p53及mdm2在脑膜瘤中的表达及意义

脑膜瘤是中枢神经系统常见肿瘤之一,其发生机制仍然不清楚,随着肿瘤分子生物学研究的进展,目前认为脑膜瘤的发生和发展与癌基因活化及抑癌基因失活有关,mdm2瘤基因产物过表达可能使脑膜瘤中野生性p53失活,p53和mdm2在脑膜瘤的发生发展中可能发挥协同作用。     

颅内高度恶性非生殖细胞瘤性生殖细胞肿瘤

目的探讨颅内高度恶性非生殖细胞瘤性生殖细胞肿瘤（non-germinomatous malignant germ cell tumors,NGMGCTs）的临床特点、治疗和预后.方法回顾性分析了19例高度恶性NGMGCTs患者的临床特点、血清肿瘤标记物监测、治疗方法以及预后.其中胚胎癌2例,卵黄囊瘤4例,绒毛膜上皮癌7例,混合性生殖细胞肿瘤6例.有7例术前肿瘤标记物监测均异常,所有患者均行手术切除肿瘤,全切除7例,近全切除10例,大部分切除2例.所有患者均行放疗,有11例行术后化疗.结果共随访到17例患者,平均随访3.5年,1年生存率为29.4%,3年生存率为5.9%.其中卵黄囊瘤1年生存率为25.0%;混合性生殖细胞肿瘤3年生存率为20.0%,胚胎癌和绒毛膜上皮癌患者皆于1年内死亡.结论高度恶性NGMGCTs预后很差.根据临床表现、影像学资料和肿瘤标记物甲胎蛋白（AFP）和（或）β-绒毛膜促性腺激素（β-HCG）增高,多数患者在术前可确诊为高度恶性NGMGCTs.治疗应先采用化疗后放疗,对治疗后肿瘤标记物水平降至正常而影像学上肿瘤仍未完全消失者,可考虑手术切除,术后再行化疗和（或）放疗.治疗结束后注意随诊,如肿瘤标记物再次升高,经影像学证实肿瘤复发,可再行化疗和手术治疗.这样会延长高度恶性NGMGCTs患者的生存期.     

肿瘤抑制基因p53在脑胶质瘤中的研究进展

胶质瘤是神经外科常见肿瘤，约占原发性脑肿瘤的50%，尽管采用了新的治疗手段，如立体定向放射外科、新化疗药物等．但胶质瘤病人生存时间仍无显改善，部分原因是对其病因、发病机理认识不足。随着分子生物学的发展，在基因、分子水平研究肿瘤的发生、发展，为胶质瘤的诊治开辟了新方向。     

肿瘤抑制基因p53在脑胶质瘤中的研究进展

胶质瘤是神经外科常见肿瘤.约占原发性脑肿瘤的 50％,尽管采用了新的治疗手段,如立体定向放射外科,     

p53、p16和Rb在原发和继发胶质母细胞瘤中的表达及意义

目的探讨p53、p16和Rb在原发和继发胶质母细胞瘤（GBM）中表达的差异性及其意义。方法对28例原发、32例继发GBM和6例正常脑组织应用免疫组织化学法检测Rb表达，并用RT．PCR和Western blot检测其p53、p16mRNA和蛋白的表达。结果免疫组织化学染色示正常脑组织中无Rb表达，28例原发GBM中有6例表达缺失（21．4％）．32例继发GBM中有4例表达缺失（12．5％），两者相比差异无显著性意义（P〉0．05）。RT．PCR和Western blot检测p53和p16mRNA和蛋白表达，发现所有继发GBM中p53表达强度较原发GBM明显增加（P〈0．051，同时28例原发GBM中有10例p16表达缺失（35．7%），32例继发GBM中仅有2例p16表达缺失（6．25％），两者相比差异有显著性意义（P〈0．01）。结论细胞周期调节基因p53在mRNA和蛋白水平表达增加和p16在同样水平表达缺失是原发与继发GBM重要的细胞周期调控基因的变化，可能是基因治疗GBM的重要靶点。     

松果体区非生殖细胞瘤性恶性生殖细胞肿瘤的治疗

目的 探讨松果体区非生殖细胞瘤性恶性生殖细胞肿瘤(NGMGCTs)的临床特点、治疗和预后.方法 回顾性分析了2000年1月至2010年1月经病理证实的34例高度恶性NGMGCTs 患者的临床特点、血清肿瘤标记物检测、治疗方法及预后.所有患者均行枕部经小脑幕(Poopen)入路显微手术切除肿瘤,并行辅助放化疗.结果 全切除32例,近全切除2例,术后病理示未成熟畸胎瘤11例,畸胎瘤恶性变2例,胚胎癌2例,卵黄囊瘤l例,绒毛膜上皮癌6例,混合性生殖细胞肿瘤12例.共随访31例患者,随访时间6个月至10年,1年生存率为97％,3年生存率为62％,5年生存率为44％.结论 多数松果体区NGMGCTs根据临床表现、影像学资料和肿瘤标记物可在术前定性,以手术为主术后辅以化疗和放疗的综合治疗可以获得良好疗效.     

p53,CerbB—2和PCNA在脑胶质瘤中表达的意义及其 …

目的 研究７６例脑质瘤的ｐ５３ＣｅｒｂＢ－２和ＰＣＮＡ表达意义及其相关性。方法 应用ＳＰ微波免疫组化技术和统计学分析。结果 （１）在７６例脑胶质瘤组织中；ｐ５３，ＣｅｒｂＢ－２和ＰＣＮＡ的阳性表达率分别是４４．７４％（３４／７６），３４．２１％（２６／７６）和８０．２６％（６１／７６）。（２）ｐ５３的表达强度与胶质瘤的组织学类型和恶性程度呈显著正相关（Ｐ〈０．０１）。（３）ｐ５３ＣｅｒｂＢ－２和Ｐ     

p53及其调控基因在胶质瘤和脑肿瘤干细胞中的作用

胶质瘤是成人最常见的原发性脑肿瘤,抑癌基因p53突变在胶质瘤中十分常见,但其机制尚未明确.近期研究显示:P53蛋白能控制肿瘤干细胞的自我更新并抑制其多能性.与胶质瘤相关的p53调控因子Pict1、Nanog、Bcl2L 12以及miRNA 则可能为胶质瘤及其干细胞提供新的基因治疗靶点.活化脑肿瘤干细胞中的P53联合现行治疗方案可能成为胶质瘤有效的治疗方法.     

星形细胞瘤中肿瘤抑制基因p53的表达及PCNA,GFA …

目的 检测３０例不同病理级别星形细胞瘤标本中ｐ５３基因的表达状况及肿瘤其它生物学特性。方法 采用常规ＨＥ染色及免疫组化技术检测３０例标本中ｐ５３，增殖细胞核抗原（ＰＣＮＡ）胶质纤维酸性蛋白（ＧＦＡＰ）波形蛋白（ＶＩＭ），Ｓ１００蛋白的表达。结果 ｐ５３免疫组化染色阳性率随病理级别增高而增高，Ⅳ级染色阳性率８３．３％，Ⅰ～Ⅱ级１５．４％，且不同级别染色有差异；ＰＣＮＡ均呈阳性，Ⅳ级病理染色阳性强度大     

星形细胞肿瘤PCNA、p53蛋白表达与细胞增殖和肿瘤预后

目的研究星形细胞肿瘤PCNA、p53蛋白表达与细胞增殖和肿瘤预后的关系.方法应用免疫组化技术对57例星形细胞肿瘤PCNA和p53进行标记;病例随访资料采用Kaplan-Meier生存曲线处理,分析PCNA和p53表达与肿瘤分化状况和预后的关系.结果48例(84.2%)星形细胞肿瘤表达PCNA,45例(78.9%)表达p53.PCNA表达与肿瘤恶性程度和预后显著相关;p53蛋白表达多见于分化不良的星形细胞肿瘤,但表达水平与肿瘤预后无明显相关.结论PCNA和p53对评价星形细胞肿瘤生物学行为有参考价值.PCNA对肿瘤增殖潜能和预后判断价值大于p53;p53基因突变可能是肿瘤细胞恶性转化的分子基础.     

Molecular analysis for p53 and mdm2 in intracranial germ cell tumors

Intracranial germ cell tumors (ICGTs) are uncommon neoplasms. The histological appearance of ICGTs is indistinguishable from that of the usual testicular germ cell tumors (TGTs). Recently, several reports have associated molecular abnormalities of p53 and mdm2 in TGTs with their malignancies. However, whether ICGTs are associated with molecular abnormalities is still unknown. We analyzed a series of 16 ICGTs for mutations in the TP53 gene by single-strand conformation polymorphisms, and for amplification of the MDM2 gene using differential PCR. In addition, the same 16 tumors were examined for p53 and mdm2 protein overexpression using antibodies directed against p53 [monoclonal antibodies (mAb) 1801 and DO7] and mdm2 (IF2), respectively. Twelve (75%) and 2 (13%) of the 16 ICGTs reacted with DO7 and PAb1801, respectively, and 1 (6%) carried a TP53 gene mutation. Thirteen (81%) of the 16 ICGTs reacted with IF2, and 3 (19%) carried MDM2 gene amplification. The less frequent TP53 gene mutation compared with MDM2 gene amplification, and the frequently expressed p53 and mdm2 protein, are similar to the case for TGTs. It is tempting to speculate that ICGTs might have the same cellular origins as TGTs with abnormalities in p53 and mdm2, which could play an important role of tumorigenesis. Received: 9 March 1999 / Revised, accepted: 10 May 1999     

颅内生殖细胞肿瘤的免疫组织化学研究

目的：探讨各种颅内生殖细胞肿瘤中免疫组织化学染色的诊断意义。方法：对７６例颅内生殖细胞肿瘤进行５种抗体的免疫组织化学染色。结果：胎盘碱性磷酸酶（ＰＬＡＰ）阳性率８２％（６２／７６），绒毛膜促性腺激素（ＨＣＧ）阳性率３０％（２３／７６），胎盘催乳素（ＨＰＬ）仅占５％（４／７６），甲胎蛋白（ＡＦＰ）和妊娠特异性β１糖蛋白（ＳＰ１）在卵黄囊癌中阳性率１００％（５／５）。结论：ＰＬＡＰ可用于生殖细胞肿瘤与其他肿瘤鉴别诊断。ＡＦＰ和ＳＰ１可检出畸胎瘤中不易察觉的卵黄囊癌成分。ＳＰ１阳性可能提示肿瘤恶性程度高，预后差。     

Overexpression of mdm2 and p53 and association with progesterone receptor expression in benign meningiomas

The progesterone receptor is frequently found expressed in meningiomas at robust levels. As several studies of breast and endometrial tumors have shown an inverse correlation between progesterone receptor expression and p53 overexpression, we sought to determine if a similar relationship existed in meningiomas. As p53 may also be inactivated by the overexpression of mdm2, we examined a cohort of 90 benign meningiomas immunohistochemically for the presence of the progesterone receptor as well as overexpression of p53 and mdm2. The progesterone receptor was detected in 67% (61/90) of cases, while p53 and mdm2 overexpression were detected in 14% (13/90) and 46% (42/90) of cases, respectively. An absolute correlation was observed between the overexpression of nuclear mdm2 and overexpression of the progesterone receptor, with nuclear mdm2 overexpression being confined to progesterone receptor‐positive tumors (P = 0.001). While p53 overexpression was not associated with progesterone receptor expression, a combination of mdm2 overexpression and/or p53 overexpression was significantly associated with the presence of the progesterone receptor (P = 0.025). These results suggest the existence of a novel relationship between p53 (and its regulatory control) and the presence of the progesterone receptor and, as such, may have fundamental consequences in developing progesterone receptor‐targeted therapies for meningiomas.     

Combined treatment with chemotherapy and radiation therapy for intracranial germ cell tumors

We analyzed our treatment results in 153 patients with histologically verified intracranial germ cell tumors and proposed classifying them into three therapeutic groups with good prognosis, intermediate prognosis, and poor prognosis. In this work, we selected patients treated with chemotherapy (cisplatin or carboplatin combinations) in each subgroup, and we discuss the role of chemotherapy in their treatment. Our combination chemotherapy regimens are: cisplatin-vinblastine-bleomycin, cisplatin-etoposide, and carboplatin-etoposide. We delivered these chemotherapies to the last 33 patients and compared their treatment results with those obtained in the previous 31 patients, who were treated with conventional radiation therapy alone. A combination with chemotherapy and a reduced dose of irradiation with local field was given to 7 patients with germinoma to increase the cure rate and reduce radiation-induced side effects, including anterior pituitary dysfunction. We obtained an excellent initial response to chemotherapy. The chemotherapy we delivered had significantly better effects in the group with intermediate prognosis, but not in the group with poor prognosis. More aggressive chemotherapy and radiation therapy should be given as the initial treatment.     

bcl-2 protein expression in astrocytomas in relation to patient survival and p53 gene status

bcl-2 protein expression was characterized in a series of 58 astrocytomas from 21 pediatric and 37 adult patients. As part of a continuing attempt to define relevant prognostic factors which may predict clinical outcome, we have determined the impact of bcl-2 accumulation in malignant astrocytes on the length of patient survival. Aberrant overexpression of bcl-2 protein in tumor cells was detected in 57% (12 of 21) of pediatric and 73% (27 of 37) of the adult cases. Among pediatric patients, the median survival in months showed no relationship with the incidence of bcl-2-positive tumors. Among the adult patients, a favorable prognostic indicator was low-tumor grade (P = 0.05). bcl-2-positive tumors occurred with similar frequencies in WHO grades III and IV of malignancy. When bcl-2 expression in tumor cells was tested as a variable to predict for patient survival, the 6 patients without bcl-2 expression among 23 adult patients with grade IV tumors had a shorter median survival. The same 58 tumors had been previously analyzed for alterations of p53: 4 pediatric and 16 adult tumors had p53 gene mutations. There was no significant difference in median survival related to p53 gene status. There was no relationship between bcl-2 expression and p53 gene status: approximately equal numbers of tumors with either wild-type or mutant p53 were bcl-2 negative or bcl-2 positive. bcl-2 expression is high (40–100%) among other tumors of the central nervous system which also show low malignant potential. Up-regulation of bcl-2 in malignant astrocytes or constitutive expression in some tumor types may be a factor leading to a more favorable clinical outcome. Received: 27 January 1997 / Revised: 21 March 1997 / Accepted: 28 March 1997     

100例脑肿瘤中p53基因突变与P53蛋白积聚的研究

目的:研究不同类型脑肿瘤中的p53基因突变与P53蛋白积聚及其相关性。方法:采用聚合酶链反应-单链构象多态性(PCR-SSCP)分析及免疫组化法检测100例脑肿瘤p53基因突变及蛋白表达。结果:p53基因突变率为11%(11/100),其中高恶度胶质瘤为37.5%(6/16),低恶度胶质瘤4.3%(1/23),脑膜瘤6.9%(2/29),转移瘤40.0%(2/5)。P53蛋白表达阳性率为22%(22/100),其中高恶度胶质瘤为62.5%(10/16),低恶度胶质瘤为26.1%(6/23),脑膜瘤10.3%(3/29),转移瘤60%(3/5);其他肿瘤均未发现p53基因突变或蛋白表达。P53蛋白表达阳性的22例中伴有p53基因突变者11例,多见于高恶度肿瘤。结论:p53基因失活在脑肿瘤恶性进展过程中起重要作用。p53基因突变与P53蛋白积聚相关,但并非唯一因素。     

p53基因、PTEN基因协同对胶质瘤U251细胞系生长抑制作用的研究

目的探讨p53基因和PTEN基因在脑胶质瘤细胞系U251发生发展过程中的作用机制。方法用不同MOI的p53腺病毒表达载体pAdCMV-p53及空载体pAdCMV-lacZ分别感染表达野生型PTEN基因和突变型PTEN基因的细胞系,RT-PCR及Westernblot方法检测转染效率;并通过MTT检测生长抑制率、流式细胞仪检测细胞周期及TUNEL检测分析细胞凋亡等指标观察p53基因及PTEN基因对U251细胞生长的影响。结果MOI为100时,p53基因可引起U251细胞G0G1期阻滞、诱导细胞凋亡,生长抑制;MOI为50时,U251-p53 PTEN生长抑制率明显高于U251-p53,并能出现细胞凋亡,而U251-p53仅出现少量细胞凋亡。结论p53基因可以通过细胞周期G0G1期阻滞及诱导细胞凋亡抑制胶质瘤细胞系U251的生长;PTEN基因可以促进p53基因对胶质瘤细胞系U251的生长抑制作用,并能增加U251细胞对p53基因诱导凋亡的敏感性。     

松果体区生殖细胞肿瘤放射外科治疗的合理性探讨

目的 探讨立体定向放射外科作为一线方案治疗松果体区生殖细胞肿瘤的合理性.方法 回顾性分析14例经伽玛刀或X-刀治疗的松果体区生殖细胞肿瘤患者的临床资料,重点研究肿瘤放射外科治疗后变化及复发、转移情况.结果 14例患者于放射外科治疗后11 d至106个月再次入院.肿瘤放射外科治疗后缓慢增大1例,无明显变化2例,缩小后再增大1例,基本消失后原位复发2例,消失后周边复发4例,原位复发并种植转移2例,原位消失但出现种植转移2例.病理为:生殖细胞瘤5例、混合型生殖细胞肿瘤4例、成熟畸胎瘤3例、非成熟畸胎瘤和卵黄囊瘤各1例.结论 放射外科不能作为松果体区生殖细胞肿瘤的单一治疗方法.假使已采用放射外科治疗,则应依据肿瘤标记物结果和治疗后肿瘤的变化情况,及时手术或综合治疗.

Abstract：

Objective To discuss the rationality of the stereotaxic radiosurgery as the first therapy strategy on pineal region germ cell tumors.Methods To retrospectively analyze the clinical materials of 14cases which received the treatment of gamma knife or X- knife.The condition of tumor changing,recurring and metastasize post- radiosurgery were emphasized.Methods All the patients of 14 cases were admitted again from 11 days to 106 months after which had received radiosurgery.The tumor increasing slowing with 1cases,no marked change with 2 cases,repeated increasing after diminution with 1 case,situ recur after essential disappear with 2 cases,ambitus recur after disappear with 4 cases,situ recur and implantation metastasis 2 cases,situ disappear but implantation metastasis with 2 cases.The pathology results were 5germinomas,4 mixed germ cell tumors,3 mature teratomas,1 unmature teratoma and 1 yolo sac tumor.Conclusion Radiosurgery cant be regarded as the exclusive treatment for pineal region germ cell tumors.If the patients received the radiosurgery,they should be operated or combined therapy in time according the results of tumor marker and the condition of tumor changing.