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Less than half of all patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) respond to chemotherapy, and the prognosis of PDAC is poor, which may be mediated by the gut microbiota. We investigated the clinical improvement effects of 1-kestose, a fructooligosaccharide, on PDAC chemotherapy in this single-center, randomized, controlled pilot trial conducted at Fujita Health University Hospital, which enrolled patients with PDAC. The trial included 1-kestose administration and non-administration groups. The 1-kestose group received 9 g of 1-kestose daily for 12 weeks, and their blood markers, imaging studies, physical findings, and gut microbiota were evaluated. In the 1-kestose administration group, the cancer marker CA19-9 significantly decreased, and there was a reduction in the neutrophil-to-lymphocyte ratio (NLR). There was also suppression of the reduction of albumin levels and of an increase in C-reactive protein. Additionally, Escherichia coli , which typically increases in PDAC, significantly decreased in the 1-kestose group. Thus, 1-kestose altered the gut microbiota and improved the prognostic factors for PDAC. Large-scale, long-term trials of 1-kestose interventions for PDAC are thus warranted to improve the prognosis of PDAC.

This study group aimed to revise the 2017 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and mainly focused on five topics; the revision of high-risk stigmata (HRS) and worrisome features (WF), surveillance of non-resected IPMN, surveillance after resection of IPMN, revision of pathological aspects, and investigation of molecular markers in cyst fluid. A new development from the prior guidelines is that systematic reviews were performed for each one of these topics, and published separately to provide evidence-based recommendations. One of the highlights of these new "evidence-based guidelines" is to propose a new management algorithm, and one major revision is to include into the assessment of HRS and WF the imaging findings from endoscopic ultrasound (EUS) and the results of cytological analysis from EUS-guided fine needle aspiration technique, when this is performed. Another key element of the current guidelines is to clarify whether lifetime surveillance for small IPMNs is required, and recommends two options, "stop surveillance" or "continue surveillance for possible development of concomitant pancreatic ductal adenocarcinoma", for small unchanged BD-IPMN after 5 years surveillance. Several other points are also discussed, including identifying high-risk features for recurrence in patients who underwent resection of non-invasive IPMN with negative surgical margin, summaries of the recent observations in the pathology of IPMN. In addition, the emerging role of cyst fluid markers that can aid in distinguishing IPMN from other pancreatic cysts and identify those IPMNs that harbor high-grade dysplasia or invasive carcinoma is discussed., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This systematic review aimed to assess the diagnostic accuracy of the International Consensus Fukuoka Guidelines (ICG2017) in identifying high-risk lesions of Intraductal Papillary Mucinous Neoplasms (IPMNs)., Methods: The ICG2017 revision committee conducted a comprehensive literature review to establish evidence-based statements on IPMNs. The review focused on articles examining the diagnostic value of imaging features (e.g., cyst or main pancreatic duct diameter), clinical symptoms associated with IPMN, and serum biomarkers. Five clinical questions regarding high-risk stigmata (HRS) and worrisome features (WF) in the ICG2017 guidelines were addressed., Results: A total of 210 articles were reviewed. The findings revealed a significant association between the presence of mural nodules ≥5 mm in diameter or solid components with contrast enhancement and the diagnosis of high-grade dysplasia or invasive carcinoma. Contrast-enhanced diagnostic tools, such as CT, MRI, or EUS, demonstrated the highest prediction rate and were recommended. Positive cytology was identified as an HRS, while symptoms like acute pancreatitis and cyst diameter growth ≥2.5 mm per year were considered WFs. The use of nomograms and multiple diagnostic factors was recommended for optimal IPMN management., Conclusions: This systematic review provides evidence supporting the improved diagnostic accuracy of ICG2017 in identifying high-risk lesions of IPMN. The multidisciplinary incorporation of HRS and WF based on imaging findings and clinical symptoms is crucial. These findings should inform the revision of ICG2017, enhancing the evaluation and management of IPMN patients. By implementing these recommendations, clinicians can make more informed decisions, leading to better diagnosis and treatment outcomes for high-risk IPMN cases., (Copyright © 2023. Published by Elsevier B.V.)

Background and Aim: There is currently no established number of actuations (to-and-fro movements) per pass during endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). This study aimed to compare 15 vs 5 actuations in terms of adequate specimen acquisition of solid pancreatic lesions., Methods: In this prospective, randomized, crossover, noninferiority, single-center study, eligible patients underwent EUS-FNB using a 22-G Franseen needle with both 15 and 5 actuations per pass, performed in a randomized order, from October 2020 to December 2021. The acquired specimens from each pass were separately evaluated. The primary outcome was the accuracy of the histological diagnosis per pass. The noninferiority margin was set as 15%., Results: Data from 85 patients were analyzed, revealing pancreatic cancer in 73 patients. The accuracy of the histological diagnosis in the 15 and 5 actuations groups was 83.5% (71/85) and 77.7% (66/85), respectively. The difference was -5.8% (95% confidence interval -15.6-3.4), which does not indicate noninferiority of the five actuations group. Among the secondary outcomes, the 15 actuations group was significantly superior to the five actuations group in terms of the obtained core tissues (1.88 [interquartile range 0.89-3.64] mm 2 vs 1.66 [0.83-2.71] mm 2 [P = 0.031]) and subjective evaluation of cytology specimens for pancreatic cancer (69.0% vs. 31.0%, P = 0.005)., Conclusions: The noninferiority of five actuations in the accuracy of the histological diagnosis was not confirmed, and 15 actuations are preferred during EUS-FNB for solid pancreatic lesions., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Competing Interests: Declaration of Competing Interest Dr. Kawashima receives grants from Otsuka Pharmaceutical Co., Ltd., TAIHO Phamaceutical Co., Ltd., Chugai Phamaceutical Co., Ltd., EA Pharma Co., Ltd., Eisai Co., Ltd., AbbVie Inc., and Mitsubishi Tanabe Pharma Corporation, which are unrelated to the submitted work. Dr. Ando receives grants and personal fees from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Nippon Kayaku Co., Ltd., Yakult Honsha Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Ltd., and Eisai Co., Ltd., grants from Mochida Pharmaceutical Co., Ltd., personal fees from Eli Lilly Japan K·K., Novartis Pharma K.K., Bayer Holding Ltd., Bristol-Myers Squibb, Sawai Pharmaceutical Co., Ltd., Roche Diagnostics K.K., MSD K.K, Astellas Pharma Inc., Otsuka Holdings Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., and Hisamitsu Pharmaceutical Co., Inc., which are unrelated to the submitted work. All other authors have no disclosures or conflicts of interest.

This study aimed to evaluate the feasibility and efficacy of Endoscopic ultrasound elastography-guided fine needle biopsy (EUS-EG-FNB) for the diagnosis of pancreatic mass lesions. EUS-EG images were classified into heterogeneous and homogeneous groups. For the heterogeneous group, EUS-FNB was separately performed in both hard areas and soft areas. Only samples obtained during the first two passes (hard/soft areas) were used to compare the diagnostic accuracy as well as the quality and quantity of the specimens. We investigated the association of EUS-EG findings using strain histogram analysis with the histological findings. Fifty-five patients were enrolled including 25 patients with heterogeneous group. The homogeneous group had significantly lower mean strain value (hard) lesions. The adequate sampling rates from hard and soft areas were 88 and 92%, respectively (P = 0.6374). Comparison of the diagnostic accuracy and the quality and quantity of the histological core between hard and soft areas showed no significant differences. In pancreatic adenocarcinoma cases, the proportion of fibrous stroma in the core tissue was significantly correlated with the elasticity of the region. (R 2  = 0.1226: P = 0.0022) EUS-EG may reflect tissue composition in pancreatic tumors, however, EUS-EG did not affect either the quality and quantity of the tissues obtained.Clinical Trial Registry No: UMIN-000033073., (© 2022. The Author(s).)

Background: The overall survival (OS) of pancreatic cancer (PC) has been prolonged by advances in chemotherapy, and the number of cases of recurrent biliary obstruction (RBO) after self-expandable metal stent (SEMS) placement is expected to increase. We herein compared outcomes between secondary fully covered SEMS (FC) and uncovered SEMS (UC) for RBO of PC with FC placed as the 1st SEMS., Methods: Between May 2010 and March 2021, 62 PC patients who underwent SEMS exchange to FC (n = 34) or UC (n = 28) for RBO were retrospectively analyzed. Patient characteristics, OS, time to RBO (TRBO), and stent-related adverse events were compared between the FC and UC groups. Cox's proportional hazard model was used to identify risk factors for RBO with the 2nd SEMS., Results: There was a significant difference between the FC and UC groups only in the 2nd SEMS diameter. Median OS and TRBO were 195 and 238 days in FC patients and 306 and 455 days in UC patients, respectively, with no significant differences between the two groups. No significant differences were observed in the stent-related adverse event rate. In multivariate analyses, only the 2nd SEMS diameter was significant (P = 0.009). Median TRBO were 455, 238, and 103 days in 10-mm UC, 10-mm FC, and 8-mm UC patients, with 10-mm UC patients having significantly longer TRBO than 10-mm FC and 8-mm UC patients (P = 0.020 and 0.001)., Conclusion: SEMS exchange to 10-mm UC may be appropriate for RBO of PC with FC as the 1st SEMS., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Pancreatic cystic lesions (PCLs) include various types of cysts. Accurate preoperative diagnosis is essential to avoid unnecessary surgery on benign cysts. In this study, we aimed to identify the factors associated with misdiagnosis in preoperative endoscopic ultrasound (EUS) imaging and clinicopathological findings for PCLs., Methods: This study included 302 surgically resected patients with PCLs who underwent preoperative EUS. The preoperative EUS findings were re-evaluated and compared with the pathological diagnosis. Additionally, the factors associated with misdiagnosis of PCLs were investigated by multivariate analysis., Results: The preoperative diagnoses of PCLs were intraductal papillary mucinous neoplasm (IPMN) in 213 patients (70.5%), mucinous cystic neoplasm (MCN) in 33 patients (10.9%), serous neoplasm (SN) in 7 patients (2.3%), cystic degeneration cyst of solid tumor in 46 patients (15.2%), and pancreatic cancer with cystic degeneration in three patients (1.0%). A discrepancy between preoperative and postoperative diagnosis was found in 47 patients (15.6%). Based on the pathological diagnosis, the sensitivity of preoperative EUS imaging was IPMN 97.6% (206/211), MCN 90.0% (18/19), cystic degeneration 87.1% (27/31), and SN 15.4% (2/13). Multivariate analysis revealed that main pancreatic duct (MPD) communication ( - ) (odds ratio (OR), 4.54; 95% confidence interval (CI) 1.29-15.9), honeycomb-like structure ( +) (OR, 14.7; 95% CI 2.61-83.3), and MPD size ≦ 2 mm (OR, 16.3; 95% CI 3.93-67.6) were independently associated with misdiagnosis., Conclusion: For cases in which MCN and cystic degeneration of solid tumor are presumed based on preoperative EUS imaging and cases with PCLs with a honeycomb-like structure, diagnosis with multimodalities or fluid analysis with EUS-guided fine-needle aspiration should be considered., (© 2022. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Purpose: To compare contrast-enhanced transabdominal ultrasonography (CE-US) following contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) with enhanced magnetic resonance imaging using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI) in the diagnosis of liver metastases in patients with pancreatic cancer., Methods: Patients who underwent contrast-enhanced computed tomography for possible pancreatic cancer and required further evaluation with CH-EUS were enrolled in this study, and the diagnostic performance of CE-US following CH-EUS for liver metastasis was compared with that of EOB-MRI., Results: A total of 228 patients were included in the final analysis. Two hundred thirty-four hepatic lesions were found in 81 patients, and 178 lesions were finally diagnosed as metastases. EOB-MRI had a higher sensitivity (0.837 vs 0.949), while CE-US had a higher specificity and positive predictive value (PPV) (0.982 and 0.993 vs 0.911 and 0.971, respectively) in the diagnosis of liver metastasis. CE-US with defect reperfusion imaging had a higher diagnostic performance than EOB-MRI (0.866 vs 0.667) in the differentiation between liver metastasis and abscess., Conclusion: EOB-MRI had a higher sensitivity than CE-US for diagnosing liver metastasis in patients with pancreatic cancer, but CE-US following CH-EUS demonstrated a higher specificity and PPV than EOB-MRI and was especially useful in the differentiation between liver metastasis and abscess., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: Given the frequent adverse events with multidrug chemotherapy, not only the survival benefit but also the feasibility of using neoadjuvant chemotherapy to treat pancreatic cancer need to be clarified., Summary of Background Data: Although the development of multidrug chemotherapy regimens has improved the survival outcomes of patients with unresectable pancreatic cancer, the benefits of these treatments in the neo-adjuvant setting remain controversial., Methods: Patients with borderline-resectable pancreatic cancer were enrolled and randomly assigned to receive neoadjuvant chemotherapy with either FOLFIRINOX or gemcitabine with nab-paclitaxel (GEM/nab-PTX). After the completion of chemotherapy, patients underwent surgical resection when feasible. This study (NUPAT-01) was a randomized phase II trial, and the primary endpoint was the R0 resection rate., Results: Fifty-one patients were enrolled in this study [FOLFIRINOX (n = 26) and GEM/nab-PTX (n = 25)]. A total of 84.3% (n = 43/51) of the patients eventually underwent surgery, and R0 resection was achieved in 67.4% (n = 33/ 51) of the patients. Adverse events (grade >3) due to neoadjuvant treatment were observed in 45.1% of the patients (n = 23/51), and major surgical complications occurred in 30.0% (n = 13/43), with no mortality noted. The intention-to-treat analysis showed that the 3-year overall survival rate was 54.7%, with a median survival time of 39.4 months, and a significant difference in overall survival was not observed between the FOLFIRINOX and GEM/nab-PTX groups., Conclusions: These results indicate that neoadjuvant chemotherapy with FOLFIRINOX or GEM/nab-PTX is feasible and well tolerated, achieving an R0 resection rate of 67.4%. The survival of patients was even found to be favorable in the intention-to-treat analysis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we showed that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, nonnatural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The prognostic nutritional index (PNI) and Charlson comorbidity index (CCI) have been useful for predicting the prognosis based on nutritional condition and comorbidities in surgery and endoscopic mucosal dissection. The age-adjusted CCI (ACCI) has also been reported to be useful in surgery, but it has not been applied to endoscopic treatment. We therefore clarified the prognostic factors associated with ampullary tumors treated with endoscopic papillectomy (EP)., Methods: From January 2003 to December 2020, 236 patients who underwent EP for sporadic ampullary tumors at Nagoya University Hospital were included in this study. The 5-year survival and ability to predict the prognosis were evaluated in terms of the sex, PNI, ACCI, final pathological diagnosis, and intraductal extension., Results: During a median follow-up period of 1558 days, 17 patients died. No patient died of the primary disease. The 5-year survival rate was 91.1%. In a univariate analysis, only a high ACCI (≥ 5) was extracted as a significant prognostic factor (Odds ratio, 12.2; 95% confidence interval, 3.81-39.3; p < 0.001). The 5-year survival rates for a low ACCI (≤ 4) and high ACCI were 96.6% and 73.5%, respectively (p < 0.001)., Conclusions: A high ACCI is an important prognostic factor associated with the 5-year survival and a risk of death from other illness. Ampullary tumors suitable for EP are less likely to be a prognostic factor, and treatment-free follow-up may be acceptable in patients with a high ACCI., (© 2022. Japanese Society of Gastroenterology.)

Background: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer., Methods: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II., Discussion: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma., Trial Registration: Clinicaltrial.gov: NCT05064618 , registered on 1 October 2021. jRCT: jRCT2041210056 , registered on 27 August 2021., (© 2022. The Author(s).)

Methods: We reviewed a total of 60 consecutive patients who underwent both S-MOSE and rapid on-site cytopathological evaluation (ROSE) during EUS-FNB between July 2019 and October 2020, and the usefulness of S-MOSE in comparison with histology was evaluated. A 22-gauge Franseen needle was used to perform EUS-FNB in all patients, and only the specimens obtained by the first pass were evaluated. The final diagnosis was based on the surgical specimen or the clinical course consistent with the EUS-FNB results., Results: The final diagnoses of the 60 patients included 45 patients with pancreatic ductal adenocarcinoma, 6 with autoimmune pancreatitis, 4 with mass-forming pancreatitis, 1 with pancreatic metastasis, 2 with pancreatic neuroendocrine tumor, and 2 with intraductal papillary mucinous carcinoma. The histological diagnostic accuracy of the first pass of EUS-FNB was 83.3% (50/60). The agreement between the S-MOSE and the histological diagnosis was 90% (54/60). The positive predictive value of S-MOSE for histological diagnosis was 90.7%, which can be an indicator of when to stop the EUS-FNB procedure. There were no immediate or delayed adverse events reported after the FNB based on the chart and medical visit history review., Conclusion: In the EUS-FNB of SPLs, S-MOSE can be an alternative to ROSE for specimen evaluation and has the potential to shorten the procedure time., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Takuya Ishikawa et al.)

Objectives: We investigated the utility of endoscopic ultrasound (EUS) for differentiating between solid pseudopapillary neoplasm of the pancreas (SPN) and pancreatic neuroendocrine neoplasm (PanNEN)., Methods: A retrospective analysis was performed on 29 and 77 consecutive patients with pathologically proven SPN and nonfunctional PanNEN. In patients who underwent contrast-enhanced harmonic EUS (CH-EUS), lesions were classified into 3 vascular patterns (hypoechoic/isoechoic/hyperechoic), and the presence of "the alveolus nest sign," which we previously reported as a characteristic feature of SPN on CH-EUS, was also assessed., Results: Conventional EUS findings showed that calcification echoes were significantly more frequent in SPN lesions than in PanNEN lesions (19/29 [66%] vs 21/77 [27%], P = 0.001) as was internal isoechogenicity or hyperechogenicity (10/29 [34%] vs 11/77 [14%], P = 0.029). Contrast-enhanced harmonic EUS findings showed that SPN lesions more frequently had the isoechoic or hypoechoic vascular pattern, and significantly more frequently had the alveolus nest sign (18/25 [72%] vs 4/60 [7%], P < 0.001). In a multivariate analysis, the presence of the alveolus nest sign contributed the most to the SPN diagnosis (odds ratio, 70; 95% confidence interval, 6.2-786)., Conclusions: Endoscopic ultrasound, particularly the presence of the alveolus nest sign on CH-EUS, is useful for differentiating SPN from PanNEN., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The diagnosis of autoimmune pancreatitis (AIP) is challenging and should be achieved through the comprehensive evaluation of clinical, radiological, serological, and pathological evidence, as there is currently no single reliable diagnostic modality. Endoscopic ultrasonography (EUS) can reveal pancreatic parenchymal and ductal features in much more detail than any other existing imaging modality. In this article, we focused on three applications of EUS, i.e., conventional EUS imaging, EUS elastography (EUS-EG), and contrast-enhanced harmonic EUS (CEH-EUS), for the diagnosis of AIP. Diffuse hypoechoic areas, diffuse enlargement, bile duct wall thickening, and peripancreatic hypoechoic margins on conventional EUS are characteristic features of AIP, and the frequencies of these findings are significantly higher in AIP than in pancreatic cancer (PC). EUS-EG of the pancreatic parenchyma in AIP showed homogenous stiffness and that the elasticity of the pancreas may change after steroid therapy. CEH-EUS revealed focal or diffuse iso-enhancement in most AIP cases and hypo-enhancement in most PC cases. However, some AIP cases show a contrast enhancement pattern similar to that of PC. It should be noted that EUS findings of AIP may differ depending on its stage or disease activity. Differentiation from PC has become an increasingly important issue in the process of diagnosing AIP, and EUS, including elastography and contrast enhancement, could be a promising imaging modality for this purpose., (© 2021. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Objectives: Pancreatic metastases from renal cell carcinoma (PRCC) often appear many years after treatment of the primary tumor, and differentiation from pancreatic neuroendocrine neoplasm (PanNEN) can be challenging due to their hypervascularity. Here, we investigated the utility of endoscopic ultrasound (EUS) for differentiation of these conditions., Methods: A retrospective analysis was performed in 17 and 79 consecutive patients with pathologically proven PRCC and non-functional PanNEN who were examined by EUS. In cases examined by EUS elastography or contrast-enhanced harmonic EUS (CH-EUS), the lesions were classified as stiff or soft, or into three vascular patterns as hypoechoic, isoechoic, and hyperechoic. CH-EUS images at 20 s, 40 s, 60 s, 3 min and 5 min were used for evaluation. EUS images were independently reviewed by two readers who were blinded to all clinical information., Results: The patients with PRCC were significantly older than those with PanNEN (median, 71 (range, 45-81) vs. 58 (22-76), P = 0.001) and more often had multiple tumors (6/17 (35%) vs. 7/79 (9%), P = 0.010). In EUS findings, PRCC lesions significantly more frequently had a marginal hypoechoic zone (MHZ) (11/17 (65%) vs. 27/79 (34%), P = 0.028), being classified as soft (12/13 (92%) vs. 26/58 (45%), P = 0.002), and showed sustained hyperechoic vascular patterns at 5 min (7/8 (88%) vs. 4/59 (7%), P < 0.001) compared to PanNEN lesions., Conclusions: The presence of a MHZ, a soft lesion, and a sustained hyperechoic vascular pattern in EUS may be useful for differentiating PRCC from PanNEN., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Endoscopic ultrasound (EUS) elastography (EUS-EG) is a minimally invasive diagnostic method for evaluating tissue elasticity. The aim of this study was to evaluate the feasibility of newly developed EUS shear-wave measurement (EUS-SWM) and to compare diagnostic performance between EUS-SWM and the conventional strain elastography (SE) for the measurement of elasticity of solid pancreatic lesions (SPLs)., Methods: From December 2017 until August 2019, we retrospectively reviewed 64 consecutive cases with SPLs who underwent both EUS-SWM and SE. EUS-SWM was used to measure the shear-wave velocity, Vs (m/s), and the unique measurement reliability index, VsN (%), in the target lesion. SE images were assessed by strain histogram (SH) analysis, and the mean strain value of the elasticity index was measured. We evaluated the diagnostic performance of EUS-SWM and SE with SH to characterize the SPLs., Results: The Vs (m/s) values of SPLs were 2.19 for pancreatic cancer (PC), 1.31 for pancreatic neuroendocrine neoplasm (PanNEN), 2.56 for mass-forming pancreatitis (MFP) and 1.58 for metastatic tumors. Vs showed no significant difference based on the disease. The mean strain values were 45.5 for PC, 47.3 for PanNEN, and 74.5 for MFP. In the comparison of tissue elasticity between PC and MFP, Vs showed no significant difference (P = 0.5687); however, the mean strain value was significantly lower in PC cases (45.4 vs 74.5: P = 0.0007)., Conclusion: Endoscopic ultrasound SWM tended to be unstable for the measurement of elasticity of SPLs, and conventional SE with SH was superior for their characterization., (© 2020 Japan Gastroenterological Endoscopy Society.)

Shear wave elastography (SWE) is a technique to non-invasively and quantitatively evaluate tissue stiffness. We aimed to investigate whether we can differentiate pancreatic cancer (PC) from normal pancreatic parenchyma (NPP) by SWE using transabdominal ultrasound. We investigated a total of 106 patients (84 with NPP and 22 with PC) whose pancreatic elastic modulus was measured by two-dimensional SWE (2D-SWE). Intra-rater reliability in this study was examined, and three measurements were sufficiently reliable. There were no differences between the two groups in factors that could affect SWE measurements. The median value of the elastic modulus was 5.70 kPa in the PC patients and 5.66 kPa in the NPP group, which was not significantly different (P = 0.785). On the contrary, the range was 8.64 kPa and 4.72 kPa, with a significantly greater range in the PC patients (P = 0.001). In conclusion, the median elastic modulus measured by 2D-SWE was not significantly different between PC and NPP, and evaluating the obtained elastic modulus itself is not useful in differentiation. However, the variability was significantly greater in PC than in NPP. Evaluating the range of elasticities will provide additional information in SWE, which may be useful in the diagnosis of PC.

Background and Aim: We examined the differences in the risks and characteristics of pancreatic relapse (PR) and pancreatic cancer (PC) in patients with autoimmune pancreatitis (AIP)., Methods: We retrospectively reviewed 123 type 1 AIP patients with a median follow-up of 55 months (interquartile range, 27-98). The following items were evaluated: (i) cumulative relapse rates and risk factors, (ii) the incidence of PC, (iii) PR versus PC, and (iv) outcomes after the appearance of morphological changes in the pancreas (focal enlargement, apparent mass lesions, or main pancreatic duct dilation)., Results: (i) The cumulative PR rates were 1.7% within 1 year, 11.5% within 3 years, and 22.6% within 5 years. Lack of maintenance therapy, IgG4-related sclerosing cholangitis, and IgG4-related kidney disease were identified as independent predictors of relapse. (ii) Two patients (1.6%) were diagnosed with PC at 17 and 22 months after initial AIP diagnosis. (iii) Thirteen (59.1%) and four (18.2%) patients with PR had focal enlargement and main pancreatic duct dilation, respectively. The median CA19-9 level at initial diagnosis was significantly higher in PC patients (21 vs 220.5 U/mL, P = 0.014). (iv) Eight PR patients underwent endoscopic ultrasound-guided fine-needle aspiration, none of whom had malignant findings. PC was diagnosed by ultrasound-guided fine-needle aspiration in both cancer patients., Conclusions: Although the incidence of PC is low, it may mimic PR in AIP patients. Surveillance is important, and when morphological changes occur, biopsy and evaluation of serum IgG4 and CA19-9 levels (particularly if the levels were high before) should be considered., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Main pancreatic duct (MPD) involvement in branch duct-type intraductal papillary mucinous neoplasms (BD-IPMNs) is a high risk finding for malignant IPMNs. However, discrepancies exist in the identification of MPD involvement between imaging findings and pathological diagnosis. The purpose of this study was to evaluate the diagnostic accuracy of preoperative assessment of MPD involvement in IPMNs using contrast-enhanced harmonic endoscopic ultrasound (CH-EUS)., Methods: This study involved 166 consecutive patients with BD-IPMNs who underwent surgical resection. CH-EUS was used to evaluate the MPD involvement according to the presence of mural nodules (MN) that advanced into the MPD or involved the MPD. The CH-EUS findings were compared with the pathological findings. Additionally, we analyzed the risk factors for malignant BD-IPMNs using multivariate analysis., Results: A total of 77, 51, and 38 patients were pathologically diagnosed with low-grade or intermediate-grade dysplasia, high-grade dysplasia and invasive IPMNs, respectively. MPD involvement was diagnosed using CH-EUS (MPD-inv.-EUS) in 90 (54.2%) patients with a sensitivity, specificity and accuracy of 83.5%, 87.0% and 84.9%, respectively. The malignancy rate in patients with MPD-inv.-EUS was 71.6% (63/90). Multivariate logistic regression analysis showed that MPD-inv.-EUS (OR, 3.61; 95% CI:1.45-8.98), age (OR, 5.70; 95% CI: 1.47-22.2), cyst size (OR, 2.45; 95% CI:1.04-5.78) and MN size (OR, 7.05; 95% CI:2.48-20.0) were significant for malignant BD-IPMNs., Conclusions: MPD-inv.-EUS accurately represents the pathological involvement of IPMN and may be a useful predictor of malignant BD-IPMNs., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Endoscopic ultrasonography (EUS) is a modality with high spatial resolution that enables comprehensive observation of the entire pancreas and plays an important role in the diagnosis of pancreatic lesions. Recent advances in diagnostic imaging methods such as ultrasound, computed tomography, and magnetic resonance imaging have increased the incidental detection of pancreatic cystic lesions (PCLs). EUS has been recognized as an essential diagnostic method for the detection and evaluation of PCLs. EUS has two important roles: as a detailed (high-resolution) imaging diagnostic method and as an approach for collecting cyst fluid content by EUS-guided fine needle aspiration for pathological diagnosis or biomarker evaluation. Furthermore, in recent years, the usefulness of contrast-enhanced EUS for the differential diagnosis of PCLs or evaluation of grade of malignancy, and a novel imaging technique called needle-based confocal laser endomicroscopy to observe intraductal structures through a needle, has been reported. An understanding of the morphological characteristics of PCLs depicted by ultrasound imaging and of the benefits and limitations of EUS diagnosis in daily practice is needed.

Background: Solid-pseudopapillary neoplasm (SPN) is a rare tumour that is mostly observed in young females. However, onset in males is also observed, and they do not necessarily present with typical findings. A comparison between male and female SPN patients focusing on the ultrasound findings was performed., Methods: Sixteen patients including 5 males who received transabdominal ultrasounds and were diagnosed with SPN based on their resected specimens were compared by sex in terms of the following: 1) age, 2) symptoms, 3) ultrasound findings, 4) preoperative ultrasound diagnoses, and 5) histology., Results: 1) The age was significantly higher in males (43 vs. 31, P = 0.004). 2) Symptoms were not observed in any of the males while 4/11 females were symptomatic (P = 0.245). 3) Tumour size was significantly smaller in males (20 mm vs. 33 mm, P = 0.014), and there was a higher percentage of cystic components in females (0% vs. 73%, P = 0.026). 4) SPN was listed as the first differential diagnosis in 9/11 females as opposed to 2/5 males (P = 0.139). 5) Cystic areas on the ultrasound corresponded to necrosis and hemorrhage. All cases showed expression of progesterone and androgen receptors regardless of sex., Conclusions: There were significant differences between male and female SPN patients in terms of age, tumour size, and presence of cystic components. Attention should be paid to the finding that onset in males was more common from middle age onwards in comparison to females and that a cystic component was not observed., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Vascular invasion is an important criterion for resectability and deciding the therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC), but imaging diagnosis is currently difficult. Endoscopic ultrasound (EUS) elastography (EG) images have band-like artifacts on the border between tumor and vessel due to different movement if the tumor is not connected to the vessel, i.e., no invasion. Based on this phenomenon, we assessed the usefulness of EUS-EG in the diagnosis of vascular invasion in PDAC., Methods: The subjects were 44 out of 313 patients with PDAC who underwent EUS between January 2015 and November 2018, followed by surgery, no chemotherapy or radiotherapy, and pathological evaluation. Diagnostic accuracies of vascular invasion using dynamic computed tomography (CT), EUS B-mode and EUS-EG were compared with histopathological diagnosis., Results: In 44 subjects (48 sites) who underwent both dynamic CT and EUS-B mode, the sensitivity, specificity and accuracy were 0.733, 0.697 and 0.708 on dynamic CT (48 sites); 0.733, 0.606 and 0.646 in EUS B-mode (48 sites); and 0.917, 0.900 and 0.906 in EUS-EG (32 sites). In 27 subjects (29 sites) with a tumor contacting a vessel with no vascular obstruction or stenosis on dynamic CT, the sensitivity, specificity and accuracy were 0.556, 0.750 and 0.690 on dynamic CT; 0.667, 0.700 and 0.690 in EUS B-mode; and 0.889, 0.850 and 0.862 in EUS-EG., Conclusions: These results suggest that EUS combined with EG improves diagnostic performance of vascular invasion in PDAC, especially in cases of which vascular invasion cannot be clearly assessed by dynamic CT.

Ultrasonographic imaging techniques have been rapidly developing. The new transesophageal echocardiography (TEE) system made it possible to obtain the real-time three-dimensional (3D) image of the cardiac system through the esophagus, that can be applied to the field of gastroenterology. We herein present a case of 72-year-old woman who was referred for evaluation of an incidentally found cystic lesion in the tail of the pancreas. The real-time 3D imaging with TEE probe clearly demonstrated the internal features of the cyst consistent with MCN, which helped narrow down the differential diagnosis. The patient was proceeded with distal pancreatectomy and a definite diagnosis of MCN was confirmed with the histopathological findings of the resected specimen associated with ovarian-type stroma. This is the first report which showed the real-time 3D image of MCN in the pancreas obtained with TEE. Further investigation is warranted to determine the clinical relevance of 3D ultrasonographic techniques used to evaluate the pancreatic cystic lesions.

The efficacy of nab-paclitaxel combined with gemcitabine (GnP) and of chemoradiotherapy (CRT) for unresectable locally advanced pancreatic ductal adenocarcinoma (UR-LA PDAC) is still unclear. We previously conducted a phase I study of CRT using GnP and determined the recommended dose and have now designed a phase II trial to evaluate the efficacy of CRT incorporating GnP for UR-LA PDAC. Eligibility criteria are chemotherapy-naïve patients with UR-LA PDAC as defined by the NCCN guidelines version 2. 2016. Study patients will receive 100 mg/m 2 nab-paclitaxel and 800 mg/m 2 gemcitabine on Days 1, 8, and 15 per 4-week cycle with concurrent radiation therapy (total dose of 50.4 Gy in 28 fractions of 1.8 Gy per day, 5 days per week). Treatment will be continued until disease progression or surgery, which is to be performed only for patients in whom the disease is well-controlled at 8 months from beginning the protocol treatment. Primary endpoint is 2-year overall survival rate and co-primary endpoint is resection rate. Secondary endpoints are overall survival, progression free survival, time to treatment failure, response rate, disease control rate, early tumor shrinkage, depth of response, reduction of SUV-max on PET-CT, serum tumor markers, relative dose intensity, safety, and Quality of life. This study will show the efficacy and safety of chemoradiotherapy combined with GnP.

Background and Aims: Several studies have shown the benefits of endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a Franseen needle for histological assessment. However, studies focusing on pancreatic diseases are limited and the safety of this method has not been well assessed. We aimed to assess the current status and issues of EUS-FNB in the diagnosis of pancreatic diseases., Materials and Methods: We retrospectively reviewed 87 consecutive EUS-FNB specimens using either a 22-gauge Franseen needle (Group A, N = 51) or a conventional 22-gauge fine-needle aspiration needle (Group B, N = 36) for pancreatic diseases, and the diagnostic accuracy and safety were compared. Final diagnoses were obtained based on surgical pathology or a minimum six-month clinical follow-up., Results: Although the diagnostic accuracy for malignancy was 96.1% in Group A versus 88.9% in Group B, with no statistically significant difference ( P = 0.19), the median sample area was significantly larger in Group A (4.07 versus 1.31mm 2 , P < 0.0001). There were no differences between the two needles in the locations from which the specimens were obtained. Adverse events occurred in one case (2%) in Group A (mild pancreatitis) and none in Group B with no statistical significance ( P = 0.586). Although there was no case of bleeding defined as adverse events, 2 cases in Group A showed active bleeding during the procedure with increase in the echo-free space, which required CT scanning to rule out extravasation. Eventually, the bleeding stopped spontaneously., Conclusions: Given its guaranteed ability to obtain core specimens and comparable safety, and although the risk of bleeding should be kept in mind, EUS-FNB using a Franseen needle is likely to become a standard procedure for obtaining pancreatic tissue in the near future.

Objective: To evaluate the efficacy and safety of alternate-day administration of S-1 as second-line chemotherapy for unresectable pancreatic cancer in a multicenter, randomized, phase II study., Methods: Patients with histologically proven, unresectable pancreatic cancer treated with chemotherapy not including S-1 as first-line therapy were randomly assigned to receive either daily or alternate-day treatment with S-1. The primary end point was overall survival (OS), and the secondary end points were progression-free survival (PFS), time to treatment failure (TTF), response rate, and adverse events., Results: A total of 77 patients were enrolled, of which 75 were included in the final analysis. The median OS was 4.5 months in the daily group and 4.4 months in the alternate-day group (HR 1.178; 95% CI 0.741-1.875), with no significance in PFS and TTF. The response rate was 2.8% in the daily group and 0% in the alternate-day group. Grade 3 or higher adverse events occurred with significantly higher incidence in the daily group (47.2 vs. 25.6%, p = 0.044)., Conclusion: As a second-line chemotherapy for unresectable pancreatic cancer, although the efficacy in both groups was comparable and we can expect fewer toxicities with alternate-day administration of S-1, the noninferiority of alternate-day treatment to daily treatment with S-1 was not verified., (© 2018 S. Karger AG, Basel.)

Endoscopic ultrasound is increasingly being used for evaluation of pancreatic diseases and pancreatic tumors. Among various pancreatic cystic lesions, cystic degeneration of pancreatic neuroendocrine neoplasm is of the challenge in making diagnosis. Although unique characteristic of each type of pancreatic cystic lesions has been proposed abundantly, typical morphology of cystic degeneration of pancreatic neuroendocrine neoplasm is still unclear. We, herein, reported a case of 66-year-old woman who was incidentally found to have a cystic lesion in the tail of pancreas upon screening transabdominal ultrasonography. A well-defined cystic lesion with rim calcification was noted on subsequent abdominal computed tomography. Endoscopic ultrasound revealed a markedly thick-wall cystic lesion containing solid nodule inside which was not enhanced following contrast-enhanced study. A mucinous cystic neoplasm was suspected and the patient was proceeded with distal pancreatectomy. A definite diagnosis of neuroendocrine neoplasm was confirmed after staining with synaptophysin and chromogranin A. We performed a meticulous review on current literatures focusing on endoscopic characteristics of pancreatic neuroendocrine neoplasms with cystic degeneration.

Background: Prognosis of pancreatic cancer is poor with a 5-year survival rate of only 7%. Although several new chemotherapy treatments have shown promising results, all patients will eventually progress, and we need to develop newer chemotherapy treatments to improve response rates and overall survival (OS). HF10 is a spontaneously mutated oncolytic virus derived from a herpes simplex virus-1, and it has potential to show strong antitumor effect against malignancies without damaging normal tissue. We aimed to evaluate the safety and anti-tumor effectiveness in phase I dose-escalation trial of direct injection of HF10 into unresectable locally advanced pancreatic cancer under endoscopic ultrasound (EUS)-guidance in combination with erlotinib and gemcitabine administration. The mid-term results have been previously reported and here we report the final results of our study., Methods: This was a single arm, open-label Phase I trial. HF10 was injected once every 2 weeks and continued up to four times in total unless dose-limiting toxicity (DLT) appears. A total of nine subjects in three Cohorts with dose-escalation were planned to be enrolled in this trial. The primary endpoint was the safety assessment and the secondary endpoint was the efficacy assessment., Results: Twelve patients enrolled in this clinical trial, and ten subjects received this therapy. Five patients showed Grade III myelosuppression and two patients developed serious adverse events (AEs) (perforation of duodenum, hepatic dysfunction). However, all of these events were judged as AEs unrelated to HF10. Tumor responses were three partial responses (PR), four stable diseases (SD), and two progressive diseases (PD) out of nine subjects who completed the treatment. Target lesion responses were three PRs and six SDs. The median progression free survival (PFS) was 6.3 months, whereas the median OS was 15.5 months. Two subjects from Cohort 1 and 2 showed downstaging and finally achieved surgical complete response (CR)., Conclusions: HF10 direct injection under EUS-guidance in combination with erlotinib and gemcitabine was a safe treatment for locally advanced pancreatic cancer. Combination therapy of HF10 and chemotherapy should be explored further in large prospective studies., Trial Registration: This study was prospectively registered in UMIN-CTR (UMIN000010150) on March 4th, 2013.

Background/objectives: Time-intensity curve (TIC) under contrast-enhanced EUS (CE-EUS) allows continuous and quantitative evaluation of targeted area in the pancreas. However, TIC is not always available and the procedure is complicated. We aimed to propose a simplified method by evaluating multiple phases of CE-EUS in the diagnosis of pancreatic solid lesions., Methods: We retrospectively reviewed 210 patients with pancreatic solid lesions including 142 with pancreatic ductal cancer (PDAC), 31 with pancreatic neuroendocrine neoplasm, 13 with solid pseudopapillary neoplasm and 24 with mass-forming pancreatitis who underwent CE-EUS and achieved final diagnoses. The CE-EUS images were continuously recorded for 60 s, and each image at 20, 40 and 60 s was used for the evaluation. The images were classified into three patterns as hypoechoic, hyperechoic and isoechoic vascular patterns compared with the surrounding pancreas, and the relevance between the multiphase evaluation of CE-EUS and each disease group was investigated., Results: In PDAC group, majority of the lesions showed hypovascular pattern at 20 or 40 s after injection of contrast medium following early enhancement. The sensitivity, specificity and accuracy of PDAC pattern in the differentiation of PDAC from other lesions was 83.1%, 86.8% and 84.3%, respectively. On histopathological analysis, significant differences were seen in histologic types, infiltration (INF), and neural invasion (ne) between those who showed PDAC pattern and those who didn't., Conclusions: Multiphase evaluation of CE-EUS is convenient and useful method for the differentiation of pancreatic solid lesions which can be alternatively used for TIC., (Copyright © 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background and Aim: The aim of this study is to elucidate the natural history of pancreatic cystic lesions (PCLs), including branch duct-type intraductal papillary mucinous neoplasm (BD-IPMN), via midterm follow-up analysis of a multicenter prospective observational study (NSPINAL study)., Methods: From July 2011 to October 2016, 881 patients with PCLs were enrolled in NSPINAL study, and 664 patients with > 12 months of follow up were analyzed. Every patient was asymptomatic, and endoscopic ultrasound was performed at the initial diagnosis to exclude high-risk individuals. Follow up included endoscopic ultrasound, computed tomography, or magnetic resonance imaging at least once a year. Serial morphological changes and the pancreatic cancer (PC) incidence, including malignant progression of PCLs, were evaluated., Results: The 664 patients (358 men) were followed for a median of 33.5 months (interquartile range 29). The cyst and main pancreatic duct sizes were 16.6 ± 9.3 and 2.3 ± 1.0 mm, respectively. Morphologically, 518 cases were multilocular, 137 were unilocular, and 9 had a honeycomb pattern; 269 cases involved multifocal lesions. Ninety-six patients (14.5%) showed worsening progression on imaging. There were two resectable and four unresectable cases of pancreatic ductal adenocarcinoma and three cases of malignant BD-IPMN. The 3-year risk of developing PC was 1.2%. The standardized incidence ratio for PC among PCLs was 10.0 (95% confidence interval 3.5-16.5), and the standardized incidence ratio among BD-IPMN was 16.6 (95% confidence interval 5.1-28.1). Multivariate analysis showed that development of symptoms and worsening progression were significant predictors of PC., Conclusions: Malignant progression of PCLs, including PC development, is not uncommon. Patients with PCLs should be carefully monitored to detect pancreatic ductal adenocarcinoma at early stages., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background & Aims: There is no established non-invasive method for diagnosis of pancreatic fibrosis. Shear wave elastography (SW-EG) may be a candidate for this purpose. The aims of this study were to assess the reproducibility of SW-EG in the normal imaging pancreas (Phase 1) and to evaluate the diagnostic performance of SW-EG for pancreatic fibrosis classified histologically (Phase 2)., Methods: Phase 1: This included 127 cases that underwent SW-EG of the normal imaging pancreas. SW-EG was measured at least five times in the pancreatic parenchyma and the median of repeated measurements was defined as the pancreatic elastic modulus (PEM). Phase 2: This included 53 cases that underwent SW-EG of the pancreatic parenchyma preoperatively and in which pancreas parenchyma were evaluated histologically. Histological fibrosis was graded in 4 stages: normal, mild, moderate, and severe., Results: Phase 1: Median PEM in the head, body, and tail of the pancreas were 3.23, 3.17, and 2.91 kPa, respectively, with no significant difference among regions (P = 0.554). The intraclass correlation coefficient showed good reproducibility (ρ = 0.71) after 5 measurements. Phase 2: There was a significant positive correlation between PEM and the histological pancreatic fibrosis stage (r s  = 0.63, P < 0.001). Areas under the receiver operating characteristic curve for the accuracy of SW-EG for diagnosis of pancreatic fibrosis were 0.85 (≥mild), 0.84 (≥moderate), and 0.87 (severe)., Conclusion: SW-EG can be used to determine the stage of pancreatic fibrosis non-invasively with high accuracy and reproducibility., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background and Aim: Patients with advanced pancreatic cancer have severe pain, anxiety, and depression, and these symptoms deteriorate quality of life (QOL). Previous study reported that early psychiatric intervention for advanced cancer patients may improve QOL. We evaluated the trajectory of health-related QOL (HRQOL) in patients with pancreatic cancer after an early psychiatric intervention., Methods: A prospective cohort study was performed in 108 pancreatic cancer patients who received consultation liaison psychiatry from November, 2011 to October, 2014 at Nagoya University Hospital. Longitudinal changes in HRQOL and the association between aspects of HRQOL and survival were evaluated using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 before treatment and every month after the start of treatment., Results: Physical functioning significantly decreased after 1, 3, and 6 months of treatment compared with baseline, but global health status (GHS), role functioning, emotional functioning, and social functioning showed a tendency to improve. Severe impairment of GHS, fatigue, and appetite loss were apparent at 3 months prior to death. In multivariate analysis, pain was a significant prognostic factor for survival (hazard ratio [HR], 1.109; 95% confidence interval [CI], 1.021-1.204; P = 0.013), in addition to poor performance status (HR, 5.473; 95%CI, 2.338-12.816; P < .0001) and distant metastases at diagnosis (HR, 3.274; 95%CI, 1.872-5.725; P < .0001)., Conclusions: Early psychiatric intervention in patients with pancreatic cancer may maintain HRQOL. More effective pain management and reduction of psychological distress are important for patients with pancreatic cancer., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: The aim of this study was to investigate the relationship between pancreas and small intestine evaluating the endoscopic and histopathologic findings of the proximal small intestine in pancreatic diseases., Methods: Fifty patients (18 patients with chronic pancreatitis, 17 patients with pancreatic cancer, 15 control subjects) underwent enteroscopy using a prototype enteroscope. The villous height of the jejunum on bioptic specimens was measured, and the mean values of the villi were compared among the 3 groups. Exocrine function was calculated by the pancreatic function diagnostic test, and the correlation between the recovery rate of p-aminobenzoic acid and the villous height was assessed. Finally, the distribution of the K cells secreting glucose-dependent insulinotropic polypeptide and the L cells secreting glucagon-like peptide 1 in the duodenum and jejunum was investigated using immunohistochemistry for glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1., Results: The mean villous height in chronic pancreatitis (328 ± 67 μm) was significantly lower than that in pancreatic cancer (413 ± 57 μm) and control subjects (461 ± 97 μm) (P = 0.004 and P < 0.0001, respectively). A positive correlation was found between the recovery rate of p-aminobenzoic acid and the villous height (r = 0.52, P = 0.0001). The presence of K and L cells was verified in the duodenum and the jejunum., Conclusions: Close relationship between pancreas and small intestine was demonstrated.

Objectives: The natural history of branch duct-type intraductal papillary mucinous neoplasms (BD-IPMNs) of the pancreas remains unclear. We conducted a retrospective long-term follow-up study for malignant transformation (MT) of BD-IPMNs focusing on morphological changes., Methods: The subjects consisted of 142 patients who underwent contrast-enhanced endoscopic ultrasonography for initial diagnosis from January 2001 with more than 12 months of follow-up. The MT rate, including the co-occurrence of invasive ductal cancer, was evaluated by univariate and multivariate analysis. In addition, on the basis of morphological changes in patients who underwent surgery, the predictive factors for malignant IPMNs were evaluated., Results: Median follow-up term was 42.5 months (range, 12-105 months). Thirty patients who exhibited morphological changes underwent surgery. Malignant transformation occurred in 9 patients (6.3%), and 5-year MT rate was 10.7%. The co-occurrence of invasive ductal cancer was seen in 5 patients. Multivariate analysis showed that the existence of mural nodules at initial diagnosis and involvement of main pancreatic duct were significant predictors of MT of BD-IPMN., Conclusions: Malignant transformation of BD-IPMN is not rare. The observation of morphological changes of main pancreatic duct and nodules, mainly on contrast-enhanced endoscopic ultrasonography, is practical and useful for predicting MT of BD-IPMN itself.

Objectives: This study aimed to investigate the usefulness of contrast-enhanced endoscopic ultrasonography (EUS) with time-intensity curve (TIC) in differentiating pancreatic diseases., Methods: Patients who underwent contrast-enhanced EUS between January 2007 and June 2009 were analyzed retrospectively, including 48 with pancreatic ductal cancer (PC), 14 with autoimmune pancreatitis (AIP), 13 with mass-forming pancreatitis (MFP), and 16 with pancreatic endocrine tumor (PET). After intravenous injection of contrast agent, contrast imaging pattern, TIC-based quantitative evaluation, and diagnostic ability of EUS in combination with TIC to diagnose benignancy or malignancy were assessed., Results: Hypovascular and heterogeneous pattern (42/48) in PC, isovascular and homogenous (21/27) in AIP and MFP, and hypervascular and rapid stained (16/16) in PET were observed. The echo intensity reduction rate from the peak at 1 minute was the greatest in PC followed by MFP, AIP, and PET (P < 0.05). The diagnostic accuracies based on contrast imaging pattern (84.0%) and TIC (88.0%) were higher than those based on B-mode imaging (82.6%) and dynamic computed tomography (81.3%). In EUS in combination with TIC, sensitivity, specificity, and accuracy rose up to 95.8%, 92.6%, and 94.7%, respectively., Conclusions: Contrast-enhanced EUS with the dynamic quantitative analysis preparing TIC increased the diagnostic accuracy for pancreatic diseases.

Purpose: S-1 is one of the second-line candidate agents for gemcitabine-refractory unresectable pancreatic cancer. Two phase II studies have been reported for second-line chemotherapy with S-1, but these studies did not investigate introduction rate and suitable dose of second-line S-1. Therefore, we conducted a prospective multicenter study in which chemo-naïve patients were enrolled and had two levels of S-1 dose., Methods: Chemo-naïve patients with unresectable pancreatic cancer were enrolled. This study started with 80 mg/m(2)/day dose of S-1 as second-line chemotherapy and tolerability was checked. When tolerability was not confirmed in initial patients, the dose of S-1 was shifted to 60 mg/m(2)/day. When tolerability was confirmed at 80 or 60 mg/m(2)/day, the study continued, and up to 20 patients were accumulated with the dose. In addition, the introduction rate of second-line S-1 was examined., Results: Six of the initial 7 patients with 80 mg/m(2)/day dose of S-1 completed one course of second-line chemotherapy. Twenty patients were accumulated with an 80 mg/m(2)/day dose of S-1. With the exception of one patient continued gemcitabine chemotherapy, two of the remaining 19 patients withdrew from this study because of toxicity during the period of gemcitabine chemotherapy. Fifteen of the remaining 17 gemcitabine-refractory patients could complete one course of S-1 as second-line chemotherapy with acceptable toxicity., Conclusions: This prospective multicenter study showed that 15 (78.9%) out of 19 chemo-naïve unresectable pancreatic cancer patients could complete one course of 80 mg/m(2)/day dose of S-1 as second-line chemotherapy after first-line gemcitabine chemotherapy failure with tolerable toxicity.

Background: Pancreatic endocrine tumors (PETs) develop in relatively few patients, but they are often difficult to diagnose because of their small size and various clinical symptoms., Objective: The aim of this study was to investigate the usefulness of EUS combined with contrast enhancement (CE-EUS) in the preoperative localization of PETs and the differentiation between malignant and benign PETs., Design and Setting: Single-center retrospective study., Patients: Sixty-two pathologically certified PETs of 41 patients who underwent EUS, multiphasic multidetector computed tomography (MDCT), and transabdominal US at our institute since 2001., Interventions: Intravenous injection of US contrast media., Main Outcome Measurements: Comparison of EUS, MDCT, and US in the preoperative identification of PETs, and the characteristic findings of EUS with malignancy., Results: EUS showed high sensitivity (95.1%) in identifying PETs compared with MDCT (80.6%) and US (45.2%). Multivariable logistic regression analysis showed that heterogeneous ultrasonographic texture was the most significant factor for malignancy (OR = 53.33; 95% CI, 10.79-263.58). Most heterogeneous hypoechoic areas and anechoic areas corresponded to hemorrhage or necrosis on pathologic examination. They were identified as filling defects in CE-EUS and were more clearly recognized than in conventional EUS., Limitations: Retrospective study., Conclusion: EUS has higher sensitivity in preoperative localization of PETs compared with MDCT and US. The characteristics of EUS and CE-EUS findings in malignant PETs were clarified, and they will improve the diagnostic accuracy of PETs., (2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background: Analysis of gene expression and gene mutation may add information to be different from ordinary pathological tissue diagnosis. Since samples obtained endoscopically are very small, it is desired that more sensitive technology is developed for gene analysis. We investigated whether gene expression and gene mutation analysis by newly developed ultra-sensitive three-dimensional (3D) microarray is possible using small amount samples from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens and pancreatic juices., Methods: Small amount samples from 17 EUS-FNA specimens and 16 pancreatic juices were obtained. After nucleic acid extraction, the samples were amplified with labeling and analyzed by the 3D microarray., Results: The analyzable rate with the microarray was 46% (6/13) in EUS-FNA specimens of RNAlater storage, and RNA degradations were observed in all the samples of frozen storage. In pancreatic juices, the analyzable rate was 67% (4/6) in frozen storage samples and 20% (2/10) in RNAlater storage. EUS-FNA specimens were classified into cancer and non-cancer by gene expression analysis and K-ras codon 12 mutations were also detected using the 3D microarray., Conclusions: Gene analysis from small amount samples obtained endoscopically was possible by newly developed 3D microarray technology. High quality RNA from EUS-FNA samples were obtained and remained in good condition only using RNA stabilizer. In contrast, high quality RNA from pancreatic juice samples were obtained only in frozen storage without RNA stabilizer.

Objectives: Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer., Methods: Patients (n = 5) received the treatment course, which consisted of intravenous GEM administration at 1000 mg/m (day 1) and the endoscopic ultrasound-guided fine-needle injection of OK432-pulsed DCs into a tumor, followed by intravenous infusion of lymphokine-activated killer cells stimulated with anti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals., Results: No serious treatment-related adverse events were observed during the study period. Three of the 5 patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2 had long stable disease more than 6 months. In the patient with partial remission, it has been shown that DC-based vaccination combined with GEM administration induces tumor antigen-specific CTLs., Conclusion: This combined therapy was considered to be synergistically effective and may have a role in the therapy of pancreatic cancer for inducing tumor antigen-specific CTLs.

Background and Aim: Intraductal papillary mucinous neoplasms (IPMNs)have a wide pathologic spectrum and it is difficult to differentiate malignant from benign tumors. The aim of this study was to identify predictors of malignancy using contrast-enhanced endoscopic ultrasound (CE-EUS)., Subjects and Methods: In our institute, main duct type and mixed type IPMNs, branch duct type IPMNs with mural nodules, and IPMNs with coexistent invasive ductal cancer were indications for surgery. Eighty-seven IPMNs (14 main duct, 25 mixed, and 48 branch duct type) were resected and CE-EUS findings were compared with pathologic findings. Twelve clinicopathological variables and CE-EUS morphologic findings were assessed.Mural nodules defined as blood flow supplied protrusions were classified into 4 types: type I: low papillary nodule, type II: polypoid nodule, type III:papillary nodule, and type IV: invasive nodule., Results: Forty-two, 26, 16, and 3 were pathologically diagnosed as adenoma,noninvasive carcinoma, invasive IPMNs, and coexistent invasive ductal cancer, respectively. Multivariable logistic regression analysis showed that types III/IV mural nodule (odds ratio = 10.8; 95% confidential intervals = 2.75-56.1) and symptomatic IPMNs (odds ratio = 4.31; 95% confidential intervals = 1.37-14.7) were significant for malignancy. For mural nodule diameter, invasive IPMNs were significantly larger, but types III and IV mural nodules were more frequently associated with malignancy, particularly invasive cancer, at 88.9% and 91.7%, respectively. The diagnosis of IPMNs with types III or IV mural nodule as malignant resulted in a sensitivity of 60%, specificity of 92.9%, and accuracy of 75.9%., Conclusions: In conclusion, new morphologic criteria were useful to identify the malignant potentials of IPMNs.

Objectives: Pancreatic cystic (PC) lesions are not necessarily rare, and it is important to diagnose whether PC lesions are neoplastic such as intraductal papillary mucinous neoplasm (IPMN) because of its malignant potential. Reports on PC lesions in hemodialysis (HD) patients are remarkably limited. The aim of this study was to clarify the prevalence and characteristics of PC lesions in HD patients., Methods: We reviewed 1012 consecutive HD patients and 11,100 patients (controls) without renal disease who underwent transabdominal ultrasonography between January 2003 and December 2005. Patients' sex ratio (female-to-male) was less, and the age was older in HD patients. Clinical findings of these patients were examined., Results: The prevalence both of PC lesions and IPMNs was significantly higher in HD patients than in controls (9.3% vs 1.3% and 2.8% vs 0.2%, P < 0.0001). The incidence of IPMNs in HD patients with PC lesions was higher than that in controls with PC lesions (29.8% vs 17.0%, P = 0.021). Multivariate logistic regression analysis revealed that the odds ratios of PC lesions and IPMNs were 6.38 (95% confidence interval, 4.82-8.45) and 9.39 (95% confidence interval, 5.36-16.49) in HD patients compared with controls., Conclusion: The prevalence of PC lesions in HD patients is higher, and HD patients with PC lesions have high prevalence of IPMNs.

Objectives: We investigated the feasibility of using real-time tissue elastography (EG) with transcutaneous ultrasonography (EG-US) for pancreatic diseases., Methods: A preliminary study (phase I) and a prospective (phase II) study were conducted. Phase I: subjects were 10 volunteers, 5 with cancer, 2 with endocrine tumor, 5 with chronic pancreatitis, 14 with intraductal papillary-mucinous neoplasm. To determine the characteristic EG images (diagnostic criteria for phase II), B-mode images were compared with EG images and histopathologic findings. Phase II: 53 consecutive patients were enrolled. The visualization rate by EG-US in lesions visualized by B mode was assessed, and the correct diagnosis rate by B mode alone (B diagnosis) or in combination with EG-US was evaluated., Results: Phase I: normal parenchyma was a homogeneous color. In cancer, EG-US showed a markedly hard area with soft spots inside. Endocrine tumor was uniform and soft comparable to parenchyma. Chronic pancreatitis showed a mixture of various colors. Phase II: we identified 77.4% (41/53) of the lesions and observed 60.0% (15/25) of the cancers, 100% (3/3) of the endocrine tumor, 92.0% (23/25) of the cases of chronic pancreatitis cases on EG-US. The B-diagnosis rates ranged from about 70% to 80%. The diagnosis rates of the combination were more than 90% of lesions of each type., Conclusions: The EG-US is feasible in the diagnosis of pancreatic diseases.