复旦大学：《循证医学》课程教学资源（参考教材）Unit 03 疾病诊断证据的分析与评价.pdf_大学文库

Ut3：疾病诊断证据的分析与评价主讲教师：陈世耀助理救师：张宁萍一、教学目的 1.掌握诊断试验的概念和评价指标： 2.熟悉诊断试验评价标准，在临床实践中合理选择诊断试验： 3.初步了解诊断试验研究设计。一。教学内诊断试验的基本概念诊断试验评价指标-大课讲授(45分钟文献阅读评价与应用问题分析，课前阅读，小组讨论(60分钟》分析诊断试验设计(45分钟) 4.问题点评与总结(30分钟) 三、教学重点：基本概念，包括灵敏度、特异度、预测值、OC曲线、似然比四、教学难点：诊断试验文献评价原则，诊断试验设计与应用选择五、中文和英文关键词诊断试验Diagnostic test:灵敏度Sensitivity:特异度Specificity 预测值Predictiv alue 似然比：,LR 受试者工作特性曲线： Receiver Operator Characteristic Curve,ROC 六、阅读文献 1.Comparison of endoscopic ultrasonography (EUS).positron emission tomography (PET),and computed tomography (CT)in the preoperative locoregio aging of resectable esophag nce 2 Coronary CTA vers s St rd Eval in Acute Chest Pain 定量与定性粪隐血试验在结直肠癌筛查中的效果评 4. 诊断准确性研究报告标准(STARD20l5 guidelines for reporting diagnostic accuracy studies:explanation and elaboration Towards complete and accurate reporting of studies of diagnostic accuracy the STARD initiative 6.STARD 2015:an updated list of essential items for reporting diagnostic accuracy studies 七、课堂讨论思考题 1.诸阅读立就后，对照STARD标准(2015版)回答下列间顺 )研究目的是什么？采用何种研 2) 文献中临床诊断研究评价的诊断试验是什么？金标准是什么？是否存在金标准选择缺陷？如果存在，研究者如何避免或者替代？ 3)文献是否存在研究对象选择缺陷，如何看待研究对象选择缺陷？ 4)文献是否采用了诊断试验与金标准盲法比较？在比较方法方面存在哪些 5) 文献在诊断试验的重复性即精确性以及测量变异如何评价？ 6 文献所评价的诊断试验是否具有实用性：是否方便，有无副作用，对病人有无危害？

Unit 3：疾病诊断证据的分析与评价主讲教师：陈世耀助理教师：张宁萍一、教学目的 1. 掌握诊断试验的概念和评价指标； 2. 熟悉诊断试验评价标准，在临床实践中合理选择诊断试验； 3. 初步了解诊断试验研究设计。二、教学内容 1. 诊断试验的基本概念，诊断试验评价指标 –大课讲授（45 分钟） 2. 文献阅读评价与应用问题分析，课前阅读，小组讨论（60 分钟） 3. 分析诊断试验设计（45 分钟） 4. 问题点评与总结（30 分钟）三、教学重点：基本概念，包括灵敏度、特异度、预测值、ROC 曲线、似然比四、教学难点：诊断试验文献评价原则，诊断试验设计与应用选择五、中文和英文关键词诊断试验 Diagnostic test；灵敏度 Sensitivity；特异度 Specificity 预测值 Predictive value；似然比：Likelihood ratio, LR 受试者工作特性曲线：Receiver Operator Characteristic Curve, ROC 曲线六、阅读文献 1. Comparison of endoscopic ultrasonography (EUS), positron emission tomography (PET), and computed tomography (CT) in the preoperative locoregional staging of resectable esophageal cancer. 2. Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain. 3. 定量与定性粪隐血试验在结直肠癌筛查中的效果评价 4. 诊断准确性研究报告标准（STARD 2015 guidelines for reporting diagnostic accuracy studies: explanation and elaboration） 5. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative 6. STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies 七、课堂讨论思考题 1. 请阅读文献后，对照 STARD 标准（2015 版）回答下列问题： 1) 研究目的是什么？采用何种研究设计？ 2) 文献中临床诊断研究评价的诊断试验是什么？金标准是什么？是否存在金标准选择缺陷？如果存在，研究者如何避免或者替代？ 3) 文献是否存在研究对象选择缺陷，如何看待研究对象选择缺陷？ 4) 文献是否采用了诊断试验与金标准盲法比较？在比较方法方面存在哪些问题？研究者做了哪些努力？ 5) 文献在诊断试验的重复性，即精确性以及测量变异如何评价？ 6) 文献所评价的诊断试验是否具有实用性：是否方便，有无副作用，对病人有无危害？

2.阅读案例，通过提供的文献13和背景资料，结合当前临床实践展开讨论：案例1（文献1）：患者男性，70岁，因进食梗阻感1月来院就诊，进固体食物明显液体食物不明显。无反酸、烧心，无咳嗽、咳痰，无黑、便呕血无发热、消瘦等症状。胃镜检查发现食管中段距门齿30cm后壁见1.2cm轻度隆起病灶，表面糜烂，活检病理诊断鳞癌。你认为下一步需要做什么：超声胃镜检查， CT检查，PET-CT检查，为完善诊断你认为该患者接受何种检查更合适？选择的依据是什么？案例2（文献2）：患者女性，50岁，持续胸前区压榨样疼痛加重2小时，以往有高血压/糖尿病史，平时控制良好。急诊心电图轻度ST段改变，除采血进行心肌酶谱检查外，下一步处理如何选择：随访心电图+酶谱观察变化，或者直接 CTA检查，依据是什么？案例3（文献3）：针对当前上海人饮食西化，肠癌发病率增加这一问题，市政府投入巨资，群开展问卷粪隐血-肠镜筛查并治疗项目，你如何看待在上海开展的肠癌筛查项目，需要考虑哪些因素 3.研究设计胃瘟是一种常见恶性种南，通讨胃箱检查+活检确诊。处理句括早期胃癌的内镜下治疗、进展期胃癌的根治性手术治疗和晚期胃癌的化疗。采用何种处理方式，除了根据患者意愿、病人状态，最主要的依据是胃癌的分期。目前临床上用于胃癌分期(TNM分期)的手段主要包括超声胃镜(EUS)、增强CT。请设计一项临床研究，比较EUS、增强CT检查用于胃癌侵犯深度和是否周围淋巴结转移的分期诊断价值。八、参考书及文献目录《循证医学与临床实践》（第3版），王吉耀主编，科学出版社，2012 2.Leeflang MMG et al.Systematic Reviews of Diagnostic Test Accuracy.Ann Intern Med2008:149(12):889-897. 3 Lord sI et al when is measuring sensitivity and Specificity Sufficient To Evaluate a diag ostie Test and When Do We Need R ndomized Trials?Ann Intern Med.2006:144:850-855 (课前提供以下文献4-6电子版) 4.Zhang Z.Wang G Kang k.Wu G Wang p:Diagnostic accuracy and clinical utility of a n vasive index for her steatosis atients with hepatitis Bv irus infe ection.Sci R 201 .6:32875. 5. Boursier Vergniol J,Guillet A.Hiriart JB,LannesA,Le Bail B.Michalak S Chermak F,Bertrais S,Foucher J et al:Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.J HEPATOL 2016, 65(3:570-578. 6. Deng H,Qi X.Zhang Y,Peng Y,Li J,Guo X:Diagnostic accuracy of contrast-enhanced computed tomography for esophageal varices in liver cirrhosis:A retrospective observational study.J Evid Based Med 2016

2. 阅读案例，通过提供的文献 1-3 和背景资料，结合当前临床实践展开讨论：案例1(文献1)：患者男性，70岁，因进食梗阻感1月来院就诊，进固体食物明显，液体食物不明显。无反酸、烧心，无咳嗽、咳痰，无黑、便呕血，无发热、消瘦等症状。胃镜检查发现食管中段距门齿30cm 后壁见1.2cm 轻度隆起病灶，表面糜烂，活检病理诊断鳞癌。你认为下一步需要做什么：超声胃镜检查， CT 检查，PET-CT 检查，为完善诊断你认为该患者接受何种检查更合适？选择的依据是什么？案例2(文献2)：患者女性，50 岁，持续胸前区压榨样疼痛加重2 小时，以往有高血压/糖尿病史，平时控制良好。急诊心电图轻度ST 段改变，除采血进行心肌酶谱检查外，下一步处理如何选择：随访心电图+酶谱观察变化，或者直接 CTA检查，依据是什么？案例3(文献3)：针对当前上海人饮食西化，肠癌发病率增加这一问题，市政府投入巨资，在45-70 岁人群开展问卷-粪隐血-肠镜筛查并治疗项目，你如何看待在上海开展的肠癌筛查项目，需要考虑哪些因素？ 3. 研究设计胃癌是一种常见恶性肿瘤，通过胃镜检查+活检确诊。处理包括早期胃癌的内镜下治疗、进展期胃癌的根治性手术治疗和晚期胃癌的化疗。采用何种处理方式，除了根据患者意愿、病人状态，最主要的依据是胃癌的分期。目前临床上用于胃癌分期(TNM 分期)的手段主要包括超声胃镜(EUS)、增强CT。请设计一项临床研究，比较EUS、增强CT 检查用于胃癌侵犯深度和是否周围淋巴结转移的分期诊断价值。八、参考书及文献目录 1. 《循证医学与临床实践》(第 3 版),王吉耀主编,科学出版社,2012. 2. Leeflang MMG, et al. Systematic Reviews of Diagnostic Test Accuracy. Ann Intern Med 2008;149(12):889-897. 3. Lord SJ, et al. When Is Measuring Sensitivity and Specificity Sufficient To Evaluate a Diagnostic Test, and When Do We Need Randomized Trials? Ann Intern Med. 2006;144:850-855. (课前提供以下文献 4-6 电子版) 4. Zhang Z, Wang G, Kang K, Wu G, Wang P: Diagnostic accuracy and clinical utility of a new noninvasive index for hepatic steatosis in patients with hepatitis B virus infection. Sci Rep 2016, 6:32875. 5. Boursier J, Vergniol J, Guillet A, Hiriart JB, Lannes A, Le Bail B, Michalak S, Chermak F, Bertrais S, Foucher J et al: Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease. J HEPATOL 2016, 65(3):570-578. 6. Deng H, Qi X, Zhang Y, Peng Y, Li J, Guo X: Diagnostic accuracy of contrast-enhanced computed tomography for esophageal varices in liver cirrhosis: A retrospective observational study. J Evid Based Med 2016

S6ilhi7kmH64wno3 Comparison of endoscopic ultrasonography (EUS),positron emission tomography (PET),and computed tomography (CT) in the preoperative locoregional staging of resectable esophageal cancer Hyun Chae Keywords the nography (EUS)has Computed tomography Endosonography on tomography ompare the diagnostic staging cancer This study aimed to co formance of EUS,positron emission tomography (PET), and computed tomography (CT)in the locoregional staging Patients with a diagnosis of esophageal cancer have a poor of resectable esophage cancer prognosis with 5-year survival rate of 6-11%.The sur thod A total of 109 patients with ectable esopha en s wn t correlate with the stage of t EUS.PET t da CT The sensitivity specificity,and accuracy of tum depth (T)staging and regional lymph nodal (N)staging for ment option for patients without distant metastasis,but each test were compared with the postoperative histo- even after surgery with curative intent,the prognosis still pathologic stage as ne gold stand In a ddition,surgery is associated with significan The oh bidity and evenmo of the 42%for EUS.49%for PET.and 3%for CT.and thein specificities were,respectively,91.87,and 93%. The considered for surgical resection.many staging methods accuracy for N staging was 66%for EUS.68%for PET. hav been used including endoscopic ultras nography nd 63%for CT.and it did not differ significantly across (EUS).chest computed tomo aphy (CT).and positron mography (PET).Of t tive EUS for the of reoper The Of PET ha accuracy and similar accuracy for N stagir ng com ared with show it to be useful in the staging PET and CT.Especially in T staging.EUS could play an cancer 12-41.Although PET has been able to identify important role in the choice of candidates for esophageal distant met stasis more accurately than CT,neither metho cancer surgery he rinvas he real wall [5] e of its diagnostic accuracy.EUS has beco me the aoi S.G.KimsKi:H.C.Jung Song standard practice for staging esonhs eal cancer finding have shown that eus has the ability to delineate the individual esophageal layers and accurately assess the e-mail:.net depth of tumor invasion 6. Published online:24 December 2009

Comparison of endoscopic ultrasonography (EUS), positron emission tomography (PET), and computed tomography (CT) in the preoperative locoregional staging of resectable esophageal cancer Jeongmin Choi • Sang Gyun Kim • Joo Sung Kim • Hyun Chae Jung • In Sung Song Received: 27 August 2009 / Accepted: 12 November 2009 Springer Science+Business Media, LLC 2009 Abstract Background Endoscopic ultrasonography (EUS) has been a useful method for the accurate staging of esophageal cancer. This study aimed to compare the diagnostic performance of EUS, positron emission tomography (PET), and computed tomography (CT) in the locoregional staging of resectable esophageal cancer. Methods A total of 109 patients with resectable esophageal cancer were prospectively enrolled and retrospectively reviewed for evaluation of preoperative EUS, PET, and CT. The sensitivity, specificity, and accuracy of tumor depth (T) staging and regional lymph nodal (N) staging for each test were compared with the postoperative histopathologic stage as the gold standard. Results The overall accuracy of EUS for T staging was 72%, and it was the only method for delineating the layers of the esophageal wall. The sensitivities for N staging were 42% for EUS, 49% for PET, and 35% for CT, and their specificities were, respectively, 91, 87, and 93%. The accuracy for N staging was 66% for EUS, 68% for PET, and 63% for CT, and it did not differ significantly across the three tests. Conclusions Preoperative EUS for the locoregional staging of esophageal cancer provides excellent T staging accuracy and similar accuracy for N staging compared with PET and CT. Especially in T staging, EUS could play an important role in the choice of candidates for esophageal cancer surgery. Keywords Computed tomography Endosonography Esophageal cancer Positron emission tomography Tumor staging Patients with a diagnosis of esophageal cancer have a poor prognosis, with 5-year survival rate of 6–11%. The survival rate has been shown to correlate with the stage of the disease. Accurate staging of esophageal cancer is critical because treatment decisions are heavily affected by initial staging [1]. Surgical resection is the best curative treatment option for patients without distant metastasis, but even after surgery with curative intent, the prognosis still is poor. In addition, surgery is associated with significant morbidity and even mortality. Therefore, it is important to select those patients who will potentially benefit from surgery. For patients with esophageal cancer who are being considered for surgical resection, many staging methods have been used including endoscopic ultrasonography (EUS), chest computed tomography (CT), and positron emission tomography (PET). Of these three methods, CT is the method commonly used to detect distant and nodal metastasis. The routine use of PET has been increasing, and reports show it to be useful in the staging of esophageal cancer [2–4]. Although PET has been able to identify distant metastasis more accurately than CT, neither method can accurately identify the depth of primary tumor invasion because both methods lack the ability to differentiate the layers of esophageal wall [5]. Because of its diagnostic accuracy, EUS has become the standard practice for staging esophageal cancer. Findings have shown that EUS has the ability to delineate the individual esophageal layers and accurately assess the depth of tumor invasion [6]. J. Choi S. G. Kim (&) J. S. Kim H. C. Jung I. S. Song Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Yongun-dong 28, Chongno-gu, Seoul 110-744, South Korea e-mail: harley1333@hanmail.net 123 Surg Endosc DOI 10.1007/s00464-009-0783-x

Surg Endosc Although eyond the ot th ades the nd TA 12.4.7,8].the role of EUS in the detection of regional invades the adjacent organs).The criteria for malig nodal metastasis still is controversial.This large po ston lymph nodes included a round shape,a diameter exceeding erative study aimed to compare the accuracy of EUS 10 mm,hypoechogenecity.and well-demarcated borders staging ith that of PET and staging using postopera [9].Celiac lymph nodes were defined by their location staging of PET/CT imaging Methods All scans were performed using a PET/CT system(Philips Gemini,DA best,Ne lands)wit 2-(Huorne-18)-fuoro Patients 2deoypehcoDC Aherleaa6hfsL nosis of hion -nr trast CT scan was performed before PET.and the resultin tively enrolled in Seoul National University Hospital to data were used to create an attenuation correction map for undergo a pre perative staging protocol that included EUS. whole-body P and chest CI scan cor the skull base to the mid thigh region. patients emission the staging p dimensional tations.In the and extens ive regional lymph node dissection.The Insti- walitative assessment of the images foci with increased tutional Review Board of the Seoul National University FDG uptake compared with the surrounding structures Hospital approved this study,and written informed con- were defined as malignancies.For quantitative analysis of from all the patients All information FDG uptake.the maximal standardized uptake value (SUVmax)was assessed EUS imaging CT imaging All EUS examinations were performed by a single expe All CT scans were performed with a Genesis High-Speed (S.G.K.),who had a high volume of CT(GE Medical Systems,Milwaukee,WI,USA).Scans S.The exa min a radial 370 14 mi/kg of with 12 MHz asse ssed the depth of 120 kVn and 230 mAs The in ing data were re (T stage)whereas imaging with 5 MHz detected the structed with 7-mm collimation The CT seans were per malignant-appearing perigastric or mediastinal lymph formed from the lower neck to the lower pole of the nodes (N stage).c liac nodes,or hepatic metastases (M kidney.Images were evaluated for the presence of primary stage).Minimal alloo Ito avoid tumo tumor,locoregional and/ metast mpus)were sed for mm)were cons ered pos sitive fo uperficial lesion or malignant strictur metastasis The HFUS examinations were performed after water instillation into the esophageal lumen and suctioning of Pathologic stage luminal air.If the echoendoscope could not pass the e patients did notn the proxima proce Pathologic metastas cation system ng to th The EUS criteria used for T staging were as follows:TI cancer staging 0.The ional lymph nodes included (tumor invades the mucosa or submucosa but not the paratracheal posterior and anterior mediastinal subcarinal muscularis propria).T2(tumor invades but does not extend paraesophageal,pericardial,inferior pulmonary ligament, Springer

Although several reports have compared the performance of EUS, CT, and PET in staging esophageal cancer [2, 4, 7, 8], the role of EUS in the detection of regional nodal metastasis still is controversial. This large postoperative study aimed to compare the accuracy of EUS staging with that of PET and CT staging using postoperative pathologic staging as a gold standard. It also aimed to determine the impact of EUS in preoperative locoregional staging of resectable esophageal cancer. Methods Patients From September 2005 to July 2008, patients with a diagnosis of biopsy-proven esophageal cancer were prospectively enrolled in Seoul National University Hospital to undergo a preoperative staging protocol that included EUS, whole-body PET/CT, and chest CT scan concomitantly. All patients eligible for surgical resection who had no distant metastasis or extensive adjacent organ invasion in the staging protocol were allocated to esophageal resection and extensive regional lymph node dissection. The Institutional Review Board of the Seoul National University Hospital approved this study, and written informed consents were obtained from all the patients. All information was collected and analyzed retrospectively. EUS imaging All EUS examinations were performed by a single experienced endoscopist (S.G.K.), who had a high volume of EUS. The examination was performed using a radial array echoendoscope (Olympus GF-UM 2000;Tokyo, Japan) with the patient under sedation using midazolam. Imaging with 12 MHz assessed the depth of primary tumor invasion (T stage), whereas imaging with 5 MHz detected the malignant-appearing perigastric or mediastinal lymph nodes (N stage), celiac nodes, or hepatic metastases (M stage). Minimal balloon inflation was used to avoid tumor compression. In addition, high-frequency ultrasonic (HFUS) probes (UM-2R, 20 MHz; Olympus) were used for superficial lesion or malignant stricture. The HFUS examinations were performed after water instillation into the esophageal lumen and suctioning of luminal air. If the echoendoscope could not pass the stricture, the patients did not undergo the dilation procedure, and staging was assessed from the proximal tumor margin. The EUS criteria used for T staging were as follows: T1 (tumor invades the mucosa or submucosa but not the muscularis propria), T2 (tumor invades but does not extend beyond the muscularis propria), T3 (tumor invades the adventitia but not the adjacent organs), and T4 (tumor invades the adjacent organs). The criteria for malignant lymph nodes included a round shape, a diameter exceeding 10 mm, hypoechogenecity, and well-demarcated borders [9]. Celiac lymph nodes were defined by their location within a 2-cm area from the celiac trunk and indicated distant metastasis. PET/CT imaging All scans were performed using a PET/CT system (Philips Gemini, DA best, Netherlands) with 2-(fluorine-18)-fluoro- 2-deoxy-D-glucose (FDG). After at least a 6-h fast, images were obtained 60 min after intravenous injection of 555– 740 MBq (15–20 mCi; 0.22 mCi/kg) of 18FDG. A noncontrast CT scan was performed before PET, and the resulting data were used to create an attenuation correction map for PET. Sections 5 mm thick were obtained at 50 mA and 120 kVp from the skull base to the mid thigh region. The PET scan was performed at a 5-min emission acquisition per image level, and the images were reconstructed into three-dimensional representations. In the qualitative assessment of the images, foci with increased 18FDG uptake compared with the surrounding structures were defined as malignancies. For quantitative analysis of FDG uptake, the maximal standardized uptake value (SUVmax) was assessed. CT imaging All CT scans were performed with a Genesis High-Speed CT (GE Medical Systems, Milwaukee, WI, USA). Scans were obtained after 1.4 ml/kg of a nonionic contrast medium (Ultravist 370, Schering, Berlin, Germany) had been injected intravenously. The scanning parameters were 120 kVp and 230 mAs. The imaging data were reconstructed with 7-mm collimation. The CT scans were performed from the lower neck to the lower pole of the kidney. Images were evaluated for the presence of primary tumor, locoregional and/or distant lymph node metastasis, and distant organ metastasis. The lymph nodes with the shortest diameter ([8 mm) were considered positive for metastasis. Pathologic stage Pathologic staging was determined using the tumor node metastasis (TNM) classification system according to the American Joint Committee on Cancer (AJCC) esophageal cancer staging [10]. The regional lymph nodes included paratracheal, posterior and anterior mediastinal, subcarinal, paraesophageal, pericardial, inferior pulmonary ligament, Surg Endosc 123

Surg Endose and recurrent laryngeal nerve node metastases.Cervical Table 1 Patient characteristics and celiac lymph nodes and distant organ metastases were Characteristics staged as distant metastasis (M). nde Data analysis 103 945 e (years) 62.7±85 compared.The sensitivity,specificity.positive predictive 5 4.6 value,negative predictive value,and accuracy were cal- 36.7 culated for each individual T and N stage by using standard Lower 53 48.6 definition GEJ l01 tatistical significance.Analyses were performed using the Statistical Package for the Social Sciences.version 12.0 18 (SPSS.Chicago.IL.USA). 9 Well differentiad 21. Results Moderate 69.7 Poor Clinical characteristics Undetermined Total In this study,109 patients were evaluated.Men predomi- 109 100.0 GE/gastroesophageal junction of theh carcinomas or carcin comas.Histologically,the involved tumors were mainly the pathologic T sta ges were TI (n 2).T2 (n 2).T3 (n =11).and T4 (n=3).respectively.In 11 examina A total c racic esopha ons HFUS probes were used to evaluate gectomy with 1 node dissectio and 8 patients underwent esophagectomy with lymph EUS T staging node sampling.Five patients (4.5%)had preoperative neoadiuvant chemotherapy (n =1)or concurrent chemo- Because CT and PET cannot differentiate the individual radiation therapy (n =4)before surgery. layers of the esophageal wall,no attempt was made to thre meth Identification of primary tumor ofT1(80%) T3 (786) For 103(94.5%)of the 109 patients,EUS identified the ng of T2 disease (53%)(p<0.05).The a 0 primary tumor.For 93 patients(85.3%),PET scan identi- EUS was91%for T1,78%for T2.and 80%for T3.The fied the primary tumor by detecting an increased uptake in sensitivity,specincity,and accuracy of EUS for 12 were he esophagus.For 68 patients (o )CT scan identified significantl wer than P<0.05) accuracy Us was 729 109) able 2). ed the T stao in 17 case EUS and understaged it in 13 cases.Among the 91 patients for whom EUS was completed,the overall accuracy rate was Examination by EUS was completed for 91 patients(84%) 76%,whereas it was 50%among 18 patients in whom the For 18 patients (16%),obstructing tumors did not permit passage of an endoscope was limited

and recurrent laryngeal nerve node metastases. Cervical and celiac lymph nodes and distant organ metastases were staged as distant metastasis (M). Data analysis The histopathology of the surgical specimen was the gold standard to which the results of the imaging methods were compared. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for each individual T and N stage by using standard definitions. A McNemar test was used to compare the accuracy of EUS, PET, and CT staging [11]. All tests of significance were two-tailed, and p values \0.05 denoted statistical significance. Analyses were performed using the Statistical Package for the Social Sciences, version 12.0 (SPSS, Chicago, IL, USA). Results Clinical characteristics In this study, 109 patients were evaluated. Men predominated (94.5%) among the subjects, and the mean age was 62.7 years. Most tumors were located in the lower (48.2%) or middle (36.4%) esophagus. Squamous cell carcinomas made up the majority of the histopathologic tumor types, and the remainder were adenocarcinomas or carcinosarcomas. Histologically, the involved tumors were mainly moderately and well differentiated (Table 1). A total of 89 patients underwent transthoracic esophagectomy with two-field (thoracoabdominal) lymph node dissection, whereas 12 patients had three-field (thoracoabdominal and cervical) lymph node dissection, and 8 patients underwent transhiatal esophagectomy with lymph node sampling. Five patients (4.5%) had preoperative neoadjuvant chemotherapy (n = 1) or concurrent chemoradiation therapy (n = 4) before surgery. Identification of primary tumor For 103 (94.5%) of the 109 patients, EUS identified the primary tumor. For 93 patients (85.3%), PET scan identi- fied the primary tumor by detecting an increased uptake in the esophagus. For 68 patients (62.4%), CT scan identified the primary tumor either by identification of a mass density or by wall thickening. EUS Examination by EUS was completed for 91 patients (84%). For 18 patients (16%), obstructing tumors did not permit passage of an endoscope, so they had an incomplete examination. For the patients with nontraversable tumors, the pathologic T stages were T1 (n = 2), T2 (n = 2), T3 (n = 11), and T4 (n = 3), respectively. In 11 examinations, HFUS probes were used to evaluate superficial esophageal cancer (n = 8), lye stricture (n = 2), and malignant stricture (n = 1). EUS T staging Because CT and PET cannot differentiate the individual layers of the esophageal wall, no attempt was made to compare T staging among the three methods. Findings showed EUS to be significantly more sensitive for T staging of T1 (80%) and T3 disease (78%) than for T staging of T2 disease (53%) (p\0.05). The accuracy of EUS was 91% for T1, 78% for T2, and 80% for T3. The sensitivity, specificity, and accuracy of EUS for T2 were significantly lower than for T1 (p\0.05). The overall accuracy of EUS was 72% (79/109) of cases (Table 2). In the EUS examinations, 30 cases (28%) had incorrect T staging. Of these, EUS overstaged the T stage in 17 cases and understaged it in 13 cases. Among the 91 patients for whom EUS was completed, the overall accuracy rate was 76%, whereas it was 50% among 18 patients in whom the passage of an endoscope was limited. Table 1 Patient characteristics Characteristics n % Gender Male 103 94.5 Female 6 5.5 Mean age (years) 62.7 ± 8.5 Location Upper 5 4.6 Middle 40 36.7 Lower 53 48.6 GEJ 11 10.1 Histologic type Squamous 101 92.7 Adenocarcinoma 5 4.6 Adenoid cystic tumor 2 1.8 Carcinosarcoma 1 0.9 Histologic grade Well differentiated 23 21.1 Moderate 76 69.7 Poor 7 6.4 Undetermined 3 2.8 Total 109 100.0 GEJ gastroesophageal junction Surg Endosc 123

N staging In N staging, EUS had a sensitivity of 42%, a specificity of 91%, and an accuracy of 66%. The sensitivity, specificity, and accuracy did not differ significantly across the three tests (p = 0.30, 0.62, and 0.77, respectively). For EUS, the positive predictive value was 82%, and the negative predictive value was 60%. Combining the use of these techniques improved sensitivity (65%) and accurately predicted N stage for 72% of the patients (Table 3). Metastatic disease Of the 109 patients, 5 (4.6%) had distant metastases at cervical (n = 3), celiac (n = 1), and retropancreatic (n = 1) lymph node sites. Whereas EUS could not detect any suspicious metastatic foci, CT or PET detected distant metastasis in two (16%) of five patients. However, PET showed a false-positive adrenal metastasis, and CT showed a false-positive lung metastasis in one patient. No additional information was given by EUS about distant metastasis, including one case of celiac nodal metastasis. Although the sensitivity of PET and CT for metastasis was unacceptably low, these two methods showed both high specificity and accuracy. Combined use of PET and CT did not improve sensitivity (Table 4). Discussion Our study aimed to investigate the impact of EUS for staging esophageal cancer by comparing it with PET and CT staging. For T staging, EUS is the most accurate technique because it can delineate the esophageal wall layers with histologic correlates [12]. A metaanalysis of 49 studies that evaluated the accuracy of EUS in detecting esophageal cancer reported that its pooled sensitivity for T staging was 81–90% and its specificity was 99% [13]. Another metaanalysis of 27 studies demonstrated the accuracy of EUS for T staging to be 89% [14]. Table 2 Accuracy of endoscopic ultrasonography (EUS) tumor depth (T) staging Pathologic stage Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) T1 T2 T3 T4 EUS T stage T1 39 0 0 0 80 100 100 86 91 T2 8 8 9 0 53 82 32 91 78 T3 2 7 32 4 78 80 71 86 80 T4 0 0 0 0 PPV positive predictive value, NPV negative predictive value Table 3 Comparison of endoscopic ultrasonography (EUS), positron emission tomography (PET), and computed tomography (CT) for lymph nodal (N) staging Pathologic stage Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) N0 N1 EUS N0 49 32 42 91 82 60 66 N1 5 23 PET N0 47 28 49 87 79 63 68 N1 7 27 CT N0 50 36 35 93 83 58 63 N1 4 19 Combined 3 methods N0 43 19 65 80 77 69 72 N1 11 36 PPV positive predictive value, NPV negative predictive value Surg Endosc 123

Surg Endose Table Comparison of (PETand computed (CT or metastasis (M)san Pathologic stage Sensitivity (% Specificity ( PPV ( NPV (% MO PET MO 103 40 96 MI 103 20 99 96 95 ned m 102 40 97 MI PPV positive predictive value,NPV negative predictive value In our study.the of FUS for T sta shown to be n s did no urativ dance with Shimpi et al.[6],who had similar study set- gery,and thus pathologic staging as a gold standard was tings.Our results could be explained by patient selection not completely determined.A major advantage of our study bias because we included only patients who were potential was that a large number of patients with esophageal cancer andida ere there re enrolle All of th the complete slear Ta cases In addition the d tion of T2 stage had the least accuracy.and equal numbers of lesions were under-and overstaged,which may be associated with tion of celiac nodal involvement,which indicates distant microscopic tumor invasion or peritumoral inflammatory cancer.Regardless of echo tea change r factor that nay affe eofuracy in s dy than 1 er .Up to one-third of patients metaanalysis of 25 studies.EUS for celiac node metastasis with esophageal cancer present with marked luminal ste- showed a sensitivity of 67 and a specificity of9%19] nosis that does not permit passage of EUS [15]and We performed EUS for surgically resectable patients at therefore prohibits complete staging by EUS An EUS hac node a position proxim e tumor has pmeeTrairesthene.andoo8eientNhag met was not identified by EUS due to agndy 18 of PET's ability to st had malignant stricture.for which we did no form a dilation procedure before EUS.An earlier study has shown a sensit vity of 88.a s pecificity of93%and an accuracy Our findings showed that the ion was dminis verall accuracy of P lete ng dis tant metasta EUS than the ed in s in its vield of detected celiac i h n [15 171 However perforations during the dilation can In our study.the ability of PET to predict N stage occur occasionally.and the patient must be individually remained unsatisfactory.For detecting N stage.PET had a determined for assessment of the risk-benefit relation sensitivity of 42%and a specificity of 91%.Recent data before the dilation procedure have shown that for N staging.PET has a sensitivity of studies evalu nd Cr mg2.4.781H weve udi (51% reported in Springer

In our study, the accuracy of EUS for T staging was shown to be no greater than 72%, which was in concordance with Shimpi et al. [6], who had similar study settings. Our results could be explained by patient selection bias because we included only patients who were potential candidates for curative surgery. All our cases were therefore pathologic T1 to T3 stages except for four cases, which were more difficult to distinguish from another than clear T4 cases. In addition, the designation of T2 stage had the least accuracy, and equal numbers of lesions were under- and overstaged, which may be associated with microscopic tumor invasion or peritumoral inflammatory change. Another factor that may affect accuracy in staging of esophageal cancer is the presence of strictures that limit passage of an echoendoscope. Up to one-third of patients with esophageal cancer present with marked luminal stenosis that does not permit passage of EUS [15] and therefore prohibits complete staging by EUS. An EUS examination from a position proximal to the tumor has been shown to result in inaccurate T staging and inadequate evaluation of the celiac axis. In our study, 18 patients (16%) had malignant stricture, for which we did not perform a dilation procedure before EUS. An earlier study reported an unacceptably high perforation rate when dilation was administered before EUS [16]. Several studies have recently reported that dilation was safe as long as the rules of sequential dilation were followed. Thus, EUS gained increases in its yield of detected celiac lymph nodes [15, 17]. However, perforations during the dilation can occur occasionally, and the patient must be individually determined for assessment of the risk-benefit relation before the dilation procedure. Previous studies evaluated the comparative accuracy of esophageal cancer staging by EUS, PET, and CT with pathologic staging [2, 4, 7, 8]. However, these studies were somewhat limited by their relatively small size. Furthermore, some of the patients did not undergo curative surgery, and thus pathologic staging as a gold standard was not completely determined. A major advantage of our study was that a large number of patients with esophageal cancer were enrolled. All of these patients provided the complete information regarding pathologic staging, and the accuracy of EUS, CT, and PET was concomitantly evaluated for locoregional staging of esophageal cancer. Endoscopic ultrasonography plays a role in the evaluation of celiac nodal involvement, which indicates distant metastasis in esophageal cancer. Regardless of echo features and size, 90% of all detected celiac lymph nodes were proved to be malignant in one study [18]. Moreover, 100% of celiac nodes larger than 1 cm were malignant. In a metaanalysis of 25 studies, EUS for celiac node metastasis showed a sensitivity of 67% and a specificity of 98% [19]. We performed EUS for surgically resectable patients at preoperative staging, and only one patient had celiac node metastasis, which was not identified by EUS due to malignant stricture. Promising reports of PET’s ability to stage esophageal cancer have been published. For distant metastasis, PET has shown a sensitivity of 88%, a specificity of 93%, and an accuracy of 91% [20]. Our findings showed that the overall accuracy of PET in detecting distant metastasis was not any better than the ability of CT. This was mostly due to the lack of sensitivity in detecting distant lymph node metastases. In our study, the ability of PET to predict N stage remained unsatisfactory. For detecting N stage, PET had a sensitivity of 42% and a specificity of 91%. Recent data have shown that for N staging, PET has a sensitivity of only 57%, a specificity of only 83%, and an accuracy of only 71% [21]. Our result was comparable with the pooled sensitivity (51%) and specificity (84%) reported in a Table 4 Comparison of positron emission tomography (PET) and computed tomography (CT) for metastasis (M) staging Pathologic stage Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) M0 M1 PET M0 103 3 40 99 66 97 96 M1 1 2 CT M0 103 4 20 99 50 96 95 M1 1 1 Combined 2 methods M0 102 3 40 98 50 97 95 M1 2 2 PPV positive predictive value, NPV negative predictive value Surg Endosc 123

metaanalysis [13]. Not surprisingly, lymph nodes adjacent to the primary tumor are difficult to differentiate from the primary tumor with PET. In addition, PET may not detect microscopic metastasis of lymph nodes due to its limited resolution effects. In a metaanalysis of the EUS, PET, and CT results for esophageal cancer staging, the pooled sensitivities for N stage were 0.80 for EUS, 0.57 for PET, and 0.50 for CT, although these three methods were not performed and analyzed concomitantly [22]. However, the overall diagnostic accuracy for N staging did not differ significantly and was in line with our results. Regarding the relatively low accuracy and sensitivity of these tests for N staging, EUS-guided fine-needle aspiration (EUS-FNA) may be considered for preoperative staging method. The use of EUS-FNA increases both sensitivity and accuracy for the detection of nonperitumoral lymph node metastases [23]. However, lymph nodes at the level of the primary tumor often are not accessible to EUS-FNA because the needle would have to traverse the tumor to obtain a specimen. This carries the potential risk of cancer cells spreading into lymph nodes that may not be malignant. Our data are limited by the inclusion of patients with a somewhat narrowed clinical spectrum of disease because only surgically resectable patients were enrolled in this study. Patients with advanced disease stages were excluded, which may be related to underestimation of both sensitivity and accuracy in the detection of metastasis to lymph nodes. In conclusion, our study shows good diagnostic accuracy for EUS T staging of esophageal cancer, and our findings show that the diagnostic accuracy of N staging by EUS is as good as that of PET or CT. Therefore, EUS could be useful for determining a therapeutic strategy for esophageal cancer, especially for resectable diseases. Disclosures Jeongmin Choi, Sang Gyun Kim, Joo Sung Kim, Hyun Chae Jung, and In Sung Song have no conflicts of interest or financial ties to diclose. References 1. Enzinger PC, Mayer RJ (2003) Esophageal cancer. N Engl J Med 349:2241–2252 2. Lowe VJ, Booya F, Fletcher JG, Nathan M, Jensen E, Mullan B, Rohren E, Wiersema MJ, Vazquez-Sequeiros E, Murray JA, Allen MS, Levy MJ, Clain JE (2005) Comparison of positron emission tomography, computed tomography, and endoscopic ultrasound in the initial staging of patients with esophageal cancer. Mol Imaging Biol 7:422–430 3. van Westreenen HL, Heeren PA, van Dullemen HM, van der Jagt EJ, Jager PL, Groen H, Plukker JT (2005) Positron emission tomography with F-18-fluorodeoxyglucose in a combined staging strategy of esophageal cancer prevents unnecessary surgical explorations. J Gastrointest Surg 9:54–61 4. 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n engl j med 367;4 nejm.org july 26, 2012 299 The new england journal of medicine established in 1812 july 26, 2012 vol. 367 no. 4 Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain Udo Hoffmann, M.D., M.P.H., Quynh A. Truong, M.D., M.P.H., David A. Schoenfeld, Ph.D., Eric T. Chou, M.D., Pamela K. Woodard, M.D., John T. Nagurney, M.D., M.P.H., J. Hector Pope, M.D., Thomas H. Hauser, M.D., M.P.H., Charles S. White, M.D., Scott G. Weiner, M.D., M.P.H., Shant Kalanjian, M.D., Michael E. Mullins, M.D., Issam Mikati, M.D., W. Frank Peacock, M.D., Pearl Zakroysky, B.A., Douglas Hayden, Ph.D., Alexander Goehler, M.D., Ph.D., Hang Lee, Ph.D., G. Scott Gazelle, M.D., M.P.H., Ph.D., Stephen D. Wiviott, M.D., Jerome L. Fleg, M.D., and James E. Udelson, M.D., for the ROMICAT-II Investigators A BS TR AC T The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Hoffmann at Massachusetts General Hospital, Cardiac MR PET CT Program, 165 Cambridge St., Suite 400, Boston, MA 02114, or at uhoffmann@partners.org. N Engl J Med 2012;367:299-308. DOI: 10.1056/NEJMoa1201161 Copyright © 2012 Massachusetts Medical Society. Background It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes. Methods In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes. Results The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standardevaluation group ($4,289 and $4,060, respectively; P=0.65). Conclusions In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.)