放射性粒子^125I联合TACE治疗兔VX2肝肿瘤的实验研究

目的：通过研究不同活度的125I粒子以及联合TACE治疗兔VX2肝移植癌的疗效及其病理基础,探讨125I粒子组织间植入治疗肝癌的有效性。方法：建立兔VX2肝癌模型。60只肝癌模型兔随机分成5组,对照组（A组）植入空白剂量（0mCi）125I粒子,B组植入1.0mCi125I粒子,C组植入0.7mCi125I粒子,D组植入0.4mCi125I粒子,E组植入0.7mCi125I粒子＋TACE。观察植入前后各组肿瘤体积并计算抑瘤率,切除肿瘤组织及周围正常组织进行常规病理检查。结果：各治疗组肿瘤大小在治疗前后比较具有统计学差异（P〈0.01）,均小于同期对照组（A组）（P〈0.01）。在不同观察时期抑瘤率差别均有统计学意义（P〈0.05）,各个组间抑瘤率差异在治疗后2周最为明显（P〈0.01）,但均高于D组（P〈0.01）。治疗后6周病理提示D组部分组织内仍可见少量肿瘤细胞,而其余各治疗组均未见明显的肿瘤细胞残存,B组对周围肝组织损伤较大,C组、E组适中。总体疗效E组优于其余各治疗组。结论：125I粒子联合TACE治疗肝癌效果明显优于单一的治疗方案,是肝癌目前较为理想的治疗方案,其中单个粒子活度以0.7mCi左右较为适宜。     

氩氦刀联合~(125)I粒子植入治疗原发性肝癌的疗效观察

目的探讨氩氦刀联合125I粒子植入治疗中晚期原发性肝癌(PHC)的疗效及安全性。方法选择我院2010年1月~2014年12月收治的中晚期PHC患者72例,将其中38例采用氩氦刀联合125I粒子植入治疗的中晚期PHC患者为观察组,34例单纯予氩氦刀治疗的中晚期PHC患者为对照组,观察两组患者的临床疗效、肿瘤组织CT值和KPS评分及AFP值变化,比较两组不良反应发生率。结果观察组术后3个月和6个月的治疗总有效率为100%和97.4%,显著高于对照组的82.3%和76.5%(均P0.01);而且观察组术后3个月和6个月CT值均较对照组显著降低(均P0.01),KPS评分较对照组明显升高(P0.01),AFP值较对照组显著降低(P0.01)。两组术中均无严重并发症发生,术后不良反应发生率比较差异无统计学意义(P0.05)。结论氩氦刀联合125I粒子植入治疗中晚期PHC,具有微创、安全、高效的优点,有广阔的临床应用前景。     

肝动脉化疗栓塞术联合碘125粒子植入对原发性肝癌合并门静脉癌栓患者血清TSGF、TK-1、sB7-H3水平的影响

摘要 目的：观察肝动脉化疗栓塞术（TACE）联合碘125粒子植入治疗原发性肝癌（PHC）合并门静脉癌栓（PVTT）的疗效及对血清恶性肿瘤特异性生长因子（TSGF）、胸苷激酶1（TK-1）、可溶性B7-H3（sB7-H3）的影响。方法：选择新疆医科大学附属肿瘤医院2019年1月到2020年1月期间收治的PHC合并PVTT患者120例,按照随机数字表法分为对照组（TACE治疗,60例）和联合组（TACE结合碘125粒子植入治疗,60例）。观察两组疗效、肝功能指标[丙氨酸氨基转移酶（ALT）、谷草转氨酶（AST）、总胆红素（TBiL）]、血清肿瘤标志物[甲胎蛋白（AFP）、细胞角蛋白19片段（CYFRA21-1）及癌胚抗原（CEA）]、TSGF、TK-1、sB7-H3。随访3年,采用Kaplan-Meier曲线分析（Log-Rank检验）两组患者总生存期（OS）的差异。结果：联合组的临床总有效率高于对照组（P<0.05）。与治疗前相比,两组治疗后ALT、AST、TBiL均下降,且联合组均低于对照组同期（P<0.05）。与治疗前相比,两组治疗后AFP、CYFRA21-1、CEA均下降,且联合组均低于对照组同期（P<0.05）。与治疗前相比,两组治疗后TSGF、TK-1、sB7-H3均下降,且联合组均低于对照组同期（P<0.05）。联合组的OS长于对照组（P<0.05）。结论：TACE联合碘125粒子植入治疗PHC合并PVTT患者,可提高临床疗效,降低血清肿瘤标志物水平,减轻肝功能损伤,延长患者OS并调节血清TSGF、TK-1、sB7-H3水平。     

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。     

全程关护护理模式在放射性粒子植入治疗肝癌患者中的应用

目的探讨在B超或CT引导下经皮穿刺组织间植入125I放射性粒子治疗中晚期肝癌的护理方法。方法对2015年1月~2016年12月在我院行B超或CT引导下125I放射性粒子植入治疗的50例患者实施全程关护护理模式,包括术前评估及干预、术中护理、术后护理、营养干预、出院指导。结果 50例患者对放射防护相关知识完全知晓,均能顺利配合治疗及护理,护理满意度达98.0%;本组患者中主要并发症为穿刺部位轻度疼痛6例,穿刺口少量渗血3例。结论 B超或CT引导下经皮穿刺组织间植入125I放射性粒子治疗中晚期肝癌是一种安全、有效的微创介入法,并发症轻、发生率低,通过全程关护护理干预可提高患者对放射性粒子植入防护相关知识知晓率,提高防护意识,从而提高患者满意度及生活质量。     

~(125)I粒子联合深部热疗在骨转移瘤治疗中的应用

目的:探讨~(125)I粒子植入联合深部热疗治疗骨转移瘤的临床疗效。方法:将63例骨转移瘤患者随机分为~(125)I粒子植入联合深部热疗治疗组和单独采用~(125)I粒子植入的对照组,比较分析两组患者治疗后的疼痛缓解情况与临床疗效差异。结果:两组患者治疗期间未出现严重不良反应;两组患者治疗后疼痛缓解,但治疗组缓解更明显,具有统计学意义;治疗组患者的局部病灶完全缓解率明显高于对照组。结论:~(125)I粒子植入联合深部热疗在骨转移瘤的治疗中疗效确切,不良反应小,是一种值得推广的治疗方法。     

兔脑种植VX2肿瘤动物模型的建立

目的建立兔VX2肿瘤脑内种植动物模型,观察其生长特性。方法采用兔脑内VX2肿瘤组织块种植法将VX2肿瘤组织块种植入24只成年New Zealand大白兔右侧大脑皮质内,用B超检测肿瘤的生长情况,在实验兔在肿瘤种植后第13、171、9、21、232、5天取材,进行组织学观察。并观察实验兔在种植VX2肿瘤后的生存期及出现厌食、偏瘫等神经系统体征和死亡的时间。结果VX2肿瘤组织块种植入脑内后荷瘤兔的中位生存期为24.5 d,平均生存期为24.8 d,肿瘤体积随种植后的时间在对数坐标中接近一条直线。VX2肿瘤种植入兔脑17 d后血供较丰富、呈鱼肉状生长,与正常脑组织边缘界限不清楚,第17~19天肿瘤中心出现坏死并出现腹腔内转移。光镜下从VX2肿瘤种植后第17天开始肿瘤细胞向正常脑组织浸润,并形成瘤巢,瘤周脑组织形成水肿带。结论在缺乏兔源性脑肿瘤的情况下,采用兔VX2肿瘤组织块颅内种植能较好模拟颅内肿瘤生长,为对脑肿瘤的某些实验研究提供条件。     

动态增强磁共振监测VEGF反义核酸对兔颌面部VX2肿瘤放疗的增敏作用

目的:研究动态增强磁共振成像(dynamic contrast enhanced magnetic resonance imaging,DCE-MRI)监测VEGF反义核酸对兔颌面部VX2肿瘤放疗后的影响。方法:24只颌面部VX2荷瘤兔模型随机分4组:放疗组(A组):给予16Gy放疗;VEGF反义核酸治疗组(B组):肿瘤局部注入VEGF反义核酸150μg;VEGF反义核酸联合放疗组(C组):16Gy放疗后立即局部肿瘤内注射VEGF反义核酸150μg;对照组(D组):肿瘤内注射300μl5%葡萄糖水溶液。治疗后第3天、14天分别行DCE-MRI检查,计算MER(Maximal enhancement ratio,最大强化率)及SLE(Slope of enhancement,强化率斜率)值,14天处死动物行病理检查和VEGF免疫组化染色。结果:C组治疗后14天肿瘤体积明显缩小,与治疗前和治疗后三天及其它组比较差别具有统计学意义(P<0.01)。MER值降低和SLE值降低,与治疗前比较差别有统计学意义(P<0.05)。病理切片显示肿瘤细胞水肿、出血,坏死,血管壁增厚闭塞,VEGF免疫阳性表达下降,经IHS评分与A...     

肝动脉导管化疗栓塞序贯经皮微波消融治疗原发性肝癌的临床应用

目的:探讨肝动脉导管化疗栓塞(TACE)序贯B超/CT精准引导下经皮微波消融(MWA)在原发性肝癌中的治疗应用,分析比较疗效。方法:回顾性分析2016年1月至2018年7月在上海交通大学附属第一人民医院接受治疗的96例原发性肝癌患者,42例行TACE序贯联合B超/CT精准引导下MWA治疗(联合组),另54例仅行单纯TACE治疗(TACE组)。术后1月、3月、6月、1年、2年复查增强CT/MRI、AFP、肝功能,随访2年比较两组患者肿瘤坏死、复发、进展和生存情况,评价两组疗效。结果:联合组肿瘤坏死率92.9%,TACE组肿瘤坏死率48.1%,差异有统计学意义(P0.05);联合组肿瘤复发率7.1%,TACE组肿瘤复发率24.1%,差异有统计学意义(P0.05);联合组肿瘤进展率19.1%,TACE组肿瘤进展率27.8%,差异无统计学意义(P0.05);联合组肿瘤进展时间13.2个月,TACE组肿瘤进展时间7.6个月,差异有统计学差异(P0.05);联合组1年生存率83.3%,TACE组1年生存率57.4%,差异有统计学意义(P0.05);联合组2年生存率62%,TACE组2年生存率31.5%,差异有统计学意义(P0.05);联合组中位生存时间28.9个月,TACE组中位生存时间16.9个月,差异有统计学意义(P0.05)。结论:TACE序贯MWA治疗肝癌安全有效,互补增益,是肝癌综合治疗的新模式。     

VX2肿瘤侵犯兔下腔静脉的生物学行为观察

目的建立VX2肿瘤侵犯新西兰兔下腔静脉(IVC)的动物模型,并观察相应的生物学行为。方法经腹直视下,将VX2肿瘤组织块分别种植在28只兔肾以下IVC附近的软组织内,然后随机分为A、B两组。A组术后每周在超声下观察肿瘤的大小、IVC和腹主动脉(AA)管径大小;DSA观察侧支循环建立。B组每周随机解剖4只,取IVC和AA做病理和免疫组化(PCNA)检查,并观察转移情况。结果 1.超声显示:所有肿瘤均种植成功,肿瘤面积大小与生长时间呈明显正相关(r=0.879),IVC管径与肿瘤面积大小显著负相关(r=-0.8295);4周时25%的IVC管腔闭塞,5周时达到91.7%。2.病理和免疫组化显示:3周时IVC管壁中见大量肿瘤细胞;5周时AA管壁中未见肿瘤细胞。3.DSA显示:IVC慢性受侵犯过程中侧枝循环建立良好。4.解剖观察:模型动物在第4周开始出现肝、肺和腹腔转移。结论 VX2肿瘤成瘤率高,其生长变化、对IVC的侵犯和远处器官转移均随生长时间而变化明显。     

Chloroquine Promotes the Anticancer Effect of TACE in a Rabbit VX2 Liver Tumor Model

Background: To investigate the efficacy of TACE combined with CQ, an autophagic inhibitor, in a rabbit VX2 liver tumor model.Methods: Tumor size was measured. And tumor growth rate was calculated to examine the effect of the combined treatment. Apoptosis was detected by TUNEL assay. Meanwhile, autophagic activity was detected by immunohistochemistry and Western blotting to investigate the mechanism underlying. Liver function was also examined to assess feasibility and safety of the combined therapy.Results: Tumors in the control grew more than 4 times bigger after 14 days, while that in the group of TACE alone just showed mild growth. But a slight shrinkage was shown after the treatment of CQ+TACE. Growth ratio of TACE alone was 96.45% ± 28.958% while that of CQ+TACE was -28.73% ± 12.265%. Compared with TACE alone, necrosis in CQ+TACE showed no significant difference, however, the apoptosis was much higher. There were only 14.8±3.11% apoptotic cells in TACE, but 33±4.18% in CQ+TACE, which suggests the increased apoptosis in CQ+TACE contributed to the decrease of tumor volume. In terms of autophagic activity, the result is negative when we immunostained sections of the control with LC3 antibody, but positive in TACE alone and CQ+TACE. And the result of Western blot showed that there was just a low level of LC3Ⅱexpressed in the control and CQ alone, but higher in TACE, and much higher in CQ+TACE because CQ inhibited its degradation in autophagy. Compared with control, p62 decreased in TACE, but the decrease was partially reversed in CQ+TACE. In addition, toxicity of CQ+TACE was assessed not higher than TACE alone, which supports the safety of CQ+TACE.Conclusion: CQ+TACE works better than TACE alone in rabbit VX2 liver tumor model because CQ inhibits autophagy induced by TACE. The inhibited autophagy loses its resistance to apoptosis that apoptosis increased, which contributes to the inhibition of tumor growth. This study indicates CQ may be a promising adjuvant to promote the effect of TACE.     

Percutaneous Ultrasound Guided Implantation of VX2 for Creation of a Rabbit Hepatic Tumor Model

Creation of a VX2 tumor model has traditionally required a laparotomy and surgical implantation of tumor fragments. Open surgical procedures are invasive and require long procedure times and recovery that can result in post-operative morbidity and mortality. The purpose of this study is to report the results of a percutaneous ultrasound guided method for creation of a VX2 model in rabbit livers. A total of 27 New Zealand white rabbits underwent a percutaneous ultrasound guided approach, where a VX2 tumor fragment was implanted in the liver. Magnetic resonance imaging was used to assess for tumor growth and necropsy was performed to determine rates of tract seeding and metastatic disease. Ultrasound guided tumor implantation was successful in all 27 rabbits. One rabbit died 2 days following the implantation procedure. Two rabbits had no tumors seen on follow-up imaging. Therefore, tumor development was seen in 24/26 (92%) rabbits. During the follow-up period, tract seeding was seen in 8% of rabbits and 38% had extra-hepatic metastatic disease. Therefore, percutaneous ultrasound guided tumor implantation safely provides reliable tumor growth for establishing hepatic VX2 tumors in a rabbit model with decreased rates of tract seeding, compared to previously reported methods.     

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.     

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.     

Optimization of 131I ablation in patients with differentiated thyroid carcinoma: comparison of early outcomes of treatment with 100 mCi versus 60 mCi

INTRODUCTION: The aim of this study was to compare the early outcomes between two groups of patients with differentiated thyroid carcinoma (DTC) who received 60 or 100 mCi of (131)I for remnant ablation. MATERIAL AND METHODS: 224 DTC patients with primary tumor > 1 cm of diameter or multifocal were randomised into prospective clinical trial. Patients with extrathyroideal extension of primary tumor and nodal metastases or M1 were not enrolled. 99 patients received 60 mCi, and 125--100 mCi of radioiodine as the first ablative dose. RESULTS: The effectiveness of thyroid ablation was evaluated after one year, during endogenous TSH (thyroid stimulating hormone) stimulation, and after two years during Lthyroxine therapy. Whole body scintigraphy (WBS) was performed under thyroxine withdrawal and thyroglobulin serum level was assessed. Distant micrometastases were detected in 9.8% of patients by post-therapy WBS, 11 patients in group A treated with 60 mCi and 11 in group B treated with 100 mCi. In other patients no symptoms of persistent disease were detected. At one year follow up full remission was diagnosed in 176 patients: 76 in group A and 100 in group B. The remaining ones, 13.3% and 11.2% respectively, received the second course of (131)I for remnant ablation. There were no statistically significant differences in Tg (thyroglobulin) serum level either 12 or 24 months after 131I treatment. CONCLUSIONS: Our evaluation of early efficacy of adjuvant radioiodine treatment in low risk DTC patients shows no differences between two radioiodine activities - 60 and 100 mCi in relation to thyroid ablation. Thus, the activity of 60 mCi is recommended.     

Tumor Angiogenesis after Heated Lipiodol Infusion via the Hepatic Artery in a Rabbit Model of VX2 Liver Cancer

Objectives

This study aimed to observe the changes in tumor angiogenesis after heated lipiodol (60°C) infusion via the hepatic artery in a rabbit model of VX2 liver cancer.

Materials and Methods

Twenty rabbits with VX2 hepatic tumors were randomly divided into 2 groups (10 rabbits in each group). Under anesthesia, a trans-catheter hepatic arterial infusion was performed, and lipiodol (37°C; control group) or heated lipiodol (60°C; treated group) was injected into the hepatic arteries of the animals. Then, changes in tumor angiogenesis were assessed using the following markers and methods. 1. Vascular endothelial growth factor receptor (VEGFR) and vascular endothelial growth factor (VEGF) expression levels in the tumor were assessed using western blotting and real-time quantitative polymerase chain reaction (PCR). 2. Proliferating cell nuclear antigen (PCNA) expression in the tumor was assessed through immunohistochemical staining. 3. The morphological changes in tumor vascular endothelial cells were observed using transmission electron microscopy (TEM).

Results

VEGFR and VEGF mRNA and protein expression levels were reduced in the treated group compared to the control group. PCNA protein showed reduced expression levels in the treated group compared to the control group. TEM indicated that the endothelial cell endoplasmic reticulum expanded, the chondriosome was swollen, and the endothelial cell microvilli were decreased after heated lipiodol infusion.

Conclusions

The tumor angiogenesis of rabbits with VX2 cancer was inhibited after arterial heated lipiodol infusion compared to lipiodol infusion.     

兔VX2肝癌模型制作改良及影像学评价

目的 对兔VX2 肝癌模型制作进行改良,以用于介入治疗学研究,同时探讨瘤灶的CT 表现及CT 在检测瘤灶中的作用.方法 将VX2瘤细胞接种于兔皮下使其成瘤并传代;新西兰兔24只,以改良嵌插法建立移植性肝癌模型,于建模后7、14、21 d分别行超声、CT及血管造影检查,用于检测兔肝VX2 瘤灶,评估瘤灶生长变化;随后处死动物,进行尸解,评估影像检查结果.结果 24只（100%） 动物以改良嵌插法建立移植性肝癌模型全部成功.瘤灶以种植后2周CT显示最清楚和典型,直径1 cm～2 cm 左右,平扫呈低密度或等密度,动脉早期明显强化,门脉期呈低密度,与周围肝组织分界较清楚.肝动脉造影显示肿瘤富血供.而种植后超过3 周的肿瘤大部分发生坏死.结论 嵌插改良法是一种值得推广的建立移植性肝癌模型的方法;在对瘤灶进行影像学评价上应尽量选择CT检查,接种后1 周左右的瘤灶较小而难以观察;2 周左右呈肝动脉源性血供丰富的约1 cm～2 cm的实体瘤,造影征像为肿瘤血管与肿瘤染色;3 周以上瘤灶大多出现明显示坏死;因此对1～2cm大小的兔VX2 肝癌瘤体,最适合行血管造影检查.