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The Chinese Guidelines for the Diagnosis and Treatment of Pancreatic Neuroendocrine Neoplasms (2020)
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摘要: 胰腺神经内分泌肿瘤具有高度异质性，患者的临床管理存在一定难度。为了应对这一挑战，中华医学会外科学分会胰腺外科学组牵头成立了由肿瘤外科、消化内科、肿瘤内科、内分泌科、影像科、病理科、核医学科等多领域学者组成的专家委员会。该委员会回顾了与胰腺神经内分泌肿瘤诊断和治疗相关的重要问题，并基于循证医学证据提出了相应的诊疗建议，以期进一步改进中国胰腺神经内分泌肿瘤患者的诊疗流程。Abstract: Pancreatic neuroendocrine neoplasms (pNENs) are highly heterogeneous, and the management of pNENs patients can be intractable. To address this challenge, an expert committee was established on behalf of the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association, which consisted of surgical oncologists, gastroenterologists, medical oncologists, endocrinologists, radiologists, pathologists, and nuclear medicine specialists. By reviewing the important issues regarding the diagnosis and treatment of pNENs, the committee concluded evidence-based statements and recommendations in this article, in order to further improve the management of pNENs patients in China.
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Keywords:
- pancreatic neoplasms /
- guidelines /
- diagnosis /
- therapy
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冠心病是我国最主要的致死性疾病之一，其发病率和死亡率一直呈上升趋势[1]，给社会造成了巨大的疾病负担。对冠心病及其相关危险因素进行更精准的筛查、诊断和治疗，是实现健康中国的必由之路。精准医学理念的提出是基于不同个体对于特定疾病的易感性或特定治疗方案反应的差异性，而基因检测技术的发展和检测成本的下降不仅推动了该领域的飞速发展，也推动了冠心病精准医疗的进程。基因遗传风险评分(genetic risk score, GRS)、单/多基因遗传学检测和药物基因组学检测是现阶段冠心病及其相关危险因素预测、诊断和治疗的主要内容和方向。
1. 冠心病发病风险预测
风险预测可以评估特定个体的冠心病发病风险，筛查冠心病高危人群，并可为不同危险分层的患者提供有效干预措施。目前基于传统和遗传因素的冠心病风险评估系统已相对成熟，但二者联合应用将是未来趋势。
1.1 基于传统因素的冠心病风险预测模型
Framingham队列研究揭示了诸多危险因素与冠心病的相关性，并于1967年开始建立心血管病风险评估模型[2]，将性别、年龄、血压、吸烟、总胆固醇以及高密度脂蛋白胆固醇(high density lipoprotein-cholesterol，HDL-C)等风险因素纳入多元回归方程，校正后的模型可适用于世界各地人群[3]。此模型对中老年短期疾病风险的预测较准确，但对年轻个体的预测效果不佳且不能预测终生疾病风险。随后，美国社区动脉粥样硬化组织、美国国立卫生研究院国家心肺和血液研究所等组织在Framingham模型的基础上进行了风险因素和评分系统改良[4-5]，中国医学科学院阜外医院流行病学研究室、复旦大学公共卫生学院建立了适合中国人群的预测模型，可用于不同个体的冠心病发病风险预测[6-7]。上述模型以年龄、性别、血脂、血压和是否吸烟等传统冠心病危险因素为基础，只有当风险因素累积到一定程度时，预测结果才较为可信，故在个体生命早期尤其是年轻患者中的预测价值不高，也很难预测早发型冠心病。
1.2 基于遗传因素的冠心病风险预测模型
传统危险因素(如高血压、高胆固醇)均具有年龄相关性，且未考虑个体遗传背景差异，即使涵盖了家族史，遗传因素的考量仍较模糊。此外，某些传统危险因素也包含潜在的遗传成份，例如血脂、血压水平均受遗传因素的调控。其中，血浆中的低密度脂蛋白胆固醇(low density lipoprotein-cholesterol，LDL-C)、HDL-C、甘油三酯水平约70%~80%是由遗传因素调节[8]。GRS利用包含这些遗传风险变异的微阵列对人群进行基因分型，经加权计算得出预测模型，可消除传统危险因素偏差，提供潜在的解决方案[9]。冠状动脉疾病遗传学联盟和全球脂质遗传学会等权威机构发现了157个可调节血脂水平的遗传变异位点[10-11]。高血压、糖尿病最近也被发现与多个遗传变异位点相关[12]。至于无潜在遗传机制的传统风险因素——吸烟，在近期的研究中被发现可与基因型相互作用而影响冠心病的发生，如单核苷酸多态性位点rs7178051[13]。一项纳入100余万人的研究证实，遗传风险分层较传统危险因素分层在某些方面具备一定的优越性，且独立于传统危险因素[14]。
GRS的另一主要优点是遗传信息与生俱来，终生不变且不受年龄的影响。DNA序列信息在人体终生稳定，遗传风险在个体出生时即可评估，因此GRS尤其适用于年轻群体。日本一项纳入168 228人的大规模研究显示，GRS对于远期心血管死亡事件具有较好的预测效果[15]。另一项纳入48 421人的研究发现，GRS不仅可预测冠心病事件的发生，且可独立于其他所有传统风险因素预测冠心病事件的复发[16]。
遗传风险分层不仅可有效区分冠心病高危人群，且可有效区分他汀类药物的受益人群。新近研究显示，GRS的应用具有巨大优势，通过初级和二级预防均可改善冠心病的结局。在遗传高危人群中，良好生活方式组比不良生活方式组冠心病的发生率降低了46%[17]。同样，使用他汀类药物亦可降低遗传高危人群的冠心病发生风险近50%[18]。GRS的应用标志着冠心病预防模式的重要转变。
1.3 传统因素联合遗传因素评估冠心病风险是未来趋势
遗传风险分层的技术门槛正在逐步降低，可在全球范围内提供任何年龄段的风险分析，因此有可能彻底改变初级预防的筛查模式。由于大部分冠心病风险等位基因都属于数量性状位点，而已知冠心病风险位点只能解释其遗传力的21%[19]，因此，在传统风险评分系统中加入单个风险位点对风险评估能力的提高意义不大；而将全基因组关联分析研究得到的位点进行整合，再结合传统风险预测因素即可显著提高对冠心病发病风险的预测能力。Abraham等[20]对5个前瞻性队列进行传统风险和遗传风险预测，二者的预测风险比分别为1.28 (95% CI：1.18~1.38)和1.74(95% CI：1.61~1.86)。若将二者结合，其预测能力将提高1.5%~1.6%(P < 0.001)，而当受试者年龄 > 60岁时，其预测能力的提高则更为显著(4.6%~5.1%, P < 0.001)。
2. 冠心病相关遗传学诊断
冠心病属于环境因素和遗传因素共同作用下的复杂疾病，无法仅从遗传学角度解释大部分患者的病因。家族性高胆固醇血症(familial hypercholesterolemia, FH)是一种常见遗传性脂代谢异常疾病，也是冠心病的独立危险因素。FH遗传学检测是冠心病精准医疗的代表。FH曾被认为是一种经典的孟德尔单基因遗传病。随着遗传学研究的深入，人们逐渐发现FH是具有多种遗传模式的复杂单基因病[21]。5个常见致病基因(APOB、APOE、LDLR、PCSK9和LDLRAP1)中一个等位基因出现突变即可产生明显的疾病表型[22]，其中LDLR异常占全部遗传病因的70%以上。其主要致病机制是胆固醇代谢基因功能异常导致的胆固醇水平终生过高，因此极大促进了冠心病的发生。
FH并不罕见，实际发病率为1/200[23]。中国医学科学院阜外医院对1.3万例急性心肌梗死患者评估发现，FH患者占比高达4.2%[24]。FH患者较普通人发生冠心病的概率高10倍，早发型冠心病的概率高20倍[25]。
尽管LDL-C水平在FH相关临床决策中处于首要地位，但对早发型冠心病患者仍有必要进行FH致病基因筛查。国际常用的荷兰DLCN和Simon诊断标准均强调诊断FH时应联合基因检测。确定致病基因不仅有助于明确诊断、提高诊断效率，还可指导治疗方案、精细化风险分层。与携带LDLR突变的患者相比，无LDLR等位基因缺陷的患者使用他汀类药物治疗效果更好[26]。PCSK9功能获得性突变患者或LDLR受体纯合突变患者对PCSK9抑制剂反应较差[27]。即使相同LDL-C水平下，携带FH基因突变患者的冠状动脉病变风险也会显著增加[28]。鉴于FH多为常染色体显性遗传，先证者确诊后，其他家庭成员应进行致病基因筛查以提早进行预防和药物治疗。
3. 冠心病精准药物治疗
冠心病的个体化用药基因检测是冠心病精准医疗的主要应用之一。将基因组中的药物效应位点信息纳入常规临床用药管理，通过个体化药物种类和药物剂量选择，可最大限度地提高疗效和降低副作用，实现临床个体化用药。冠心病常用药物的疗效多与基因变异有关，依据美国食品药品监督管理局给出的药品标签，冠心病药物基因组学临床应用最成熟的部分主要集中于以下两类：(1)抗栓类药物，又分为抗血小板药物(如阿司匹林、氯吡格雷等)和抗凝药物(如肝素、华法林等)；(2)他汀类药物。
3.1 抗栓类药物
抗血小板药物氯吡格雷常与阿司匹林联用进行血栓二级预防，最新指南明确指出常规应用药物基因检测可使高危血栓风险人群及抗血小板降阶治疗患者获益[29]。氯吡格雷是一种前体药物，口服后经肝脏细胞色素P450酶系统代谢为活性代谢产物。氯吡格雷代谢通路上的CYP2C19功能缺失性等位基因与氯吡格雷反应性低及不良临床预后相关[30-32]。现临床主要针对CYP2C19的两个位点(636GG、681GG)进行基因检测，其中，野生型*1/*1(636 GG、681 GG) 属于快代谢类型，临床应用氯吡格雷时疗效较佳，但需关注药物剂量过剩带来的出血风险；若其中一个位点出现杂合突变[*1/*2(636 GG、681 GA)，*1/*3(636 GA、681 GG)]则属于中代谢型，在临床应用时常规剂量疗效不佳，需增加药物剂量；其他情况则属于慢代谢型，氯吡格雷无效且风险显著增加，易发生氯吡格雷抵抗事件，在临床应用时建议更换为替格瑞洛等其他抗血小板药物。
N Engl J Med近期发表的大规模随机对照试验结果表明，支架植入术后的心肌梗死患者通过CYP2C19基因型指导个体化抗血小板降阶治疗的获益不比强效抗栓标准治疗差：对于预防1年内血栓事件的疗效不劣于替格瑞洛或普拉格雷强效标准治疗，而且出血发生率更低[33]。另一项基因检测指导氯吡格雷用药的大规模随机对照试验发现，CYP2C19基因型指导个体化抗血小板药物治疗对于预防3个月内缺血事件的疗效优于氯吡格雷标准治疗，且出血风险无显著差异[34]。以上研究结果进一步巩固了CYP2C19基因检测能够改善抗血小板治疗转归的理念，可使高危血栓风险人群及抗血小板降阶治疗患者获益，为药物基因组学指导个体化P2Y12受体抑制剂治疗提供了强有力的循证医学证据。
3.2 他汀类药物
他汀类药物是目前最有效的降低LDL-C水平的药物，也是另外一种已广泛应用于冠心病临床药物基因检测的药物。无法预测具体患者的药物疗效和安全性是他汀类药物治疗中的一大难题[35]。目前已发现40余个与之相关的基因，特别是参与他汀类药物代谢的阴离子转运多肽以及载脂蛋白E，其基因多态性分别可影响他汀类药物的安全性和有效性[36]。Pandya等[37]在一项经济评论中写到，将基因筛查应用于指导他汀类药物种类和剂量选择其实是更经济的手段。肌痛风险或降LDL-C能力等因素会改变他汀类药物临床应用的效益风险比，因此基因检测对辅助临床制定个体化治疗方案具有重要意义。
在临床用药实践中合理应用药物基因位点的变异信息，结合不同患者的血药浓度进行检测，是未来冠心病精准用药的方向。
4. 小结与展望
冠心病精准医疗有助于正确识别冠心病发病相关危险因素、进行遗传风险评估及危险分层，为疾病预防和药物治疗提供理论基础和实践指导。随着基因编辑技术的发展，在冠心病领域实施针对特异性靶点的个性化预防和基因治疗正在逐步展开。因此，未来10年，基因检测将为冠心病预防、药物开发以及预测药物的安全性和有效性等提供更多重要的个体化信息。
志谢: “中国医学科学院医学与健康科技创新工程(2017-I2M-1-001)”对会议提供支持；北京协和医院基本外科王先泽医师对指南中参考文献的收集、更新、整理和整合工作，以及对指南历次共识会议的组织协调工作。作者贡献：赵玉沛院士领导了指南更新项目、组织了指南编辑委员会(编委会)并任命吴文铭教授和陈洁教授全权负责编委会对指南的撰写工作。吴文铭教授和陈洁教授共同起草了指南初稿，并组织编委会其他成员依照指南编写流程对指南初稿进行审校；在吴文铭教授和陈洁教授的主持和参与下，白春梅教授、依荷芭丽·迟教授、杜奕奇教授、冯仕庭教授、霍力教授、姜玉新教授、李景南教授、楼文晖教授、罗杰教授、邵成浩教授、沈琳教授、王峰教授、王理伟教授、王鸥教授、王于教授、吴焕文教授、邢小平教授、徐建明教授、薛华丹教授、薛玲教授、杨扬教授、虞先濬教授、原春辉教授、赵宏教授、朱雄增教授共同参加了三轮指南修订会议，并根据各自专业对指南的相应章节进行了修订；吴文铭教授、陈洁教授、白春梅教授、霍力教授、姜玉新教授、邢小平教授、薛华丹教授、薛玲教授作为各自章节的负责人，参加或委派代表参加了指南定稿会并对指南终稿内容进行确认；吴文铭教授和陈洁教授对指南终稿全文进行了最终审校后，所有作者均通过了指南终稿并形成指南定稿，同时签署了作者贡献声明及版权转让协议。利益冲突：无吴文铭、陈洁对本文同等贡献 -
表 1 2019年世界卫生组织第5版胃肠胰神经内分泌肿瘤病理学分类和分级标准
命名 分化程度 分级 核分裂象数a(/2 mm2) Ki-67指数(%)a 神经内分泌瘤，G1级 高分化 低 ＜2 ＜3 神经内分泌瘤，G2级 高分化 中 2~20 3~20 神经内分泌瘤，G3级b 高分化 高 ＞20 ＞20 神经内分泌癌，小细胞型 低分化c 高c ＞20 ＞20 神经内分泌癌，大细胞型 低分化c 高c ＞20 ＞20 混合性神经内分泌-非神经内分泌肿瘤 高或低分化 多样的d 多样的d 多样的d a核分裂象数表示为核分裂象计数/2 mm2(该面积等于40倍放大倍数及每个视野最大径0.5 mm情况下的10个高倍镜视野)，计数50个0.2 mm2的视野；Ki-67增殖指数通过计数高染色区域(即热点区)至少500个细胞获得；最终分级采用两种增殖指数所对应分级中的较高者；bG3级神经内分泌瘤的核分裂数和Ki-67指数未设上限，其理由是G3级神经内分泌瘤(尤其G3级胰腺神经内分泌瘤)的Ki-67指数偶可高达70%~80%，故不能仅根据Ki-67指数的高低进行分级，还需结合其形态学分化良好的特点；对难以区分的G3级神经内分泌瘤和神经内分泌癌，需进行TP53、RB1、ATRX和DAXX染色协助鉴别诊断；c神经内分泌癌根据定义为高级别，无需再分级；d在大部分混合性神经内分泌-非神经内分泌肿瘤中，神经内分泌肿瘤和非神经内分泌肿瘤成分均为低分化，且神经内分泌肿瘤成分的增殖指数与其他神经内分泌癌一致，但该类型肿瘤亦允许这两种成分均为高分化，这种情况下，应分别对两种成分进行分级；胰腺的混合性神经内分泌-非神经内分泌肿瘤包括4个亚型：混合性导管癌-神经内分泌癌(小细胞或大细胞)、混合性导管癌-神经内分泌瘤、混合性腺泡细胞癌-神经内分泌癌和混合性腺泡细胞癌-导管癌-神经内分泌癌 
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表 2 2017年AJCC第8版胰腺神经内分泌肿瘤的TNM分期标准
分期 特征 分期 特征 T分期 原发肿瘤a M分期 远处转移 TX 原发肿瘤无法评价 M0 无远处转移 T1 局限于胰腺内b，且最大径＜2 cm M1 有远处转移 T2 局限于胰腺内b，且最大径2~4 cm M1a 仅存在肝脏转移 T3 局限于胰腺内b，且最大径＞4 cm；或侵犯十二指肠或胆管 M1b 仅存在至少一个肝脏外器官转移(如肺、卵巢、非区域淋巴结、腹膜、骨) T4 侵犯邻近器官(如胃、脾、结肠、肾上腺)或大血管壁(腹腔干或肠系膜上动脉) M1c 同时存在肝脏和肝脏外器官转移 N分期 区域淋巴结 NX 区域淋巴结无法评价 N0 无区域淋巴结转移 N1 有区域淋巴结转移 AJCC：美国癌症联合委员会；a若原发肿瘤为多发，则以最大的肿瘤进行T分期；若多发肿瘤数量已知，则记为T(#)，如pT3(4)N0M0；若多发肿瘤数量未知或难以计数，则记为T(m)，如pT3(m) N0 M0；b“局限于胰腺内”定义为无邻近器官(如胃、脾、结肠、肾上腺)或大血管壁(如腹腔干或肠系膜上动脉)侵犯，肿瘤对胰周脂肪的侵犯不作为分期依据
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表 3 2017年AJCC第8版综合分期标准
分期 T分期 N分期 M分期 Ⅰ期 T1 N0 M0 Ⅱ期 T2 N0 M0 T3 N0 M0 Ⅲ期 T4 N0 M0 任何T N1 M0 Ⅳ期 任何T 任何N M1 AJCC：同表 2
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类型 年发病率(/106) 分泌激素 常见部位 恶性比率(%) 主要症状 功能性pNEN 胰岛素瘤 1~32 胰岛素 胰腺 5~10 低血糖 胃泌素瘤 0.5~21.5 胃泌素 十二指肠、胰腺 50~60 腹泻、腹痛、反酸 胰高血糖素瘤 0.01~0.1 胰高血糖素 胰腺 50~80 坏死游走性红斑、贫血、葡萄糖不耐受、体质量下降 生长抑素瘤 少见 生长抑素 胰腺、十二指肠、空肠 50~60 糖尿病、胆石症、腹泻 产生ACTH的神经内分泌瘤 少见 ACTH 胰腺 ＞90 库欣综合征 血管活性肠肽瘤 0.05~0.2 血管活性肠肽 胰腺 40~80 水样泻、低钾血症 无功能性pNEN 可能有激素水平的升高但未引起相关临床症状 胰腺 60~90 无特异性症状，常为肿瘤压迫、侵袭、转移引起的相关症状，如消化道梗阻、出血、腹痛、黄疸等 pNEN：胰腺神经内分泌肿瘤；ACTH：促肾上腺皮质激素
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附表 1 本指南使用的指南证据特征分类
类别 水平 来源 专家共识度 1A 高 严谨的Meta分析、大型随机对照临床研究 一致共识 1B 高 严谨的Meta分析、大型随机对照临床研究 基本一致共识，但争议小 2A 稍低 一般质量的Meta分析、小型随机对照研究、设计良好的大型回顾性研究、病例对照研究 一致共识 2B 稍低 一般质量的Meta分析、小型随机对照研究、设计良好的大型回顾性研究、病例对照研究 基本一致共识，但争议小 3 低 非对照的单臂临床研究、病例报告、专家观点 无共识，且争议大
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附表 2 本指南使用的指南证据等级分类
推荐等级 标准 Ⅰ级推荐 一般情况下，将1A类证据和部分专家共识度高且在中国可及性好的2A类证据作为Ⅰ级推荐。具体来说，Ⅰ级推荐具有如下特征：可及性好的普适性诊治措施(包括适应证明确)，肿瘤治疗价值相对稳定，基本为国家医保所收录；Ⅰ级推荐的确定，不因商业医疗保险而改变，主要考虑的因素是患者的明确获益性 Ⅱ级推荐 一般情况下，将1B类证据和部分专家共识度稍低或在中国可及性不太好的2A类证据作为Ⅱ级推荐。具体来说，Ⅱ级推荐具有如下特征：在国际或国内已有随机对照的多中心研究提供的高级别证据，但是可及性差或者效价比低，已超出平民经济承受能力的药物或治疗措施；对于获益明显但价格昂贵的措施，以肿瘤治疗价值为主要考虑因素，也可以作为Ⅱ级推荐 Ⅲ级推荐 对于正在探索的诊治手段，虽然缺乏强有力的循证医学证据，但是专家组具有一致共识的，可以作为Ⅲ级推荐供医疗人员参考 不推荐或反对 对于已有充分证据证明不能使患者获益的，甚至导致患者伤害的药物或者医疗技术，专家组具有一致共识的，应写明“专家不推荐”或者必要时“反对”。可以是任何类别等级的证据
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[1] WHO Classification of Tumours. Digestive System Tumours[M]. 5th ed. World Health Organization Press, 2019.
[2] Hallet J, Law CH, Cukier M, et al. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes[J]. Cancer, 2015, 121: 589-597. DOI: 10.1002/cncr.29099
[3] Dasari A, Shen C, Halperin D, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States[J]. JAMA Oncol, 2017, 3: 1335-1342. DOI: 10.1001/jamaoncol.2017.0589
[4] Fan JH, Zhang YQ, Shi SS, et al. A nation-wide retrospective epidemiological study of gastroenteropancreatic neuroendocrine neoplasms in china[J]. Oncotarget, 2017, 8: 71699-71708. DOI: 10.18632/oncotarget.17599
[5] Ito T, Igarashi H, Nakamura K, et al. Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis[J]. J Gastroenterol, 2015, 50: 58-64. DOI: 10.1007/s00535-014-0934-2
[6] Wu W, Jin G, Li H, et al. The current surgical treatment of pancreatic neuroendocrine neoplasms in China: a national wide cross-sectional study[J]. J Pancreatol, 2019, 2: 35-42. DOI: 10.1097/JP9.0000000000000019
[7] Amin MB, Edge, S, Greene F, et al. AJCC Cancer Staging Manual[M]. 8th ed. New York: Springer, 2017.
[8] Luo G, Javed A, Strosberg JR, et al. Modified Staging Classification for Pancreatic Neuroendocrine Tumors on the Basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society Systems[J]. J Clin Oncol, 2017, 35: 274-280. http://europepmc.org/abstract/MED/27646952
[9] Crona J, Norlén O, Antonodimitrakis P, et al. Multiple and Secondary Hormone Secretion in Patients With Metastatic Pancreatic Neuroendocrine Tumours[J]. J Clin Endocrinol Metab, 2016, 101: 445-452. DOI: 10.1210/jc.2015-2436
[10] Grant CS. Insulinoma[J]. Best Pract Res Clin Gastroenterol, 2005, 19: 783-798. DOI: 10.1016/j.bpg.2005.05.008
[11] Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors[J]. Gastroenterology, 2008, 135: 1469-1492. DOI: 10.1053/j.gastro.2008.05.047
[12] Gao H, Wang W, Xu H, et al. Distinct clinicopathological and prognostic features of insulinoma with synchronous distant metastasis[J]. Pancreatology, 2019, 19: 472-477. DOI: 10.1016/j.pan.2019.02.011
[13] Whipple AO, Frantz VK. Adenoma of lslet cells with hyperinsulinism: a review[J]. Ann Surg, 1935, 101: 1299-1335. DOI: 10.1097/00000658-193506000-00001
[14] Alexakis N, Connor S, Ghaneh P, et al. Hereditary pancreatic endocrine tumours[J]. Pancreatology, 2004, 4: 417-435. http://www.karger.com/article/pdf/79616
[15] Jensen RT, Niederle B, Mitry E, et al. Gastrinoma (duodenal and pancreatic)[J]. Neuroendocrinology, 2006, 84: 173-182. DOI: 10.1159/000098009
[16] Gibril F, Schumann M, Pace A, et al. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature[J]. Medicine(Baltimore), 2004, 83: 43-83.
[17] Luo G, Liu Z, Guo M, et al. A comprehensive comparison of clinicopathologic and imaging features of incidental/symptomatic non-functioning pancreatic neuroendocrine tumors: A retrospective study of a single center[J]. Pancreatology, 2015, 15: 519-524. DOI: 10.1016/j.pan.2015.08.009
[18] Jensen RT, Berna MJ, Bingham DB, et al. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies[J]. Cancer, 2008, 113: 1807-1843. DOI: 10.1002/cncr.23648
[19] Thakker RV. Multiple endocrine neoplasia type 1[J]. Endocrinol Metab Clin North Am, 2000, 29: 541-567. DOI: 10.1016/S0889-8529(05)70150-X
[20] Falconi M, Eriksson B, Kaltsas G, et al. ENETS Cons-ensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors[J]. Neuroendocrinology, 2016, 103: 153-171. DOI: 10.1159/000443171
[21] Fendrich V, Waldmann J, Bartsch DK, et al. Surgical management of pancreatic endocrine tumors[J]. Nat Rev Clin Oncol, 2009, 6: 419-428. DOI: 10.1038/nrclinonc.2009.82
[22] Yang X, Yang Y, Li Z, et al. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: a systematic review and meta-analysis[J]. PLoS One, 2015, 10: e0124884. DOI: 10.1371/journal.pone.0124884
[23] Han X, Zhang C, Tang M, et al. The value of serum chromogranin A as a predictor of tumor burden, therapeutic response, and nomogram-based survival in well-moderate nonfunctional pancreatic neuroendocrine tumors with liver metastases[J]. Eur J Gastroenterol Hepatol, 2015, 27: 527-535. DOI: 10.1097/MEG.0000000000000332
[24] Panzuto F, Severi C, Cannizzaro R, et al. Utility of combined use of plasma levels of chromogranin A and pancreatic polypeptide in the diagnosis of gastrointestinal and pancreatic endocrine tumors[J]. J Endocrinol Invest, 2004, 27: 6-11. http://www.researchgate.net/publication/8648427_Panzuto_F_Severi_C_Cannizzaro_R_et_al_Utility_of_combined_use_of_plasma_levels_of_chromogranin_A_and_pancreatic_polypeptide_in_the_diagnosis_of_gastrointestinal_and_pancreatic_endocrine_tumors
[25] Baudin E, Bidart JM, Bachelot A, et al. Impact of chromogranin A measurement in the work-up of neuroendocrine tumors[J]. Ann Oncol, 2001, 12 Suppl 2: S79-S82. http://www.tandfonline.com/servlet/linkout?suffix=CIT0003&dbid=8&doi=10.1080%2F2331205X.2018.1484602&key=11762357
[26] Di Giacinto P, Rota F, Rizza L, et al. Chromogranin A: From Laboratory to Clinical Aspects of Patients with Neuroendocrine Tumors[J]. Int J Endocrinol, 2018, 2018: 8126087. http://europepmc.org/articles/PMC6051263/
[27] Cimitan M, Buonadonna A, Cannizzaro R, et al. Somatostatin receptor scintigraphy versus chromogranin A assay in the management of patients with neuroendocrine tumors of different types: clinical role[J]. Ann Oncol, 2003, 14: 1135-1141. DOI: 10.1093/annonc/mdg279
[28] Qiao XW, Qiu L, Chen YJ, et al. Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas[J]. BMC Endocr Disord, 2014, 14: 64. DOI: 10.1186/1472-6823-14-64
[29] Korse CM, Taal BG, Vincent A, et al. Choice of tumour markers in patients with neuroendocrine tumours is dependent on the histological grade. A marker study of Chromogranin A, Neuron specific enolase, Progastrin-releasing peptide and cytokeratin fragments[J]. Eur J Cancer, 2012, 48: 662-671. DOI: 10.1016/j.ejca.2011.08.012
[30] Yao JC, Pavel M, Phan AT, et al. Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus[J]. J Clin Endocrinol Metab, 2011, 96: 3741-3749. DOI: 10.1210/jc.2011-0666
[31] Chen L, Zhang Y, Lin Y, et al. The role of elevated serum procalcitonin in neuroendocrine neoplasms of digestive system[J]. Clin Biochem, 2017, 50: 982-987. DOI: 10.1016/j.clinbiochem.2017.06.010
[32] Tao M, Yuan C, Xiu D, et al. Analysis of risk factors affecting the prognosis of pancreatic neuroendocrine tumors[J]. Chin Med J (Engl), 2014, 127: 2924-2928. http://www.ncbi.nlm.nih.gov/pubmed/25131229
[33] Öberg K, Califano A, Strosberg JR, et al. A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood[J]. Ann Oncol, 2020, 31: 202-212. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX201719005.htm [34] Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline[J]. J Clin Endocrinol Metab, 2009, 94: 709-728. DOI: 10.1210/jc.2008-1410
[35] Berna MJ, Hoffmann KM, Serrano J, et al. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature[J]. Medicine (Baltimore), 2006, 85: 295-330. DOI: 10.1097/01.md.0000236956.74128.76
[36] Roy PK, Venzon DJ, Feigenbaum KM, et al. Gastric secretion in Zollinger-Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis--a prospective NIH study of 235 patients and a review of 984 cases in the literature[J]. Medicine (Baltimore), 2001, 80: 189-222. DOI: 10.1097/00005792-200105000-00005
[37] Berna MJ, Hoffmann KM, Long SH, et al. Serum gastrin in Zollinger-Ellison syndrome: Ⅱ. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features[J]. Medicine (Baltimore), 2006, 85: 331-364. DOI: 10.1097/MD.0b013e31802b518c
[38] Corleto VD, Annibale B, Gibril F, et al. Does the widespread use of proton pump inhibitors mask, complicate and/or delay the diagnosis of Zollinger-Ellison syndrome?[J]. Aliment Pharmacol Ther, 2001, 15: 1555-1561. DOI: 10.1046/j.1365-2036.2001.01085.x
[39] Sundin A, Arnold R, Baudin E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine & Hybrid Imaging[J]. Neuroendocrinology, 2017, 105: 212-244. DOI: 10.1159/000471879
[40] Luo Y, Chen J, Huang K, et al. Early evaluation of sunitinib for the treatment of advanced gastroenteropancreatic neuroendocrine neoplasms via CT imaging: RECIST 1.1 or Choi Criteria?[J]. BMC Cancer, 2017, 17: 154. DOI: 10.1186/s12885-017-3150-7
[41] Luo Y, Dong Z, Chen J, et al. Pancreatic neuroendocrine tumours: correlation between MSCT features and pathological classification[J]. Eur Radiol, 2014, 24: 2945-2952. DOI: 10.1007/s00330-014-3317-4
[42] Luo Y, Chen X, Chen J, et al. Preoperative Prediction of Pancreatic Neuroendocrine Neoplasms Grading Based on Enhanced Computed Tomography Imaging: Validation of Deep Learning with a Convolutional Neural Network[J]. Neuroendocrinology, 2020, 110: 338-350. DOI: 10.1159/000503291
[43] Liu Y, Chen W, Cui W, et al. Quantitative Pretreatment CT Parameters as Predictors of Tumor Response of Neuroendocrine Tumor Liver Metastasis to Transcatheter Arterial Bland Embolization[J]. Neuroendocrinology, 2020, 110: 697-704. DOI: 10.1159/000504257
[44] Liang W, Yang P, Huang R, et al. A Combined Nomo-gram Model to Preoperatively Predict Histologic Grade in Pancreatic Neuroendocrine Tumors[J]. Clin Cancer Res, 2019, 25: 584-594. DOI: 10.1158/1078-0432.CCR-18-1305
[45] Zhu L, Wu WM, Xue HD, et al. Sporadic insulinomas on volume perfusion CT: dynamic enhancement patterns and timing of optimal tumour-parenchyma contrast[J]. Eur Radiol, 2017, 27: 3491-3498. DOI: 10.1007/s00330-016-4709-4
[46] Zhu L, Xue HD, Sun H, et al. Isoattenuating insulinomas at biphasic contrast-enhanced CT: frequency, clinicopathologic features and perfusion characteristics[J]. Eur Radiol, 2016, 26: 3697-3705. DOI: 10.1007/s00330-016-4216-7
[47] Zhu L, Xue HD, Sun H, et al. Insulinoma detection with MDCT: is there a role for whole-pancreas perfusion?[J]. AJR Am J Roentgenol, 2017, 208: 306-314. DOI: 10.2214/AJR.16.16351
[48] Li J, Chen XY, Xu K, et al. Detection of insulinoma: one-stop pancreatic perfusion CT with calculated mean temporal images can replace the combination of bi-phasic plus perfusion scan[J]. Eur Radiol, 2020, 30: 4164-4174. DOI: 10.1007/s00330-020-06657-4
[49] d'Assignies G, Assignies G, Couvelard A, et al. Pancreatic endocrine tumors: tumor blood flow assessed with perfusion CT reflects angiogenesis and correlates with prognostic factors[J]. Radiology, 2009, 250: 407-416. DOI: 10.1148/radiol.2501080291
[50] Zhu L, Xue H, Sun Z, et al. Prospective comparison of biphasic contrast-enhanced CT, volume perfusion CT, and 3 Tesla MRI with diffusion-weighted imaging for insulinoma detection[J]. J Magn Reson Imaging, 2017, 46: 1648-1655. DOI: 10.1002/jmri.25709
[51] He M, Xu J, Sun Z, et al. Prospective Comparison of Reduced Field-of-View (rFOV) and Full FOV (fFOV) Diffusion-Weighted Imaging (DWI) in the Assessment of Insulinoma: Image Quality and Lesion Detection[J]. Acad Radiol, 2020, 27: 1572-1579. DOI: 10.1016/j.acra.2019.11.019
[52] Pamuklar E, Semelka RC. MR imaging of the pancreas[J]. Magn Reson Imaging Clin N Am, 2005, 13: 313-330. DOI: 10.1016/j.mric.2005.03.012
[53] Sun H, Zhou J, Liu K, et al. Pancreatic neuroendocrine tumors: MR imaging features preoperatively predict lymph node metastasis[J]. Abdom Radiol (NY), 2019, 44: 1000-1009. DOI: 10.1007/s00261-018-1863-y
[54] Tirumani SH, Jagannathan JP, Braschi-Amirfarzan M, et al. Value of hepatocellular phase imaging after intravenous gadoxetate disodium for assessing hepatic metastases from gastroenteropancreatic neuroendocrine tumors: comparison with other MRI pulse sequences and with extracellular agent[J]. Abdom Radiol (NY), 2018, 43: 2329-2339. DOI: 10.1007/s00261-018-1496-1
[55] Chiti A, Fanti S, Savelli G, et al. Comparison of somatostatin receptor imaging, computed tomography and ultrasound in the clinical management of neuroendocrine gastro-entero-pancreatic tumours[J]. Eur J Nucl Med, 1998, 25: 1396-1403. DOI: 10.1007/s002590050314
[56] Dietrich CF, Jenssen C. Modern ultrasound imaging of pancreatic tumors[J]. Ultrasonography, 2020, 39: 105-113. DOI: 10.14366/usg.19039
[57] Wu W, Chen MH, Yin SS, et al. The role of contrast-enhanced sonography of focal liver lesions before percutaneous biopsy[J]. AJR Am J Roentgenol, 2006, 187: 752-761. DOI: 10.2214/AJR.05.0535
[58] Liu Y, Shi S, Hua J, et al. Differentiation of solid-pseudopapillary tumors of the pancreas from pancreatic neuroendocrine tumors by using endoscopic ultrasound[J]. Clin Res Hepatol Gastroenterol, 2020, 44: 947-953. DOI: 10.1016/j.clinre.2020.02.002
[59] Di Leo M, Poliani L, Rahal D, et al. Pancreatic Neuroendocrine Tumours: The Role of Endoscopic Ultrasound Biopsy in Diagnosis and Grading Based on the WHO 2017 Classification[J]. Dig Dis, 2019, 37: 325-333. DOI: 10.1159/000499172
[60] Choi JH, Park DH, Kim MH, et al. Outcomes after endoscopic ultrasound-guided ethanol-lipiodol ablation of small pancreatic neuroendocrine tumors[J]. Dig Endosc, 2018, 30: 652-658. DOI: 10.1111/den.13058
[61] He G, Wang J, Chen B, et al. Feasibility of endoscopic submucosal dissection for upper gastrointestinal submucosal tumors treatment and value of endoscopic ultrasonography in pre-operation assess and post-operation follow-up: a prospective study of 224 cases in a single medical center[J]. Surg Endosc, 2016, 30: 4206-4213. DOI: 10.1007/s00464-015-4729-1
[62] Li W, An L, Liu R, et al. Laparoscopic ultrasound enhances diagnosis and localization of insulinoma in pancreatic head and neck for laparoscopic surgery with satisfactory postsurgical outcomes[J]. Ultrasound Med Biol, 2011, 37: 1017-1023. DOI: 10.1016/j.ultrasmedbio.2011.04.003
[63] Ruf J, Heuck F, Schiefer J, et al. Impact of Multiphase 68Ga-DOTATOC-PET/CT on therapy management in patients with neuroendocrine tumors[J]. Neuroendocrinology, 2010, 91: 101-109. DOI: 10.1159/000265561
[64] Luo Y, Pan Q, Yao S, et al. Glucagon-Like Peptide-1 Receptor PET/CT with 68Ga-NOTA-Exendin-4 for Detecting Localized Insulinoma: A Prospective Cohort Study[J]. J Nucl Med, 2016, 57: 715-720. DOI: 10.2967/jnumed.115.167445
[65] Binderup T, Knigge U, Loft A, et al. Functional imaging of neuroendocrine tumors: a head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, and 18F-FDG PET[J]. J Nucl Med, 2010, 51: 704-712. DOI: 10.2967/jnumed.109.069765
[66] Rinzivillo M, Partelli S, Prosperi D, et al. Clinical usefulness of (18)F-fluorodeoxyglucose positron emission tomography in the diagnostic algorithm of advanced entero-pancreatic neuroendocrine neoplasms[J]. Oncologist, 2018, 23: 186-192. DOI: 10.1634/theoncologist.2017-0278
[67] Grillo F, Albertelli M, Brisigotti MP, et al. Grade incre-ases in gastroenteropancreatic neuroendocrine tumor metas-tases compared to the primary tumor[J]. Neuroendocrinology, 2016, 103: 452-459. DOI: 10.1159/000439434
[68] Botling J, Lamarca A, Bajic D, et al. Longitudinal increase in Ki67 and high-grade transformation in pancreatic neuroendocrine tumours(PNETs)[J]. Ann Oncol, 2019, 30: v564-v573. http://www.researchgate.net/publication/336195649_1386PDLongitudinal_increase_in_Ki67_and_high-grade_transformation_in_pancreatic_neuroendocrine_tumours_PNETs
[69] Rindi G, Bordi C, La Rosa S, et al. Gastroenteropan-creatic (neuro)endocrine neoplasms: the histology report[J]. Dig Liver Dis, 2011, 43 Suppl 4: S356-S360. DOI: 10.1016/S1590-8658(11)60591-4
[70] Schmitt AM, Riniker F, Anlauf M, et al. Islet 1 (Isl1) expression is a reliable marker for pancreatic endocrine tumors and their metastases[J]. Am J Surg Pathol, 2008, 32: 420-425. DOI: 10.1097/PAS.0b013e318158a397
[71] Sangoi AR, Ohgami RS, Pai RK, et al. PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma[J]. Mod Pathol, 2011, 24: 412-424. DOI: 10.1038/modpathol.2010.176
[72] Al-Hawary MM, Francis IR, Chari ST, et al. Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the society of abdominal radiology and the american pancreatic association[J]. Gastroenterology, 2014, 146: 291-304. e1. DOI: 10.1053/j.gastro.2013.11.004
[73] Goode PN, Farndon JR, Anderson J, et al. Diazoxide in the management of patients with insulinoma[J]. World J Surg, 1986, 10: 586-592. DOI: 10.1007/BF01655532
[74] Ito T, Igarashi H, Uehara H, et al. Pharmacotherapy of Zollinger-Ellison syndrome[J]. Expert Opin Pharmacother, 2013, 14: 307-321. DOI: 10.1517/14656566.2013.767332
[75] Oberg KE, Reubi JC, Kwekkeboom DJ, et al. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy[J]. Gastroenterology, 2010, 139: 742-753, 753. e1. DOI: 10.1053/j.gastro.2010.07.002
[76] Eldor R, Glaser B, Fraenkel M, et al. Glucagonoma and the glucagonoma syndrome - cumulative experience with an elusive endocrine tumour[J]. Clin Endocrinol (Oxf), 2011, 74: 593-598. DOI: 10.1111/j.1365-2265.2011.03967.x
[77] Graham GW, Unger BP, Coursin DB. Perioperative management of selected endocrine disorders[J]. Int Anesthesiol Clin, 2000, 38: 31-67. DOI: 10.1097/00004311-200010000-00004
[78] Chua TC, Yang TX, Gill AJ, et al. Systematic Review and Meta-Analysis of Enucleation Versus Standardized Resection for Small Pancreatic Lesions[J]. Ann Surg Oncol, 2016, 23: 592-599. http://europepmc.org/abstract/MED/26307231
[79] Tian F, Hong XF, Wu WM, et al. Propensity score-matched analysis of robotic versus open surgical enucleation for small pancreatic neuroendocrine tumours[J]. Br J Surg, 2016, 103: 1358-1364. DOI: 10.1002/bjs.10220
[80] Partelli S, Cirocchi R, Crippa S, et al. Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms[J]. Br J Surg, 2017, 104: 34-41. DOI: 10.1002/bjs.10451
[81] Lee LC, Grant CS, Salomao DR, et al. Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management[J]. Surgery, 2012, 152: 965-974. DOI: 10.1016/j.surg.2012.08.038
[82] Lombardi M, De Lio N, Funel N, et al. Prognostic factors for pancreatic neuroendocrine neoplasms (pNET) and the risk of small non-functioning pNET[J]. J Endocrinol Invest, 2015, 38: 605-613. DOI: 10.1007/s40618-014-0219-x
[83] Liu Y, Ye S, Zhu Y, et al. Impact of tumour size on metastasis and survival in patients with pancreatic neuroen-docrine tumours (PNETs): A population based study[J]. J Cancer, 2019, 10: 6349-6357. DOI: 10.7150/jca.27779
[84] Mao WL, Han X, Lyu Y, et al. Propensity score-matched analysis of clinical outcome after enucleation versus regular pancreatectomy in patients with small non-functional pancreatic neuroendocrine tumors[J]. Pancreatology, 2020, 20: 169-176. DOI: 10.1016/j.pan.2019.12.007
[85] Mao R, Zhao H, Li K, et al. Outcomes of Lymph Node Dissection for Non-metastatic Pancreatic Neuroendocrine Tumors: A Propensity Score-Weighted Analysis of the National Cancer Database[J]. Ann Surg Oncol, 2019, 26: 2722-2729. DOI: 10.1245/s10434-019-07506-5
[86] Sallinen V, Haglund C, Seppänen H. Outcomes of resected nonfunctional pancreatic neuroendocrine tumors: Do size and symptoms matter?[J]. Surgery, 2015, 158: 1556-1563. DOI: 10.1016/j.surg.2015.04.035
[87] Kuo EJ, Salem RR. Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size[J]. Ann Surg Oncol, 2013, 20: 2815-2821. DOI: 10.1245/s10434-013-3005-7
[88] Curran T, Pockaj BA, Gray RJ, et al. Importance of lymph node involvement in pancreatic neuroendocrine tumors: impact on survival and implications for surgical resection[J]. J Gastrointest Surg, 2015, 19: 152-160; discussion 160. DOI: 10.1007/s11605-014-2624-z
[89] Hashim YM, Trinkaus KM, Linehan DC, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs)[J]. Ann Surg, 2014, 259: 197-203. DOI: 10.1097/SLA.0000000000000348
[90] Yang M, Zeng L, Zhang Y, et al. Surgical treatment and clinical outcome of nonfunctional pancreatic neuroendocrine tumors: a 14-year experience from one single center[J]. Medicine (Baltimore), 2014, 93: e94. DOI: 10.1097/MD.0000000000000094
[91] Wu L, Sahara K, Tsilimigras DI, et al. Therapeutic index of lymphadenectomy among patients with pancreatic neuroendocrine tumors: A multi-institutional analysis[J]. J Surg Oncol, 2019, 120: 1080-1086. DOI: 10.1002/jso.25689
[92] Luo G, Jin K, Cheng H, et al. Revised nodal stage for pancreatic neuroendocrine tumors[J]. Pancreatology, 2017, 17: 599-604. DOI: 10.1016/j.pan.2017.06.003
[93] Sahara K, Tsilimigras DI, Mehta R, et al. Trends in the Number of Lymph Nodes Evaluated Among Patients with Pancreatic Neuroendocrine Tumors in the United States: A Multi-Institutional and National Database Analysis[J]. Ann Surg Oncol, 2020, 27: 1203-1212. DOI: 10.1245/s10434-019-08120-1
[94] Zhang XF, Lopez-Aguiar AG, Poultsides G, et al. Minimally invasive versus open distal pancreatectomy for pancreatic neuroendocrine tumors: An analysis from the U.S. neuroendocrine tumor study group[J]. J Surg Oncol, 2019, 120: 231-240. http://www.ncbi.nlm.nih.gov/pubmed/31001868
[95] Chen L, Chen J. Perspective of neo-adjuvant/conversion and adjuvant therapy for pancreatic neuroendocrine tumors[J]. J Pancreatol, 2019, 2: 91-99. DOI: 10.1097/JP9.0000000000000023
[96] Solorzano CC, Lee JE, Pisters PW, et al. Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients[J]. Surgery, 2001, 130: 1078-1085. DOI: 10.1067/msy.2001.118367
[97] Sarmiento JM, Heywood G, Rubin J, et al. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival[J]. J Am Coll Surg, 2003, 197: 29-37. DOI: 10.1016/S1072-7515(03)00230-8
[98] Kleine M, Schrem H, Vondran FW, et al. Extended surgery for advanced pancreatic endocrine tumours[J]. Br J Surg, 2012, 99: 88-94.
[99] Lin C, Dai H, Hong X, et al. The prognostic impact of primary tumor resection in pancreatic neuroendocrine tumors with synchronous multifocal liver metastases[J]. Pancreatology, 2018, 18: 608-614. DOI: 10.1016/j.pan.2018.04.014
[100] Schurr PG, Strate T, Rese K, et al. Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience[J]. Ann Surg, 2007, 245: 273-281. DOI: 10.1097/01.sla.0000232556.24258.68
[101] Frilling A, Li J, Malamutmann E, et al. Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease[J]. Br J Surg, 2009, 96: 175-184. DOI: 10.1002/bjs.6468
[102] Jin K, Xu J, Chen J, et al. Surgical management for non-functional pancreatic neuroendocrine neoplasms with synchronous liver metastasis: A consensus from the Chinese Study Group for Neuroendocrine Tumors (CSNET)[J]. Int J Oncol, 2016, 49: 1991-2000. DOI: 10.3892/ijo.2016.3711
[103] De Jong MC, Farnell MB, Sclabas G, et al. Liver-directed therapy for hepatic metastases in patients undergoing pancreaticoduodenectomy: a dual-center analysis[J]. Ann Surg, 2010, 252: 142-148. DOI: 10.1097/SLA.0b013e3181dbb7a7
[104] Bertani E, Fazio N, Botteri E, et al. Resection of the primary pancreatic neuroendocrine tumor in patients with unresectable liver metastases: possible indications for a multimodal approach[J]. Surgery, 2014, 155: 607-614. DOI: 10.1016/j.surg.2013.12.024
[105] Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system[J]. Ann Oncol, 2004, 15: 966-973. DOI: 10.1093/annonc/mdh216
[106] Han X, Lou W. Concomitant pancreatic neuroendocrine tumors in hereditary tumor syndromes: who, when and how to operate?[J]. J Pancreatol, 2019, 2: 48-53. DOI: 10.1097/JP9.0000000000000016
[107] Yates CJ, Newey PJ, Thakker RV. Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1[J]. Lancet Diabetes Endocrinol, 2015, 3: 895-905. DOI: 10.1016/S2213-8587(15)00043-1
[108] Nell S, Verkooijen HM, Pieterman C, et al. Management of MEN1 Related Nonfunctioning Pancreatic NETs: A Shifting Paradigm: Results From the DutchMEN1 Study Group[J]. Ann Surg, 2018, 267: 1155-1160. DOI: 10.1097/SLA.0000000000002183
[109] Triponez F, Sadowski SM, Pattou F, et al. Long-term Follow-up of MEN1 Patients Who Do Not Have Initial Surgery for Small ≤2 cm Nonfunctioning Pancreatic Neuroendocrine Tumors, an AFCE and GTE Study: Association Franco-phone de Chirurgie Endocrinienne & Groupe d'Etude des Tumeurs Endocrines[J]. Ann Surg, 2018, 268: 158-164. DOI: 10.1097/SLA.0000000000002191
[110] Kim H, Song KB, Hwang DW, et al. Time-trend and recurrence analysis of pancreatic neuroendocrine tumors[J]. Endocr Connect, 2019, 8: 1052-1060. DOI: 10.1530/EC-19-0282
[111] Chouliaras K, Newman NA, Shukla M, et al. Analysis of recurrence after the resection of pancreatic neuroendocrine tumors[J]. J Surg Oncol, 2018, 118: 416-421. DOI: 10.1002/jso.25146
[112] Gao H, Liu L, Wang W, et al. Novel recurrence risk stratification of resected pancreatic neuroendocrine tumor[J]. Cancer Lett, 2018, 412: 188-193. DOI: 10.1016/j.canlet.2017.10.036
[113] Dong DH, Zhang XF, Lopez-Aguiar AG, et al. Resection of pancreatic neuroendocrine tumors: defining patterns and time course of recurrence[J]. HPB (Oxford), 2020, 22: 215-223. DOI: 10.1016/j.hpb.2019.05.020
[114] Marchegiani G, Landoni L, Andrianello S, et al. Patterns of Recurrence after Resection for Pancreatic Neuroendocrine Tumors: Who, When, and Where?[J]. Neuroendocrinology, 2019, 108: 161-171. DOI: 10.1159/000495774
[115] Ausania F, Senra Del Rio P, Gomez-Bravo MA, et al. Can we predict recurrence in WHO G1-G2 pancreatic neuroendocrine neoplasms? Results from a multi-institutional Spanish study[J]. Pancreatology, 2019, 19: 367-371. DOI: 10.1016/j.pan.2019.01.007
[116] Dong DH, Zhang XF, Poultsides G, et al. Impact of tumor size and nodal status on recurrence of nonfunctional pancreatic neuroendocrine tumors ≤2 cm after curative resection: A multi-institutional study of 392 cases[J]. J Surg Oncol, 2019, 120: 1071-1079. DOI: 10.1002/jso.25716
[117] Zhou B, Duan J, Yan S, et al. Prognostic factors of long-term outcome in surgically resectable pancreatic neuroendocrine tumors: A 12-year experience from a single center[J]. Oncol Lett, 2017, 13: 1157-1164. DOI: 10.3892/ol.2017.5561
[118] Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study[J]. Ann Oncol, 2013, 24: 152-160. DOI: 10.1093/annonc/mds276
[119] Lu Y, Zhao Z, Wang J, et al. Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: A meta-analysis[J]. Medicine (Baltimore), 2018, 97: e12784. DOI: 10.1097/MD.0000000000012784
[120] Barrett JR, Rendell V, Pokrzywa C, et al. Adjuvant therapy following resection of gastroenteropancreatic neuroendocrine tumors provides no recurrence or survival benefit[J]. J Surg Oncol, 2020, 121: 1067-1073. DOI: 10.1002/jso.25896
[121] Gao S, Shi X, Ma H, et al. The effect of using long-acting octreotide as adjuvant therapy for patients with grade 2 pancreatic neuroendocrine tumors after radical resection[J]. J Pancreatol, 2020, 3: 167-172. DOI: 10.1097/JP9.0000000000000058
[122] Kvols LK, Moertel CG, O'Connell MJ, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue[J]. N Engl J Med, 1986, 315: 663-666. DOI: 10.1056/NEJM198609113151102
[123] Ruszniewski P, Ish-Shalom S, Wymenga M, et al. Rapid and sustained relief from the symptoms of carcinoid syndrome: results from an open 6-month study of the 28-day prolonged-release formulation of lanreotide[J]. Neuroendocrinology, 2004, 80: 244-251. DOI: 10.1159/000082875
[124] Rinke A, Krug S. Neuroendocrine tumours-Medical therapy: Biological[J]. Best Pract Res Clin Endocrinol Metab, 2016, 30: 79-91. DOI: 10.1016/j.beem.2015.09.004
[125] Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors[J]. N Engl J Med, 2014, 371: 224-233. DOI: 10.1056/NEJMoa1316158
[126] Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group[J]. J Clin Oncol, 2009, 27: 4656-4663. DOI: 10.1200/JCO.2009.22.8510
[127] Oberg K. Interferon in the management of neuroendocrine GEP-tumors: a review[J]. Digestion, 2000, 62 Suppl 1: 92-97. http://www.karger.com/Article/Abstract/51862
[128] Pavel ME, Baum U, Hahn EG, et al. Efficacy and tolerability of pegylated IFN-alpha in patients with neuroendocrine gastroenteropancreatic carcinomas[J]. J Interferon Cytokine Res, 2006, 26: 8-13. DOI: 10.1089/jir.2006.26.8
[129] de Mestier L, Walter T, Brixi H, et al. Comparison of Temozolomide-Capecitabine to 5-Fluorouracile-Dacarbazine in 247 Patients with Advanced Digestive Neuroendocrine Tumors Using Propensity Score Analyses[J]. Neuroendocrinology, 2019, 108: 343-353. DOI: 10.1159/000498887
[130] Cives M, Ghayouri M, Morse B, et al. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors[J]. Endocr Relat Cancer, 2016, 23: 759-767. DOI: 10.1530/ERC-16-0147
[131] Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas[J]. J Clin Oncol, 2004, 22: 4762-4771. DOI: 10.1200/JCO.2004.04.024
[132] Kunz PL, Catalano PJ, Nimeiri H, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: a trial of the ECOG-ACRIN Cancer Research Group(E2211)[J]. J Clin Oncol, 2018, 36: 4004. DOI: 10.1200/JCO.2018.36.15_suppl.4004
[133] Wang W, Zhang Y, Peng Y, et al. A Ki-67 index to predict treatment response to the capecitabine temozolomide(CAPTEM) regimen in neuroendocrine neoplasms: a retrospective multicenter study[J]. Neuroendocrinology, 2020. doi: 10.1159/000510159[Epub ahead of print].
[134] Mitry E, Baudin E, Ducreux M, et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin[J]. Br J Cancer, 1999, 81: 1351-1355. DOI: 10.1038/sj.bjc.6690325
[135] Iwasa S, Morizane C, Okusaka T, et al. Cisplatin and etoposide as first-line chemotherapy for poorly differentiated neuroendocrine carcinoma of the hepatobiliary tract and pancreas[J]. Jpn J Clin Oncol, 2010, 40: 313-318. DOI: 10.1093/jjco/hyp173
[136] Lu ZH, Li J, Lu M, et al. Feasibility and efficacy of combined cisplatin plus irinotecan chemotherapy for gastroenteropancreatic neuroendocrine carcinomas[J]. Med Oncol, 2013, 30: 664. DOI: 10.1007/s12032-013-0664-y
[137] Nakano K, Takahashi S, Yuasa T, et al. Feasibility and efficacy of combined cisplatin and irinotecan chemotherapy for poorly differentiated neuroendocrine carcinomas[J]. Jpn J Clin Oncol, 2012, 42: 697-703. DOI: 10.1093/jjco/hys085
[138] Bajetta E, Catena L, Procopio G, et al. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours?[J]. Cancer Chemother Pharmacol, 2007, 59: 637-642. DOI: 10.1007/s00280-006-0306-6
[139] Hadoux J, Malka D, Planchard D, et al. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma [J]. Endocr Relat Cancer, 2015, 22: 289-298. DOI: 10.1530/ERC-15-0075
[140] Hentic O, Hammel P, Couvelard A, et al. FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3[J]. Endocr Relat Cancer, 2012, 19: 751-757. DOI: 10.1530/ERC-12-0002
[141] Chan JA, Stuart K, Earle CC, et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors[J]. J Clin Oncol, 2012, 30: 2963-2968. DOI: 10.1200/JCO.2011.40.3147
[142] Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors[J]. N Engl J Med, 2011, 364: 514-523. DOI: 10.1056/NEJMoa1009290
[143] Kulke MH, Ruszniewski P, Van Cutsem E, et al. A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in adv-anced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial[J]. Ann Oncol, 2017, 28: 1309-1315. DOI: 10.1093/annonc/mdx078
[144] Panzuto F, Rinzivillo M, Fazio N, et al. Real-world study of everolimus in advanced progressive neuroendocrine tumors[J]. Oncologist, 2014, 19: 966-974. DOI: 10.1634/theoncologist.2014-0037
[145] Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors[J]. N Engl J Med, 2011, 364: 501-513. DOI: 10.1056/NEJMoa1003825
[146] Wang Y, Jin K, Tan H, et al. Sunitinib is effective and tolerable in Chinese patients with advanced pancreatic neuroendocrine tumors: a multicenter retrospective study in China[J]. Cancer Chemother Pharmacol, 2017, 80: 507-516. DOI: 10.1007/s00280-017-3367-9
[147] Xu J, Shen L, Bai C, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study[J]. Lancet Oncol, 2020, 21: 1489-1499. DOI: 10.1016/S1470-2045(20)30493-9
[148] Capdevila J, Fazio N, Lopez CL, et al. Final results of the TALENT trial(GETNE1509): a prospective multicohort phase Ⅱ study of lenvatinib in patients(pts) with G1/G2 advanced pancreatic(panNETs) and gastrointestinal(giNETs) neuroendocrine tumors(NETs)[J]. J Clin Oncol, 2019, 37: 4106. DOI: 10.1200/JCO.2019.37.15_suppl.4106
[149] Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors[J]. N Engl J Med, 2017, 376: 125-135. DOI: 10.1056/NEJMoa1607427
[150] Villard L, Romer A, Marincek N, et al. Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus[(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers[J]. J Clin Oncol, 2012, 30: 1100-1106. DOI: 10.1200/JCO.2011.37.2151
[151] McStay MK, Maudgil D, Williams M, et al. Large-volume liver metastases from neuroendocrine tumors: hepatic intraarterial 90Y-DOTA-lanreotide as effective palliative therapy[J]. Radiology, 2005, 237: 718-726. DOI: 10.1148/radiol.2372041203
[152] Claringbold PG, Brayshaw PA, Price RA, et al. Phase Ⅱ study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours[J]. Eur J Nucl Med Mol Imaging, 2011, 38: 302-311. DOI: 10.1007/s00259-010-1631-x
[153] Kashyap R, Hofman MS, Michael M, et al. Favourable outcomes of (177)Lu-octreotate peptide receptor chemoradionuclide therapy in patients with FDG-avid neuroendocrine tumours[J]. Eur J Nucl Med Mol Imaging, 2015, 42: 176-185. DOI: 10.1007/s00259-014-2906-4
[154] Vezzosi D, Bennet A, Rochaix P, et al. Octreotide in insulinoma patients: efficacy on hypoglycemia, relationships with Octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies[J]. Eur J Endocrinol, 2005, 152: 757-767. DOI: 10.1530/eje.1.01901
[155] Healy ML, Dawson SJ, Murray RM, et al. Severe hypoglycaemia after long-acting octreotide in a patient with an unrecognized malignant insulinoma[J]. Intern Med J, 2007, 37: 406-409. DOI: 10.1111/j.1445-5994.2007.01371.x
[156] Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma treated with everolimus[J]. N Engl J Med, 2009, 360: 195-197. DOI: 10.1056/NEJMc0806740656566.7.2.169
[157] Nieto JM, Pisegna JR. The role of proton pump inhibitors in the treatment of Zollinger-Ellison syndrome[J]. Expert Opin Pharmacother, 2006, 7: 169-175. DOI: 10.1517/14656566.7.2.169
[158] Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium[J]. Curr Gastroenterol Rep, 2010, 12: 448-457. DOI: 10.1007/s11894-010-0141-0
[159] Lamberts SW, van der Lely AJ, de Herder WW, et al. Octreotide[J]. N Engl J Med, 1996, 334: 246-254. DOI: 10.1056/NEJM199601253340408
[160] Delaunoit T, Neczyporenko F, Rubin J, et al. Medical management of pancreatic neuroendocrine tumors[J]. Am J Gastroenterol, 2008, 103: 475-483; quiz 484. DOI: 10.1111/j.1572-0241.2007.01643.x
[161] Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients[J]. J Clin Endocrinol Metab, 2015, 100: 4146-4154. DOI: 10.1210/jc.2015-2616
[162] Yuen KC, Williams G, Kushner H, et al. Association between mifepristone dose, efficacy, and tolerability in patients with cushing syndrome[J]. Endocr Pract, 2015, 21: 1087-1092. DOI: 10.4158/EP15760.OR
[163] Wang YH, Lin Y, Xue L, et al. Relationship between clinical characteristics and survival of gastroenteropancreatic neuroendocrine neoplasms: a single-institution analysis (1995-2012) in South China[J]. BMC Endocr Disord, 2012, 12: 30. DOI: 10.1186/1472-6823-12-30
[164] Farley HA, Pommier RF. Treatment of Neuroendocrine Liver Metastases[J]. Surg Oncol Clin N Am, 2016, 25: 217-225. DOI: 10.1016/j.soc.2015.08.010
[165] Du S, Ni J, Weng L, et al. Aggressive Locoregional Treatment Improves the Outcome of Liver Metastases from Grade 3 Gastroenteropancreatic Neuroendocrine Tumors[J]. Medicine (Baltimore), 2015, 94: e1429. DOI: 10.1097/MD.0000000000001429
[166] Kitano M, Davidson GW, Shirley LA, et al. Transarterial Chemoembolization for Metastatic Neuroendocrine Tumors With Massive Hepatic Tumor Burden: Is the Benefit Worth the Risk?[J]. Ann Surg Oncol, 2016, 23: 4008-4015. DOI: 10.1245/s10434-016-5333-x
[167] Engelman ES, Leon-Ferre R, Naraev BG, et al. Compar-ison of transarterial liver-directed therapies for low-grade metastatic neuroendocrine tumors in a single institution[J]. Pancreas, 2014, 43: 219-225. DOI: 10.1097/MPA.0000000000000030
[168] Vogl TJ, Naguib NN, Zangos S, et al. Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and thermal ablation[J]. Eur J Radiol, 2009, 72: 517-528. DOI: 10.1016/j.ejrad.2008.08.008
[169] Kose E, Kahramangil B, Aydin H, et al. Outcomes of laparoscopic tumor ablation for neuroendocrine liver metastases: a 20-year experience[J]. Surg Endosc, 2020, 34: 249-256. DOI: 10.1007/s00464-019-06759-1
[170] Mohan H, Nicholson P, Winter DC, et al. Radiofre-quency ablation for neuroendocrine liver metastases: a systematic review[J]. J Vasc Interv Radiol, 2015, 26: 935-942. e1. DOI: 10.1016/j.jvir.2014.12.009
[171] Rossi RE, Burroughs AK, Caplin ME. Liver transplanta-tion for unresectable neuroendocrine tumor liver metastases[J]. Ann Surg Oncol, 2014, 21: 2398-2405. DOI: 10.1245/s10434-014-3523-y
[172] Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation?[J]. J Hepatol, 2007, 47: 460-466. DOI: 10.1016/j.jhep.2007.07.004
[173] Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975—2016[EB/OL]. https://seer.cancer.gov/archive/csr/1975_2016/.
[174] Feng T, Lv W, Yuan M, et al. Surgical resection of the primary tumor leads to prolonged survival in metastatic pancreatic neuroendocrine carcinoma[J]. World J Surg Oncol, 2019, 17: 54. DOI: 10.1186/s12957-019-1597-5
[175] Mehrabi A, Fischer L, Hafezi M, et al. A systematic review of localization, surgical treatment options, and outcome of insulinoma[J]. Pancreas, 2014, 43: 675-686. DOI: 10.1097/MPA.0000000000000110
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