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Competing Interests: Declaration of Competing Interest Yousuke Nakai has received research grants by Taiho Pharmaceutical. No funding agency had input into the design and conduct of this study.

Objective: Current guidelines recommend long-term image-based surveillance for patients with low-risk intraductal papillary mucinous neoplasms (IPMNs). This simulation study aimed to examine the comparative cost-effectiveness of continued versus discontinued surveillance at different ages and define the optimal age to stop surveillance., Design: We constructed a Markov model with a lifetime horizon to simulate the clinical course of patients with IPMNs receiving imaging-based surveillance. We calculated incremental cost-effectiveness ratios (ICERs) for continued versus discontinued surveillance at different ages to stop surveillance, stratified by sex and IPMN types (branch-duct vs mixed-type). We determined the optimal age to stop surveillance as the lowest age at which the ICER exceeded the willingness-to-pay threshold of US$100 000 per quality-adjusted life year. To estimate model parameters, we used a clinical cohort of 3000 patients with IPMNs and a national database including 40 166 patients with pancreatic cancer receiving pancreatectomy as well as published data., Results: In male patients, the optimal age to stop surveillance was 76-78 years irrespective of the IPMN types, compared with 70, 73, 81, and 84 years for female patients with branch-duct IPMNs <20 mm, =20-29 mm, ≥30 mm and mixed-type IPMNs, respectively. The suggested ages became younger according to an increasing level of comorbidities. In cases with high comorbidity burden, the ICERs were above the willingness-to-pay threshold irrespective of sex and the size of branch-duct IPMNs., Conclusions: The cost-effectiveness of long-term IPMN surveillance depended on sex, IPMN types, and comorbidity levels, suggesting the potential to personalise patient management from the health economic perspective., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Trajectories of serological and morphological signatures have not been documented in pancreatic carcinogenesis related to intraductal papillary mucinous neoplasms (IPMNs)., Methods: Using a prospective cohort of 3437 IPMN patients, we identified 100 IPMN patients who developed pancreatic carcinomas during long-term surveillance. We examined serial changes of blood markers (carbohydrate antigen 19-9 [CA19-9], hemoglobin A1c [HbA1c], and pancreatic enzymes) and morphological features (worrisome features and high-risk stigmata) during the prediagnostic period of pancreatic carcinomas, overall and by carcinoma types (IPMN-derived vs. concomitant pancreatic carcinomas)., Results: CA19-9 elevation was observed in 39 patients and was associated with a metastatic stage. Compared to IPMN-derived carcinomas, concomitant carcinomas were more likely to represent CA19-9 elevation (60% vs. 30%, respectively; P = 0.005). HbA1c levels elevated only in 3 patients. Pancreatic enzyme elevation was observed in 18 patients with no differences in frequencies between the carcinoma types. All patients with elevated levels of blood markers had positive findings on cross-sectional imaging. High-risk stigmata or worrisome features were observed in all patients but one with concomitant carcinoma. The most common types of worrisome features were the main pancreatic duct dilatation and CA19-9 elevation in IPMN-derived and concomitant carcinomas, respectively. Compared to IPMN-derived carcinomas, concomitant carcinomas were less likely to harbor high-risk stigmata (16% vs. 86%, respectively; P < 0.001)., Conclusions: The usefulness of currently available blood biomarkers was limited in early detection of pancreatic carcinomas related to IPMNs. Morphological alterations were well correlated with long-term risk of IPMN-derived carcinomas, but not with that of concomitant carcinomas., (© 2023. The Author(s).)

Background: Abundant collagen deposition is a hallmark of pancreatic ductal adenocarcinomas (PDACs). This study clarified the interactive relationship between tumor-stromal collagen, molecular and immune characteristics, and tumor pr ogression in human PDAC., Methods: We performed a comprehensive examination using an integrative molecular pathological epidemiology database on 169 cases with resected PDAC . The amount of tumor-stromal collagen was quantified through digital imaging analysis for Elastica van Gieson-stained whole-section tumor slides. We analyzed the association of tumor-stromal collagen with gene alterations (KRAS, TP53, CDKN2A/p16, and SMAD4), immune parameters (CD4 + tumor-infiltrating lymphocytes [TILs], CD8 + TILs, FOXP3 + TILs, and tertiary lymphoid structures), and patient prognosis., Results: Low amounts of tumor-stromal collagen were associated with poor differentiation (multivariable OR = 3.82, 95%CI = 1.41-12.2, P = 0.008) and CDKN2A/p16 alteration (OR [95%CI] = 2.06 [1.08-4.02], P = 0.03). Tumors with low collagen levels had shorter overall survival (HR [95%CI] = 2.38 [1.59-3.56], P < 0.0001). In the S-1 and gemcitabine (GEM) treatment groups, low tumor-stromal collagen was linked to poor prognosis of patients with PDAC (S-1 group: multivariable HR [95%CI] = 2.76 [1.36-5.79], P = 0.005; GEM group: multivariate HR [95%CI] = 2.91 [1.34-6.71], P = 0.007). Additionally, low amounts of tumor-stromal collagen were also linked to low levels of CD4 + TILs (P = 0.046), CD8 + TILs (P = 0.09), and tertiary lymphoid structures (P = 0.001)., Conclusions: Tumor-stromal collagen deposition may play a crucial role in modulating tumor-immune microenvironment and determining response to adjuvant chemotherapy and patient survival outcomes., (© 2023. The Author(s).)

Alterations in KRAS, CDKN2A (p16), TP53, and SMAD4 genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of KRAS mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post-operative survival outcomes. To test this hypothesis, we utilised a multi-institutional cohort of 1,146 resected pancreatic carcinomas and assessed KRAS mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09-1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10-1.46). Compared to cases with 0-2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09-1.51) and 1.47 (95% CI, 1.22-1.78), respectively (p trend  < 0.001). Patients with an increasing number of altered genes were more likely to have short DFS time (p trend  = 0.003) and to develop liver metastasis (p trend  = 0.006) rather than recurrence at local or other distant sites. In conclusion, loss of SMAD4 expression and an increasing number of altered genes were associated with unfavourable outcomes in pancreatic cancer patients. This study suggests that the accumulation of the four major driver alterations can confer a high metastatic potential to the liver, thereby impairing post-operative survival among patients with pancreatic cancer., (© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Background & Aims: Dilatation of the main pancreatic duct (MPD) has been a surgical indication for intraductal papillary mucinous neoplasms (IPMNs). Few studies have investigated long-term outcomes of IPMNs with MPD dilatation., Methods: Among 3610 patients diagnosed with pancreatic cysts between 1994 and 2021, we identified 2829 IPMN patients, including 282 patients with MPD ≥5 mm, and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma. Utilizing competing risks proportional hazards models, we estimated subdistribution hazard ratios for incidence of pancreatic carcinoma with adjustment for potential confounders., Results: In analyses of short-term outcomes of the 282 patients with MPD dilatation, 72 (26%) patients were diagnosed with pancreatic carcinoma based on surgical or nonsurgical exploration. During long-term follow-up of 168 patients, we documented 24 (14%) patients diagnosed with pancreatic carcinoma (18 with IPMN-derived carcinoma and 6 with concomitant ductal adenocarcinoma). The patients with the MPD = 5-9.9 mm had cumulative incidence rates of pancreatic carcinoma diagnosis of 8.1% (95% confidence interval [CI], 4.3%-13.5%) and 10.0% (95% CI, 5.5%-15.9%) at 2 and 5 years, respectively; and the patients with the MPD ≥10 mm had the corresponding rates of 16.0% (95% CI, 3.6-36.5%) and 33.3% (95% CI, 10.3%-58.8%). The multivariable subdistribution hazard ratios were 2.78 (95% CI, 1.57-4.90) and 7.00 (95% CI, 2.58-19.0) for the MPD = 5-9.9 mm and ≥10 mm (vs <5 mm), respectively., Conclusions: IPMNs with MPD dilatation at baseline were associated with higher prevalence and incidence of pancreatic carcinoma compared with IPMNs with no MPD dilatation., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Pathological examination by endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has been reported to be useful in diagnosing pancreatic malignant lymphoma (ML), but some ML cases are difficult to be differentiated from pancreatic ductal adenocarcinoma (PDAC)., Methods: This retrospective study included 8 patients diagnosed with ML that had a pancreatic-head lesion at initial diagnosis and 46 patients with resected PDAC in the pancreatic head between April 2006 and October 2021 at our institute. ML and PDAC were compared in terms of patients' clinical features and imaging examinations., Results: The median tumor size was larger in ML than in PDAC (45.8 [24-64] vs. 23.9 [8-44] mm), but the median diameter of the caudal main pancreatic duct (MPD) was larger in PDAC (2.5 [1.0-3.5] vs. 7.1 [2.5-11.8] mm), both showing significant differences between these malignancies (both, P < 0.001). In the analysis of covariance, MLs showed a smaller caudal MPD per tumor size than PDACs, with a statistical difference (P = 0.042). Sensitivity and specificity using sIL-2R ≥ 658 U/mL plus CA19-9 < 37 U/mL for the differentiation of ML from PDAC were 80.0% and 95.6%, respectively., Conclusions: Diagnosing pancreatic ML using cytohistological examination through EUS-FNA can be difficult in some cases. Thus, ML should be suspected if a patient with a pancreatic tumor has a small MPD diameter per tumor size, high serum sIL-2R level, normal CA19-9 level. If the abovementioned features are present and still cannot be confirmed as PDAC, re-examination should be considered., (© 2023. The Author(s).)

Rationale: Recently, the incidence of polyoncosis has been increasing due to advancements in treatment, such as antitumor therapy, which led to a prolonged survival. However, few patients with metastatic pancreatic ductal adenocarcinoma (PDAC) develop second tumors, which render a poor prognosis. We report a rare case of PDAC, which is metachronous with a fatal malignant lymphoma (ML)., Patient Concerns: A 68-year-old woman who had been monitored due to liver cirrhosis secondary to hepatitis C virus infection presented with a 10-mm pancreatic head cancer with lung metastasis and had started an anticancer therapy with gemcitabine. Approximately 18 months after diagnosis, lymphadenopathies around the pancreas were noted, which eventually spread to the entire body over time., Diagnosis: Diffuse large B-cell lymphoma was diagnosed using biopsies from cervical lymph nodes., Interventions and Outcomes: The patient started a gemcitabine + rituximab regimen; however, the patient died from cachexia-associated lymphoma progression, not PDAC., Lessons: ML should be considered when intra-abdominal lymphadenopathies are detected in patients with pancreatic cancer, and ML should be differentiated from lymph node metastasis of pancreatic cancer., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Patients with pancreatic cancer often have cancer cachexia at diagnosis. Recent studies suggested that loss of skeletal muscle mass was related to cancer cachexia, which hindered continuance of chemotherapy and could be one of prognostic factors in pancreatic cancer, however the association remains unclear in patients receiving gemcitabine and nab-paclitaxel (GnP)., Methods: We retrospectively studied 138 patients with unresectable pancreatic cancer receiving first-line GnP at the University of Tokyo from January 2015 to September 2020. We calculated body composition in CT images before chemotherapy and at initial evaluation, and evaluated the association of both body composition before chemotherapy and its changes at initial evaluation., Results: Compared by skeletal muscle mass index (SMI) change rate between pre-chemotherapy and initial evaluation, there were statistically significantly differences in the median OS: 16.3 months (95%CI 12.3-22.7) and 10.3 months (95%CI 8.3-18.1) between SMI change rate ≥ -3.5% and < -3.5% groups (P = 0.01). By multivariate analysis for OS, CA19-9 (HR 3.34, 95%CI 2.00-5.57, P < 0.01), PLR (HR 1.68, 95%CI 1.01-2.78, P = 0.04), mGPS (HR 2.32, 95%CI 1.47-3.65, P < 0.01) and relative dose intensity (HR 2.21, 95%CI 1.42-3.46, P < 0.01) were significantly poor prognostic factors. SMI change rate (HR 1.47, 95%CI 0.95-2.28, P = 0.08) showed a trend to poor prognosis. Sarcopenia before chemotherapy was not significantly associated with PFS or OS., Conclusion: Early skeletal muscle mass decline was associated with poor OS. Further investigation is warranted whether the maintenance of skeletal muscle mass by nutritional support would improve prognosis., (© 2023. The Author(s).)

Background: Tertiary lymphoid structure (TLS) reflects an intense immune response against cancer, which correlates with favorable patient survival. However, the association of TLS with tumor-infiltrating lymphocytes (TILs) and clinical outcomes has not been investigated comprehensively in pancreatic ductal adenocarcinoma (PDAC)., Methods: We utilized an integrative molecular pathological epidemiology database on 162 cases with resected PDAC, and examined TLS in relation to levels of TILs, patient survival, and treatment response. In whole-section slides, we assessed the formation of TLS and conducted immunohistochemistry for tumor-infiltrating T cells (CD4, CD8, CD45RO, and FOXP3). As confounding factors, we assessed alterations of four main driver genes (KRAS, TP53, CDKN2A [p16], and SMAD4) using next-generation sequencing and immunohistochemistry, and tumor CD274 (PD-L1) expression assessed by immunohistochemistry., Results: TLSs were found in 112 patients with PDAC (69.1%). TLS was associated with high levels of CD4 + TILs (multivariable odds ratio [OR], 3.50; 95% confidence interval [CI] 1.65-7.80; P = 0.0002), CD8 + TILs (multivariable OR, 11.0; 95% CI 4.57-29.7, P < 0.0001) and CD45RO + TILs (multivariable OR, 2.65; 95% CI 1.25-5.80, P = 0.01), but not with levels of FOXP3 + TILs. TLS was associated with longer pancreatic cancer-specific survival (multivariable hazard ratio, 0.37; 95% CI 0.25-0.56, P < 0.0001) and favorable outcomes of adjuvant S-1-treatment. TLS was not associated with driver gene alterations but tumor CD274 negative expression., Conclusions: Our comprehensive data supports the surrogacy of TLS for vigorous anti-tumor immune response characterized by high levels of helper and cytotoxic T cells and their prognostic role., (© 2023. Japanese Society of Gastroenterology.)

Multiple cancer patients who achieve long-term survival are sometimes encountered. Multiple carcinogenesis may occur due to genetic or environmental characteristics. We report the case of a 74-year-old woman who was diagnosed with synchronous double carcinoma of the duodenal papilla and gall bladder without clinical symptoms, who underwent postoperative follow-up for familiar adenomatous polyposis coli with multiple colonic adenocarcinomas, ileal adenocarcinoma, left urinary tract neoplasm, and left upper lobe lung adenocarcinoma. Computed tomography also showed an intraductal papillary mucinous neoplasm of the pancreas and a lesion that was suspected to be uterine body carcinoma; however, they did not show any clear malignant behavior. No metastatic lesions of either of these biliary cancers were observed. Based on preoperative diagnostic imaging, subtotal stomach preserving pancreaticoduodenectomy with gall bladder bed liver resection with D2 lymphadenectomy was planned and R0 resection was achieved. The postoperative histological diagnosis showed early carcinoma of the duodenal papilla and gall bladder pyloric gland adenoma without node metastasis. The postoperative course was uneventful and the patient had a good prognosis without tumor recurrence or new malignant lesions for two years after the last operation, without adjuvant therapy. Six metachronous carcinomas of eight different organ neoplasms were diagnosed, which is rare. This represents the first reported case of ampullary carcinoma in a patient with sextuple cancer., (© 2022. Japanese Society of Gastroenterology.)

Background: As liquid-based cytology (LBC) specimens preserve high-quality DNA, clinical sequencing of LBC specimens using next-generation sequencing (NGS) is becoming a common strategy. This study aimed to evaluate the feasibility of NGS-based custom-made panels for evaluating MUC promoter methylation in LBC specimens., Methods: Thirty-one patients with pancreatic cancer were enrolled in the study. Cancer tissue samples were obtained using endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB). LBC, formalin-fixed paraffin-embedded (FFPE), and fresh frozen specimens were prepared for DNA extraction after pathological diagnosis. These specimens were then subjected to NGS analysis using custom-made cancer gene screening and methylation panels comprising 28 cancer-related genes and 13 gene promoter regions, including MUC1, MUC2, and MUC4., Results: The success rate of NGS using the cancer gene panel was comparable among the LBC, FFPE, and frozen specimens, and the presence of cancer cell-derived somatic mutations in each specimen was confirmed. The specimens were then tested using a methylation panel that revealed the sequential methylation status of CpG islands located in the promoter regions of MUC genes. The methylation status results obtained from LBC specimens were almost comparable with those from FFPE and frozen specimens., Conclusions: MUC and other gene methylation analyses using an NGS-based panel were successfully performed in residual LBC specimens obtained by EUS-FNA/FNB. Therefore, this approach provides an alternative source of molecular tests for gene mutations and methylation, especially in the pancreatic cancers, which are often unresectable and unsuitable for obtaining FFPE specimens., (© 2022 Wiley Periodicals LLC.)

KRAS mutation is a major driver of pancreatic carcinogenesis and will likely be a therapeutic target. Due to lack of sensitive assays for clinical samples of pancreatic cancer with low cellularity, KRAS mutations and their prognostic association have not been fully examined in large populations. In a multi-institutional cohort of 1162 pancreatic cancer patients with formalin-fixed paraffin-embedded tumor samples, we undertook droplet digital PCR (ddPCR) for KRAS codons 12/13/61. We examined detection rates of KRAS mutations by clinicopathological parameters and survival associations of KRAS mutation status. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed using the Cox regression model with adjustment for potential confounders. KRAS mutations were detected in 1139 (98%) patients. The detection rate did not differ by age of tissue blocks, tumor cellularity, or receipt of neoadjuvant chemotherapy. KRAS mutations were not associated with DFS or OS (multivariable HR comparing KRAS-mutant to KRAS-wild-type tumors, 1.04 [95% CI, 0.62-1.75] and 1.05 [95% CI, 0.60-1.84], respectively). Among KRAS-mutant tumors, KRAS variant allele frequency (VAF) was inversely associated with DFS and OS with HRs per 20% VAF increase of 1.27 (95% CI, 1.13-1.42; p trend  <0.001) and 1.31 (95% CI, 1.16-1.48; p trend  <0.001), respectively. In summary, ddPCR detected KRAS mutations in clinical specimens of pancreatic cancer with high sensitivity irrespective of parameters potentially affecting mutation detections. KRAS VAF, but not mutation positivity, was associated with survival of pancreatic cancer patients., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Although adjuvant chemotherapy (AC) with S-1 is currently the standard treatment for pancreatic ductal adenocarcinoma (PDAC) in Japan, the associations between its relative dose intensity (RDI) and survival outcomes remain unclear., Patients and Methods: We reviewed 310 patients with PDAC who had undergone pancreatectomy from January 2014 to June 2020 at three institutions. Of these, patients who had received adjuvant S-1 monotherapy were analyzed. Patients who had died or developed recurrences within 6 months, or received neoadjuvant chemotherapy, were excluded from the analyses. Possible predictors of overall survival (OS), including RDI, were analyzed using Cox regression. The cutoff value for RDI was determined by receiver operating characteristic analysis., Results: Ninety-four patients with a median age of 69 years (range=39-84 years) were analyzed. In the high-RDI group (RDI≥72.3%, n=74), the OS rates were 98.5% and 80.8% at 1 and 3 years, respectively, whereas in the low-RDI group (RDI <72.3%, n=20) they were 88.9% and 51.6%, respectively (p=0.001). By multivariate analysis, lymph node metastasis [hazard ratio (HR)=3.06; p=0.020], low RDI (HR=2.95; p=0.020), and time interval from surgery to initiation of AC > 51 days (HR=2.50; p=0.046) were independently associated with inferior OS. The combination of the latter two factors clearly stratified both OS and recurrence-free survival (p<0.001 and p=0.017, respectively)., Conclusion: Early initiation and maintenance of RDI of S-1 monotherapy after pancreatectomy may improve the OS of PDAC patients., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The microbial population of the intestinal tract and its relationship to specific diseases has been extensively studied during the past decade. However, reports characterizing the bile microbiota are rare. This study aims to investigate the microbiota composition in patients with pancreaticobiliary cancers and benign diseases by 16S rRNA gene amplicon sequencing and to evaluate its potential value as a biomarker for the cancer of the bile duct, pancreas, and gallbladder., Results: We enrolled patients who were diagnosed with cancer, cystic lesions, and inflammation of the pancreaticobiliary tract. The study cohort comprised 244 patients. We extracted microbiome-derived DNA from the bile juice in surgically resected gallbladders. The microbiome composition was not significantly different according to lesion position and cancer type in terms of alpha and beta diversity. We found a significant difference in the relative abundance of Campylobacter, Citrobacter, Leptotrichia, Enterobacter, Hungatella, Mycolicibacterium, Phyllobacterium and Sphingomonas between patients without and with lymph node metastasis., Conclusions: There was a significant association between the relative abundance of certain microbes and overall survival prognosis. These microbes showed association with good prognosis in cholangiocarcinoma, but with poor prognosis in pancreatic adenocarcinoma, and vice versa. Our findings suggest that pancreaticobiliary tract cancer patients have an altered microbiome composition, which might be a biomarker for distinguishing malignancy., (© 2022. The Author(s).)

Background/aims: Endoscopic ultrasound (EUS)-guided tissue acquisition is widely utilized as a diagnostic modality for intra-abdominal masses, but there remains debate regarding which suction technique, slow pull (SP) or conventional suction (CS), is better. A meta-analysis of reported studies was conducted to compare the diagnostic yields of SP and CS during EUS-guided tissue acquisition., Methods: We conducted a systematic electronic search using MEDLINE/PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials to identify clinical studies comparing SP and CS. We meta-analyzed accuracy, sensitivity, blood contamination and cellularity using the random-effects model., Results: A total of 17 studies (seven randomized controlled trials, four prospective studies, and six retrospective studies) with 1,616 cases were included in the analysis. Compared to CS, there was a trend toward better accuracy (odds ratio [OR], 1.48; 95% confidence interval [CI], 0.97 to 2.27; p=0.07) and sensitivity (OR, 1.67; 95% CI, 0.95 to 2.93; p=0.08) with SP and a significantly lower rate of blood contamination (OR, 0.48; 95% CI, 0.33 to 0.69; p<0.01). However, there was no significant difference in cellularity between SP and CS, with an OR of 1.28 (95% CI, 0.68 to 2.40; p=0.45). When the use of a 25-gauge needle was analyzed, the accuracy and sensitivity of SP were significantly better than those of CS, with ORs of 4.81 (95% CI, 1.99 to 11.62; p<0.01) and 4.69 (95% CI, 1.93 to 11.40; p<0.01), respectively., Conclusions: Compared to CS, SP appears to provide better accuracy and sensitivity in EUSguided tissue acquisition, especially when a 25-gauge needle is used.

Background: ABO blood group has been associated with risks of various malignancies, including pancreatic cancer. No study has evaluated the association of ABO blood group with incidence of pancreatic carcinogenesis during follow-up of patients with intraductal papillary mucinous neoplasms (IPMN)., Methods: Among 3,164 patients diagnosed with pancreatic cysts at the University of Tokyo (Tokyo, Japan) from 1994 through 2019, we identified 1,815 patients with IPMN with available data on ABO blood group. We studied the association of ABO blood group with incidence of pancreatic carcinoma, overall and by carcinoma types [IPMN-derived carcinoma or concomitant pancreatic ductal adenocarcinoma (PDAC)]. Utilizing competing-risks proportional hazards models, we estimated subdistribution hazard ratios (SHR) for incidence of pancreatic carcinoma with adjustment for potential confounders, including cyst characteristics., Results: During 11,518 person-years of follow-up, we identified 97 patients diagnosed with pancreatic carcinoma (53 with IPMN-derived carcinoma and 44 with concomitant PDAC). Compared with patients with blood group O, patients with blood groups A, B, and AB had multivariable SHRs (95% confidence intervals) for pancreatic carcinoma of 2.25 (1.25-4.07; P = 0.007), 2.09 (1.08-4.05; P = 0.028), and 1.17 (0.43-3.19; P = 0.76), respectively. We observed no differential association of ABO blood group with pancreatic carcinoma incidence by carcinoma types., Conclusions: In this large long-term study, patients with IPMN with blood group A or B appeared to be at higher risk of pancreatic carcinoma compared with those with blood group O., Impact: ABO blood group can be a biomarker for pancreatic cancer risk among patients with IPMNs., (©2021 American Association for Cancer Research.)

Background: Intraductal tubulopapillary neoplasm (ITPN) of the pancreas is a new disease concept defined by the World Health Organization in 2010. ITPN progresses with tubulopapillary growth in the pancreatic duct and is known to have a fair prognosis. Localization in the main pancreatic duct (MPD) is one characteristic. There are few case reports of ITPN in a branch of the pancreatic duct (BD)., Case Presentation: We encountered a case of ITPN localized in BD. An 85-year-old man was followed after colonic surgery for rectal carcinoma. An abdominal computed tomography scan revealed a cystic mass in the pancreatic head and further examination was done. A T2 weighted intension picture in magnetic resonance imaging showed a 20 mm cystic lesion with an internal mass of 15 mm. Duodenal papilla were slightly open and endoscopic retrograde pancreatography revealed mild and diffuse dilatation of the main pancreatic duct and mucin in the MPD. In consideration with the image examinations, we diagnosed the tumor as an intraductal papillary mucinous neoplasm with carcinoma because of its large mural nodule (> 10 mm in size) in a cyst. Consequently, a pancreaticoduodenectomy was performed. Macroscopically, a white solid tumor sized 2.5 × 1.8 × 1.0 was identified in the head of the pancreas. The cut surface of the resected pancreas showed a side-branch type intraductal tumor with tubulopapillary architecture without mucin secretion. Immunohistochemical staining was positive for MUC1, and negative for MUC2 and MUC5AC. The final diagnosis was determined to be pancreatic ITPN from BD. At the time of this report (48 months post-surgery), the patient remains disease-free without evidence of recurrence., Conclusion: ITPNs localized in BD are rare and diagnosis prior to surgery is difficult. In our case, the shape was round, not papillary, and with little fluid. These characteristics are different from a branch duct type IPMN and can be a clue to suspect ITPN in BD.

Purpose: The aim of this study was to evaluate the efficacy and tolerability of S-IROX and modified FOLFIRINOX (mFFX) after gemcitabine plus nab-paclitaxel for advanced pancreatic cancer (PC) in the real world setting., Methods: Consecutive patients receiving S-IROX or mFFX as a second-line chemotherapy for advanced PC refractory to gemcitabine plus nab-paclitaxel were retrospectively studied. Patients were treated every 2 weeks: S-1 40 mg/m 2 was administered orally twice daily on days 1 to 7 in S-IROX and 5-fluorouracil 2400 mg/m 2 was intravenously administered for 46 h without bolus infusion in mFFX, in addition to intravenous oxaliplatin 85 mg/m 2 and irinotecan 150 mg/m 2 on day 1 in both regimens., Results: Fifty-four patients with advanced PC who received S-IROX (n = 19) or mFFX (n = 35) were retrospectively studied. The disease control rate and response rate were 73.7% and 10.5% in the S-IROX group and 62.2% and 2.7% in the mFFX group, respectively. The median progression free survival (PFS) was 7.8 and 5.7 months in the S-IROX and mFFX groups (p = 0.24). The median overall survival (OS) was 14.2 and 11.5 months in the S-IROX and mFFX groups (p = 0.34). There were no significant differences in the incidences of grade 3-4 adverse effects. The subgroup analyses suggested S-IROX demonstrated favorable OS in patients with PFS ≥6 months of first-line gemcitabine plus nab-paclitaxel (p for interaction = 0.02)., Conclusions: S-IROX and mFFX were similarly tolerable and effective as a second-line chemotherapy in patients with PC refractory to gemcitabine plus nab-paclitaxel.

Purpose: A phase I study of intraperitoneal paclitaxel (ip PTX) combined with gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) (GnP) was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in pancreatic cancer patients with peritoneal metastasis in first-line setting., Methods: Based on the 3 + 3 dose-escalation model, ip PTX, GEM and nab-PTX were administered at doses of 20 or 30 mg/m 2 , 800 or 1000 mg/m 2 and 100 or 125 mg/m 2 (level 1, 2 and 3, respectively) on days 1, 8 and 15 in 4-week cycles. Dose-limiting toxicity (DLT) defined as severe adverse events was evaluated during the first cycle of the treatment. Safety and preliminary efficacy were also investigated., Results: In total, 12 patients were enrolled. While 2 of the first 6 patients enrolled at level 1 experienced DLTs (grade 3 ip port dysfunction and grade 3 pneumonia), no DLT was observed in the next 6 patients enrolled at level 2 and 3. Therefore, we did not reach the MTD and the RD was determined to be level 3 (ip PTX of 30 mg/m 2 , GEM of 1000 mg/m 2 , and nab-PTX of 125 mg/m 2 ). The major grade 3/4 adverse events included neutropenia (58%), anemia (33%), and ip port dysfunction (25%). The response rate was 25% and the median PFS was 5.4 (95% confidence interval; 2.4-16.0). The cytological status in peritoneal lavage turned negative in 8 patients (67%)., Conclusions: Ip PTX combined with GnP was feasible and potentially effective in pancreatic cancer with peritoneal metastasis as a first-line treatment deserved further evaluations.

Background: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes., Methods: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors., Results: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; P trend = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; P trend = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m 2 (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; P interaction = 0.032). KRAS -mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in IGF1R were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, P < 0.001)., Conclusions: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC., Impact: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting., (©2020 American Association for Cancer Research.)

Purpose: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable prognostic factor in pancreatic neoplasia. This study investigates whether the methylation status of three mucin genes from postoperative tissue specimens from patients with pancreatic neoplasms could serve as a predictive biomarker for outcome after surgery., Experimental Design: We evaluated the methylation status of MUC1, MUC2, and MUC4 promoter regions in pancreatic tissue samples from 191 patients with various pancreatic lesions using methylation-specific electrophoresis. Then, integrating these results and clinicopathologic features, we used support vector machine-, neural network-, and multinomial-based methods to develop a prognostic classifier., Results: Significant differences were identified between the positive- and negative-prediction classifiers of patients in 5-year overall survival (OS) in the cross-validation test. Multivariate analysis revealed that these prognostic classifiers were independent prognostic factors analyzed by not only neoplastic tissues but also nonneoplastic tissues. These classifiers had higher predictive accuracy for OS than tumor size, lymph node metastasis, distant metastasis, and age and can complement the prognostic value of the TNM staging system., Conclusions: Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with pancreatic ductal adenocarcinoma., (©2020 American Association for Cancer Research.)

BACKGROUND Myoepithelioma is a rare neoplasm that differentiates toward myoepithelial cells. This condition mainly occurs in the salivary gland and rarely in the  soft tissue or internal organs. Long-term survival with repeated multiple rounds of resection for recurrence is rarely reported. CASE REPORT A 69-year-old man was diagnosed with metachronous pancreatic and thyroid metastases from myoepithelioma, which initially originated from a resected soft-tissue lesion in the left clavicular region in 2007. In addition, a locally recurrent lesion was resected and the patient received brachytherapy in 2015. Moreover, a metachronous metastatic lesion in the right lung was resected in 2017. Histopathological examination confirmed that all lesions were myoepithelioma. In the present case, pancreatoduodenectomy and right hemithyroidectomy for both metastatic lesions were successfully performed. Histopathology revealed small round-to-spindle-shaped tumor cells with atypia, proliferating in reticular formation, accompanied by myxoid stroma with chondromyxoid and hyalinized stroma, and the histology was similar to that observed in the previous specimen. Immunohistochemistry revealed positivity for cytokeratin (AE1/AE3), glial fibrillary acidic protein, vimentin, and S-100, and confirmed the diagnosis of myoepithelioma. To the best of our knowledge, this is the first study presenting a long-term survivor of soft-tissue myoepithelioma who underwent repeated multiple rounds of resection for recurrence in various organs. CONCLUSIONS We reported the case of a long-term survivor of soft-tissue myoepithelioma requiring multiple rounds of surgical resection for local recurrence and metachronous metastases in the lung, pancreas, and thyroid. When managed appropriately, some patients might benefit in terms of survival from repeated resection of recurrent lesions.

Background & Aims: Long-term outcomes of patients with branch-duct intraductal papillary mucinous neoplasms (IPMNs), particularly those after 5 years of surveillance, have not been fully evaluated in large studies. We analyzed incidences of IPMN-derived carcinoma and concomitant ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]) over 20 years in a large population of patients., Methods: We identified 1404 consecutive patients (52% women; mean age, 67.5 years) with a diagnosis of branch-duct IPMN, from 1994 through 2017, at the University of Tokyo in Japan. Using a competing risk analysis, we estimated cumulative incidence of pancreatic carcinoma, overall and by carcinoma type. We used competing risks proportional hazards models to estimate subdistribution hazard ratios (SHRs) for incidences of carcinomas. To differentiate IPMN-derived and concomitant carcinomas, we collected genomic DNA from available paired samples of IPMNs and carcinomas and detected mutations in GNAS and KRAS by polymerase chain reaction and pyrosequencing., Results: During 9231 person-years of follow-up, we identified 68 patients with pancreatic carcinomas (38 patients with IPMN-derived carcinomas and 30 patients with concomitant PDACs); the overall incidence rates were 3.3%, 6.6%, and 15.0% at 5, 10, and 15 years, respectively. Among 804 patients followed more than 5 years, overall cumulative incidence rates of pancreatic carcinoma were 3.5% at 10 years and 12.0% at 15 years from the initial diagnosis. The size of the IPMN and the diameter of the main pancreatic duct associated with incidence of IPMN-derived carcinoma (SHR 1.85; 95% confidence interval 1.38-2.48 for a 10-mm increase in the IPMN size and SHR 1.56; 95% confidence interval 1.33-1.83 for a 1-mm increase in the main pancreatic duct diameter) but not with incidence of concomitant PDAC., Conclusions: In a large long-term study of patients with branch-duct IPMNs, we found the 5-year incidence rate of pancreatic malignancy to be 3.3%, reaching 15.0% at 15 years after IPMN diagnosis. We observed heterogeneous risk factor profiles between IPMN-derived and concomitant carcinomas., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Leukocyte telomere length has been associated with risk of subsequent pancreatic cancer. Few prospective studies have evaluated the association of prediagnostic leukocyte telomere length with pancreatic cancer survival., Methods: We prospectively examined the association of prediagnostic leukocyte telomere length with overall survival (OS) time among 423 participants diagnosed with pancreatic adenocarcinoma between 1984 and 2008 within the Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, and Women's Health Initiative. We measured prediagnostic leukocyte telomere length in banked blood samples using quantitative PCR. Cox proportional hazards models were used to estimate HRs for OS with adjustment for potential confounders. We also evaluated 10 SNPs at the telomerase reverse transcriptase locus., Results: Shorter prediagnostic leukocyte telomere length was associated with reduced OS among patients with pancreatic cancer ( P trend = 0.04). The multivariable-adjusted HR for OS comparing the lowest with highest quintiles of leukocyte telomere length was 1.39 (95% confidence interval, 1.01-1.93), corresponding to a 3-month difference in median OS time. In an analysis excluding cases with blood collected within 2 years of cancer diagnosis, the association was moderately stronger (HR, 1.55; 95% confidence interval, 1.09-2.21; comparing the lowest with highest quintiles; P trend = 0.01). No prognostic association or effect modification for the prognostic association of prediagnostic leukocyte telomere length was noted in relation to the studied SNPs., Conclusions: Prediagnostic leukocyte telomere length was associated with pancreatic cancer survival., Impact: Prediagnostic leukocyte telomere length can be a prognostic biomarker in pancreatic cancer., (©2019 American Association for Cancer Research.)

Background: Individuals with a family history of cancer may be at increased risk of pancreatic cancer. Ashkenazi Jewish (AJ) individuals carry increased risk for pancreatic cancer and other cancer types., Methods: We examined the association between family history of cancer, AJ heritage, and incident pancreatic cancer in 49 410 male participants of the prospective Health Professionals Follow-up Study. Hazard ratios (HRs) were estimated using multivariable-adjusted Cox proportional hazards models., Results: During 1.1 million person-years (1986-2016), 452 participants developed pancreatic cancer. Increased risk of pancreatic cancer was observed in individuals with a family history of pancreatic (HR, 2.79; 95% confidence interval [CI], 1.28-6.07) or breast cancer (HR, 1.40; 95% CI, 1.01-1.94). There was a trend towards higher risk of pancreatic cancer in relation to a family history of colorectal cancer (HR, 1.21; 95% CI, 0.95-1.55) or AJ heritage (HR, 1.29; 95% CI, 0.94-1.77). The risk was highly elevated among AJ men with a family history of breast or colorectal cancer (HR, 2.61 [95% CI, 1.41-4.82] and 1.92 [95% CI, 1.05-3.49], respectively)., Conclusion: Family history of pancreatic cancer was associated with increased risk of this malignancy. Family history of breast or colorectal cancer was associated with the increased risk among AJ men.

Purpose Our previous phase I trial suggested feasibility of addition of leucovorin (LV) to S-1 and gemcitabine therapy in advanced pancreatic cancer. The aim of this phase II trial was to assess the efficacy and toxicity of gemcitabine, S-1 and LV (GSL) combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naïve patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1000 mg/m2 by 30 min infusion on days 1, S-1 40 mg/m2 orally twice daily and LV 25 mg orally twice daily on days 1 to 7 every 2 weeks. Primary end point was progression free survival (PFS). Results A total of 49 patients with advanced pancreatic cancer (19 locally advanced and 30 metastatic) were enrolled. Overall response rate and disease control rate were 32.7% and 87.8%. The median PFS and overall survival (OS) were 10.8 (95% confidence interval [CI], 7.4-13.5) and 20.7 (95% CI 13.0-NA) months with 1-year survival rate of 73.4%. Major Grade 3-4 toxicities were neutropenia (22.4%) and stomatitis (14.3%). No toxicity related death was observed. Conclusions In this single center, phase II trial, gemcitabine, S-1 and LV combination therapy was tolerable and can potentially be a treatment option for advanced pancreatic cancer.

Objective: Exocrine pancreatic insufficiency may impair the nutritional status in pancreatic cancer (PC), but the role of pancreatic enzyme replacement therapy (PERT) is not fully evaluated. Therefore, we conducted this multicenter open-label randomized controlled trial to evaluate the role of PERT in PC patients., Methods: Patients with unresectable PC receiving chemotherapy were randomly assigned to pancrelipase and nonpancrelipase groups. Patients in the pancrelipase group took oral pancrelipase of 48,000 lipase units per meal. N-benzoyl-tryrosyl para-aminobenzoic acid (NBT-PABA) test was performed at baseline. Our primary endpoint was change in body mass index (BMI) at 8 weeks. Secondary endpoints were change in other nutritional status at 8 weeks and overall survival., Results: A total of 88 patients were enrolled between May 2014 and May 2016. The NBT-PABA test was lower than the normal range in 90%. There were no significant differences in change in BMI at 8 weeks: 0.975 and 0.980 in the pancrelipase and the nonpancrelipase groups, respectively (P = 0.780). The other nutritional markers were also comparable. The median overall survival was 19.0 and 12.0 months (P = 0.070)., Conclusions: In this randomized controlled trial, pancrelipase failed to improve the change in BMI at 8 weeks in PC patients receiving chemotherapy.

Background & Aims: Statin medications, most commonly prescribed to reduce lipid levels and prevent cardiovascular disease, may be associated with longer survival times of patients with cancer. However, the association of statins with outcomes of patients with pancreatic adenocarcinoma is not clear., Methods: We analyzed the association of statin use before a diagnosis of pancreatic cancer with survival times of 648 participants in the Nurses' Health Study and Health Professionals Follow-up Study who were diagnosed with pancreatic adenocarcinoma from 2000 through 2013. We estimated hazard ratios (HRs) for overall mortality using Cox proportional hazards models with adjustment for potential confounders. We assessed the temporal association between prediagnosis statin use and cancer survival by 2-year lag periods to account for a possible latency period between statin use and cancer survival., Results: Regular statin use before diagnosis of pancreatic cancer was associated with modestly prolonged survival compared with nonregular use (adjusted HR, 0.82; 95% CI, 0.69-0.97; P = .02). A 1-month longer median survival was observed in regular statin users compared with nonregular users. Regular statin use within the 2 years prior to cancer diagnosis was most strongly associated with longer survival. We observed no statistically significant effect modification by smoking status, body mass index, diabetes, or cancer stage (all P interaction > .53). Regular statin use before diagnosis was similarly associated with survival in the Nurses' Health Study (HR, 0.79; 95% CI, 0.64-0.97) and Health Professionals Follow-up Study (HR, 0.86; 95% CI, 0.63-1.15)., Conclusions: Regular statin use before diagnosis of pancreatic cancer was associated with modest increases in survival times in 2 large prospective cohort studies., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are common lipid-lowering agents and may reduce the risk of several cancer types including pancreatic cancer. However, the association between statin use and pancreatic cancer risk has not been fully evaluated in prospective studies., Methods: We studied the association between statin use and incident pancreatic cancer in 113,059 participants from the prospective Nurses' Health Study and Health Professionals Follow-up Study. Statin use was self-reported via study questionnaires and updated biennially. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of pancreatic cancer were estimated using multivariable Cox proportional hazards models with adjustment for potential confounders., Results: In total, 583 participants developed incident pancreatic cancer during 1.4 million person-years of follow-up. No difference was identified in pancreatic cancer risk for regular versus non-regular statin users (multivariable-adjusted HR 0.98; 95% CI 0.82-1.16). There was no significant heterogeneity in the association of statin use with pancreatic cancer risk between the cohorts. Similarly, longer duration of regular statin use was not associated with decreased risk of pancreatic cancer (P trend  = 0.65). The results remained similar when we examined statin use status at baseline or accounting for 4-year latency period. We observed no statistically significant effect modification for the association of statin use with pancreatic cancer risk by body mass index, smoking status, or diabetes mellitus status (all P interaction  > 0.21)., Conclusions: Regular statin use was not associated with pancreatic cancer risk in two large prospective cohort studies in the U.S.

Background/aims: The role of endoscopic preoperative biliary drainage (PBD) for pancreatic head cancer is controversial because of the high incidence of stent occlusion before surgery. This study was performed to evaluate the feasibility and safety of PBD using a fully covered self-expandable metallic stent (FCSEMS)., Patients and Methods: This multicenter prospective study involved 26 patients treated for pancreatic head cancer with distal bile duct obstruction from April 2011 to March 2013. An FCSEMS was endoscopically placed in 24 patients. Among these, 7 patients were diagnosed with unresectable cancer, and 17 underwent surgery at a median of 18 days after FCSEMS placement. The main outcome measure was preoperative and postoperative adverse events., Results: Two adverse events (cholecystitis and insufficient resolution of jaundice) occurred between FCSEMS placement and surgery (12%). Postoperative adverse events occurred in eight patients (47%). The cumulative incidence of stent-related adverse events 4 and 8 weeks after FCSEMS placement among the 24 patients who underwent this procedure were 19%., Conclusions: PBD using an FCSEMS is feasible in patients with resectable pancreatic head cancer. Placement of an FCSEMS can be an alternative PBD technique when surgery without delay is impossible. A larger randomized controlled trial is warranted., Competing Interests: There are no conflicts of interest

Background & Aims: Use of aspirin and/or non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of several cancers, but it is not clear if use of these drugs is associated with risk of pancreatic cancer., Methods: We evaluated aspirin and non-aspirin NSAID use and risk of pancreatic adenocarcinoma in 141,940 participants from the Health Professionals Follow-up Study and Nurses' Health Study using multivariable-adjusted Cox proportional hazards regression. We considered several exposure classifications to model differing lag times between NSAID exposure and cancer development. We also conducted a nested case-control study of participants from 3 prospective cohorts using conditional logistic regression to evaluate pre-diagnosis levels of plasma salicylurate, a major metabolite of aspirin, in 396 pancreatic cancer cases and 784 matched individuals without pancreatic cancer (controls)., Results: In the prospective cohort study, 1122 participants developed pancreatic adenocarcinoma over 4.2 million person-years. Use of aspirin or non-aspirin NSAIDs was not associated with pancreatic cancer risk, even after considering several latency exposure classifications. In a pre-planned subgroup analysis, regular aspirin use was associated with reduced pancreatic cancer risk among participants with diabetes (relative risk, 0.71; 95% CI, 0.54-0.94). In the nested case-control study, pre-diagnosis levels of salicylurate were not associated with pancreatic cancer risk (odds ratio, 1.08; 95% CI, 0.72-1.61; P trend 0.81; comparing participants in the highest quintile with those in the lowest quintile of plasma salicylurate)., Conclusions: Regular aspirin or non-aspirin NSAID use was not associated with future risk of pancreatic cancer in participants from several large prospective cohort studies. A possible reduction in risk for pancreatic cancer among people with diabetes who regularly use aspirin should be further examined in preclinical and human studies., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Pancreatic cancer patients have a poor prognosis because of a low rate of resection that results from distant metastases or local advancement. We report a successful case of unresectable locally advanced pancreatic cancer in a patient who was curatively resected after combination therapy with nab-paclitaxel (nab-PTX) and gemcitabine (GEM). A 61-year-old man was referred for treatment of a 45-mm pancreatic tail tumor involving the celiac axis, common hepatic artery, and splenic artery that appeared as an abnormal soft-density mass on imaging. This patient's tumor was defined as unresectable due to local advancement, and, therefore, the powerful combined chemotherapy regimen of nab-PTX with GEM was initiated to allow for possible resection later. After three cycles of chemotherapy, a CT scan revealed that the soft-density mass around the celiac axis and common hepatic artery had dramatically disappeared, and the tumor was then determined to be a resectable lesion. Thus, distal pancreatectomy with en bloc celiac axis resection was performed and curability was achieved. There has been no tumor recurrence or distant metastasis at more than 12 months after surgery, and the patient remains alive at 17 months after initial chemotherapy.

Objectives: Pancreatic cancer is reported to be highly associated with thromboembolism (TE). The aim of this analysis is to clarify risk factors for TE and its clinical impact in Japanese patients with pancreatic cancer., Methods: Data on consecutive pancreatic cancer patients receiving systemic chemotherapy between August 1999 and July 2015 were retrospectively studied. Both symptomatic and asymptomatic, arterial and venous TEs were included in the analysis. Risk factors for TE development were analyzed using a proportional hazards model with death without TE as a competing risk. The impact of TE on survival was also evaluated using a time-dependent covariate multiple Cox model., Results: A total of 475 patients were included in the analysis, and 57 TEs (12%) were identified: 45 venous TEs and 12 arterial TEs. The median time to TE was 169 days and the median survival from TE was 65 days. Liver metastasis was the only significant risk factor for TE (subdistribution hazards ratio, 2.15; P = 0.01), and TE was significantly associated with poor prognosis (hazards ratio, 3.31; P < 0.01)., Conclusions: Thromboembolism was not uncommon in Japanese patients receiving chemotherapy for advanced pancreatic cancer and was associated with poor prognosis. Liver metastasis was the risk factor for TE.

Objectives: Although patients with pancreatic cancer (PC) are prone to exocrine pancreatic insufficiency, there are little evidence about pancreatic enzyme replacement therapy (PERT) in patients with PC, especially those receiving chemotherapy., Methods: This is a prospective consecutive observational study of PERT in patients with unresectable PC. We prospectively enrolled patients receiving chemotherapy for unresectable PC from April 2012 to February 2014 and prescribed oral pancrelipase of 48,000 lipase units per meal (pancrelipase group). N-benzoyl-tryrosyl para-aminobenzoic acid test was performed at baseline. Patients receiving chemotherapy before April 2012 were retrospectively studied as a historical cohort. Data on the nutritional markers at baseline and 16 weeks were extracted, and serial changes, defined as the ratio of markers at 16 weeks/baseline, were compared between 2 groups., Results: A total of 91 patients (46 in the pancrelipase group and 45 in the historical cohort) were analyzed. N-benzoyl-tryrosyl para-aminobenzoic acid test was low in 94% of the pancrelipase group. Serial change in the pancrelipase group versus historical cohort was 1.01 versus 0.95 in body mass index (P < 0.001) and 1.03 versus 0.97 in serum albumin (P = 0.131)., Conclusions: The rate of exocrine pancreatic insufficiency in unresectable PC was high, and PERT can potentially improve the nutritional status during chemotherapy.

Background/aims: In distal malignant biliary obstruction, an antireflux metal stent (ARMS) with a funnel-shaped valve is effective as a reintervention for metal stent occlusion caused by reflux. This study sought to evaluate the feasibility of this ARMS as a first-line metal stent., Methods: Patients with nonresectable distal malignant biliary obstruction were identified between April and December 2014 at three Japanese tertiary centers. We retrospectively evaluated recurrent biliary obstruction and adverse events after ARMS placement., Results: In total, 20 consecutive patients were included. The most common cause of biliary obstruction was pancreatic cancer (75%). Overall, recurrent biliary obstruction was observed in seven patients (35%), with a median time to recurrent biliary obstruction of 246 days (range, 11 to 246 days). Stent occlusion occurred in five patients (25%), the causes of which were sludge and food impaction in three and two patients, respectively. Stent migration occurred in two patients (10%). The rate of adverse events associated with ARMS was 25%: pancreatitis occurred in three patients, cholecystitis in one and liver abscess in one. No patients experienced nonocclusion cholangitis., Conclusions: The ARMS as a first-line biliary drainage procedure was feasible. Because the ARMS did not fully prevent stent dysfunction due to reflux, further investigation is warranted.

A 65-year-old male was referred to our hospital 2 years ago for a multilocular cyst accompanied with a protein plug in the pancreas tail. He was diagnosed as having branch duct-type intraductal papillary mucinous neoplasm and was followed-up. Two years later, endoscopic ultrasonography revealed a hypoechoic lesion, 10mm in diameter, near the cyst-like lesion. Finally, he was diagnosed with small pancreatic adenocarcinoma concomitant with intraductal papillary mucinous neoplasm and underwent radical distal pancreatectomy with splenectomy. Resected specimen revealed that the protein plug in the main pancreatic duct had caused distal pancreatic duct dilatation, resembling a multilocular cyst and pancreatic duct stenosis with inflammatory changes and fibrosis around the pancreatic parenchyma. Here, we report a rare case of protein plugs in the pancreatic duct mimicking pancreatic cancer concomitant with branch-type intraductal papillary mucinous neoplasm.

Background: Overall survival (OS), as the primary end-point in first-line chemotherapy trials, requires a prolonged follow-up time and may be confounded by subsequent regimens. This study aimed to evaluate the correlation between OS and surrogate end-points (progression-free survival [PFS], response rate and disease control rate), and to identify a potential surrogate for OS in advanced pancreatic cancer., Methods: Based on an electronic search, we identified randomized controlled phase II and III trials of first-line chemotherapy for advanced pancreatic cancer. Correlation analyses were performed between surrogate end-points and OS, and between improvements in surrogates and those in OS., Results: Fifty trials (II/II-III/III, 17/2/31) with 111 treatment arms were identified, and 15,906 patients were analysed. PFS was most strongly correlated with OS (correlation coefficient, 0.76). Weighted linear regression models revealed the greatest determinant coefficient of 0.84 between the hazard ratio (HR) of the experimental arms compared with the control arms of PFS and that of OS. The approximate equation was log HROS = 0.01 + 0.77 × log HRPFS, indicating that risk reduction of OS via chemotherapy would translate into a 77% risk reduction of PFS. The surrogacy of PFS for OS was robust throughout our subgroup analyses: e.g., biologic versus non-biologic regimens, locally advanced versus metastatic disease., Conclusions: The surrogacy of PFS for OS in pancreatic cancer was validated. Therefore, the use of PFS as the primary end-point in clinical trials could facilitate the early introduction of new effective chemotherapy regimens into clinical practice., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC., Competing Interests: We do not have any disclosure or conflicts of interest in the study.

Purpose: The role of local renin-angiotensin system (RAS) as a target for the treatment of pancreatic cancer has been increasingly reported, but the addition of candesartan, one of angiotensin system inhibitors (ASIs), to gemcitabine in our prospective trial failed to demonstrate activity against pancreatic cancer. The aim of this study was to explore subgroups that would benefit from the inhibition of RAS by the use of ASIs., Methods: Consecutive patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy were retrospectively studied. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were estimated by a Cox proportional hazards model. Interactions between the use of ASIs and each subgroup were tested., Results: Between 2001 and 2013, 349 patients received gemcitabine-based chemotherapy for advanced pancreatic cancer; 232 were metastatic, 210 received gemcitabine monotherapy, 108 took ASIs, 166 were never smokers and 188 were diabetic. The median PFS and OS were 4.9 and 11.2 months, respectively. When the effects of the use of ASIs were evaluated by a Cox proportional hazard model, there were two subgroups with P interaction <0.10 both in PFS and OS: never smokers and gemcitabine monotherapy. HRs for PFS and OS by the inhibition of RAS were 0.71 (P = 0.021) and 0.68 (P = 0.014) in never smokers and 0.70 (P = 0.027) and 0.77 (P = 0.124) in patients receiving gemcitabine monotherapy., Conclusion: The inhibition of RAS in advanced pancreatic cancer might improve clinical outcomes in cases without a history of smoking or in cases receiving gemcitabine monotherapy.

Objectives: Malignant ascites (MA) caused by peritoneal carcinomatosis is not uncommon in patients with pancreatic cancer. However, the clinical features and outcomes in these patients remain to be elucidated., Methods: Baseline characteristics and overall survival (OS) of consecutive patients with advanced pancreatic cancer who presented with MA were retrospectively evaluated., Results: Of 494 patients with advanced pancreatic cancer, 73 (15%) presented with MA. Patients with synchronous MA (n = 21), compared with those with metachronous MA (n = 52), had better performance status (P = 0.02), smaller amount of ascites (P < 0.01), and higher chance of receiving chemotherapy (57% vs 17%, P < 0.01), and resulted in longer OS (115 vs 42 days, P < 0.01). Overall survival was significantly longer in patients receiving chemotherapy than in those with best supportive care alone (124 vs 50 days, P < 0.01). In a multivariate analysis, chemotherapy was prognostic in addition to performance status, CRP, and small amount of MA; the hazard ratio of chemotherapy was 0.46, compared with best supportive care alone (P = 0.02)., Conclusions: Although the prognosis of pancreatic cancer patients with MA remains poor, selected patients may be candidate for chemotherapy, regardless of the timing of appearance of MA.

Background: Wire-guided cannulation (WGC) was reported to decrease post-ERCP pancreatitis (PEP), but risk factors for PEP in WGC are not fully elucidated., Objective: To evaluate the incidence and risk factors of PEP in WGC., Design: Single-center retrospective study., Setting: Academic center., Patients: A total of 800 consecutive patients with a native papilla., Interventions: Biliary therapeutic ERCP by using WGC., Main Outcome Measurements: The rate of PEP and its risk factors., Results: Biliary cannulation was successful by using WGC alone in 70.5%, and the final cannulation rate was 96.1%. Unintentional guidewire insertion and contrast material injection into the pancreatic duct (PD) during cannulation occurred in 55.3% and 21.8%, respectively. The incidence of PEP was 9.5% (mild 5.6%, moderate 2.9%, severe 1.0%). Multivariate analysis revealed a common bile duct (CBD) diameter of <9 mm (odds ratio [OR] 2.03; P = .006) and unintentional guidewire insertion into the PD (OR 2.25; P = .014) as risk factors for PEP. PD opacification was not a risk factor for PEP (OR 1.15; P = .642), but the incremental increase of the PEP rate was seen in patients with CBDs <9 mm: 4.6% without any PD manipulation, 8.3% with contrast material alone, 16.9% with guidewire alone, and 22.1% with both contrast material and guidewire., Limitations: Retrospective design in a single center., Conclusion: Unintentional PD manipulation was not uncommon in WGC. Guidewire insertion into the PD and a small CBD were risk factors for PEP in biliary therapeutic ERCP with the use of WGC., (Copyright © 2015. Published by Elsevier Inc.)

Purpose: In our previous randomized controlled trial, the addition of S-1 to gemcitabine for advanced pancreatic cancer did not prolong overall survival (OS) significantly, despite its higher response rate and longer progression-free survival (PFS). Leucovorin is known to enhance efficacy of S-1, and we conducted this phase I trial of combination therapy of gemcitabine, S-1 and leucovorin (GSL)., Methods: Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Gemcitabine was administered at an escalating dose of 600, 800 and 1,000 mg/m(2) over 30 min on day 1, and oral S-1 at a dose of 40 mg/m(2) twice daily and oral leucovorin at a dose of 25 mg twice daily on days 1-7, every 2 weeks. A standard "3 + 3" phase I dose escalation design was utilized., Results: Fifteen patients were enrolled across three dose levels. Three patients developed DLTs: two patients in level 1 (grade 3 anorexia in 1 and grade 3 anorexia, stomatitis and diarrhea in 1) and one patient in level 2 (grade 3 deep vein thrombosis). No DLT was observed in level 3. Response rate and the disease control rate were 33 and 93 %, respectively. The median PFS and OS were 5.4 and 16.6 months. Ten of 12 patients (83 %) with elevated CA19-9 at baseline had a ≥ 50 % decline., Conclusions: RD of gemcitabine in GSL was determined as 1,000 mg/m(2). GSL was well tolerable and showed promising results in advanced pancreatic cancer.

Objectives: The aim of this study was to examine the association of risk factors including diabetes mellitus (DM) with the age of onset in Japanese pancreatic cancer (PC) patients., Methods: We retrospectively reviewed 688 PC patients diagnosed at our institute. We analyzed the association between the age of onset of PC and the following variables: sex, smoking, alcohol, DM, and a family history of cancer especially PC., Results: The mean age of PC diagnosis was 67.6 years. The onset of PC occurred earlier in current smokers (63.6 years old, P < 0.001) compared with past smokers (69.5 years old) and never smokers (68.6 years old). Patients with long-standing DM (>2 years) were older (70.5 years, P < 0.001) when diagnosed with PC than patients with new-onset DM (within 2 years) (66.9 years old) and patients without DM (66.7 years old). In the multivariate analysis, current smokers and a family history of cancer other than PC were associated with earlier onset. Conversely, long-standing DM was associated with later onset., Conclusions: In Japanese PC patients, current smokers and a family history of cancer other than PC were associated with a younger age of onset. Conversely, long-standing DM was associated with a later onset.

Objectives: Here, we reported an interim analysis of feasibility and safety in the first 10 cases of 30 cases in a phase II trial of intravenous and intraperitoneal paclitaxel combined with S-1 for gemcitabine-refractory pancreatic cancer with malignant ascites., Methods: Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8 every 3 weeks, and S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7-day rest., Results: Between April 2011 and February 2012, ten patients were enrolled. A partial response was achieved in two patients (20%) and a disease control rate of 50%. The median time to progression and overall survival were 2.1 and 3.4 months, respectively. Malignant ascites was completely resolved in two patients (20%). Major grade 3/4 adverse events were myelosuppression including neutropenia (50%) and catheter-related infection (10%)., Conclusions: This novel combination chemotherapy was feasible and showed promising results in pancreatic cancer patients with malignant ascites (clinical trial registration number: UMIN000005306).

Background and Aim: Covered metallic stents (CMSs) were developed to overcome tumor ingrowth in uncovered metallic stents (UMSs) for malignant biliary obstruction, but superiority of CMSs over UMSs is still controversial due to the high migration rate in CMS. Therefore, we conducted this retrospective analysis to clarify risk factors for stent migration, including mechanical properties of CMSs., Methods: Patients with unresectable pancreatic cancer, receiving CMS for distal malignant biliary obstruction in five tertiary care centers, were retrospectively studied. Univariate and multivariate analyses to identify prognostic factors for early (< 6 months) stent migration were performed using a proportional hazards model with death or stent occlusion without stent migration as a competing risk. Two mechanical properties were included in the analysis: axial force, the recovery force that leads to a CMS straightening, and radial force (RF), the expansion force against the stricture., Results: Among 290 patients who received CMS placement for distal malignant biliary obstruction, stent migration rate was 15.2%. CMS migrated early (< 6 months) in 10.0% and distally in 11.7%, respectively. In the multivariate analysis, significant risk factors for early stent migration were chemotherapy (subdistribution hazard ratios [SHR] 4.46, P = 0.01), CMS with low RF (SHR 2.23, P = 0.03), and duodenal invasion (SHR 2.25, P = 0.02)., Conclusion: CMS with low RF, chemotherapy, and duodenal invasion were associated with CMS migration from our study., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)