p21 and p27 immunoexpression in gastric well differentiated endocrine tumors （ECL-cell carcinoids）

INTRODUCTION Carcinoid tumors arise from proliferating enter- ochromaffin-like cells (ECL) of fundus. Elevated plasma gastrin levels are responsible of the neoplastic changes in these cells, but neoplastic transformation can also be observed in absence of…     

Gastrin and Colon Cancer

The classical peptide hormone gastrin was identified originally as a stimulant of gastric acid secretion, but is now known to also act as a growth factor for the gastrointestinal mucosa. In an earlier review the existing evidence that gastrin and related peptides act as growth factors for the normal colonic mucosa and for colorectal carcinomas was summarised. In this review I will highlight some recent developments in the field.     

Effect of environmental hyperthermia on gastrin,somatostatin and motilin in rat ulcerated antral mucosa

AIM:TO study the effect of environmental hyperthermiaon gastrin,somatostatin and motilin in rat ulcerated antralmucosa.METHODS:Forty-two Wistar rats were equally divided intosix groups,according to the room temperature(high andnormal)and the treatment(acetic acid,normal saline andno treatment).Levels of gastrin,somatostatin and motilinin rat ulcerated antral mucosa were measured with aradioimmunoassay method.RESULTS:The average temperature and humidity were32.5℃ and 66.7% for the high temperature group,and21.1℃ and 49.3% for the normal temperature group,respectively.Gastric ulcer model was successfully inducedin rat injected with 0.05 mL acetic acid into the antrum.Inrats with gastric ulcers,the levels of gastrin and motilinincreased,whereas the somatostatin level declined in antralmucosa,compared with those in rats treated with normalsaline and the controls.However,the change extent in thelevels of gastrin,motilin and somatostatin in antral mucosawas less in the high temperature group than in the normaltemperature group.CONCLUSION:The levels of gastrin,somatostatin andmotilin in rat ulcerated antral mucosal tissue remain relativelystable in a high temperature environment,which may relateto the equilibration of the dynamic system.     

光学相干断层成像评价植入不同药物洗脱支架后的血管愈合情况

目的应用光学相干断层成像（OCT）比较急性心肌梗死（AMI）患者植入不同药物洗脱支架（DES）后的新生内膜覆盖和支架贴壁情况以评估血管愈合。方法 49例AMI患者植入不同DES后9个月时进行OCT检查。其中20个雷帕霉素药物洗脱支架（SES,Cypher）,12个紫杉醇药物洗脱支架（PES,Taxus）和17个雷帕霉素衍生物药物洗脱支架（ZES,Endeavor）。每隔1mm评估OCT横断面影像每个支架柱的新生内膜覆盖和贴壁情况,同时观察每个支架内的血栓发生情况。结果总计对12378个支架柱进行了分析。SES的新生内膜增生最少,新生内膜厚度：SES（77±60）μm、PES（153±82）μm、ZES（265±130）μm,且新生内膜增生面积百分比最低,SES（10±8）%、PES（19±8）%、ZES（28±9）%,但SES和PES有更多未被新生内膜覆盖的支架柱,SES（15.1±16）%、PES（7.1±10）%、ZES（0.6±1.5）%,且贴壁不良支架柱的发生率也高于ZES,SES（3.8±7.2）%、PES（2.1±4.4）%、ZES（0±0）%,而有完全新生内膜覆盖的支架比例以ZES为高,SES5%、PES33.3%、ZES82.4%。血栓的发生率SES和PES高于ZES,SES34%、PES33%、ZES6%。结论 AMI患者植入不同类型DES后,其支架的新生内膜覆盖程度和贴壁不良的发生率是显著不同的,因此DES的类型可能影响了AMI血栓性病变的血管愈合过程。     

卓—艾综合征诊断和治疗的研究现状

传统观念认为治疗卓－艾综合征（ZES）应用全胃切除术,以消除过量胃泌素作用的靶器官,近年随着选择性动脉造影及超声内错检查等影响像学技术的发展,ZES术前位诊断的阳性率越来越高,其治疗已倾向于以局限性肿瘤的根治性切除为目标,这对ZES的定性,定位诊断有了更高的要求,也为治疗提供了新思路,本文就ZES诊断和治疗的研究现状作一综述。     

Pharmacodynamic and kinetic effect of rabeprazole on serum gastrin level in relation to CYP2C19 polymorphism in Chinese Hans

AIM: To observe the pharmacokinetics and pharmaco-dynamics of rabeprazole and compare serum gastrin concentrations in different CYP2C19 genotype groups. METHODS: The CYP2C19 genotype status of Chinese Han healthy volunteers was determined by polymerase chain reaction-restriction fragment length polymorphism method. Twenty H pylori-negative healthy subjects voluntary participated in the study. They were divided into the following three groups: homozygous extensive metabolizers (homEM), heterozygous extensive metabolizers (hetEM) and poor metabolizers (PM). After they orally received rabeprazole 20 mg once daily in the morning of d 1 and d 8, blood samples were collected at various time-points until 24 h after administration and intragastric pH values were monitored for 24 h by Digitrapper pH. Serum gastrin concentrations were measured by radioimmunoassay. Serum concentrations of rabeprazole were measured by high performance liquid chromatography. RESULTS: The mean AUC values for rabeprazole after a single and repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM, or the hetEM and PM groups. No significant differences in intragastric pH medians were observed among the three different genotype groups after a single dose or repeated doses. The ratio of pH medians between d 1 and d 8 ranged from 84% to 108%. The mean gastrin AUC values were also different among the three genotype groups, with a relative ratio of 1.0, 1.2 and 1.5 after a single dose and 1.0, 1.5 and 1.6 after repeated doses in the homEM, hetEM and PM groups, respectively. The gastrin AUC values among the three different genotype groups showed no significant difference either after a single dose or repeated doses. The subject who had lower intragastric acidity showed higher serum gastrin levels and concentrations of rabeprazole. CONCLUSION: In Chinese Han healthy people, the pharmacokinetics of rabeprazole are dependent on the CYP2C19 genotype status, but acid-inhibitory efficacy of rabeprazole and the gastrin level are not influenced significantly.     

甲氰咪胍治疗Zallinger-Ellison综合征病人的药物动力学研究

组胺H_2受体拮抗剂治疗Zollinger-Ellison综合征(ZES)常获得满意效果,大多数病人需大剂量才能有效地抑制胃酸过度分泌。本文报道9名ZES患者和5名健康志愿者(对照组)应用甲氰咪胍后药物动力学研究的结果。研究对象:9名ZES患者每天需2.4 g以上的     

Mechanisms for regulation of gastrin and somatostatin release from isolated rat stomach during gastric distention

AIM: To investigate the intragastric mechanisms forregulation of gastric neuroendocrine functions during gastricdistention in isolated vascularly perfused rat stomach.METHODS: Isolated vascularly perfused rat stomach wasprepared, then the gastric lumen was distended with either5,10 or 15 ml pH7 isotonic saline during a period of 20 min.During the distention, the axonal blocker tetrodotoxin (TTX),the cholinergic antagonist atropine, or the putativesomatostatin-antagonist cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] were applied by vascular perfusion. Thereleases of gastrin and somatostatin were then examinedby radioimmunoassay.RESULTS: The graded gastricdistention caused a significantvolume-dependent decrease in gastrin secretion [-183±75 (5ml), -385±86 (10 ml) and -440±85 (15 ml) pg/20 min] and asignificant increase of somatostatin secretion [260±102 (5 ml),608±148 (10 ml) and 943±316 (15 ml) pg/20 min]. In responseto 10 ml distention, the infusion of either axonal blocker TTX(10-6 M) or cholinergic blocker atropine (10-7 M) had a similaraffect. They both attenuated the decrease of gastrin releaseby approximately 50 %, and attenuated the increase ofsomatostatin release by approximately 40 %. The infusion ofsomatostatin-antagonist cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr (Bzl)] (10-6M) attenuated the decrease of gastrin releaseby about 60 %. Furthermore, combined infusion of thesomatostatin-antagonist and atropine completely abolisheddistention-induced inhibition of gastrin release.CONCLUSION: The present data suggest that distention ofisolated rat stomach stimulates somatostatin release viacholinergic and non-cholinergic TTX-insensitive pathways. Bothsomatostatin and intrinsic cholinergic pathways are responsiblefor distention-induced inhibition of gastrin release.     

光学相干断层成像比较猪冠状动脉西罗莫司洗脱支架与佐他莫司洗脱支架置入后早期新生内膜覆盖情况

目的应用光学相干断层成像(OCT)比较西罗莫司洗脱支架(SES)与佐他莫司洗脱支架(ZES)置入后1月内新生内膜覆盖情况。方法 18只中华小型猪平均分为3组,每只猪分别在前降支和右冠状动脉随机置入SES和ZES支架各一枚,3组实验动物分别在第7天、14天、28天进行OCT检查,测量新生内膜厚度、支架内面积、管腔内面积、新生内膜面积、面积狭窄百分比和新生内膜覆盖率,比较ZES与SES置入后1月内新生内膜覆盖情况。结果 OCT测量结果显示,支架置入7天和14天时,ZES与SES两种支架丝表面新生内膜厚度和新生内膜覆盖率均存在显著统计学差异(P<0.001)。同样支架术后28天时ZES与SES支架丝表面新生内膜厚度存在显著统计学差异(244.3±282.3μmvs136.3±91.1μm,P<0.001),新生内膜覆盖率存在显著差异(94.88%±2.93%vs90.96%±4.35%,P=0.008)。结论在支架置入后1个月内,ZES与SES比较新生内膜增生更显著,支架丝表面新生内膜覆盖率更高。     

Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity

Somatostatin-producing neuroendocrine tumors (SOM-NETs) of the duodenum and pancreas appear to be heterogeneous. To determine their clinicopathological profiles, respective data were analyzed on a series of 82 duodenal and 541 pancreatic NETs. In addition, the clinical records of 821 patients with duodenal or pancreatic NETs were reviewed for evidence of a somatostatinoma syndrome. Predominant or exclusive expression of somatostatin was found in 21 (26%) duodenal and 21 (4%) pancreatic NETs. They were classified as sporadic (n=31) or neurofibromatosis type 1 (NF1)-associated duodenal NETs (n=3), gangliocytic paragangliomas (GCPGs; n=6), or poorly differentiated neuroendocrine carcinomas (pdNECs; n=2). In addition, five duodenal and four pancreatic SOM-NETs were found in five patients with multiple endocrine neoplasia type 1 (MEN1). Metastases occurred in 13 (43%) patients with sporadic or NF1-associated SOM-NETs, but in none of the duodenal or pancreatic MEN1-associated SOM-NETs or GCPGs. Sporadic advanced (stage IV) SOM-NETs were more commonly detected in the pancreas than in the duodenum. None of the patients (including the 821 patients for whom only the clinical records were reviewed) fulfilled the criteria of a somatostatinoma syndrome. Our data show that somatostatin expression is not only seen in sporadic NETs but may also occur in GCPGs, pdNECs, and hereditary NETs. Surgical treatment is effective in most duodenal and many pancreatic SOM-NETs. MEN1-associated SOM-NETs and GCPGs follow a benign course, while somatostatin-producing pdNECs are aggressive neoplasms. The occurrence of the so-called somatostatinoma syndrome appears to be extremely uncommon.     

Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions

BACKGROUND: Patients with a multiple endocrine neoplasia type 1 (MEN1)-associated Zollinger-Ellison syndrome (ZES) show multifocal duodenal gastrinomas and precursor lesions. AIMS: To test these lesions for loss of heterozygosity (LOH) of the MEN1 gene locus on chromosome 11q13, and to investigate whether the MEN1-related endocrine cell changes also involved somatostatin cells. MATERIAL AND METHODS: Tissue specimens from six patients with MEN1 and ZES were analysed by immunohistochemistry and immunofluorescence. LOH analysis was performed by fluorescence in situ hybridisation (FISH), using probes containing the MEN1 gene locus and the centromere 11 (C11) region. For simultaneous analysis of hormones and allelic deletions, a combined FISH/immunofluorescence protocol was established. RESULTS: 28 of a total of 33 duodenal neuroendocrine tumours (NETs) were gastrin-producing tumours; 13/28 (46.4%) revealed LOH on 11q13 and/or C11. Five of the NETs were somatostatin-expressing tumours, two revealing LOH. Allelic loss was detected in tumours as small as 300 microm (gastrin) and 400 microm (somatostatin) in diameter. The gastrin-producing tumours showed different deletion/retention patterns. Hyperplastic somatostatin cell lesions, similar to those of the gastrin cells, were present in all patients. The hyperplastic lesions of both cell lines consistently retained both 11q13 alleles. CONCLUSIONS: Allelic deletion of the MEN1 gene may reflect a pivotal event in the development of multifocal gastrin and somatostatin cell neoplasms in the duodenum of patients with MEN1. The observation of distinct deletion patterns in small synchronous tumours supports the concept that each gastrin-producing tumour in an individual MEN1 patient arises from an independent cell clone.     

Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome

AIM:To describe our patients affected with ectopic biliary tree gastrinoma and review the literature on this topic.METHODS:Between January 1992 and June 2012,28 patients affected by duodenopancreatic endocrine tumors in multiple endocrine neoplasia type 1(MEN1)syndrome underwent surgery at our institution.This retrospective review article analyzes our experience regarding seventeen of these patients subjected to duodenopancreatic surgery for Zollinger-Ellison syndrome(ZES).Surgical treatment consisted of duodenopancreatectomy(DP)or total pancreatectomy(TP).Regional lymphadenectomy was always performed.Any hepatic tumoral lesions found were removed during surgery.In MEN1 patients,removal of duodenal lesions can sometimes lead to persistence or recurrence of hypergastrinemia.One possible explanation for this unfavorable outcome could be unrecognized ectopic localization of gastrin-secreting tumors.This study described three cases among the seventeen patients who were found to have an ectopic gastrinoma located in the biliary tree.RESULTS:Seventeen MEN1 patients affected with ZES were analyzed.The mean age was 40 years.Fifteen patients underwent DP and two TP.On histopathological examination,duodeno pancreatic endocrine tumors were found in all 17 patients.Eighty-one gastrinomas were detected in the first three portions of the duodenum.Only one gastrinoma was found in the pancreas.The mean number of gastrinomas per patient was 5(range 1-16).Malignancy was established in 12 patients(70.5%)after lymph node,liver and omental metastases were found.Three patients exhibited biliary tree gastrinomas as well as duodenal gastrinoma(s).In two cases,the ectopic gastrinoma was removed at the same time as pancreatic surgery,while in the third case,the biliary tree gastrinoma was resected one year after DP because of recurrence of ZES.CONCLUSION:These findings suggest the importance of checking for the presence of ectopic gastrinomas in the biliary tree in MEN1 patients undergoing ZES surgery.     

Recent standardization of treatment strategy for pancreatic neuroendocrine tumors

Recent advances in localization techniques,such as the selective arterial secretagogue injection test(SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors(PNET).For patients with sporadic functioning PNET,curative resection surgery has been established by localization with the SASI test using secretin or calcium.For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1(MEN 1) which are usually multiple and sometimes numerous,resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test.As resection surgery of PNET has increased,several important pathological features of PNET have been revealed.For example,in patients with Zollinger-Ellison syndrome(ZES),duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma,and in patients with MEN 1 and ZES,gastrinomas have been located mostly in the duodenum,and pancreatic gastrinoma has been found to co-exist in 13% of patients.Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation.The most important prognos-tic factor in patients with PNET is the development of hepatic metastases.The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit.The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed.     

The surgical management of hyperparathyroidism and endocrine disease of the pancreas in the multiple endocrine neoplasia type 1 patient

Abstract. The surgical management of multiple endocrine neoplasia type 1 (MEN1) parathyroid disease and involvement of the endocrine pancreas remains controversial. Hyperparathyroidism, usually the first clinical manifestation of the syndrome, requires surgical treatment in nearly all patients. We favour a subtotal parathyroidectomy and cervical thymectomy rather than a total parathyroidectomy and autotransplant because of good long-term results and the absence of permanent hypoparathyroidism. The results of treating 34 MEN1 patients during a 20-year period are reported. The most common functional pancreatic or duodenal tumours in MEN1 patients are gastrinomas and insulinomas. In addition to the management of functional syndromes, another major concern is the malignant potential of the neuroendocrine tumours that frequently develop. Our surgical management of gastrinomas and the ZES has evolved over a period of 15 years. We have found that distal pancreatectomy, enucleation of any neoplasms in the head, and duodenotomy and excision of any neuroendocrine tumours (gastrinomas) combined with a regional node dissection are effective in the majority of patients. The results of treating 21 MEN1 patients with ZES are reported.     

Surgery and prognosis of duodenal gastrinoma as a duodenal neuroendocrine tumor

It has become increasingly clear that duodenal gastrinomas are the most common cause of Zollinger-Ellison syndrome (ZES). However, attempts to find these tumors before and during surgery for ZES have had limited success until duodenotomy (opening the duodenum) was described. The routine use of duodenotomy in patients with non-familial gastrinoma increases the number of duodenal tumors found, and the immediate and long-term cure-rate. The increase in cure-rate appears to be secondary to increased detection of small, previously undetectable duodenal gastrinomas. Duodenotomy detects small tumors (<1 cm) in the proximal duodenum. It does not detect more duodenal gastrinomas per patient, nor does it detect tumors in unusual duodenal locations. Duodenotomy decreases the death-rate associated with these tumors. However, it has not affected the rate of development of liver metastases. Duodenotomy is a critical method to find duodenal gastrinomas. It should be routinely performed in all surgery to find and remove gastrinoma for cure of ZES.     

Diagnostic and therapeutic criteria in patients with Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1

: Mignon M, Cadiot G (Bichat and Claude Bernard Hospital, Paris, France). Diagnostic and therapeutic criteria in patients with Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 489–94. About 25% of patients with ZES have MEN-1. Except for diarrhoea, less frequent in patients with ZES MEN-1 than in sporadic ZES, and specific MEN-1-related signs, clinical characteristics are similar in both ZES types. Acid output and gastrin level are also similar whether in the basal state or after secretin. Primary hyperparathyroidism (pHPT) exists in the majority of ZES MEN-1 patients, 30% have pituitary adenoma (prolactinomas for half), 30% adrenal involvement, 25–30% have ECLomas: bronchial and thymic carcinoids have probably been underevaluated. Gastrinomas are multiple predominantly located in the duodenal wall, but also in the pancreas in association with clinically silent endocrine tumours. The spread of the disease metastases to the liver (LM), mediastinum, bones, is evaluated best by Octreoscan. Associated endoscopic ultrasonography evaluates the number, size and anatomical characteristics of gastrinomas. Patients without LM have an excellent prognosis. Surgery never cures ZES, but is necessary in cases of associated life-threatening conditions such as insulinoma. Although the size of the tumour, when located in the pancreas >3 cm, favours metachronous LM occurrence, surgery in our experience has not been able to prevent LM development.     

Intra-operative secretin test for the rapid evaluation of curative operation in a case of Zollinger-Ellison syndrome

The intra-operative measurements of serum gastrin levels and an intra-operative secretin test were carried out as the rapid evaluation of curative operation in a case of Zollinger-Ellison syndrome (ZES). In this case, pre-operative investigations suggested that the tumours were located in the head of the pancreas and the duodenal wall. The surgeon planned a pan-creato-duodenectomy. Serum gastrin levels were reduced after the resection of the head of the pancreas and duodenum, and the secretin test after resection was negative. The surgeon ensured that gastrinomas were resected completely during the operation. The secretin test carried out 1 month post operatively was also negative. The patient has experienced no further complications, to date. This case suggests that intra-operative secretin test is useful for the rapid evaluation of curative operation in case of ZES.     

Prospective study of the standard meal provocative test in Zollinger-Ellison syndrome

PURPOSE: The purpose of this work was to evaluate the proposed usefulness of a standard meal-stimulated gastrin provocative test in: (1) distinguishing Zollinger-Ellison syndrome (ZES) from antral syndromes; (2) localizing duodenal gastrinomas; or (3) suggesting that patients with multiple endocrine neoplasia type I (MEN-I) may have an increased incidence of antral syndromes. PATIENTS AND METHODS: Seventy-four consecutive patients with ZES referred to the National Institutes of Health were studied prospectively. The extent and location of gastrinomas, acid secretory studies, and the presence or absence of MEN-I were determined and correlated with the results of the gastrin response to standard meal provocative testing. RESULTS: For patients with fasting serum gastrin levels less than 1,000 pg/mL (n = 43), only 44% had a less than 50% increase over the pre-meal value, which is reported to be the typical response in ZES, and 40% had a 50% to 99% increase. Furthermore 16% had a 100% or greater increase, 9% a 150% or greater increase, and 5% a 200% or greater increase, which overlaps with values reported to be characteristic of 98%, 92%, and 46% of patients with antral syndromes. Results did not differ for patients with or without MEN-I, depend on the extent of the gastrinoma (duodenal versus pancreatic gastrinomas), the presence of previous gastric surgery or type of gastric surgery, or for patients with fasting serum gastrin concentrations greater than or equal to 1,000 pg/mL or less than 1,000 pg/mL. studies of four patients before and after resection of the gastrinoma, who prior to surgery had a greater than 100% increase in gastrin secretion after the meal, demonstrated that all patients had a less than 100% increase postoperatively even though no gastric resection was done. CONCLUSIONS: Approximately half of the patients with ZES have a greater than 50% increase in serum gastrin concentration following a standard test meal and one fifth have a 100% or greater increase. Therefore, they cannot be distinguished on this basis from patients with antral syndromes. The increased serum gastrin level after the meal in these patients with ZES appears to be due to the gastrinoma. Furthermore, the current study provides no evidence for the proposals that antral syndromes are more common in patients with MEN-I, that gastric surgery affects the meal response in patients with gastrinomas, or that the meal test is useful in localizing duodenal gastrinomas.     

Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients

AIM: To search for the optimal surgery for gastrinoma and duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. METHODS: Sixteen patients with genetically confirmed multiple endocrine neoplasia type 1 (MEN 1) and Zollinger-Ellison syndrome (ZES) underwent resection of both gastrinomas and duodenopancreatic neuroendocrine tumors (NETs) between 1991 and 2009. For localization of gastrinoma, selective arterial secretagogue injection test (SASI test) with secretin or calc...