1型多发性内分泌腺肿瘤综合征Men1基因变异

1型多发性内分泌瘤综合征（multiple endocrine neoplasia type1,MEN1）是一种主要以累及甲状旁腺、胰岛细胞和垂体的家族性常染色体显性遗传性肿瘤疾病,其致病基因是Men1的基因突变。目前在MEN1患者中发现了大量Men1基因突变位点,其中9个位点突变频率较高,占据所有胚系细胞突变的20％,同时,MEN1患者中还存在Men1基因大片段的外显子缺失,具有外显率高和临床表现多样化的特点,与1型多发性内分泌瘤以及零散型内分泌肿瘤都可能相关。因此,在部分疑似MEN1患者中开展Men1基因变异分析可辅助确诊,在Men1基因突变携带者及其家属中开展Men1变异筛选将有助于对MEN1发生做好提前预防和治疗。     

INSM1在神经内分泌系统和胰腺发育中的调控作用

INSMl(Insulinoma associated-1,IA-1)是一类含有锌指结构的转录因子。INSM1在小鼠胚胎神经内分泌细胞和胰岛细胞发育中发挥关键作用。INSM1在许多神经内分泌肿瘤中有异常高表达。深入理解INSM1在神经内分泌细胞和胰岛发育中的分子机制将有助于研究神经内分泌发育、肿瘤等相关疾病的治疗措施。为此,我们就近年来INSM1的研究进展作一综述。     

硬脊膜内外多发性神经鞘膜瘤7例诊治分析

目的:回顾分析硬脊膜内外多发性的神经鞘膜瘤的手术治疗疗效及注意事项.方法:我院2001-2011年间脊柱病区收治的椎管内肿瘤患者中,共发现7例硬脊膜内外多发性的神经鞘膜瘤.肿瘤发生部位:胸段3例,腰段2例,2例为胸段肿瘤位于硬膜内,腰段肿瘤位于硬膜外呈哑铃型向椎管外生长.临床表现为隐袭性、进行性双下肢麻木、无力、僵硬和不灵活,行走不稳等症状.治疗方法:全部手术肿瘤摘除,5例一期行硬膜内外同时摘除肿瘤,2例不同节段的肿瘤采取分期手术.结果:全部病例经1-9年随访,肿瘤未见复发.病理报告:均为神经鞘膜瘤.结论:临床上硬脊膜内外多发性的神经鞘膜瘤较少见,容易漏诊漏治.术前应注意详细查体,仔细阅片,术中注意切除硬膜外的肿瘤后,观察硬膜有无异常表现,手术是治疗该病的有效方法.     

功能性胰岛细胞瘤的CT和MR定位

功能性胰岛细胞瘤是一种少见的肿瘤。诊断主要依靠激素水平的监测,影像学检查的目的主要为肿瘤的定位。近年来,随着CT,MR和超声等技术的发展,胰岛细胞瘤的早期定位诊断已有明显提高,复习近年来有关文献,评价MRI、CT在胰岛细胞瘤定位中的价值。 一、病理基础 胰岛细胞瘤按其有无分泌激素的功能分为功能性和无功能性胰岛细胞瘤。功能性胰岛细胞瘤约占85％。功能性胰岛细胞瘤根据其来源不同及分泌激素的不同可分为:胰岛素瘤,胰高糖素瘤,生长抑素瘤和胰多肽瘤等,它们分别来源于胰岛的B细胞,A细胞,D细胞和PP细     

生长抑素受体介导的肿瘤靶向治疗

许多肿瘤,如神经内分泌肿瘤、甲状腺癌、乳腺癌等能高表达生长抑素受体,从而为生长抑素及其类似物的治疗提供了靶点。生长抑素受体介导的肿瘤靶向治疗主要包括放射性核素治疗、放射导向手术治疗、细胞毒素治疗和溶瘤病毒治疗。目前,生长抑素受体介导的放射性核素治疗已应用于神经内分泌肿瘤,尤其在胃肠胰神经内分泌肿瘤的诊断和治疗中占据重要地位。另外,生长抑素受体介导的放射导向手术治疗、细胞毒素治疗和溶瘤病毒治疗的潜在价值也越来越引起研究者们的重视。本文通过查阅近五年来关于生长抑素受体介导的肿瘤靶向治疗的国内外文献,综述了生长抑素受体介导的肿瘤靶向治疗的最新研究进展。     

慢性复合应激对大鼠胰腺HAP1表达的影响

目的探讨慢性复合应激大鼠胰腺内胰岛内分泌细胞HAP1表达的变化及其意义。方法36只大鼠随机分为两组:慢性复合应激组和正常对照组。应激组动物无规律交替暴露于垂直旋转、睡眠剥夺、捆绑(6h/d)和夜间光照等慢性复合性应激,共6周;实验结束后,采用免疫组织化学和Western-blot等方法检测两组大鼠胰腺胰岛内分泌细胞内HAP1蛋白表达的变化。结果HAP1在大鼠胰腺内选择性表达于胰岛内分泌细胞中。与对照组相比,慢性复合应激组大鼠胰腺HAP1的表达明显增强(P<0.05)。结论6周慢性复合性应激可使大鼠胰腺中胰岛内分泌细胞的HAP1表达加强,提示HAP-1在慢性复合应激促进胰腺内分泌功能中可能发挥一定作用。     

多发性软骨瘤术后复发的治疗及护理措施

骨软骨瘤又名外生骨疣,也属软骨肿瘤,最为常见有单发性及多发性两种。单发性多见,多发性较少见,常合并骨骼发育异常。骨软骨瘤由纤维组织包膜、软骨帽和骨性基底构成。少数的单发性骨软骨瘤可恶变,但多发性骨软骨瘤发生恶变的几率却很高,若肿瘤过大,生长较快,或影响功能,应考虑作切除术,切除范围应较广,包括肿瘤基底四周部分正常骨组织,以免遗漏,引起复发。     

内分泌腺疾病(摘登)

胰岛素与糖尿病胰腺包括两类组织:一是分泌消化液,由管道通入十二指肠腔,属外分泌腺.二是胰腺中有许多内分泌细胞,聚集成细胞群,形成小岛,叫做胰岛,总数1—2百万个,总重量约1克,占胰重的1—2％.胰岛集中在胰头部分,包括四种不同的细胞:α细胞占20％,分泌胰高血糖素(glucagon);β细胞较α细胞小,占75％,分泌胰岛素(insulin);δ细胞占5％,可能分泌胃泌素(gastrin),生理作用尚不明;γ细胞,人、猴、兔的胰岛有之.α、β两种细胞相互靠近,只隔一狭小的空隙,α细胞所分泌的胰高血糖素可迅速作用于β细胞而促使胰岛素的分泌. 胰岛素是一种可溶性蛋白质激素,分子量5,743,等电点5.35. 胰岛素的分泌主要受血糖浓度的调节.当血糖浓度升高时,直接使β细胞分泌的胰岛素增加.因为胰岛邻近有丰富的血管,每个胰岛细胞几乎都和毛细血管直接接触;胰岛及其邻近血管均富于神经支配,交感神经与副交感神经纤维进入胰岛后直接终止于胰岛细胞.此外,中枢神经系统可通过迷走神经促进胰岛素的分泌.     

膀胱平滑肌瘤合并子宫多发性平滑肌瘤一例报道并文献复习

目的对一例膀胱平滑肌瘤合并子宫多发性平滑肌瘤患者诊疗进行回顾性分析。方法回顾分析一例膀胱平滑肌瘤合并子宫多发性平滑肌瘤患者临床资料,并结合相关文献进行复习。结果膀胱平滑肌瘤行局部切除,子宫多发性平滑肌瘤行全子宫切除,术后随访5年,未见肿瘤复发、恶变、侵袭转移及盆腔其他并发症。结论膀胱平滑肌瘤是一种少见的良性肿瘤,术前诊断主要依赖彩超、CT等影像学检查。手术探查能明确肿瘤部位,确诊依赖病理。手术治疗为主,预后良好。     

大鼠胰岛甲硫氨酸脑啡肽免疫细胞化学的阳性显示

本实验用免疫细胞化学PAP法和尚度敏感的免疫金银法,对大鼠胰腺石蜡切片,用相邻切片比较法,进行免疫细胞化学反应,发现在大鼠胰岛A细胞内,呈现出甲硫氨酸脑啡肽的阳性免疫反应。根据文献报道,胰岛内分泌细胞十还有几种其它的调节肽类的物质存在,可以推测,胰岛内分泌功能受较复杂的神经体液(包括旁分泌和自分泌)调节机制的影响。文中对甲硫氨酸脑啡肽与其它神经肽类物质在胰岛A细胞中共存的意义也进行了讨论。     

Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1

Multiple endocrine neoplasia type 1 (MEN1) is a rare but informative syndrome for endocrine tumorigenesis. Since its isolation, several groups have begun to determine the role of menin, the protein product of MEN1, in sporadic endocrine tumors as well as tumors of the MEN1 syndrome. Mutations of menin have been reported in more than 400 families and tumors, most of which are truncating mutations, thus supporting the function of menin as a tumor suppressor. The exact function of menin is unknown, but overexpression of menin inhibits proliferation of Ras-transformed NIH3T3 cells. Since menin interacts with proteins from both the TGF beta and AP-1 signaling pathways, perhaps its tumor suppressor function is related to these key cell growth pathways. In this review we will discuss the various clinical manifestations of MEN1 syndrome, potential mechanisms of MEN1 tumorigenesis, and mutations associated with MEN and sporadic endocrine tumors.     

Diagnostic and therapeutic difficulties in MEN 1 syndrome

MEN 1 syndrome (Multiple Endocrine Neoplasia type 1) is a rare endocrine disorder characterized by the association of tumors in several endocrine glands, mainly in parathyroids, gut and pituitary. At our institution in the years 1982-2004 we have followed 26 patients with MEN 1 syndrome belonging to 19 families. The diagnosis of MEN 1 was based on Gubbio Consensus (JCEM 86: 5658-5671, 2001). Mean age at the diagnosis of MEN 1 was 35 years. Primary hyperparathyroidism was the most frequent pathology, which was diagnosed in 25 of 26 patients (96%). Gut endocrine tumors were found in 20 patients (77%), while pituitary tumors in 18 (70%). Non-functioning gut tumors were most frequent (n=9), followed by insulinoma (n=7) and gastrinoma (n=4). Prolactinoma was the most frequent pituitary tumor found in 12 patients (67%). Three patients died during the observation period - all of them of generalized gut endocrine tumor (gastrinoma in 2 cases and foregut carcinoid in one case). The management of MEN 1 is not easy and careful analysis of clinical picture is necessary in each individual case. Several important observations can be made on the basis of own experience and the literature: 1. In each sporadic pathology, which may be a part of MEN 1, one should consider. the possibility of MEN 1. The individual MEN 1 abnormalities are often diagnosed after 40 and later 2. MEN 1 tumor are usually multiple thus necessitating a different therapeutic approach (more radical surgery) 3. The most valuable screening tests are: Ca++, PP, CgA and prolactin 4. Endoscopic ultrasound is the most specific method for the localization of pancreatic endocrine tumors. 5. The results of surgical treatment of MEN 1 tumors are worse than that of sporadic tumors. 6. Prognosis in MEN 1 is determined by the behaviour of gut neuroendocrine tumor 7. No genotype/phenotype correlation in MEN 1 syndrome was found so far. In summary, it should be underlined that MEN 1 syndrome is an endocrine disorder, in which early diagnosis and optimal treatment may significantly improve the prognosis.     

Menin, a gene product responsible for multiple endocrine neoplasia type 1, interacts with the putative tumor metastasis suppressor nm23

Although the gene responsible for multiple endocrine neoplasia type 1 (MEN1) has been identified, the function of its gene product, menin, is unknown. To examine the biological role of the MEN1 gene, we searched for associated proteins with a yeast two-hybrid system using the MEN1 cDNA fragment as bait. On screening a rat fetal brain embryonic day 17 library, in which a high level of MEN1 expression was detected, we identified a putative tumor metastasis suppressor nm23/nucleoside diphosphate (NDP) kinase as an associated protein. This finding was confirmed by in vitro interaction assays based on glutathione S-transferase pull down experiments. The association required almost the entire menin protein, and several missense MEN1 mutations reported in MEN1 patients caused a loss of the binding activity for nm23. This result suggests that this interaction may play important roles in the biological functions of the menin protein, including tumor suppressor activity.     

Exclusion of the phosphatidylinositol-specific phospholipase C β3 (PLC β3) gene as candidate for the multiple endocrine neoplasia type 1 (MEN 1) gene

Multiple endocrine neoplasia type 1 (MEN 1) is inherited as an autosomal dominant disorder, characterized by hyperplasia and neoplasia in several endocrine organs. The MEN 1 gene, which is most probably a tumor suppressor gene, has been localized to a 900-kb region on chromosome 11q13. The human phosphatidylinositol-specific phospholipase C β3 (PLC β3) gene, which is located within this region, was considered to be a good candidate for the MEN 1 gene. In this study, the structure and expression of the PLC β3 gene in MEN 1 patients were investigated in more detail, to determine its potential role in MEN 1 tumorigenesis. Southern blot analysis, using blood and tumor DNA from affected persons from seven different MEN 1 families, did not reveal structural abnormalities in the PLC β3 gene. To detect possible point mutations, or other small structural aberrations, direct sequencing of PLC β3 cDNAs from two affected persons from two different MEN 1 families was performed, but no MEN 1-specific abnormalities were revealed. Several common nucleotide sequence polymorphisms were detected in these cDNAs, proving that both alleles of the PLC β3 gene were expressed and analyzed. In conclusion, these results exclude the PLC β3 gene as a candidate gene for MEN 1. Received: 20 March 1996     

Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by the occurrence of multiple endocrine tumors of the parathyroid, pancreas, and anterior pituitary in patients. To study tumorigenesis related to the MEN1 syndrome, we have generated Men1 knockout mice using the gene targeting approach. Heterozygous Men1 mutant mice developed the same range of major endocrine tumors as is seen in MEN1 patients, affecting the parathyroid, pancreatic islets, pituitary and adrenal glands, as well as the thyroid, and exhibiting multistage tumor progression with metastatic potential. In particular, extrapancreatic gastrinoma, pancreatic glucagonoma, and mixed hormone-producing tumors in islets were observed. In addition, there was a high incidence of gonadal tumors of endocrine origin, i.e. Leydig cell tumors, and ovary sex-cord stromal cell tumors in heterozygous Men1 mutant mice. Hormonal disturbance, such as abnormal PTH and insulin levels, was also observed in these mice. These tumors were associated with loss of heterozygosity of the wild-type Men1 allele, suggesting that menin is involved in suppressing the development of these endocrine tumors. All of these features are reminiscent of MEN1 symptoms in humans and establish heterozygous Men1 mutant mice as a suitable model for this disease.     

Exclusion of the phosphoinositide-specific phospholipase Cβ3 (PLCB3) gene as a candidate for multiple endocrine neoplasia type 1

The predisposing genetic defect in multiple endocrine neoplasia type 1 has been assigned to chromosomal region 11q13. Our previous attempts to identify the MEN1 gene have resulted in the isolation of the phospholipase Cβ3 gene from the actual region. PLCB3 plays an important role in signal transduction and, moreover, shows loss of expression in some endocrine tumors, in accordance with a putative tumor suppressor gene function, and thus appears to be an excellent candidate for MEN1. We have therefore undertaken screening for constitutional mutations in individuals from MEN1 families. Several sequence alterations have been discovered, none of them however fulfilling the criteria for a disease-related mutation. We can now exclude PLCB3 from candidacy as the MEN1 gene. Received: 24 July 1996 / Revised: 16 August 1996