氩氦靶向冷冻射频微波消融对犬肝门区域结构影响的实验研究
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摘要
肝癌是严重影响人类健康和生命的恶性疾病之一,恶性程度高,发展非常迅速,预后不良。在我国其发病率、死亡率分别列恶性疾病第三、第二位。手术切除一直以来是肝癌的标准治疗手段,但是,在我国绝大部分的肝癌病人都伴有不同程度的肝炎、肝硬化,肝脏贮备功能有限,手术切除率低,仅20%～30%。同时,肝脏又是消化道恶性肿瘤的最常见的转移部位,由于其呈现多中心生长或位于肝门区域,也仅10-15%的病例可获手术切除。因此,外科手术虽是治疗肝恶性肿瘤的最佳选择,但其适应症窄,难以满足临床需要,大多数的病人需要接受非手术治疗。
近10年来,以冷冻射频微波消融为代表的局部治疗发展迅猛,成为继手术切除、介入治疗后,肝癌治疗的第三大治疗手段。同时,随着技术的改进和创新,其治疗效果不断提高,特别是在小肝癌的治疗方面,不少的研究均表明其治疗效果与手术切除相近,因此受到广泛的重视,与手术切除,肝移植并列肝癌的根治性治疗手段。与手术切除相比,局部治疗具有创伤小、恢复快、适应症广、操作简单、可以门诊进行等优势。目前NCCN指南已经将以冷冻射频为代表的局部消融手段推荐为不宜手术肝癌的标准治疗。在我国,以灭活肿瘤细胞、消除肿瘤负荷为目的的微创局部消融治疗近年来引起了广泛的关注,局部消融治疗可以为失去常规手术根治性治疗机会的实体肿瘤患者提供新的治疗选择。其中,经皮穿刺氩氦冷冻、射频和微波消融治疗肝癌由于其具有微创靶向、并发症少、恢复快、操作简单、治疗效果确切等优点已被广泛应用于临床,成为了肝癌的常规治疗方式。
冷冻疗法是一种原位肿瘤消融手段,与手术切除相比较,冷冻治疗更具有优点。1970年德国Stucke和Hirte首先介绍冷冻治疗肝恶性肿瘤。1976年Ikeda在实验研究中发现冷冻肝肿瘤后出现对远隔部位的免疫反应。随后,包括我国在内许多国家应用冷冻治疗肝肿瘤。目前,冷冻治疗已经成为不能手术切除的肝癌的重要手段。
氩氦刀治疗肿瘤是通过氩气在刀尖的急速膨胀,快速(6秒内)将病变组织温度降至-140℃,再借氦气在刀尖快速将冰球解冻及急速升温,超低温可使细胞内形成冰晶,导致肿瘤组织细胞低温坏死,细胞冰晶体形成是导致细胞死亡的主要原因,构成了现代冷冻治疗技术发展的理论基础。同时高压氦气的快速升温热融可使细胞内的冰晶发生膨胀,引起冰球爆裂,从而导致肿瘤组织细胞结构的进一步破坏及崩解,也是造成肿瘤细胞坏死的重要环节。氩氦刀冷冻技术代表国际上九十年代超低温冷冻仪器的先进水平,是超低温手术和治疗的一场新的革命,是医学史上的一次重大突破。氩氦靶向治疗因其能快速摧毁肿瘤组织的临床特点在国内外已广泛应用于肝癌、肺癌等实体肿瘤的治疗,并取得了可喜的结果。CT引导下经皮穿刺氩氦刀冷冻治疗肝癌这一方法在国内已广泛开展,并取得了较好的疗效。许多临床和实验研究显示,氩氦刀冷冻对于肿瘤的损毁是肯定的。同时证实,冷冻治疗肝癌可增强机体的免疫水平,有助于降低肿瘤的转移率和复发率。由于氩氦刀靶向消融治疗不需要剥除冷冻后的肿瘤组织,手术操作简便,患者术后并发症少,多数不影响其它治疗措施的选择。氩氦刀联合介入、放疗治疗、中药治疗均可提高治疗效果。氩氦刀作为一种肿瘤微创治疗的手段,经皮穿刺靶向治疗肝癌疗效确切,尤其为不适合手术、年老体弱或不愿接受手术治疗的患者提供了一个可供选择的治疗方法。而关于经皮穿刺氩氦冷冻治疗对Glisson管道系统的影响及消融后肝组织病理变化过程如何,未见报道。需要进行相关的研究为临床应用提供依据。
射频消融治疗肝癌是近年发展较快的一种新型微创性手术。其优点就在于能预测、掌握治疗范围,反馈局部温度,可随肿瘤复发而重复治疗等。采用单极或多极探针,在超声或CT引导下,经皮穿刺,将探针定位于肿瘤组织,通过射频输出,使靶区组织细胞离子振荡摩擦产生热量,局部温度可达80—90℃,足以使肿瘤组织产生凝固性坏死,并最终形成液化灶或纤维组织,达到治疗目的。临床上应用的冷循环射频治疗仪,采用中空电极,使冷却水在其中循环,通过在加热过程中降低电极尖部的温度,可防止电极周围组织的炭化和水分丢失,使热毁损范围扩大。近年来,随着RFA技术在肿瘤综合治疗中的应用日益广泛,各种实验研究相继展开,取得了很大进展,已被广泛应用于不能手术的、小的、孤立性肝癌、肺癌等实体肿瘤的治疗。CT引导下经皮射频靶向消融治疗肝癌在国内外已广泛应用,与手术、化疗和放疗相比,具有创伤性小,副作用少,对骨髓及肝、肾功能无损害,可以反复应用等优点,明显减轻患者的症状,提高生活质量。为不能手术的肝癌患者提供了一种可选择的治疗方法。有实验研究表明,在肝组织中应用RFA是安全、有效的,同时RFA治疗有提高机体免疫功能的作用,有利于肿瘤的治疗。但是对于有严重的肝肾功能不全、黄疸、大量腹水、凝血酶原时间明显延长、肝脏肿瘤已有远处转移、巨大肝癌或弥漫性肝癌、肝硬化门静脉高压症、食管胃底静脉曲张有严重出血倾向、安装有心脏起搏器等则不适于射频治疗。而关于经皮穿刺射频消融治疗对Glisson管道系统的影响及消融后肝组织病理变化过程如何,未见报道。需要进行相关的研究为临床应用提供依据。
微波靶向消融是通过微创手段穿刺到肿瘤组织,利用局部高温原位灭活肿瘤,是近年发展起来的新的肿瘤治疗技术。生物组织含有许多极性分子及带电离子,在高速交变的微波电场作用下,极性分子快速转动,带电离子快速移动,与相邻分子相互摩擦及碰撞产生热能,使靶组织温度升高达至50℃以上,靶区肿瘤细胞脱水、干燥,发生凝固性坏死。临床上应用的内置循环冷媒(高压常温氩气)冷却气道的植入式微波固化技术可以降低杆温,降低微波治疗过程中对穿刺道周围正常组织的损伤。随着微波技术设备的发展以及微波靶向消融技术在临床不断应用,现微波靶向消融疗法已应用于肝癌、肺癌等实体肿瘤的治疗。其中,CT引导下经皮穿刺微波消融治疗肝癌已在临床逐渐开展,尤其在国内进行了一些临床和实验研究,并取得了一定的效果。经皮穿刺微波消融治疗除穿刺局部创伤、肿瘤及周围少量正常肝组织的热损伤外,对机体影响不大,是一种可供临床选择的微创治疗方法之一。研究表明,微波消融可彻底杀死肿瘤细胞,同时还可凝固肿瘤周围血管,使之不能继续向肿瘤供血,并在正常组织和癌组织之间形成一个反应带,包裹肿瘤,在一定程度上起到防止肿瘤转移的作用。此外,微波治疗还能激活机体的免疫状态,从而取得较好的远期疗效。然而,对于经皮穿刺微波消融治疗肝癌的研究还十分有限,未见到关于微波消融对于肝组织及管道系统影响的系统研究的报道。有待进一步的研究为临床应用提供依据。
本研究包括以下三部分内容:
第一部分氩氦刀消融对肝门区域组织影响的实验研究
目的:通过观察肝脏Glisson管道系统一级分支区域组织的病理变化,探讨氩氦靶向消融对第一肝门区域的效应,为其临床应用提供依据。方法:14只健康犬随机分为A、B两组,进行经皮穿刺肝脏氩氦靶向冷冻,于消融后3d和28d分批宰杀,观察消融靶区和Glisson管道系统一级分支的病理变化。结果:术后门静脉血管壁及内皮细胞未见明显损伤,血管周围肝组织均被灭活坏死。一级胆管系统在氩氦刀冷冻消融后出现不同程度的损伤,但未见穿孔、胆管壁全层坏死等严重损伤,大部分损害表现为可逆的短暂性损伤。28d时活检消融损伤区大小明显小于3d时(p＜0.05)。在术后急性期(1-3d),其ALT,AST值均较术前显著增高(各组p＜0.05)。而在术后(1-4w)ALT,AST值较术前均无显著差异。氩氦靶向冷冻区与病理坏死区范围基本一致(p＞0.05)。结论:经皮微创近距离的氩氦靶向冷冻消融治疗可以确实可靠地完全灭活门静脉周围的肝组织。门静脉血管壁在热池效应的保护下不致损伤。氩氦冷冻消融对于肝门部胆管的损伤较轻。该治疗对于肝功能的影响不大。可用肉眼所见的冷冻区大小预测冷冻坏死范围。肝脏肿瘤的氩氦靶向冷冻消融技术是一种安全可靠、疗效确实的微创外科手术方法。
第二部分射频消融对肝门区域组织影响的实验研究
目的:通过观察肝脏Glisson管道系统一级分支组织的病理变化,探讨射频对第一肝门区域的影响,为其临床应用提供依据。方法:14只健康犬随机分为A、B两组,进行经皮穿刺肝脏射频消融,于消融后3 d和28 d分批宰杀,观察消融靶区和Glisson管道系统一级分支组织的病理变化。结果:术后门静脉血管壁在肉眼及光镜下未见明显损伤,血管周围肝组织均被灭活坏死。一级胆管系统在射频消融后出现较严重损伤,部分损害表现为不可逆的进行性损伤。28 d时活检消融损伤区大小明显小于3d时。在术后急性期(1-3d),其ALT,AST值均较术前显著增高(各组p＜0.05)。而在术后(1-4w)ALT,AST值较术前均无显著差异。结论:经皮微创近距离的射频消融治疗可以确实可靠地完全灭活门静脉周围的肝组织。门静脉血管壁在血流的保护下不致损伤。RFA对于肝门部胆管的损伤作用十分明显,故对肝门部血管旁的组织进行射频灭活时要注意保护胆管系统。射频治疗对于肝功能的影响不大。
第三部分微波消融对肝门区域组织影响的实验研究
目的:通过观察肝脏Glisson管道系统一级分支区域组织的病理变化,探讨微波对第一肝门区域的效应,为其临床应用提供依据。方法:14只健康犬随机分为A、B两组,进行经皮穿刺肝脏微波凝固消融,于消融后3 d和28 d分批宰杀,观察消融靶区和Glisson管道系统一级分支组织的病理变化。结果:术后门静脉血管壁在肉眼及光镜下未见明显损伤,血管周围肝组织均被灭活坏死。部分一级胆管系统在微波凝固消融后出现不同程度的损伤;28d时消融损伤区大小明显小于3d时(p＜0.05)。在术后急性期(1-3d),其ALT,AST值均较术前显著增高(各组p＜0.05)。而在术后(1-4w)ALT,AST值较术前均无显著差异。肉眼微波凝固区大于病理坏死区(p＜0.05)。结论:经皮微创近距离的微波凝固消融治疗可以确实可靠地完全灭活门静脉周围的肝组织。肝动脉、门静脉血管壁在血流的保护下不致损伤。而且微波治疗对于肝功能的影响不大。但PMCT可造成肝门部胆管一定程度的损伤,故对肝门部血管旁的组织进行微波灭活时要注意保护好胆管系统。
Liver cancer is one of the seriously malignant diseases that affect human health and life,with a high degree of malignancy,and extraordinarily rapid development and poor prognosis.In China,the morbidity and mortality were listed as the second and the third malignant disease respectively.Surgical resection of liver cancer is the standard treatment,however,the majority of liver cancer patients have different degrees of hepatitis,cirrhosis,limited liver reserves,and the surgical resection rate is low,about 20%～30%.At the same time,the liver is one of the most common malignant gastrointestinal metastasis,due to its multi-center regional growth or located in liver door area,only 10-15%of cases can be surgically removed. Therefore,surgical treatment is the best option for liver malignancies,but its narrow indications,it is difficult to meet clinical needs,and the majority of patients need to receive non-surgical treatment.
In the past 10 years,being a representative of the local therapy,freezing of microwave ablation had been developed rapidly and become the third-largest HCC treatment,after surgical resection and interventional therapy.At the same time,with technology improvements and innovation,its treatment effect is getting improved continuously,especially in the treatment of small HCC.A number of studies have shown that its therapeutic effect is close to surgical resection,therefore subject to a wide range of attention,freezing of microwave ablation has become one of radical treatments,along with surgical excision,liver transplantation.Compared with surgical excision??l treatment has many advantages,such as small trauma,rapid recovery and simple operation can be carried out for out-patient.Currently,NCCN guideline has listed partial ablation treatment represented by freezing of microwave ablation,as a recommendation of standard treatment for non-suitable surgery liver cancer.In China,the minimally invasive ablation for the local treatment,intention on inactivation of tumor cells,the elimination of tumor burden,has widely aroused the concern in recent years.Local ablation therapy could provide an option for the patients who lose the opportunity of conventional surgical treatment of solid tumors. Among these,percutaneous argon-helium frozen,radio frequency and microwave ablation for the treatment of liver cancer have been widely used in clinical due to their minimally invasive targeted,fewer complications,fast recovery,simple operation,and has become a conventional treatment for liver cancer.Cryotherapy is a means of in situ tumor ablation.Compared with surgical excision,cryotherapy has more advantages.In 1970,Stucke and Hirte introduced cryotherapy of liver malignancies for the first time in German.In 1976,Ikeda found that hematogenously immune response appeared after frozen liver tumor.After that, cryotherapy of liver tumors was applied in many countries including China. Currently,cryotherapy has become an important treatment of liver cancer,which could not be treated with the surgical resection.
Argon-helium Cryoablation makes use of the rapid dilation of the argon at the probe tip and reduces the temperature of the tissues that undergo pathological changes to -140℃and then rapidly thaws the ice ball and elevates the temperature at the probe tip by the helium.The ultra low temperature can lead to the formation of ice crystals in the cells and subsequently induce the cellular necrosis at low temperature.The formation of ice crystals in cells is the main reason of cell necrosis which constitutes the theoretical basis for the development of modern cryoablation techniques. Meanwhile,the rapid elevation of the temperature and the thermal thawing of the high pressure helium can cause the dilation of the ice crystals and the blowout of the ice ball,which finally lead to the further destruction and breakdown of the cell structures in the tumor tissues,and this is also an important element that leads to the cellular necrosis of the tumors.Argon-helium Cryoablation represents the advanced level of freezing equipments in the 1990's around the world,and it is a new revolution for the operations at ultra low temperature and an important breakthrough in the medical history.The Argon-Helium targeted cryoablation therapy with its rapid destroys to tumor tissues has been widely applied in worldwide in the treatment of solid tumors,such as liver cancer,lung cancer and achieved exciting achievements. Percutaneous cryoablation under CT conduction in the treatment of liver cancer has been widely used in our country and it achieved pretty results.The investigations of many clinical and experimental institutes have been demonstrated that using Argon-helium Cryoablation can obtain definit therapeutic effect to damage tumors.It is also confirmed that cryoablation on liver cancer can enhance bodies immunological level as well as can decrease the metastasis recurrence rate of tumor.Since cryoablation does not need to get rid of the freezing tumor tissues and the operation is simple to handle,and there are few complications after the operation,most of them do not affect the choices for other treatments.Argon-Helium cryoablation combined with,interventional therapy,radiotherapy or traditional Chinese medicine without exception can improve the effects of the treatment.As a kind of minimal invasion therapy,percutaneous targeting treatment for liver cancer has advantage of accurate therapeutic effects,especially for the patients who are not suitable for surgical resection or unwilling for operations or elderly people.However,it has been no reported how about the effects on the piping system of Glisson and pathological change of the liver tissue by percutaneous cryoablation.Related investigations are needed to provide bases for its clinical applications.
Being a new kind of minimally invasive surgery,radiofrequency catheter ablation for liver cancer is developing rapidly in recent years.Its advantages include being predictable,controlling the scope of treatment,the local temperature feedback and repeat treatment of tumor recurrence,etc.Using monopolar or multipolar electrode, under CT or Ultrasonic waves conduction for percutaneous puncture and then the electrode is located at the tumor tissues and produces heat by the ion vibration and scrape of the cells in the target region induced by RF output.The local temperature can reach 80-90℃,which is enough to induce coagulative necrosis of the tumor tissues and finally gives rise to fluidity focus or fibrous tissues for effective treatments.RF treating device with cold circulation in the clinical application circulates the cooling water in it by using hollowed electrode,and the charring of tissues and the loss of water in the tissues nearby the electrode can be avoided by reducing the temperature at the tip of the electrode during the process of heating,and thus the extent of heat damages is enlarged.
With the more and more extensive application of RFA technique in the comprehensive treatment of tumors,various kinds of experimental investigations have been successively carried out in the recent years and great progresses have been achieved.RFA technique has been widely used in the treatment for small or isolated solid tumors such as lung cancer,liver cancer which are unsuitable for surgical resection.Percutaneous RFA under CT conduction for the treatment of liver cancer has been widely used all over the world.It has some advantages such as minimal invasion,few adverse effects,no damages to marrow,liver and renal functions,repeat usage when compared with operation,chemotherapy and radiotherapy.These advantages can significantly reduce the symptoms of the patients and improve their living quality.It provides an alternative therapy for the patients with liver cancer who can't bear operations.It has been proven by experiments that the application of RFA in the liver tissues is safe and effective,in the mean time RFA can improve body's immunological functions which are benefit for tumor's treatment.But the following symptoms are not suitable for the application of radiofrequency therapy,including the severe liver dysfunction,jaundice,ascites,prothrombin time significantly extend, liver cancer with distant metastasis,huge liver cancer or diffuse liver cancer,cirrhosis, portal hypertension,and stomach esophagus varicosity with serious bleeding tendency,installation of a cardiac pacemaker.However,it has been no reported how about the effects on the piping system of Glisson and pathological change of the liver tissue by RFA.Related investigations are needed to provide bases for its clinical applications.
MCT use local temperature to deactivate the tumors by puncturing the tumor tissues with minimal invasion,and it is a new therapy for tumors developed in the recent years.The body contains many polar molecules and charged ions,these polar molecules rotate rapidly under the effects of microwave electric field that is alternative in high rate,and the charged ions move rapidly and heat is produced by the scrape and the collision with the adjacent ions.The temperature in the target tissue is thus elevated to more than 50℃.The tumor cells in the target region are dehydrated and dried,and then develop coagulative necrosis.The embedded microwave solidification technique with,cooling air passage by inner circulating refrigerant used in clinical investigations(high pressure argon at normal temperature) can reduce the temperature of the pole and reduce the damages to the normal tissues near the puncture path during the process of MCT.With the development of microwave technique and equipments as well as continuous application of MCT in the clinical practice,MCT has been used in the treatment of some solid tumors such as liver cancer lung cancer.Among them,CT-directed percutaneous MCT in the treatment of liver cancer have been gradually carried out in the clinical practice,and particularly some clinical and experimental investigations performed in our country have obtained certain achievements.CT-directed percutaneous MCT have few side-effect on the body except local wounds by puncture and heat damages around tumor and a small quantity of normal liver tissues,as one of the minimally invasive therapies,MCT can be selected for clinical practice.Previous investigations showed that MCT can completely kill the tumor cells as well as coagulate the adjacent blood vessels near the tumors at the same time which can directly cut down the blood supplication to the tumors.A reaction zone formed between the normal tissues and the cancer tissue wrap up the rumor and function in the prevention of tumor metastasis in some degree.Besides this,MCT can achieve long-term effect for preventing the tumor metastasis via activating the body's immunological status. However,it has been no reported how about the effects on the piping system of Glisson and pathological change of the liver tissue by MCT.Related investigations are needed to provide bases for its clinical applications.
This study includes three parts:
1、The Influence Of Targeted ar-he Cryablation On The Area Of The Porta
Hepatis
Objective:To discuss an impact of targeted ar-he cryablation over the first hepatic portals area by observing the pathological change of the hepar Glisson pipeline system first grading branch tissue in order to provide a theory basis to clinical practice.Methods:The 14 healthy dogs ablated by the percutaneous puncture hepar targeted ar-he cryablation were individed into A and B groups randomly.These dogs of the two groups were put to death in batches in 3 days and 28 days after ablation, respectively.Then the pathological change about the ablation target area and the first grading branch of the Glisson pipeline system was observed.Results:The obvious damage was not found in the portal vein blood vessel wall by the naked eyes or the light microscope;however,the blood vessel vicinity of liver tissue was damaged to necrosis entirely.Though the injuries in different degrees were seen in the one-level bile duct system after ar-he cryablation operation,we had not found sever damages,such as perforation、negrosis,and most of the injuries were reversible.The size of the ablated area in 28 days is smaller than that of 3 days obviously (p＜0.05).And on the acute stage(1-3d),ALT and AST increased more highly than those of pre-radio frequency operation(p＜0.05).However after operation(l-4w), there was no statistical difference comparing with preablation.Moreover,The cryablated area is mainly consistent with the pathological necrosis range(p＞0.05). Conclusion:Targeted ar-he cryablation can not only cause the blood vessel vicinity of liver tissue necrosed entirely,but also let the portal vein blood vessel wall undamaged under the protection of hot pool effection.And the ar-he cryablation injury effect on bile duct of hepatic portal section is relatively light.Moreover,ar-he cryablation has no obvious damage to the liver function.The range of necrosis could also be forecasted by the size of freezing area.Therefore,ar-he cryablation is a safe minimal invasive operation with reliable therapeutic effect.
2、The Influence Of Radio Frequency Ablation On The Area Of The First Porta Hepatis
Objective:To discuss an impact of radio frequency over the first hepatic portals area by observing the pathological change of the hepar Glisson pipeline system first grading branch tissue in order to provide a theory basis to clinical practice.
Methods:The 14 healthy dogs ablated by the percutaneous puncture hepar radio frequency ablation were individed into A and B groups randomly.These dogs of the two groups were put to death in batches in 3 days and 28 days after ablation, respectively.Then the pathological change about the ablation target area and the first grading branch of the Glisson pipeline system was observed.Results:The obvious damage was not found in the portal vein blood vessel wall by the naked eyes or the light microscope;hoyvever,the blood vessel vicinity of liver tissue was damaged to necrosis entirely,and injury was seen in the one-level bile duct system after radio frequency operation.The size of the ablated area in 28 days is smaller than that of 3 days obviously.And on the acute stage(1-3d),ALT and AST increased more highly than those of pre-radio frequency operation(p＜0.05).However after operation(l-4w), there was no statistical difference comparing with preablation.Conclusion:Though RFA can not only cause the blood vessel vicinity of liver tissue necrosed entirely,but also let the portal vein blood vessel wall undamaged under the protection of hot pool effection,the RFA injury effect on bile duct of hepatic portal section is very obvious. Therefore,we should pay more attention to protecting bile duct system during radio frequency operation.Another conclusion we draw is that the effect of radio frequency on liver function is little significant.
3、Study On Reliability And Safety Of PMCT In The Area Of First Porta Hepatis
Objective:To discuss an impact of targeted microwave ablation on the first hepatic portals area by observing the pathological change of the hepar Glisson pipeline system first grading branch tissue in order to provide a theory basis to clinical practice.Methods:The 12 healthy dogs ablated by the percutaneous puncture hepar targeted microwave ablation were individed into A and B groups randomly.These dogs of the two groups were put to death in batches in 3 days and 28 days after ablation,respectively.Then the pathological change about the ablation target area and the first grading branch of the Glisson pipeline system was observed.Results:The obvious damage was not found in the portal vein blood vessel wall by the naked eyes or the light microscope;however,the blood vessel vicinity of liver tissue was damaged to necrosis entirely.The injuries,to some degree,were seen in the one-level bile duct system after ar-he cryablation operation.The size of the ablated area in 28 days is smaller than that of 3 days obviously(p＜0.05).And on the acute stage(l-3d),ALT and AST increased more highly than those of pre-radio frequency operation (p＜0.05).However after operation(l-4w),there was no statistical difference comparing with preablation.Moreover,The cryablated area is bigger than the pathological necrosis range(p＞0.05).Conclusion:Targeted microwave ablation can not only cause the blood vessel vicinity of liver tissue necrosed entirely,but also let the portal vein blood vessel wall undamaged under the protection of hot pool effection.Moreover,microwave ablation has no obvious damage to the liver function.Because of the damages to the hepar Glisson pipeline system,we should protect the system carefully during the targeted microwave ablation operation.
近10年来,以冷冻射频微波消融为代表的局部治疗发展迅猛,成为继手术切除、介入治疗后,肝癌治疗的第三大治疗手段。同时,随着技术的改进和创新,其治疗效果不断提高,特别是在小肝癌的治疗方面,不少的研究均表明其治疗效果与手术切除相近,因此受到广泛的重视,与手术切除,肝移植并列肝癌的根治性治疗手段。与手术切除相比,局部治疗具有创伤小、恢复快、适应症广、操作简单、可以门诊进行等优势。目前NCCN指南已经将以冷冻射频为代表的局部消融手段推荐为不宜手术肝癌的标准治疗。在我国,以灭活肿瘤细胞、消除肿瘤负荷为目的的微创局部消融治疗近年来引起了广泛的关注,局部消融治疗可以为失去常规手术根治性治疗机会的实体肿瘤患者提供新的治疗选择。其中,经皮穿刺氩氦冷冻、射频和微波消融治疗肝癌由于其具有微创靶向、并发症少、恢复快、操作简单、治疗效果确切等优点已被广泛应用于临床,成为了肝癌的常规治疗方式。
冷冻疗法是一种原位肿瘤消融手段,与手术切除相比较,冷冻治疗更具有优点。1970年德国Stucke和Hirte首先介绍冷冻治疗肝恶性肿瘤。1976年Ikeda在实验研究中发现冷冻肝肿瘤后出现对远隔部位的免疫反应。随后,包括我国在内许多国家应用冷冻治疗肝肿瘤。目前,冷冻治疗已经成为不能手术切除的肝癌的重要手段。
氩氦刀治疗肿瘤是通过氩气在刀尖的急速膨胀,快速(6秒内)将病变组织温度降至-140℃,再借氦气在刀尖快速将冰球解冻及急速升温,超低温可使细胞内形成冰晶,导致肿瘤组织细胞低温坏死,细胞冰晶体形成是导致细胞死亡的主要原因,构成了现代冷冻治疗技术发展的理论基础。同时高压氦气的快速升温热融可使细胞内的冰晶发生膨胀,引起冰球爆裂,从而导致肿瘤组织细胞结构的进一步破坏及崩解,也是造成肿瘤细胞坏死的重要环节。氩氦刀冷冻技术代表国际上九十年代超低温冷冻仪器的先进水平,是超低温手术和治疗的一场新的革命,是医学史上的一次重大突破。氩氦靶向治疗因其能快速摧毁肿瘤组织的临床特点在国内外已广泛应用于肝癌、肺癌等实体肿瘤的治疗,并取得了可喜的结果。CT引导下经皮穿刺氩氦刀冷冻治疗肝癌这一方法在国内已广泛开展,并取得了较好的疗效。许多临床和实验研究显示,氩氦刀冷冻对于肿瘤的损毁是肯定的。同时证实,冷冻治疗肝癌可增强机体的免疫水平,有助于降低肿瘤的转移率和复发率。由于氩氦刀靶向消融治疗不需要剥除冷冻后的肿瘤组织,手术操作简便,患者术后并发症少,多数不影响其它治疗措施的选择。氩氦刀联合介入、放疗治疗、中药治疗均可提高治疗效果。氩氦刀作为一种肿瘤微创治疗的手段,经皮穿刺靶向治疗肝癌疗效确切,尤其为不适合手术、年老体弱或不愿接受手术治疗的患者提供了一个可供选择的治疗方法。而关于经皮穿刺氩氦冷冻治疗对Glisson管道系统的影响及消融后肝组织病理变化过程如何,未见报道。需要进行相关的研究为临床应用提供依据。
射频消融治疗肝癌是近年发展较快的一种新型微创性手术。其优点就在于能预测、掌握治疗范围,反馈局部温度,可随肿瘤复发而重复治疗等。采用单极或多极探针,在超声或CT引导下,经皮穿刺,将探针定位于肿瘤组织,通过射频输出,使靶区组织细胞离子振荡摩擦产生热量,局部温度可达80—90℃,足以使肿瘤组织产生凝固性坏死,并最终形成液化灶或纤维组织,达到治疗目的。临床上应用的冷循环射频治疗仪,采用中空电极,使冷却水在其中循环,通过在加热过程中降低电极尖部的温度,可防止电极周围组织的炭化和水分丢失,使热毁损范围扩大。近年来,随着RFA技术在肿瘤综合治疗中的应用日益广泛,各种实验研究相继展开,取得了很大进展,已被广泛应用于不能手术的、小的、孤立性肝癌、肺癌等实体肿瘤的治疗。CT引导下经皮射频靶向消融治疗肝癌在国内外已广泛应用,与手术、化疗和放疗相比,具有创伤性小,副作用少,对骨髓及肝、肾功能无损害,可以反复应用等优点,明显减轻患者的症状,提高生活质量。为不能手术的肝癌患者提供了一种可选择的治疗方法。有实验研究表明,在肝组织中应用RFA是安全、有效的,同时RFA治疗有提高机体免疫功能的作用,有利于肿瘤的治疗。但是对于有严重的肝肾功能不全、黄疸、大量腹水、凝血酶原时间明显延长、肝脏肿瘤已有远处转移、巨大肝癌或弥漫性肝癌、肝硬化门静脉高压症、食管胃底静脉曲张有严重出血倾向、安装有心脏起搏器等则不适于射频治疗。而关于经皮穿刺射频消融治疗对Glisson管道系统的影响及消融后肝组织病理变化过程如何,未见报道。需要进行相关的研究为临床应用提供依据。
微波靶向消融是通过微创手段穿刺到肿瘤组织,利用局部高温原位灭活肿瘤,是近年发展起来的新的肿瘤治疗技术。生物组织含有许多极性分子及带电离子,在高速交变的微波电场作用下,极性分子快速转动,带电离子快速移动,与相邻分子相互摩擦及碰撞产生热能,使靶组织温度升高达至50℃以上,靶区肿瘤细胞脱水、干燥,发生凝固性坏死。临床上应用的内置循环冷媒(高压常温氩气)冷却气道的植入式微波固化技术可以降低杆温,降低微波治疗过程中对穿刺道周围正常组织的损伤。随着微波技术设备的发展以及微波靶向消融技术在临床不断应用,现微波靶向消融疗法已应用于肝癌、肺癌等实体肿瘤的治疗。其中,CT引导下经皮穿刺微波消融治疗肝癌已在临床逐渐开展,尤其在国内进行了一些临床和实验研究,并取得了一定的效果。经皮穿刺微波消融治疗除穿刺局部创伤、肿瘤及周围少量正常肝组织的热损伤外,对机体影响不大,是一种可供临床选择的微创治疗方法之一。研究表明,微波消融可彻底杀死肿瘤细胞,同时还可凝固肿瘤周围血管,使之不能继续向肿瘤供血,并在正常组织和癌组织之间形成一个反应带,包裹肿瘤,在一定程度上起到防止肿瘤转移的作用。此外,微波治疗还能激活机体的免疫状态,从而取得较好的远期疗效。然而,对于经皮穿刺微波消融治疗肝癌的研究还十分有限,未见到关于微波消融对于肝组织及管道系统影响的系统研究的报道。有待进一步的研究为临床应用提供依据。
本研究包括以下三部分内容:
第一部分氩氦刀消融对肝门区域组织影响的实验研究
目的:通过观察肝脏Glisson管道系统一级分支区域组织的病理变化,探讨氩氦靶向消融对第一肝门区域的效应,为其临床应用提供依据。方法:14只健康犬随机分为A、B两组,进行经皮穿刺肝脏氩氦靶向冷冻,于消融后3d和28d分批宰杀,观察消融靶区和Glisson管道系统一级分支的病理变化。结果:术后门静脉血管壁及内皮细胞未见明显损伤,血管周围肝组织均被灭活坏死。一级胆管系统在氩氦刀冷冻消融后出现不同程度的损伤,但未见穿孔、胆管壁全层坏死等严重损伤,大部分损害表现为可逆的短暂性损伤。28d时活检消融损伤区大小明显小于3d时(p＜0.05)。在术后急性期(1-3d),其ALT,AST值均较术前显著增高(各组p＜0.05)。而在术后(1-4w)ALT,AST值较术前均无显著差异。氩氦靶向冷冻区与病理坏死区范围基本一致(p＞0.05)。结论:经皮微创近距离的氩氦靶向冷冻消融治疗可以确实可靠地完全灭活门静脉周围的肝组织。门静脉血管壁在热池效应的保护下不致损伤。氩氦冷冻消融对于肝门部胆管的损伤较轻。该治疗对于肝功能的影响不大。可用肉眼所见的冷冻区大小预测冷冻坏死范围。肝脏肿瘤的氩氦靶向冷冻消融技术是一种安全可靠、疗效确实的微创外科手术方法。
第二部分射频消融对肝门区域组织影响的实验研究
目的:通过观察肝脏Glisson管道系统一级分支组织的病理变化,探讨射频对第一肝门区域的影响,为其临床应用提供依据。方法:14只健康犬随机分为A、B两组,进行经皮穿刺肝脏射频消融,于消融后3 d和28 d分批宰杀,观察消融靶区和Glisson管道系统一级分支组织的病理变化。结果:术后门静脉血管壁在肉眼及光镜下未见明显损伤,血管周围肝组织均被灭活坏死。一级胆管系统在射频消融后出现较严重损伤,部分损害表现为不可逆的进行性损伤。28 d时活检消融损伤区大小明显小于3d时。在术后急性期(1-3d),其ALT,AST值均较术前显著增高(各组p＜0.05)。而在术后(1-4w)ALT,AST值较术前均无显著差异。结论:经皮微创近距离的射频消融治疗可以确实可靠地完全灭活门静脉周围的肝组织。门静脉血管壁在血流的保护下不致损伤。RFA对于肝门部胆管的损伤作用十分明显,故对肝门部血管旁的组织进行射频灭活时要注意保护胆管系统。射频治疗对于肝功能的影响不大。
第三部分微波消融对肝门区域组织影响的实验研究
目的:通过观察肝脏Glisson管道系统一级分支区域组织的病理变化,探讨微波对第一肝门区域的效应,为其临床应用提供依据。方法:14只健康犬随机分为A、B两组,进行经皮穿刺肝脏微波凝固消融,于消融后3 d和28 d分批宰杀,观察消融靶区和Glisson管道系统一级分支组织的病理变化。结果:术后门静脉血管壁在肉眼及光镜下未见明显损伤,血管周围肝组织均被灭活坏死。部分一级胆管系统在微波凝固消融后出现不同程度的损伤;28d时消融损伤区大小明显小于3d时(p＜0.05)。在术后急性期(1-3d),其ALT,AST值均较术前显著增高(各组p＜0.05)。而在术后(1-4w)ALT,AST值较术前均无显著差异。肉眼微波凝固区大于病理坏死区(p＜0.05)。结论:经皮微创近距离的微波凝固消融治疗可以确实可靠地完全灭活门静脉周围的肝组织。肝动脉、门静脉血管壁在血流的保护下不致损伤。而且微波治疗对于肝功能的影响不大。但PMCT可造成肝门部胆管一定程度的损伤,故对肝门部血管旁的组织进行微波灭活时要注意保护好胆管系统。
Liver cancer is one of the seriously malignant diseases that affect human health and life,with a high degree of malignancy,and extraordinarily rapid development and poor prognosis.In China,the morbidity and mortality were listed as the second and the third malignant disease respectively.Surgical resection of liver cancer is the standard treatment,however,the majority of liver cancer patients have different degrees of hepatitis,cirrhosis,limited liver reserves,and the surgical resection rate is low,about 20%～30%.At the same time,the liver is one of the most common malignant gastrointestinal metastasis,due to its multi-center regional growth or located in liver door area,only 10-15%of cases can be surgically removed. Therefore,surgical treatment is the best option for liver malignancies,but its narrow indications,it is difficult to meet clinical needs,and the majority of patients need to receive non-surgical treatment.
In the past 10 years,being a representative of the local therapy,freezing of microwave ablation had been developed rapidly and become the third-largest HCC treatment,after surgical resection and interventional therapy.At the same time,with technology improvements and innovation,its treatment effect is getting improved continuously,especially in the treatment of small HCC.A number of studies have shown that its therapeutic effect is close to surgical resection,therefore subject to a wide range of attention,freezing of microwave ablation has become one of radical treatments,along with surgical excision,liver transplantation.Compared with surgical excision??l treatment has many advantages,such as small trauma,rapid recovery and simple operation can be carried out for out-patient.Currently,NCCN guideline has listed partial ablation treatment represented by freezing of microwave ablation,as a recommendation of standard treatment for non-suitable surgery liver cancer.In China,the minimally invasive ablation for the local treatment,intention on inactivation of tumor cells,the elimination of tumor burden,has widely aroused the concern in recent years.Local ablation therapy could provide an option for the patients who lose the opportunity of conventional surgical treatment of solid tumors. Among these,percutaneous argon-helium frozen,radio frequency and microwave ablation for the treatment of liver cancer have been widely used in clinical due to their minimally invasive targeted,fewer complications,fast recovery,simple operation,and has become a conventional treatment for liver cancer.Cryotherapy is a means of in situ tumor ablation.Compared with surgical excision,cryotherapy has more advantages.In 1970,Stucke and Hirte introduced cryotherapy of liver malignancies for the first time in German.In 1976,Ikeda found that hematogenously immune response appeared after frozen liver tumor.After that, cryotherapy of liver tumors was applied in many countries including China. Currently,cryotherapy has become an important treatment of liver cancer,which could not be treated with the surgical resection.
Argon-helium Cryoablation makes use of the rapid dilation of the argon at the probe tip and reduces the temperature of the tissues that undergo pathological changes to -140℃and then rapidly thaws the ice ball and elevates the temperature at the probe tip by the helium.The ultra low temperature can lead to the formation of ice crystals in the cells and subsequently induce the cellular necrosis at low temperature.The formation of ice crystals in cells is the main reason of cell necrosis which constitutes the theoretical basis for the development of modern cryoablation techniques. Meanwhile,the rapid elevation of the temperature and the thermal thawing of the high pressure helium can cause the dilation of the ice crystals and the blowout of the ice ball,which finally lead to the further destruction and breakdown of the cell structures in the tumor tissues,and this is also an important element that leads to the cellular necrosis of the tumors.Argon-helium Cryoablation represents the advanced level of freezing equipments in the 1990's around the world,and it is a new revolution for the operations at ultra low temperature and an important breakthrough in the medical history.The Argon-Helium targeted cryoablation therapy with its rapid destroys to tumor tissues has been widely applied in worldwide in the treatment of solid tumors,such as liver cancer,lung cancer and achieved exciting achievements. Percutaneous cryoablation under CT conduction in the treatment of liver cancer has been widely used in our country and it achieved pretty results.The investigations of many clinical and experimental institutes have been demonstrated that using Argon-helium Cryoablation can obtain definit therapeutic effect to damage tumors.It is also confirmed that cryoablation on liver cancer can enhance bodies immunological level as well as can decrease the metastasis recurrence rate of tumor.Since cryoablation does not need to get rid of the freezing tumor tissues and the operation is simple to handle,and there are few complications after the operation,most of them do not affect the choices for other treatments.Argon-Helium cryoablation combined with,interventional therapy,radiotherapy or traditional Chinese medicine without exception can improve the effects of the treatment.As a kind of minimal invasion therapy,percutaneous targeting treatment for liver cancer has advantage of accurate therapeutic effects,especially for the patients who are not suitable for surgical resection or unwilling for operations or elderly people.However,it has been no reported how about the effects on the piping system of Glisson and pathological change of the liver tissue by percutaneous cryoablation.Related investigations are needed to provide bases for its clinical applications.
Being a new kind of minimally invasive surgery,radiofrequency catheter ablation for liver cancer is developing rapidly in recent years.Its advantages include being predictable,controlling the scope of treatment,the local temperature feedback and repeat treatment of tumor recurrence,etc.Using monopolar or multipolar electrode, under CT or Ultrasonic waves conduction for percutaneous puncture and then the electrode is located at the tumor tissues and produces heat by the ion vibration and scrape of the cells in the target region induced by RF output.The local temperature can reach 80-90℃,which is enough to induce coagulative necrosis of the tumor tissues and finally gives rise to fluidity focus or fibrous tissues for effective treatments.RF treating device with cold circulation in the clinical application circulates the cooling water in it by using hollowed electrode,and the charring of tissues and the loss of water in the tissues nearby the electrode can be avoided by reducing the temperature at the tip of the electrode during the process of heating,and thus the extent of heat damages is enlarged.
With the more and more extensive application of RFA technique in the comprehensive treatment of tumors,various kinds of experimental investigations have been successively carried out in the recent years and great progresses have been achieved.RFA technique has been widely used in the treatment for small or isolated solid tumors such as lung cancer,liver cancer which are unsuitable for surgical resection.Percutaneous RFA under CT conduction for the treatment of liver cancer has been widely used all over the world.It has some advantages such as minimal invasion,few adverse effects,no damages to marrow,liver and renal functions,repeat usage when compared with operation,chemotherapy and radiotherapy.These advantages can significantly reduce the symptoms of the patients and improve their living quality.It provides an alternative therapy for the patients with liver cancer who can't bear operations.It has been proven by experiments that the application of RFA in the liver tissues is safe and effective,in the mean time RFA can improve body's immunological functions which are benefit for tumor's treatment.But the following symptoms are not suitable for the application of radiofrequency therapy,including the severe liver dysfunction,jaundice,ascites,prothrombin time significantly extend, liver cancer with distant metastasis,huge liver cancer or diffuse liver cancer,cirrhosis, portal hypertension,and stomach esophagus varicosity with serious bleeding tendency,installation of a cardiac pacemaker.However,it has been no reported how about the effects on the piping system of Glisson and pathological change of the liver tissue by RFA.Related investigations are needed to provide bases for its clinical applications.
MCT use local temperature to deactivate the tumors by puncturing the tumor tissues with minimal invasion,and it is a new therapy for tumors developed in the recent years.The body contains many polar molecules and charged ions,these polar molecules rotate rapidly under the effects of microwave electric field that is alternative in high rate,and the charged ions move rapidly and heat is produced by the scrape and the collision with the adjacent ions.The temperature in the target tissue is thus elevated to more than 50℃.The tumor cells in the target region are dehydrated and dried,and then develop coagulative necrosis.The embedded microwave solidification technique with,cooling air passage by inner circulating refrigerant used in clinical investigations(high pressure argon at normal temperature) can reduce the temperature of the pole and reduce the damages to the normal tissues near the puncture path during the process of MCT.With the development of microwave technique and equipments as well as continuous application of MCT in the clinical practice,MCT has been used in the treatment of some solid tumors such as liver cancer lung cancer.Among them,CT-directed percutaneous MCT in the treatment of liver cancer have been gradually carried out in the clinical practice,and particularly some clinical and experimental investigations performed in our country have obtained certain achievements.CT-directed percutaneous MCT have few side-effect on the body except local wounds by puncture and heat damages around tumor and a small quantity of normal liver tissues,as one of the minimally invasive therapies,MCT can be selected for clinical practice.Previous investigations showed that MCT can completely kill the tumor cells as well as coagulate the adjacent blood vessels near the tumors at the same time which can directly cut down the blood supplication to the tumors.A reaction zone formed between the normal tissues and the cancer tissue wrap up the rumor and function in the prevention of tumor metastasis in some degree.Besides this,MCT can achieve long-term effect for preventing the tumor metastasis via activating the body's immunological status. However,it has been no reported how about the effects on the piping system of Glisson and pathological change of the liver tissue by MCT.Related investigations are needed to provide bases for its clinical applications.
This study includes three parts:
1、The Influence Of Targeted ar-he Cryablation On The Area Of The Porta
Hepatis
Objective:To discuss an impact of targeted ar-he cryablation over the first hepatic portals area by observing the pathological change of the hepar Glisson pipeline system first grading branch tissue in order to provide a theory basis to clinical practice.Methods:The 14 healthy dogs ablated by the percutaneous puncture hepar targeted ar-he cryablation were individed into A and B groups randomly.These dogs of the two groups were put to death in batches in 3 days and 28 days after ablation, respectively.Then the pathological change about the ablation target area and the first grading branch of the Glisson pipeline system was observed.Results:The obvious damage was not found in the portal vein blood vessel wall by the naked eyes or the light microscope;however,the blood vessel vicinity of liver tissue was damaged to necrosis entirely.Though the injuries in different degrees were seen in the one-level bile duct system after ar-he cryablation operation,we had not found sever damages,such as perforation、negrosis,and most of the injuries were reversible.The size of the ablated area in 28 days is smaller than that of 3 days obviously (p＜0.05).And on the acute stage(1-3d),ALT and AST increased more highly than those of pre-radio frequency operation(p＜0.05).However after operation(l-4w), there was no statistical difference comparing with preablation.Moreover,The cryablated area is mainly consistent with the pathological necrosis range(p＞0.05). Conclusion:Targeted ar-he cryablation can not only cause the blood vessel vicinity of liver tissue necrosed entirely,but also let the portal vein blood vessel wall undamaged under the protection of hot pool effection.And the ar-he cryablation injury effect on bile duct of hepatic portal section is relatively light.Moreover,ar-he cryablation has no obvious damage to the liver function.The range of necrosis could also be forecasted by the size of freezing area.Therefore,ar-he cryablation is a safe minimal invasive operation with reliable therapeutic effect.
2、The Influence Of Radio Frequency Ablation On The Area Of The First Porta Hepatis
Objective:To discuss an impact of radio frequency over the first hepatic portals area by observing the pathological change of the hepar Glisson pipeline system first grading branch tissue in order to provide a theory basis to clinical practice.
Methods:The 14 healthy dogs ablated by the percutaneous puncture hepar radio frequency ablation were individed into A and B groups randomly.These dogs of the two groups were put to death in batches in 3 days and 28 days after ablation, respectively.Then the pathological change about the ablation target area and the first grading branch of the Glisson pipeline system was observed.Results:The obvious damage was not found in the portal vein blood vessel wall by the naked eyes or the light microscope;hoyvever,the blood vessel vicinity of liver tissue was damaged to necrosis entirely,and injury was seen in the one-level bile duct system after radio frequency operation.The size of the ablated area in 28 days is smaller than that of 3 days obviously.And on the acute stage(1-3d),ALT and AST increased more highly than those of pre-radio frequency operation(p＜0.05).However after operation(l-4w), there was no statistical difference comparing with preablation.Conclusion:Though RFA can not only cause the blood vessel vicinity of liver tissue necrosed entirely,but also let the portal vein blood vessel wall undamaged under the protection of hot pool effection,the RFA injury effect on bile duct of hepatic portal section is very obvious. Therefore,we should pay more attention to protecting bile duct system during radio frequency operation.Another conclusion we draw is that the effect of radio frequency on liver function is little significant.
3、Study On Reliability And Safety Of PMCT In The Area Of First Porta Hepatis
Objective:To discuss an impact of targeted microwave ablation on the first hepatic portals area by observing the pathological change of the hepar Glisson pipeline system first grading branch tissue in order to provide a theory basis to clinical practice.Methods:The 12 healthy dogs ablated by the percutaneous puncture hepar targeted microwave ablation were individed into A and B groups randomly.These dogs of the two groups were put to death in batches in 3 days and 28 days after ablation,respectively.Then the pathological change about the ablation target area and the first grading branch of the Glisson pipeline system was observed.Results:The obvious damage was not found in the portal vein blood vessel wall by the naked eyes or the light microscope;however,the blood vessel vicinity of liver tissue was damaged to necrosis entirely.The injuries,to some degree,were seen in the one-level bile duct system after ar-he cryablation operation.The size of the ablated area in 28 days is smaller than that of 3 days obviously(p＜0.05).And on the acute stage(l-3d),ALT and AST increased more highly than those of pre-radio frequency operation (p＜0.05).However after operation(l-4w),there was no statistical difference comparing with preablation.Moreover,The cryablated area is bigger than the pathological necrosis range(p＞0.05).Conclusion:Targeted microwave ablation can not only cause the blood vessel vicinity of liver tissue necrosed entirely,but also let the portal vein blood vessel wall undamaged under the protection of hot pool effection.Moreover,microwave ablation has no obvious damage to the liver function.Because of the damages to the hepar Glisson pipeline system,we should protect the system carefully during the targeted microwave ablation operation.
引文
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[1]Rossi S,Buscarini E,Garbagnati F,Di Stasi M,Quaretti P,Rago M et al.Percutaneous treatment of small hepatictumors by an expandable RF needle electrode.AJR Am JRoentgenol 1998;170:1015-1022.
[2]Livraghi T,Goldberg SN,Lazzaroni S,Meloni F,Solbiati L,Gazelle GS.Small hepatocellular carcinomartreatment with radio-frequency ablation versus ethanol injection.Radiologyl999;210:665-661.
[3]Curley SA,Izzo F,Delrio P,Ellis LM,Granchi J,Vallone Pet al.Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies :results in 123 patients.Ann Surg 1999;230:1-8.
[4]Curley SAJzzo F,Ellis LM,Nicolas Vauthey J,Vallone P.Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis.Ann Surg 2000;232:381-391.
[5]Wood TF,Rose DM,Chung M,Allegra DP,Foshag LJ,Bilchik AJ.Radio frequency ablation of 231 unresectablehepatic tumors:indications,limitations,and complications.Ann Surg Oncol 2000;7:593-600.
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