复旦大学：《循证医学》课程教学资源（教材教案）循证医学各章教案及相关文献.pdf_P11-P15

Unit3:疾病诊断证据的分析与评价主讲教师：陈世耀助理教师：张宁弹一、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 2.诊断试验文献评价与应用，课前阅读，课堂讨论 (1)提供中英文文献（见附件），课堂讨论（文献评价）-45分钟 (2)提出临床问题（案例见附件），课堂讨论（诊断试验临床应用）45分钟 3.问题点评分析，诊断试验设计。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与诊断试验临床应用方法五、中文和英文关健词诊断式验预测值 Predictive va 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)色素放大内镜与普通电子内镜诊断结肠黏膜病变的价值比较 (2)Comparison of endoscopic utr tomograph (PET).and computed tomography(CT)in the preoperative locoregional staging of resectable esophageal cancer 七、讨论思考题： (1)诊断试验科学性评价的标准有哪些？通讨文献阅读分析和讨论，明确诊断试验评价的范畴、诊断试验研究的科学性（文献评价标准），包括金标准的确立病例组非病例组的选择、诊断试验与金标准的实施、可能影响结果的因素如盲法原则是否与如何实施。 (2)诊断试验中包括哪些基本概念？各自特点是什么？通过临床问题分析和讨论，进一步强调诊断试验文献科学性评价原则。掌握诊断试验研究评价中的基本概念及其临床应用。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 (2).Leeflang MMG,et al.Systematic Reviews of Diagnostic Test Accuracy.Ann Intern Med 2008:14912):889-897 (3).Lord SJ.et al.When Is Measuring Sensitivity and Specificity Sufficient To Evaluate a Diagnostic Tes and When Do Need Randomized Trials? Ann Intemn Med 2006:144:850-855. 第11页

Unit 3᧶⯴⯻䈀ᯣ䇷ᦤⲺ࠼᷆ф䇺ԭ ѱ䇨ᮏᐾφ䱸ц㘰 ࣟ⨽ᮏᐾφᕐᆱ㨽 жȽᮏᆜⴤⲺφ 1. ᦼᨑ䇺ᯝ䈅傼Ⲵᾲᘥ઼䇴ԧᤷḷ˗ 2. ⟏ᚹ䇺ᯝ䈅傼䇴ԧḷ߶ˈ൘Ѥᒺᇎ䐥ѝਸ⨶䘹ᤙ䇺ᯝ䈅傼˗ 3. ࡍ↕Ҷ䀓䇺ᯝ䈅傼⹄ウ䇮䇑 ӂȽᮏᆜ޻ᇯφ 1. 䇺ᯝ䈅傼Ⲵสᵜᾲᘥˈ䇺ᯝ䈅傼䇴ԧᤷḷ ̢བྷ䈮䇢ᦸ 2. 䇺ᯝ䈅傼᮷⥞䇴ԧоᓄ⭘ˈ䈮ࡽ䰵䈫ˈ䈮า䇘䇪 (1) ᨀ׋ѝ㤡᮷᮷⥞(㿱䱴Ԧ)ˈ 䈮า䇘䇪 (᮷⥞䇴ԧ)-45 ࠶䫏 (2) ᨀࠪѤᒺ䰞仈(Ṹֻ㿱䱴Ԧ)ˈ䈮า䇘䇪 (䇺ᯝ䈅傼Ѥᒺᓄ⭘)-45 ࠶䫏 3. 䰞仈⛩䇴࠶ˈ᷀䇺ᯝ䈅傼䇮䇑Ǆ пȽᮏᆜ䠃⛯φสᵜᾲᘥˈवᤜ⚥᭿ᓖǃ⢩ᔲᓖǃ亴⍻٬ǃROC ᴢ㓯ǃլ❦∄ ഑Ƚᮏᆜ䳴⛯φ䇺ᯝ䈅傼᮷⥞䇴ԧ৏ࡉо䇺ᯝ䈅傼Ѥᒺᓄ⭘ᯩ⌅ ӊȽѣᮽૂ㤧ᮽީ䭤䈃䇺ᯝ䈅傼 Diagnostic test˗⚥᭿ᓖ Sensitivity˗⢩ᔲᓖ Specificity 亴⍻٬ Predictive value˗լ❦∄˖Likelihood ratio, LR ਇ䈅㘵ᐕ֌⢩ᙗᴢ㓯˖Receiver Operator Characteristic Curve, ROC ᴢ㓯 ⥤ᮽȽ䰻䈱ޣ (1) 㢢㍐᭮བྷ޵䮌оᲞ䙊⭥ᆀ޵䮌䇺ᯝ㔃㛐哿㟌⯵ਈⲴԧ٬∄䖳 (2) Comparison of endoscopic ultrasonography (EUS), positron emission tomography (PET), and computed tomography (CT) in the preoperative locoregional staging of resectable esophageal cancer йȽ䇞䇰ᙓ㘹从φ (1) 䇺ᯝ䈅傼、ᆖᙗ䇴ԧⲴḷ߶ᴹଚӋ˛䙊䗷᮷⥞䰵䈫࠶઼᷀䇘䇪ˈ᰾⺞䇺 ᯝ䈅傼䇴ԧⲴ㤳⮤ǃ䇺ᯝ䈅傼⹄ウⲴ、ᆖᙗ(᮷⥞䇴ԧḷ߶)ˈवᤜ䠁ḷ߶Ⲵ⺞・ǃ ⯵ֻ㓴઼䶎⯵ֻ㓴Ⲵ䘹ᤙǃ䇺ᯝ䈅傼о䠁ḷ߶Ⲵᇎᯭǃਟ㜭ᖡ૽㔃᷌Ⲵഐ㍐ྲⴢ ⌅৏ࡉᱟ੖оྲօᇎᯭǄ (2) 䇺ᯝ䈅傼ѝवᤜଚӋสᵜᾲᘥ˛਴㠚⢩⛩ᱟӰѸ˛䙊䗷Ѥᒺ䰞仈࠶᷀ ઼䇘䇪ˈ䘋а↕ᕪ䈳䇺ᯝ䈅傼᮷⥞、ᆖᙗ䇴ԧ৏ࡉǄᦼᨑ䇺ᯝ䈅傼⹄ウ䇴ԧѝⲴ สᵜᾲᘥ৺ަѤᒺᓄ⭘Ǆ ޡȽ৸㘹Ҝ਀ᮽ⥤ⴤᖋ (1).ǉᗚ䇱५ᆖоѤᒺᇎ䐥Ǌ˄ㅜ 3 ⡸˅ˈ⦻ਹ㘰ѫ㕆ˈ、ᆖࠪ⡸⽮ (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. 第 11 页

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 ㄀义第 12 页

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 ㄀义第 13 页

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 ㄀义 123 第 14 页

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 ㄀义第 15 页