贺克武1 高斌1 李嘉嘉2(1安徽省合肥市第一人民医院影像中心,安徽,合肥,230061,2安徽医科大学第一附属医院中心实验室,安徽,合肥,230032)【摘要】 目的 探讨CT导引下125I粒子组织间植入兔VX2肿瘤模型对细胞凋亡率的影响。方法 在20只兔两侧大腿肌肉内建立VX2肿瘤模型,3周后待肿瘤灶长至直径约2cm备用,每只兔随机选择一侧肿瘤灶作为治疗组,另一侧作为对照组,治疗组在CT导引下经皮穿刺将活度为0.9mCi的125I粒子植入肿瘤组织内,对照组肿瘤灶内植入无活性的空心粒子,于术后即刻、72h、1w、2w、3w在CT导引下分别穿刺距粒子0.5cm~1cm、1.0cm~1.5cm处组织进行流式细胞仪检测细胞凋亡率。结果 125I粒子植入后即刻、72h、1w、2w、3w距粒子0.5~1.0cm处对照组和治疗组细胞凋亡率分别为(5.43±0.67)%、(5.48±0.66)%(P>0.05),(5.45±0.58)%、(11.60±0.87)%(P<0.05),(6.07±0.69)%、(18.8±0.64)%(P<0.05),(5.94±0.43)%、(37.20±0.39)%(P<0.01),(6.30±0.58)%、(36.56±0.67)%(P<0.01)。距125I粒子1.0~1.5cm处各个时间点对照组与实验组之间细胞凋亡率均无差别(P>0.05)。结论 125I粒子组织间植入可诱导肿瘤细胞凋亡,植入后72小时细胞凋亡率开始增加,术后2周达高峰并维持在高水平,且随距125I粒子的距离增加细胞凋亡率迅速下降。—————————————————————————————通讯作者:高斌合肥市重点科研立项项目(2006004);合肥市人才发展基金资助项目【关键词】肿瘤细胞,VX2肿瘤;碘放射性同位素;近距离疗法;兔;体层摄影术,X线计算机;The study of CT-guided iodine-125 implantation in the treatment of rabbit VX2 tumor GAO Bin,HE Ke-wu, LI Jia-jia. Medical Imaging center, The First People,s Hospital of Hefei City, Hefei 230061, Anhui Province, China【Abstract】Objective To evaluate the effect of CT-guided iodine-125 seed(125I) implantation to rabbit VX2 tumor cell apoptosis. Methods VX2 tumor cell was implanted into muscle of 40 legs of rabbit, 3 weeks later, as the diameter of tumor was 2cm and could be used for test. Random sample tumor on one leg of rabbit as test team and tumor on the other leg as control team, under CT guidance, 125I seeds were implanted into 20 tumor lesions of test team, hollow seeds were implanted into 20 tumor lesions of control team. Instantly, 72h, 1w, 2w, 3w after operation, percutaneous tumor away from seed 0.5-1.0cm and 1.0-1.5cm guided by CT and apoptosis was investigated by FCM.Results Instantly, 72h, 1w, 2w, 3w after treated with iodine-125(125I) implantation, away from seed 0.5-1.0cm , the apoptosis rate of control team and test team was respectively as follow: (5.43±0.67)% and(5.48±0.66)%,(P>0.05),(5.45±0.58)% and (11.60±0.87)%,(P<0.05),(6.07±0.69)% and (18.8±0.64)%,(P<0.05),(5.94±0.43)% and (37.20±0.39)%,(P<0.01),(6.30±0.58)% and (36.56±0.67)%,(P<0.01). Away from seed 1.0-1.5cm , the apoptosis rate of control team and test team have no different(P>0.05). Conclusion 125I seed could induced tumor cell apoptosis, 72h after 125I seed be implanted, the tumor cell apoptosis increased and reached peak 2w after 125I seed be implanted and keep the high level herefrom. It also be discovered that apoptosis rate descend rapidly along with the distance away from the 125I seed.【Key words】Neoplasm; VX2 tumor; iodine radioisotopes; Brachytherapy; rabbit; computed tomography放射线治疗是肿瘤治疗四大手段之一。组织间近距离放疗始于20世纪初[1],但由于当时生产的放射性核素均释放高能光子,难以进行防护,加之没有精确的立体定位系统、治疗计划系统和质量验证系统,临床应用受到了极大限制。80年代后期随着新型放射性125I粒子的研制成功,以及B超、CT导引下精确定位系统和计算机三维治疗计划系统的出现,放射性粒子种植治疗肿瘤得到了迅速推广,但其治疗肿瘤的机制尚不明确。本研究通过建立兔肌肉VX2肿瘤模型,观察125I粒子植入对肿瘤细胞凋亡率的影响,为125I粒子组织间植入近距离治疗肿瘤提供理论依据。材料与方法1.材料 荷瘤种兔1只(由苏州医科大学第一附院惠赠),实验用兔20只,均为雄性,体重约2.5~3.0Kg(由安徽医科大学实验动物中心提供,许可证号:SYXK(皖)2002-0038)。EPICS XL-MCL 型流式细胞仪(美国Backman coulter公司),光学显微镜(OLYMPUS),Annexin V/PI试剂盒(Immunotech 公司),匀浆机(意大利DAKO公司),低速台式离心机(coulter公司),螺旋CT扫描仪(GE16层),TPS-2000系统(珠海和佳),0.9mCi125I粒子、植入枪、穿刺针、顶针均为上海欣科公司生产,手术相关器械。2.动物模型的制备及125I粒子组织间植入近距离治疗 按文献[2]方法在每只实验兔两条后腿肌肉内各制备一个肌肉VX2肿瘤模型,将兔送回饲养室,单笼饲养,3周后待肿瘤灶长至直径约2.0cm时开始用于实验,每只兔随机选择一侧肿瘤灶作为治疗组,另一侧作为对照组,治疗组在CT导引下经皮穿刺将活度为0.9mCi的125I粒子1粒植入肿瘤组织内,对照组肿瘤灶内植入无活性的空心粒子,于术后即刻、72h、1w、2w、3w在CT导引下分别穿刺距粒子0.5cm~1cm、1.0cm~1.5cm处组织,放入冰预冷的培养皿中备用(如图9-12所示)。3.单细胞悬液的制备 将肿瘤组织放入匀浆机样本槽内,加适量PBS液,打开匀浆机开关,1min后关闭匀浆机开关,打开样本槽,20ml注射器抽取组织匀浆,用200目细胞滤网过滤到冰预冷的试管内;1500r/min×5min离心沉淀,去上清,试管内加PBS液轻微振荡混匀后,200目细胞滤网过滤去细胞团块,500r/min×5min离心沉淀去上清,试管内加15mlPBS液轻微振荡混匀后,300目细胞滤网过滤去细胞块。细胞计数并调整细胞浓度为1×106/ml~5×106/ml,4oC保存,待用。4.流式细胞仪检测肿瘤细胞凋亡率 取细胞悬液用100ml Binding Buffer 和FITC标记的Annexin V(20ug/ml)10ml,室温下避光卵育30min。再加入PI(50ug/ml)5ml,避光反应5min。加入400ul Binding Buffer 4℃下卵育20min,避光并不时振动。上FCM检测。主要检测指标:细胞凋亡率(apoptosis rate, AR)。5. 统计学处理 采用STATA软件对配对设计资料进行t检验,检验水准α=0.05。结果125I粒子植入后距粒子0.5~1.0cm处2组在各时间点细胞凋亡率(表1)表明125I粒子植入后72小时治疗组细胞凋亡率开始增加,术后2周细胞凋亡率达峰值并维持在高水平,对照组细胞凋亡率在各个时间点无变化,如图1~8所示,图片右下象限凋亡细胞随时间延长逐渐增加。125I粒子植入后距粒子1.0~1.5cm处2组在各时间点细胞凋亡率(表2)表明治疗组随距离增加,细胞凋亡率迅速下降。表1 125I粒子植入后距粒子0.5~1.0cm处2组在各时间点细胞凋亡率( ±S)%组别 术后即刻 72小时 1周 2周 3周对照组 5.43±0.67 5.45±0.58 6.07±0.69 5.94±0.43 6.30±0.58治疗组 5.48±0.66 11.60±0.87 18.07±0.64 37.20±0.39 36.56±0.70P值 >0.05 <0.05 <0.01 <0.01 <0.01表2 125I粒子植入后距粒子1.0~1.5cm处2组在各时间点细胞凋亡率( ±S)%组别 术后即刻 72小时 1周 2周 3周对照组 5.43±0.67 5.45±0.58 6.07±0.69 5.94±0.43 6.30±0.58治疗组 5.48±0.66 5.78±0.64 8.07±0.87 7.43±0.55 4.36±0.69P值 >0.05 >0.05 >0.05 >0.05 >0.05讨论早在20世纪初,国外有学者提出将放射性125I核素混悬液直接注入肿瘤灶内以治疗肿瘤,但是由于放射性核素固化问题、放射防护问题,加之没有精确的立体定位系统和治疗计划系统与质量验证系统,使临床应用受到了极大的限制。80年代后期随着新型放射性125I粒子研制成功,以及B超、CT导引下精确定位系统、计算机三维治疗计划系统、精细的粒子植入器械和良好的放射防护设备的相续出现,使放射性粒子种植治疗肿瘤得以迅速推广。1972年美国Whitomore等[3]开创经耻骨后组织间125I粒子治疗前列腺癌,成为现代近距离治疗的基础。对于低中危险组前列腺癌患者,以PSA为指标的5年无瘤生存率,单纯125I粒子近距离治疗与外放疗或根治术相当,125I粒子近距离治疗单一效价比高,并发症发生率低[4~6]。Chauveinc, L.等[7]报道,单纯125I粒子近距离治疗前列腺癌10-12年生化控制结果优于手术或外放疗而并发症发生率低,尤其适于T1-T2期,PSA<10ng/ml,gleason评分<7分患者。对于不适于手术的前列腺癌患者,125I粒子治疗后10年生存率为70%,总的生存率与手术相当,与同时代外放疗情况相似。对于晚期前列腺癌患者125I粒子近距离治疗配合外放疗可获得靶区剂量的提升[8]。国内外也有多篇研究报道,125I粒子组织间植入治疗在乏血供或TACE治疗失败的肝癌、转移性骨肿瘤、胰腺癌、消化道肿瘤、妇科肿瘤及头颈部肿瘤治疗中近期治疗效果满意[9-14]。细胞凋亡(apoptosis),又称程序性细胞死亡,是指细胞在一定的生理或病理条件下,遵循自身的程序,自己结束生命的过程。它是一个主动的、高度有序的、由基因控制及一系列酶参与的过程,在保证多细胞生物的生存过程中扮演着关键的角色。细胞凋亡概念的提出引起了广大研究者的浓厚兴趣。随着凋亡研究的不断深入,各种各样检测凋亡的新技术和新方法相继建立,其中不少检测试剂已经商品化,从而有力推动了该领域研究的进展。磷脂酰丝氨酸(phosphatidylserine,PS)正常位于细胞膜的内侧,但在细胞凋亡的早期,Ps可从细胞膜的内侧翻转到细胞膜表面。膜联蛋白V(Annexin V)是一种相对分子质量为35~36 kb的Ca2+ 依赖性磷脂结合蛋白,能与PS高亲和力特异性结合。因此。应用膜联蛋白V法可鉴定早期细胞凋亡。将膜联蛋白V用荧光素(F1TC,PE)或biotin标记,以标记的膜联蛋白V作为荧光探针,利用流式细胞仪或荧光显微镜可检测凋亡的细胞。荧光染料PI是一种核染色剂,能够特异性的与核DNA结合,而凋亡细胞的细胞膜尚未破裂,PI染料不能进入细胞内部,因此PI是阴性的。利用Annexin V/PI双染法可将细胞分为正常细胞、凋亡细胞及坏死细胞。在流式细胞仪检测图像上,正常细胞不被膜联蛋白V及Pl染色,位于图像的左下象限,而凋亡细胞呈膜联蛋白V强阳性、Pl阴性或弱阳性,位于图像的右下象限,坏死细胞则膜联蛋白V/PI均呈强阳性,位于图像的右上象限。我们通过动物实验,模拟125I粒子体内插植的照射模式,利用流式细胞仪观察了125I粒子低剂量率持续照射对VX2肿瘤细胞的早期影响。结果表明,125I粒子组织间植入治疗可诱导肿瘤细胞凋亡,且随着照射时间的延长而增加。125I粒子植入后即刻细胞凋亡率为(5.48±0.66)%,与对照组无统计学差异,植入72小时后肿瘤细胞凋亡率开始增加,治疗组为(11.60±0.87)%,而对照组细胞凋亡率未增加,两组间有统计学差异(P<0.05),植入后2周细胞凋亡率达到高峰(37.20±0.39)%,并维持在较高的水平,对照组细胞凋亡率仍维持在治疗前的水平。我们的研究还表明,随着距离的增加,细胞凋亡率迅速下降,这是因为125I粒子有效治疗距离仅为1.7cm,且组织剂量遵循距离反平方定律,随距离增加组织剂量迅速下降。这一特性可有效防止125I粒子组织间植入治疗产生过热点以及增加靶区与正常组织剂量比,从而最大限度的杀伤肿瘤组织和保护正常组织。本实验证实了125I粒子组织间植入可诱导肿瘤细胞凋亡,但对于125I粒子诱导凋亡的相关基因的研究还没有统一的意见,125I粒子诱导凋亡的分子生物学机制还有待于进一步研究。参考文献1. 黄振国 张雪哲 王武,等. 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贺克武,高 斌, 张秀珊,文刚,巢惠民,黄永翠【摘要】 目的 探讨CT导引下移植肝脏穿刺活检技术及其临床意义。 方法 25例次移植肝脏在CT导引下行穿刺活检,用HE染色的方法显示其病理形态学的改变。 结果 25例次肝脏穿刺检查成功lanshan率为100%,其中诊断为急性排斥9例次,保存性灌注再损伤6例次,胆道并发症4例次,药物性肝脏损伤4例次,慢性排斥1例,急性肝坏死1例。 结论 CT导引下肝脏穿刺组织学检查是临床判断移植肝再损伤的重要方法,对鉴别引起肝脏损害的原因有很大的价值。【关键词】 肝移植;活检;CT导引CT-guided percutaneous transplant liver biopsy GAO Bin, HE Ke-wu. Medical Imaging Center, Department of CT, The First People’s Hospital of Hefei, Anhui province, Hefei 230061, China【Abstract】 Objective To study the technique and clinical significance of percutaneous transplant liver biopsy guided by CT. Methods 25 times in 19 transplant cases were undergone this procedure. Results The successful rate of the procedure was 100%, acute rejection was diagnosed on 9 episodes, preservation injury in 6, bile —————————————————————————————作者单位:230061 合肥,合肥市第一人民医院影像中心CT室通讯作者:贺克武duct strictures in 4, drug-induced injury in 4, chronic rejection in 2 and acute hepatic failure in 1. Conclusions CT-guided liver biopsy is an important method for diagnosed transplant liver injury in clinic, simultaneously with great value for distinguish the reason of transplant liver injury.【Key words】 liver transplantation; biopsy; CT-guided肝移植后再损伤的原因较多,仅凭临床症状及生化检查常难以鉴别,因此,CT导引下肝脏穿刺活检在判断移植肝损害中有重要意义。我们分析了25例次移植肝经皮穿刺活检并讨论移植肝穿刺技术及其临床意义。1 材料与方法1.1 一般资料本组搜集2004年3月至2007年2月19例、25例次CT导引下 经皮穿刺的移植肝脏。其中,男15例,女4例,年龄14~76岁,平 均57岁。穿刺术前患者血小板计数、出凝血时间和凝血酶原时间均在正常范围内。1.2 使用设备GE lightspeed 8排16层螺旋CT,采用18G C2型切割式活检针(cook)进行穿刺及取材,自制的体表定位栅条。1.3 方法患者仰卧位或左侧卧位,先CT扫描,选择远离肝内大血管肝右叶作为穿刺平面,于定位平面上贴体表定位栅条,再次CT扫描确定穿刺点和拟进针角度、深度。常规消毒、铺巾、局麻,按既定路线穿刺,必要时可行CT扫描以调整进针方向。针尖刺入肝脏内并经CT薄层扫描确认后,取远离被膜下肝组织,10%甲醛溶液固定,石蜡包埋,病理切片,苏木精-伊红(HE)染色。术后常规以穿刺层面为中心,上下层面CT扫描观察有无肝脏撕裂、肝包膜下出血等并发症,在我科观察半小时后推车送入病房(图1~3)。2 结果2.1 穿刺结果25例次穿刺均成功获得移植肝脏组织学样本,技术成功率为100%。2.2 25例次肝脏穿刺组织学形态改变结果急性排斥反应9例次,保存性灌注损伤6例次,胆道并发症4例次,药物性肝损害4例次,慢性排斥反应1例,急性肝坏死1例。2.3 穿刺并发症本组穿刺后CT扫描发现2例肝包膜下少量出血,5例穿刺路径少量出血,均未予处理。3讨论3.1 CT导引在移植肝脏穿刺活检中的应用 肝脏移植后再损伤的原因很多,如急、慢性排斥反应、保存性灌注损伤、胆道并发症、药物性肝损害等,仅凭临床症状及生化检查常难以鉴别,近年来在临床上开展的CT导引活检技术使诊断正确率明显提高。CT穿刺活检作用主要体现在以下方面[1~3]:①激光导引系统可从轴位、矢状位上观察模拟进针路径、肝内大血管及胆囊等器官的位置关系,使进针路径更为安全、准确,提高诊断正确率,降低了并发症的发生率;②能够进行多次检查,有利于并发症的治疗随访;③组织分辨率稿,重叠少,解剖关系显示清晰。3.2肝移植后,肝脏组织穿刺活检的目的①明确肝功能障碍的原因。②判断肝损伤程度和/或纤维化程度。③评价治疗后肝组织形态学变化及病变演变趋势④评估供肝质量[4]。由于组织学诊断在肝移植后病变诊断中具有重要作用,为避免取材不当而延误诊断,一般要求送检标本应足够大,至少包含5个汇管区成分[5]。因为,一方面,急、慢性排斥反应主要位于门管区;另一方面,肝移植后肝内病变呈弥漫性、不均一或非同步性分布,一个汇管区改变缺乏代表性。3.2 移植肝脏穿刺活检部位主张选择远离肝内大血管肝右叶深部组织进行穿刺活检,而非文献报道的选取肝被膜下肝组织[6]。因为:①肝包膜下的肝细胞对缺血、缺氧敏感,在肝脏移植围手术期表现出较重的出血、坏死,而不能真实反应肝实质内的病变。②肝包膜下纤维组织成分较多,易误诊为结节样肝硬化。③手术中边缘肝组织受到的创伤较大,常可见急性炎细胞浸润。3.3 肝移植后,穿刺活检时间对于肝移植后进行肝穿刺活检的时间,目前各移植中心做法不一。本中心只有在临床出现不可解释的肝酶升高等情况下,才进行活检;有的中心则计划性进行活检,且在一定的间隔时间进行。急性排斥反应、保存和再灌注损伤是肝移植早期肝功能异常最常见的原因,可发生于肝移植后2天到数月,平均7天到3周内发生。急性排斥反应发生率为60~70%,所有的慢性排斥反应都是从急性排斥反应发展而来[7]。故临床上常规在移植后第1周、第2周、第一个月、第二个月、第三个月、第六个月、第12个月分别进行肝活检,以后每年一次,连续5年[8]。3.4 肝移植术并发症的病理改变急性排斥反应60%以上发生于术后的5~30天,高峰在术后的第6~7天。主要表现为:①汇管区混合性炎细胞浸润,包括淋巴细胞、单核细胞、嗜酸性粒细胞、中性粒细胞等。②中等以下胆管上皮的炎性损伤,表现为细胞浆空泡化,胞浆嗜伊红,核固缩,甚至坏死和消失。③血管内皮炎,主要累及终末肝静脉和小叶间静脉,表现为淋巴细胞附着于血管内皮表面或出现血管内皮下浸润,造成内皮的隆起或破裂。至少符合以上3项中的2项即可确立诊断[9](图4、5)。慢性排斥反应可发生于移植术后数周到数年,多于移植后3~6月出现高峰。诊断依据为:①泡沫细胞阻塞性动脉病。②50%以上汇管区胆管消失。此外,终末肝静脉周围的肝细胞出现胆汁淤积、气球样变及坏死也提示慢性排斥反应[10-12](图6、7)。保存/再灌注损伤本组发生率为24%,多出现于移植后2周内,多数是可逆性病变,于肝移植术后数天至数周内可自行恢复,但严重者可持续数月,甚至导致肝早期无功能。形态学表现为肝细胞气球样变、肝内淤胆、肝组织严重的缺血性凝固性坏死等,主要位于中央静脉周围,严重者也可呈弥漫性分布[13]。本组胆道并发症的发生率为16%,多发生于术后1周至2年,其中以胆管狭窄最常见。组织学表现为:①小胆管变形、破坏,管周水肿,炎细胞浸润,汇管区边缘的胆管增生。②汇管区急、慢性炎症,间质水肿或不同程度的纤维化。③小叶中心性肝毛细胆管胆汁淤积[14]。肝移植后药物性肝损害主要取决于患者所用的药物。如硫唑嘌呤、环孢素A、FK506可引起胆汁淤积,硫唑嘌呤还可引起静脉栓塞性疾病,皮质类固醇引起肝窦扩张、结节性增生及脂肪变。 总之,我们认为在CT导引下对移植肝脏进行穿刺活检是一种方便、安全、有效的诊断方法。可以提供肝脏移植后各种并发症的诊断信息,避免了一部分患者为了诊断需要剖腹探察,给临床治疗提供了诊断依据,从而对肝移植后各种并发症进行及时、正确地治疗,具有重要的临床意义。参考文献1. 黄振国,张雪哲,王武.CT导引下肺内病变穿刺活检诊断正确率相关因素分析[J].介入放射学杂志,2006,15(2):81-84.2. 吴达明,陆勇,度联军,等.CT导引下的纵隔病变穿刺活检[J].介入放射学杂志,2006,15(7):421-423.3. 汪健文,周勤,张章,等.胸部病变CT导引下穿刺活检的临床应用[J].介入放射学杂志,2005,14(4):418-420.4. 于颖彦,计骏,周光文,等. 肝移植后肝脏组织活检的动态病理学分析[J]. 外科理论与实践杂志,2003,8(6):463-466.5. Blakolmer K, Seaberg EC, Batts KP, et a1.Analysis of the reversibility of chronic liver allograft rejection implications for a staging schema[J]. Am J Surg Pathol, 1999,23(11):1328-39.6. 王燕庆,夏强,张建军,等. 肝脏穿刺活检在诊断移植肝病理改变中的价值[J].中华普通外科杂志,2005,20(11):693-695.7. 纪小龙. 如何发挥病理在肝移植中的作用[J]. 中华肝胆外科杂志,2005,11(1):6-7.8. Sebagh M, Samuel D. Place of the liver biopsy in liver transplantation[J].J Hepatol , 2004,41 (6):897-901.9. 王政禄,张淑英,李卉,等. 肝移植术后急性排斥反应的病理诊断一200例次肝穿刺活检的病理组织学分析[J]. 肝脏杂志,2004,9(4):217-220.10. Demetris A,Adams D ,Bellamy C,et a1. Update of the International Banff Schema for Liver Allograft Rejection:working recommendations for the histopathologic staging and reporting of chronic rejection.An International Pane1.Hepatology,2000,31(3):792-799.11. 王政禄,张淑英,李卉,等. 肝移植慢性排斥反应早期病理组织学分析[J]. 肝脏杂志,2006,11 (1):4-6.12. 余英豪,姚丽青. 肝移植排异反应的病理学诊断[J]. 中国误诊学杂志,2006,6(12): 2268-70.13. Busquets J,Figueras J,Serrano T,et a1.Postreperfusion biopsies are useful in predicting complications after liver transplantation[J].Liver Transpl,2001,7(5):432-435.14. 王政禄,张淑英,朱丛中,等. 肝移植术后胆道并发症的临床及病理分析[J]. 中华肝脏病杂志,2006,l4(4):247-249.
CT-guided percutaneous permanent 125I implantation for patients with malignant tumorHE ke-wu, GAO Bin, LI Jin-song,CHAO hui-ming, WANG Jia-mi, HU Yong-sheng, XU Sheng-de, JI Ya-liDepartment of Radiology, The First People,s Hospital of Hefei , Anhui province, China.Objective To evaluate the procedure, feasibility, safety and efficacy of CT-guided iodine-125 implantation for malignant tumors.Methods 26 lesions in 21 patients with malignant tumor were treated with iodine-125 implantation brachytherapy, of which 9 lesions were primary unresectable carcinoma and 17 lesions were metastasis tumors. There were 16 males and 5 females. The ages of these patients were from 42 to 89 years old with a mean of 58.2 years. Under CT guidance, 125I seeds were implanted into malignant tumor according to computerized Treatment Plan System (TPS). The radioactivity quantum of a single 125I seed was of 22, 26, 30 and 33MBq. Plane implantation technique was adopted. The distance of adjacent 125I seeds was between 1.0cm to 1.5cm depending on their radioactivity of the seeds.Result 125I seeds have been put into the right location according to TPS. The implantation was completed successfully for all lesions of 21 patients. No complications were observed. The number of seeds implanted into individual lesion was between 5 to 40 (mean 14 ). Pain relief was realized in all 10 cases of malignant tumors of bone. The follow-up CT examination demonstrates that 18 lesions diminish clearly, necrosis was found in 8 lesions and the remaining 4 lesions have no significant change in size.Conclusion CT-guided iodine-125 implantation was a safe, effective and feasible method in treatment of patients with malignant tumor.Key words neoplasm, brachytherapy, Iodine radioisotopes, radiology, interventionalIntroductionAs the increase of incidence of malignant tumor in recent years, the combined treatment for malignant tumor patients who have missed the opportunity of operation or been unwilling to be operated was getting much more concerned. As a new therapy, inter-tissues brachytherapy, for the patients with late stage malignant tumors, was gradually accepted by most patients and medical workers. Compared with radiotherapy in vitro, the advantage of the brachytherapy was that it can result in less complication, light damage to peripheral tissues, good safety and reliability. Moreover the therapy can kill cancer cells to the maximum extent and destroy the normal tissues and their functions to the minimum[1~2]. In this paper, a critical review on the treatment of 26 lesions in 21 malignant tumor patients with iodine-125 implantation brachytherapy was carried out. The objective was to evaluate the methodology, feasibility, safety and efficacy of CT-guided iodine-125 implantation.Patients and MethodsPatient population 26 lesions in 21 patients (16 males and 5 females), in which 9 lesions were primary unresectable carcinoma and 17 lesions were metastasis tumors. The ages of the patients were from 42 to 89 years with a mean age of 58.2 years.Instrument and Facility GE lightspeed Ultra 8 CT, purpose-designed software for intervention treatment ; Radio-partical Treatment Planning System(TPS), HGGR-2000, provided by HeJia Medicine Corporation of China. Includes computerized Treatment Planning System (TPS), implantation guns, needles etc; The implantation seeds were radioactive 125I (type 6711) made by Nuclear Research Institute of China. Each seed was tightly sealed with titanium-Nickel alloy, and has a length of 4.5mm and diameter 0.8mm, with a half-life of T1//2=59.43d. The radioactivity quantum per seed was of 22, 26, 30 and 33MBq. The effective inter-tissues radiation radius of every seed was about 1.7cm; Protection: Lead-rubber apron, scarf, protective gloves and protective glasses made of lead glass.Interventional Treatment 1. Preparation Before Operation:(1) General preparation: Blood routine examination, bleeding and blood coagulation time tests, electrocardiogram examination and antitussive medicine.(2) Scanning of CT: Determination of the location, size of focus and its invasion of peripheral tissues in order to reduce the uncertainty of the operation and prevent from the complication. 2. Application of TPS: It was intended to observe the size, shape and location of a lesion in order to select a suitable puncture position, design implantation route and direction based on 3D reconstruction image of CT scanning. The procedure was as follows: Firstly, calculation of total required radiation of 125I based on the size of a focus and Heller’s factor (Da), total radiation = Da 185MBq, in which Da= (focus’ length+width+height)/3. Secondly, selection of the radiation type of 125I seeds, larger radiation 125I (e.g., 30, 33 MBq) was suitable for the implantation in the centre of a lesion and smaller ones (22, 26MBq) were for the margin of the lesion and the peripheral region of some important organisms such as vascular and nerves. Thirdly, estimation of the total required number of 125I seeds. To do this estimation, it was generally to calculate the required number and the radioactivity for smaller seeds and then to determine the number and the radioactivity for larger seeds. Finally,determination of implantation interval of 125I seeds. To increase the efficacy of implantation treatment, it was decided that the interval between larger seeds was about 1.5cm whereas the interval between smaller ones was around 1.0cm. 3. Method of Implantation: There were two methods to implant radioactive seeds: one was to lay out seeds in the location of residual focus and possible metastatic region of a tumor in ordinary operation; the other was to implant radioactive seeds directly into a tumor and its peripheral tissue under the guidance of CT, ultrasonoscope or abdominoscope.Implantation Operation The procedure of CT scanning in seed implantation was exact the same as that in a CT-guided biopsy, as stated in many references. It was firstly to perform CT scanning in the region of a focus. The thickness of scan layer was 5 mm and the interval between layers was 5 mm too, which should be in consistent with the specification in a planned implantation treatment scheme. It was then to determine the most suitable puncture position and the optimal implantation route based on the number and the location of the seeds specified in the prepared treatment scheme. The puncture position will be labeled with a metal tag. After the confirmation of the correctness of the puncture position by CT scanning, routine disinfection, drape and local anesthesia around the position will be carried out. The CT scanning will be done once more when the implantation needle has reached a pre-defined depth in order to put the needle into the prescribed target location exactly. After withdrawal of stylet from the implantation needle, the seed will be planted into the lesion through the syringe of the implantation needle. Finally, CT scanning will be performed again to observe the overall distribution of the seeds.Post-operation Treatment Check if there was any complication and observe the distribution of the implanted seeds by CT scanning immediately after the implantation. The information will be then input into a 3D post seed-implantation quality review system following the same procedure specified in the treatment scheme by a responsible radiologist. The practical radiation distribution curve will be computationally drawn according to the practical distribution of the implanted seeds. The physical property, the time of radioactive protection and other precautions should be introduced to the patients and their family members.ResultsThe implantation for all 21 patients were completed successfully. No complication was found. The practical distribution of the implanted seeds was basically the same as the scheduled scheme before implantation. The number of implanted seeds for each lesion was between 5 to 40 (average 14 per lesion). The pains were remitted obviously for 8 patients with metastatic tumor of bone after implantation. The follow-up observation for all 21 patients between 20 days and 5 months after implantation shows a considerable diminishing in 18 lesions of 12 patients, necrotic tissues in 8 lesions of 6 patients and no significant variation in 4 lesions of 3 patients. No seed was missed. Figs. 1, 2 and 3 were shown the follow-up CT results after 20 days implantation for a patient of lung cancer with metastasis to the second cervical vertebrae. A lesion in the left side of the vertebrae was about 3×3×3cm3 before the implantation (Fig.1). 10 125I seeds were implanted based on the treatment scheme of TPS (Fig.2). The lesion diminishes dramatically and large amount of new bones were formed in the inversion zone of the tumor. Figs. 4, 5, 6, 7and 8 show 125I seeds were differently implanted into different tumors. 3D reconstruction of CT images after the implantation for the patient of Fig.8. 10 125I seeds were clearly shown and distributed reasonably in the lesion(fig.9). Figs. 10, 11 and 12 show the CT scanning results for another patient of left lung cancer with metastasis to the left chest wall. The size of the tumor was about 6×8×10cm3 before the implantation. 34 125I seeds were required according to the treatment scheme of TPS, in which 9 of them were implanted first (Fig.10), the remains (25 seeds) were implanted one week late (Fig.11). The follow-up CT inspection shows the necrosis within the lesion (Fig.12).Fig.1, CT image for a patient of lung cancer with metastasis to the second cervical vertebrae. Large scale of tumor inversion zone of the bone in the left side of the vertebrae and its surrounding area was seen.Fig.2, 10 125I seeds were implanted under the guide of CT for the patient of Fig.1.Fig.3, The inversion zone was reduced dramatically and large amount of new bones were formed for the patient of Fig.1.Fig.4, 20 125I seeds were implanted into sarcomatous soft tissue of right side ilium.Fig.5, Ball shape lesion in the caudate lobe of liver was still seen for a patient with primary carcinoma of liver after numbers of implantations. Totally 5 125I seeds were implanted.Fig.6, Observation of seeds distribution after 3D reconstruction of CT images for the patient of Fig.5. Five seeds were distributed reasonably.Fig.7, Right side buccal lymphadenoma. 5 125I seeds were implanted with good distribution.Fig.8, A distinct mass of the soft tissue for a lung cancer patient accompanying with metastasis of upper right side femoral. 5 125I seeds were implanted in this case.Fig. 9, 3D reconstruction of CT images after the implantation for the patient of Fig.8. 10 125I seeds were clearly shown and distributed reasonably in the lesion.Fig.10, Left lung cancer with metastasis to the left chest wall. Huge tumor in left chest wall. The first implantation of 9 seeds was performed under the guide of CT.Fig.11, The remaining 25 seeds were implanted one week late after first implantation for the patient of Fig.10. The distribution of all 34 seeds was located by Take-off Position(TOP).Fig.12, The follow-up CT inspection after one month of the second implantation for the patient of Fig.10 shows the necrosis within the lesion.DiscussionApplication of the Radioactive Seed Implantation in the Treatment of Malignant TumorThe implantation of radioactive seeds brachytherapy for the patients with malignant tumor was a new treatment method. As the introduction of seed implantation TPS and the constant improvement of CT- and ultrasonoscope-guided precision location system, the inter-tissues implantation of radioactive seeds was getting more applications. The treatment principle of this therapy was based on the effects of continuous low strength g-ray of 125I on molecular chains of DNA: (1) direct effect, monochain break and double bond damage, and (2) indirect effect at the same time, that was, ionization of H2O in an organism and resulting in free radical. The inter-action between free radial and biological macromolecules causes the cell damage of the organism. Persistent radiation will act on the tumor cells of different division stages in a tumor organism. The treatment has a slight damage[3~5 to the peripheral normal cells which were in resting stage and insensitive to the radiation of seeds. Sogani et.al[6] experimented with interstitial implantation 125I for 300 prostatic carcinoma patients the 5-year survival rate had been increased clearly. Fukada et.al[7] also reported a considerable effect in the treatment of prostatic carcinoma by intracorporal brachytherapy. Currently brachytherapy was considered as a first choice in the treatment of prostatic carcinoma[5] in USA. As to the implantation number of radioactive seeds, Han B H et.al[8] has used 52~78 seeds in the treatment of prostatic carcinoma. The average seed number used in Merrick et. al[9] was 131. Relatively less seeds were implanted in this paper, only 14 seeds were required averagely. It might be due to the difference of type of seed and its radioactivity.Comments on the EfficacyIndication Various primary carcinomas such as prostatic carcinoma, carcinoma of liver, lung cancer, maxillofacial malignant tumor etc. Suitable for some solitary metastatic tumors which have been missed the optimal opportunity of operation, particularly for metastatic tumor of bone.Contraindication Severe cardiac, hepatic and renal insufficiency, severe dysfunction of blood coagulation and the tumor closed to great vessels etc[10].Clinic efficacy Lesion diminish or thrombin of tumor have been observed in 18 out of 21 patients in this paper. The efficiency was 85.8%. Hu X K et.al[4] treated 22 patients of central type carcinoma of lung by 125I implantation, with an efficiency 81.8%; while Huang Z G et. al[11] reported a 100% treatment efficiency for 10 patients of malignant tumors using the same method. It was seen that 125I implantation brachytherapy for malignant tumor was superior to purely chemotherapy (68%)[12] and purely radiotherapy (72%)[13], and was close to the reported efficiency 93.3%[5 and 90%[6] of the combined treatment. For the treatment of obstinate pain in malignant tumor of bone, 100% efficiency can be realised. Because of longer half-life of 125I (59.43d), the radioactive treatment can sustain longer once seed implantation has been completed. The life quality for patients has been improved considerably. The implantation of 125I has been widely applied for the treatment of various malignant tumors with very good efficiency.Health Safety of the ImplantationThe main hazard was a radioactive damage to the patients, operation radiologists and the nearby people. Since radiant energy of 125I used in this paper was small (less than 37 MBq/per seed), its radioactive radius was only about 1.7cm. The seed was sealed in a Titanium-Nickel alloy container and no direct contact with humor. The sealed radioactive source causes no pollution to environment and patients. The applied radiation was the combination of many micro seeds. Their limited penetrating power has no radioactive damage to the nearby people.On the basis of discussion and relevant literature review[3~13], the author thinks that CT-guided 125I implantation for patients with malignant tumor has a very good efficiency, less side effect, light complication. It can prevent the damage to the peripheral tissue caused by ordinary operation and radiotherapy in vitro. It was an effective therapy for the treatment of various tumors, particularly for the obstinate pain in malignant tumor of bone and deserved to be widely applied.Reference1. Wan J J, Huang Y and Ma L W eds. Implantation of radioactive seeds in the treatment of prostatic carcinoma. Beijing Medical University Press, Beijing, 2002: 47-73.2. Langley S E M,Laing RW.Iodine seed prostate brachytherapy:an alternative first-line choice for early prostate cancer [J].Prostate Cancer &Prostatic Diseases,2004,7,2013. Sneed P,Mcdermott MW,Gutin P,et al.Interstitial brachytherapy procedures for brain tumors [J]. Seminars in Surgical Oncology, 1997,13:1574. Hu X K, Wang M Y, et al. The application research of CT-guided percutaneous 125I radioactive micro seed inter-tissue implantation for the patients with central type carcinoma of lung. J. of Radiology of China, 2004, 9: 906-915.5. Matsumoto S,akeda M,Shibuya H,et al.T1 and T2 squamous cell carcinomas of the mouth:Results of brachytherapy mainly using 198Au grains [J].Int J Radait Oncol Bio Phys,1996,34:8336. Sogani PC, Whitmore WF Jr, et al. Experience with interstitial implantation of iodine 125 in the treatment of prostatic carcinoma. Scand J Ural Nephrol Suppl, 1980, 55: 2057. Fukada J, Yorozu A, et al. Pulmonary embolization of permanently implanted radioactive iodine-125 seeds for carcinoma of the prostate .Nippon Igaku Hoshasen Gakkai Zasshi. 2005, 65: 1218. Han BH,Wallner K, et al. The effect of interobserver differences in post-implant prostate CT image interpretation on dosimetric parameters. Med Phys. 2003, 30: 10969. Merrick GS,Butler WM et al. The dependence of prostate postimplant dosimetric quality on CT volume determination. Int J Radiat Oncol Biol Phys. 1999 Jul 15; 44(5):111110. Jia B, Li L S, et al. Clinic application of percutaneous 125I implantation for the patients with malignant tumor. J. Interventional Radiology, 2005, 8: 398-40011. Huang Z G, Zhang X Z, et al. The application of CT-guided 125I implantation for the patients with malignant tumor. J. of Radiology of China, 2004, 9: 921-92512. Rieber A,Brambs H J,Kauffmann G, et al .Combined intraarterial chemotherapy and radiotherapy in inoperable non-small cell bronchial carcinoma.Strhlenter Onkol (German),1991,167:1413. Miyaji N,Oyama T,Uchiyama N, et al. Results of radiotherapy combined with BAI(bronchial artery infusion)for non-small cell lung cancer----analysis of 104 cases.Nippon Igaku Hoshasen Gakkai Zsshi(Japanese),1991,51:270
贺克武 高斌 李劲松 巢惠民 胡永胜 黄永翠作者单位:合肥市第一人民医院影像中心合肥市重点科研立项项目(2006004);合肥市人才发展基金资助项目【摘要】目的 探讨125I粒子组织间植入在恶性骨肿瘤中的治疗价值。资料与方法 在CT导引下对19例25个恶性骨肿瘤病灶进行125I粒子组织间植入术,术后观察患者病灶影像学变化及疼痛缓解情况。结果 125I粒子组织间植入治疗恶性骨肿瘤疼痛缓解有效率为89.5%(17/19),术后1、2及6个月病灶影像学观察结果显示25个恶性骨肿瘤病灶中,明显缓解(OR)2个,部分缓解(PR)15个,轻度缓解(SD)7个,无效(PD)1个,总缓解率(OR+PR)为68%。所有患者均未出现严重不良反应。结论 CT导引下125I粒子组织间植入治疗恶性骨肿瘤是一种安全、有效、微创的治疗方法,值得进一步在临床推广应用。【关键词】骨肿瘤 近距离放射疗法 碘放射性同位素CT-guided iodine-125 Implantation in the Treatment of Malignant Osseous TumorGAO Bin,HE Kewu, LI Jinsong,et al. Imaging Center, First People,s Hospital of Hefei City, Hefei Anhui Province 230061, P.R.China【Abstract】Objective To evaluate the value of CT-guided iodine-125(125I) implantation for malignant osseous tumors. Methods Under CT guidance, 125I seeds were implanted into 25 malignant osseous tumor lesions of nineteen patients, the curative effect was appraised according to the change in the radiology imaging and the degree of ostealgia relieving of patients. Results After treated with iodine-125(125I) implantation, the pain in 17cases among 19 cases were relieved .The effective rate was 89.5%. Follow-up CT reexamination in 1,2 and 6 months demonstrated that in 25 lesions in 19 cases, 2 obtained OR, 15 obtained PR, 7 SD and 1 PD. The responsive rate was 68%.Severe side-effect did not appear in these case. Conclusion CT-guided 125I implantation for malignant osseous tumor is a method with safety, validity and feasible, and it was worthy to be farther used widely in clinic.Results Pain relief was obtained in 17 cases of 19 malignant osseous tumors after implantation and the effective rate is 89.5%. Follow-up CT reexamination in 1,2 and 6 months demonstrated that 25 lesions in 19 cases, 2 obtained OR, 15 obtained PR, 7 SD and 1 PD. The responsive rate was 68%.Conclusion CT-guided 125I implantation is a safe, effective and feasible method for the treatment of malignant osseous tumor, and it was worthy to be generalized in clinic.【Key words】Bone diseases; Neoplasm; iodine radioisotopes; Brachytherapy;对于无法手术或不愿手术的恶性骨肿瘤患者,尤其是转移性脊柱肿瘤患者,疼痛和压迫脊髓,引起运动和大小便功能障碍是影响其生活质量和生存率重要因素,如何缓解疼痛,预防病理性骨折,提高患者的运动功能和生活质量,是丞待解决的难题。CT导引下125I粒子组织间植入术是20世纪80年代兴起的一种高科技肿瘤治疗技术,由于其精确的靶向定位、低毒副作用,高肿瘤控制率而迅速应用于临床。笔者自2003年1月至2007年6月应用CT导引下125I粒子组织间植入治疗恶性骨肿瘤19例,取得了良好疗效,报道如下。1资料与方法一般资料:本组19例中,男11例,女8例,年龄25~83岁,中位年龄45岁。其中原发性骨肿瘤2例(骨肉瘤和骨巨细胞瘤各1例),转移性骨肿瘤17例,共25个病灶,单发病灶15例,多发病灶4例。病灶部位:脊柱15个,肋骨3个,股骨3个,下颌骨1个,髂骨2个,胫骨1个。原发病灶及转移病灶均经影像学及穿刺活检病理明确诊断。所有患者均有骨疼痛症状,疼痛程度按WHO疼痛程度分级标准[1,2]:0级:无疼痛;Ⅰ级:虽有疼痛但可以耐受,并能正常生活,睡眠不受干扰;Ⅱ级:疼痛明显不能忍受,要求服用镇痛药物,睡眠受干扰;Ⅲ级:疼痛剧烈不能忍受,需要镇痛药物,睡眠严重受干扰,可伴有植物神经功能紊乱表现或被动体位。按此标准分类,本组Ⅰ级1例,Ⅱ级8例,Ⅲ级10例。设备:螺旋CT扫描仪(GE16层),TPS-2000系统(珠海,和佳),0.6mCi~0.8 mCi125I粒子、植入枪、穿刺针、顶针均为上海欣科公司生产。方法:将所有患者术前影像资料输入TPS-2000系统,根据肿瘤形态、体积计算所需放射剂量和粒子数量及粒子布源位置,原发肿瘤粒子植入边界为肿瘤影像学检查所示边界外放1.5cm,转移肿瘤边界以影像学检查所示边界为准,制定等剂量曲线及安全剂量曲线。按照TPS所制定的布源方案,在CT Pinpoint定位系统下将125I粒子植入恶性骨肿瘤灶内。放射剂量:如果患者既往接受外照射,其125I粒子推荐剂量为90~110Gy;如果未接受过外照射,则推荐剂量为110~120Gy;如为外放射补量照射,则只需补足外放射剩余剂量即可。疗效评价标准:(1)止痛效果评价标准[3]:疼痛消失或分级标准下降2级者为显效;疼痛分级标准下降1级者为有效;疼痛分级标准无下降或上升者为无效。(2)影像学评价标准[4]:在术后1、2及6个月分别对患者进行CT检查。由两位以上有经验的放射科医师对其评价。按公式V=0.5×a×b2计算体积(a为肿瘤长径,b为肿瘤短径),根据肿瘤大小变化、成骨多少及临床症状缓解程度对疗效进行评价:明显缓解(OR),肿瘤缩小50%以上;部分缓解(PR),肿瘤缩小25%~50%;轻度缓解或肿瘤大小无明显变化,但骨化明显,临床症状明显缓解(SD),肿瘤缩小1%~25%;无效(PD),肿瘤大小无变化或增大,病灶无骨化,临床症状亦无缓解。统计方法:应用直接统计法对患者的疗效和并发症进行统计。2结果2.1疼痛缓解情况:经治疗后患者骨骼疼痛症状明显缓解,总的疼痛缓解率为89.5%,生活质量提高(见表1)表1 恶性骨肿瘤患者经125I粒子组织间植入治疗后骨痛缓解情况(例)疼痛分级 例数 显效 有效 无效Ⅰ级 1 0 1 0Ⅱ级 8 3 4 1Ⅲ 级 10 5 5 02.2.影像学评价疗效情况:肿块明显缩小17个,总缓解率(OR+PR)为68%,其中有7例可见新骨形成(图1~4,表2)。表2 不同部位恶性骨肿瘤灶经125I粒子组织间植入治疗后病灶缓解情况(个)病灶部位 例数 OR PR SD PD脊柱 15 1 10 4 0肋骨 3 0 2 1 0股骨 3 1 2 0 0下颌骨 1 0 0 1 0髂骨 2 0 1 1 0胫骨 1 0 0 0 1合计 25 2 15 7 1 2.3.不良反应:本组主要不良反应为穿刺部位少量出血,一过性疼痛加剧,少数出现短期低热症状,均未予以处理,不良反应症状自行消失。3讨论对于骨肉瘤、骨转移瘤等恶性骨肿瘤的治疗,过去多采取截肢手术,患者5年生存率低于20%[5]。现在多采用手术、放疗、化疗、射频消融、激素治疗、基因治疗等综合治疗,90%以上的患者得以保留肢体,患者5年生存率达到了60%[6]。对于无法手术或不愿手术的恶性骨肿瘤患者,如何迅速地减轻疼痛并减少病理性骨折以及预防由于椎体转移压迫而引起截瘫等并发症是治疗的关键。用止痛药物、化疗、激素治疗有一定疗效但难以持久且具有较重的副反应而限制了其在临床的应用。传统外放疗具有方法简便,止痛快而效力持久,提高患者生活质量等优点而成为目前恶性骨肿瘤姑息治疗的首选方法。文献报道放疗止痛总有效率为85%以上,50%以上的疼痛在放疗开始1~2周内显示疗效,且随剂量提高,总有效率也提高[7]。尽管外放疗研究取得了一定的进展,但笔者认为以下几个因素制约了外放疗在恶性骨肿瘤中的应用:(1)骨髓及脊髓耐受剂量较低,限制放疗剂量的提高;(2)在放射分隔间期,细胞放射亚致死损伤及潜在致死损伤的修复,降低了恶性骨肿瘤的放疗敏感性;(3)处于不同周期的细胞对放射敏感性不同,处于S期细胞对放射耐受,处于G2和M期的细胞对放射敏感,一次放疗只能有效杀死处于放射敏感期的细胞;(4)不同氧合状态的肿瘤细胞对放射敏感性不同,乏氧细胞对放射耐受,多次放疗之后肿瘤血管床受到破坏,乏氧细胞明显增多,肿瘤放射敏感性降低;(5)放疗后期肿瘤内存活的克隆源细胞加速再群体化,降低了放射治疗的效果。125I粒子是20世纪80年代开始应用于临床的一种新型放射源,在多种肿瘤治疗中显示了令人鼓舞的疗效,在国外目前已成为早期前列腺癌的首选治疗方法[8]。在恶性骨肿瘤治疗方面,作为手术的重要补充,放射性粒子植人治疗越来越受到人们的重视。125I粒子组织间内放疗的优点:(1)125I粒子辐射距离只有1.7cm,组织剂量遵循距离反平方定律,随距离增加组织剂量迅速下降,靶区与正常组织剂量比增加,从而最大限度地杀伤肿瘤组织和保护正常组织;(2)125I粒子可不断释放γ射线,在肿瘤生长过程中,只有一小部分细胞持续增殖,在G2期及M期,少量的γ射线即能破坏肿瘤细胞的繁殖能力,而G1期和S期细胞对γ射线敏感度较差,G0期肿瘤细胞对γ射线相对不敏感。125I粒子半衰期长(59.6天),对肿瘤细胞起持续性放疗作用,能不断杀伤肿瘤干细胞;(3)125I粒子释放的射线能量较低,易于防护,不易产生过热点而损伤主要脏器;(4)连续低剂量率照射抑制肿瘤细胞的有丝分裂,致肿瘤细胞集聚在G2期,降低了肿瘤细胞的再增殖率;(5)近距离放疗时,乏氧细胞放射护抗性降低,同时在持续低剂量照射下乏氧细胞再氧合,增加了放射损伤的敏感性;(6)持续低剂量照射降低了肿瘤细胞亚致死损伤和潜在致死损伤的修复率;(7)CT导引下组织间植入125I粒子治疗肿瘤方法简便、微创,毒副作用小,明显减少了并发症的发生。125I粒子组织间植入治疗骨肿瘤的作用原理是抑制或杀死肿瘤细胞,胶原蛋白合成增加。继之,血管纤维基质大量产生,成骨细胞活性增加而形成新骨。溶骨病变产生再钙化,一般在照射后3~6周开始,高峰在2~3个月[9,10]。本组患者中肿块明显缩小17个,总缓解率为68%,其中有7例可见新骨形成,与国内学者报道的125I粒子组织间植入治疗骨转移肿瘤总缓解率68.7%相近[2]。125I粒子组织间植入治疗恶性骨肿瘤的止痛生物学效应仍不清楚,一般认为,放疗使肿瘤缩小或抑制了正常骨细胞释放化学性的疼痛介质,或是释放止痛性化学介质(前列腺素、神经肽、5-羟色胺)参与止痛。本组患者中疼痛明显缓解8例,疼痛得到有效控制10例,1例晚期骨肉瘤患者疼痛在治疗后无明显缓解,总的疼痛缓解率为89.5%,略低于张福军等[2]报道的125I粒子组织间植入治疗骨转移肿瘤总的疼痛缓解率91%,略高于传统的外放疗止痛效果[7]。放射性粒子植人治疗目前存在最大的不足是不同增殖速率的恶性骨肿瘤难以选择不同释放量的放射性核素粒子,以及在肿瘤被抑制后放射剂量难以根据肿瘤体积、形态的变化而调整。植入粒子的主要副作用是被植入器官和邻近器官受射线所累,如放射性骨坏死、组织水肿等[11,12]。粒子在种植术后可能发生移位、迁移或丢失而引起感染、放射热点和冷点、栓塞等并发症[13,14]。与外放疗相比其技术难度较大,治疗费用较高。总之,125I粒子组织间植入治疗恶性骨肿瘤可以有效杀伤肿瘤细胞,明显缓解疼痛,提高患者生活质量,是一种安全、有效、微创的治疗手段,值得进一步在临床上推广应用。参考文献1. 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Nippon Igaku Hoshasen Gakkai Zasshi, 2005,65(2):12114. Tsui G, Gillan C, Pond G, et al. Posttreatment complications of earlystage prostate cancer patients: brachytherapy versus three-dimensional conformal radiation therapy. Cancer J, 2005,11(2):12215. Carlsson G, Gullberg B, Hafstrm L. Estimation of liver tumor volume using different formulas - an experimental study in rats[J]. J Cancer Res Clin Oncol,1983,105(1):20-3.图1图2 图3图4图1~4 男,56岁,肺癌第二颈椎转移。图1术前CT检查示第二颈椎转移,颈椎右侧见大片骨质破坏并累及椎管。图2 治疗计划系统(TPS)所绘制的治疗计划图,红线为病灶范围,黄色点为125I粒子位置,粉红色线等剂量曲线,绿色线为安全剂量曲线。图3根据TPS所制定的治疗计划,在CT导引下将10粒125I粒子植入颈椎病灶内,病灶内白色点为125I粒子。图4 一个月后复查CT示原颈椎骨质破坏区大量骨质增生,病灶明显缩小,患者疼痛明显缓解。