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Background Pancreatic ductal adenocarcinoma（PDAC）is the seventh leading cause of cancer-related death globally. It has an extremely poor prognosis, and its incidence rate and mortality are considered to increase sharply over the next few years. Combined chemotherapy after surgery is still the best treatment, and it is also the only curative option. Improvements in the understanding of genetic mutations, the tumor microenvironment (TME), and targeted therapies continue to improve the progression of PDAC. Nerves are an important component of the TME of pancreatic cancer. However, the role of cancer-nerve crosstalk-related genes in PDAC is still unclear. Results In our study, we constructed a prognostic model based on cancer-nerve crosstalk-related genes with prognostic value. The xCell algorithm was used to analyse the cell component enriched from samples in The Cancer Genome Atlas (TCGA) PDAC cohort. We found the neuronal content was significantly correlated with prognosis. Protein-protein interaction (PPI) network, GO, and KEGG enrichment analyses were used to identify nerve-related genes in PDAC. From the forty-two nerve-cancer crosstalk genes, we used K-M plotter to identify the canditate genes for LASSO regression. We constructed a three-gene prognostic model (CHRNB2, CHRNA10, NGFR). The model could effectively test and verify its 1-, 3- and 5-year survival rates in the TCGA-PDAC cohort. The effectiveness of the model was verified by external test data. The genes of this model were highly related to tumor progression and other immune microenvironments. Conclusion In summary, we used bioinformatics analysis to construct an effective prognostic model, explored the key mechanism of nerve-cancer cross-talk and revealed the potential of cancer-nerve cross-talk-related genes as prognostic biomarkers and therapeutic targets in PDAC.

To introduce sub-adventitial divestment technique (SDT), a procedure to remove the tumor while preserving the artery during curative pancreatectomy. Peri-operative safety profile was also evaluated. In a single center consecutive series of pancreatectomy for pancreatic cancer, the outcome of patients who had pancreatectomy with SDT was compared to standard pancreatic surgery. From June 2014 to June 2016, 72 patients had pancreatectomy with SDT and 235 had standard surgery. Tumor stage was T4 in all 72 (100%) tumors removed using SDT compared to four (2%) with standard pancreatectomy (p

Yong Gao,1,* Baobao Cai,1,* Lingdi Yin,1,* Guoxin Song,2 Zipeng Lu,1 Feng Guo,1 Jianmin Chen,1 Chunhua Xi,1 Jishu Wei,1 Junli Wu,1 Wentao Gao,1 Kuirong Jiang,1 Yi Miao1,3 1Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People’s Republic of China; 3Pancreas Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Miao, Email miaoyi@njmu.edu.cnBackground: Undifferentiated carcinoma of pancreas with osteoclast-like giant cells is an extremely rare tumor in pancreas. It is relatively difficult to have preoperative diagnosis due to the lack of specific tumor markers and pre-operative images.Methods: In the present study, database of the pancreas center in the First Affiliated Hospital of Nanjing Medical University was retrospectively screened. A total of thirteen cases diagnosed as undifferentiated carcinoma of pancreas with osteoclast-like giant cells were included. Their clinical data and treatments were collected.Results: Thirteen patients include eight males and five females, and the median age was 67 (60– 72) years old. The lesions were found in more than half patients through health examination with no symptoms. NSE was elevated in eight cases (66%). CT scan revealed that cystic and solid lesions often had thick (4/5), contrast-enhanced (5/5) wall with smooth edges (5/5) and the boundary of lesions mainly with solid composition (4/10) is not well demarcated with normal pancreatic parenchyma. All patients received surgical resection. Eight patients had adjuvant chemotherapy and only one patient had adjuvant radiotherapy. The median survival time was 13 months. Five patients had postoperative metastasis or recurrence of tumor and four of them had died of this disease during follow-up.Conclusion: Our data showed that elevated level of NSE and characteristic pre-operative images might provide aid with the pre-operative diagnosis for undifferentiated carcinoma of pancreas with osteoclast-like giant cells. Patients with suspected diagnosis should receive surgical intervention as soon as possible, supplemented with postoperative chemotherapy, in order to prolong the survival of patients.Keywords: pancreatic cancer, undifferentiated carcinoma of pancreas, osteoclast-like giant cells, retrospective, pre-operative image

Multimodal sentiment analysis has been an active subfield in natural language processing. This makes multimodal sentiment tasks challenging due to the use of different sources for predicting a speaker’s sentiment. Previous research has focused on extracting single contextual information within a modality and trying different modality fusion stages to improve prediction accuracy. However, a factor that may lead to poor model performance is that this does not consider the variability between modalities. Furthermore, existing fusion methods tend to extract the representational information of individual modalities before fusion. This ignores the critical role of intermodal interaction information for model prediction. This paper proposes a multimodal sentiment analysis method based on cross-modal attention and gated cyclic hierarchical fusion network MGHF. MGHF is based on the idea of distribution matching, which enables modalities to obtain representational information with a synergistic effect on the overall sentiment orientation in the temporal interaction phase. After that, we designed a gated cyclic hierarchical fusion network that takes text-based acoustic representation, text-based visual representation, and text representation as inputs and eliminates redundant information through a gating mechanism to achieve effective multimodal representation interaction fusion. Our extensive experiments on two publicly available and popular multimodal datasets show that MGHF has significant advantages over previous complex and robust baselines.

Middle segment-preserving pancreatectomy (MPP) can treat multilocular diseases in the pancreatic head and tail while avoiding impairments caused by total pancreatectomy (TP). We conducted a systematic literature review of MPP cases and collected individual patient data (IPD). MPP patients (N = 29) were analyzed and compared to a group of TP patients (N = 14) in terms of clinical baseline characteristics, intraoperative course, and postoperative outcomes. We also conducted a limited survival analysis following MPP. Pancreatic functionality was better preserved following MPP than TP, as new-onset diabetes and exocrine insufficiency each occurred in 29% of MPP patients compared to near-ubiquitous prevalence among TP patients. Nevertheless, POPF Grade B occurred in 54% of MPP patients, a complication avoidable with TP. Longer pancreatic remnants were a prognostic indicator for shorter and less eventful hospital stays with fewer complications, whereas complications of endocrine functionality were associated with older patients. Long-term survival prospects after MPP appeared strong (median up to 110 months), but survival was lower in cases with recurring malignancies and metastases (median < 40 months). This study demonstrates MPP is a feasible treatment alternative to TP for selected cases because it can avoid pancreoprivic impairments, but at the risk of perioperative morbidity.

Simple Summary Pancreatic ductal adenocarcinoma is a devastating illness but guidelines consider it unresectable once metastasized. However, resection of the primary tumor is carried out in select cases and retrospective analyses indicate that this may improve survival. Even so, these analyses are limited to single centers or fail to account for biased patient selection. We overcome these limitations with a propensity score-matched SEER database analysis that reliably demonstrates surgery can extend overall survival. Furthermore, we identify prognostic factors that could aid the selection of patients for randomized controlled trials. Thus, this study paves the way for future work that aims to update treatment guidelines in accordance with surgical developments. Abstract Guidelines do not recommend resection surgery for oligometastatic pancreatic ductal adenocarcinoma (PDAC). However, reports in small samples of selected patients suggest that surgery extends survival. Thus, this study aims to gather evidence for the benefits of cancer-directed surgery (CDS) by analyzing a national cohort and identifying prognostic factors that aid the selection of candidates for CDS or recruitment into experimental trials. Data for patients with PDAC and hepatic metastasis were extracted from the population-based Surveillance, Epidemiology, and End Results database (SEER). The bias between CDS and non-CDS groups was minimized with Propensity Score Matching (PSM), and the prognostic role of CDS was investigated by comparing Kaplan-Meier estimators and Cox proportional hazard models. A total of 12,018 patients were extracted from the database, including 259 patients who underwent CDS that were 1:1 propensity score-matched with patients who did not receive CDS. CDS appeared to significantly prolong median overall survival from 5 to 10 months. Multivariate analysis revealed chemotherapy as a protective prognostic, whilst survival was impaired by old age and tumors that were poorly differentiated (Grades III–IV). These factors can be used to select patients likely to benefit from CDS treatment, which may facilitate recruitment into randomized controlled trials.

Pancreatic anastomosis reconstruction is one of the most technically demanding and complicated procedures in general surgery. No single technique has been demonstrated to be superior to the others in the prevention of postoperative pancreatic fistula (POPF), and the accumulation of surgical experience is closely related to the quality of this anastomosis. The aim of the current study was to evaluate the feasibility of our simplified technique, single-layer continuous duct-to-mucosa pancreaticojejunostomy.A single-center prospective single-arm trial was performed. The first 20 patients who underwent Whipple's procedure with the new technique performed by a single surgeon in our center were recruited. General information, preoperative treatments, risk factors for POPF, and postoperative morbidity of the patients were prospectively recorded and reported.From January to February 2020, 13 male and 7 female patients were included. Ten cases were classified as intermediate/high risk according to validated fistula prediction models. The median operation time was 260 min, including a median pancreaticojejunostomy time of 7.7 min. There were 2 cases (10%) of grade B POPF, and no grade C POPF occurred. The overall morbidity rate was 30%, including 2 cases with severe complications (Clavien-Dindo grade ≥ 3). No patients underwent reoperation, and no patient died within 90 days after surgery. The median length of hospitalization was 11 days.Single-layer continuous duct-to-mucosa pancreaticojejunostomy is a simplified and feasible method for pancreatic anastomosis. Further studies are warranted to evaluate the indications or contraindications and efficacy of preventing POPF with our new technique.

Background: Idiopathic chronic calcific pancreatitis is a rare entity. Early surgical intervention and a parenchyma sparing procedure should be advocated to prevent further decay of the pancreas and the occurrence of cancer. Case Presentations: Case 1: A 14-year-old boy presented with a 3-year history of right upper abdominal pain that has been aggravated in the last 2 months. Imaging revealed a dilated pancreatic duct of 6 mm with pancreatic duct stones in the head of pancreas. He underwent a Frey's procedure. Unfortunately, he was discharged with grade B pancreatic fistula. Case 2: A 12-year-old boy presented with a 1-year history of dull and recurring epigastric pain. Imaging studies showed multiple stones in a 12 mm dilated pancreatic duct. The patient underwent a modified Puestow procedure. Up to the 42th month follow-up, the patient had no pain complaints. Case 3: A 12-year-old boy with a 1-week history of a dull epigastric pain presented with with multiple stones in a 10 mm duct. He underwent a modified Puestow procedure and was discharged with alleviated pain. Conclusions: “Conservative” surgery allows satisfactory pancreatic duct drainage, reduced rehospitalizations, and longer pain relief than alternative endoscopic procedures.

Pancreatic cancer (PC) has posed a great health threat to a growing number of people all over the world. Detection of serum miRNAs, being sensitive, noninvasive, and easy to obtain, has a great potential of being a novel screening method for PC patients. In this study, we investigated miRNA expression levels in serum by qRT‐PCR. The study was divided into four phases: the screening, training, testing, and external validation stage. We firstly chose candidate miRNAs using Exiqon panels in the screening phase. Then, a total of 129 PC serum samples and 107 normal controls (NCs) were further analyzed in the following training and testing phases to identify differently expressed miRNAs. A cohort of 30 PC serum samples vs 30 NCs was used to confirm the diagnostic value of the identified miRNAs in the external validation phase. Moreover, miRNA expressions in additional 44 PC tumor tissue samples and the matched adjacent normal tissue samples as well as 32 pairs of serum‐derived exosomes samples were also further explored. As a result, we identified six significantly upregulated miRNAs in the serum of PC: let‐7b‐5p, miR‐192‐5p, miR‐19a‐3p, miR‐19b‐3p, miR‐223‐3p, and miR‐25‐3p. A six‐miRNA panel in serum was then established. The area under the receiver operating characteristic curves (AUC) for the panel was 0.910 for the combined training and testing phases, which showed higher diagnostic value than the individual miRNA. Prognostic value prediction using Cox's proportional hazards model and Kaplan‐Meier curves showed that increased serum miR‐19a‐3p was closely related to worse overall survival (OS). In addition, significant upregulation of miR‐192‐5p, miR‐19a‐3p, and miR‐19b‐3p was observed in both PC tissue and serum‐derived exosomes samples. In conclusion, we identified a six‐miRNA (let‐7b‐5p, miR‐192‐5p, miR‐19a‐3p, miR‐19b‐3p, miR‐223‐3p, and miR‐25‐3p) panel in the serum for PC early and noninvasive diagnosis.

Central pancreatectomy (CP) has been applied for treating benign and low-grade malignant tumors in pancreatic neck, but studies regarding CP for pancreatic ductal adenocarcinoma (PDAC) are quite limited. We aimed to investigate the role of central pancreatectomy in the treatment of PDAC in the neck of the pancreas. Patients who underwent CP at our hospital between 2009 and 2016 were identified. Patients treated by distal pancreatectomy (DP) were matched according to the tumor size, location, and staging. The surgical and survival outcomes were compared between the CP and DP groups. Nine patients had CP. Five (56%) had postoperative complications and three (33%) had clinically significant (grade B + C) fistula. No significant difference was found between the CP and DP groups for the rate of overall morbidity, pancreatic fistula, reoperation, and readmission. Tumor size was smaller in the CP group compared to the DP group. The mortality of both groups was zero. The median postoperative survival was similar between the two groups (20.4 months for CP vs 19.4 months for DP, P = 0.842). CP is safe for patients with small PDAC at the neck of the pancreas. Considering the good preservation of pancreatic endocrine and exocrine functions, CP could be considered as an alternative procedure for single small PDAC in pancreatic neck.

HHLA2 is a newly identified member of the B7 immune checkpoint family, but its function and crosstalk with immune cells is not fully understood. To gain insights into the HHLA2 expression profile and to determine the clinical significance and function of HHLA2 in pancreatic cancer, we performed immunohistochemistry (IHC) analyses on tissue microarrays (TMAs) of pancreatic ductal adenocarcinoma (PDAC, n = 92) with matched peritumoral tissues as well as in cohorts of precancerous lesions: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). We found that HHLA2 was rarely detected in normal acinar, islet, and ductal cells but widely expressed from early pancreatic precancerous lesions to invasive PDAC. The overall HHLA2 positivity was 95% (19/20) in low grade PanIN and 70.73% (29/41) in IPMN. HHLA2 expression was detected in 77.17% (71/92) of the PDAC cases and was significantly associated with better prognosis in this cohort. Our findings suggest that HHLA2 may behave as a costimulatory ligand in pancreatic cancer, which differs from other B7 family members that are largely characterized as checkpoint inhibitors. Further investigation of the HHLA2 signaling pathway and its receptors is warranted by our data and may lead to novel therapeutic interventions.

To introduce sub-adventitial divestment technique (SDT), a procedure to remove the tumor while preserving the artery during curative pancreatectomy. Peri-operative safety profile was also evaluated.In a single center consecutive series of pancreatectomy for pancreatic cancer, the outcome of patients who had pancreatectomy with SDT was compared to standard pancreatic surgery.From June 2014 to June 2016, 72 patients had pancreatectomy with SDT and 235 had standard surgery. Tumor stage was T4 in all 72 (100%) tumors removed using SDT compared to four (2%) with standard pancreatectomy (p 0.001). All 72 (100%) tumors in the SDT group were stage III compared to 24 (10%) in the standard surgery group (p 0.001). Both groups had a high proportion of poorly differentiated tumors (52 (72%) and 163 (69%) respectively) and perineural tumor invasion (62 (86%) and 186 (79%) respectively). R1 (1 mm) was found in 24 (86%) of 28 tumors in the SDT group, and in 72 (60%) out of 120 standard pancreatectomy tumors (p = 0.01). Complications occurred in 29 (40%) of the SDT group and in 88 (37%) of the standard group. The in-hospital mortality was four (6%) in the SDT group and one (0.4%) in the standard group (p = 0.01), with a 90-day mortality of 5 (8%)/60 and 6 (3%)/209 (p = 0.07) respectively.The sub-adventitial divestment technique appeared to be an effective surgical technique to remove the tumor while preserving the artery. This approach warrants further validation in prospective studies.

A higher incidence of pancreatic cancer has been reported in the Chinese population compared with the White population, but genetic differences are unknown to date. Large-sample germline testing for both familial and sporadic pancreatic cancers has been conducted predominantly in White populations, whereas similar studies in Chinese populations are limited.To assess the prevalence of germline sequence variations in patients with pancreatic diseases in China.This genetic association study was a case series that included genetic data from patients with pancreatic ductal adenocarcinoma (PDAC) or non-PDAC pancreatic diseases seen at The First Affiliated Hospital of Nanjing Medical University in Nanjing, China, between January 2006 and December 2017 (Nanjing cohort). Comparator group data were obtained for a US cohort from Johns Hopkins Hospital (JHH), a population from East Asia from the Exome Aggregation Consortium (ExAC) database, and the larger population from China from the ChinaMAP database. Data were updated and analyzed in July 2021.Next-generation sequencing technology was used to examine the prevalence of deleterious variations in 59 genes of the included Chinese patients with DNA extracted from peripheral blood samples. The Fisher exact test was used to assess differences among the frequencies of germline variations in the study patients vs the comparator groups.A total of 1009 patients with PDAC (627 [62.1%] male; mean [SD] age, 62.8 [10.2] years) and 885 with non-PDAC diseases (477 [53.9%] male; mean [SD] age, 52.0 [15.9] years) from the Nanjing cohort were included for genetic analysis; all were Han Chinese individuals. Pathogenic variations were detected in 63 patients with PDAC (6.2%; 95% CI, 4.7%-7.7%). Variations in BRCA2 (odds ratio [OR], 3.2; 95% CI, 1.4-7.7; P = .008) and PALB2 (OR, 5.2; 95% CI, 1.6-17.0; P = .007) were significantly associated with pancreatic risk in the Nanjing cohort. Pathogenic variants of genes associated with homologous recombination DNA damage repair, including ATM, BRCA1/2, PALB2, BRIP1, FANCA, FANCC, RAD51D, and XRCC2, were found in 34 patients with PDAC (3.4%). No Ashkenazi Jewish-specific BRCA2 variation (p.Ser1982fs) was detected. The odds ratio of a SPINK1 variation in patients with PDAC was 3.2 (95% CI, 1.8-5.7; P .001) in the Nanjing cohort compared with the ExAC cohort. Variations in the pancreatic secretory enzyme genes CPA1 and CPB1 were not detected in the Nanjing cohort.In this genetic association study, sporadic pancreatic cancer was associated with pathogenic germline variations in a cohort from China. These findings provide insights into the genetic background of pancreatic cancer in the Han Chinese population with PDAC.

Postoperative pancreatic fistula (POPF) is a major source of morbidity after pancreaticoduodenectomy (PD). The purpose of this retrospective study comparing 1-layer pancreaticojejunostomy (PJ) with 2-layer PJ after PD was to evaluate whether the 1-layer duct-to-mucosa PJ after PD can reduce the incidence of POPF. A total of 194 consecutive patients who underwent PD by one group of surgeons (led by Y.M.) from January 2011 to February 2014 were included in this study. Among those patients, 104 underwent 1-layer PJ (1-layer group), and 90 patients underwent 2-layer PJ (2-layer group). Preoperative clinicopathologic features, intraoperative parameters, and postoperative morbidity with a focus on POPF were compared between the 2 groups. The overall incidence of POPF was 19.6% (38 of 194 patients), and clinically relevant grade B and C POPF rates were 8.6% (16 of 194 patients) and 3.1% (6 of 194 patients), respectively. There were no differences in patient demographics and operation-related factors between the 2 groups. However, the incidence of POPF in the 1-layer group was significantly lower than in the 2-layer group [13.5% (14 of 104) of patients and 26.7% (24 of 90) of patients, respectively; P = 0.021]. The median postoperative hospital stay was also significantly shorter in the 1-layer group compared with the 2-layer group (13 versus 15 days, P = 0.035). One patient in the 2-layer group died of postoperative hemorrhage. One-layer duct-to-mucosa PJ is a simple and easy technique for pancreaticojejunal anastomosis after PD, and it can reduce the POPF rate in comparison with the 2-layer technique.

Background/Aims: PIK3R3 is a regulatory subunit of phosphatidylinositol 3-kinase (PI3K) which plays an essential role in the metastasis of several types of cancer. However, whether PIK3R3 can promote the metastasis of pancreatic cancer (PC) is still unclear. In this study, we characterized the role of PIK3R3 in metastasis of PC and underlying potential mechanisms. Methods: RT-PCR, western blot, immunofluorescence (IF) and immunohistochemistry (IHC) were applied to investigate the expression of genes and proteins in different cell lines and tissues. To assess the function of PIK3R3 and related mechanisms, the cells with RNAi-mediated knockdown or overexpression were used to perform a series of in vitro and in vivo assays. Results: PIK3R3 was significantly overexpressed in pancreatic cancer tissues, especially in metastatic cancer tissues, as well as in pancreatic cancer cells. Functional assays suggested that overexpression or knockdown of PIK3R3 could respectively promote or suppress the migration and invasion of PC cells in vitro and in vivo. Further mechanism related studies demonstrated that ERK1/2-ZEB1 pathway-triggered epithelial-mesenchymal transition (EMT) might be responsible for the PIK3R3-induced PC cell migration and invasion. Conclusion: PIK3R3 could promote the metastasis of PC by facilitating ZEB1 induced EMT, and could act as a potential therapeutic target to limit PC metastasis.

Background: Pancreatic solid pseudopapillary tumors (SPTs) are rare neoplasms with low-grade malignancy. The main treatment for them is surgical resection. However, some SPTs relapse after resection. The risk factors associated with the recurrences of resected SPTs remain controversial to date. We performed a systematic review and meta-analysis to identify the risk factors of the recurrences of pancreatic SPTs. Materials and Methods: We searched PubMed, EMBASE, and the Cochrane Library from their inception to December 2017. Studies that focused on the risk factors of postoperative relapses of pancreatic SPTs were enrolled. Combined ORs with 95% CIs were calculated to evaluate the effects of relevant factors investigated in eligible studies. Heterogeneity among combined results was assessed by Cochran's Q test and by the degree of inconsistency (I2). Statistical analyses were performed by Review Manager (version 5.3) using random effects models. Results: We included 10 studies, which enrolled 1091 patients. The pooled results suggested that patients with larger tumors (diameter > 5cm), lymphovascular invasion, lymph node metastasis, synchronous metastasis and positive margin were prone to suffer from the recurrences of SPTs. In addition, some factors like gender, location of tumors, perineural invasion, calcification and capsular invasion did not show any correlation with the relapses of resected SPTs. Conclusion: Factors including a larger tumor size (diameter > 5cm), lymphovascular invasion, lymph node metastasis, synchronous metastasis and positive margin may increase the risk of recurrences of resected pancreatic SPTs. All SPTs should be excised and patients with high-risk features should undergo a long-term follow-up.

Purpose: Glucagonoma is an extremely rare neuroendocrine tumor arising from pancreatic islet cells. Although patients with glucagonoma manifest multiple typical symptoms, early diagnosis remains difficult due to the scarcity of this disease. Methods: In this study, we retrospectively screened the database of the pancreas center of Nanjing Medical University. A total of six cases diagnosed as glucagonoma during the past 17 years were included. Their clinical characteristics and treatments were reviewed. Results: The six patients consisted of four females and two males. Their median age at diagnosis was 48.7 years (range 35–77). The time from onset of symptoms to diagnosis of glucagonoma ranged from 1.3 months to >10 years. Common symptoms included necrotizing migratory erythema shown in six of six patients (100%), diabetes mellitus in five of six patients (83%), stomatitis in four of six patients (67%), and weight loss in four of six patients (67%). Plasma glucagon levels were elevated in all patients (range 245.6–1132.2 pg/mL; n

Background Patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC) are frequently found to be unresectable on exploration due to small distant metastasis. This study was to investigate predictors of small distant metastasis in patients with potentially resectable PDAC. Methods Patients who underwent surgical exploration for potentially resectable PDAC from 2013 to 2014 were reviewed retrospectively and divided into two groups according to whether distant metastases were encountered on exploration. Then, univariate and multivariate logistic regression analyses were used to identify predictors of distant metastasis. A scoring system to predict distant metastasis of PDAC on exploration was constructed based on the regression coefficient of a multivariate logistic regression model. Results A total of 235 patients were included in this study. Mean age of the study population was 61.7 ± 10.4 years old. Upon exploration, distant metastases were found intraoperatively in 62 (26.4%) patients, while the remaining 173 were free of distant metastases. Multivariate logistic regression analysis identified that age ≤ 62 years old (p

The present study aimed to explore the effects and underlying mechanisms of microRNA (miR)-23a on pancreatic cancer (PC) cells progression. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the mRNA and protein miR-23a and PLK-1 level. Cell viability, cell cycle, migration and invasion assasy, and in vivo tumorigenicity assay were used to investigate the effects of miR-204. Further luciferase reporter assay was used to explore the mechanisms contributing to miR-204 effects. It was observed that miR-23a expression was upregulated and negatively associated with polo-like kinase-1 (PLK-1) expression in human PC tissues. PLK-1 was a direct target of miR-23a in PC cells. Functional analysis demonstrated that miR-23a overexpression suppressed cell proliferation, inhibited cell migration and invasion and promoted cell apoptosis in vitro. When PC cells were transfected with has-miR-23a PLK-1 was downregulated and its downstream molecules were deregulated, including decreased expression of B-cell lymphoma-2, cyclin B1 and vimentin, and increased expression of Bax and E-cadherin. The inhibitory effect of miR-23a on PC cell progression was observed in vivo tumor xenografts. The results of the study suggest that miR-23a inhibits PC cell progression by directly targeting PLK-1-associated signaling and promoting miR-23a expression may be a potential method for treating patients with PC.

Table S1. All primers involved in this research (5â ˛-3â ˛). (DOCX 13 kb)

As a member of the vasohibin (VASH2) family, VASH2 is localized intracellularly as a nuclear and cytoplasmic type. Cytoplasmic VASH2 is associated with carcinoma angiogenesis and malignant transformation and promotes cancer growth. However, the function of nuclear VASH2 has yet to be investigated. The aim of the present study was to detect the nuclear VASH2 expression profile in human organs and tissues by protein microarray technique. To examine the function of nuclear VASH2, we analyzed the relationship between nuclear VASH2 and Ki-67, and stably constructed VASH2 overexpression and knockdown in LO2 and HepG2 cell lines, based on a previous study in hepatic cells. The study was conducted using bromodeoxyuridine, immunofluorescent staining, western blot analysis and flow cytometry. Nuclear VASH2 was highly expressed in actively dividing cells in normal and cancer tissues. There was a significant positive correlation between nuclear VASH2 and Ki-67, indicating that nuclear VASH2 positively correlated with cell proliferation in normal and cancer tissues. The bromodeoxyuridine (BrdU) proliferation test showed that nuclear VASH2 increased the S-phase population and promoted cell proliferation, while VASH2 knockdown reduced BrdU absorbance. Cell cycle analysis revealed that nuclear VASH2 overexpression increased the S-phase population in LO2 and HepG2 cells, while nuclear VASH2 knockdown reduced the S-phase population and increased the G0/G1 population. The findings of this study challenge the classic view of VASH2, which was previously reported as an angiogenesis factor. Furthermore, to the best of our knowledge, these results are the first clinical data indicating that nuclear VASH2, but not cytoplasmic VASH2, promotes cell proliferation by driving the cell cycle from the G0/G1 to S phase.

Necrolytic migratory erythema (NME), diabetes mellitus and glucagon-secreting tumors form the hallmarks of glucagonoma syndrome, and represent the major clinical manifestations of glucagonoma. NME is usually presented as the initial complaint of patients. Due to the rare incidence of glucagonoma, its diagnosis is often delayed, which leads to its progression. Here, we report a case of NME with a typical skin rash, which was misdiagnosed and treated with corticosteroids for two years. Removal of the tumor in the pancreatic body led to the rapid relief of the symptoms. The aim of the present study is to demonstrate the typical characteristics of glucagonoma syndrome to clinicians in order to improve its diagnosis and treatment.

The outcomes of sporadic pancreatic ductal adenocarcinoma (PDAC) patients with germline mutations of BRCA1/BRCA2 remains unclear. The prognostic significance of BRCA1/BRCA2 mutations on survival is not well established.We performed targeted next-generation sequencing (NGS) to identify BRCA1/BRCA2 germline mutations in resected sporadic PDAC cases from 2000 to 2015. Germline BRCA mutation carriers were matched by age and tumor location to those with BRCA1/BRCA2 wild-type genes from our institutional database. Demographics, clinicopathologic features, overall survival (OS), and disease-free survival (DFS) were abstracted from medical records and compared between the 2 cohorts.Twenty-two patients with sporadic cancer and BRCA1 (n = 4) or BRCA2 (n = 18) germline mutations and 105 wild-type patients were identified for this case-control study. The BRCA1/BRCA2 mutations were associated with inferior median OS (20.2 vs 27.8 months, p = 0.034) and DFS (8.4 vs 16.7 months, p0.001) when compared with the matched wild-type controls. On multivariable analyses, a BRCA1/BRCA2 mutation (hazard ratio [HR] 2.10, p0.001), positive margin status (HR 1.72, p = 0.021), and lack of adjuvant therapy (HR 2.38, p0.001), were all independently associated with worse survival. Within the BRCA1/BRCA2 mutated group, having had platinum-based adjuvant chemotherapy (n = 10) was associated with better survival than alternative chemotherapy (n = 8) or no adjuvant therapy (n = 4) (31.0 vs 17.8 vs 9.3 months, respectively, p0.001).Carriers of BRCA1/BRCA2 mutation with sporadic PDAC had a worse survival after pancreatectomy than their BRCA wild-type counterparts. However, platinum-based chemotherapy regimens were associated with markedly improved survival in patients with BRCA1/BRCA2 mutations, with survival differences no longer appreciated with wild-type patients.

Background Autophagy is a highly regulated biological process that mediates the degradation of intracellular components. It is required for tumor cell metabolism and homeostasis. Yin-Yang 1 (YY1) has been reported to be involved in autophagy in several carcinomas. However, its role in autophagy in pancreatic cancer, one of the deadliest human malignancies, is unknown. Here, we investigated the function of YY1 in pancreatic cancer cells autophagy and its mechanisms of action. Methods The activity of cells undergoing autophagy was assessed using transmission electron microscopy, immunofluorescence, and Western blotting. A luciferase activity assay, real-time quantitative polymerase chain reaction (RT-qPCR), and chromatin immunoprecipitation (ChIP) were also used to identify putative downstream targets of YY1. Results YY1 was confirmed to regulate autophagy in pancreatic cancer cells. It was found to directly regulate the expression of miR-30a, a known modulator of autophagy-associated genes. Furthermore, overexpression of miR-30a attenuated the pro-autophagic effects of YY1. Conclusions Cumulatively, our data suggest that miR-30a acts in a feedback loop to modulate the pro-autophagic activities of YY1. Thus, autophagy in pancreatic cancer cells may be regulated, in part, by a tightly coordinated YY1/miR-30a regulatory circuit. These findings provide a potential druggable target for the development of treatments for pancreatic cancer.

Postoperative pancreatic fistula (POPF) is a common complication following distal pancreatectomy (DP). However, the risk factors of this complication in patients after DP still remain controversial. The aim of our study is to estimate the association between potential risk factors and POPF. Relevant articles published up to June 21, 2016 were identified via PubMed, EMBASE, Web of Science, and The Cochrane Library. Studies that examined the risk factors of POPF following DP were enrolled. 20 articles (2070 patients) were finally included in this study. The pooled data suggested that patients with soft pancreas, higher Body Mass Index (BMI), blood transfusion, elevated intraoperative blood loss, and longer operative time had a decreased risk for POPF. However, age, gender, malignant pathology, types of stump closure, octreotide therapy, history of diabetes and chronic pancreatitis, splenectomy, multiorgan resection, main duct ligation, preoperative serum albumin levels, PGA felt wrapping, and extended lymphadenectomy could not be regarded as risk factors for POPF. Our analytic data demonstrated that pancreas texture, BMI, blood transfusion, intraoperative blood loss, and operative time were clinical predictor for POPF. This study may assist surgeons to screen patients with high risk of POPF and select appropriate treatment measures.

MicroRNAs (miRNAs) play important roles in the regulation of various tumor biological processes including proliferation and apoptosis. miR-217 has been implicated in many types of cancer, whereas its expression and potential biological function in human pancreatic adenocarcinoma (HPAC) remain unclear. We aimed to investigate the clinical significance of miR-217 in patients with pancreatic carcinoma and its role and underlying molecular mechanism in HPAC. We collected 15 pairs of pancreatic cancer and normal pancreas tissues to evaluate the expression of miR-217 and tumor protein D52-like 2 (Tpd52l2). Then, we transfected AsPC-1 cells with miR-217 mimics or Tpd52l2 siRNA to detect the effect on cell proliferation, apoptosis, invasion, migration and the cell cycle. In addition, miR-217 mimics and Tpd52l2 expression plasmids were co-transfected into AsPC-1 cells to further investigate the mechanism of miR-217 and Tpd52l2 in HPAC tumorigenesis. Finally, exploration of related signaling pathways was carried out. Herein, we found that the expression of miR-217 was significantly downregulated in HPAC tissues as compared with that observed in adjacent normal tissues. Further functional assays showed that restoration of the expression of miR-217 inhibited cell proliferation, invasion and migration, induced apoptosis, and caused cell cycle arrest of HPAC cells. Notably, Tpd52l2 was identified as a functional target of miR-217 in HPAC. Furthermore, an inverse correlation between miR-217 and Tpd52l2 expression was observed in the HPAC tissues. Downregulation of Tpd52l2 had an effect similar to that following overexpression of miR-217, and upregulation of Tpd52l2 reversed the effects of the overexpression of miR-217. Finally, we found that overexpression of miR-217 or knockdown of Tpd52l2 suppressed the PIK3CA/AKT signaling pathways. In addition, this may explain the effect of miR-217/Tpd52l2 on HPAC development. Taken together, these results suggest a critical role of miR-217 in suppressing proliferation, migration and invasion of HPAC cells by targeting Tpd52l2. Targeting the miR-217/Tpd52l2 axis may be a new therapeutic application with which to treat patients with HPAC in the future.

Sequences of primers and siRNAs. (DOC 26 kb)

Vasohibin-2 (VASH2) is an angiogenic factor, and has been previously reported to be a cancer-related gene, with cytoplasmic and karyotypic forms. In the current study VASH2 expression in human breast cancer tissue and adjacent non-cancerous tissue was investigated with immunohistochemistry. MCF-7 and BT474 human breast cancer cells were transfected with lentiviral constructs to generate in vitro VASH2 overexpression and knockdown models. In addition, BALB/cA nude mice were inoculated subcutaneously with transfected cells to generate in vivo models of VASH2 overexpression and knockdown. The effect of VASH2 on cell proliferation was investigated using a bromodeoxyuridine assay in vitro and immunohistochemistry of Ki67 in xenograft tumors. Growth factors were investigated using a human growth factor array, and certain factors were further confirmed by an immunoblot. The results indicated that the expression level of cytoplasmic VASH2 was higher in breast cancer tissues with a Ki67 (a proliferation marker) level of ≥14%, compared with tissues with a Ki67 level of

Lesson This case report can argue in favour of optimal surgical management for isolated metastases to the pancreas, especially in patients with low surgical risk.

Background: Cholecystectomy is carried out as one of the most extensive abdominal surgery. Patients with a long-term history of cholecystectomy may have an increased risk of pancreatic cancer. However, it’s uncertain whether prior cholecystectomy is associated with the outcome of patients with pancreatic cancer. This study was to demonstrate that prior cholecystectomy may lead to adverse perioperative outcomes in patients with pancreatic adenocarcinoma. Methods: Retrospective study comprising 755 consecutive patients with pathological diagnosis of pancreatic adenocarcinoma in Pancreas Center of the First Affiliated Hospital of Nanjing Medical University (January 2010 to December 2015) was conducted. Demographic details, surgery, tumor stage, pathology and complications were assessed. Patients were divided into NPC (no prior cholecystectomy) group and PC (prior cholecystectomy) group. PC group consist of three subgroups: RC (recent cholecystectomy), LTC (long term cholecystectomy), MTC (medium term cholecystectomy) group. Results: A total of 9.3% (70/755) of the patients underwent prior cholecystectomy, which was significantly more frequent than other operations. The rate is also abnormally higher than Chinese population (1.2%, 31/2,579). Five hundred and fifty-three patients with radical resection were selected. Compared to NPC group, PC group has more progressive tumor with relatively higher level of serum CA19-9 and possibly higher rate of lymph node metastasis. Further analysis showed that RC group had remarkably longer surgery time and more blood loss than NPC group. There was no significant difference of operative time and blood loss between LTC/MTC group and NPC group. Postoperatively, there was no statistical difference between LTC/MTC group and NPC group in complications as POPF (postoperative pancreatic fistula), DGE (delayed gastric emptying), hemorrhage and infection. There was also no notably difference in length of hospital stay these two groups. Conclusions: There is an abnormally high proportion of patients with cholecystectomy history in Chinese patients with pancreatic cancer. Patients with recent cholecystectomy history may have adverse perioperative outcome.

Middle-segment preserving pancreatectomy (MPP) is a novel procedure for treating multifocal lesions of the pancreas while preserving pancreatic function. However, long-term pancreatic function after this procedure remains unclear. The aims of this current study are to investigate short- and long-term outcomes, especially long-term pancreatic endocrine function, after MPP. From September 2011 to December 2015, 7 patients underwent MPP in our institution, and 5 cases with long-term outcomes were further analyzed in a retrospective manner. Percentage of tissue preservation was calculated using computed tomography volumetry. Serum insulin and C-peptide levels after oral glucose challenge were evaluated in 5 patients. Beta-cell secreting function including modified homeostasis model assessment of beta-cell function (HOMA2-beta), area under the curve (AUC) for C-peptide, and C-peptide index were evaluated and compared with those after pancreaticoduodenectomy (PD) and total pancreatectomy. Exocrine function was assessed based on questionnaires. Our case series included 3 women and 2 men, with median age of 50 (37–81) years. Four patients underwent pylorus-preserving PD together with distal pancreatectomy (DP), including 1 with spleen preserved. The remaining patient underwent Beger procedure and spleen-preserving DP. Median operation time and estimated intraoperative blood loss were 330 (250–615) min and 800 (400–5500) mL, respectively. Histological examination revealed 3 cases of metastatic lesion to the pancreas, 1 case of chronic pancreatitis, and 1 neuroendocrine tumor. Major postoperative complications included 3 cases of delayed gastric emptying and 2 cases of postoperative pancreatic fistula. Imaging studies showed that segments representing 18.2% to 39.5% of the pancreas with good blood supply had been preserved. With a median 35.0 months of follow-ups on pancreatic functions, only 1 patient developed new-onset diabetes mellitus of the 4 preoperatively euglycemic patients. Beta-cell function parameters in this group of patients were quite comparable to those after Whipple procedure, and seemed better than those after total pancreatectomy. No symptoms of hypoglycemia were identified in any patient, although half of the patients reported symptoms of exocrine insufficiency. In conclusion, MPP is a feasible and effective procedure for middle-segment sparing multicentric lesions in the pancreas, and patients exhibit satisfied endocrine function after surgery.

Pancreatic neuroendocrine neoplasmas (PNENs) are classified into functioningnon-functioning tumors. The radical surgery is the only effective way for the curelong-term survival. For the locoregional resectable tumors, the surgical resection is the first choice of treatment; the surgical procedures include local resection (enucleation) and standard resection. For the insulinomas and non-functioning tumors less than 2 cm, local resection (enucleation),distal pancreatectomy with spleen-preservation or segmental pancreatectomy are the commonly selected procedures. The radical resections with regional lymph nodes dissection, including pancreaticoduodenectomy, distal pancreatectomy and middle segmental pancreatectomy, should be applied for tumors more than 2 cm or malignant ones. For the locoregional advanced or unresectable functioning tumors, debulking surgery should be performed and more than 90% of the lesions including primary and metastatic tumors should be removed; for the non-functioning tumors, if complicated with biliarydigestive tract obstruction or hemorrhage, the primary tumors should be resected. The liver is the most frequent site of metastases for PNENs and three types of metastases are defined. For typeⅠmetastasis, patients are recommended for surgery if there are no contraindications; For type II metastasis, debulking surgery should be applied and at least 90% of metastatic lesions should be resected, and for patients with primary tumors removed and no extrahepatic metastases, or for patients with well-differentiated (G1/G2) tumors, liver transplantation may be indicated. For the unresectable type Ⅲ metastasis, multiple adjuvant therapies should be chosen.

// Yun-Peng Peng 1,* , Chun-Hua Xi 1,* , Yi Zhu 1,2,* , Ling-Di Yin 1 , Ji-Shu Wei 1 , Jing-Jing Zhang 1,2 , Xin-Chun Liu 1 , Song Guo 1 , Yue Fu 1 and Yi Miao 1,2 1 Department of General Surgery, Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, P.R.China 2 Institute of Tumor Biology, Jiangsu Province Academy of Clinical Medicine, Nanjing, P.R.China * These authors have contributed equally to this work Correspondence to: Yi Miao, email: // Keywords : CD226; CD96; TIGIT; NK cells; pancreatic cancer Received : February 01, 2016 Accepted : September 02, 2016 Published : September 10, 2016 Abstract The progression of pancreatic cancer (PC) is significantly associated with tumor immune escape, which may be associated with nature killer (NK) cell dysfunction. CD226, CD96, and TIGIT, which share the ligand CD155, play important roles in the regulation of NK cell function. The present study was conducted to investigate the roles of these molecules in NK cells from PC patients. Expression of these molecules on NK cells was detected from samples of 92 pancreatic cancer patients and 40 healthy controls. The expression of CD155 was also evaluated by immunohistochemistry in 88 pancreatic cancer tissues. The percentage of CD226 + and CD96 + NK cells was significantly lower in PC patients than in the healthy controls; however, the mean fluorescence intensity of CD226 and CD96 was not significantly different between the two groups. TIGIT expression on NK cells from PC patients was similar to that in the healthy controls. Additionally, the expression of CD226 was positively correlated with CD96. Further analysis demonstrated that the decrease in the percentage of CD226 + and CD96 + NK cells was associated with tumor histological grade and lymph node metastasis. Moreover, the CD155 levels in PC tissues were significantly higher than those in adjacent tissues. Our results suggest that a lower percentage of CD226 + and CD96 + NK cells may contribute to tumor immune escape in PC patients; moreover, the use of NK cells with high CD226 and CD96 expression to treat PC cells with high CD155 expression may have potential and should be explored in the future.

Hepatic infarcts or abscesses occur after hepatic artery interruption. We explored the mechanisms of hepatic deprivation-induced acute liver injury and determine whether partial portal vein arterialization attenuated this injury in rats. Male Sprague-Dawley rats underwent either complete hepatic arterial deprivation or partial portal vein arterialization, or both. Hepatic ischemia was evaluated using biochemical analysis, light microscopy, and transmission electron microscopy. Hepatic ATP levels, the expression of hypoxia- and inflammation-associated genes and proteins, and the expression of bile transporter genes were assessed. Complete dearterialization of the liver induced acute liver injury, as evidenced by the histological changes, significantly increased serum biochemical markers, decreased ATP content, increased expression of hypoxia- and inflammation-associated genes and proteins, and decreased expression of bile transporter genes. These detrimental changes were extenuated but not fully reversed by partial portal vein arterialization, which also attenuated ductular reaction and fibrosis in completely dearterialized rat livers. Collectively, complete hepatic deprivation causes severe liver injury, including bile infarcts and biloma formation. Partial portal vein arterialization seems to protect against acute ischemia-hypoxia-induced liver injury.