Factors Affecting Nonfunctioning Small Pancreatic Neuroendocrine Neoplasms and Proposed New Treatment Strategies.

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

A comparative study between computed tomography and endoscopic ultrasound in the detection of a mural nodule in intraductal papillary mucinous neoplasm -Multicenter observational study in Japan.

BACKGROUND/OBJECTIVES: The detection of malignancy is a major concern in the management of intraductal papillary mucinous neoplasm (IPMN). The height of the mural nodule (MN), estimated using endoscopic ultrasound (EUS) and computed tomography (CT), has been considered crucial for predicting malignant IPMN. Currently, whether surveillance using CT or EUS alone is sufficient for detecting MNs remains unclear. This study aimed to compare the ability of CT and EUS to detect MNs in IPMN. METHODS: This multicenter, retrospective observational study was conducted in 11 Japanese tertiary institutions. Patients who underwent surgical resection of IPMN with MN after CT and EUS examinations were eligible to participate. The MN detection rates between CT and EUS were examined. RESULTS: Two-hundred-and-forty patients who underwent preoperative EUS and CT had pathologically confirmed MNs. The MN detection rates of EUS and CT were 83% and 53%, respectively (p < 0.001). Additionally, the MN detection rate of EUS was significantly higher than that of CT regardless of morphological type (76% vs. 47% in branch-duct-type IPMN; 90% vs. 54% in mixed IPMN; 98% vs. 56% in main-duct-type IPMN; p < 0.001). Further, pathologically confirmed MNs ≥5 mm were more frequently observed on EUS than on CT (95% vs. 76%, p < 0.001). CONCLUSIONS: EUS was superior to CT for the detection of MN in IPMN. EUS surveillance is essential for the detection of MNs.

Relapse rate and predictors of relapse after cessation of glucocorticoid maintenance therapy in type 1 autoimmune pancreatitis: a multicenter retrospective study.

BACKGROUND: Type 1 autoimmune pancreatitis responds well to glucocorticoid therapy with a high remission rate. Moreover, glucocorticoid maintenance therapy can help prevent relapse. However, the relapse rate following cessation of long-term glucocorticoid therapy is unknown. The aim of this study was to clarify the relapse rate and predictors of relapse following long-term glucocorticoid therapy cessation. METHODS: We analyzed 94 patients who achieved remission after undergoing glucocorticoid therapy, discontinued treatment after at least 6 months of maintenance therapy, and were subsequently followed up for at least 6 months. The patients were divided into three groups based on treatment duration (< 18, 18-36, and ≥ 36 months), and their relapse rates were compared. Univariate and multivariate analyses of clinical factors were conducted to identify relapse predictors. RESULTS: After discontinuing glucocorticoid therapy, relapse was observed in 43 (45.7%) patients, with cumulative relapse rates of 28.2% at 1 year, 42.1% at 3 years, 47.0% at 5 years, and a plateau of 77.6% at 9 years. Of the 43 patients who relapsed, 25 (58.1%) relapsed within 1 year after after cessation of glucocorticoid therapy. Relapse and cumulative relapse rates did not differ significantly according to treatment duration. In the multivariate analysis, an elevated serum IgG4 level at the time of glucocorticoid cessation was found to be an independent predictor of relapse (hazard ratio, 4.511; p < 0.001). CONCLUSIONS: A high relapse rate occurred after cessation of glucocorticoid maintenance therapy, regardless of the duration of maintenance therapy, especially within the first year after cessation. However, the normalization of long-term serum IgG4 levels may be a factor in considering cessation.

Efficacy of bailout surgery for preventing intraoperative biliary injury in acute cholecystitis.

BACKGROUND: Bailout surgery (BOS; partial cholecystectomy, open conversion, and fundus-first approach) has been recommended for difficult cases to ensure safe performance of cholecystectomy. However, the efficacy of BOS for preventing intraoperative massive bleeding and bile duct injury (BDI) remains unclear, especially in the context of acute cholecystitis (AC). This study aimed to retrospectively validate the feasibility of BOS for AC. METHODS: We enrolled 479 patients who underwent emergency cholecystectomies for AC between 2011 and 2021. Univariate and multivariate analyses were performed to detect the risk factors for BOS in patients with AC. Perioperative variables were compared between patients who underwent total cholecystectomy (TC) and those who underwent BOS. Propensity score matching analysis was performed to compare the two groups. RESULTS: Significant differences in American Society of Anesthesiologists physical status and Charlson Comorbidity Index scores, TG18 severity grading, white blood cell count, and albumin and C-reactive protein (CRP) levels were found between the TC and BOS groups. Preoperative CT imaging demonstrated severe inflammation evidenced by gallbladder wall thickness, enhancement of the liver bed, and duodenal edema in the BOS group compared to the TC group. Postoperative complications were significantly higher in the BOS group than in the TC group. Further, BDI was completely prevented by BOS. Multivariate analysis identified TG18 grade ≥ II, CRP ≥ 7.7, and duodenal edema as independent risk factors for BOS. After PSM analysis, postoperative complications were not worse in patients who underwent BOS rather than TC. Among BOS procedures, laparoscopic BOS (lap-BOS) was the most efficacious in preventing intraoperative blood loss and postoperative bile leakage. CONCLUSION: Severity grading > II, elevated CRP levels, or duodenum edema revealed by CT were determined to be risk factors impeding total cholecystectomy. BOS is a safe, feasible, and efficacious procedure for preventing BDI. Among BOS procedures, lap-BOS showed better postoperative outcomes.

Clinical Practice Guidelines for Pancreatic Cancer 2022 from the Japan Pancreas Society: a synopsis.

OBJECTIVES: Clinical Practice Guidelines for Pancreatic Cancer was first published in 2006 by the Japan Pancreas Society, and revised in 2009, 2013, 2016, and 2019. In July 2022, Clinical Practice Guidelines for Pancreatic Cancer was newly revised in Japanese. METHODS: For this revision, we developed an entirely new guideline according to the Minds Manual for Guideline Development 2020, which includes the concepts of GRADE-Grading Recommendations Assessment, Development, and Evaluation, to enable a better understanding of the current guidelines. Patients and the public were actively involved in both the development and implementation of the guideline. RESULTS: The guideline includes algorithms for diagnosis, treatment, chemotherapy, and precision medicine of pancreatic cancer, and addresses 7 subjects: diagnosis, surgical therapy, adjuvant therapy, radiation therapy, chemotherapy, stent therapy, and supportive & palliative medical care. It includes 73 clinical questions and 112 statements. The statements correspond to the clinical questions, evidence levels, recommendation strengths, and agreement rates. CONCLUSIONS: This guideline represents the most standard clinical and practical management guideline available until date in Japan. This is the English synopsis of the Clinical Practice Guidelines for Pancreatic Cancer 2022 in Japanese, and is an attempt to disseminate the Japanese guideline worldwide to introduce the Japanese approach to the clinical management of pancreatic cancer.

Pancreatic hamartoma: detection of harbouring NAB2::STAT6 fusion gene.

Hamartomas in the pancreas are rare and are often histologically and morphologically similar to solitary fibrous tumours (SFTs). We examined the differences between hamartomas and SFTs at the molecular level. METHODS AND RESULTS: Thirteen patients histopathologically diagnosed with pancreatic hamartoma were included in the study. We also performed STAT6 immunohistochemistry (IHC), which is used in the diagnosis of SFT. Furthermore, for the three cases in which RNA was extracted, reverse transcription polymerase chain reaction to search for NAB2::STAT6 fusions was used. Macroscopically, 13 patients had well-demarcated tumour lesions. Histologically, no islets of Langerhans were observed in the lesions, acinar tissue and ducts were unevenly distributed and elastic fibres were not observed around the ducts by Elastica van Gieson staining. One case contained a lipomatous hamartoma composed mainly of adipose tissue. Seven of the 13 cases demonstrated expression of STAT6 in the nuclei of intervening spindle cells. NAB2::STAT6 fusions were observed in two of the three cases in which RNA was extracted. These two cases also demonstrated STAT6 expression in spindle cells using STAT6 IHC. In one case of lipomatous hamartoma, we did not confirm NAB2::STAT6 fusion or STAT6 expression in STAT6 IHC. CONCLUSION: Of the 13 patients histopathologically diagnosed with hamartoma, two demonstrated NAB2::STAT6 fusions, suggesting the existence of pancreatic hamartomas with molecular-level components identical to those of SFT.

Endoscopic approach in the diagnosis of high-grade pancreatic intraepithelial neoplasia.

Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is essential for improving prognosis; however, diagnosing PDAC at an early stage is challenging. In patients with localized high-grade pancreatic intraepithelial neoplasia (HG-PanIN), whose tumorous lesion is undetectable on cross-sectional images such as computed tomography or magnetic resonance image, long-term survival is expected. Pancreatic cystic lesions or main pancreatic duct (MPD) dilatation are important indirect findings for the initial diagnosis of HG-PanIN. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) should play important roles in detecting abnormal image findings, such as local irregular MPD stenosis, caliber MPD changes, small cystic lesions, or branch duct dilatation. Additionally, EUS could detect hypoechoic areas around the MPD stenosis in some patients with HG-PanIN. Subsequently, endoscopic retrograde cholangiopancreatography (ERCP) and its associated pancreatic juice cytology, including serial pancreatic juice aspiration cytologic examination (SPACE) after placement of an endoscopic nasopancreatic drainage (ENPD) tube, may have high diagnostic accuracy for confirming the malignancy in HG-PanIN. Although ERCP and its associated pancreatic cytology, including SPACE, may be associated with post-ERCP pancreatitis (PEP), a recent randomized trial suggested that a 4-Fr ENPD tube may reduce the incidence of PEP. In the future, further prospective multicenter studies are required to establish a standard method of SPACE. Additionally, further studies for novel biomarkers could help to establish evolutionary methods with duodenal fluid and pancreatic juice for the early and accurate diagnosis of early-stage PDAC.

Endoscopic placement of covered versus uncovered self-expandable metal stents for palliation of malignant gastric outlet obstruction.

OBJECTIVE: Stenting is an established endoscopic therapy for malignant gastric outlet obstruction (mGOO). The choice of stent (covered vs uncovered) has been examined in prior randomised studies without clear results. DESIGN: In a multicentre randomised prospective study, we compared covered (CSEMS) with uncovered self-expandable metal stents (UCSEMS) in patients with mGOO; main outcomes were stent dysfunction and patient survival, with subgroup analyses of patients with extrinsic and intrinsic tumours. RESULTS: Overall survival was poor with no difference between groups (probability at 3 months 49.7% for covered vs 48.4% for uncovered stents; log-rank for overall survival p=0.26). Within that setting of short survival, the proportion of stent dysfunction was significantly higher for uncovered stents (35.2% vs 23.4%, p=0.01) with significantly shorter time to stent dysfunction. This was mainly relevant for patients with extrinsic tumours (stent dysfunction rates for uncovered stents 35.6% vs 17.5%, p<0.01). Subgrouping was also relevant with respect to tumour ingrowth (lower with covered stents for intrinsic tumours; 1.6% vs 27.7%, p<0.01) and stent migration (higher with covered stents for extrinsic tumours: 15.3% vs 2.5%, p<0.01). CONCLUSIONS: Due to poor patient survival, minor differences between covered and uncovered stents may be less relevant even if statistically significant; however, subgroup analysis would suggest to use covered stents for intrinsic and uncovered stents for extrinsic malignancies.

Endoscopic ultrasonography findings of pancreatic parenchyma for predicting subtypes of intraductal papillary mucinous neoplasms.

BACKGROUND AND AIMS: The subtypes of intraductal papillary mucinous neoplasms (IPMNs) are closely associated with the clinicopathological behavior and recurrence after surgical resection. However, there are no established non-invasive methods to confirm the subtypes of IPMNs without surgery. The aim of this study is to predict the subtypes of IPMNs using the findings of endoscopic ultrasonography (EUS). METHODS: Sixty-two consecutive patients with IPMNs who underwent EUS before surgery were retrospectively reviewed. The following EUS findings were analyzed and their relationship with the subtypes was evaluated: diameter of the main pancreatic duct, cyst size, number of cysts, height of mural nodule, early chronic pancreatitis (CP) finding, fatty parenchyma and atrophic parenchyma. RESULTS: The subtypes of IPMNs were as follows: gastric (G)-type 38 (61%), intestinal (I) -type 14 (23%) and pancreatobiliary (PB) -type 10 (16%). Fatty parenchyma was significantly associated with G-type (P < 0.0001). Early CP findings ≥2 and atrophic parenchyma were significantly correlated with I-type (P < 0.0001). PB-type was significantly associated with pancreatic parenchyma without early CP findings or fatty degeneration in comparison to the other subtypes (P < 0.0001). Using the above characteristic EUS findings, the sensitivity, specificity, and accuracy were as follows: 63%, 92% and 74%, respectively, in G-type, 57%, 96% and 87% in I-type, and 90%, 94% and 94% in PB-type. CONCLUSIONS: The evaluation of EUS findings, especially focused on the pancreatic parenchyma, has the potential to predict the subtypes of IPMN.

Adverse events of endoscopic ultrasound-guided fine-needle aspiration for histologic diagnosis in Japanese tertiary centers: Multicenter retrospective study.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is used for the histopathological diagnosis of any type of gastrointestinal disease. Few adverse events are experienced with this procedure; however, the actual rate of adverse events remains unclear. This study aimed to clarify the current status of cases that experienced adverse events related to the EUS-FNA procedure used for histopathologic diagnoses. METHODS: A retrospective analysis of cases with EUS-FNA-related adverse events in Japanese tertiary centers was conducted by assessing the following clinical data: basic case information, FNA technique, type of procedural adverse events, and prognosis. RESULTS: Of the 13,566 EUS-FNA cases overall, the total number of cases in which adverse events related to EUS-FNA occurred was 234. The incidence of EUS-FNA-related adverse events was ~1.7%. Bleeding and pancreatitis cases accounted for ~49.1% and 26.5% of all adverse events, respectively. Bleeding was the most common adverse event with only seven cases requiring blood transfusion. In cases with neuroendocrine tumors, pancreatitis was the most frequent adverse event. Needle tract seeding because of EUS-FNA was observed during the follow-up period in only ~0.1% of cases with pancreatic cancer. There was no mortality because of adverse events caused by EUS-FNA. CONCLUSIONS: This study revealed that the adverse events-related EUS-FNA for histopathologic diagnoses were not severe conditions, and had low incidence.

New Model for Predicting Malignancy in Patients With Intraductal Papillary Mucinous Neoplasm.

OBJECTIVE: To create a simple, objective model to predict the presence of malignancy in patients with intraductal papillary mucinous neoplasm (IPMN), which can be easily applied in daily practice and, importantly, adopted for any lesion types. BACKGROUND: No predictive model for malignant IPMN has been widely applied in clinical practice. METHODS: The clinical details of 466 patients with IPMN who underwent pancreatic resection at 3 hospitals were retrospectively analyzed for model development. Then, the model was validated in 664 surgically resected patients at 8 hospitals in Japan.In the preoperative examination, endoscopic ultrasonography (EUS) was considered to be essential to observe mural nodules in both the model development and external validation sets. Malignant IPMNs were defined as those with high-grade dysplasia and associated invasive carcinoma. RESULTS: Of the 466 patients, 258 (55%) had malignant IPMNs (158 high-grade dysplasia, 100 invasive carcinoma), and 208 (45%) had benign IPMNs. Logistic regression analysis resulted in 3 variables (mural nodule size, main pancreatic duct diameter, and cyst size) being selected to construct the model. The area under the receiver operating characteristic curve (AUC) for the model was 0.763. In external validation sets, the pathological diagnosis was malignant and benign IPMN in 351 (53%) and 313 (47%) cases, respectively. For the external validation, the malignancy prediction ability of the model corresponded to an AUC of 0.725. CONCLUSION: This predictive model provides important information for physicians and patients in assessing an individual's risk for malignancy and may help to identify patients who need surgery.

Comparison of a 22-gauge Franseen-tip needle with a 20-gauge forward-bevel needle for the diagnosis of type 1 autoimmune pancreatitis: a prospective, randomized, controlled, multicenter study (COMPAS study).

BACKGROUND AND AIMS: Histologic diagnosis of autoimmune pancreatitis (AIP) using EUS-guided FNA (EUS-FNA) is difficult. To address this issue, new fine-needle biopsy (FNB) needles were recently developed. Here, we prospectively evaluated 2 newly designed EUS-FNB needles for histologic evaluation in patients with type 1 AIP. METHODS: This was a prospective, randomized, multicenter trial comparing biopsy specimens obtained with a 22-gauge Franseen needle or a 20-gauge forward-bevel needle in patients with suspected type 1 AIP. AIP was diagnosed according to international consensus diagnostic criteria. The primary endpoint was the sensitivity of EUS-FNB needles, and secondary endpoints were the amount of specimen obtained, histology of the pancreas based on evaluation of lymphoplasmacytic sclerosing pancreatitis (LPSP), and contribution of histologic findings to the diagnosis of AIP. RESULTS: One hundred ten patients were randomly assigned to the Franseen group (22-gauge Franseen needle) or the forward-bevel group (20-gauge forward-bevel needle). EUS-FNB sampling was successful in all patients. Nine patients were excluded because of diagnoses other than AIP. Compared with the forward-bevel needle, the Franseen needle obtained a significantly greater number of high-power fields. Of 101 patients, 39 patients (78%) in the Franseen group and 23 patients (45%) in the Forward-bevel group were diagnosed with level 1 or 2 LPSP (P = .001). Thirty-six patients could not be diagnosed with type 1 AIP without EUS-FNB specimen results. CONCLUSIONS: The 22-gauge Franseen needle should be routinely used for histologic diagnosis of type 1 AIP. (Clinical trial registration number: UMIN 000027668.).

Preoperative anthropomorphic and nutritious status and fistula risk score for predicting clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a life-threatening postoperative complication. The aim of this study was to evaluate the efficacy of the fistula risk score (FRS) and preoperative body composition factors for predicting the occurrence of clinically relevant POPF (CR-POPF) after pancreaticoduodenectomy (PD). METHODS: In this study, 136 consecutive patients who underwent PD between 2006 and 2018 were enrolled. The risk factors of CR-POPF (grades B and C) were analyzed. Preoperative visceral adipose tissue area (VATA), skeletal mass index (SMI), and subcutaneous adipose tissue area (SATA) were calculated from computed tomography data. RESULTS: The overall 30-day mortality and morbidity rates were 0.7 and 38%, respectively. The incidence rates of grade B and C CR-POPF were 27 and 4%, respectively. A univariate analysis revealed that male sex, habitual smoking, prognostic nutritional index (PNI) < 45, VATA ≥90, VATA/SATA ≥0.9, VATA/SMI ≥ 1.4, and FRS > 4 were significantly associated with the incidence of CR-POPF. A multivariate analysis revealed that PNI < 45, VATA/SMI ≥ 1.4 and FRS > 4 were the independent risk factors of CR-POPF. CONCLUSIONS: Preoperative anthropomorphic imbalance, PNI, and FRS were independent risk factors for CR-POPF. Patients with high-risk factors should be closely monitored during the postoperative period.

Identification of risk factors for open conversion from laparoscopic cholecystectomy for acute cholecystitis based on computed tomography findings.

PURPOSE: Laparoscopic cholecystectomy (LC) is performed widely for acute cholecystitis (AC). This study was conducted to identify the predictors for conversion cholecystectomy (CC) for AC. METHODS: The subjects of this study were 395 patients who underwent emergency surgery for AC between 2011 and 2019. Univariate and multivariate analyses were performed to establish the significance of the risk factors for CC in patients with grades II and III AC. RESULTS: There were 162 TG18 GII and GIII patients in the LC group and 31 in the CC group. Univariate analysis revealed significant differences in performance status (p = 0.039), C-reactive protein levels (p = 0.016), albumin levels (p = 0.002), gallbladder (GB) wall thickness (p = 0.045), poor contrast of the GB wall (p = 0.035), severe inflammation around the GB (p < 0.001), enhancement of the liver bed (p = 0.048), and duodenal edema (p < 0.001) between the groups. Multivariate analysis identified hypoalbuminemia (p = 0.043) and duodenal edema (p = 0.014) as independent risk factors for CC. CONCLUSIONS: Most patients with grade I AC underwent LC and had better surgical outcomes than those with grades II and III AC. The most appropriate surgical procedure should be selected based on preoperative imaging of the GB and the neighboring organs and by the presence of hypoalbuminemia.

Efficacy of the Gallbladder Cancer Predictive Risk Score Based on Pathological Findings: A Propensity Score-Matched Analysis.

BACKGROUND: The optimal prognostic predictive system for gallbladder carcinoma (GBC) has not been established. The gallbladder cancer predictive risk score (GBRS) based on pathological findings identifies incidental GBC patients at risk of recurrence. OBJECTIVE: We aimed to validate the prognostic ability of the GBRS in all GBC patients following curative surgery. METHODS: Fifty-six patients with GBC who underwent curative surgery between 1996 and 2016 were included in this study. Univariate and multivariate analyses were performed to determine prognostic factors associated with overall and recurrence-free survival, and propensity score-matched analysis was performed. RESULTS: The median patient age was 71.9 years, and 39.3% of patients were males. All patients underwent curative surgery (33.9%, simple cholecystectomy; 66.1%, more advanced procedures, such as hepatectomy; and 32.1%, bile duct reconstruction). On univariate analysis, preoperative carbohydrate antigen 19-9 (CA19-9) ≥ 37 U/mL (p = 0.042), postoperative complications (p = 0.043), and a high GBRS (p < 0.001) were prognostic factors for worse overall survival. On multivariate analysis, CA19-9 ≥ 37 U/mL (p = 0.039 and p = 0.043, respectively) and a high GBRS (p = 0.001 and p = 0.010, respectively) were independent risk factors for poor overall and recurrence-free survival. After propensity score-matched analysis, the GBRS precisely predicted prognosis of patients with GBC. CONCLUSIONS: The GBRS is an easy and novel prognostic predicting score. Our validation revealed good discrimination, suggesting its clinical utility to improve individualized prediction of survival for patients undergoing resection of GBC.

Multicenter study of early pancreatic cancer in Japan.

BACKGROUND/OBJECTIVES: The diagnosis of early-stage pancreatic ductal adenocarcinoma (PDAC) is still challenging. We conducted a multicenter study to clarify the clinical features of early-stage PDAC in Japan. METHODS: We collected patients with stage 0 and stage I PDAC according to the sixth edition of the Japanese Classification of Pancreatic Carcinoma. We retrospectively analyzed the clinical profiles including opportunities for medical examination, imaging modalities and findings, methods of cytological diagnosis, and prognosis according to the stages at diagnosis. RESULTS: Two hundred cases with Stage 0 and stage I PDAC were reported from 14 institutions, which accounted for approximately 0.7% and 3% of all PDAC cases, respectively. Overall, 20% of the early-stage PDAC cases were symptomatic. Indirect imaging findings such as dilatation of the main pancreatic duct were useful to detect early-stage PDAC. In particular, local fatty changes may be specific to early-stage PDAC. For preoperative pathologic diagnosis, cytology during endoscopic retrograde cholangiopancreatography was more commonly applied than endoscopic ultrasound fine-needle aspiration. Although the overall prognosis was favorable, new PDAC lesions developed in the remnant pancreas in 11.5% cases. CONCLUSIONS: This multicenter study revealed several key points concerning the diagnosis and management of early-stage PDAC, including screening of asymptomatic cases, importance of indirect imaging findings, application of cytology during endoscopic retrograde cholangiopancreatography, and the risk of carcinogenesis in the remnant pancreas.

Outcomes of endoscopic biliary drainage in pancreatic cancer patients with an indwelling gastroduodenal stent: a multicenter cohort study in West Japan.

BACKGROUND AND AIMS: Gastroduodenal and biliary obstruction may occur synchronously or asynchronously in advanced pancreatic cancer, and endoscopic double stent placement may be required. EUS-guided biliary drainage (EUS-BD) often is performed after unsuccessful placement of an endoscopic transpapillary stent (ETS), and EUS-BD may be beneficial in double stent placement. This retrospective multicenter cohort study compared the outcomes of ETS placement and EUS-BD in patients with an indwelling gastroduodenal stent (GDS). METHODS: We recorded the clinical outcomes of patients at 5 tertiary-care medical centers who required biliary drainage after GDS placement between March 2009 and March 2014. RESULTS: Thirty-nine patients were included in this study. Patients' mean age was 68.5 years; 23 (59.0%) were men. The GDS overlay the papilla in 23 patients (59.0%). The overall technical success rate was significantly higher with EUS-BD (95.2%) than with ETS placement (56.0%; P < .01). Furthermore, the technical success rate was significantly higher with EUS-BD (93.3%) than with ETS placement (22.2%; P < .01) when the GDS overlies the papilla. The overall clinical success rate of EUS-BD also was significantly higher than for ETS placement (90.5% vs 52.0%, respectively; P = .01), and there was no significant difference in the incidence of adverse events (ETS, 32.0% vs EUS-BD, 42.9%; P = .65). CONCLUSION: Endoscopic double stent placement with EUS-BD is technically and clinically superior to ETS placement in patients with an indwelling GDS. EUS-BD should be considered the first-line treatment option for patients with an indwelling GDS that overlies the papilla. ETS placement remains a reasonable alternative when the papilla is not covered by the GDS.

International study of endoscopic management of distal malignant biliary obstruction combined with duodenal obstruction.

OBJECTIVE: Endoscopic transpapillary or endoscopic ultrasound (EUS)-guided stent placement is used for nonresectable distal malignant biliary obstruction. We conducted a retrospective study to evaluate endoscopic biliary drainage in patients with duodenal obstruction. METHODS: We included consecutive patients who underwent endoscopic biliary drainage combined with a duodenal stent at 16 referral centers in four Asian countries. The primary outcome was time to recurrent biliary obstruction (TRBO). We assessed TRBO according to the sequence of biliary and duodenal obstruction (group 1/2/3, biliary obstruction first/concurrent/duodenal obstruction first, respectively) or the location of duodenal obstruction (type I/II/III, proximal to/affecting/distal to the ampulla, respectively). We also evaluated functional success and adverse events. RESULTS: We included 110 patients (group1/2/3, 67/29/14 patients; type I/II/III, 45/46/19 patients; endoscopic retrograde cholangiopancreatography [ERCP]/EUS-guided choledocoduodenostomy/EUS-guided hepaticogastrostomy, 90/10/10 patients, respectively). The median TRBO of all cases was 450 days (interquartile range, 212-666 days) and functional success was achieved in 105 cases (95%). The TRBO did not differ significantly by the timing or location of duodenal obstruction (p = .30 and .79, respectively). The TRBO of metal stents (n = 96) tended to be longer compared with plastic stents (n = 14, p = .083). Compared with ERCP, EUS-guided biliary drainage was associated with a higher rate of adverse events. CONCLUSION: Transpapillary or transmural endoscopic biliary drainage with a duodenal stent was effective, irrespective of the timing or location of duodenal obstruction. A prospective study is required considering the tradeoff of technical success rate, stent patency, and adverse events (ClinicalTrials.gov number, NCT02376907).

Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4.

High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A Prospective Multicenter Study of a Fully Covered Metal Stent in Patients with Distal Malignant Biliary Obstruction: WATCH-2 Study.

BACKGROUND: Both fully covered (FC) and partially covered (PC) self-expandable metal stents (SEMSs) are now commercially available for distal malignant biliary obstruction (MBO). While FCSEMS can be easily removed at the time of re-interventions, it is theoretically prone to migration. However, few comparative data between FC and PC SEMSs have been reported. AIMS: The aim of this study was to compare clinical outcomes of FCSEMS with those of PCSEMS. METHODS: This was a multicenter, prospective study of FCSEMS for unresectable distal MBO with a historical control of PCSEMS, which was previously reported as the WATCH study. The primary outcome was recurrent biliary obstruction (RBO), and secondary outcomes were stent migration, stent removal, stent-related adverse events, and survival. RESULTS: A total of 151 cases with unresectable distal MBO undergoing FCSEMS placement were enrolled and compared with a historical cohort of 141 cases undergoing PCSEMS placement. No significant differences were found in the rate of RBO (29 vs. 33%; P = 0.451), time to RBO (318 vs. 373 days; P = 0.382), and survival (229 vs. 196 days; P = 0.177) between FCSEMS and PCSEMS. The rate of stent migration also did not differ significantly between the two groups (14 vs. 8%; P = 0.113). The removal of FCSEMSs was successful in all 24 attempted cases (100%). CONCLUSIONS: FCSEMSs appeared comparable to PCSEMSs in terms of RBO without a significant increase in stent migration rate in patients with unresectable distal MBO. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000007131.