty-two healthy New Zealand white rabbits were implanted VX2 liver tumor by cell suspension method (n=24) and tissue fragment method (n=8). All the rabbits underwent CT scans on day 7, 14, 21 and 28 after implantation to observe the size of the tumors, the time when metastases and ascites occurred and the survival time. Appropriate intervention times were estimated corresponding to different clinical HCC stages by using tumor diameter-time curve.

Results

The VX2 liver tumors grew rapidly within 28 days after implantation. And the tumors in the cell suspension group grew faster than those of the tissue fragment group. The appropriate intervention time corresponding to very early stage, early stage and intermediate stage were <11 days, 11–16.9 days and >16.9 days, respectively in the cell suspension group, and <19.9 days, 19.9–25.5 days and >25.5 days, respectively in the tissue fragment group.

Conclusion

Preclinical animal research needs to improve on different levels to yield best predictions for human patients. Researchers should seek for an individualized proposal to select optimal VX2 liver tumor models for their experiments. This approach may lead to a more accurate determination of therapeutic outcomes.     

Thermochemical Ablation Therapy of VX2 Tumor Using a Permeable Oil-Packed Liquid Alkali Metal

Objective

Alkali metal appears to be a promising tool in thermochemical ablation, but, it requires additional data on safety is required. The objective of this study was to explore the effectiveness of permeable oil-packed liquid alkali metal in the thermochemical ablation of tumors.

Methods

Permeable oil-packed sodium–potassium (NaK) was prepared using ultrasonic mixing of different ratios of metal to oil. The thermal effect of the mixture during ablation of muscle tissue ex vivo was evaluated using the Fluke Ti400 Thermal Imager. The thermochemical effect of the NaK-oil mixture on VX2 tumors was evaluated by performing perfusion CT scans both before and after treatment in 10 VX2 rabbit model tumors. VX2 tumors were harvested from two rabbits immediately after treatment to assess their viability using trypan blue and hematoxylin and eosin (H.E.) staining.

Results

The injection of the NaK–oil mixture resulted in significantly higher heat in the ablation areas. The permeable oil controlled the rate of heat released during the NaK reaction with water in the living tissue. Perfusion computed tomography and its parameter map confirmed that the NaK–oil mixture had curative effects on VX2 tumors. Both trypan blue and H.E. staining showed partial necrosis of the VX2 tumors.

Conclusions

The NaK–oil mixture may be used successfully to ablate tumor tissue in vivo. With reference to the controlled thermal and chemical lethal injury to tumors, using a liquid alkali in ablation is potentially an effective and safe method to treat malignant tumors.     

兔肝VX2肿瘤射频消融术后残癌中基质金属蛋白酶9表达

目的:探讨兔肝脏VX2肿瘤射频消融术(radio-frequency ablation,RFA)后残余肿瘤组织中基质金属蛋白酶9(MMP-9)表达。方法:超声引导下将VX2肿瘤组织块接种于23只新西兰大白兔肝脏中,造模成功后随机分为5组,对照组(A组,n=3),不行RFA治疗;余20只为实验组行RFA治疗,在超声引导下射频针插入肿瘤偏心位置,展开电极致损毁范围最大为肿瘤总体积的2/3,人为造成残存肿瘤组织。根据治疗结束后不同时间点分为4组:0小时组(B组,n=5)、术后1周组(C组,n=5)、术后2周组(D组,n=5)、术后4周组(E组,n=5),行超声检查结束后处死大白兔,取肿瘤组织采取免疫组化法观察残存肿瘤组织中及未治疗肿瘤组中MMP-9的表达情况。结果:RFA术后0小时、1周、2周、4周残存肿瘤组织中MMP-9的表达均较对照组明显降低(P0.05)。结论:RFA治疗后残存肿瘤细胞中MMP-9水平表达减低。     

Effect of Transcatheter Intraarterial Therapies on the Distribution of Doxorubicin in Liver Cancer in a Rabbit Model

Background and Aims

Transcatheter intraarterial techniques can effectively deliver chemotherapeutic agents to tumor and improve the efficacy of chemotherapy. The present study is designed to evaluate the effect of transcatheter intraarterial techniques on the distribution of doxorubicin in relation to blood vessels in liver cancer.

Methods

VX2 tumors were implanted in the livers of 32 rabbits. The animals were divided into 4 groups of 8 animals each. Group 1 (doxo iv) animals received doxorubicin intravenous injection; group 2 (doxo ia) received doxorubicin hepatic intraarterial infusion; group 3 (doxo ia + E) received doxorubicin hepatic intraarterial infusion followed by embolization; group 4 (doxo + L ia + E) received hepatic intraarterial infusion of doxorubicin mixed with Lipiodol followed by embolization. Ten minutes or 4 hours after treatment, the animals were sacrificed and tumors were sampled. Immunofluorescence techniques were used to evaluate the distribution of doxorubicin in relation to blood vessels.

Results

Doxorubicin fluorescence was distributed around tumor blood vessels and decreased with distance from the blood vessels. Tumor cells in avascular and adjacent regions were not exposed to detectable concentrations of doxorubicin. Tumors in the group 2, 3 and 4 had a significant increase in doxorubicin penetration compared with the group 1 tumors (P<0.05). Among the three groups of transcatheter therapies, doxorubicin penetration distance in group 3 was significantly larger than that in group 2 and 4 (P<0.05), and no significant difference was found between group 2 and 4 tumors (P>0.05) at 10 minutes. In contrast, at 4 hours and in total, both group 3 and 4 tumors had significant increases in drug penetration compared with group 2 (P<0.05), and no significant difference was noted between group 3 and 4 tumors (P>0.05).

Conclusion

Transcatheter intraarterial therapies improve doxorubicin penetration in liver cancer; nevertheless their effect on drug distribution is somewhat limited.     

Noninvasive Assessment of Response to Neoadjuvant Chemotherapy in Osteosarcoma of Long Bones with Diffusion-Weighted Imaging: An Initial In Vivo Study

Objectives

The purpose of our study is to investigate whether diffusion-weighted imaging (DWI) is useful for monitoring the therapeutic response after neoadjuvant chemotherapy in osteosarcoma of long bones.

Materials and methods

Conventional magnetic resonance imaging (MRI) and DWI were obtained from 35 patients with histologically proven osteosarcomas. MR examinations were performed in all patients before and after 4 courses of preoperative neoadjuvant chemotherapy. Apparent diffusion coefficients (ADC) were measured. The degree of tumor necrosis was assessed macroscopically and histologically by two experienced pathologists after operation. Student’s t test was performed for testing changes in ADC value. Pearson’s correlation coefficient was used to estimate the correlation between necrosis rate and post- neoadjuvant chemotherapy ADC values. P<0.05 was considered to denote a significant difference.

Results

The difference of the whole osteosarcoma between pre- neoadjuvant chemotherapy ADC value (1.24±0.17×10⁻³ mm²/s) and post- (1.93±0.39×10⁻³ mm²/s) was significant difference (P<0.01). Regarding in patients with good response, the post- neoadjuvant chemotherapy values were significantly higher than the pre- neoadjuvant chemotherapy values (P<0.01). The post- neoadjuvant chemotherapy ADC value in patients with good response was higher than that of poor response (t = 8.995, P<0.01). The differences in post- neoadjuvant chemotherapy ADC between viable (1.03±0.17×10⁻³ mm²/s) and necrotic (2.38±0.25×10⁻³ mm²/s) tumor was highly significant (t = 23.905, P<0.01). A positive correlation between necrosis rates and the whole tumor ADC values (r = 0.769, P<0.01) was noted, but necrosis rates were not correlated with the ADC values of necrotic (r = −0.191, P = 0.272) and viable tumor areas (r = 0.292, P = 0.089).

Conclusions

DWI can identify residual viable tumor tissues and tumor necrosis induced by neoadjuvant chemotherapy in osteosarcoma. The ADC value can directly reflect the degree of tumor necrosis, and it is useful to evaluate the preoperative neoadjuvant chemotherapy response in patients with osteosarcoma.     

Assessment of Early Tumor Response to Cytotoxic Chemotherapy with Dynamic Contrast-Enhanced Ultrasound in Human Breast Cancer Xenografts

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 (P<0.01) 2 days after therapy. There were significant differences of tumor volumes between control and treated groups on day 6 (P<0.001) while there were no significant differences in tumor volume on days 0, 2 and 4 (P>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 (P<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.     

Remifentanil up‐regulates HIF1α expression to ameliorate hepatic ischaemia/reperfusion injury via the ZEB1/LIF axis

Ischaemia/reperfusion (I/R)‐induced hepatic injury is regarded as a main reason of hepatic failure after transplantation or lobectomy. The current study aimed to investigate how the opioid analgesic remifentanil treatment affects I/R‐induced hepatic injury and explore the possible mechanisms related to HIF1α. Initially, an I/R‐induced hepatic injury animal model was established in C57BL/6 mice, and an in vitro hypoxia‐reoxygenation model was constructed in NCTC‐1469 cells, followed by remifentanil treatment and HIF1α silencing treatment. The levels of blood glucose, lipids, alanine transaminase (ALT) and aspartate transaminase (AST) in mouse serum were measured using automatic chemistry analyser, while the viability and apoptosis of cells were detected using CCK8 assay and flow cytometry. Our results revealed that mice with I/R‐induced hepatic injury showed higher serum levels of blood glucose, lipids, ALT and AST and leukaemia inhibitory factor (LIF) expression, and lower HIF1α and ZEB1 expression (P < .05), which were reversed after remifentanil treatment (P < .05). Besides, HIF1α silencing increased the serum levels of blood glucose, lipids, ALT and AST (P < .05). Furthermore, hypoxia‐induced NCTC‐1469 cells exhibited decreased HIF1α and ZEB1 expression, reduced cell viability, as well as increased LIF expression and cell apoptosis (P < .05), which were reversed by remifentanil treatment (P < .05). Moreover, HIF1α silencing down‐regulated ZEB1 expression, decreased cell viability, and increased cell apoptosis (P < .05). ZEB1 was identified to bind to the promoter region of LIF and inhibit its expression. In summary, remifentanil protects against hepatic I/R injury through HIF1α and downstream effectors.     

Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts

Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN-007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals [(Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05)], as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRα pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-α (platelet-derived growth factor receptor-α) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRα pathway, and could be considered as an additional therapy for pediatric brain tumor patients.     

Wnt/β‐catenin signalling controls bile duct regeneration by regulating differentiation of ductular reaction cells

Recently, the incidence of bile duct‐related diseases continues to increase, and there is no effective drug treatment except liver transplantation. However, due to the limited liver source and expensive donations, clinical application is often limited. Although current studies have shown that ductular reaction cells (DRCs) reside in the vicinity of peribiliary glands can differentiate into cholangiocytes and would be an effective alternative to liver transplantation, the role and mechanism of DRCs in cholangiole physiology and bile duct injury remain unclear. A 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC)‐enriched diet was used to stimulate DRCs proliferation. Our research suggests DRCs are a type of intermediate stem cells with proliferative potential that exist in the bile duct injury. Meanwhile, DRCs have bidirectional differentiation potential, which can differentiate into hepatocytes and cholangiocytes. Furthermore, we found DRCs highly express Lgr5, and Lgr5 is a molecular marker for neonatal DRCs (P < .05). Finally, we confirmed Wnt/β‐catenin signalling achieves bile duct regeneration by regulating the expression of Lgr5 genes in DRCs (P < .05). We described the regenerative potential of DRCs and reveal opportunities and source for the treatment of cholestatic liver diseases.