Enhancing the diagnostic performance of repeated endoscopic ultrasound-guided tissue acquisition combined with surrogate repeated endoscopic retrograde pancreatography for small pancreatic cancer Running title: EUS-TA and ERP for pancreatic cancer

Enhancing the diagnostic performance of repeated endoscopic ultrasound-guided tissue acquisition combined with surrogate repeated endoscopic retrograde pancreatography for small pancreatic cancer Running title: EUS-TA and ERP for pancreatic cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Enhancing the diagnostic performance of repeated endoscopic ultrasound-guided tissue acquisition combined with surrogate repeated endoscopic retrograde pancreatography for small pancreatic cancer Running title: EUS-TA and ERP for pancreatic cancer Yusuke Kurita, Shinichi Nihei, Kensuke Kubota, Shin Yagi, Yu Honda, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7056650/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Sep, 2025 Read the published version in Digestive Diseases and Sciences → Version 1 posted 11 You are reading this latest preprint version Abstract Purpose Diagnosing pancreatic tumors ≤10 mm is challenging due to limited visualization and low sampling sensitivity. This study aimed to evaluate the cumulative diagnostic performance of repeated endoscopic ultrasound-guided tissue acquisition (EUS-TA) and surrogate repeated endoscopic retrograde pancreatography (ERP). Methods This study analyzed 40 patients with suspected pancreatic tumors ≤10 mm who underwent EUS-TA and/or ERP retrospectively. When a diagnosis could not be determined based on the initial EUS-TA or ERP procedure, EUS-TA or ERP was repeated as necessary. The cumulative diagnostic performance of EUS-TA and ERP for pancreatic tumors was evaluated. Results EUS-TA was performed once for 35 cases, twice for seven cases, and three times for one case. ERP was performed for 15 cases, and the median number of ERP attempts was two (range, 1-8). The cumulative sensitivity of EUS-TA increased from 56.7% to 70.0% after three attempts, while ERP sensitivity rose from 54.5% to 72.7% after two attempts. The cumulative diagnostic performance of repeated EUS-TA and ERP combined by case included sensitivity and accuracy rates of 87.9% and 90.0%. When limited to pancreatic cancer, the sensitivity and accuracy rates were 95.8% and 96.8%, respectively.No severe adverse events occurred. Conclusions Repeated EUS-TA and ERP significantly improved diagnostic sensitivity for small pancreatic tumors. When a single EUS-TA or ERP procedure fails to establish a diagnosis in suspected malignant cases, repeating the procedures may be warranted. In cases where initial procedures are inconclusive, repeated application of both methods may enable accurate pathological diagnosis and inform optimal treatment strategies. endoscopic ultrasound-guided tissue acquisition endoscopic retrograde cholangiopancreatography pancreatic cancer Figures Figure 1 Figure 2 Figure 3 Introduction An accurate diagnosis of early-stage resectable pancreatic cancer is important. However, small pancreatic lesions are difficult to detect using imaging techniques. Compared to other imaging modalities such as computed tomography (CT) and transabdominal ultrasonography, endoscopic ultrasound (EUS) is considered superior for small lesion detection[1, 2]. Nevertheless, the accuracy of EUS for detecting specific morphological lesions of different pancreatic tumor types is limited [3, 4]. The efficacy of EUS-guided tissue acquisition (TA) for pathological detection has been demonstrated [5-9]. When evaluating small lesions (≤10 mm) with EUS-TA, the technical difficulty is increased, the diagnostic accuracy is decreased, and the sensitivity rates range from 64.3% to 84.5% [8, 10-12]. Therefore, EUS-TA presents challenges when used for small pancreatic lesions. The effectiveness of endoscopic retrograde pancreatography (ERP) for the histological diagnosis of intraepithelial carcinoma and small pancreatic cancer that do not form mass lesion has been evaluated [13]. and the pathological diagnostic accuracy of ERP for pancreatic cancer ranges from 21.3% to 63.6%. The diagnostic performance of EUS-TA is superior to that of ERP for lesions that can be examined by EUS-TA; however, for small tumors that cannot be examined by EUS-TA and tumors that cannot be visualized by EUS, ERP is the only alternative option for diagnosis. The results with EUS-TA for small tumor posed risks of false-negative and inconclusive, as well. As a result, the usefulness of repeated EUS-TA has been evaluated [14-17], and major guidelines recommend repeated EUS-TA [18]. Additionally, ERP improves the diagnostic sensitivity for small pancreatic cancers [19], and repeated ERP may avoid false-negative results. The number of false-negative results that can be decreased by repeating EUS-TA and ERP for small pancreatic tumors and the actual diagnostic performance are unclear. Therefore, this study aimed to evaluate the diagnostic performance of combined repeated EUS-TA and surrogate repeated ERP for small pancreatic tumors (≤10 mm). Methods Study design We retrospectively evaluated the data of 40 patients with pancreatic parenchymal lesions 10 mm or smaller and suspected tumors 10 mm or smaller who underwent EUS or ERP between 2012 and 2024. This retrospective observational study was approved by the Ethics Committee of our facility (F230400003). The present study used only medical information and did not infringe on the privacy of the patients. All participants received an opt-out form for informed consent. Patients who did not provide consent to participate in the study were excluded. All the authors approved the final manuscript. EUS-TA procedure EUS-TA was performed using a GF-UCT260 curved linear echoendoscope (Olympus Corporation, Tokyo, Japan) connected to an ultrasound scanning system (ARIETTA 850 [FUJIFILM Medical Co., Ltd., Tokyo, Japan] or EU-ME2/EU-ME1 [Olympus Corporation]). The EZ Shot 3 Plus (Olympus Corporation), Acquire (Boston Scientific, Natick, MA, USA), Trident (Micro-Tech, Nanjing, China), SonoTip Top Gain (Medi-Globe, Rohrdorf, Germany), Echo Tip Ultra (Cook Medical, Bloomington, IN, USA), and SonoTip Pro control (Medi-Globe) EUS-TA needles were used. A 22-gauge needle was used for all punctures. The size and type of needle were chosen at the discretion of the endosonographer. Acquire, Trident, and SonoTip Top Gain are defined as FNB needles. EZ Shot 3 Plus, Echo Tip Ultra, and SonoTip Pro control are defined as FNA needles. We uniformly used negative suction with a 10-mL or 20-mL syringe during all EUS-TA procedures. EUS-TA was performed by expert endosonographers for all cases. The puncture technique used during this study was not standardized and was performed at the discretion of the endosonographers. During EUS-TA, three punctures were performed for all cases. However, the EUS-TA procedure was terminated when each endoscopist visually confirmed the presence of a sufficient specimen. A specific specimen size and quantitative criteria for the termination of the specimen examination were not standardized and were determined by each endoscopist. ERP procedure Potential cancer patients with stenosis or dilation of the main pancreatic duct underwent ERP, and pancreatic juice was collected for cytological analysis. A single-channel duodenoscope was used for ERP (TJF-Q290V, JF-260V, or TJF-260V; Olympus). A cannula (PR-104Q-1; Olympus) or MTW catheter (MTW Endoskopie Manufaktur, Wesel, Germany) was inserted. A 0.025-inch guidewire was carefully advanced deep in the main pancreatic duct. Pancreatic ductography was performed to evaluate pancreatic duct stenosis and collect pancreatic juice. An uneven catheter (Piolax Medical, Yokohama, Japan) was used for washing and aspiration cytology. An RX cytology brush (Boston Scientific) was used for brush cytology. A 5-Fr endoscopic nasopancreatic drainage catheter (Cook Medical) was used for the serial pancreatic juice aspiration cytological examination (SPACE) [20]. The technique was chosen by the endoscopist. Complications associated with EUS-TA and ERP were investigated, and their severity was defined according to the American Society for Gastrointestinal Endoscopy classification [21]. Pathology sample preparation At our institution, cytopathologists and cytotechnologists do not perform rapid on-site cytological evaluations. The specimens were fixed in 10% formalin and embedded in paraffin. The EUS-TA specimens were stained with hematoxylin and eosin for histological examinations. Cytological samples for ERP were immediately centrifuged, and smear preparations were fixed in 95% ethyl alcohol and stained using the Papanicolaou method and Giemsa staining. Immunohistochemical staining was performed when necessary for diagnostic purposes using an automated system (Ventana BenchMark ULTRA; Roche Diagnostics, Basel, Switzerland). Deparaffinization was performed by heating slides to 72°C. For antigen retrieval, the slides were heated to 95°C and incubated for 8 minutes, and the required antibodies (diluted 1:50 to 1:500 depending on the type of antibody used) were titrated onto the slides and incubated for 16 minutes each. Experienced pathologists performed all analyses. Diagnostic ability of EUS-TA and ERP for small pancreatic tumors The final diagnosis of lesions was determined using EUS-TA and ERP, pathological findings of surgical specimens, and clinical follow-up observations [8]. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EUS-TA and ERP were evaluated. For malignant lesions, EUS-TA and ERP diagnoses were considered accurate when pathological diagnoses of EUS-TA and ERP not only distinguished between malignant and benign lesions but also matched the final diagnosis. Additionally, when pathological diagnoses indicated suspicion for malignancy or malignancy, they were included as accurate diagnoses of malignant lesions. When the pathological diagnoses were atypical, they were regarded as inaccurate diagnoses of malignant lesions. For benign lesions, EUS-TA and ERP diagnoses were considered accurate when malignant findings were absent during pathological examinations. These patients were followed-up every 6 months using CT, magnetic resonance cholangiopancreatography, and EUS [8, 22]. Benign lesions such as focal pancreatitis and other non-neoplastic lesions were defined as benign in the absence of malignant findings during cytological and cell block examinations and a lack of progression during at least 12 months of follow-up including CT, magnetic resonance cholangiopancreatography, and EUS. Diagnostic strategy for small pancreatic tumors at our facility If the endoscopist was able to visualize the mass using EUS and determined that EUS-TA was technically feasible, then EUS-TA was performed (Figure 1). If a pathological diagnosis was not possible after the first EUS-TA procedure, then a second EUS-TA procedure, or follow-up was considered. Alternatively, ERP was performed if there were pancreatic duct findings such as dilation or stenosis. If a diagnosis was not possible after the second EUS-TA procedure, then a third EUS-TA, ERP or follow-up was performed at the discretion of the endoscopist. ERP was performed if the tumor could not be visualized by EUS, if a diagnosis could not be determined using EUS-TA, or if the findings were potential of early pancreatic cancer, such as pancreatic atrophy, pancreatic duct stenosis, or pancreatic duct dilation [23]. If a diagnosis could not be determined using ERP, then a second EUS-TA procedure, repeated ERP, or follow-up was performed. Endpoints The primary endpoint of this study was the cumulative diagnostic performance of repeated EUS-TA and surrogate repeated ERP for small pancreatic tumors 10 mm or smaller. The secondary endpoint was the diagnostic performance of EUS-TA and that of ERP individually, and the number of procedures performed, and incidence of complications were evaluated. The diagnostic performance of EUS-TA and that of ERP were evaluated individually when multiple procedures were performed. Statistical analysis Statistical analyses were performed using SPSS version 21 software (IBM, Armonk, NY, USA). Results The characteristics of the 40 patients included in this study are shown in Table 1 . The final diagnosis was pancreatic cancer for 24 patients (60.0%), neuroendocrine tumor for eight patients (20.0%), metastatic pancreatic cancer for one patient (2.5%), and benign lesion for seven patients (17.5%). Figure 2 summarizes how the 40 cases were pathologically or clinically diagnosed. Table 1 Clinical characteristics of patients Variable Number (n = 40) Age, years, median (range) 72.5 (30–84) Sex, female (%) 20 (50.0) Size, mm, median (range) 9.5 (2–10.0) Location of lesion (%) Head 15 (37.5) Body 23 (57/5) Tail 2 (5.0) Final diagnosis (%) Pancreatic cancer 24 (60.0) Neuroendocrine tumor 8 (20.0) Metastatic tumor 1 (2.5) Benign lesion 7 (17.5) Cases who EUS-TA was performed (%) 35 (87.5) First EUS-TA procedure 35 (87.5) Second EUS-TA procedure 7 (17.5) Third EUS-TA procedure 1 (2.5) Total number of EUS-TA sessions 43 Needle type (%) FNA needle 25 (58.1) FNB needle 18 (41.9) Number of EUS-TA punctures, median (range) 3 (1–6) Adverse events of EUS-TA (%) Mild pancreatitis 3 (7.5) Cases who ERP was performed 15 (37.5) Number of ERP attempts, median (range) 2.0 (1–8) Total number of ERP sessions 30 Pancreatic juice aspiration cytology (%) 25 (83.3) Pancreatic juice washing and aspiration cytology (%) 11 (36.7) Brush cytology (%) 8 (26.7) SPACE (%) 15 (50.0) Adverse events of ERP (%) Mild pancreatitis 2 (6.7) EUS-TA, endoscopic ultrasound-guided tissue acquisition; ERP, endoscopic retrograde pancreatography; FNA, fine needle aspiration; FNB, fine needle biopsy; SPACE, serial pancreatic juice aspiration cytological examination EUS-TA was performed for 35 (87.5%) patients. Of the cases that could not be diagnosed with the first EUS-TA procedure, a second EUS-TA procedure was performed for seven of them. For one patient, EUS-TA was performed three times. A total of 43 EUS-TA sessions were performed. Three cases of mild pancreatitis were observed, but no other serious complications occurred. ERP was performed for 15 patients (37.5%), with a median of two attempts per case (range 1–8), for a total of 30 sessions. Two cases of mild pancreatitis were observed, but no other significant adverse events occurred. Diagnostic ability of EUS-TA for small pancreatic tumors The first EUS-TA procedure for 35 patients had sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rates of 56.7%, 100%, 27.7%, and 62.9%, respectively (Table 2 ). The second EUS-TA procedure for six patients had sensitivity, specificity, and accuracy rates of 60.0%, 100%, and 71.4%, respectively. A third EUS-TA procedure was performed for one patient, which resulted in a correct diagnosis. EUS-TA, which consisted of 41 sessions, had sensitivity, specificity, and accuracy rates of 58.3%, 100%, and 65.1%, respectively. The diagnostic performance by needle type is presented in Supplementary Table 1 Table 2 Diagnostic performance of EUS-TA per session EUS-TA First EUS-TA Second EUS-TA Third EUS-TA Total n = 35 n = 7 n = 1 n = 35 (43 sessions) Sensitivity 56.7% (17/30) 60.0% (3/5) 100% (1/1) 58.3% (21/36) Specificity 100% (5/5) 100% (2/2) - 100% (7/7) PPV 100% (17/17) 100% (3/3) 100% (1/1) 100% (21/21) NPV 27.7% (5/18) 50.0% (2/4) - 31.8% (7/22) Accuracy 62.9% (22/35) 71.4% (5/7) 100% (1/1) 65.1% (28/43) EUS-TA, endoscopic ultrasound-guided tissue acquisition; NPV, negative predictive value; PPV, positive predictive value; Ns, not significant Diagnostic ability of ERP for small pancreatic tumors ERP was performed for 15 patients and a total of 30 sessions. The sensitivity, specificity, and accuracy rates of the first ERP procedure were 54.5%, 100%, and 66.7%, respectively (Table 3 ). The sensitivity, specificity, and accuracy rates of the second ERP procedure were 50%, 100%, and 71.4%, respectively. The third ERP procedure was performed for three cases, with sensitivity, specificity, and accuracy rates of 0%, 100%, and 66.7%. The fourth and subsequent ERP procedures were performed for one case over the course of five sessions, and none of them detected malignant findings. The sensitivity, specificity, and accuracy rates of all 30 ERP sessions were 50%, 100%, and 73.3%, respectively. The diagnostic performance of ERP by technique is presented in Supplementary Table 2. Table 3 Diagnostic performance of ERP per session (n = 15) ERP First ERP Second ERP Third ERP Fourth ≧ ERP Total n = 15 n = 7 n = 3 n = 1 (5 sessions) (n = 15) (30 sessions) Sensitivity 54.5% (6/11) 50.0% (2/4) 0% (0/1) - 50.0% (8/16) Specificity 100% (4/4) 100% (3/3) 100% (2/2) 100% (5/5) 100% (14/14) PPV 100% (6/6) 100% (2/2) - - 100% (8/8) NPV 44.4% (4/9) 66.7% (3/5) 66.7% (2/3) 100% (5/5) 63.6% (14/22) Accuracy 66.7% (10/15) 71.4% (5/7) 66.7% (2/3) 100% (5/5) 73.3% (22/30) ERP, endoscopic retrograde pancreatography; NPV, negative predictive value; PPV, positive predictive value; Ns, not significant Diagnostic ability of repeated EUS-TA combined with repeated ERP by each case Cumulative sensitivity of repeated EUS-TA, repeated ERP, and their combination for diagnosing pancreatic tumors ≤ 10 mm is shown in Fig. 3 a. For all pancreatic tumors, the cumulative diagnostic sensitivity of EUS-TA increased from 56.7% at the first attempt to 66.7% at the second and 70.0% at the third. Similarly, ERP showed a sensitivity of 54.5% at the first attempt, which increased to 72.7% after the second. When both EUS-TA and ERP were combined and repeated, the cumulative sensitivity reached 87.9%. The cumulative diagnostic performance of repeated EUS-TA and ERP—including case inclusion, specificity, and accuracy—was 100% and 89.7%, respectively (Table 4 ). Table 4 The cumulative diagnostic ability of repeated EUS-TA combined with repeated ERP Repeated EUS-TA Repeated ERP Repeated EUS-TA Combined with repeated ERP Pancreatic tumor (n = 39) Sensitivity 70.0% (21/30) 72.7% (8/11) 87.9% (29/33) Specificity 100% (5/5) 100% (4/4) 100% (7/7) Accuracy 74.2% (26/35) 80.0% (12/15) 90.0% (36/40) Pancreatic cancer (n = 30)† Sensitivity 71.4% (15/21) 72.7% (8/11) 95.8% (23/24) Specificity 100% (5/5) 100% (4/4) 100% (7/7) Accuracy 76.9% (20/26) 80.0% (12/15) 96.8% (30/31) †Neuroendocrine tumor and metastatic tumor were excluded EUS-TA, endoscopic ultrasound-guided tissue acquisition; ERP, endoscopic retrograde pancreatography; NPV, negative predictive value; PPV, positive predictive value; Ns, not significant The cumulative sensitivity for only pancreatic cancer using repeated EUS-TA and repeated ERP is shown in Fig. 3 b. Specifically, the cumulative sensitivity of EUS-TA alone in pancreatic cancer increased from 57.1% at the first attempt to 71.4% at the second, while ERP increased from 54.5–72.7% with a second attempt. The cumulative sensitivity of repeated combined EUS-TA and ERP reached 95.8%. When limited to pancreatic cancer, the cumulative diagnostic performance of repeated EUS-TA and ERP yielded specificity, and accuracy rates of 100%, and 96.7%, respectively. Discussion The diagnostic performance of combining repeated EUS-TA and repeated ERP for small pancreatic tumors is unclear. During this study, we evaluated the performance of EUS-TA and ERP for determining the histopathological diagnosis of small pancreatic tumors 10 mm or less. The diagnostic sensitivity of the first EUS-TA procedure was 56.7%; however, by repeating EUS-TA, we were able to diagnose additional three cases, and the sensitivity increased to 70.0%. The sensitivity of the first ERP procedure was only 54.5%, but it ameliorated to 72.7% with repeated attempts. The diagnostic sensitivity increased to 87.9% with repeated EUS-TA and ERP procedures, and to 95.8% when it comes to pancreatic cancer. Combining repeated EUS-TA and repeated ERP significantly improved sensitivity. The pathological diagnosis of small pancreatic tumors less than 10mm is challenging; however, the results suggest that it is possible to achieve an efficient histopathological diagnosis by appropriately repeating EUS-TA and ERP. Small pancreatic tumors are difficult to diagnose with EUS-TA. Previous studies have shown that the diagnostic sensitivity of EUS-TA for tumors 10 mm or smaller ranges from 64.3–84.5% [ 8 , 10 – 12 ] During this study, the diagnosis of malignancy could not be determined with just one EUS-TA procedure; however, three cases of malignancy were diagnosed with two EUS-TA procedures, and one case of malignancy was diagnosed with three EUS-TA procedures. These definite diagnosis lead to suitable treatments. Based on the results of this study, in cases of pancreatic tumors measuring 10 mm or less where the initial EUS-TA fails to provide a diagnosis, it may be advisable to repeat EUS-TA at least a second time, and possibly up to a third time depending on the case. A recent meta-analysis showed that repeated EUS-TA has optimal pooled specificity (97%) and high pooled sensitivity (78%) for the diagnosis of malignant tumors [ 14 ]. Additionally, if the repeated EUS-TA yields positive results, then those results are highly reliable; however, if the results are negative, then the risk of potential malignancy is reduced but not completely eliminated. Because of the low diagnostic sensitivity of EUS-TA for tumors 10 mm or smaller, it is important to perform two to three EUS-TA procedures to rule out malignancy and make an accurate diagnosis. However, because complications [ 24 , 25 ] and dissemination [ 26 ] can occur with EUS-TA, when performing repeated EUS-TA, and EUS-TA should be repeated only after performing other imaging tests to confirm a high probability of malignancy. Difficulty determining histopathological diagnoses of intraepithelial carcinoma and small pancreatic cancer is highly likely when using EUS-TA for small lesions. If EUS-TA is difficult or impossible because of suspected pancreatic cancer, then ERP is useful or help as surrogate [ 27 – 30 ]. In the present study, the sensitivity of the initial ERP procedure was 54.5%, but it increased to 72.7%. According to previous studies, the sensitivity of the initial ERP procedure was 46.7%; however, it increased to 58.3% when performed up to six times. Repeated use of ERP increases its cumulative sensitivity for diagnosing pancreatic cancer. ERP should be considered when tumors are invisible with EUS, when the presence of cysts, pancreatic duct stenosis, pancreatic duct dilation, or localized pancreatic atrophy is observed, and when suspicion of small pancreatic cancer exists [ 31 ]. Repeated EUS-TA and ERP increased the diagnostic sensitivity for malignant cells to 87.9%; when limited to pancreatic cancer, the histopathological diagnostic sensitivity improved to 95.8% by repeating EUS-TA and ERP twice. If other imaging studies suggest pancreatic cancer, then it is important to consider re-examining the tumor with EUS-TA if it can be visualized and punctured or re-examining the tumor with ERP if it cannot be diagnosed with EUS-TA or if it cannot be visualized or punctured. In this study, pancreatic cancer was diagnosed in 95.8% of cases by repeating EUS-TA or ERP twice. Therefore, in cases where small pancreatic cancer is suspected, it may be reasonable to consider performing both EUS-TA and ERP at least twice. However, neuroendocrine tumors and metastatic pancreatic tumors generally do not exhibit pancreatic duct findings, it is infeasible to collect pathological cells, and it is considered difficult to diagnose neuroendocrine tumors and metastatic pancreatic tumors with ERP; therefore, it is important to re-examine these tumors using EUS-TA. The diagnostic strategy for pancreatic tumors demonstrated in Fig. 1 may be generally appropriate. Therefore, in cases where pancreatic tumors, including those measuring 10 mm or less, are suspected, and a diagnosis cannot be made with the initial EUS-TA, it is considered appropriate to consider at least a second EUS-TA. In some cases, a third EUS-TA may also be considered.On the other hand, in cases where pancreatic cancer measuring 10 mm or less is suspected, if EUS-guided needle biopsy is feasible, EUS-TA should be considered. If pathological diagnosis is difficult, a second EUS-TA may be considered. In addition, if the tumor cannot be visualized by EUS, EUS-TA cannot be performed, or a diagnosis cannot be made by EUS-TA, and there are findings in the main pancreatic duct, ERP should be considered at least twice. This study had several limitations. First, it was a retrospective, single-center study. Second, the number of cases was very small, so a larger, multicenter study is needed in the future. In conclusion, repeated EUS-TA and ERP showed good diagnostic sensitivity for small pancreatic cancers 10 mm or smaller. If a malignant small pancreatic tumor, such as pancreatic cancer, is suspected during imaging and cannot be diagnosed with a single EUS-TA or ERP procedure, then EUS-TA and ERP should be repeated as necessary. In cases where small pancreatic cancer is suspected, it may be reasonable to consider performing both EUS-TA and ERP at least twice. Declarations Author contributions: Author contributions : All authors participated in the research. Yusuke Kurita and Shinichi Nihei (co-first): manuscript writing, drafting conception, design and data acquisition. Shin Yagi and Kensuke Kubota: data acquisition, drafting conception and design. Yu Honda, Yuma Yamazaki, Takeshi Iizuka, Sho Hasegawa, Kunihiro Hosono, and Noritoshi Kobayashi: Patient enrollment, and providing clinical advice. Jotaro Harada and Satoshi Fujii reviewed and commented on the pathological findings and images. Itaru Endo, and Atsushi Nakajima: providing clinical advice. All authors have read and approved the final draft. Acknowledgments: The authors are grateful to Y. Nakai, K. Fujisawa, N. Kobayashi, A. Ujiie, Y. Yamazaki, and K. Kato from Yokohama City University for their assistance with this study. Funding information: None Conflicts of interest: Authors declare no conflict of interests for this article. Ethics statement Approval of the research protocol by an Institutional Reviewer Board: This retrospective observational study was approved by the Ethics Committee of our facility (F230400003). Informed Consent: All participants received an opt-out form for informed consent, and patients who did not consent to participate in the study were excluded. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A. References Canto MI, Hruban RH, Fishman EK, et al. 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Comparative study of diagnostic value of cytologic sampling by endoscopic ultrasonography-guided fine-needle aspiration and that by endoscopic retrograde pancreatography for the management of pancreatic mass without biliary stricture. J Gastroenterol Hepatol . 2005;20:1707-1711. Hanada K, Okazaki A, Hirano N, et al. Diagnostic strategies for early pancreatic cancer. J Gastroenterol . 2015;50:147-154. Yamaguchi T, Shirai Y, Nakamura N, et al. Usefulness of brush cytology combined with pancreatic juice cytology in the diagnosis of pancreatic cancer: significance of pancreatic juice cytology after brushing. Pancreas . 2012;41:1225-1229. Ohtsuka T, Tamura K, Ideno N, et al. Role of ERCP in the era of EUS-FNA for preoperative cytological confirmation of resectable pancreatic ductal adenocarcinoma. Surg Today . 2014;44:1887-1892. Kanno A, Masamune A, Hanada K, et al. Multicenter study of early pancreatic cancer in Japan. Pancreatology . 2018;18:61-67. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 06 Sep, 2025 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Revision requested 07 Aug, 2025 Reviews received at journal 03 Aug, 2025 Reviews received at journal 18 Jul, 2025 Reviewers agreed at journal 17 Jul, 2025 Reviewers agreed at journal 17 Jul, 2025 Reviewers agreed at journal 16 Jul, 2025 Reviewers agreed at journal 12 Jul, 2025 Reviewers invited by journal 10 Jul, 2025 Editor assigned by journal 08 Jul, 2025 Submission checks completed at journal 07 Jul, 2025 First submitted to journal 06 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7056650","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":484553479,"identity":"132eeb80-9ed6-4cec-a48d-2feaacf67859","order_by":0,"name":"Yusuke Kurita","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYBACCSA+AMRyDAxsDMzIMsxY1cO0APUYk6YFZE1iA7oWnEByRu7Dwx9qDqdvON6W+LigZps8A/sZA4YfNQzs5ji0SEukGxw4cOxw7oYzxw4bzzh227CBJ8eAsecYA7NlA3YtchJpQL+wAbXcSG+T5mG7zbj/Bo8BA28DA7PBAXxa/h1ONwBr+XfbvkGCx4DxLx4t0iAtB9sOJxjcSDsmzdt2OxGkhRmfLZI9zxgOnO1LN5x55liyMW/f7eQGnrSCwzLHJHD6ReJ4GvOHim/W8nzH2wwf83y7bdvAfnjjwzc1Nsm4QgwKmhkUkJ0BZEskG+DXUscgj+4MOwJaRsEoGAWjYOQAAP6vXYsFDPrwAAAAAElFTkSuQmCC","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Kurita","suffix":""},{"id":484553480,"identity":"749e0cd5-f076-4ed1-99b0-7027319af2ce","order_by":1,"name":"Shinichi Nihei","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shinichi","middleName":"","lastName":"Nihei","suffix":""},{"id":484553481,"identity":"56bbf499-bd86-4781-a557-4a73696fc177","order_by":2,"name":"Kensuke Kubota","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kensuke","middleName":"","lastName":"Kubota","suffix":""},{"id":484553482,"identity":"0df82d78-642d-49e9-9573-62e18bac0efb","order_by":3,"name":"Shin Yagi","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shin","middleName":"","lastName":"Yagi","suffix":""},{"id":484553483,"identity":"c1b05fac-8707-463f-be9b-14f3af5d3632","order_by":4,"name":"Yu Honda","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Honda","suffix":""},{"id":484553484,"identity":"526a977c-a496-44ed-a586-3054d9a44a12","order_by":5,"name":"Yuma Yamazaki","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yuma","middleName":"","lastName":"Yamazaki","suffix":""},{"id":484553485,"identity":"c708cfc0-25f8-425a-8c51-5350af5f1c5e","order_by":6,"name":"Takeshi Iizuka","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Iizuka","suffix":""},{"id":484553486,"identity":"f533dbc0-9286-45f6-968f-b808c827ed1b","order_by":7,"name":"Sho Hasegawa","email":"","orcid":"","institution":"Yokohama City University School of 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jotaro","middleName":"","lastName":"Harada","suffix":""},{"id":484553490,"identity":"151de5fe-3879-489b-919b-ca744d69a97e","order_by":11,"name":"Masato Yoneda","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Yoneda","suffix":""},{"id":484553491,"identity":"6ebf4e93-8b2e-404d-8b10-c6d41ac3178e","order_by":12,"name":"Noritoshi Kobayashi","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Noritoshi","middleName":"","lastName":"Kobayashi","suffix":""},{"id":484553492,"identity":"33fdb474-dd08-4879-84e5-4320c38828ae","order_by":13,"name":"Satoshi Fujii","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Fujii","suffix":""},{"id":484553493,"identity":"1986b7bc-e703-4d35-a504-8d06e96ceec1","order_by":14,"name":"Itaru Endo","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Itaru","middleName":"","lastName":"Endo","suffix":""},{"id":484553494,"identity":"af967dd6-8790-44a7-ac35-053031bb9d00","order_by":15,"name":"Atsushi Nakajima","email":"","orcid":"","institution":"Yokohama City University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Nakajima","suffix":""}],"badges":[],"createdAt":"2025-07-06 08:23:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7056650/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7056650/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10620-025-09373-5","type":"published","date":"2025-09-06T15:57:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86767420,"identity":"81716628-22a3-4985-a178-69c48c818328","added_by":"auto","created_at":"2025-07-15 11:12:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1153053,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopic examination strategy for suspected small pancreatic tumors at our hospital.\u003c/p\u003e\n\u003cp\u003eAt our institution, when a pancreatic tumor measuring 10 mm or smaller is suspected, we initiate the diagnostic process with EUS-TA, provided that the lesion is detectable by EUS and the procedure is technically feasible. If EUS-TA cannot be performed due to anatomical or technical limitations, ERP is considered as an alternative.\u003c/p\u003e\n\u003cp\u003eIn cases where a pathological diagnosis is not obtained after the first EUS-TA, ERP is performed if there are imaging findings suggestive of pancreatic malignancy, such as main pancreatic duct narrowing or dilation. If no such ductal abnormalities are identified, a repeat EUS-TA is undertaken.\u003c/p\u003e\n\u003cp\u003eWhen a definitive pathological diagnosis remains elusive despite the initial workup, we proceed with either repeated EUS-TA or ERP, or initiate a period of follow-up observation, depending on the clinical context and multidisciplinary assessment.\u003c/p\u003e\n\u003cp\u003eEUS-TA; endoscopic ultrasound-guided tissue acquisition\u003c/p\u003e\n\u003cp\u003eERP; endoscopic retrograde pancreatography\u003c/p\u003e","description":"","filename":"FNAERPFigurefinal1.png","url":"https://assets-eu.researchsquare.com/files/rs-7056650/v1/2fc34108dac97f8adad40a0f.png"},{"id":86767421,"identity":"8e3e572a-0147-48d3-b10b-5230958d5fb0","added_by":"auto","created_at":"2025-07-15 11:12:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1929240,"visible":true,"origin":"","legend":"\u003cp\u003eDiagnostic flowchart.\u003c/p\u003e","description":"","filename":"FNAERPFigurefinal2.png","url":"https://assets-eu.researchsquare.com/files/rs-7056650/v1/b77ed8a9826f31681c840af3.png"},{"id":86767427,"identity":"1b044c8b-da16-4644-a0e1-0b04c81dc332","added_by":"auto","created_at":"2025-07-15 11:12:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1785080,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea: \u003c/strong\u003eCumulative sensitivity of repeated EUS-TA, repeated ERP, and their combination for diagnosing pancreatic tumors ≤10 mm\u003c/p\u003e\n\u003cp\u003eSensitivity increased with the number of procedures, and the highest diagnostic yield (87.9%) was achieved with the combined use of both techniques after three attempts\u003c/p\u003e\n\u003cp\u003eEUS-TA; endoscopic ultrasound-guided tissue acquisition\u003c/p\u003e\n\u003cp\u003eERP; endoscopic retrograde pancreatography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb.\u003c/strong\u003e Cumulative sensitivity of repeated EUS-TA and ERP for diagnosing small pancreatic cancer (≤10 mm)\u003c/p\u003e\n\u003cp\u003eBar graphs show the cumulative diagnostic sensitivity after the first, second, and third procedures using repeated EUS-TA, repeated ERP, and a combination of both modalities. Sensitivity increased with the number of procedures in all groups. The third EUS-TA was not performed for pancreatic cancer in this cohort. The highest cumulative sensitivity (95.8%) was achieved after the second combined procedures of EUS-TA and ERP.\u003c/p\u003e\n\u003cp\u003eEUS-TA; endoscopic ultrasound-guided tissue acquisition\u003c/p\u003e\n\u003cp\u003eERP; endoscopic retrograde pancreatography\u003c/p\u003e","description":"","filename":"FNAERPFigurefinal3.png","url":"https://assets-eu.researchsquare.com/files/rs-7056650/v1/59a8356fb4ecd6113f74277c.png"},{"id":90828094,"identity":"9d923300-e6bd-4c89-9ad2-f73b32b8fdb4","added_by":"auto","created_at":"2025-09-08 16:05:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5683632,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7056650/v1/b1d5ecb1-82d0-446c-a8e4-bab66d2cf802.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Enhancing the diagnostic performance of repeated endoscopic ultrasound-guided tissue acquisition combined with surrogate repeated endoscopic retrograde pancreatography for small pancreatic cancer Running title: EUS-TA and ERP for pancreatic cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAn accurate diagnosis of early-stage resectable pancreatic cancer is important. However, small pancreatic lesions are difficult to detect using imaging techniques. Compared to other imaging modalities such as computed tomography (CT) and transabdominal ultrasonography, endoscopic ultrasound (EUS) is considered superior for small lesion detection[1, 2]. Nevertheless, the accuracy of EUS for detecting specific morphological lesions of different pancreatic tumor types is limited [3, 4].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe efficacy of EUS-guided tissue acquisition (TA) for pathological detection has been demonstrated [5-9]. When evaluating small lesions (≤10 mm) with EUS-TA, the technical difficulty is increased, the diagnostic accuracy is decreased, and the sensitivity rates range from 64.3% to 84.5% [8, 10-12]. Therefore, EUS-TA presents challenges when used for small pancreatic lesions. The effectiveness of endoscopic retrograde pancreatography (ERP) for the histological diagnosis of intraepithelial carcinoma and small pancreatic cancer that do not form mass lesion has been evaluated [13]. and the pathological diagnostic accuracy of ERP for pancreatic cancer ranges from 21.3% to 63.6%. The diagnostic performance of EUS-TA is superior to that of ERP for lesions that can be examined by EUS-TA; however, for small tumors that cannot be examined by EUS-TA and tumors that cannot be visualized by EUS, ERP is the only alternative option for diagnosis.\u003c/p\u003e\n\u003cp\u003eThe results with EUS-TA for small tumor posed risks of false-negative and inconclusive, as well. As a result, the usefulness of repeated EUS-TA has been evaluated [14-17], and major guidelines recommend repeated EUS-TA [18]. Additionally, ERP improves the diagnostic sensitivity for small pancreatic cancers [19], and repeated ERP may avoid false-negative results. The number of false-negative results that can be decreased by repeating EUS-TA and ERP for small pancreatic tumors and the actual diagnostic performance are unclear. Therefore, this study aimed to evaluate the diagnostic performance of combined repeated EUS-TA and surrogate repeated ERP for small pancreatic tumors (≤10 mm).\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively evaluated the data of 40 patients with pancreatic parenchymal lesions 10 mm or smaller and suspected tumors 10 mm or smaller who underwent EUS or ERP between 2012 and 2024. This retrospective observational study was approved by the Ethics Committee of our facility (F230400003). The present study used only medical information and did not infringe on the privacy of the patients. All participants received an opt-out form for informed consent. Patients who did not provide consent to participate in the study were excluded. All the authors approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEUS-TA procedure\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEUS-TA was performed using a GF-UCT260 curved linear echoendoscope (Olympus Corporation, Tokyo, Japan) connected to an ultrasound scanning system (ARIETTA 850 [FUJIFILM Medical Co., Ltd., Tokyo, Japan] or EU-ME2/EU-ME1 [Olympus Corporation]). The EZ Shot 3 Plus (Olympus Corporation), Acquire (Boston Scientific, Natick, MA, USA), Trident (Micro-Tech, Nanjing, China), SonoTip Top Gain (Medi-Globe, Rohrdorf, Germany), Echo Tip Ultra (Cook Medical, Bloomington, IN, USA), and SonoTip Pro control (Medi-Globe) EUS-TA needles were used. A 22-gauge needle was used for all punctures. The size and type of needle were chosen at the discretion of the endosonographer.\u0026nbsp;Acquire, Trident, and SonoTip Top Gain are defined as FNB needles. EZ Shot 3 Plus, Echo Tip Ultra, and SonoTip Pro control are defined as FNA needles.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; We uniformly used negative suction with a 10-mL or 20-mL syringe during all EUS-TA procedures. EUS-TA was performed by expert endosonographers for all cases. The puncture technique used during this study was not standardized and was performed at the discretion of the endosonographers.\u0026nbsp;During EUS-TA, three punctures were performed for all cases. However, the EUS-TA procedure was terminated when each endoscopist visually confirmed the presence of a sufficient specimen. A specific specimen size and quantitative criteria for the termination of the specimen examination were not standardized and were determined by each endoscopist.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eERP procedure\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePotential cancer patients with stenosis or dilation of the main pancreatic duct underwent ERP, and pancreatic juice was collected for cytological analysis. A single-channel duodenoscope was used for ERP (TJF-Q290V, JF-260V, or TJF-260V; Olympus). A cannula (PR-104Q-1; Olympus) or MTW catheter (MTW Endoskopie Manufaktur, Wesel, Germany) was inserted. A 0.025-inch guidewire was carefully advanced deep in the main pancreatic duct. Pancreatic ductography was performed to evaluate pancreatic duct stenosis and collect pancreatic juice. An uneven catheter (Piolax Medical, Yokohama, Japan) was used for washing and aspiration cytology. An RX cytology brush (Boston Scientific) was used for brush cytology. A 5-Fr endoscopic nasopancreatic drainage catheter (Cook Medical) was used for the serial pancreatic juice aspiration cytological examination (SPACE) [20]. The technique was chosen by the endoscopist. Complications associated with EUS-TA and ERP were investigated, and their severity was defined according to the American Society for Gastrointestinal Endoscopy classification [21].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePathology sample preparation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt our institution, cytopathologists and cytotechnologists do not perform rapid on-site cytological evaluations. The specimens were fixed in 10% formalin and embedded in paraffin. The EUS-TA specimens were stained with hematoxylin and eosin for histological examinations. Cytological samples for ERP were immediately centrifuged, and smear preparations were fixed in 95% ethyl alcohol and stained using the Papanicolaou method and Giemsa staining. Immunohistochemical staining was performed when necessary for diagnostic purposes using an automated system (Ventana BenchMark ULTRA; Roche Diagnostics, Basel, Switzerland). Deparaffinization was performed by heating slides to 72°C. For antigen retrieval, the slides were heated to 95°C and incubated for 8 minutes, and the required antibodies (diluted 1:50 to 1:500 depending on the type of antibody used) were titrated onto the slides and incubated for 16 minutes each. Experienced pathologists performed all analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDiagnostic ability of EUS-TA and ERP for small pancreatic tumors\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe final diagnosis of lesions was determined using EUS-TA and ERP, pathological findings of surgical specimens, and clinical follow-up observations [8]. The sensitivity, specificity, positive predictive value,\u0026nbsp;\u003ca href=\"http://d.hatena.ne.jp/keyword/Negative\"\u003enegative\u003c/a\u003e predictive value, and accuracy of EUS-TA and ERP were evaluated. For malignant lesions, EUS-TA and ERP diagnoses were considered accurate when pathological diagnoses of EUS-TA and ERP not only distinguished between malignant and benign lesions but also matched the final diagnosis. Additionally, when pathological diagnoses indicated suspicion for malignancy or malignancy, they were included as accurate diagnoses of malignant lesions. When the pathological diagnoses were atypical, they were\u0026nbsp;regarded\u0026nbsp;as inaccurate diagnoses of malignant lesions. For benign lesions, EUS-TA and ERP diagnoses were considered accurate when malignant findings were absent during pathological examinations. These patients were followed-up every 6 months using CT, magnetic resonance cholangiopancreatography, and EUS\u0026nbsp;[8, 22].\u0026nbsp;Benign lesions such as focal pancreatitis and other non-neoplastic lesions were defined as benign in the absence of malignant findings during cytological and cell block examinations and a lack of progression during at least 12 months of follow-up including CT, magnetic resonance cholangiopancreatography, and EUS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDiagnostic strategy for small pancreatic tumors at our facility\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIf the endoscopist was able to visualize the mass using EUS and determined that EUS-TA was technically feasible, then EUS-TA was performed (Figure 1). If a pathological diagnosis was not possible after the first EUS-TA procedure, then a second EUS-TA procedure, or follow-up was considered. Alternatively, ERP was performed if there were pancreatic duct findings such as dilation or stenosis. If a diagnosis was not possible after the second EUS-TA procedure, then a third EUS-TA, ERP or follow-up was performed at the discretion of the endoscopist.\u003c/p\u003e\n\u003cp\u003eERP was performed if the tumor could not be visualized by EUS, if a diagnosis could not be determined using EUS-TA, or if the findings were potential of early pancreatic cancer, such as pancreatic atrophy, pancreatic duct stenosis, or pancreatic duct dilation [23]. If a diagnosis could not be determined using ERP, then a second EUS-TA procedure, repeated ERP, or follow-up was performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEndpoints\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint of this study was the cumulative diagnostic performance of repeated EUS-TA and surrogate repeated ERP for small pancreatic tumors 10 mm or smaller. The secondary endpoint was the diagnostic performance of EUS-TA and that of ERP individually, and the number of procedures performed, and incidence of complications were evaluated. The diagnostic performance of EUS-TA and that of ERP were evaluated individually when multiple procedures were performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using SPSS version 21 software (IBM, Armonk, NY, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe characteristics of the 40 patients included in this study are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The final diagnosis was pancreatic cancer for 24 patients (60.0%), neuroendocrine tumor for eight patients (20.0%), metastatic pancreatic cancer for one patient (2.5%), and benign lesion for seven patients (17.5%). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes how the 40 cases were pathologically or clinically diagnosed.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber (n\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years, median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72.5 (30\u0026ndash;84)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex, female (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (50.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSize, mm, median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.5 (2\u0026ndash;10.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLocation of lesion (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHead\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (37.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBody\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23 (57/5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTail\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (5.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFinal diagnosis (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePancreatic cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24 (60.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeuroendocrine tumor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (20.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetastatic tumor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (2.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBenign lesion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (17.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCases who EUS-TA was performed (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35 (87.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst EUS-TA procedure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35 (87.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSecond EUS-TA procedure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (17.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThird EUS-TA procedure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (2.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal number of EUS-TA sessions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeedle type (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFNA needle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (58.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFNB needle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (41.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of EUS-TA punctures, median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (1\u0026ndash;6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdverse events of EUS-TA (%)\u003c/p\u003e\u003cp\u003eMild pancreatitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (7.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCases who ERP was performed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (37.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of ERP attempts, median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.0 (1\u0026ndash;8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal number of ERP sessions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePancreatic juice aspiration cytology (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (83.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePancreatic juice washing and aspiration cytology (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (36.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBrush cytology (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (26.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSPACE (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (50.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdverse events of ERP (%)\u003c/p\u003e\u003cp\u003eMild pancreatitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (6.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eEUS-TA, endoscopic ultrasound-guided tissue acquisition; ERP, endoscopic retrograde pancreatography; FNA, fine needle aspiration; FNB, fine needle biopsy; SPACE, serial pancreatic juice aspiration cytological examination\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eEUS-TA was performed for 35 (87.5%) patients. Of the cases that could not be diagnosed with the first EUS-TA procedure, a second EUS-TA procedure was performed for seven of them. For one patient, EUS-TA was performed three times. A total of 43 EUS-TA sessions were performed. Three cases of mild pancreatitis were observed, but no other serious complications occurred.\u003c/p\u003e\u003cp\u003eERP was performed for 15 patients (37.5%), with a median of two attempts per case (range 1\u0026ndash;8), for a total of 30 sessions. Two cases of mild pancreatitis were observed, but no other significant adverse events occurred.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiagnostic ability of EUS-TA for small pancreatic tumors\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe first EUS-TA procedure for 35 patients had sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rates of 56.7%, 100%, 27.7%, and 62.9%, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The second EUS-TA procedure for six patients had sensitivity, specificity, and accuracy rates of 60.0%, 100%, and 71.4%, respectively. A third EUS-TA procedure was performed for one patient, which resulted in a correct diagnosis. EUS-TA, which consisted of 41 sessions, had sensitivity, specificity, and accuracy rates of 58.3%, 100%, and 65.1%, respectively. The diagnostic performance by needle type is presented in Supplementary Table\u0026nbsp;1\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDiagnostic performance of EUS-TA per session\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEUS-TA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFirst EUS-TA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSecond EUS-TA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eThird EUS-TA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;35\u003c/p\u003e\u003cp\u003e(43 sessions)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSensitivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e56.7% (17/30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e60.0% (3/5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100% (1/1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e58.3% (21/36)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpecificity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100% (5/5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100% (2/2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e100% (7/7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePPV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100% (17/17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100% (3/3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100% (1/1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e100% (21/21)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNPV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.7% (5/18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50.0% (2/4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e31.8% (7/22)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAccuracy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62.9% (22/35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e71.4% (5/7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100% (1/1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e65.1% (28/43)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eEUS-TA, endoscopic ultrasound-guided tissue acquisition; NPV, negative predictive value; PPV, positive predictive value; Ns, not significant\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiagnostic ability of ERP for small pancreatic tumors\u003c/b\u003e\u003c/p\u003e\u003cp\u003eERP was performed for 15 patients and a total of 30 sessions. The sensitivity, specificity, and accuracy rates of the first ERP procedure were 54.5%, 100%, and 66.7%, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The sensitivity, specificity, and accuracy rates of the second ERP procedure were 50%, 100%, and 71.4%, respectively. The third ERP procedure was performed for three cases, with sensitivity, specificity, and accuracy rates of 0%, 100%, and 66.7%. The fourth and subsequent ERP procedures were performed for one case over the course of five sessions, and none of them detected malignant findings. The sensitivity, specificity, and accuracy rates of all 30 ERP sessions were 50%, 100%, and 73.3%, respectively. The diagnostic performance of ERP by technique is presented in Supplementary Table\u0026nbsp;2.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDiagnostic performance of ERP per session (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eERP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFirst ERP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSecond ERP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eThird ERP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFourth\u0026thinsp;≧\u0026thinsp;ERP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e\u003cp\u003e(5 sessions)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\u003cp\u003e(30 sessions)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSensitivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e54.5% (6/11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50.0% (2/4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0% (0/1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e50.0% (8/16)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpecificity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100% (4/4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100% (3/3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100% (2/2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e100% (5/5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e100% (14/14)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePPV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100% (6/6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100% (2/2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e100% (8/8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNPV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.4% (4/9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e66.7% (3/5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e66.7% (2/3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e100% (5/5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e63.6% (14/22)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAccuracy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.7% (10/15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e71.4% (5/7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e66.7% (2/3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e100% (5/5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e73.3% (22/30)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u003cp\u003eERP, endoscopic retrograde pancreatography; NPV, negative predictive value; PPV, positive predictive value; Ns, not significant\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiagnostic ability of repeated EUS-TA combined with repeated ERP by each case\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCumulative sensitivity of repeated EUS-TA, repeated ERP, and their combination for diagnosing pancreatic tumors\u0026thinsp;\u0026le;\u0026thinsp;10 mm is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea. For all pancreatic tumors, the cumulative diagnostic sensitivity of EUS-TA increased from 56.7% at the first attempt to 66.7% at the second and 70.0% at the third. Similarly, ERP showed a sensitivity of 54.5% at the first attempt, which increased to 72.7% after the second. When both EUS-TA and ERP were combined and repeated, the cumulative sensitivity reached 87.9%. The cumulative diagnostic performance of repeated EUS-TA and ERP\u0026mdash;including case inclusion, specificity, and accuracy\u0026mdash;was 100% and 89.7%, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e The cumulative diagnostic ability of repeated EUS-TA combined with repeated ERP\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRepeated EUS-TA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRepeated ERP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRepeated EUS-TA\u003c/p\u003e\u003cp\u003eCombined with repeated ERP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePancreatic tumor (n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSensitivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e70.0% (21/30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72.7% (8/11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e87.9% (29/33)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpecificity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100% (5/5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100% (4/4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100% (7/7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAccuracy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e74.2% (26/35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e80.0% (12/15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e90.0% (36/40)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePancreatic cancer (n\u0026thinsp;=\u0026thinsp;30)\u0026dagger;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSensitivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e71.4% (15/21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72.7% (8/11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95.8% (23/24)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpecificity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100% (5/5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100% (4/4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100% (7/7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAccuracy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e76.9% (20/26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e80.0% (12/15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e96.8% (30/31)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003e\u0026dagger;Neuroendocrine tumor and metastatic tumor were excluded\u003c/p\u003e\u003cp\u003eEUS-TA, endoscopic ultrasound-guided tissue acquisition; ERP, endoscopic retrograde pancreatography; NPV, negative predictive value; PPV, positive predictive value; Ns, not significant\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe cumulative sensitivity for only pancreatic cancer using repeated EUS-TA and repeated ERP is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb. Specifically, the cumulative sensitivity of EUS-TA alone in pancreatic cancer increased from 57.1% at the first attempt to 71.4% at the second, while ERP increased from 54.5\u0026ndash;72.7% with a second attempt. The cumulative sensitivity of repeated combined EUS-TA and ERP reached 95.8%. When limited to pancreatic cancer, the cumulative diagnostic performance of repeated EUS-TA and ERP yielded specificity, and accuracy rates of 100%, and 96.7%, respectively.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe diagnostic performance of combining repeated EUS-TA and repeated ERP for small pancreatic tumors is unclear. During this study, we evaluated the performance of EUS-TA and ERP for determining the histopathological diagnosis of small pancreatic tumors 10 mm or less. The diagnostic sensitivity of the first EUS-TA procedure was 56.7%; however, by repeating EUS-TA, we were able to diagnose additional three cases, and the sensitivity increased to 70.0%. The sensitivity of the first ERP procedure was only 54.5%, but it ameliorated to 72.7% with repeated attempts. The diagnostic sensitivity increased to 87.9% with repeated EUS-TA and ERP procedures, and to 95.8% when it comes to pancreatic cancer. Combining repeated EUS-TA and repeated ERP significantly improved sensitivity. The pathological diagnosis of small pancreatic tumors less than 10mm is challenging; however, the results suggest that it is possible to achieve an efficient histopathological diagnosis by appropriately repeating EUS-TA and ERP.\u003c/p\u003e\u003cp\u003eSmall pancreatic tumors are difficult to diagnose with EUS-TA. Previous studies have shown that the diagnostic sensitivity of EUS-TA for tumors 10 mm or smaller ranges from 64.3\u0026ndash;84.5% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] During this study, the diagnosis of malignancy could not be determined with just one EUS-TA procedure; however, three cases of malignancy were diagnosed with two EUS-TA procedures, and one case of malignancy was diagnosed with three EUS-TA procedures. These definite diagnosis lead to suitable treatments. Based on the results of this study, in cases of pancreatic tumors measuring 10 mm or less where the initial EUS-TA fails to provide a diagnosis, it may be advisable to repeat EUS-TA at least a second time, and possibly up to a third time depending on the case. A recent meta-analysis showed that repeated EUS-TA has optimal pooled specificity (97%) and high pooled sensitivity (78%) for the diagnosis of malignant tumors [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Additionally, if the repeated EUS-TA yields positive results, then those results are highly reliable; however, if the results are negative, then the risk of potential malignancy is reduced but not completely eliminated. Because of the low diagnostic sensitivity of EUS-TA for tumors 10 mm or smaller, it is important to perform two to three EUS-TA procedures to rule out malignancy and make an accurate diagnosis. However, because complications [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and dissemination [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] can occur with EUS-TA, when performing repeated EUS-TA, and EUS-TA should be repeated only after performing other imaging tests to confirm a high probability of malignancy.\u003c/p\u003e\u003cp\u003eDifficulty determining histopathological diagnoses of intraepithelial carcinoma and small pancreatic cancer is highly likely when using EUS-TA for small lesions. If EUS-TA is difficult or impossible because of suspected pancreatic cancer, then ERP is useful or help as surrogate [\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In the present study, the sensitivity of the initial ERP procedure was 54.5%, but it increased to 72.7%. According to previous studies, the sensitivity of the initial ERP procedure was 46.7%; however, it increased to 58.3% when performed up to six times. Repeated use of ERP increases its cumulative sensitivity for diagnosing pancreatic cancer. ERP should be considered when tumors are invisible with EUS, when the presence of cysts, pancreatic duct stenosis, pancreatic duct dilation, or localized pancreatic atrophy is observed, and when suspicion of small pancreatic cancer exists [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRepeated EUS-TA and ERP increased the diagnostic sensitivity for malignant cells to 87.9%; when limited to pancreatic cancer, the histopathological diagnostic sensitivity improved to 95.8% by repeating EUS-TA and ERP twice. If other imaging studies suggest pancreatic cancer, then it is important to consider re-examining the tumor with EUS-TA if it can be visualized and punctured or re-examining the tumor with ERP if it cannot be diagnosed with EUS-TA or if it cannot be visualized or punctured. In this study, pancreatic cancer was diagnosed in 95.8% of cases by repeating EUS-TA or ERP twice. Therefore, in cases where small pancreatic cancer is suspected, it may be reasonable to consider performing both EUS-TA and ERP at least twice. However, neuroendocrine tumors and metastatic pancreatic tumors generally do not exhibit pancreatic duct findings, it is infeasible to collect pathological cells, and it is considered difficult to diagnose neuroendocrine tumors and metastatic pancreatic tumors with ERP; therefore, it is important to re-examine these tumors using EUS-TA. The diagnostic strategy for pancreatic tumors demonstrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e may be generally appropriate. Therefore, in cases where pancreatic tumors, including those measuring 10 mm or less, are suspected, and a diagnosis cannot be made with the initial EUS-TA, it is considered appropriate to consider at least a second EUS-TA. In some cases, a third EUS-TA may also be considered.On the other hand, in cases where pancreatic cancer measuring 10 mm or less is suspected, if EUS-guided needle biopsy is feasible, EUS-TA should be considered. If pathological diagnosis is difficult, a second EUS-TA may be considered. In addition, if the tumor cannot be visualized by EUS, EUS-TA cannot be performed, or a diagnosis cannot be made by EUS-TA, and there are findings in the main pancreatic duct, ERP should be considered at least twice.\u003c/p\u003e\u003cp\u003eThis study had several limitations. First, it was a retrospective, single-center study. Second, the number of cases was very small, so a larger, multicenter study is needed in the future.\u003c/p\u003e\u003cp\u003eIn conclusion, repeated EUS-TA and ERP showed good diagnostic sensitivity for small pancreatic cancers 10 mm or smaller. If a malignant small pancreatic tumor, such as pancreatic cancer, is suspected during imaging and cannot be diagnosed with a single EUS-TA or ERP procedure, then EUS-TA and ERP should be repeated as necessary. In cases where small pancreatic cancer is suspected, it may be reasonable to consider performing both EUS-TA and ERP at least twice.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eAll authors participated in the research. Yusuke Kurita and Shinichi Nihei (co-first): manuscript writing, drafting conception, design and data acquisition. Shin Yagi and Kensuke Kubota: data acquisition, drafting conception and design. Yu Honda, Yuma Yamazaki, Takeshi Iizuka, Sho Hasegawa, Kunihiro Hosono, and Noritoshi Kobayashi: Patient enrollment, and providing clinical advice. Jotaro Harada and Satoshi Fujii reviewed and commented on the pathological findings and images. Itaru Endo, and Atsushi Nakajima: providing clinical advice. All authors have read and approved the final draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThe authors are grateful to Y. Nakai, K. Fujisawa, N. Kobayashi, A. Ujiie, Y. Yamazaki, and K. Kato from Yokohama City University for their assistance with this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information:\u003c/strong\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u0026nbsp;\u003c/strong\u003eAuthors declare no conflict of interests for this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval of the research protocol by an Institutional Reviewer Board: This retrospective observational study was approved by the Ethics Committee of our facility (F230400003).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Informed Consent: All participants received an opt-out form for informed consent, and patients who did not consent to participate in the study were excluded.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Registry and the Registration No. of the study/trial: N/A.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Animal Studies: N/A.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCanto MI, Hruban RH, Fishman EK, et al. 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Diagnostic ability and factors affecting accuracy of endoscopic ultrasound-guided fine needle aspiration for pancreatic solid lesions: Japanese large single center experience. \u003cem\u003eJ Gastroenterol\u003c/em\u003e. 2013;48:973-981.\u003c/li\u003e\n\u003cli\u003eVolmar KE, Vollmer RT, Jowell PS, Nelson RC, Xie HB. Pancreatic FNA in 1000 cases: a comparison of imaging modalities. \u003cem\u003eGastrointest Endosc\u003c/em\u003e. 2005;61:854-861.\u003c/li\u003e\n\u003cli\u003eTakahashi K, Yasuda I, Hanaoka T, et al. Diagnostic Fine-Needle Biopsy of Small Solid Pancreatic Lesions Using a Franseen Needle during Endoscopic Ultrasound Examination. \u003cem\u003eDiagnostics\u003c/em\u003e. 2021;11:27.\u003c/li\u003e\n\u003cli\u003eKurita Y, Kuwahara T, Hara K, et al. Features of chronic pancreatitis by endoscopic ultrasound influence the diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration of small pancreatic lesions. \u003cem\u003eDigestive Endoscopy\u003c/em\u003e. 2020;32:399-408.\u003c/li\u003e\n\u003cli\u003eKawasaki Y, Hijioka S, Nagashio Y, et al. Efficacy of endoscopic ultrasound-guided tissue acquisition for solid pancreatic lesions 20 mm or less in diameter suspected as neuroendocrine tumors or requiring differentiation. \u003cem\u003eJ Gastroenterol\u003c/em\u003e. 2023;58:693-703.\u003c/li\u003e\n\u003cli\u003eKitagawa K, Mitoro A, Tomooka F, et al. Diagnostic yield of liquid-based cytology in serial pancreatic juice aspiration cytological examination. \u003cem\u003eDEN Open\u003c/em\u003e. 2023;3:e177.\u003c/li\u003e\n\u003cli\u003eLisotti A, Frazzoni L, Fuccio L, et al. Repeat EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis. \u003cem\u003eGastrointestinal Endoscopy\u003c/em\u003e. 2020;91:1234-1241.e1234.\u003c/li\u003e\n\u003cli\u003eT\u0026eacute;llez-\u0026Aacute;vila FI, Mart\u0026iacute;nez-Lozano JA, Rosales-Salinas A, et al. Repeat endoscopic ultrasound fine needle aspiration after a first negative procedure is useful in pancreatic lesions. \u003cem\u003eEndosc Ultrasound\u003c/em\u003e. 2016;5:258-262.\u003c/li\u003e\n\u003cli\u003eMitchell RA, Stanger D, Shuster C, Telford J, Lam E, Enns R. Repeat Endoscopic Ultrasound-Guided Fine-Needle Aspiration in Patients with Suspected Pancreatic Cancer: Diagnostic Yield and Associated Change in Access to Appropriate Care. \u003cem\u003eCan J Gastroenterol Hepatol\u003c/em\u003e. 2016;2016:7678403.\u003c/li\u003e\n\u003cli\u003ePrachayakul V, Sriprayoon T, Asawakul P, Pongprasobchai S, Pausawasdi N, Kachintorn U. Repeated endoscopic ultrasound guided fine needle aspiration (EUS-FNA) improved diagnostic yield of inconclusive initial cytology for suspected pancreatic cancer and unknown intra-abdominal lymphadenopathy. \u003cem\u003eJ Med Assoc Thai\u003c/em\u003e. 2012;95 Suppl 2:S68-74.\u003c/li\u003e\n\u003cli\u003eTempero MA, Malafa MP, Chiorean EG, et al. NCCN Guidelines Insights: Pancreatic Adenocarcinoma, Version 1.2019: Featured Updates to the NCCN Guidelines. \u003cem\u003eJournal of the National Comprehensive Cancer Network J Natl Compr Canc Netw\u003c/em\u003e. 2019;17:202-210.\u003c/li\u003e\n\u003cli\u003eNakamura S, Ishii Y, Serikawa M, et al. Diagnostic Ability and Safety of Repeated Pancreatic Juice Cytology Using an Endoscopic Nasopancreatic Drainage Catheter for Pancreatic Ductal Adenocarcinoma: A Multicenter Prospective Study. \u003cem\u003eDiagnostics (Basel)\u003c/em\u003e. 2023;13.\u003c/li\u003e\n\u003cli\u003eIiboshi T, Hanada K, Fukuda T, Yonehara S, Sasaki T, Chayama K. Value of cytodiagnosis using endoscopic nasopancreatic drainage for early diagnosis of pancreatic cancer: establishing a new method for the early detection of pancreatic carcinoma in situ. \u003cem\u003ePancreas\u003c/em\u003e. 2012;41:523-529.\u003c/li\u003e\n\u003cli\u003eCotton PB, Eisen GM, Aabakken L, et al. A lexicon for endoscopic adverse events: report of an ASGE workshop. \u003cem\u003eGastrointest Endosc\u003c/em\u003e. 2010;71:446-454.\u003c/li\u003e\n\u003cli\u003eNayar MK, Paranandi B, Dawwas MF, et al. Comparison of the diagnostic performance of 2 core biopsy needles for EUS-guided tissue acquisition from solid pancreatic lesions. \u003cem\u003eGastrointest Endosc\u003c/em\u003e. 2017;85:1017-1024.\u003c/li\u003e\n\u003cli\u003eToshima F, Watanabe R, Inoue D, et al. CT Abnormalities of the Pancreas Associated With the Subsequent Diagnosis of Clinical Stage I Pancreatic Ductal Adenocarcinoma More Than 1 Year Later: A Case-Control Study. \u003cem\u003eAJR Am J Roentgenol\u003c/em\u003e. 2021;217:1353-1364.\u003c/li\u003e\n\u003cli\u003eYoshinaga S, Suzuki H, Oda I, Saito Y. Role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for diagnosis of solid pancreatic masses. \u003cem\u003eDig Endosc\u003c/em\u003e. 2011;23 Suppl 1:29-33.\u003c/li\u003e\n\u003cli\u003eEloubeidi MA, Gress FG, Savides TJ, et al. Acute pancreatitis after EUS-guided FNA of solid pancreatic masses: a pooled analysis from EUS centers in the United States. \u003cem\u003eGastrointest Endosc\u003c/em\u003e. 2004;60:385-389.\u003c/li\u003e\n\u003cli\u003eKitano M, Yoshida M, Ashida R, et al. Needle tract seeding after endoscopic ultrasound-guided tissue acquisition of pancreatic tumors: A nationwide survey in Japan. \u003cem\u003eDig Endosc\u003c/em\u003e. 2022. doi:10.1111/den.14346.\u003c/li\u003e\n\u003cli\u003eWakatsuki T, Irisawa A, Bhutani MS, et al. Comparative study of diagnostic value of cytologic sampling by endoscopic ultrasonography-guided fine-needle aspiration and that by endoscopic retrograde pancreatography for the management of pancreatic mass without biliary stricture. \u003cem\u003eJ Gastroenterol Hepatol\u003c/em\u003e. 2005;20:1707-1711.\u003c/li\u003e\n\u003cli\u003eHanada K, Okazaki A, Hirano N, et al. Diagnostic strategies for early pancreatic cancer. \u003cem\u003eJ Gastroenterol\u003c/em\u003e. 2015;50:147-154.\u003c/li\u003e\n\u003cli\u003eYamaguchi T, Shirai Y, Nakamura N, et al. Usefulness of brush cytology combined with pancreatic juice cytology in the diagnosis of pancreatic cancer: significance of pancreatic juice cytology after brushing. \u003cem\u003ePancreas\u003c/em\u003e. 2012;41:1225-1229.\u003c/li\u003e\n\u003cli\u003eOhtsuka T, Tamura K, Ideno N, et al. Role of ERCP in the era of EUS-FNA for preoperative cytological confirmation of resectable pancreatic ductal adenocarcinoma. \u003cem\u003eSurg Today\u003c/em\u003e. 2014;44:1887-1892.\u003c/li\u003e\n\u003cli\u003eKanno A, Masamune A, Hanada K, et al. Multicenter study of early pancreatic cancer in Japan. \u003cem\u003ePancreatology\u003c/em\u003e. 2018;18:61-67.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"endoscopic ultrasound-guided tissue acquisition, endoscopic retrograde cholangiopancreatography, pancreatic cancer","lastPublishedDoi":"10.21203/rs.3.rs-7056650/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7056650/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDiagnosing pancreatic tumors ≤10 mm is challenging due to limited visualization and low sampling sensitivity. This study aimed to evaluate the cumulative diagnostic performance of repeated endoscopic ultrasound-guided tissue acquisition (EUS-TA) and surrogate repeated endoscopic retrograde pancreatography (ERP).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study analyzed 40 patients with suspected pancreatic tumors ≤10 mm who underwent EUS-TA and/or ERP retrospectively. When a diagnosis could not be determined based on the initial EUS-TA or ERP procedure, EUS-TA or ERP was repeated as necessary. The cumulative diagnostic performance of EUS-TA and ERP for pancreatic tumors was evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEUS-TA was performed once for 35 cases, twice for seven cases, and three times for one case. ERP was performed for 15 cases, and the median number of ERP attempts was two (range, 1-8). The cumulative sensitivity of EUS-TA increased from 56.7% to 70.0% after three attempts, while ERP sensitivity rose from 54.5% to 72.7% after two attempts. The cumulative diagnostic performance of repeated EUS-TA and ERP combined by case included sensitivity and accuracy rates of 87.9% and 90.0%. When limited to pancreatic cancer, the sensitivity and accuracy rates were 95.8% and 96.8%, respectively.No severe adverse events occurred.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRepeated EUS-TA and ERP significantly improved diagnostic sensitivity for small pancreatic tumors. When a single EUS-TA or ERP procedure fails to establish a diagnosis in suspected malignant cases, repeating the procedures may be warranted. In cases where initial procedures are inconclusive, repeated application of both methods may enable accurate pathological diagnosis and inform optimal treatment strategies.\u003c/p\u003e","manuscriptTitle":"Enhancing the diagnostic performance of repeated endoscopic ultrasound-guided tissue acquisition combined with surrogate repeated endoscopic retrograde pancreatography for small pancreatic cancer Running title: EUS-TA and ERP for pancreatic cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-15 11:11:58","doi":"10.21203/rs.3.rs-7056650/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-07T13:02:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-03T18:27:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-18T18:15:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"239313475155112776195866064407679839834","date":"2025-07-17T06:12:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144680563943221808532246986853222264557","date":"2025-07-17T06:02:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335602157123116388328874084158115264070","date":"2025-07-16T07:47:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238395207295810232058356638172622508721","date":"2025-07-13T01:18:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-10T23:30:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-08T22:28:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-07T08:48:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2025-07-06T08:19:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c5213cb7-ffdb-484c-9c8c-bdbae47f09f4","owner":[],"postedDate":"July 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T16:03:51+00:00","versionOfRecord":{"articleIdentity":"rs-7056650","link":"https://doi.org/10.1007/s10620-025-09373-5","journal":{"identity":"digestive-diseases-and-sciences","isVorOnly":false,"title":"Digestive Diseases and Sciences"},"publishedOn":"2025-09-06 15:57:27","publishedOnDateReadable":"September 6th, 2025"},"versionCreatedAt":"2025-07-15 11:11:58","video":"","vorDoi":"10.1007/s10620-025-09373-5","vorDoiUrl":"https://doi.org/10.1007/s10620-025-09373-5","workflowStages":[]},"version":"v1","identity":"rs-7056650","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7056650","identity":"rs-7056650","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}