Her-2表达在食管胃结合部腺癌中的作用研究进展

近几十年来,食管胃结合部腺癌的发病率正在逐年上升。Her-2表达与食管胃结合部腺癌预后的研究结果呈现争议,研究认为这是因为Her-2检测的局限性和组织标本的异质性而导致不同的结果。对于Her-2过表达的食管胃结合部腺癌,综合治疗包括新辅助放化疗、辅助放化疗、手术治疗及靶向治疗在临床疗效中的地位越来越突出,中医药治疗也在辅助治疗中起到重要作用。     

食管胃结合部腺癌临床病理特征及术后辅助放化疗研究现状

近年来食管胃结合部腺癌(AEG)的发病率急剧上升,其解剖学部位特殊,且转移复发规律复杂。越来越多的学者认为其是一类不同于食管癌和胃癌的独立的疾病。由于多数患者确诊时已处于局部进展期,单纯手术治疗局部复发率高,生存状况较差,术后辅助治疗有其非常重要的临床价值。目前无专门针对于食管胃结合部腺癌术后辅助治疗价值的研究数据,多数包括在食管癌或胃癌进行研究,也未将食管胃结合部腺癌的病例进行亚组分析,术后辅助治疗的获益人群及放疗靶区勾画范围等还存在争议。放疗勾画靶区时应根据食管胃结合部腺癌临床病理特征、不同Siewert分型和淋巴结转移规律以及术后复发转移特点进行综合考虑。     

SATB1在SiewertⅡ、Ⅲ型胃食管结合部腺癌中的表达及与临床病理特征的关系

目的:研究特异性核基质结合区蛋白质-1(SATB1)在SiewertⅡ、Ⅲ型胃食管结合部腺癌组织中的表达及与临床病理特征的关系.方法:经免疫组化染色(SP法)检测80例SiewertⅡ、Ⅲ型胃食管结合部组织中SATB1蛋白表达.结果:SiewertⅡ、Ⅲ型胃食管结合部腺癌组织中SATB1的阳性表达共30例,阳性表达率为37.5%;而正常胃黏膜组织中SATB1阳性表达18例,阳性表达率为22.5%,差异具有统计学意义(x2=4.286,P<0.05).淋巴结转移(x2=5.150,P<0.05)及肿瘤浸润深度(x2=4.364,P<0.05)是胃食管结合部腺癌的独立影响因素.结论:SATB1蛋白在SiewertⅡ、Ⅲ型胃食管结合部腺癌中表达强于正常黏膜组织.SATB1蛋白阳性表达与肿瘤浸润程度、淋巴结转移成正相关性,可作为评估SiewertⅡ、Ⅲ型胃食管结合部腺癌肿瘤进展的一种指标.     

HER2靶向药物及其联合治疗方案在胃及食管胃结合部腺癌治疗中的研究进展

人表皮生长因子受体2(HER2)过表达或扩增胃及食管胃结合部腺癌可从抗HER2治疗中显著获益。目前, 除曲妥珠单抗、帕妥珠单抗等人源化单克隆抗体外, 多种针对HER2的抗体偶联药(恩美曲妥珠单抗、维迪西妥单抗、德喜曲妥珠单抗、ARX788)及酪氨酸激酶抑制剂(拉帕替尼、阿法替尼、吡咯替尼), 可作为单一疗法或联合疗法应用于晚期胃及食管胃结合部腺癌的治疗, 已在临床研究中显示出良好疗效, 改善了患者预后及生命质量。进一步研究新型HER2靶向药物及联合治疗方案在临床治疗中的疗效与安全性, 有望为HER2阳性晚期胃及食管胃结合部腺癌患者的治疗提供更有效的策略。     

食管胃结合部腺癌外科治疗研究进展

食管胃结合部腺癌作为一类独立的疾病在解剖、发病率等方面与胃其他部位的肿瘤存在明显差异,对其定义、分型、淋巴结转移等方而的研究已基本达成共识,但对于外科治疗的手术路径、切除范围、淋巴结清扫等问题长期以来各学派意见不一.本文就近年来食管胃结合部腺癌外科治疗研究相关的国内外文献复习并加以综述,为临床诊治提供更加合理、有效的方法.     

食管胃结合部腺癌及胃癌Cox模型预后影响因素分析

  目的  分析食管胃结合部腺癌及胃癌各自的独立预后影响因素。  方法  收集本院2007年1月至2011年6月院340例术后食管胃结合部腺癌及胃癌病例, 选择13项临床病理因素(性别、年龄、病变长度、病理类型、淋巴结转移情况、浸润深度、临床分期、周围器官受侵情况、残端情况、脉管瘤栓、术中淋巴结清扫程度及出现症状到首诊治疗时间)分别进行Cox单因素及多因素分析。  结果  1) 食管胃结合部腺癌与胃癌比较预后更差; 2)淋巴结清扫及淋巴结转移均为二者的独立预后影响因素, 淋巴结转移个数越多, 患者预后越差, D2式手术较D1式手术可能带来更大的生存获益; 3)浸润深度为食管胃结合部腺癌的独立预后影响因素, 浸润越深预后越差; 而病变长度为胃癌的独立预后影响因素, 病变越长预后越差。  结论  与胃癌相比, 食管胃结合部腺癌预后更差, 并且有其独特的临床病理特征及预后影响因素, 提示二者有所区别, 今后应将食管胃结合部腺癌做为一种独立的疾病开展更加深入的研究。      

No.6组淋巴结活检在胃食管结合部腺癌全胃切除中的意义

目的探讨No.6组淋巴结活检在胃食管结合部腺癌全胃切除中的意义。方法行近端胃切除能达到根治的胃食管结合部腺癌病例,术中切除No.6组淋巴结送术中快速冰冻切片病理学检查,如淋巴结转移则行全胃切除,反之行近端胃切除。结果 372例中,No.6组淋巴结活检阳性32例,总阳性率8.60%,且随着肿瘤浸润深度增加No.6组淋巴结转移率明显增加。结论 No.6组淋巴结有一定的转移比例,当No.6组淋巴结转移需行全胃切除。No.6组淋巴结术中冰冻切片病理诊断在指导胃食管结合部腺癌手术切除范围中具有重要意义。     

115例食管胃结合部腺癌术后发生吻合口瘘患者预后营养指数与预后相关性分析

[目的]研究食管胃结合部腺癌术后发生吻合口瘘的患者预后营养指数(PNI)与临床病理因素的关系,以及PNI对预测术后发生吻合口瘘的患者生存期的临床意义。[方法]回顾性分析2004年1月1日至2013年12月31日在河北医科大学第四医院胸外科行食管胃结合部腺癌根治术的115例术后发生吻合口瘘患者的临床病理资料和随访资料。计算PNI值[PNI=淋巴细胞绝对值(109/L)×5+血清白蛋白(g/L)],根据PNI均值进行分组,分析PNI与患者性别、年龄、肿瘤大小、肿瘤分化程度、肿瘤分期、肿瘤位置、淋巴结转移情况的关系。同时对患者进行生存分析,采用Log-rank法进行单因素分析,Cox法进行多因素分析。[结果]发生吻合口瘘患者PNI均值为48.51 (43.25~56.25)。PNI≤48.51组患者5年生存率为58.9%,PNI>48.51组患者5年生存率为59.3%,两组比较差异无统计学意义(χ~2=0.127,P=0.722)。单因素、多因素分析显示,PNI≤48.51组患者中,N分期是影响发生吻合口瘘的食管胃结合部腺癌患者预后的独立危险因素。PNI>48.51组患者中,是否给予术后辅助治疗是发生吻合口瘘的食管胃结合部腺癌患者预后的独立影响因素。PNI与治疗方式存在交互作用(P=0.037)。[结论 ] N分期和术后是否给予辅助治疗分别是PNI低值组(PNI≤48.51)和高值组(PNI>48.51)发生吻合口瘘的食管胃结合部腺癌患者生存的独立影响因素。对于发生吻合口瘘的食管胃结合部腺癌患者,应回顾术前预后营养指数这一指标,以指导选择适宜的后续治疗方式。     

胃食管结合部腺癌区域淋巴廓清的临床研究

目的  探讨胃型胃食管结合部腺癌淋巴清扫范围与淋巴结转移区域分布规律。 方法  分析2004年1月至2015年12月,山西省人民医院普外科收治的胃食管结合部癌患者肿瘤数据库,基于Nishi分型选取其中胃型胃食管结合部腺癌肿瘤,直径≤40 mm并R0切除患者相关肿瘤学数据勾勒胃型胃食管结合部腺癌淋巴高频转移站别区域图。 结果  纳入306例胃型胃食管结合部腺癌患者,结果显示：pT4期肿瘤占87％、pN阳性占778％、pTNM分期Ⅲ期占745％;肿瘤直径（2544±1803）mm;腹腔淋巴结转移高频区域依次是贲门左右侧（第1、2组）、小弯侧胃左血管周围（第3组）、胰腺上缘腹腔干（第9组）及其主干分支胃左动脉（第7组）、肝总动脉（第8a组）、脾动脉近端（第11p组）、肝动脉（第12a组）周围以及食管裂孔周围（第19、20组）;胃远端区域转移较为罕见。 结论  瘤体直径≤40 mm胃型胃食管结合部腺癌淋巴清扫区域应集中在贲门左右侧、小弯侧、胰腺上缘腹腔干及其主干分支以及食管裂孔周围,胃远端及大弯侧区域淋巴清扫外科获益价值存疑。     

紫杉醇联合卡铂方案与联合替吉奥方案新辅助同步放化疗治疗Ⅲ期胃食管结合部癌的疗效比较

目的:评价紫杉醇联合卡铂单周方案同步放化疗在Ⅲ期胃食管结合部癌中的近期疗效和安全性,以探索Ⅲ期胃食管结合部腺癌新辅助治疗的合理治疗方案。方法:回顾分析2014年至2017年Ⅲ期胃食管结合部腺癌40例患者,分为紫杉醇卡铂单周方案联合同步放化疗组（TP组）20例和紫杉醇替吉奥3周方案同步放化疗组（TS组）20例。比较两组间的R0切除率、淋巴结转移率、手术死亡率及术后并发症发生率;比较两组新辅助同步放化疗的不良反应、有效率以及治疗前后临床分期变化;评价紫杉醇卡铂单周方案新辅助同步放化疗的近期疗效与安全性。结果:统计分析显示,临床TNM分期、分化程度、脉管癌栓、R0切除率、手术方式、并发症发生率比较无统计学差异（P＞0.05）;阳性淋巴结数目和清扫淋巴结数量间有统计学差异（P＜0.05）,TS组均较多。两组间放化疗不良反应、血液学毒性、红细胞、血小板、转氨酶比较无统计学差异（P＞0.05）;白细胞毒性反应,两组间有差异（P＜0.05）,TS组Ⅲ-Ⅳ度不良反应较多;非血液毒性,两组间比较无统计学差异（P＞0.05）。术后病理分期降期比较,明显降期患者所占比例,TP组（18例）优于TS组（12例）（P＜0.05）。结论:紫杉醇联合卡铂单周方案同步放化疗与紫杉醇联合替吉奥3周方案同步放化疗比较,患者不良反应小,耐受性好,降期率高,可以作为胃食管结合部癌的优选治疗方案,值得推广。     

Frequency and clinical impact of lymph node micrometastasis and tumor cell microinvolvement in patients with adenocarcinoma of the esophagogastric junction

BACKGROUND: Tumor involvement of regional lymph nodes has a crucial impact on the prognosis of patients with adenocarcinoma of the esophagogastric junction (AEG). Although additional tumor cell deposits can be detected by sensitive methods (e.g., immunohistochemistry and polymerase chain reaction), their prognostic significance is uncertain. METHODS: Using immunohistochemistry for cytokeratins (AE1/AE3 antibody), the authors studied 3987 regional lymph nodes from 145 patients with completely resected adenocarcinoma of the esophagus (AEG I; n = 46 patients), cardia (AEG II; n = 79 patients), and subcardial region (AEG III; n = 20 patients). The newly detected cells were categorized with tumor cell microinvolvement (TCM) or with micrometastases (MM) based on tumor size and histology. RESULTS: Of the 75 pathologic lymph node negative (pN0) patients, 3 of 30 patients in the AEG I group (10%) and 8 of 45 patients in the AEG II and III groups (18%) had TCM (no significant difference). MM was found in 2 of 30 tumors in the AEG I group (7%) and in 11 of 45 tumors in the AEG II and III groups (24%), a significantly lower rate that that in the AEG I group (P < 0.05). Neither TCM nor MM showed a significant prognostic impact in AEG I tumors (P > 0.05). For the AEG II and III tumors, MM (new lymph node positive [pN+] cases) had a prognostic impact similar to metastases found by routine methods, with reclassification based on MM resulting in improvement in the pN0 group from 72.8 months to 82.6 months, but almost no change was seen in the pN+ group (49.9-49.2 months). TCM had no adverse impact on survival in any tumor type. CONCLUSIONS: These results highlight important differences between AEG I tumors and AEG II and III tumors and argue for different lymphadenectomy strategies for patients with these tumor types.     

Lymphatic vessel invasion as a prognostic factor in patients with primary resected adenocarcinomas of the esophagogastric junction.

PURPOSE: To evaluate the value of lymphatic vessel invasion (LVI) as a predictor of survival in patients with primary resected adenocarcinomas of the esophagogastric junction (AEG). PATIENTS AND METHODS: We prospectively evaluated 459 patients undergoing primary surgical resection for tumors of the esophagogastric junction at our institution between 1992 and 2000 (180 adenocarcinomas of the distal esophagus, AEG I; 140 carcinomas of the cardia, AEG II; and 139 subcardial gastric cancers, AEG III). Median follow-up was 36.8 months. The prevalence of LVI was evaluated by two independent pathologists. Univariate and multivariate analysis of prognostic factors was performed. RESULTS: The total rate of LVI was 49.9%, with a significant difference between AEG I (38.9%) and AEGII/III (57.0%, P = .0002). Univariate analysis showed a significant correlation between LVI and T category (P < .0001), N category (P < .0001), and resection status (R [residual tumor] category; P < .0001). This was shown for the group of all AEG tumors, as well as for the subgroups AEG I and AEG II/III. On multivariate analysis, LVI was identified as a significant and independent prognostic factor (P = .050) in the population of all patients and in patients with AEG II/III, but not in the subgroup with AEG I. CONCLUSION: These data demonstrate the prognostic significance of LVI in patients with AEG tumors, with marked differences between the subgroups AEG I versus AEG II/III. The lower prevalence and lack of prognostic significance of LVI in AEG I might be explained by inflammation involved in the pathogenesis of this entity.     

Astrocyte elevated gene‐1 interacts with β‐catenin and increases migration and invasion of colorectal carcinoma

To investigate the astrocyte elevated gene‐1 (AEG‐1) expression and its relationship with the clinicopathological features of colorectal carcinoma (CRC) and β‐catenin signaling pathway. Real‐time PCR, Western blot, immunohistochemistry, and immunofluorescence staining were performed to detect AEG‐1 expression in CRC cell lines, 8 pairs of fresh CRC and adjacent nontumor tissues (ANT), 120 pairs of paraffin‐embedded CRC specimens and ANT tissues, and 60 samples of lymph node metastatic CRC tissues. Scratch wound assay and transwell matrix penetration assay were performed to determine migration and invasion of SW480 cell lines with stable AEG‐1 overexpression or SW620 cell lines with AEG‐1 knockdown. AEG‐1 expression was upregulated in CRC cell lines and tissues compared with ANT. Furthermore, AEG‐1 expression level significantly correlated with UICC stage, and the N classification. AEG‐1 overexpression significantly enhanced migration and invasion of SW480 cell lines. However, AEG‐1 knockdown suppressed migration and invasion of SW620 cell lines. Meanwhile, there was a positive correlation between AEG‐1 high expression and β‐catenin nuclear expression in CRC. AEG‐1 overexpression increased nuclear β‐catenin accumulation in CRC cell lines. AEG‐1 knockdown decreased nuclear β‐catenin accumulation in CRC cell lines. Moreover, we firstly found that AEG‐1 interacted with β‐catenin in SW480 cell lines. Our results for the first time showed that AEG‐1 interacted with β‐catenin in CRC cells and AEG‐1 expression was closely associated with progression of CRC. AEG‐1 might be a potential therapeutic target in CRC. © 2012 Wiley Periodicals, Inc.     

Adenocarcinoma of the esophagogastric junction: the pattern of metastatic lymph node dissemination as a rationale for elective lymphatic target volume definition

PURPOSE: Regional nodal metastasis after neoadjuvant chemoradiation of adenocarcinoma of the esophagogastric junction (AEG) predicts survival. We aimed to clarify the lymph node (LN) distribution of AEG according to location of the tumor mass and invasion of neighboring areas for the selection of radiotherapy planning target volume (PTV) margins. METHODS AND MATERIALS: Patterns of regional spread were analyzed in pathology reports of 326 patients patients with AEG who had undergone primary resection, with > or = 15 lymph nodes examined. Tumors were classified into AEG types based on endoscopy and pathology reports. Fisher's exact test was used to compare nodal disease and tumor characteristics. Pulmonary dose-volume histograms were tested in 8 patients. RESULTS: Nodes were positive in 81% of T2 to T4 tumors. Type of AEG, tumor size, lymphovascular invasion, and grading significantly influenced nodal distribution. We found that marked esophageal invasion of AEG II/III significantly correlated with paraesophageal nodal disease, and T3 to T4 AEG II/III had a significant rate of splenic hilum/artery nodes. Middle and lower paraesophageal nodes should be treated in T2 to T4 AEG I and AEG II with > or = 15 mm involvement above the Z-line, and T3 to T4 AEG II. The splenic hilum and artery nodes can be spared in T2 AEG tumors, especially Type I tumors. The influence of paraesophageal nodal treatment on the risk of postoperative pulmonary complications can be estimated from dose-volume histograms. CONCLUSIONS: Accurate pretherapeutic staging predicts the risk of subclinical nodal disease and should be used to select the appropriate radiotherapeutic PTV. Careful selection of the PTV can be used to maximize the therapeutic window in multimodal therapy for AEG.     

PTCH1在胃食管连接部腺癌组织中的表达及临床意义

[目的]评价PTCH1在胃食管连接部腺癌（AEG）组织中的表达及意义。[方法]选择64例AEG组织、癌旁组织标本,应用RT-PCR和Western blot方法检测标本中PTCH1mRNA和蛋白的表达情况,并分析PTCH1蛋白的表达与AEG临床病理特征的关系。[结果]与癌旁组织相比,AEG组织中PTCH1 mRNA和蛋白的表达均明显下调,差异有统计学意义（P〈0.05）。PTCH1蛋白表达与AEG患者性别、年龄、肿瘤大小和淋巴结转移无关,与肿瘤分化程度有关（P〈0.05）。[结论]PTCH1在AEG组织中低表达可能与胃食管连接处腺癌的发生、发展相关。     

食管-胃结合部腺癌手术治疗的共识与争议

食管-胃结合部腺癌（adenocarcinoma of esophagogastric junction，AEG）在全球的发病率不断升高，因其特殊的解剖位置、独特的生物学行为被越来越多的临床工作者所重视。目前国内外虽然对AEG的发病、分型等已形成了一定共识，但在更多方面，尤其是外科治疗手段，诸如手术路径、胃的切除范围、淋巴结的清扫范围、消化道重建等方面仍存在较多争议。这些争议不仅限制了对AEG治疗的探索与发展，同时使得对AEG的规范化诊疗变得更加困难。本文结合近些年的相关文献，就目前AEG治疗的国内外相关共识与争议进行综述，以期为临床诊治提供更加合理、有效的方法。      

Biologic and clinical variations of adenocarcinoma at the esophago-gastric junction: relevance of a topographic-anatomic subclassification

A topographic-anatomic subclassification of adenocarcinomas of the esophago-gastric junction (AEG) in distal esophageal adenocarcinoma (AEG Type I), true carcinoma of the cardia (AEG Type II), and subcardial gastric cancer (AEG Type III) was introduced in 1987 and is now increasingly accepted and used worldwide. Our experience with now more than 1,300 resected AEG tumors indicates that the subtypes differ markedly in terms of surgical epidemiology, histogenesis and histomorphologic tumor characteristics. While underlying specialized intestinal metaplasia can be found in basically all patients with AEG Type I tumors, this is uncommon in Type II tumors and virtually absent in Type III tumors. Stage distribution and overall long-term survival after surgical resection also shows marked differences between the AEG subtypes. Surgical treatment strategies based on tumor type allow a differentiated approach and result in survival rates superior to those reported with other approaches. The subclassification of AEG tumors thus provides a useful tool for the selection of the surgical procedure and allows a better comparison of treatment results.     

Snail2、IMP3和Wif-1在胃食管交界腺癌中的表达特点及临床意义

目的:探究Snail2、胰岛素样生长因子Ⅱ mRNA结合蛋白3(insulin-like growth factor Ⅱ mRNA-binding protein 3,IMP3)和Wnt通路抑制因子1(Wnt inhibitory factor-1,Wif-1)在食管胃交界处的腺癌(ade-nocarcinoma of...     

食管胃交界腺癌的外科治疗

食管胃交界腺癌（ＡＥＧ）指发生于食管远端和胃贲门区域的腺癌,其发生率明显上升。由于两种腺癌发生部位接近、生物学行为相似、预后均较差,多数学者认为ＡＥＧ是一独特的临床病理类型。目前对ＡＥＧ分型采用最广泛的是Ｓｉｅｗｅｒｔ分型方法;在分期方面尚无单独的分期研究,一般根据病灶主体所在部位,按现行ＴＮＭ分期系统,Ⅰ型和Ⅱ、Ⅲ型分别按食管癌和胃癌分期。手术切除是ＡＥＧ最主要的治疗手段,在保证手术安全的前提下应力争达到Ｒ０切除,切缘应距肿瘤边缘５ｃｍ。常规手术径路有经胸、经腹、胸腹联合３种,一般Ⅰ型者多采用经胸途径,Ⅱ、Ⅲ型者多采用经腹途径。对于Ｔ２期以上者应按Ｄ２标准进行淋巴结清扫,扩大切除（联合脾或胰腺体尾切除）仅限于特定的较晚期病例。早期病例（Ｔ１ｂ）可行Ｄ１手术。有关ＡＥＧ综合治疗的研究很少,对病期较晚（Ｔ２分期以上）者可以选择ＥＣＦ为主的新辅助化疗或辅助化疗、化放疗。     

不同截短型癌基因AEG-1启动子活性分析

目的:分析不同截短型癌基因AEG-1启动子活性,证实与E6/E7表达相关的转录调控因子对AEG-1启动子活性的影响。方法:以宫颈癌HeLa细胞基因组DNA为模版,扩增AEG-1启动子全长序列（-2710/-491）,并应用本实验室改造的启动子活性研究专用绿色荧光蛋白报告载体构建pGL3-basic-EGFP/AEG-1质粒,通过转染HeLa细胞及血管内皮细胞ECV304检测启动子活性。同时,根据AEG-1启动子序列上与E6/E7作用相关的转录调控因子结合位点位置,设计不同截短型AEG-1启动子序列引物,应用pGL3-basic-EGFP载体构建不同截短型AEG-1启动子载体,并分别转染细胞检测启动子活性。结果:AEG-1启动子全长序列pGL3-basic-EGFP/AEG-1载体转染HeLa细胞可见明显绿色荧光蛋白表达,而在血管内皮细胞ECV304中表达为痕量。包含不同转录调控因子C-Myc、SP1、NF-κB、E2F结合位点的不同截短型AEG-1启动子载体在肿瘤细胞中有活性但存在差异。结论:AEG-1启动子为肿瘤特异性启动子,含有与E6/E7表达相关的转录调控因子NF-κB、E2F结合位点的启动子序列为影响AEG-1基因启动子活性的关键区域。