多巴胺D2受体在垂体腺瘤中的表达及临床意义

目的垂体腺瘤约占颅内原发性肿瘤的10%~15%。多巴胺受体激动剂是治疗泌乳素(PRL)腺瘤的一线药物,并且对其它垂体腺瘤类型部分病例有效。研究表明:多巴胺受体激动剂是通过结合并激活多巴胺D2受体(D2R)发挥作用。本研究通过免疫组化的方法检测垂体腺瘤中D2R的表达情况。方法本研究所用197例垂体腺瘤标本均来自南京军区南京总医院神经外科手术病例。采用SP免疫组织化学染色法检测垂体腺瘤中D2R的表达。在光学显微镜下分析D2R在细胞中的定位及用半定量方法分析标本中阳性细胞的表达情况。免疫反应低表达定义为最终评分≤2分,高表达定义最终评分为>2分。结果 D2R定位于垂体腺瘤细胞胞浆。D2R在垂体腺瘤细胞中高表达率为65%,在PRL腺瘤和生长激素(GH)腺瘤的高表达率最高分别为为92.9%、90%;无功能性腺瘤(NFPA)D2R高表达率最低,仅为37.1%。D2R高表达率和垂体腺瘤的类型相关,与患者性别、肿瘤大小、肿瘤质地、侵袭性、是否复发或是否服用溴隐亭无显著相关性。结论 PRL腺瘤和GH腺瘤中D2R表达量高,适合多巴胺受体激动剂治疗;NFPA中D2R表达量低,不适合多巴胺受体激动剂治疗。     

垂体腺瘤中雌激素受体基因的表达

垂体腺瘤的发生发展与肿瘤中雌激素受体 (ER)基因的表达关系密切。PRL腺瘤中ER基因表达水平较高 ,ER基因的表达与溴隐亭的疗效有关 ;肿瘤中的ER受体突变率不高 ,但如其发生突变产生截断性受体 ,可能与肿瘤持续增长 ,不受相应激素的调控有关。抗雌激素治疗可以抑制一些溴隐亭治疗无效的PRL腺瘤生长     

垂体腺瘤中雌激素受体基因的表达

目的　研究人垂体腺瘤中雌激素受体基因 (estrogenreceptorgene ,ER)mRNA与蛋白水平的表达及其与垂体腺瘤生物学特性的关系。方法　用免疫组化法和逆转录 聚合酶链反应 (RT PCR法 ) ,检测 6 0例各种类型垂体腺瘤标本中ER蛋白的表达 ,比较不同类型垂体腺瘤ER蛋白表达的差异及ER蛋白表达与mRNA表达的差异。结果　泌乳素腺瘤、促性腺激素细胞瘤中均有ER蛋白表达 ,其表达与mRNA表达一致 ;无功能腺瘤中 2例有ER蛋白表达 ,其蛋白表达与mRNA表达不一致 ;其它类型垂体腺瘤未发现ER基因表达。结论　ER基因表达的检测可有助于评价PRL腺瘤的增殖活性及筛选抗雌激素治疗对象。ER基因的表达异常可能与PRL腺瘤及促性腺激素细胞瘤的发生、发展有关     

骨桥蛋白和CD44v6在垂体腺瘤中的表达及意义

目的 检测骨桥蛋白(OPN)、CD44v6在垂体腺瘤中表达并探讨其与垂体腺瘤临床病理特征的关系.方法 应用免疫组化SP法检测80例垂体腺瘤组织中OPN和CD44v6蛋白的表达,并对二者表达与垂体腺瘤临床病理特征之间的关系进行分析.结果 OPN、CD44v6在垂体腺瘤中阳性表达率分别为66.3%、65.0%,OPN、CD44v6的表达均与患者的年龄、性别、肿瘤组织学类型无关,但在侵袭性垂体腺瘤组与非侵袭性垂体腺瘤组、复发组及非复发组之间的差异均有统计学意义(P＜0.01),而且二者在垂体腺瘤中表达呈正相关(r=0.585,P＜0.01).结论 OPN和CD44v6蛋白在垂体腺瘤中高表达与肿瘤侵袭性生长及复发相关,且两者在肿瘤侵袭性改变中可能起协同作用,二者联合检测有望更客观评价垂体腺瘤的侵袭性.

Abstract：

Objective To explore the expressions of osteopontin (OPN) and CD44v6 in pituitary adenomas and to evaluate the relationship between the expressions and invasiveness of the tumor.Methods Immunohistochemistry was used to detect the expressions of OPN and CD44v6 in 80 pituitary adenomas,and the relationships between the expressions of OPN and CD44v6 and the clinicopathologic characteristics were also analyzed.Methods The positive expression rates of OPN and CD44v6 were 66.3% and 65.0% respectively in the pituitary adenomas.Both OPN and CD44v6 expressions were different statistically in invasive group and recurrent group(P<0.01 ),but not correlated with patient' s age,sex and histological types.There was also a significantly positive relation between OPN and CD44v6 expression in pituitary adenomas (P<0.01 ).Conclusion The increased expressions of OPN and CD44v6 are associated with the invasiveness and recurrence of pituitary adenomas.They might have a synergetic effect in the invasive growth of the tumor,which can be taken as leading candidates for evaluating the biological behavior.     

男性巨大垂体泌乳素腺瘤的临床特征及手术治疗

目的 探讨男性巨大垂体泌乳素（PRL）腺瘤的临床特征及手术治疗效果。方法 回顾性分析2018年7月~2019年7月手术治疗的8例男性巨大垂体PRL腺瘤的临床资料。结果 术前血清PRL水平在50.8~9 852 ng/ml,平均3 505.6 ng/ml。肿瘤全切除3例,近全切除4例,大部分切除1例。术后血清PRL恢复正常4例。8例术后症状均有好转。结论 男性巨大垂体PRL腺瘤,可首选溴隐亭治疗,若颅内压增高症状明显,可选择手术治疗。术中尽可能全切除肿瘤,保护正常垂体,术后酌情继续应用溴隐亭治疗或放疗。     

伽玛刀治疗对垂体泌乳素腺瘤内分泌功能的影响

目的 分析不同放射剂量γ-刀治疗对功能性泌乳素(PRL)腺瘤的PRL水平的影响,判断PRL在γ-刀治疗功能性PRL腺瘤预后和指导激素替代治疗的作用.方法 回顾性分析山东淄博万杰医院和广东深圳罗湖人民医院自2004年9月至2008年3月应用γ-刀治疗的248例功能性PRL腺瘤患者的临床资料,按治疗剂量将患者分组:Ⅰ组:50 Gy≤中心剂量<60 Gy;边缘剂量:20～30 Gy;Ⅱ组:40 Gy≤中心剂量<50 Gy;边缘剂量:15～25 Gy;Ⅲ组:30 Gy≤中心剂量<40Gy;边缘剂量12～20 Gy;术前、术后1月、3月、12月采用放射免疫法检测患者血清PRL水平,术后1年、2年复查头颅MRI观察肿瘤大小的变化.结果 3组患者术前PRL水平的差异有统计学意义(p<0.05),与Ⅰ、Ⅱ组比较,Ⅲ组PRL值偏低,术后12个月与Ⅰ组比较,Ⅲ组PRL值偏高;与术前相比,3组患者术后PRL水平均降低,差异有统计学意义(P<0.05);术后1年MRI显示肿瘤缩小198例(80%);术后2年肿瘤消失203例(82%),增大19例(7.7%),无变化26例(10.4%).结论 不同剂量γ-刀治疗功能性PRL腺瘤对术后内分泌的恢复有很大的影响,中心剂量和边缘剂量(尤其是中心剂量)较高时,术后PRL易恢复正常.但远期是否会造成垂体低功需要长期随访.

Abstract：

Objective To analyze the effects of-γ-knife treatment with different dosages on level of prolactin (PRL) in patients with different sizes of functional pituitary prolactinomas, and determine an index to guide hormone replacement therapy and the prognosis of -γ-knife treatment in patients with functional pituitary prolactinomas through comparing the changes of tumor sizes and the levels of PRL before and after -γ-knife treatment. Methods A retrospective analysis of the clinical data of 248 patients with functional pituitary prolactinomas was performed; gamma knife treatment was performed on these patients from September 2004 to March 2008. We divided the patients into 3 groups: group Ⅰ (50 Gy≤central dose<60 Gy, 20 Gy＜marginal dose<30 Gy), group Ⅱ (40 Gy≤ central dose＜50 Gy, 15 Gy＜marginal dose<25 Gy) and group Ⅲ (30 Gy ≤ central dose<40 Gy, 12 Gy＜marginal dose<20 Gy). The irradiation dose on optic nerves in the 3 groups was under 9 Gy. Radioimmunoassay was employed to detect the serum PRL level before and 1, 3 and 12 months after γ-knife treatment. The changes of the tumor sizes were observed and compared with cranial MRI 1 and 2 years after -γ-knife treatment.Results Significant differences on the PRL level were noted before -γ-knife treatment between each 2 groups (P<0.05); the PRL level in group Ⅲ was lower as compared with that in group Ⅰ and Ⅱ before γ-knife treatment; however, the PRL level in group Ⅲ was higher as compared with that in group 112 months after -γ-knife treatment; the PRL level in all the 3 groups after γ-knife treatment was significantly lower as compared with that before γ-knife treatment (P<0.05). MRI showed that the tumor had 80% partial response rate (198/248) in the 1st year, 82% complete response rate (203/248) in the 2nd year, increased volume in 19 patients (7.7%) and no change in 26 patients (10.4%). Conclusion Different treatment doses of Gamma knife on functional pituitary prolactinomas has great influences on postoperative recovery of endocrine; the higher doses of the center and edge (especially center), the higher normal rate of postoperative PRL level. Whether it will cause long-term hypopituitarism needs continue follow-up.     

替莫唑胺治疗难治性垂体腺瘤一例报告并文献复习

目的 探讨难治性垂体腺瘤有效的综合治疗方法.方法 采用手术、伽玛刀及再次手术治疗1例难治性垂体腺瘤患者,然后根据其原代肿瘤细胞培养结果,选用替莫唑胺治疗2个疗程,总结分析其疗效.结果 由于肿瘤生长迅速,常规手术、放疗、药物等治疗方法均难以控制难治性垂体腺瘤生长.根据切除肿瘤病理(Ki-67 LI,MGMT表达水平)及原代肿瘤细胞替莫唑胺敏感实验结果选用替莫唑胺治疗,患者肿瘤停止快速生长,并有肿瘤液化坏死.结论 对于常规手术、放疗及药物治疗无效的难治性垂体腺瘤,替莫唑胺化疗可能是一种替代治疗方法.

Abstract：

Objective To explore the effective treatment for refractory pituitary adenomas.Method Based on MGMT expression and sensitive test of the primary pituitary adenoma cells to temozolomide, we treated a refractory pituitary adenoma patient.Results MGMT expression in this case was at low level,and primary pituitary adenoma cells were sensitive to temozolomide in vitro.The tumor volume decreased after the first cycle temozolomide therapy.Conclusions Temozolomide may be a salvage therapy for those refractory pituitary adenomas with low MGMT expression.     

垂体催乳素腺瘤的临床研究近况

催乳素(PRL)腺癌是最常见的垂体腺癌类型,约占外科切除垂体腺癌的30%。其组织学及超微结构有多种形态,采用免疫细胞化学染色和免疫电镜检查是测定PRL腺癌可靠且准确的方法。多巴胺激动剂——溴隐亭能使PRL腺癌细胞的细胞浆、内浆网和Golgi体的体积大大减小,腺瘤体积缩小,激素合成减少。对于不同体积大小的PRL腺癌,溴隐亭有其重要的治疗作用。     

雌激素受体在人类垂体腺瘤中的表达

目的研究雌激素受体(ER)在人类垂体腺瘤中的表达及其与垂体腺瘤临床特征及所分泌激素类型的关系.方法应用免疫组化S-P法和原位杂交法检测55例垂体腺瘤中ER蛋白及ERmRNA的表达,并采用S-P法对其中53例标本进行激素分型.结果在不同性别及不同病程垂体腺瘤患者中,ER蛋白及ERmRNA在肿瘤组织中的表达差异无显著性.不同体积垂体腺瘤中,ER蛋白及ERmRNA表达阳性率有随肿瘤体积增大而增高的趋势,但ER蛋白表达仅在大腺瘤组和巨大腺瘤组具有显著差异(P＜0.05).53例大腺瘤及巨大腺瘤中,部分PRL、FSH、LH单激素腺瘤及部分多激素腺瘤有ER蛋白及ERmRNA表达,而全部GH、ACTH、TSH单激素腺瘤均无ER蛋白及ERmRNA表达,4例无功能腺瘤均无ER蛋白表达,仅1例有ERmRNA表达.结论垂体腺瘤患者的性别和病程不影响肿瘤组织中ER的表达.推测ER蛋白及ERmRNA表达与垂体腺瘤的高增殖性及垂体腺瘤的激素分泌类型有关.     

泌乳素腺瘤药物治疗耐药性的分子机制研究

泌乳素腺瘤是激素分泌性垂体腺瘤中最常见的一种,药物即多巴胺受体激动剂是首选的治疗方法,其中溴隐亭是代表性药物.泌乳素腺瘤的耐药性是多因素、多机制造成的,其直接原因是多巴胺D2受体数量下降,或受体亚型D2S/D2L的比例下降.而多巴胺D2受体水平下降的原因包括:mRNA交替剪接修饰缺陷、腺苷酸环化酶活性下降及D2R基因调控因子(如NGF水平)的影响等.     

FRα在垂体腺瘤中的表达及其与无功能垂体腺瘤侵袭性的关系

目的 检测叶酸受体α(FRα)在各型垂体腺瘤和正常腺垂体中的表达情况;寻找对无功能垂体腺瘤(NFPA)诊断及其侵袭性判断具有重要意义的分子生物学指标.方法 收集垂体腺瘤组织标本44例和正常腺垂体组织3例,利用免疫荧光共聚焦,实时定量反转录(real-time RT-PCR)方法检测FRα在各标本中的表达.结果 FRa仅在NFPA中特异性表达,在其他类型的垂体腺瘤和正常腺垂体中不表达,差异具有统计学意义(P＜0.01);FRa的表达水平与NFPA侵袭性存在显著相关性(P＜0.05).结论 FRα可能在NFPA的发生发展中起到重要的作用;同时FRα可能作为NFPA特异性的诊断指标,为肿瘤的靶向诊治提供理论基础.     

Pattern of FGF-2 isoform expression correlated with its biological action in experimental prolactinomas

Fibroblast growth factor-2 (FGF-2) synthesized in the pituitary is involved in the formation and progression of pituitary tumors. The aim of this study was to analyze the pattern expression of two FGF-2 isoforms at different subcellular levels and to determine its correlation with prolactinoma development. Estrogen administration to male rats for 7, 20, and 60 days generated pituitary tumors, with lactotrophs being the prevalent cell type. Ultrastructural immunolabeling showed FGF-2 in the cytosolic and nuclear compartments of somatotrophs, lactotrophs and gonadotrophs, as well as in folliculo-stellate cells of normal rats. Estrogen stimulation increased FGF-2 immunoreactivity in various tumors and enhanced the expression of two FGF-2 isoforms, 18 and 22 kDa, as quantified by western blot. The 18 kDa isoform observed in cytosol extracts reached the highest levels after 60 days of hormonal stimulation and this was related to lactotroph proliferation. However, the 22 kDa FGF-2 isoform was only detected in the nuclear compartment and achieved the maximum expression at 7 days of estrogen treatment, without any correlation with lactotroph proliferation. These results suggest that the 18 kDa FGF-2 may play a role in the modulation of lactotroph proliferation in prolactinomas induced by estrogen. The overproduction of both FGF-2 isoforms appears to be implicated in autocrine–paracrine–intracrine mitogenic loops; this FGF-2 activity could lead to uncontrolled cell growth, angiogenesis, and tumor formation.     

Effects of an estrogen receptor antagonist on proliferation, prolactin secretion and growth factor expression in the MMQ pituitary prolactinoma cell line

The aim of this study was to investigate the functional role of estrogen receptor α (ERα) in MMQ pituitary prolactinoma cells in the absence of estrogen with respect to proliferation, prolactin (PRL) secretion, and expression of growth factors. MMQ cells were treated with the ERα antagonist fulvestrant, then proliferation and PRL secretion were measured using MTS and enzyme-linked immunosorbent assays. Levels of ERα, vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) and B cell leukemia/lymphoma-2 (BCL-2) were measured using quantitative polymerase chain reaction and western blot analysis. Fulvestrant acted as a potent inhibitor of ERα expression, and significantly inhibited cell proliferation (by up to 57.6±2.2%) and PRL secretion (by up to 81.0%). Fulvestrant also significantly altered the expression levels of VEGF, MMP-9 and BCL-2. We conclude that ERα plays an important functional role in pituitary prolactinomas and is also involved in the expression of particular growth factors, even in the absence of estrogen. Fulvestrant treatment may be an effective therapy for such tumors.     

Expression for peroxisome proliferator-activated receptor gamma in pituitary adenomas☆ 38 cases for semi-quantitative immunohistochemical analysis

BACKGROUND： It has been reported that peroxisome proliferator-activated receptor γ （PPAR γ ） is highly expressed in lung cancer, colon cancer, and gastric cancer, as well as other tumors.
OBJECTIVE： To study expression of PPAR γ in pituitary adenomas and analyze the role of PPAR γ in hormonal typing of pituitary adenomas.
DESIGN, TIME AND SETTING： Semi-quantitative immunohistochemistry of pathological specimens. The experiment was conducted at the Department of Neurosurgery, Wuxi Second Hospital Affiliated to Nanjing Medical University between January 2002 and May 2005.
MATERIALS： Surgical resection samples of pituitary adenomas from 38 cases （18 male and 20 female） were analyzed. Eight cases were determined to be invasive pituitary adenomas and 30 cases were non-invasive pituitary adenomas. Hormonal classification of the types of pituitary adenomas revealed somatotrophic adenomas in six cases, corticotrophic adenoma in five cases, prolactinomas in 13 cases, multi-hormone secreting adenomas in six cases, and eight cases of adenoma without altered endocrine function. Five autopsy specimens were collected during the same period from patients of matching age that died from unrelated diseases and were included as normal anterior pituitar3, controls.
METHODS： Cell counts for positive immunohistochemical signals were recorded from histopathological sections. The percentage of positive cells was reported as a semi-quantitative analysis.
MAIN OUTCOME MEASURES： The rate of PPAR γ positive cells in different types of adenoma was based on hormonal levels and invasiveness of pituitary tumor cells.
RESULTS： All tumor biopsies were determined to express PPAR γ. The rate of PPAR γ -positive cells ranged between 8%-65% in the pituitary adenomas. According to hormonal type, PPAR γ expression did not vary between the groups. In addition, there was no significant difference in PPAR γ expression between the non-invasive and invasive pituitary adenomas.
CONCLUSIONS： Human pituitary adenom     

垂体泌乳素腺瘤垂体特异转录因子表达的实验研究

目的研究垂体特异转录因子pit-1与PRL水平、肿瘤侵袭性的关系,探讨Pit-1在垂体瘤发病机制中的作用。方法免疫组化和RT—PCR分别测定Pit-1蛋白和pit—1 mRNA的表达,分析Pit-1与肿瘤侵袭性的关系。结果与对照组相比,Pit-1在PRL腺瘤中均有高表达,Pit-1、pit-1 mRNA表达与PRL水平呈正相关并与肿瘤侵袭性相关。结论Pit-1及pit-1 mRNA的表达在垂体PRL腺瘤发病机制中发挥一定作用。     

利用全基因组芯片初步筛选亚类垂体腺瘤特异性相关基因

目的 探讨人类垂体腺瘤发生、发展中相关基因的表达与功能.方法 应用人全基因组寡核苷酸芯片HG-U133A2.0检测8例垂体腺瘤组织(生长激素腺瘤、泌乳素腺瘤、促性腺激素腺瘤以及裸细胞激素腺瘤各2例)和2例混合的正常垂体组织的基因表达谱.差异表达基因进行筛选和生物信息学分析.芯片结果予以qRT-PCR验证.结果与正常对照组比较,与垂体腺瘤发生关联的基因功能上主要涉及分子结合、凋亡或肿瘤相关、代谢、信号传导、细胞周期、物质运输等多个牛物过程.数个差异基因的表达特异性与亚类腺瘤的发展相关.结论 垂体腺瘤的发生、发展是一多基因、多分子、多通路的网络调控过程.但对于各亚类腺瘤,其分子机制不尽相同.     

利用全基因组芯片初步筛选亚类垂体腺瘤特异性相关基因

目的 探讨人类垂体腺瘤发生、发展中相关基因的表达与功能.方法 应用人全基因组寡核苷酸芯片HG-U133A2.0检测8例垂体腺瘤组织(生长激素腺瘤、泌乳素腺瘤、促性腺激素腺瘤以及裸细胞激素腺瘤各2例)和2例混合的正常垂体组织的基因表达谱.差异表达基因进行筛选和生物信息学分析.芯片结果予以qRT-PCR验证.结果与正常对照组比较,与垂体腺瘤发生关联的基因功能上主要涉及分子结合、凋亡或肿瘤相关、代谢、信号传导、细胞周期、物质运输等多个牛物过程.数个差异基因的表达特异性与亚类腺瘤的发展相关.结论 垂体腺瘤的发生、发展是一多基因、多分子、多通路的网络调控过程.但对于各亚类腺瘤,其分子机制不尽相同.