经颈动脉灌注ACNU、VM-26联合治疗复发性脑胶质瘤的临床研究

目的研究经颈动脉灌注盐酸尼莫司汀（ACNU）和替尼泊苷（VM-26）联合治疗复发性脑胶质瘤的效果及相关问题。方法治疗组选择幕上颈内动脉供血范围的复发性脑胶质瘤164例，肿瘤同侧颈总动脉ACNU和VM-26联合灌注化疗。对照组选择复发性脑胶质瘤26例，口服司莫司汀治疗，并行疗效对比。结果治疗组完全缓解率和部分缓解率明显高于对照组（P〈0．05），恶化率明显低于对照组（P〈0.05），生存期明显长于对照组（P〈0.05）。结论经颈动脉灌注ACNU、VM-26治疗复发性脑胶质瘤疗效好，副作用小，安全可靠，可作为常规化疗手段。     

注射维生素C治疗脑胶质瘤的实验研究

目的探讨维生素C治疗脑胶质瘤的作用机制,为胶质瘤的临床治疗提供实验室依据。方法制作大鼠C6脑胶质瘤模型。荷瘤7d后将Wistar大鼠随机分为5组,每组10只,即对照组;维生素C低剂量组（2．0g／kg）;维生素C中剂量组（4．0g／kg）;维生素C高剂量组（8．0g／kg）;5-Fu组（20mg／kg）。于用药结束后次日处死各组小鼠,计算肿瘤体积和抑瘤率;流式细胞术检测各组肿瘤组织细胞凋亡率;免疫组化法检测各组肿瘤组织Ki-67蛋白表达情况。结果维生素C可抑制大鼠肿瘤生长,且呈剂量依赖性,实验组肿瘤体积与对照组相比有显著差异（P〈0.05）,维生素C高剂量组与5--Fu组肿瘤体积比较无统计学差异（P〉0.05）。维生素C可诱导大鼠肿瘤细胞凋亡,维生素C各组与对照组相比均有极显著性差异（P〈0.01）,维生素C高剂量组凋亡率高于5-Fu组（P〈0.05）。免疫组化法检测肿瘤组织细胞Ki-67蛋白表达中,维生素C各组与对照组相比均有极显著性差异（P〈0.01）,维生素C高剂量组与5-Fu组细胞凋亡率比较无统计学差异（P〉0.05）。结论维生素C在-定剂量范围内可抑制C6大鼠脑胶质瘤的生长,诱导肿瘤细胞发生凋亡是其机制之一;药理剂量的维生素C能降低C6大鼠脑胶质瘤细胞增殖活性,具有-定的抗肿瘤作用。     

全反式维甲酸抑制大鼠C6脑胶质瘤细胞增殖的实验研究

目的探讨全反式维甲酸对大鼠C6脑胶质瘤细胞增殖的抑制作用及其机制。方法建立大鼠C6脑胶质瘤模型，腹腔注射全反式维甲酸后．MRI检测胶质瘤的体积变化、流式细胞仪检测细胞增殖时相变化及免疫组化检测p27Kip1蛋白的变化。结果治疗组较对照组肿瘤体积明显减小（P〈0．05）；G1期细胞比例明显增加（P〈0．05），S期细胞比例明显减少（P〈0．05）；p27Kip1蛋白的表达明显增加（P〈0．05）。结论全反式维甲酸通过上调p27Kip1蛋白的表达而抑制大鼠C6脑胶质瘤细胞增殖。     

58例脑恶性胶质瘤术后放化疗疗效临床观察

目的 观察脑恶性胶质瘤术后同步选择性动脉灌注尼莫司汀(ACNU)联合三维适形放疗与单纯三维适形放疗的疗效、生存率及安全性比较.方法 治疗组为脑恶性胶质瘤28例经开颅显微手术后同步选择性动脉灌注ACNU联合三维适形放疗;对照组为脑恶性胶质瘤30例术后单纯二维适形放疗.结果 同步放化疗组脑恶性胶质瘤治疗CR、PR高丁对照组(P<0.05),生存期也长于对照绢(P<0.05),其不良反应小、生存质量明显提高.结论 显微手术后同步选择性动脉灌注ACNU联合适形放疗治疗脑恶性胶质瘤疗效较好,有望成为目前脑恶件胶质瘤的常规治疗方案之一.     

5-ALA介导的光动力治疗鼠C6胶质瘤的实验研究

目的研究以5-氨基乙酰丙酸（5-ALA）作为光敏剂的光动力治疗（PDT）对大鼠C6胶质瘤移植瘤的效果。方法通过皮下接种C6胶质瘤细胞建立大鼠移植胶质瘤模型。将24只荷瘤大鼠平均随机分成3组：A组按剂量20mg／kg在瘤内注射5-ALA，2h后在肿瘤局部行激光照射；B组行单纯激光照射，不予任何光敏剂；C组为荷瘤空白对照组，不给任何治疗。PDT后不同时间，测量肿瘤体积并观察其组织学变化。结果治疗后第4、8和14天A组肿瘤体积与B、C组相比明显缩小（P〈0．05），组织学上可见大量肿瘤细胞坏死。结论5-ALA作为光敏剂介导的PDT能使大鼠C6胶质瘤移植瘤组织坏死，生长速度明显减慢，有望成为胶质瘤治疗的新途径。     

动脉内灌注替尼泊甙和嘧啶亚硝脲治疗脑胶质瘤的体会

目的:观察动脉内交替灌注替尼泊甙(VM_(26))和嘧啶亚硝脲(ACNU)治疗脑胶质瘤的临床疗效。方法:经颞浅动脉逆行插管、留置,然后采用微泵交替灌注VM_(26)和ACNU治疗脑胶质瘤7例,术后4～8周采用CT检查肿瘤体积的变化,评估疗效。结果:显效2例,有效4例,无效1例。结论:经颞浅动脉逆行插管序贯增强化疗是治疗脑胶质瘤的一种简便、安全、有效的手段。     

甲基强的松龙和地塞米松治疗放射性脑水肿的差异

目的研究甲基强的松龙及地塞米松治疗放射性脑水肿的差异。方法建立大鼠脑胶质瘤模型。实验分组：A组（大剂量甲基强的松龙组）、B组（小剂量甲基强的松龙组）、C组（地塞米松组）、D组（对照组）、E组（空白组）。各组均颅内种植肿瘤，于种植15天后A、B、C、D各组给予C060照射，A、B、C组大鼠照射前后分别给予甲基强的松龙和地塞米松治疗。测量大鼠脑水肿情况。结果治疗后，与其他各组比较，D组大鼠脑组织含水率最高，E组最低（P〈0．05）；C组大鼠脑组织含水率明显高于A、B两组（P〈0．05）；但A、B两组间无显著性差异（P〉O．05）。结论甲基强的松龙和地塞米松都可以有效防治放射性脑水肿，且甲基强的松龙比地塞米松疗效更好。     

冷冻联合全反式维甲酸抑制大鼠C6脑胶质瘤增殖的实验研究

目的探讨冷冻联合全反式维甲酸（ATRA）抑制大鼠c6脑胶质瘤细胞的增殖及其机制。方法在120只Wistar大鼠建立c6脑胶质瘤模型,并随机将其平均分为冷冻治疗、ATRA治疗、冷冻联合ATRA治疗及对照组。接种c6细胞第22天MRI检测10只动物的胶质瘤体积的变化,每组并处死10只动物取肿瘤组织,采用免疫组化法检测p27kipl蛋白的表达;观察余下10只荷瘤鼠的生存期。结果各治疗组较对照组肿瘤体积明显缩小（P〈O．05）,大鼠生存期明显延长,p27kipl蛋白的表达水平明显增多,以联合治疗组最为显著（P〈0．05）;p27kipl蛋白的表达与肿瘤体积呈明显负相关（P〈0．05）,与大鼠生存期呈明显正相关（P〈O．05）。结论与单一治疗相比,冷冻联合ATRA治疗能显著抑制大鼠c6胶质瘤细胞增殖,其机制可能与其表达p27kipl蛋白的上调有关。     

超选择性颈内动脉灌注ACNU治疗颅内恶性肿瘤的疗效分析

目的分析超选择性颈内动脉灌注ACNU治疗颅内恶性肿瘤的临床疗效。方法选取2008-05—2013-04收治的120例颅内恶性肿瘤患者并采用随机数字表法分为2组。对照组60例患者采用常规灌注化疗进行治疗,观察组60例采用超选择性颈内动脉灌注ACNU治疗。对比2组治疗效果。结果对照组总有效率43.33%,观察组总有效率73.33%,2组比较差异有统计学意义（P〈0.05）。结论超选择性颈内动脉灌注ACNU在治疗颅内恶性肿瘤具有较好的疗效,值得临床推广。     

表皮生长因子受体反义RNA联合γ-刀治疗大鼠C6胶质瘤的实验研究

目的研究表皮生长因子受体（EGFR）反义RNA联合γ-刀治疗对鼠C6胶质瘤的生长抑制作用。方法将1×10^6／15mL C6胶质瘤细胞（每只15mL）接种至SD大鼠右侧尾状核头部，建立SD大鼠C6脑胶质瘤模型。6d后进行MRI检查，确定成瘤后随机分为4组（A：对照组；B：EGFR反义RNA基因治疗组；C：γ-刀治疗组；D：EGFR反义RNA＋γ-刀治疗组），每组12只。B、D组在第6、8天进行脂质体介导的反义EGFR质粒治疗。C、D组第10天进行γ-刀放射外科治疗，给予边缘剂量15Gy。A组未作任何治疗。第11天每组处死2只大鼠进行生物学特性检测，包括PCNA（免疫组化法）、凋亡（TUNEL法）；其余10只在γ-刀治疗后1、2、4及8周进行MRI检查，并观察生存期。结果EGFR反义RNA联合γ-刀治疗组较单一治疗组动物生存期显著延长（P〈0．05），肿瘤细胞PCNA阳性率下降、凋亡率增加，MRI检查证实肿瘤生长缓慢。结论γ-刀放射外科联合EGFR反义RNA治疗C6胶质瘤大鼠，具有更高的肿瘤生长抑制率及肿瘤细胞凋亡率，动物生存时间显著延长。     

ACNU delivery to malignant tumor tissue and serum--route of administration and combined use of phenobarbital

Since nitrosourea compounds as chemotherapeutic agent can cross the blood brain barrier, they are widely used in the treatment of malignant brain tumors. ACNU (3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride) has become a popular agent, as it is water-soluble and has shown potent effectiveness for treating gliomas. Only a few studies have ever been reported concerning the pharmacokinetics of ACNU in human brain tumors. Intra-arterial administration of chemotherapeutic agents has recently been paid special attention, because it is expected to be more effective than intravenous administration. On the other hand, phenobarbital as an anticonvulsant, widely used in clinical management of malignant brain tumor patients has been reported to reduce the toxicity of nitrosourea compounds by induction of hepatic microsomal enzyme relating to their metabolism. In this report, malignant brain tumor patients were divided into two groups; ACNU was administered either by internal carotid or intravenous route. ACNU concentrations in blood or tumor tissue following the administration were serially compared between these two groups. Patients were also divided into another two groups; ACNU was administered in combination with or without phenobarbital. Between these two groups, ACNU in concentrations in blood were serially compared in order to detect the influence of phenobarbital. ACNU concentrations in tumor tissues were measured at 5, 10, 15, 20, 25, 30, (40, 45, 50), 60 minutes after intravenous (IV) or internal carotid arterial (ICA) administration of ACNU (2-3 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

骨髓基质干细胞向大鼠脑胶质瘤的趋向迁移作用

目的 研究骨髓基质干细胞(BMSCs)向大鼠脑胶质瘤的趋向性.方法 在体外分离培养Fisher344大鼠BMSCs.流式细胞仪检测细胞免疫表型;Transwell法分别将BMSCs、NIH3T3细胞与9L细胞进行共培养.24 h后计算细胞迁移率:立体定向法建立Fisher344大鼠/9L细胞脑胶质瘤模型,2周后经神经行为学、MRI、HE染色证实模型成功后.将5-溴脱氧核苷尿嘧啶(BrdU)标记的BMSCs、N1H3T3细胞由颈内动脉进行移植,2周后,Fisher344大鼠灌注固定取脑,免疫组织化学检测BMSCs的趋向迁移规律.结果 体外分离培养的3～6代BMSCs表面标志CD34、CD45阴性而CD29、CD44阳性;BMSCs在体外能够向9L细胞迁移;立体定向法建立Fisher344大鼠/9L细胞脑胶质瘤模型符合胶质瘤的特征:颈内动脉移植的BMSCs也能够向9L细胞胶质瘤趋向迁移,主要分布在肿瘤组织与正常组织的边界.结论 BMSCs在体内、外均能够向脑胶质瘤迁移,颈内动脉移植是一种简单、有效的方法.     

恶性脑肿瘤的超选择性脑动脉灌注治疗

目的:对恶性脑胶质细胞瘤术后残留的肿瘤组织,用化疗方法将其杀灭和抑制生长,以延长病人的生存期和改善生存质量;并比较嘧啶亚硝脲(ACNU)加氨甲喋呤(MTX)(A组)以及三尖杉酯碱加MTX(B组)的疗效。方法:将ACNU2～3mg/kg,三尖杉酯碱0.1～0.5mg/kg,MTX0.1～0.2mg/kg按A、B两组方案,采用超选择性脑动脉内联合灌注化疗,每例1～5次不等。结果:A组12例中CR1例,PR3例,NC7例,PD1例;B组12例中CR1例,PR2例,NC7例,PD2例。A组和B组对恶性脑胶质瘤的有效率分别为33.33％和25％,化疗后肿瘤体积缩小率分别为48.32％和46.21％,各组治疗前后肿瘤体积变化均有显著性差异,但两组疗效对比无明显差异。结论:恶性脑胶质细胞瘤术后辅以超选择性脑血管内化疗,能抑制肿瘤生长,ACNU加MTX与三尖杉酯碱加MTX的联合化疗方案合理,毒副作用小。     

Antitumor effect and peritumoral brain edema formation in relation to MX2, ACNU, and doxorubicin therapy: a comparative analysis using rodent models of gliomas

The potential antitumor effect of MX2, a new lipophilic morpholino anthracycline, was compared with those of ACNU or doxorubicin (DOX) using two different rodent glioma models. A mouse subcutaneous glioma model (203 glioma) was used to measure the effect of each drug on reducing the glioma size and a rat 9L intracerebral glioma model (9L glioma) was used to assess the antitumor effect on survival rate in a clinically similar fashion. Treatment with ACNU inhibited tumor growth by 94.6% (p < 0.0001) and complete regression of the tumor was observed in 3 of 25 (12.0%) of the ACNU-treated cases. Tumor growth was inhibited by 32.4% with DOX despite a tendency (p < 0.16) and by 59.4% with MX-2 (p < 0.001); neither of these drugs resulted in complete tumor regression. In the intracerebral glioma rats, only ACNU tended to ameliorate survival rate, but there was no statistical significance. These results suggest that ACNU has the most potent effect but MX2 can be an option for chemotherapy of malignant gliomas. Interestingly, all three drugs significantly elevated the brain water content on both the ipsilateral and contralateral sides of the tumor, although they did not induce brain edema in the normal rat brains. Careful management of brain edema might be required regardless of the drug used during chemotherapy to maximize the prognosis of glioma patients.     

外伤性颈动脉海绵窦瘘的血管内治疗

目的 探讨外伤性颈动脉海绵窦瘘的血管内治疗的技术特点。方法 对于不同的病例采用了不同的方法．包括海绵窦瘘口球囊栓塞，保持颈内动脉通畅，以及连同瘘口闭塞的颈内动脉闭塞术。对于动脉途径难以进行的病例采取了经静脉途径弹簧圈的栓塞结果 53例球囊闭塞瘘口且保持颈内动脉通畅。14例连同瘘口闭塞颈内动脉。3例通过静脉途径栓塞满意。结论 外伤性颈动脉海绵窦瘘应首选血管内栓塞治疗。一般情况下海绵窦瘘均表现为良性过程．应力争解剖治愈，不可轻易牺牲颈内动脉。     

Antitumor effect and peritumoral brain edema formation in relation to MX2, ACNU,and doxorubicin therapy: A comparative analysis using rodent models of gliomas

Abstract

The potential antitumor effect of MX2, a new lipophilic morpholino anthracycline, was compared with those of ACNU or doxorubicin (DOX) using two different rodent glioma models. A mouse subcutaneous glioma model (203 glioma) was used to measure the effect of each drug on reducing the glioma size and a rat 9L intracerebral glioma model (9L glioma) was used to assess the antitumor effect on survival rate in a clinically similar fashion. Treatment with ACNU inhibited tumor growth by 94.6% ip ? 0.0001) and complete regression of the tumor was observed in 3 of 25 (12.0%) of the ACNU-treated cases. Tumor growth was inhibited by 32.4% with DOX despite a tendency (p?0.16) and by 59.4% with MX-2 7p ? 0.001); neither of these drugs resulted in complete tumor regression. In the intracerebral glioma rats, only ACNU tended to ameliorate survival rate, but there was no statistical significance. These results suggest that ACNU has the most potent effect but MX2 can be an option for chemotherapy of malignant gliomas. Interestingly, all three drugs significantly elevated the brain water content on both the ipsilateral and contralateral sides of the tumor, although they did not induce brain edema in the normal rat brains. Careful management of brain edema might be required regardless of the drug used during chemotherapy to maximize the prognosis of glioma patients. [Neurol Res 2000; 22: 819-824]     

The effect on the tumor vessel permeability by hyperosmotic blood brain barrier disruption

The limited effect of chemotherapy on malignant brain tumors has been related to tumor cell insensitivity to the drugs and to their ineffectual delivery to the tumor. The studies by Groothuis and Neuwelt et al have shown that the studies of tumor vessel permeability show considerable variability in different areas of tumors and between different tumor models. The present studies used the 9L gliosarcoma model in Fischer 344 rats to evaluate the increase of tumor vessel permeability by osmotic BBB opening on drug delivery to the tumor, brain adjacent to tumor (BAT), and brain distant to tumor using cis-diamminedichloroplatinum (CDDP) as a chemotherapeutic agent which was water soluble and rarely permeable to BBB. In addition the difference of delivery to normal brain and tumor tissue were studied on intravenous or intracarotid administration of cisplatin with or without intracarotid infusion of graded (20%, 25%) hyperosmolar mannitol. Evans blue, which binds to plasma albumin, was used to provide a visual marker of BBB opening. 20% or 25% hyperosmolar mannitol infusion to right internal carotid artery for BBB disruption was done at 0.12 ml/sec for 30 sec with controlled respiration after temporally clipping of right common carotid artery. Then cis-diamminedichloroplatinum (CDDP) was infused at 0.5 mg/ml/100 gr (body weight). In control studies isotonic saline instead of mannitol was infused to intracarotid artery at identical rate and volume. In 14 9L gliosarcoma bearing rats and 3 normal rats cis-diamminedichloroplatinum (CDDP) delivery to tumor and normal brain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined preoperative onyx embolization and protective internal carotid artery covered stent placement for treatment of glomus vagale tumor: review of literature and illustrative case

Abstract

Objective: Surgical resection of complex glomus vagale tumors can be complicated by extensive blood loss and might require surgical sacrifice of an encased internal carotid artery.

Methods: A young patient presented with mass effect from glomus valage tumor. Computerized tomography angiography showed an encased internal carotid artery. Cerebral angiography demonstrated a highly vascular tumor. A literature review was performed for endovascular treatment options for neck tumors.

Results: Staged preoperative embolization of feeder arteries via internal maxillary artery, and thyrocervical trunk with onyx was performed. A covered stent was implanted in the cervical internal carotid artery to the common carotid artery; this resulted in complete devascularization of the tumor with exclusion of external carotid artery from the circulation. This is followed by surgical resection of the tumor.

Conclusion: Preoperative embolization with onyx decreased the amount of blood loss intra-operatively. The implantation of a covered stent in the cervical internal carotid artery through the common carotid artery contributed for further devasculatization of the tumor bed, as well as provided a lumen continuity in case iatrogenic carotid injury is encountered intra-operatively.     

骨髓间充质干细胞向脑胶质瘤趋向性的初步研究

背景骨髓间充质干细胞(MSCs)是存在于骨髓中的非造血类干细胞,具有自我更新及多向分化潜能.在大鼠脑外伤模型中的迁移能力已得到证实,而其对于脑胶质瘤的趋向性的研究尚处于初期.本实验通过将标记的MSCs移植到大鼠脑胶质瘤模型体内,观察它的迁移情况.方法采用全骨髓细胞培养法,利用MSCs的贴壁生长及可在体外长期培养的特性,获取纯化的MSCs.采用流式细胞术鉴定其表面抗原及细胞周期.在处于对数生长期的MSCs培养皿中加入BrdUrd(终浓度10μg/mL),培养24～48 h后进行移植.采用立体定向技术建立大鼠脑胶质瘤模型,3 d后移植标记好的MSCs在大脑半球组,BrdUrd标记的MSCs被注入大鼠脑胶质瘤模型肿瘤对侧大脑;在颈内动脉组,BrdUrd标记的MSCs被注入大鼠脑胶质瘤模型肿瘤同侧的颈内动脉.分别以BrdUrd标记的3T3细胞作为对照组.2周后,处死大鼠取脑组织制作病理切片,进行抗BrdUrd免疫组化及免疫荧光染色,观察MSCs的迁移情况.结果全骨髓培养法获得了纯化的MSCs.移植到脑组织及颈内动脉的BrdUrd标记的MSCs表现出了明显的向脑胶质瘤迁移的特性.在大脑半球组,MSCs主要集中在肿瘤与正常脑组织的交界部位,在瘤内只有少量分布.在颈内动脉组,MSCs主要分布于肿瘤内部,在肿瘤与正常脑组织的交界位置有少量分布.结论MSCs具有明显的向脑胶质瘤迁移的特性,同时亦可通过血脑屏障,有可能成为胶质瘤基因治疗的理想载体.     

The anti-tumor effect of ACNU and X-irradiation on mouse glioma (author's transl)

Anti-tumor activities of ACNU and X-irradiation on methylcholanthrene induced glioma in C57BL mice were studied in vitro and in vivo. In vitro experiments using cultured glioma cells (MGB cells), the synchronization of cell cycle was done by excess addition of thymidine, and the anti-tumor cell effect were investigated by mean of determinations of DNA synthesis, mitotic index and the number of the living cells following the treatments. As the results, it appeared obvious that ACNU was most effective on MGB cells in S phase and X-irradiation in M phase. As to the combined therapy of ACNU and X-irradiation, the anti-tumor effect was most remarkable when the cells were treated by X-irradiation in the G2, M phase, which were hervested by addition of ACNU 44 hours before irradiation. However simultaneous treatment of ACNU and X-irradiation on the cells in G1 phase was not so remarkable. In vivo experiments the anti-tumor effect of ACNU and X-irradiation on subcutaneously or intracranially transplanted glioma in mice was investigated. Either ACNU 10 mg/kg or local X-irradiation 1240 rads showed inhibitory effect on the tumor growth and prolonged the survival time of the tumor bearing mice. The combination therapy was more effective than ACNU or X-irradiation alone, particularly combination therapy of ACNU and repeated small doses irradiation of X-ray was remarkably effective. Evidence obtained indicates that the combination therapy of ACNU and X-irradiation have synnergistic anti-tumor effect on experimental mouse glioma.