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1Management of hilar cholangiocarcinoma in the North of England: Pathology, treatment, and outcome显示文摘AIM: To assess the management and outcome of hilar cholangiocarcinoma (Klatskin tumor) in a single tertiary referral center.METHODS: The notes of all patients with a diagnosis of hilar cholangiocarcinoma referred to our unit for over an 8-year period were identified and retrospectively reviewed. Presentation, management and outcome were assessed.RESULTS: Seventy-five patients were identified. The median age was 64 years (range 34-84 years). Male to female ratio was 1:1. Eighty-nine percent of patients presented with jaundice. Most patients referred were under Bismuth classification 3a, 3b or 4. Seventy patients required biliary drainage, 65 patients required 152percutaneous drainage procedures, and 25 had other complications. Forty-one patients had 51 endoscopic drainage procedures performed (15 failed). Of these,36 subsequently required percutaneous drainage. The median number of drainage procedures for all patients was three, 18 patients underwent resection (24%), nine had major complications and three died post-operatively.The 5-year survival rate was 4.2% for all patients, 21%for resected patients and 0% for those who did not undergo resection (P = 0.0021). The median number of admissions after diagnosis in resected patients was two and three in non-resected patients (P<0.05).Twelve patients had external-beam radiotherapy, seven brachytherapy, and eight chemotherapy. There was no significant benefit in terms of survival (P = 0.46) or hospital admissions.CONCLUSION: Resection increases survival but carries the risk of significant morbidity and mortality.Percutaneous biliary drainage is almost always necessary and endoscopic drainage should be avoided if possible.SD Mansfield O Barakat RM Charnley BC Jaques CB O'Suilleabhain PJ Atherton D Manas 2005World Journal of Gastroenterology2005,11,48:37
2Complications of radiofrequency ablation of hepatic tumors:Frequency and risk factors显示文摘Radiofrequency ablation(RFA)has become an important option in the therapy of primary and secondary hepatic tumors.Surgical resection is still the best treatment option,but only a few of these patients are candidates for surgery:multilobar disease,insufficient liver reserve that will lead to liver failure after resection,extra-hepatic disease,proximity to major bile ducts and vessels,and co-morbidities.RFA has a low mortality and morbidity rate and is considered to be safe.Thus,complications occur and vary widely in the literature.Complications are caused by thermal damage,direct needle injury,infection and the patient’s co-morbidities.Tumor type,type of approach,number of lesions,tumor localization,underlying hepatic disease,the physician’s experience,associated hepatic resection and lesion size have been described as factors significantly associated with complications.The physician in charge should promptly recognize high-risk patients more susceptible to complications,perform a close post procedure follow-up and manage them early and adequately if they occur.We aim to describe complications from RFA of hepatic tumors and their risk factors,as well as a few techniques to avoid them.This way,others can decrease their morbidity rates with better outcomes.Alexandre Zanchenko Fonseca Stephanie Santin Luiz Guilherme Lisboa Gomes Jaques Waisberg Marcelo Augusto Fontenelle Ribeiro Jr. 2014World Journal of Hepatology2014,6,3:24
3Liver-first approach of colorectal cancer with synchronous hepatic metastases: A reverse strategy显示文摘Recently, there has been a change in the strategy of how synchronous colorectal hepatic metastases are attributed to the development of more valuable protocols of chemotherapy and radiotherapy for neoadjuvant treatment of colorectal neoplasms and their hepatic metastases. There is a consensus that patients with synchronous colorectal hepatic metastases have lower survival than those with metachronous colorectal hepatic metastases. Currently, controversy remains concerning the best approach is sequence in a patient with colorectal cancer and synchronous hepatic metastases resection. To obtain a better patient selection, the authors have suggested the initial realization of systemic chemotherapy in the circumstance of patients with colorectal tumor stage Ⅳ, since these patients have a systemic disease. The rationale behind this liver-first strategy is initially the control of synchronous hepatic metastases of colorectal carcinoma, which can optimize a potentially curative hepatic resection and longstanding survival. The liver-first strategy procedure is indicated for patients with colorectal hepatic metastases who require downstaging therapy to make a curative liver resection possible. Thus, the liver-first strategy is considered an option in cases of rectal carcinoma in the early stage and with limited or advanced synchronous colorectal hepatic metastases or in case of patients with asymptomatic colorectal carcinoma, but with extensive liver metastases. Patients undergoing systemic chemotherapy and with progression of neoplastic disease should not undergo hepatic resection, because it does not change the prognosis and may even make it worse. To date, there have been no randomized controlled trials on surgical approach of colorectal synchronous hepatic metastases, despite the relatively high number of available manuscripts on this subject. All of these published studies are observational, usually retrospective, and often non-comparative. The patient selection criteria for the liver-first strategy should be individualized, and the approach of these patients should be performed by a multidisciplinary team so its benefits will be fully realized.Jaques Waisberg Ivan Gregorio Ivankovics 2015World Journal of Hepatology2015,7,11:15
4人骨关节炎软骨细胞的体外培养显示文摘目的:对人骨关节炎软骨细胞的分离、消化和培养进行初步研究,并就其生物学活性同人正常软骨细胞进行比较和评价。方法:以含血清培养液配制的0.05%和0.2%Ⅱ型胶原酶顺序消化关节软骨分离细胞,检测细胞存活率;体外传代培养观察细胞形态、生长、增殖和Ⅱ型胶原、蛋白多糖聚集体等的变化,以及用流式细胞仪检测有或无IL-1β诱导的细胞凋亡和周期变化。结果:①消化后骨关节炎组原代细胞活力平均为82%,少于正常组的95%(P<0.01)。②MTT检测骨关节炎组细胞增殖低于正常组(P<0.01),Ⅱ型胶原免疫组化和甲苯胺蓝O异染反应均较弱,传至第4代软骨细胞生物学特性基本消失。③骨关节炎组细胞凋亡率为6.9%,而正常组为0.5%,IL-1β诱导后凋亡率增加了27.4%,正常组只有12.7%。结论:酶二步消化法具有较高细胞存活率、低污染率和操作简便等特点,分离培养的骨关节炎软骨细胞符合人患骨关节炎时软骨细胞退变的表现,能很好的为骨关节炎细胞水平的研究提供最佳实验对象。秦俊 陈廖斌 汪晖 Magdalou Jaques 2007武汉大学学报(医学版)2007,28,2:9
5Wnt-/-β-catenin pathway signaling in human hepatocellular carcinoma显示文摘The molecular basis of the carcinogenesis of hepatocellular carcinoma(HCC) has not been adequately clarified, which negatively impacts the development of targeted therapy protocols for this overwhelming neoplasia. The aberrant activation of signaling in the HCC is primarily due to the deregulated expression of the components of the Wnt-/-β-catenin. This leads to the activation of β-catenin/T-cell factor-dependent target genes that control cell proliferation, cell cycle, apoptosis, and cell motility. The deregulation of the Wnt pathway is an early event in hepatocarcinogenesis. An aggressive phenotype was associated with HCC, since this pathway is implicated in the proliferation, migration, and invasiveness of cancer cells, regarding the cell's own survival. The disruption of the signaling cascade Wnt-/-β-catenin has shown anticancer properties in HCC's clinical evaluations of therapeutic molecules targeted for blocking the Wnt signaling pathway for the treatment of HCC, and it represents a promising perspective. The key to bringing this strategy in to clinical practice is to identify new molecules that would be effective only in tumor cells with aberrant signaling β-catenin.Jaques Waisberg Gabriela Tognini Saba 2015World Journal of Hepatology2015,7,26:9
6CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment显示文摘Andy Trotti A.Dimitrios Colevas Ann Setser Valerie Rusch David Jaques Volker Budach Corey Langer Barbara Murphy Richard Cumberlin C.Norman Coleman Philip Rubin 2003Seminars in Radiation Oncology2003,,3:8
7Biliary cast syndrome:literature review and a single centre experience in liver transplant recipients显示文摘BACKGROUND:Biliary cast syndrome(BCS)is an unusual complication of orthotopic liver transplantation (OLTx),and its management is difficult.Limited success using endoscopic retrograde cholangiopancreatography (ERCP)or open exploration to clear casts has been reported, but failure usually results in re-transplantation.We aimed to review our experience with BCS and highlight a novel combined percutaneous and endoscopic approach for duct clearance.A brief review of the literature is given. METHODS:We retrospectively reviewed our experience of managing BCS using case notes review.Details were also gathered from radiology,where interventional procedures were carried out. RESULTS:We had a total of three cases of BCS reported between 2002 and 2005.Multiple attempts were made to remove these casts.All three were treated in a variety of ways.Management is discussed along with highlighting a novel combined percutaneous and endoscopic approach for duct clearance. CONCLUSIONS:BCS is a potential complication of OLTx. Surgical and endoscopic methods of removing casts are used.However,in circumstances where these methods are technically difficult,a percutaneous endoscopic approach with serial dilatation of the cutaneous port and surgical removal of casts can be done.Narasimhaiah Srinivasaiah Mettu Srinivas Reddy Schlok Balupuri David Talbot Bryon Jaques Derek Manas 2008Hepatobiliary & Pancreatic Diseases International2008,7,3:8
8Biliary carcinoembryonic antigen levels in diagnosis of occult hepatic metastases from colorectal carcinoma显示文摘AIM: To prospectively explore the role of carcinoembryonic antigen (CEA) in gallbladder bile in patients with colorectal carcinoma and the morphological and clinical features of neoplasia and the occurrence of hepatic metastases.METHODS: CEA levels in the gallbladder and peripheral blood were studied in 44 patients with colorectal carcinoma and 10 patients with uncomplicated cholelithiasis. CEA samples were collected from the gallbladder bile and peripheral blood during the operation, immediately before extirpating the colorectal neoplasia or cholecystectomy.Values of up to 5 ng/ml were considered normal for bile and serum CEA.RESULTS: In the 44 patients with colorectal carcinoma who underwent operation with curative intent, the average level of serum CEA was 8.5 ng/ml (range: 0.1 to 111.0 ng/ml) and for bile CEA it was 74.5 ng/ml (range: 0.2 to 571.0ng/ml). In the patients with uncomplicated cholelithiasis who underwent cholecystectomy, the average level of serum CEA was 1.9 ng/ml (range: 1.0 to 3.5 ng/ml) and for bile CEA it was 1.2 ng/ml (range: 0.3 to 2.9 ng/ml).The average duration of follow-up time was 16.5 months (range: 6 to 48 months). Four patients who underwent extirpation of the colorectal carcinoma without evidence of hepatic metastasis and with an average bile CEA value of 213.2 ng/ml presented hepatic metastases between three and seventeen months after removal of the primary colorectal neoplasia. Three of them successfully underwent extirpation of the hepatic lesions.CONCLUSION: High CEA levels in gallbladders of patients undergoing curative operation for colorectal carcinoma may indicate the presence of hepatic metastases. Such patients must be followed up with special attention to the diagnosis of such lesions.Jaques Waisberg Rogério T.Palma Luís Contim Neto Lourdes C.Martins Maurício S.L.Oliveira Carlos A. Nagashima Antonio C.Godoy Fabio S.Goffi 2003World Journal of Gastroenterology2003,9,7:5
9论西澳大利亚钾镁煌斑岩和金伯利岩的成因显示文摘对西澳大利亚金伯利岩和钾镁煌斑岩的差别和相似性重新进行研究,旨在解决岩石成因论问题。与金伯利岩岩筒不同,在火山口钾镁煌斑岩中常有玻璃质和多孔状火山碎屑物,在火山口带发现有岩浆岩。在矿物学上,钾镁煌斑岩含有金伯利岩中非典型的矿物,特别是白榴石、钾碱镁闪石、柱红石和钾钙板锆石。钾镁煌斑岩的组成变化较大,是低压分离作用以及橄榄石、铬尖晶石、透辉石、金云母和钙钛矿分离的结果,尽管它们可能不是来自同一母岩浆。高压结晶作用在北金伯利和东金伯利地区的金伯利岩岩墙中更为显著,这可用金伯利岩中相对普遍地产出诸如镁铬矿、钛镁铝榴石、辉石、尖晶石和锆石等矿物的巨晶来说明,而在钾镁煌斑岩中这些矿物巨晶非常罕见或不存在。 在西澳大利亚钾镁煌斑岩和金伯利岩岩筒中,地幔捕虏体罕见并常有蚀变。对存在的岩石类型(包括纯橄榄岩、石榴石橄榄岩、石榴石二辉橄榄岩、方辉橄榄岩)进行了阐述。没有发现榴辉岩捕虏体,但金刚石中的包裹体以及重砂精矿含有榴辉岩套的矿物。从而得出结论:金伯利地区下方的地幔是耐火耐熔的亏损地幔,可能含有一些榴辉岩。 象金伯利岩一样,钾镁煌斑岩也被认为是形成于地幔深部的、体积很小的部分熔触体。而西金伯利地区的钾镁煌斑岩,象云母质(含云母的)A. L. Jaques 刘德镒 刘延 1993地质地球化学1993,,3:4
10Prognostic significance of vascular endothelial growth factor polymorphisms in colorectal cancer patients显示文摘AIM To investigate the associations of the genetic polymor-phisms of vascular endothelial growth factor A(VEGF-A)-1498C>T and-634G>C, with the survival of patients with colorectal cancer(CRC). METHODS A prospective cohort consisting of 131 Brazilians patients consecutively operated on with a curative intention as a result of sporadic colorectal carcinoma was studied. DNA was extracted from peripheral blood and its amplification and allelic discrimination for each genetic polymorphism was performed using the technique of polymerase chain reaction(PCR) in real-time. The real-time PCR technique was used to identify the VEGF-A-1498C>T(rs833031) and-634G>C(rs2010963) polymorphisms. Genotyping was validated for VEGF-A-1498C>T polymorphism in 129 patients and for VEGF-A-634G>C polymorphism in 118 patients. The analysis of association between categorical variables was performed using logistic regression, survival by Kaplan-Meier method and multivariate analysis by the Cox regression method. RESULTS In the univariate analysis there was a significant association(OR = 0.32; P = 0.048) between genotype CC of the VEGF-A-1498C>T polymorphism and the presence of CRC liver metastasis. There was no association between VEGF-A-1498C>T polymorphism and VEGF-A-634G>C polymorphism with further clinical or anatomopathologic variables. The genotype CC of the VEGF-A-1498C>T polymorphism was significantly correlated with the 5-year survival(P = 0.032), but not significant difference(P = 0.27) was obtained with the VEGF-A-634G>C polymorphism with the 5-year survival in the univariate analysis. The genotype CT(HR = 2.79) and CC(HR = 4.67) of the polymorphism VEGF-A-1498C>T and the genotype CC(HR = 3.76) of the polymorphism VEGF-A-634C>G acted as an independent prognostic factor for the risk of death in CRC patients. CONCLUSION The CT and CC genotypes of the VEGF-A-1498C>T and the CC genotype of the VEGF-A-634C>G polymorphisms are prognostic factors of survival in Brazilians patients with sporadic colorectal carcinoma.Gilmar Ferreira do Espírito Santo Bianca Borsatto Galera Elisabeth Carmen Duarte Elisabeth Suchi Chen Lenuce Azis Amilcar Sabino Damazo Gabriela Tognini Saba Flávia de Sousa Gehrke Ismael Dale Cotrim Guerreiro da Silva Jaques Waisberg 2017World Journal of Gastrointestinal Oncology2017,9,2:4
11Oncological Feasibility of Laparoscopic Distal Pancreatectomy for Adenocarcinoma: A Single-Institution Comparative Study显示文摘S. Rehman S. K. P. John R. Lochan B. C. Jaques D. M. Manas R. M. Charnley J. J. French S. A. White 2014World Journal of Surgery2014,,2:3
12Detection of anti-Helicobacter pyloriantibodies in serum and duodenal fluid in peptic gastroduodenal disease显示文摘AIM: To study the diagnosis of He/icobacterpy/ori(H pylori) infection through the determination of serum levels of anti-H pylori IgG and IgA antibodies, and the levels of anti- H pylori IgA antibodies in duodenal fluid. METHODS: Data were collected from 93 patients submitted to upper digestive endoscopy due to dyspeptic symptoms. The patients were either negative (group A) or positive (group B) to Hpyloriby means of both histological detection and urease tests. Before endoscopy, peripheral blood was collected for the investigation of anti-H pylori IgG and IgA antibodies. To perform the urease test, biopsies were obtained from the gastric antrum. For the histological evaluation, biopsies were collected from the gastric antrum (greater and lesser curvatures) and the gastric body. Following this, duodenal fluid was collected from the first and second portions of the duodenum. For the serological assaying of anti-Hpy/oriIgG and IgA, and anti-Hpy/oriIgA in duodenal fluids, the ELISA method was utilized. RESULTS: The concentration of serum IgG showed sensitivity of 64.0%, specificity of 83.7%, positive predictive value of 82.0%, negative predictive value of 66.6% and accuracy of 73.1% for the diagnosis of H pyloriinfection. For the same purpose, serum IgA showed sensitivity of 72.0%, specificity of 65.9%, positive predictive value of 72.0%, negative predictive value of 67.4% and accuracy of 69.8%. If the serological tests were considered together, i.e. when both were positive or negative, the accuracy was 80.0%, sensitivity was 86.6%, specificity was 74.2%, positive predictive value was 74.2% and negative predictive value was 86.6%. When values obtained in the test for detecting IgA in the duodenal fluid were analyzed, no significant difference (P=0.43) was observed between the values obtained from patients with or without Hpyloriinfection. CONCLUSION: The results of serum IgG and IgA tests for H pylori detection when used simultaneously, are more efficient in accuracy, sensitivity and negative predictive value, than those when used alone. The concentration of IgA antibodies in duodenal fluid is not useful in identifying patients with or without H pylori.Angelo Locateili Wilson Roberto Catapani Claudio Rufino Gomes Junior Claudilene Battistin Paula Silva Jaques Waisberg 2004World Journal of Gastroenterology2004,10,20:3
13碱性成纤维细胞生长因子及相关细胞因子转染对兔骨关节炎的作用显示文摘目的 观察重组人碱性成纤维细胞生长因子(bFGF)单独及联合白细胞介素-1受体拮抗蛋白(IL-1Ra)和胰岛素样生长因子(IGF)-1基因转染对兔膝骨关节炎(OA)模型的治疗效果.方法 前交叉韧带切断法将新西兰兔膝关节制成OA模型.分别向膝关节内注射单独bFGF或多重组合的重组腺病毒载体各1×108 PFU.3周后关节液分析目的 基因表达和糖胺聚糖(GAG)浓度.关节标本行Mankin评分及Ⅱ型胶原免疫组织化学检测.结果 基因转染后,在关节液中可检测到相应目的基因的表达.OA组软骨损伤较大,Mankin评分为(8.60±1.14),关节液中GAG为(69.96±8.32)mg/L.与OA组相比,单独bFGF转染后软骨Mankin评分降低(P<0.05),为(6.00±0.71) bFGF与IL-1Ra和IGF-1联合转染后,Mankin评分进一步降低(P<0.05),为(3.80±0.84).单独bFGF转染后对GAG释放无明显抑制作用,联合基因转染可显著抑制基质降解,减少GAG的释放.结论 bFGF单独转染可对OA发挥一定的治疗作用.bFGF、IL-1Ra和IGF-1联合转染可有效改善OA病程,其疗效优于bFGF单独转染,提示多基因联合转染治疗OA更为有效.陈彪 陈廖斌 秦俊 Jaques Magdalou 汪晖 2010中华实验外科杂志2010,27,11:2
14Management of neuroblastoma in limited-resource settings显示文摘BACKGROUND Neuroblastoma(NB)is a heterogeneous disease with variable outcomes among countries.Little is known about NB in low-and middle-income countries(LMICs).AIM The aim of this review was to evaluate regional management protocols and challenges in treating NB in paediatric oncology units in LMICs compared to high-income countries(HICs).METHODS PubMed,Global Health,Embase,SciELO,African Index Medicus and Google Scholar were searched for publications with keywords pertaining to NB,LMICs and outcomes.Only English language manuscripts and abstracts were included.A descriptive review was done,and tables illustrating the findings were constructed.RESULTS Limited information beyond single-institution experiences regarding NB outcomes in LMICs was available.The disease characteristics varied among countries for the following variables:sex,age at presentation,MYCN amplification,stage and outcome.LMICs were found to be burdened with a higher percentage of stage 4 and high-risk NB compared to HICs.Implementation of evidence-based treatment protocols was still a barrier to care.Many socioeconomic variables also influenced the diagnosis,management and followup of patients with NB.CONCLUSION Patients presented at a later age with more advanced disease in LMICs.Management was limited by the lack of resources and genetic studies for improved NB classification.Further research is needed to develop modified diagnostic and treatment protocols for LMICs in the face of limited resources.Jaques van Heerden Mariana Kruger 2020World Journal of Clinical Oncology2020,11,8:2
15Nd3+ ion based self frequency doubling solid state lasers显示文摘JAQUE D CAPMANY J GARCIA J 1999Optical Materials1999,13,2:2
16Long-term Survival Following Treatment of Pseudomyxoma Peritonei: An Analysis of Surgical Therapy显示文摘Thomas J. Miner Jinru Shia David P. Jaques David S. Klimstra Murray F. Brennan Daniel G. Coit 2005Annals of Surgery2005,,2:2
17Esophagogastric anastomosis with invagination into stomach:New technique to reduce fistula formation显示文摘AIM: To present a new technique of cervical esophagogastric anastomosis to reduce the frequency of fistula formation. METHODS: A group of 31 patients with thoracic and abdominal esophageal cancer underwent cervical esophagogastric anastomosis with invagination of the proximal esophageal stump into the stomach tube. In the region elected for anastomosis, a transverse myotomy of the esophagus was carried out around the entire circumference of the esophagus. Afterwards, a 4-cm long segment of esophagus was invaginated into the stomach and anastomosed to the anterior and the posterior walls. RESULTS: Postoperative minor complications occurred in 22 (70.9%) patients. Four (12.9%) patients had serious complications that led to death. The discharge of saliva was at a lower region, while attempting to leave the anastomosis site out of the alimentary transit. Three (9.7%) patients had fistula at the esophagogastric anastomosis, with minimal leakage of air or saliva and with mild clinical repercussions. No patients had esophago- gastric fistula with intense saliva leakage from either the cervical incision or the thoracic drain. Fibrotic stenosis of anastomoses occurred in seven (22.6%) patients. All these patients obtained relief from their dysphagia with endoscopic dilatation of the anastomosis.CONCLUSION: Cervical esophagogastric anastomosis with invagination of the proximal esophageal stump into the stomach tube presented a low rate of esophagogastric fistula with mild clinical repercussions.Alexandre Cruz Henriques Carlos Alberto Godinho Roberto Saad Jr Daniel Reis Waisberg Aline Biral Zanon Manlio Basilio Speranzini Jaques Waisberg 2010World Journal of Gastroenterology2010,16,45:2
18Infrared fluorescence imaging of infarcted hearts with A@S nanodots显示文摘Ag2S nano dots have already bee n dem onstrated as promisi ng n ear-i nfrared (NIR-II, 1.0-1.45 pm) emitting nan oprobes with low toxicity, high penetration and high resolution for in vivo imaging of, for example, tumors and vasculature. In this work, we have systematically investigated the pote ntial applicati on of function alized Ag2S nano dots for accurate imaging of damaged myocardium tissues after a myocardial in farction in duced by either partial or global ischemia. Ag2S nano dots surface-function alized with the an giote nsin II peptide (ATI I) have show n over 10-fold enhanced binding efficiency to damaged tissues than non-specifically (PEG) functionalized Ag2S nanodots due to their interaction with the upregulated angiotensin II receptor type I (AT1R). It is demonstrated how the NIR-II images generated by ATII-functionalized Ag2S nanodots contain valuable information about the location and extension of damaged tissue in the myocardium allowing for a proper identification of the occluded artery as well as an in direct evaluati on of the damage level. The pote ntial applicati on of Ag2S nano dots in the n ear future for in vivo imaging of myocardial infarction was also corroborated by performing proof of concept whole body imaging experiments.Dirk H. Ortgies Angel Luis Garcia-Villalon Miriam Granado Sara Amor Emma Martin Rodriguez Harrisson DA Santos Jingke Yao Jorge Rubio-Retama Daniel Jaque 2019Nano Research2019,12,4:2
19Limitations of Ampullectomy in the Treatment of Nonfamilial Ampullary Neoplasms显示文摘Kevin K. Roggin MD Jen Jen J. Yeh MD Cristina R. Ferrone MD Elyn Riedel MS Hans Gerdes MD David S. Klimstra MD David P. Jaques MD Murray F. Brennan MD 2005Annals of Surgical Oncology2005,,12:2
20Extended local resection for advanced gastric cancer: increased survival versus increased morbidity显示文摘Martin RC Jaques DP Brennan MF 2002Ann Surg2002,236,2:1
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