Clinical and experimental study on regional administration of phosphorus32 glassmicrospheres in treating hepatic carcinoma

AIM To study the therapeutical effectiveness, dosage range and toxic adverse effects of domestic phosphorus 32 glass microsphere and evaluate its clinical significance. METHODS Ⅰ. Fifty two BALB/*!c tumor bearing male nude mice were allocated into treatment group( n =38) and control group( n =14). In the former group different doses of 32 P GMS were injected into the tumor mass, while in the latter 31 P GMS or no treatment was given. The experimental animals were sacrificed in batches, and then the tumors and their nearby tissues were examined by light and electron microscopy. Ⅱ. Through selective catheterization of hepatic artery, 32 P GMS was infused to 5 healthy domestic pigs in a dosage equivalent to the therapeutic dose for human being, and 31 P GMS was infused to another 5 healthy domestic pigs. Two pigs infused with contrast medium served as whole course blank controls. One pig from each group was surrendered to euthanasia at week 1, 4, 8 and 16 respectively. The ultrastructural histopath ological changes in liver tissues taken from different sites were evaluated semiquan titatively. Ⅲ. One hundred and twenty seven times of 32 P GMS intrahepatic artery interventional therapies were performed on 93 patients with hepatic carcinoma, including 79 cases of primary hepatic carcinoma and 14 cases of secondary hepatic carcinoma. 32 P GMS ( n =30), and group B, 32 P GMS and half dose of trans hepatic artery embolization (TAE) ( n =49) , and 18 patients with HCC by TAE only as control group C. Fourteen patients with secondary hepatic carcinoma were treated in the same way as group B or C. RESULTS Ⅰ. Comparing with the control group, the treatment group of tumor bearing nude mice attained the tumor inhibition rates of 59 7%-93 7% ( F =579 62, P <0 01) at 14*!d . At an absorbed dose of 7320Gy, the tumor cells were completely destroyed. When the absorbed doses ranged from 1830Gy to 3660Gy, most of the tumor cells showed the evidences of injury or necrosis, but there appeared some well differentiated tumor cells and enhanced effect of the autoimmunocytes. At an absorbed dose of 366Gy or less, some tumor cells still remained active proliferative ability. The definite anticancer effect appeared as early as 3d after intratumoral injection of 32 P GMS. Ⅱ. The cumulative amount of 32 P GMS in the target tissue after trans hepatic artery instillation attained more than 90% of the total dose administrated. Semiquantitative analysis of ultrastructral morphology in the experimental group showed no statistical difference between the nuclear abnormality (N abn ) and mitochondrial variability (M var ) at week 1 or 2, but revealed prominent difference (χ 2=6 70-9 68, P <0 01 , χ 2=65 09-115 09, P <0 001 ) as compared with those in the other groups. In the experimental group the N abn in tissues showed no significant difference between week 8 and week 16. No apparent changes were found in the stomach, spleen, kidney and lung tissues of the experimental pigs. Ⅲ. The therapeutical results of HCC patients in group A were closely approximated to those of group C, no hematological toxic side effects were noted, and the systemic reaction was mild. In some patients 2*!mos - 3*!mos after treatment some secondary foci appeared around the periphery of the primary lesion. In general better effectiveness was obtained in patients with small lesion. After analyzing by RIDIT method, the therapeutic result in group B was significantly better than that in group C, and secondary foci around the original lesion were rarely seen at 3*!mos after treatment. In group C the collateral circulation was reestablished along the periphery of primary foci and the secondary foci appeared more frequently, and required to undergo several courses of treatment. In group B, 4 cases of HCC were treated surgically as their mass decreased in size after 32 P GMS treatment.

Preventive effect of regional radiotherapy with phosphorus-32 glass microspheres in hepatocellular carcinoma recurrence after hepatectomy

AIM: To evaluate the preventive effects of phosph-orus-32 glass microspheres (P32-GMS) in the recurrence of massive hepatocellular carcinomas (HCCs) after tumor resection. METHODS: Twenty-nine patients with massive HCCs received local P32-GMS implantation after liver tumors were removed,while the other 38 patients with massive HCCs were not treated with P32-GMS after hepatectomies. The radioactivity of the blood,urine and liver were examined. The complications,HCC recurrence and overall survival rates in the patients were analyzed. RESULTS: P32-GMS implanted in the liver did not cause systemic absorption of P32. There were no significant differences of postoperative complications between the patients with and without P32-GMS treatment. The short-term (six months and 1 year) and long-term (2,3 and over 3 years) recurrence rates in patients who received P32-GMS radiotherapy were signifi cantly decreased,and the overall survival rates in this group were signifi cantly improved. CONCLUSION: P32-GMS implantation in the liver can significantly decrease the postoperative recurrence and improve the overall survival in HCCs patients after hepatectomy. This therapy may provide an innovative method in prevention of HCC recurrence after operation.

Effect of Phosphorus-32 Glass Microspheres on the Human Hepatocellular Carcinoma in Nude Mice

Objective To study anticancer effect and ultrastructural influence of phosphorus 32 glass microspheres( 32 P GMS) injected in the hepatocellular carcinoma in nude mice. MethodsThe ultrastructural changes of tumor in both the treatment group and control group were examined by transmission electron microscope. ResultsIn the treatment group,a large number of tumor cells were killed and the death rate of tumor cells was much higher(35%-70%). Ultrastructurally, severe nuclear damage was observed in the dead cells. The early characteristics of necrosis such as margination of heterochromatin were also found in some tumor cells. Besides,well differentiated tumor cells, degenerative tumor cells and some lymphocytes were seen. The skin and muscle close to the tumor were normal. In the control group,the tumor consisted of poor differentiated tumor cells,in which there were only a few appototic cells(5%). ConclusionThe results suggest that the local administration of 32 P GMS produces obviously the anticancer effect.

^(32)P-玻璃微球介入治疗肝细胞肝癌的临床初步应用

采用 Ｓｅｌｄｉｎｇｅｒｓ穿刺法，导管超选择至肝固有动脉以远，灌注^（３２）Ｐ－玻璃微球（^（３２）Ｐ－ＧＭＳ），对７９例肝细胞肝癌（ＨＣＣ）实施了９９次内照射介入治疗。结果表明，Ａ方案半年及１、２、３年生存率分别为１００％、９６．７％、５６．７％和４３．３％；Ｂ方案分别为９７．９％、９１８％、６１．２％和５１．０％。经治后的中位生存时间为５８５天。多因素分析显示：肝功能、肿瘤大小、临床类型及^（３２）Ｐ－ＧＭＳ在瘤体内积聚情况是影响生存率的预后因素。说明^（３２）Ｐ－ＧＭＳ是一种安全、有效的肝癌治疗方法。

经肝动脉注射^(32)P-玻璃微球治疗肝癌临床与实验研究

目的:评价经肝动脉注射32P-玻璃微球治疗肝癌的临床疗效,并测定其对肿瘤组织多药耐药基因的表达率的影响。方法:116例原发性肝癌随机分成两组,A组58例,TACE+32P-GMS治疗;B组58例,单纯TACE治疗。每例分别在B超或CT引导下经皮穿刺活检,获取肿瘤组织标本,运用RT-PCR法定量分析mdr-1基因表达水平,根据影像学判定肿瘤血管侧支循环、肿瘤缩小情况、血清AFP下降率,比较两种方案的疗效。结果:①血管造影:A组肿瘤血管栓塞程度为97%±3%,侧支循环形成很少;B组肿瘤血管栓塞的程度为90%±8%,有侧支循环形成;②肿瘤坏死面积:A组为76%±17%,B组为60%±14%;③肿瘤缩小平均值:A组为60.54%±10.14%;B组为43.27%±9.12%;④AFP下降率:A组为84.48%;B组为51.72%;⑤1年生存率:A组为81%,B组为56%;⑥mdr-1cDNA\β2-mGcDNA:A组为0.3036±0.0825;B组为0.4755±0.1259。所有数据经μ检验或χ2检验,A组疗效优于B组,统计学上有显著差异(P<0.01)。结论:TACE+32P-GMS治疗原发性肝癌疗效优于单纯应用TACE。

^(32)磷玻璃微球组织内照射对肿瘤细胞凋亡影响的实验研究

目的 :观察32 磷玻璃微球组织内植入对小鼠移植瘤肿瘤细胞凋亡的影响。方法 :建立小鼠移植瘤S180动物模型 ,分别将剂量为 0、1 85、5 5 5、16 6 5MBq 只的32 磷玻璃微球组织内植入实验小鼠进行放射治疗 ,第 15天取标本检测细胞凋亡情况。结果 :空白对照组及实验组的细胞凋亡指数分别为 0 39、0 41、0 5 9和 0 95 ,其中内植入剂量为 5 5 5MBq 只和 16 6 5MBq 只的实验组较空白对照组明显增高 (P <0 0 5 )。结论 :32 磷玻璃微球组织内植入使小鼠移植瘤S180的细胞凋亡活动增强 ,且随着剂量的增加 ,凋亡指数升高。

^(32)磷玻璃微球组织内照射联合加热对肿瘤细胞凋亡影响的实验研究

目的 :探索32 磷玻璃微球组织内照射及联合加热治疗对小鼠移植瘤S180肿瘤细胞凋亡的影响。方法 :分别给予小鼠移植瘤S180动物模型32 磷玻璃微球组织内照射、加热治疗及联合治疗 ,第 15天取标本检测细胞凋亡情况。结果 :空白对照组、加热组、内照射组及联合治疗组细胞凋亡指数 (AI)分别为 0 39、0 5 3、0 5 9和 0 91;加热组、内照射组及联合治疗组AI值明显较空白对照组高 (P分别为 <0 0 5、<0 0 5、<0 0 1) ,联合治疗组AI值较其它治疗组高(P <0 0 5 )。结论 :32 磷玻璃微球组织内照射及加热治疗均可促进小鼠移植瘤S180的细胞凋亡 ,加热可使内照射治疗的凋亡反应增强。

^(32)磷玻璃微球内放射栓塞治疗肝癌的临床研究

目的 :探讨 32磷玻璃微球 (32 P- GMS)对中晚期肝癌的内放射治疗效果。方法 :应用 32 P- GMS治疗肝癌 2 1例。结果 :治疗后彩色多普勒超声检查 ,17例肿瘤血流明显减少甚至完全消失 ;SPECT肝扫描显示 ,32 P- GMS聚集在肿瘤区内 ,平均癌/肝比 2 .5∶ 1;治疗后 6 ,12 ,18个月生存率分别为 85 .7% ,6 1.9% ,5 7.1% ;16例肿瘤有不同程度的缩小 ;无明显毒副反应。结论 :32 P- GMS内放射栓塞对中晚期原发性肝癌是一种有效的治疗手段。

^(32)磷-玻璃微球治疗裸鼠人肝癌移植瘤的超微结构观察和立体定量学研究

目的 探讨32 P GMS对肝癌的治疗作用和超微结构影响。方法 建立裸鼠人肝癌移植瘤后用32 P GMS进行治疗 ,取治疗后瘤组织进行电镜观察和立体定量学研究。结果 实验组瘤细胞大量坏死 ,部分瘤细胞出现了高分化肝癌的形态特征。实验组线粒体和粗面内质网体密度、毛细胆管和微绒毛面密度高于对照组(P <0 .0 1、0 .0 5、0 .0 1)。结论 研究表明32 P GMS抗肝癌作用明显 。

^(32)磷玻璃微球间质治疗对肿瘤微血管作用的实验研究

为了探讨间质治疗对肿瘤微血管的影响，作者观察了移植性小鼠Ｓ１８０实体瘤在３２磷玻璃微球间质治疗后的血管铸型及墨汁灌注切片。结果表明：治疗后肿瘤毛细血管数量减少，排列不规则，血管扩张；瘤周血管密度下降。提示间质治疗同外照射一样对肿瘤微血管有损伤作用。

^32磷玻璃微球肝动脉栓塞治疗肝癌的临床疗效观察

目的国产32磷玻璃微球（32P－GMS）治疗肝癌疗效观察。方法经度股动脉穿刺，导管选择性插管至肝动脉灌注32P－GMS超液化碘油混悬液，治疗原发性肝癌32例；转移性肝癌14例；随机对照组原发性肝癌18例用肝动脉栓塞化疗。结果治疗后3月观察原发性肝癌32P－GMS治疗组病灶缩小＞50％6例，50％～25％11例，＜25％～10％12例，有效率为90．63％（29／32），对照组18例中14例有效（77．78％），经Ridit分析和X2检验，二组无显著差异。转移性肝癌14例中11例有效。32P－GMS治疗肝癌总有效率86．96％（40／46）。32P－GMS治疗组未出现明显血液毒性。结论32P－GMS肝动脉栓塞是治疗肝癌的有效手段之一。

^(32)P-GMS在肝动脉放射性栓塞化疗治疗肝癌中的作用

目的 研究3 2 磷 玻璃微球 ( 3 2 P GMS)在肝动脉放射性栓塞化疗治疗肝癌中的作用。方法 将3 2 P GMS与碘油混悬液直接注入 44只裸鼠人肝细胞癌负荷瘤内 ,观察瘤体的组织学反应及多药耐药基因 (MDR )表达的P 蛋白变化。对 2 2例肝细胞癌患者 (Ⅰ组 )采用常规肝动脉栓塞化疗治疗 ;2 4例肝癌患者 (Ⅱ组 )采用3 2 P GMS与肝动脉栓塞化疗联合治疗。结果 鼠负荷瘤在吸收剂量达 770～ 30 80cGy时 ,肿瘤生长抑制率达 6 1.6 6 %～ 90 .41%。MDR表达的P 蛋白阳性表达率也相应降低。Ⅰ组患者肝内病灶缩小 ,有效率达 5 9.0 9% ( 13/2 2 ) ;Ⅱ组患者有效率达 83.33% ( 2 0 /2 2 ) ,P <0 .0 5。结论 3 2 P GMS局部照射与化疗药物联合治疗 ,可提高肝癌患者肝动脉栓塞化疗的疗效 ,其机制可能与3 2 磷局部照射影响MDR表达有关。

P-32玻璃微球与I-125粒子治疗晚期恶性肿瘤比较

目的：比较p-32玻璃微球局部注射与I-125粒子植入在治疗晚期恶性肿瘤中的特点。方法：采用常规方法，将放射性核素P-32玻璃微球（32例）及I-125粒子（57例）在B超或CT引导下，经皮穿刺导入肿瘤组织内。结果：治疗后1-6月影像学复查，肿瘤体积有不同程度缩小，I-125粒子植入的放射性药物价格是P-32玻璃微球局部注射的10-15倍。结论：放射性核素内照射治疗晚期恶性肿瘤，确实可控制肿瘤发展，缩小肿瘤，缓解症状。I-125粒子较P-32玻璃微球储存使用更方便，适用于增殖较慢的恶性肿瘤。两种方法的合理使用具有较强的临床应用价值。

^(32)磷-玻璃微球区域给药治疗肝癌的实验研究和组织吸收剂量估算

目的：研究３２磷－玻璃微球（３２Ｐ－ＧＭＳ）区域给药的药代动力学特点，探讨靶组织内辐照量和吸收剂量的估算方法。方法：模拟人类对７只家猪经肝动脉灌注给药或间质注射，对２０只人肝癌移植瘤裸鼠瘤体内注射，动态观测３２Ｐ－ＧＭＳ的分布与放射性计数率的衰减。结果：３２Ｐ－ＧＭＳ通过肝动脉给药，可有效栓塞至肝窦前小动脉，通过瘤体内注射可滞留在靶组织内不被排泄，给药第１４天的衰减分数为０．４８，其有效半减期与３２Ｐ物理半衰期值接近。经计算，３２Ｐ－ＧＭＳ放射性活度为３７ＭＢｑ时，在１ｋｇ肝组织内完全衰变，组织所接受的宏观平均吸收剂量是７３２ｃＧｙ。结论：本研究为３２Ｐ－ＧＭＳ对肝癌治疗的实验研究和临床应用提供了科学的剂量学依据。３２Ｐ－ＧＭＳ区域给药的稳定性使它逐步成为一种安全有效的内放射治疗肝癌的重要手段。

^(32)P-玻璃微球治疗原发性肝癌的临床研究

目的:探讨^(32)p-玻璃微球(^(32)P-GMS)综合化疗栓塞治疗中晚期原发性肝癌的临床效果。材料与方法:1995年6月～1999年6月,32例中晚期原发性肝癌分为2组,第一组16例,系^(32)P-GMS综合化疗栓塞组,首先注入^(32)P-GMS超液化碘油悬浮液,然后注入3联化疗药,最后用明胶海绵颗粒栓塞第二组16例,系单纯化疗栓塞组。结果:^(32)P-GMS综合化疗栓塞组16例中,9例肿瘤缩小大于50％,6例AFP降至正常,12例生存超过24个月,肿瘤缩小率及AFP下降率两组比较均有显著差异性。^(32)P-GMS综合组12个月、18个月和24个月生存率分别为87.5％、81.0％、75.5％,而单纯化疗栓塞组分别为56％、31％、18.7％,统计学处理亦有显著性差异。结论:^(32)p-GMS是治疗中晚期原发性肝癌可行的内放射性核素之一,采用^(32)P-GMS综合化疗栓塞是提高治疗原发性肝癌患者生存率的有效方法。

^(32)P-玻璃微球局部给药治疗裸鼠人肝癌移植瘤的实验研究和电镜观察

探讨32P-玻璃微球（32P-GMS）局部注射对裸鼠人肝癌移植瘤的治疗作用和超微结构影响。建立裸鼠人肝癌移植瘤模型后用32P-GMS进行治疗，取治疗后瘤组织用透射电镜观察。结果：实验组癌细胞大量坏死（35％～70％），残留的瘤细胞在分化上出现了一些差异，部分癌细胞出现了高分化肝癌的形态特征；肿瘤间质见淋巴细胞浸润和纤维结缔组织增生，但无强烈的急性放射性炎反应；瘤体周围肌纤维和皮肤均无改变。对照组肿瘤示低分化肝癌，其中有少量死亡瘤细胞（4％）。研究表明，32P-GMS抗肝癌作用明显，并有一定的免疫调节和促分化功能，对治疗区周围组织亦无损伤。

^(32)P玻璃微球在肿瘤治疗中的应用

的 3 2 P玻璃微球是一种新型的组织内放射抗肿瘤制剂 ,有局部栓塞和组织内局部照射杀死肿瘤细胞的作用 ,临床应用有重要意义。综述了3 2 P玻璃微球治疗肿瘤的机理及应用现状。

瘤体内注射^(32)磷-玻璃微球对裸鼠人肝癌移植瘤的抗癌效应研究

目的 研究瘤体内注射32 磷 -玻璃微球 (32 P -GMS)对裸鼠人肝癌移植瘤的抗癌作用。方法 动态观察治疗组和对照组裸鼠的肿瘤生长状况 ,分批处死 ,取瘤体及其邻近组织进行光镜和电镜观察。结果 与对照组相比 ,14d治疗组抑瘤率为 5 9.7%～ 93 .6 % (P <0 .0 1)。瘤体吸收剂量为 732 0Gy ,肿瘤细胞可被一次性杀死 ;吸收剂量为 1830～ 3 6 6 0Gy时 ,瘤细胞大多损伤坏死 ,并出现分化较好的瘤细胞 ;吸收剂量为 36 6Gy或更低时 ,仍残存有增殖活跃的瘤细胞。结论 瘤体内注射 1830～ 3 6 6 0Gy的32 P -GMS 。

^(32)P玻璃微球瘤内注射抗肿瘤作用及对免疫功能的影响

目的观察32P玻璃微球(32P-GMS)的抑瘤效果及对免疫功能的影响。方法称重法检测32P-GMS对小鼠S180肉瘤的抑瘤率,脾淋巴细胞转化实验检测32P-GMS对S180肉瘤小鼠淋巴细胞转化功能的影响,观察小鼠淋巴细胞对豆刀素A(ConA)和脂多糖(LPS)的刺激增殖作用。结果32P-GMS瘤内注射抗肿瘤的抑瘤率分别为15.1%,20.3%,32.4%,模型组和32P-GMS治疗组小鼠胸腺细胞和脾淋巴细胞的免疫功能均有不同程度抑制,并随32P-GMS剂量的增大,抑制愈明显。结论32P-GMS瘤内注射很强的抗肿瘤作用,32P-GMS照射亦可加重小鼠免疫功能抑制。

^(32)P玻璃微球间质治疗联合加热对肿瘤微血管作用的实验研究

目的为了解间质治疗对肿瘤微血管的作用以及加热作用对其的影响。方法采用光镜和电镜观察了移植性小鼠S180实体瘤在32P－GMS间质治疗后及其联合加热治疗后的血管铸型及墨汁灌注切片。结果加热组、放疗组均可引起肿瘤微血管的扩张，新生血管抑制，毛细血管数量减少及瘤周血管密度降低，联合治疗组作用更明显。结论加热对肿瘤微血管的损伤与射线对其损伤在形态学方面相似；内照射的损伤作用与外照射的作用相似。放射及加热联合对肿瘤微血管的损伤可能增强。