缺氧诱导因子-1α在兔VX2肝癌模型TACE术后的表达及其临床意义

目的 探讨缺氧诱导因子-1α(HIF-1α)在兔VX2肝癌模型TACE术后的表达及其与肿瘤血管生成的相关性.方法 24只荷VX2瘤兔随机分为3组,每组8只.对照组:经肝动脉注入生理盐水2ml;TAE组:单纯碘油(UFLP)0.5～0.8 ml栓塞,TACE组:碘油抗癌药混悬液(UFLP THP)栓塞,UFLP 0.5～O.8 ml,THP 2 mg.于术后2周应用免疫组化法分别检测肿瘤组织中HIF-1α、血管内皮生长因子(VEGF)的表达,用CD34单克隆抗体标记肿瘤血管内皮细胞,计数肿瘤组织中的微血管密度(MVD).结果 TAE组和TACE组HIF-1α、VEGF表达与MVD值均明显高于对照组,差异有统计学意义(P＜0.05),HIF-1α与VEGF的表达及MVD的变化呈正相关(rs=0.537,P＜0.01;rs=0.423,P＜0.05).结论 TACE能明显上调HIF-1α的表达,HIF-1α通过调控其下级基因VEGF的表达而促进肿瘤血管的生成,影响肝癌的预后.     

Transcatheter arterial embolization with 188Rhenium-HDD-labeled iodized oil in rabbit VX2 liver tumor

PURPOSE: To evaluate the antitumor effect of transcatheter arterial embolization (TAE) with use of rhenium 188 HDD (4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol)-labeled iodized oil and to compare it with that of transcatheter arterial chemoembolization (TACE) with use of an established chemotherapeutic agent and iodized oil in experimentally induced liver tumor. MATERIALS AND METHODS: VX2 carcinoma was grown in the livers of 57 rabbits. TAE was performed with (188)Re-HDD-labeled iodized oil (Re-Lp group; n = 21), doxorubicin/iodized oil emulsion (Dx-Lp group; n = 21), and iodized oil alone (n = 15). Sequential conjugated planar imaging was performed for dosimetry of the radioisotope in the Re-Lp group (n = 15). Growth ratio and percentage of viable tumor were estimated by computed tomography and histopathologic examination. Hepatic and hematologic toxicities were evaluated by biochemical analysis. RESULTS: On conjugated planar imaging, radioactivity was concentrated on the tumor (effective half-life, 16.2 hours), and mean radiation dose to the tumor was 147.7 Gy. The mean growth ratios 1, 2, and 3 weeks after TAE and the percentage of viable tumor in the Re-Lp group (-3.4, -7.6, -11.1, and 0.3%) and the Dx-Lp group (-3.2, -5.3, 29.0, and 2.6%) were significantly lower than the respective values in the iodized oil group (45.5, 145.4, 283.0, and 30.1%; P < .001). However, the differences between the values in the Re-Lp group and those in the Dx-Lp group were not significant (P values of .165-0.497 for growth ratios; P = .134 for percentage of viable tumor). There was similar transient hepatotoxicity in all three groups. CONCLUSIONS: TAE with (188)Re-HDD-labeled iodized oil has potent antitumor effect in VX2 liver tumor that is comparable with that of TACE with an established chemotherapeutic agent.     

Heated lipiodol as an embolization agent for transhepatic arterial embolization in VX2 rabbit liver cancer model

Purpose

To evaluate the therapeutic effect of heated (60 °C) lipiodol via hepatic artery administration in a rabbit model of VX2 liver cancer.

Materials and methods

Thirty male New Zealand white rabbits were randomly divided into three groups with 10 rabbits assigned to each group. VX2 carcinoma cells were surgically implanted into the left hepatic lobe. The tumors were allowed to grow for 2 weeks, and studies were performed until the diameter of the tumors detected by ultrasonograph reached 2-3 cm. Under anesthesia, trans-catheter hepatic arterial embolization was performed and doxorubicin-lipiodol (37 °C) (1 mL), lipiodol (60 °C) (1 mL) or control (physiological saline (37 °C) (1 mL)) solution was injected into the hepatic arteries of animals in the three groups. One week later, the volume of the tumor was measured by ultrasonograph again. The serum of all rabbits was collected before injection and at 4 and 7 days after injection, and the level of aspartate aminotransferase (AST) was checked. The survival period of the three groups of rabbits after treatment was also recorded. During the last course of their disease, the rabbits were given analgesics to relieve suffering.

Results

The tumor growth rate in the lipiodol (60 °C) group (0.92 ± 0.21, tumor volume from 1811 ± 435 to 1670 ± 564 mm³) was significantly lower than that in the control group (3.48 ± 1.17, tumor volume from 1808 ± 756 to 5747 ± 1341 mm³) (P < 0.05) and in the doxorubicin-lipiodol (37 °C) group (1.69 ± 0.26, tumor volume from 1881 ± 641 to 2428 ± 752 mm³) (P < 0.05). Consequently, the survival period of the animals in the lipiodol (60 °C) group (41.0 ± 3.0 days) was significantly greater than that in the doxorubicin-lipiodol (37 °C) group (38.0 ± 2.5 days) (P < 0.05). On the other hand, there was no statistically significant difference in serum AST levels between the lipiodol (60 °C) group (148.2 ± 11.3 U L⁻¹) and the doxorubicin-lipiodol (37 °C) group (139.7 ± 12.3 U L⁻¹) (P > 0.05). However, the serum AST level in the lipiodol (60 °C) group was significantly higher at 4 days after injection (P < 0.05) than in the control group (68.6 ± 6.6 U L⁻¹).

Conclusions

Treatment with lipiodol (60 °C) resulted in an effect on serum AST levels similar to that caused by treatment with doxorubicin-lipiodol (37 °C). Thus, lipiodol (60 °C) treatment could greatly prolong the survival period of rabbits with VX2 cancer by inhibiting tumor growth.     

Four-dimensional transcatheter intraarterial perfusion MRI monitoring of radiofrequency ablation of rabbit VX2 liver tumors

Purpose:

To investigate the hypothesis that four‐dimensional (4D) transcatheter intraarterial perfusion (TRIP) magnetic resonance imaging (MRI) can quantify immediate perfusion changes after radiofrequency (RF) ablation in rabbit VX2 liver tumors.

Materials and Methods:

Nine New Zealand White rabbits were used to surgically implant VX2 liver tumors. During ultrasound‐guided RF ablation, tumors received either a true or sham ablation. After selective catheterization of the left hepatic artery under x‐ray fluoroscopy, we acquired pre‐ and post‐RF ablation 4D TRIP MR images using 3 mL of 2.5% intraarterial gadopentetate dimeglumine. Two regions‐of‐interest were drawn upon each tumor to generate signal‐intensity time curves. Area under the curve (AUC) was calculated to provide semiquantitative perfusion measurements that were compared using a paired t‐test (α = 0.05). Ablated tissue was visually confirmed on pathology using Evans blue dye.

Results:

Mean AUC perfusion of VX2 tumors for the true ablation group decreased by 92.0% (95% confidence interval [CI]: 83.3%–100%), from 1913 (95% CI: 1557, 2269) before RF ablation to 76.6 (95% CI: 18.4, 134.8) after RF ablation (a.u., P < 0.001). Sham‐ablated tumors demonstrated no significant perfusion changes.

Conclusion:

4D TRIP MRI can quantify liver tumor perfusion reductions in VX2 rabbits after RF ablation. This MRI technique can potentially be used to improve tumor response assessment at the time of RF ablation. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.     

Comparison of transcatheter intraarterial perfusion MR imaging and fluorescent microsphere perfusion measurements during transcatheter arterial embolization of rabbit liver tumors

PURPOSE: Transcatheter intraarterial perfusion (TRIP) magnetic resonance (MR) imaging is clinically used in the interventional MR imaging setting to verify distribution of injected embolic or chemoembolic material during liver-directed transcatheter therapies and to monitor reductions in perfusion. The accuracy of this technique remains unknown. In the present study, rabbit VX2 liver tumors were used to test the hypothesis that TRIP MR imaging accurately measures changes in tumor perfusion during transcatheter arterial embolization (TAE), with injection of fluorescent microspheres used as the gold-standard technique. MATERIALS AND METHODS: Five New Zealand White rabbits were used for this study (two donor rabbits and three with VX2 liver tumors). In three rabbits with implanted VX2 liver tumors, catheters were superselectively placed under digital subtraction angiographic guidance into the left hepatic artery supplying the targeted tumor. Fluorescent microspheres were injected into each rabbit's left ventricle before and after TAE. TRIP MR images were obtained at baseline and after embolizations for all rabbits with intraarterial injections of 2.5% gadopentetate dimeglumine solution. Linear regression was used to compare relative reductions in tumor perfusion between TRIP MR imaging and fluorescent microspheres. Results were considered statistically significant at a P value less than .05. RESULTS: There was good correlation between TRIP MR imaging and fluorescent microsphere measurements of reduction in tumor perfusion (r = 0.722, P < .012). CONCLUSIONS: TRIP MR imaging provides accurate semiquantitative measurement of perfusion reduction during TAE in rabbit liver tumors.     

兔VX2肝癌动脉栓塞治疗前后血供变化与病理分析

目的：探讨兔VX2肝癌经导管肝动脉碘化油栓塞术前后的血供变化及病理特征。方法：将36只荷VX2肝癌实验兔随机分为实验组（A组,n=24）、假手术组（B组,n=6）及空白对照组（C组,n=6）。均于接种后第14、15天分别行CT扫描及肝动脉、门静脉DSA检查,A组同时行经导管碘化油栓塞肿瘤供血动脉,C组于DSA后处死。A、B组于第21、22天分别行CT平扫及DSA检查,并于DSA后处死。结果：CT及DSA检查证实35例（97．22％,35／36）为富血供肿瘤,且主要由肝动脉供血,仅1例为门静脉供血。第3周时A、B组DSA均示仍为肝动脉供血,无门静脉供血。栓塞后肿瘤组织主要由凝固性坏死及周边残存癌组织组成。结论：兔VX2肝癌大多数为富血供肿瘤且主要由肝动脉供血。经动脉碘化油栓塞不能完全阻断肿瘤血供,残癌组织仍为肝动脉供血,肝癌组织中的门静脉仅仅是解剖上的血流通过,并不参与肿瘤血供。     

Anti-tumour effects of transcatheter arterial embolisation administered in combination with thalidomide in a rabbit VX2 liver tumour model

Objective

Using a liver tumour model we investigated whether thalidomide enhances the anti-tumour effect of transcatheter arterial embolisation (TAE).

Method

First, the viability of VX2 tumour cells co-cultured with thalidomide in a 21% and 1% O₂ atmosphere was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Second, we randomly assigned 20 rabbits bearing VX2 liver tumours to 4 groups: Group 1 (thalidomide plus TAE), Group 2 (TAE only), Group 3 (thalidomide only) and Group 4 (control). Thalidomide was orally administered for 5 days. The anti-tumour effects were assessed by the tumour proliferation rate using MRI and by immunohistochemical analysis of the area of intratumoural vessels. Analysis of variance and Tukey''s honestly significant difference test were used for statistical analysis.

Results

The viability of cells grown under hypoxic and normal conditions was not significantly different, nor was there a difference among the four groups. The tumour size increased by 55.9±29.3% in Group 1, 250.6±73.3% in Group 2, 355.2±51.7% in Group 3 and 424.7±110.7% in Group 4; the difference between Group 1 and the other three groups was significant. The area of intratumour vessels in specimens was 0.22±0.28% in Group 1, 0.42±0.29% in Group 2, 1.44±1.00% in Group 3 and 6.00±2.17% in Group 4; the difference between Group 1 and the other groups was statistically significant, as was the difference between Groups 3 and 4.

Conclusion

Thalidomide used in combination with TAE enhanced anti-tumour effects in rabbits bearing VX2 liver tumours.     

Effects of the type of embolization particles on carboplatin concentration in liver tumors after transcatheter arterial chemoembolization in a rabbit model of liver cancer

PURPOSE: To study the effect of particle type used during transarterial hepatic chemoembolization (TACE) on carboplatin concentration after TACE in an animal model of liver cancer (VX2) and to determine the concentration of carboplatin within tumor, liver, and plasma. MATERIALS AND METHODS: The VX2 tumors were grown in the livers of 23 rabbits. Carboplatin (5 mg/kg) was selected because of its known potency against VX2 tumor. Group 1 was treated with TACE with tris-acryl gelatin microspheres (100-300 microm), group 2 was treated with TACE with polyvinyl alcohol (PVA; 150-250 microm), group 3 (control) was treated with intraarterial saline solution, and group 4 (pharmacokinetic) was treated with intraarterial carboplatin. Animals were killed after 48 hours, and concentrations of carboplatin were measured by atomic absorption spectroscopy from samples of blood and liver (central and peripheral zones of tumor and nontumorous liver tissue). RESULTS: In group 1 (tris-acryl gelatin microspheres) and group 2 (PVA), the mean carboplatin concentrations were 117 microg/g and 31.8 microg/g, respectively, within the central zone of the tumor and 38.5 mug/g versus 7.9 microg/g, respectively, in the peripheral zone. No carboplatin was detected in nontumorous liver tissue and plasma concentrations were low in both treated groups (<0.079 microg/mL). CONCLUSIONS: Carboplatin concentration was significantly greater (by a factor of two to four) within the central zone of the tumor compared with the peripheral zone in both treated groups. The overall tumor carboplatin concentrations were significantly greater in the tris-acryl gelatin microsphere group than in the PVA group (P < .001), which could translate into greater potency and tumor kill. Administration of tris-acryl gelatin microspheres may be clinically advantageous during TACE, as it contributed to greater delivery of chemotherapy to tumor in the present study.     

骨和肌肉组织肿瘤的超选择动脉栓塞术

目的 :探讨骨和肌肉组织肿瘤的超选择动脉栓塞术的临床价值。方法 :运用Seldinger技术 ,对 18例骨和肌肉组织肿瘤进行造影 ,灌注和超选择动脉栓塞术 ,栓塞材料运用明胶海绵粒加抗癌药浸泡。结果 :18例骨和肌肉组织肿瘤中14例进行了栓塞 ,其中彻底栓塞者 8例 ,部分栓塞 6例 ;栓后肿块明显缩小 ,有 10例栓后肿瘤切除术 ,术中出血减少 ,肿瘤切除容易、彻底 ;4例孤息性栓塞 ,疼痛减轻 ,生存质量改善。结论 :骨和肌肉组织肿瘤的超选择动脉栓塞术 ,能使肿块缩小 ,提高生存质量 ;特别是术前栓塞能减少术中出血 ,以利肿瘤切除     

Evaluation of different calibrated spherical polyvinyl alcohol microspheres in transcatheter arterial chemoembolization: VX2 tumor model in rabbit liver

PURPOSE: To assess whether porosity and compressibility of calibrated spherical polyvinyl alcohol (PVA) microspheres affect doxorubicin plasma and tumor concentrations after transcatheter arterial chemoembolization (TACE) in a VX2 rabbit model. MATERIALS AND METHODS: Fifteen rabbits were divided into three groups of five rabbits each. Three different types of calibrated spherical PVA microspheres with variable levels of porosity and compressibility were blindly evaluated. TACE was performed by injecting a mixture of doxorubicin (5 mg) and iodized oil (0.5 mL) followed by injection of the embolic material (0.3-0.5 mL). Plasma concentrations of doxorubicin and doxorubicinol were analyzed 20, 40, 60, and 120 minutes and 2 days after TACE, and liver tissue and tumor doxorubicin concentrations were measured 2 days after TACE. RESULTS: All calibrated spherical PVA microspheres showed similar patterns of plasma doxorubicin and doxorubicinol release and tumor concentration of doxorubicin. There were no significant differences of drug levels in either plasma or tumor in each group (P > .05). CONCLUSIONS: After TACE in a rabbit model of liver cancer, testing of three different types of spherical PVA microspheres with varying degrees of porosity and compressibility showed no significant differences in the plasma doxorubicin release pattern and tumor doxorubicin uptake.     

多体素1H-MRS对经导管肝动脉化疗栓塞联合内皮抑制素治疗兔VX2肝移植瘤的动态随访研究

目的 探讨多体素质子波谱(1H-MRS)在兔VX2肝移植瘤经导管肝动脉化疗栓塞(TACE)联合内皮抑制素(endostatin,ES)治疗过程中的动态随访应用价值.方法 建立兔VX2肝癌模型24只,二维超声监测肿瘤生长情况.待肿瘤长至约1 cm3大小,随机分为3组(每组8只):对照组(A组)经耳缘静脉给予生理盐水10 ml,连用9 d;TACE+ES组(B组)经肝动脉给予超液化碘油0.2 ml/kg和阿霉素2 mg/kg,并经耳缘静脉给予内皮抑制素0.7 mg·kg-1·d-1,连续应用9 d;ES组(C组)经耳缘静脉给予内皮抑制素0.7 mg·kg-1·d-1,连用9 d.干预处理前1天及处理后3,6,9 d行T1WI、T2WI及多体素1H-MRS检查.对Cho、Lip、Cr、Glyu、Glx的峰下面积及其与Lip峰下面积比值等指标行统计分析.结果 (1)3组肿瘤组织中各指标均有各自的动态变化趋势(P<0.01);(2)治疗后9 d,B组Glyu峰下面积及各代谢物峰下面积比值均小于C组(P<0.000 1);A组各代谢物峰下面积大于B、C组(P<0.000 1),而峰下面积比值小于B、C组(P<0.000 1).(3)干预处理后较前:①A组Cho、Lip、Cr、Glyu峰下面积升高(P<0.000 1),Cho/Lip、Cr/Lip、Glyu/Lip比值降低(P<0.014);②B组Cho、Cr、Glyu峰下面积降低(P<0.033),Cho/Lip、Cr/Lip、Glyu/Lip、Glx/Lip比值降低(P<0.002);③C组Cho峰下面积降低(P<0.000 1),Lip、Cr、Glyu、Glx峰下面积升高(P<0.048),Cho/Lip比值降低(P=0.015),Glx/Lip比值升高(P=0.027).结论 多体素1H-MRS可检测到兔VX2肝移植瘤TACE联合内皮抑制素治疗过程中主要代谢物的动态变化,从而可用于动态随访研究,还可对肿瘤治疗疗效及不同治疗方法的疗效进行比较.     

经肝动脉加热碘油栓塞治疗肝转移癌的疗效分析

目的评价经肝动脉加热碘油栓塞治疗肝转移癌的临床疗效。方法 126例肝转移癌患者分为两组,采用肝动脉加热碘油栓塞治疗的63例为加热组,采用常温碘油栓塞治疗的63例为常温组。并进行治疗前后肿瘤大小及肝功能等变化的对比分析。结果加热组有效率为61.90%(39/63),常温组有效率为47.62%(30/63),两组比较,差异有统计学意义(P<0.05)。两组术后肿瘤大小变化比较差异有统计学意义,肝功能变化比较差异无统计学意义。加热组6、12、18、24个月生存率分别为100%(63/63),84.13%(53/63),49.21%(31/63),25.40%(16/63);常温组分别为90.48%(57/63),63.49%(41/63),34.92%(22/63),12.70%(8/63)。同时,两组的术后恶心呕吐、肝区疼痛的发生率相比较,均有明显的统计学差异。结论经肝动脉加热碘油栓塞治疗肝转移癌的效果优于常温组的治疗,且不良反应发生率低。     

Transcatheter arterial chemoembolization with paclitaxel-lipiodol solution in rabbit VX2 liver tumor

PURPOSE: To evaluate the antitumor effects of transcatheter arterial chemoembolization (TACE) with a solution of an anticancer drug (Paclitaxel; Bristol-Myers Squibb, Princeton, NJ) and iodized oil (Lipiodol; Laboratoire Gurerbet, Aulnay-Sous-Bois, France) (hereafter, the solution), as well as intratumor concentration and hepatotoxicity, in experimentally induced liver tumor. MATERIALS AND METHODS: VX2 carcinoma was grown in livers of 30 rabbits. In 18 rabbits, TACE was performed with the high-dose solution (4 mg anticancer drug and 0.4 mL iodized oil, n = 6), the low-dose solution (1 mg anticancer drug and 0.4 mL iodized oil, n = 6), or iodized oil alone (0.4 mL, n = 6) in a control group. One week later, the growth ratio and residual viable proportion of the tumors were calculated on the basis of findings at spiral computed tomography and histopathologic examination. Hepatic and hematologic toxicities were evaluated by means of biochemical analysis. Differences between the three groups were statistically assessed with the Kruskal-Wallace and Mann-Whitney U tests. The remaining 12 animals were treated with the high-dose solution and serially sacrificed for clarification of chronologic change of concentration of the anticancer drug in liver tissues. RESULTS: Growth ratios and residual viable proportions of the tumors were significantly lower in the solution groups (high dose, 3.3% +/- 6.2 [mean +/- SD] and 2.8% +/- 3.6, respectively; low dose, 18.7% +/- 7.4 and 12.7% +/- 6.1, respectively) than in the control group (68.3% +/- 12.7 and 31.1% +/- 8.8, respectively) (P <.05). Hepatotoxicity was transient in all but one rabbit, which died 2 days after TACE with substantial biochemical changes. The anticancer drug accumulated in tumor where the concentration peaked at day 3 and returned to levels comparable to those for normal hepatic parenchyma at 7 days after TACE. CONCLUSION: TACE with the Paclitaxel-Lipiodol solution has dose-dependent antitumor effects without major toxicities in VX2 liver tumor.     

Effect of C-arm angiographic CT on transcatheter arterial chemoembolization of liver tumors

Rotational C-arm angiographic computed tomography (CT) with a flat-panel radiography unit permits three-dimensional (3D) reconstruction of soft tissues and blood vessels. The usefulness of this C-arm technique during transcatheter arterial chemoembolization (TACE) is unknown. The authors analyzed the role of the C-arm technique in 18 patients with unresectable liver tumors during TACE. The technique altered the catheter position anticipated by attending interventional radiologists in seven of the 18 patients (39%; 95% confidence interval [CI]: 20%, 61%) and improved the diagnostic confidence in the selected catheter position in 14 of the 18 patients (78%; 95% CI: 55%, 91%). The technique provides CT-like images that are useful to interventional radiologists during TACE.