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Post-translational modifications of proteins in malignant transformation and tumor maintenance of pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remain poorly understood. Here, we use the KPC mouse model to examine the effect of palmitoylation on pancreatic cancer progression. ZDHHC20, upregulated by KRAS, is abnormally overexpressed and associated with poor prognosis in patients with pancreatic cancer. Dysregulation of ZDHHC20 promotes pancreatic cancer progression in a palmitoylation-dependent manner. ZDHHC20 inhibits the chaperone-mediated autophagic degradation of YTHDF3 through S-palmitoylation of Cys474, which can result in abnormal accumulation of the oncogenic product MYC and thereby promote the malignant phenotypes of cancer cells. Further, we design a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulates MYC expression and inhibits the progression of KRAS mutant pancreatic cancer. Thus, these findings highlight the therapeutic potential of targeting the ZDHHC20-YTHDF3-MYC signaling axis in pancreatic cancer., (© 2024. The Author(s).)

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Pyroptosis, as a type of inflammatory programmed cell death, has been studied in inflammatory diseases and numerous cancers but its role in pancreatic ductal adenocarcinoma (PDAC) remains further exploration., Methods: A TCGA-PDAC cohort was enrolled for bioinformatics analysis to investigate the effect of pyroptosis on the prognosis and drug sensitivity of patients. PA-TU-8988T and CFPAC-1 cells were selected for investigating the role of GSDMC in PDAC., Results: A distinct classification pattern of PDAC mediated by 21 pyroptosis-related genes (PRGs) was identified. It was suggested that higher pyroptosis activity was associated with poor prognosis of patients and higher tumor proliferation rates. We further established a prognostic model based on three PRGs (GSDMC, CASP4 and NLRP1) and the TCGA-PDAC cohort was classified into low and high-risk subgroups. It is noteworthy that the high-risk group showed significantly higher tumor proliferation rates and was proved to be highly correlated with oxaliplatin resistance. Further experiments suggested that overexpression of GSDMC promoted the proliferation and oxaliplatin resistance of PA-TU-8988T cells in vitro and vivo, while downregulation of GSDMC showed opposite effects in CFPAC-1 cells. Finally, we found that the activation of pentose phosphate pathway (PPP) was the mechanism by which GSDMC overexpression promoted the proliferation and oxaliplatin resistance of pancreatic cancer cells., Conclusions: In this study, we found that higher pyroptosis activity is associated with worse prognosis and oxaliplatin resistance of PDAC patients. In addition, as a core effector of pyroptosis, GSDMC promoted proliferation and oxaliplatin resistance of pancreatic cancer cells, which will provide new therapeutic target for PDAC patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate the safety and efficacy of the TRIANGLE operation after neoadjuvant chemotherapy in locally advanced pancreatic cancer(LAPC). Methods: This study is a retrospective case series analysis. Between January 2020 and December 2022, a total of 103 patients were diagnosed as LAPC who underwent neoadjuvant chemotherapy at the Pancreas Center, the First Affiliated Hospital of Nanjing Medical University. Among them, 26 patients (25.2%) underwent the TRIANGLE operation. There were 15 males and 11 females,with a age of (59±7) years (range: 49 to 74 years). The pre-treatment serum CA19-9( M (IQR)) was 248.8(391.6)U/ml (range: 0 to 1 428 U/ml),and the serum carcinoembryonic antigen was 4.1(3.8)μg/L(range: 1.4 to 13.4 μg/L). The neoadjuvant chemotherapy regimens included: mFOLFIRINOX regimen in 6 cases(23.1%), GnP regimen in 14 cases(53.8%), and mFOLFIRINOX+GnP regimen in 6 cases(23.1%). The follow-up duration extended until June 2023 or until the occurrence of the patient's death or loss to follow-up. The Kaplan-Meier method was employed to estimate the 1-year and 3-year overall survival rates. Results: After neoadjuvant chemotherapy,CA19-9 levels decreased by 92.3(40.1)%(range:2.1% to 97.7%). Evaluation of the response to treatment revealed 13 cases(50.0%) of stable disease,11 cases(42.3%) of partial response,and 2 cases(7.7%) of complete response. The surgical operation consisted of 12 cases(46.2%) of pancreaticoduodenectomy,12 cases(46.2%) of distal pancreatectomy,and 2 cases(7.7%) of total pancreatectomy. Margin determination was based on the "standardised pathology protocol" and the "1 mm" principle. No R2 and R1(direct) resections were observed,while the R0 resection rate was 61.5%(16/26), and the R1(1 mm) resection rate was 38.5%(10/26).The R1(1 mm) resection rates for the anterior margin,posterior margin,transected margin,portal vein groove margin,and uncinate margin were 23.1%(6/26),19.2%(5/26),12.5%(3/24),2/14, and 1/12, respectively. The overall postoperative complication rate was 57.8%(15/26),with major complications including grade B/C pancreatic fistula 25.0%(6/24,excluding 2 cases of total pancreatectomy),delayed gastric emptying in 23.1%(6/26),wound complications 11.5%(3/26),postoperative hemorrhage 7.7%(2/26), chylous fistula 7.7%(2/26) and bile fistula 3.8%(1/26). No reoperation was performed during the perioperative period(<90 days). One patient died on the 32 nd day postoperatively due to a ruptured pseudoaneurysm. A total of 25 patients were followed up,with a follow-up time of 21(24)months(range: 8 to 42 months). During the follow-up period,8 cases(32.0%) died due to tumor recurrence and metastasis,while 17 patients(68.0%) remained alive,including 11 cases of disease-free survival,5 cases of distant metastasis,and 1 case of local recurrence. The overall survival rates at 1- and 3-year after the initiation of neoadjuvant chemotherapy were 95.8% and 58.9%, respectively. The overall survival rates at 1- and 3-year after surgery were 77.7% and 57.8%, respectively. Conclusion: Performing pancreatoduodenectomy according to the Heidelberg triangle protocol in LAPC patients after neoadjuvant chemotherapy might increase the R0 resection rate without increasing perioperative mortality or the incidence of major postoperative complications.

Background: Pancreatic cancer (PC) is an extremely malignant tumor with low survival rate. Effective biomarkers and therapeutic targets for PC are lacking. The roles of circular RNAs (circRNAs) in cancers have been explored in various studies, however more work is needed to understand the functional roles of specific circRNAs. In this study, we explore the specific role and mechanism of circ&#95;0035435 (termed circCGNL1) in PC., Methods: qRT-PCR analysis was performed to detect circCGNL1 expression, indicating circCGNL1 had low expression in PC cells and tissues. The function of circCGNL1 in PC progression was examined both in vitro and in vivo. circCGNL1-interacting proteins were identified by performing RNA pulldown, co-immunoprecipitation, GST-pulldown, and dual-luciferase reporter assays., Results: Overexpressing circCGNL1 inhibited PC proliferation via promoting apoptosis. CircCGNL1 interacted with phosphatase nudix hydrolase 4 (NUDT4) to promote histone deacetylase 4 (HDAC4) dephosphorylation and subsequent HDAC4 nuclear translocation. Intranuclear HDAC4 mediated RUNX Family Transcription Factor 2 (RUNX2) deacetylation and thereby accelerating RUNX2 degradation. The transcription factor, RUNX2, inhibited guanidinoacetate N-methyltransferase (GAMT) expression. GAMT was further verified to induce PC cell apoptosis via AMPK-AKT-Bad signaling pathway., Conclusions: We discovered that circCGNL1 can interact with NUDT4 to enhance NUDT4-dependent HDAC4 dephosphorylation, subsequently activating HDAC4-RUNX2-GAMT-mediated apoptosis to suppress PC cell growth. These findings suggest new therapeutic targets for PC., (© 2024. The Author(s).)

Background: Pancreatic cancer (PC) is a malignant tumor with extremely poor prognosis, exhibiting resistance to chemotherapy and immunotherapy. Nowadays, it is ranked as the third leading cause of cancer-related mortality. Glycation is a common epigenetic modification that occurs during the tumor transformation. Many studies have demonstrated a strong correlation between glycation modification and tumor progression. However, the expression status of glycosylation-related genes (GRGs) in PC and their potential roles in PC microenvironment have not been extensively investigated., Method: We systematically integrated RNA sequencing data and clinicopathological parameters of PC patients from TCGA and GTEx databases. A GRGs risk model based on glycosylation related genes was constructed and validated in 60 patients from Pancreatic biobank via RT-PCR. R packages were used to analyze the relationships between GRGs risk scores and overall survival (OS), tumor microenvironment, immune checkpoint, chemotherapy drug sensitivity and tumor mutational load in PC patients. Panoramic analysis was performed on PC tissues. The function of B3GNT8 in PC was detected via in vitro experiments., Results: In this study, we found close correlations between GRGs risk model and PC patients' overall survival and tumor microenvironment. Multifaceted predictions demonstrated the low-risk cohort exhibits superior OS compared to high-risk counterparts. Meanwhile, the low-risk group was characterized by high immune infiltration and may be more sensitive to immunotherapy or chemotherapy. Panoramic analysis was further confirmed a significant relationship between the GRGs risk score and both the distribution of PC tumor cells as well as CD8 + T cell infiltration. In addition, we also identified a unique glycosylation gene B3GNT8, which could suppress PC progression in vitro and in vivo., Conclusion: We established a GRGs risk model, which could predict prognosis and immune infiltration in PC patients. This risk model may provide a new tool for PC precision treatment., (© 2023. The Author(s).)

Objective: To investigate the clinical efficacy of distal pancreatectomy with celiac axis resection(DP-CAR). Methods: A total of 89 consecutive patients (50 males and 39 females) who were diagnosed with pancreatic body cancer and underwent DP-CAR in Pancreas Center,First Affiliated Hospital of Nanjing Medical University between September 2013 and June 2022 were retrospectively reviewed. There were 50 males and 39 females,with age( M (IQR)) of 63(12) years(range:43 to 81 years). Perioperative parameters,pathology results and follow-up data of these patients were analyzed, χ 2 or Fisher's test for categorical data while the Wilcoxon test for quantitative data. Survival results were estimated by the Kaplan-Meier survival method. Results: Among 89 cases,cases combined with portal vein-superior mesenteric vein or organ resection accounted for 22.5% (20/89) and 42.7% (38/89),respectively. The operative time,blood loss and postoperative hospital stay were 270 (110) minutes,300 (300) ml and 13 (10) days,respectively. The overall morbidity rate was 67.4% (60/89) while the major morbidity was 11.2% (10/89). The increase rate in transient liver enzymes was 42.7% (38/89),3.4% (3/89) for liver failure,53.9% (48/89) for clinically relevant postoperative pancreatic fistula,1.1% (1/89) for bile leak,3.4% (3/89) for chylous leak of grade B and C,11.2% (10/89) for abdominal infection,9.0% (8/89) for postoperative hemorrhage of grade B and C,4.5% (4/89) for delayed gastric emptying,6.7% (6/89) for deep vein thrombosis,3.4% (3/89) for reoperation,4.5% (4/89)for hospital mortality,7.9% (7/89) for 90-day mortality. The pathological type was pancreatic cancer for all 89 cases and pancreatic ductal adenocarcinoma made up 92.1% (82/89). The tumor size was 4.8(2.0) cm, ranging from 1.5 to 12.0 cm. The number of lymph nodes harvested was 14 (13)(range:2 to 33),with a positive lymph node rate of 13.0% (24.0%). The resection R0 rate was 30.0% (24/80) and the R1 (<1 mm) rate was 58.8% (47/80). The median overall survival time was 21.3 months (95% CI : 15.6 to 24.3) and the median disease-free survival time was 19.1 months (95% CI : 11.7 to 25.1). The overall survival at 1-year and 2-year were 69.60% and 39.52%. The median survival time of 58 patients with adjuvant chemotherapy was 24.3 months (95% CI : 17.8 to 32.3) while that of 13 patients without any kind of adjuvant therapy was 8.4 months (95% CI : 7.3 to 22.3). Seven patients accepted neoadjuvant chemotherapy and there was no significant morbidity among them,with a resection rate of R0 of 5/7. Conclusion: DP-CAR is safe and feasible for selective cases,which could be more valuable in improving long-term survival when combined with (neo) adjuvant therapy.

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor, with extremely low survival rates. Identifying key signaling pathways driving PDAC progression is crucial for the development of therapies to improve patient response rates. Kindlin-2, a multi-functional protein, is involved in numerous biological processes including cell proliferation, apoptosis and migration. However, little is known about the functions of Kindlin-2 in pancreatic cancer progression in vivo . Methods: In this study, we employ an in vivo PDAC mouse model to directly investigate the role of Kindlin-2 in PDAC progression. Then, we utilized RNA-sequencing, the molecular and cellular assays to determine the molecular mechanisms by which Kindlin-2 promotes PDAC progression. Results : We show that loss of Kindlin-2 markedly inhibits Kras G12D -driven pancreatic cancer progression in vivo as well as in vitro . Furthermore, we provide new mechanistic insight into how Kindlin-2 functions in this process, A fraction of Kindlin-2 was localized to the endoplasmic reticulum and associated with the RNA helicase DDX3X, a key regulator of mRNA translation. Loss of Kindlin-2 blocked DDX3X from binding to the 5'-untranslated region of c-Myc and inhibited DDX3X-mediated c-Myc translation, leading to reduced c-Myc-mediated glucose metabolism and tumor growth. Importantly, restoration of the expression of either the full-length Kindlin-2 or c-Myc, but not that of a DDX3X-binding-defective mutant of Kindlin-2, in Kindlin-2 deficient PDAC cells, reversed the inhibition of glycolysis and pancreatic cancer progression induced by the loss of Kindlin-2. Conclusion: Our studies reveal a novel Kindlin-2-DDX3X-c-Myc signaling axis in PDAC progression and suggest that inhibition of this signaling axis may provide a promising therapeutic approach to alleviate PDAC progression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: To evaluate the positive rate of left posterior lymph nodes of the superior mesenteric artery (14cd-LN) in patients undergoing pancreaticoduodenectomy for pancreatic head carcinoma,to analyze the impact of 14cd-LN dissection on lymph node staging and tumor TNM staging. Methods: The clinical and pathological data of 103 consecutive patients with pancreatic cancer who underwent pancreaticoduodenectomy at Pancreatic Center,the First Affiliated Hospital of Nanjing Medical University from January to December 2022 were analyzed,retrospectively. There were 69 males and 34 females,with an age( M (IQR))of 63.0 (14.0) years (range:48.0 to 86.0 years). The χ 2 test and Fisher's exact probability method was used for comparison of the count data between the groups,respectively. The rank sum test was used for comparison of the measurement data between groups. Univariate and multivariate Logistic regression analyzes were used for the analysis of risk factors. Results: All 103 patients underwent pancreaticoduodenectomy successfully using the left-sided uncinate process and the artery first approach. Pathological examination showed pancreatic ductal adenocarcinoma in all cases. The location of the tumors was the pancreatic head in 40 cases,pancreatic head-uncinate in 45 cases,and pancreatic head-neck in 18 cases. Of the 103 patients,38 cases had moderately differentiated tumor and 65 cases had poorly differentiated tumor. The diameter of the lesions was 3.2 (0.8) cm (range:1.7 to 6.5 cm),the number of lymph nodes harvested was 25 (10) (range:11 to 53),and the number of positive lymph nodes was 1 (3) (range:0 to 40). The lymph node stage was stage N0 in 35 cases (34.0%),stage N1 in 43 cases (41.7%),and stage N2 in 25 cases (24.3%). TNM staging was stage ⅠA in 5 cases (4.9%),stage ⅠB in 19 cases (18.4%),stage ⅡA in 2 cases (1.9%),stage ⅡB in 38 cases (36.9%),stage Ⅲ in 38 cases (36.9%),and stage Ⅳ in 1 case (1.0%). In 103 patients with pancreatic head cancer,the overall positivity rate for 14cd-LN was 31.1% (32/103),and the positive rates for 14c-LN and 14d-LN were 21.4% (22/103) and 18.4% (19/103),respectively. 14cd-LN dissection increased the number of lymph nodes ( P <0.01) and positive lymph nodes ( P <0.01). As a result of the 14cd-LN dissection,the lymph node stage was changed in 6 patients,including 5 patients changed from N0 to N1 and 1 patient changed from N1 to N2. Similarly,the TNM stage was changed in 5 patients,including 2 patients changed from stage ⅠB to ⅡB,2 patients changed from stage ⅡA to ⅡB,and 1 patient changed from stage ⅡB to Ⅲ. Tumors located in the pancreatic head-uncinate ( OR =3.43,95% CI :1.08 to 10.93, P =0.037) and the positivity of 7,8,9,12 LN ( OR =5.45,95% CI :1.45 to 20.44, P =0.012) were independent risk factors for 14c-LN metastasis; while tumors with diameter >3 cm ( OR =3.93,95% CI :1.08 to 14.33, P =0.038) and the positivity of 7,8,9,12 LN ( OR =11.09,95% CI :2.69 to 45.80, P =0.001) were independent risk factors for 14d-LN metastasis. Conclusion: Due to its high positive rate in pancreatic head cancer,dissection of 14cd-LN during pancreaticoduodenectomy should be recommended,which can increase the number of lymph nodes harvested,provide a more accurate lymph node staging and TNM staging.

Obesity has been linked to a higher risk of pancreatic cancer. However, the mechanism by which obesity promote pancreatic carcinogenesis is still unclear. We investigated the effect of obesity on pancreatic carcinogenesis in Pdx1-Cre; LSL-Kras G12D+/- (KC) mice. Metformin was administrated to rescue the effects of obesity and NETs. The pro-tumorigenic effects of neutrophil extracellular traps (NETs) were further evaluated in vivo and vitro. We found that obesity significantly promoted the progression of murine pancreatic ductal intraepithelial neoplasia (mPanIN). The proliferation rate and epithelial-mesenchymal transition (EMT) of mPanIN ductal cells were increased in obese mice. More visceral adipocytes, PD-L1 + neutrophil infiltration and NETs formation were found in the pancreas of obese mice and visceral adipocytes could recruit neutrophils and promote NETs formation. The latter could induce an inflammatory response in ductal cells via TLR4-dependent pathways both in vivo and vitro, as demonstrated by upregulation of IL-1β. Metformin and DNase I significantly reversed the pro-tumorigenic effects of obesity and NETs in vivo and in vitro. Our study provides causal evidence for the contribution of obesity in promoting pancreatic carcinogenesis in genetic model and reveals the mechanism by NETs to regulate mPanIN progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pancreatic cancer is a lethal condition with a rising incidence and often presents at an advanced stage, contributing to abysmal five-year survival rates. Unspecific symptoms and the current lack of biomarkers and screening tools hamper early diagnosis. New technologies for liquid biopsies and their respective evaluation in pancreatic cancer patients have emerged over recent years. The term liquid biopsy summarizes the sampling and analysis of circulating tumor cells (CTCs), small extracellular vesicles (sEVs), and tumor DNA (ctDNA) from body fluids. The major advantages of liquid biopsies rely on their minimal invasiveness and repeatability, allowing serial sampling for dynamic insights to aid diagnosis, particularly early detection, risk stratification, and precision medicine in pancreatic cancer. However, liquid biopsies have not yet developed into a new pillar for clinicians' routine armamentarium. Here, we summarize recent findings on the use of liquid biopsy in pancreatic cancer patients. We discuss current challenges and future perspectives of this potentially powerful alternative to conventional tissue biopsies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Annexin A2 (ANXA2) encodes an oncoprotein whose expression has been found to correlate with poorer overall survival (OS) of pancreatic adenocarcinoma (PAAD) patients. Although peptides are available for targeting ANXA2, none of these were initially selected to target this protein specifically. Here, we took ANXA2 as a molecular target for PAAD and employed the phage display technique to screen for a new ANXA2-targeted peptide. The resultant heptapeptide, YW7, was firstly labeled with fluorescein isothiocyanate (FITC) to evaluate its selectivity in cellular uptake, and further with the near-infrared fluorescent (NIRF) dye Cy7 to assess in vivo distribution in a mouse model bearing PANC-1 human pancreatic cancer xenografic tumors. We found that both FITC-YW7 and Cy7-YW7 probes showed significantly higher uptake in PANC-1 cells compared to the HPDE6-C7 pancreatic epithelium cells. Mice intravenously injected with Cy7-YW7 showed higher tumor-to-background ratios (TBRs) (~ 2.7-fold) in tumor tissues compared to those injected with Cy7 alone. Our study suggested that YW7 is a novel peptide targeting ANXA2 and Cy7-YW7 is an NIRF probe potentially useful for the early detection of PAAD., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background/objectives: To evaluate perioperative safety and outcome of parenchyma-preserving pancreatectomy and risk factors of metastasis and recurrence for patients with solid pseudopapillary neoplasm (SPN)., Methods: Demographic data, operative and pathological parameter, follow-up data of patients with SPN undergoing their first operation were collected in our single center from May 2016 to October 2021 and compared between regular pancreatectomy group and parenchyma-preserving surgery group. Risk factors for metastasis and recurrence were investigated., Results: A total of 194 patients were included, 154 of whom were female and the average age of all patients was 33 years old. Most patients were asymptomatic, with the most common complaint being abdominal pain or discomfort. Of them, 62 patients underwent parenchyma-preserving pancreatectomy including middle segment pancreatectomy and enucleation, and 132 patients underwent regular pancreatectomy including pancreaticoduodenectomy, distal pancreatectomy and total pancreatectomy. Patients in the parenchyma-preserving surgery group had a shorter duration of operation, less intraoperative bleeding, and decreased risk of combined organ removal and blood transfusion, with no statistical significance yet. The two groups exhibited a similar incidence of postoperative complications including grade B and C pancreatic fistula, delayed gastric emptying, postoperative pancreatic hemorrhage, and other complications, as well as radiological intervention, relaparotomy and the length of postoperative hospital stay. There were no perioperative deaths. All the patients, except 18 of those who discontinued follow-up, were alive with a median follow-up time of 31 months. Three patients in the regular pancreatectomy group were observed to have liver metastasis, and no metastasis was observed in the parenchyma-preserving surgery group. Significant risk factors for tumor metastasis and recurrence were tumor size, angioinvasion, and nerve infiltration., Conclusions: Parenchyma-preserving surgery did not significantly increase the frequency of perioperative complications or recurrence and might be preferable if comprehensive conditions allow., (© 2023. The Author(s).)

Background: Pancreatic cancer (PC) is a malignant cancer with poor prognosis and high mortality rate. Sine oculis homeobox homolog 1 (SIX1) participates in the development of many cancers. However, the function of SIX1 in PC is not fully understood., Methods: SIX1 expression was determined using immunohistochemistry in PC tissues and cell lines. Glucose consumption, lactate production, and ATP assays were used to detect the function of SIX1. PC cells and NK cells were cocultured to study the effect of SIX1 overexpression in PC cells on NK cell function. Chromatin immunoprecipitation (ChIP) assays were used to study the relationship between SIX1 and lactate dehydrogenase A (LDHA). A series of in vitro and in vivo assays were further applied to elucidate the important role of the SIX1/LDHA axis in metabolism and NK cell dysfunction in PC., Results: SIX1 was significantly upregulated in PC tissue; SIX1 overexpression promoted the glycolysis capacity of PANC-1 and CFPAC-1 cells and resulted in NK cell dysfunction after the NK cells had been cultured with PC cells. LDHA inhibitor partially restored the promotion of PC caused by SIX1 overexpression. According to ChIP assays, SIX1 directly binds to the LDHA promoter region. Moreover, LDHA inhibitor and lactate transporter blocker treatment promoted the function of NK cells cocultured with PC cells. In vivo experiments yielded the same results., Conclusion: The SIX1/LDHA axis promotes lactate accumulation and leads to NK cell dysfunction in PC., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wanli Ge et al.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors and approximately 5% of patients with chronic pancreatitis (CP) inevitably develop PDAC. This study aims explore the key gene regulation involved in the progression of CP to PDAC, with a particular emphasis on the function of lncRNAs., Results: A total of 103 pancreatic tissue samples collected from 11 to 92 patients with CP and PDAC, respectively, were included in this study. After normalizing and logarithmically converting the original data, differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEGs) in each dataset were selected. To determine the main functional pathways of differential mRNAs, we further annotated DEGs using gene ontology (GO) and analyzed the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. In addition, the interaction between lncRNA-miRNA-mRNA was clarified and the protein-protein interaction (PPI) network was constructed to screen for key modules and determine hub genes. Finally, quantitative real-time polymerase chain reaction (qPCR) was used to detect the changes in non-coding RNAs and key mRNAs in the pancreatic tissues of patients with CP and PDAC. In this study, 230 lncRNAs and 17,668 mRNAs were included. There were nine upregulated lncRNAs and 188 downregulated lncRNAs. Furthermore, 2334 upregulated differential mRNAs and 10,341 downregulated differential mRNAs were included in the enrichment analysis. From the KEGG enrichment analysis, cytokine-cytokine receptor interaction, calcium signaling pathway, cAMP signaling pathway, and nicotine addiction exhibited significant differences. Additionally, a total of 52 lncRNAs, 104 miRNAs, and 312 mRNAs were included in the construction of a potential lncRNA-miRNA-mRNA regulatory network. PPI network was established and two of the five central DEGs were created in this module, suggesting that lysophosphatidic acid receptor 1 (LPAR1) and regulator of calcineurin 2 (RCAN2) may play significant roles in the progression from CP to PDAC. Finally, the PCR results suggested that LINC01547/hsa-miR-4694-3p/LPAR1 and LINC00482/hsa-miR-6756-3p/RCAN2 play important roles in the carcinogenesis process of CP., Conclusion: Two signaling axes critical in the progression of CP to PDAC were screened out. Our findings will be useful for novel insights into the molecular mechanism and potential diagnostic or therapeutic biomarkers for CP and PDAC., (© 2023. The Author(s).)

Backgroud: Pancreatic cancer (PC) is a highly invasive malignancy with extremely poor prognosis. STK31 has been identified as a cancer-testis (CT) gene, but its function in PC has not been elucidated well., Methods: The effect of STK31 on cell proliferation, migration and invasion was investigated by in vitro and in vivo experiments and total RNA sequencing and targeted bisulfite sequencing was applied to explore the potential regulatory mechanisms of STK31 in PC., Results: By analysis of tissue samples and the clinicopathologic features, we found that STK31 was reactivated in PC and associated with poor prognosis. In addition, the vitro and vivo studies indicated that STK31 could promote PC progression by facilitating cell proliferation, migration and invasion, and the indication. Targeted Bisulfite Sequencing showed that STK31 was regulated by methylation. Furthermore, the results of total RNA sequencing suggested that STK31 was closely related to signal transduction, metabolism, and the immune system., Conclusions: This study demonstrates that STK31, as a CT gene, can promote the development of PC and is regulated by methylation. STK31 could be considered as a potential therapeutic target for PC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions to pancreatic ductal adenocarcinoma that are challenging to manage due to limited imaging, cytologic, and molecular markers that accurately classify lesions, grade of dysplasia, or focus of invasion preoperatively. The objective of this pilot study was to determine the frequency and type of DNA mutations in a cohort of surgically resected, pathologically confirmed IPMN, and to determine if concordant mutations are detectable in paired pretreatment plasma samples. Formalin-fixed paraffin-embedded (FFPE) tissue from 46 surgically resected IPMNs (31 low-grade, 15 high-grade) and paired plasma from a subset of 15 IPMN cases (10 low-grade, 5 high-grade) were subjected to targeted mutation analysis using a QIAseq Targeted DNA Custom Panel. Common driver mutations were detected in FFPE from 44 of 46 (95.6%) IPMN cases spanning all grades; the most common DNA mutations included: KRAS (80%), RNF43 (24%), and GNAS (43%). Of note, we observed a significant increase in the frequency of RNF43 mutations from low-grade to high-grade IPMNs associated or concomitant with invasive carcinoma (trend test, P = 0.01). Among the subset of cases with paired plasma, driver mutations identified in the IPMNs were not detected in circulation. Overall, our results indicate that mutational burden for IPMNs is a common occurrence, even in low-grade IPMNs. Furthermore, although blood-based biopsies are an attractive, noninvasive method for detecting somatic DNA mutations, the QIAseq panel was not sensitive enough to detect driver mutations that existed in IPMN tissue using paired plasma in the volume we were able to retrieve for this retrospective study., Competing Interests: Conflicts of interest None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Genetics Society of America.)

Purpose: This study aims to study the depth of artery wall tumour invasion in patients undergoing surgery for pancreatic ductal adenocarcinoma., Methods: Specimens from 47 pancreatic cancer patients with major arterial (splenic, SA; celiac, CA; common hepatic, CHA) invasion were examined: 45 left (distal) pancreatectomies, including 11 celiac artery resections, and two total pancreatectomies. Dissection of tumour-invaded arteries in 25 fresh specimens was attempted ex vivo using the sub-adventitial dissection technique (SDT). Tumour invasion of 66 arteries was graded using the tumour-free distance (TFD) from the external elastic lamina (EEL): 0 = no arterial invasion; I = TFD ≥ 1 mm; II = TFD < 1 mm; and grade III = EEL invasion., Results: AJCC TNM staging was IA = 1 (2%), IB = 4 (9%), IIA = 5 (11%), IIB = 17(36%) and III = 20 (43%). Grade III tumour invasion was found in 17/47(36%) SAs, in 5/11 (45%) CAs and in 1/8 (13%) CHAs (p = 0.318). Attempted ex vivo SDT undertaken in 33 arteries from 25 specimens was complete in 16 and incomplete in 17 arteries. The median (IQR) TFD was 0.97 (0.11-2.54) mm in dissected and 0.14 (0.10, 0.14) mm in non-dissected SAs (p = 0.034). EEL tumour invasion occurred in 0/12 (0%) dissected compared to 7/13 (54%) non-dissected SAs (p = 0.005). Grades 0, I, II and III invasion were found in four (33%), two (17%) and six (50%), respectively, of 12 dissected SAs and grades II and III in six 6 (46%) and seven (54%), respectively, of 13 non-dissected SAs (p = 0.002)., Conclusions: The grading system described may form the basis for classification to further develop arterial dissection techniques for pancreatic cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Secreted protein acidic and rich in cysteine-like 1 (SPARCL1) was a kind of extracellular matrix glycoprotein. SPARCL1 was strongly inhibited in most cancers. However, the potential functions of SPARCL1 in the pan-cancer cohort have not been widely studied. Methods: We evaluated the transcriptional level and the prognostic value of SPARCL1 in 33 types of cancer and revealed the relationship between genetic alterations of SPARCL1 and the tumor mutation burden. Meanwhile, we assessed the correlations between SPARCL1 and tumor-infiltrating lymphocytes across cancers. Results: The transcriptional level of SPARCL1 was inhibited in most cancers. Although SPARCL1 was down-regulated in most cancers, SPARCL1 might play a protective or detrimental role in different cancers. We demonstrated that mutation count was elevated in the altered SPARCL1 group in several cancers. Additionally, we found a significant positive correlation between SPARCL1 and macrophage infiltration levels in most cancers. Especially, marker sets of M2 macrophages were strongly related to SPARCL1 in cholangiocarcinoma, colon adenocarcinoma, rectum adenocarcinoma, and pancreatic adenocarcinoma. Conclusion: Our study found that SPARCL1 might work as a biomarker for prognosis and immune infiltration in pan-cancer analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 He, Li, Yuan, Jiang and Deng.)

Background: Portal vein/superior mesenteric vein (PV/SMV) resection during distal pancreatectomy (DP) is often associated with technical difficulties due to the close anatomic relationship between pancreatic head and PV/SMV. In this paper, we present our operative technique and short-term outcomes of DP combined with venous resection (DP-VR) for left-sided pancreatic cancer (PC)., Methods: We reviewed 368 consecutive cases of DP for PC from January 2013 to December 2018 in our institution, and identified 41 patients (11.1%) who had undergone DP-VR. The remaining 327 DP patients (88.9%) were matched to DP-VR using propensity scores in the proportion of 1:2. Demographics, intraoperative details, postoperative complications and the pathological results were compared between the two groups., Results: Out of the 41 DP-VR cases, in 14 (34.1%) venous resection with primary closure was performed, while the remaining 27 (65.9%) underwent end-to-end anastomosis without graft. A propensity-score-matched analysis revealed that DP-VR caused an increased risk of postoperative bleeding (17.1% vs. 3.7%, P = 0.016) and delayed gastric emptying (9.8% vs. 1.2%, P = 0.042) compared to standard DP. Overall morbidity (46.3% vs. 36.6%, P = 0.332), postoperative pancreatic fistula (31.7% vs. 26.8%, P = 0.672), R0 resection (58.5% vs. 67.1%, P = 0.223), 30-day reoperation (2.4% vs. 3.7%, P = 0.719), and 90-day mortality (0% vs. 2.5%, P = 0.550) were comparable between the two groups. In postoperative computed tomographic scans of 34 patients (82.9%) at a 90-day follow-up, PV/SMV stenosis was suggested in two patients (5.9%)., Conclusion: Despite the higher rates of postoperative bleeding, DP-VR was found to be a feasible and safe surgery with acceptable postoperative morbidity and mortality compared to standard DP for left-sided pancreatic cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We aimed to explore whether body mass index (BMI) and albumin were associated with overall survival (OS) in individuals who underwent pancreaticoduodenectomy (PD) for cancer., Methods: Three-hundred twenty-nine consecutive patients who underwent PD for cancer were enrolled from January 2020 to December 2020. All clinicopathological information was extracted based on medical records. The survival follow-ups were regularly performed and ended on June 30, 2021. The Kaplan-Meier survival analysis and univariate and multivariate Cox proportional-hazards models were used to assess the association of BMI and albumin with OS., Results: Of the 329 patients, 186 (56.5%) were male, and median age at admission was 65.0 (56.0-71.0) years. There were 258 patients (78.4%) with BMI < 25.0 kg/m 2 and 89 patients (27.05%) with albumin < 35.0 g/L respectively. In overall cohort, BMI < 25.0 kg/m 2 was associated with OS (adjusted HR = 3.516, 95% CI = 1.076-11.492, P = 0.037). In contrast, albumin < 35.0 g/L did not affect OS. Subgroup analysis showed, in patients with pancreas lesion, BMI < 25.0 kg/m 2 had a higher risk for OS compared to BMI ≥ 25.0 kg/m 2 (adjusted HR = 3.209, 95% CI = 0.985-10.451, P = 0.048), while albumin < 35.0 g/L was not linked to OS. In patients with lesion in ampulla of Vater, duodenum, or common bile duct, there was no significant association of BMI and albumin with OS., Conclusions: BMI, rather than serum albumin, was associated with OS in patients who underwent PD for cancer., (© 2022. The Author(s).)

Background: circular RNAs (circRNAs) have been reported to play crucial roles in the biology of different cancers. However, little is known about the function of circSTX6 (hsa&#95;circ&#95;0007905) in pancreatic ductal adenocarcinoma (PDAC)., Methods: circSTX6, a circRNA containing exons 4, 5, 6 and 7 of the STX6 gene, was identified by RNA sequencing and detected by quantitative reverse transcription PCR (qRT-PCR). The biological function of circSTX6 was assessed in vitro and in vivo. The relationship between circSTX6 and miR-449b-5p was confirmed by biotin-coupled circRNA capture, fluorescence in situ hybridization (FISH) and luciferase reporter assays. The interaction of circSTX6 with Cullin 2 (CUL2) was verified by RNA-protein RNA pull-down, RNA immunoprecipitation (RIP) and western blotting assays., Results: circSTX6 was frequently upregulated in PDAC tissues, and circSTX6 overexpression promoted tumor proliferation and metastasis both in vitro and in vivo. Furthermore, circSTX6 expression was associated with tumor differentiation and N stage. Mechanistically, circSTX6 regulated the expression of non-muscle myosin heavy chain 9 (MYH9) by sponging miR-449b-5p. Moreover, circSTX6 was confirmed to participate in the ubiquitin-dependent degradation of hypoxia-inducible factor 1-alpha (HIF1A) by interacting with CUL2 and subsequently accelerating the transcription of MYH9., Conclusions: Our findings indicate that circSTX6 facilitates proliferation and metastasis of PDAC cells by regulating the expression of MYH9 through the circSTX6/miR-449b-5p axis and circSTX6/CUL2/HIF1A signaling pathway. Therefore, circSTX6 could serve as a potential therapeutic target for the treatment of PDAC., (© 2022. The Author(s).)

Objective: To compare the outcomes of modified Appleby procedure and sub-adventitial divestment technique for locally advanced or borderline resectable pancreatic body cancer. Methods: A total of consecutive 58 patients(33 males and 25 females) who were diagnosed as locally advanced or borderline resectable pancreatic body cancer and underwent distal pancreatectomy at Pancreas Center, First Affiliated Hospital of Nanjing Medical University between September 2013 and May 2019 were retrospectively reviewed. The age( M (IQR)) was 62(9)years(range: 43 to 79 years). Thirty-one patients underwent distal pancreatectomy with celiac axis resection (DP-CAR) and 27 patients underwent distal pancreatectomy with sub-adventitial divestment technique(SDT). Perioperative parameters and follow-up data of these patients were analyzed. Quantitative data were compared with Wilcoxon test while categorical variables were compared with χ 2 test or Fisher's exact test. Survival results were estimated by the Kaplan-Meier survival method with a Log-rank test. Results: There were no differences in age,gender,body mass index,abdominal symptoms,comorbidity or preoperative serum CA19-9 between two groups(all P >0.05). Obvious preoperative weight loss was more common in the group of SDT(48.1%(13/27) vs. 19.4%(6/31),χ²=5.431, P =0.020). Longer operative time(310(123) minutes vs . 254(137)minutes, Z =2.277, P =0.023),higher rate of combined organ resection(41.9%(13/31) vs. 14.8%(4/27),χ²=5.123, P =0.041) and longer postoperative hospital stay(15(10) days vs. 11(5)days, Z =2.292, P =0.022) were observed in the group of DP-CAR. Moreover,rate of overall morbidities was also higher (71.0%(22/31) vs. 29.6%(8/27),χ 2 =9.876, P =0.003),implicated by clinically relevant postoperative pancreatic fistula(61.3%(19/31) vs. 29.6%(8/27),χ 2 =5.814, P =0.020) in the DP-CAR group. Tumor size of the DP-CAR group was bigger(4.9(1.5)cm vs. 4.0(1.2)cm, Z =2.343, P =0.019) but no difference was seen between the DP-CAR group and SDT group in R0+R1(<1 mm) resection rate (84.0%(21/25) vs. 90.0%(18/20), P =0.678) and LNR(12.0(23.0)% vs . 9.0(18.0)%, Z =1.238, P =0.216),as well as median disease free survival(11.7 months vs. 11.4 months, Z =0.019, P =0.892) and median overall survival(16.3 months vs. 13.7 months, Z =0.172, P =0.679). Conclusions: Both DP-CAR and distal pancreatectomy with SDT are relatively safe and feasible for locally advanced or borderline resectable pancreatic body cancer. Compared with arterial resection,SDT may contribute to lower rates of postoperative complications and shorter duration of hospitalization,but no significant benefit is seen in long-term survival.

Competing Interests: Declaration of interests The authors report no conflict of interests.

Importance: 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., Objective: To assess the prevalence of germline sequence variations in patients with pancreatic diseases in China., Design, Setting, and Participants: 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., Main Outcomes and Measures: 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., Results: 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., Conclusions and Relevance: 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.

Objective: To compare and analyze the clinical efficacy of pancreaticoduodenectomy for distal bile duct cancer and pancreatic head cancer. Methods: Clinical data of 1 005 patients who underwent pancreaticoduodenectomy and postoperative pathological examination confirmed the diagnosis of distal bile duct cancer and pancreatic head cancer at the Pancreas Center of the First Affiliated Hospital of Nanjing Medical University from January 2016 to December 2020 were analyzed retrospectively. There were 112 cases in the distal bile duct cancer group, 71 males and 41 females,with age ( M (IQR)) of 65(15) years(range: 40 to 87 years); 893 cases in the pancreatic head cancer group, 534 males and 359 females,with age of 64(13)years(range: 16 to 91 years). The differences between clinicopathological characteristics and postoperative overall survival of the two groups were analyzed by χ 2 test, Fisher's exact probability method, rank sum test or log-rank test, respectively. The difference in postoperative overall survival between the two groups was compared using Kaplan-Meier method after propensity score matching (1∶1). Results: Compared with the pancreatic head cancer group,the distal bile duct cancer group had shorter operative time (240.0(134.0) minutes vs. 261.0(97.0) minutes, Z =2.712, P =0.007),less proportion of combined venous resection (4.5% (5/112) vs. 19.4% (173/893), χ²=15.177, P <0.01),smaller tumor diameter (2.0(1.0) cm vs. 3.0(1.5) cm, Z =10.567, P <0.01),higher well/moderate differentiation ratio (51.4% (56/112) vs. 38.0% (337/893), χ²=7.328, P =0.007),fewer positive lymph nodes (0(1) vs . 1(3), Z =5.824, P <0.01),and higher R0 resection rate (77.7% (87/112) vs. 38.3%(342/893), χ²=64.399, P <0.01),but with a higher incidence of overall postoperative complications (50.0% (56/112) vs. 36.3% (324/892), χ²=7.913, P =0.005),postoperative pancreatic fistula (28.6% (32/112) vs. 13.9% (124/893), χ²=16.318, P <0.01),and postoperative abdominal infection (21.4% (24/112) vs. 8.6% (77/892), χ²=18.001, P <0.01). After propensity score matching, there was no statistical difference in postoperative overall survival time between patients in the distal bile duct cancer group and the pancreatic head cancer group (50.6 months vs. 35.1 months, Z =1.640, P =0.201),and multifactorial analysis showed that tumor site was not an independent risk factor affecting the prognosis of patients in both groups after matching ( HR =0.73,95% CI :0.43 to 1.23, P =0.238). Conclusions: Patients with distal bile duct cancer are more likely to benefit from early diagnosis and surgical treatment than patients with pancreatic head cancer,but with a relative higher postoperative complication rates. The different tumor origin site is not an independent risk factor for prognosis of patients with distal bile duct cancer and pancreatic head cancer after propensity score matching.

RNA methylation modification is a key process in epigenetics that regulates posttranscriptional gene expression. With advances in next-generation sequencing technology, 5-methylcytosine (m5C) modification has also been found in multiple RNAs. Long non-coding RNAs (lncRNAs) were proved to have a key role in cancer progression and closely related to the tumor immune microenvironment. Thus, based on the PDAC patients' clinical information and genetic transcriptome data from the TCGA database, we performed a detailed bioinformatic analysis to establish a m5C-related lncRNA prognostic risk model for PDAC patients and discovered the relationship between the risk model and PDAC immune microenvironment. Pearson correlation coefficient analysis was applied to conduct a m5C regulatory gene and m5C-related lncRNA co-expression network. Expression of m5C-related lncRNAs screened by univariate regression analysis with prognostic value showed a significant difference between pancreatic cancer and normal tissues. The least absolute shrinkage and selection operator (LASSO) Cox regression method was applied to determine an 8-m5C-related lncRNA prognostic risk model. We used principal component analysis to indicate that the risk model could distinguish all the samples clearly. The clinical nomogram also accurately predicted 1-, 1.5-, 2-, and 3-year survival time among PDAC patients. Additionally, this risk model was validated in the entire group and sub-test groups using KM analysis and ROC analysis. Combined with the clinical characteristics, the risk score was found to be an independent factor for predicting the survival of PDAC patients. Furthermore, the association between the risk model and tumor immune microenvironment was evaluated via the ESTIMATE R package and CIBERSORT method. Consequently, the results indicated that immune cells were associated with m5C-related lncRNA risk model scores and had different distribution in the high- and low-risk groups. Based on all these analyses, the m5C-related lncRNA risk model could be a reliable prognostic tool and therapeutic target for PDAC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yuan, Liu, Zhao, Wu, Chen, Chen, Shen, Yang, Fan, Xiao and Jiang.)

Long non-coding RNAs (LncRNAs) have crucial function in epithelial-mesenchymal transition (EMT) in pancreatic cancer. It is necessary to comprehensively analyze the potential role of EMT-related lncRNA in pancreatic cancer. In the present study, genomic data of pancreatic cancer from the TCGA database were downloaded and we found 368 EMT-related lncRNAs. According to the expression characteristics of prognostic-related lncRNAs, all samples could be divided into two clusters with different clinical outcomes and different tumor microenvironments. Moreover, an eleven EMT-related lncRNAs signature was established and verified. Patients with pancreatic cancer in the high-risk group had a shorter overall survival than those in the low-risk group and the signature could act as an independent prognostic factor. Further analysis suggested that the EMT-related lncRNAs might affect the prognosis of patients through immune mechanisms. All findings indicated that the signature and eleven lncRNAs might serve as potential prognostic biomarkers and therapeutic targets in the treatment of pancreatic cancer.

Pancreatic adenocarcinoma (PAAD) ranks among the most lethal cancers worldwide with high mortality. A marked increase in the level of long non-coding RNA LINC00460 was reported in PAAD patients, in comparison with the healthy controls. However, the underlying mechanisms of the above phenomenon are not yet well understood. Hence, the present study was designed to investigate the molecular mechanism underlying the role of LINC00460 in proliferation, migration and invasion of pancreatic cancer (PC) cells. It was found in our study that LINC00460 knockdown inhibited SW1990 cell proliferation, migration and invasion and promoted its apoptosis. Moreover, miR-320b was targeted straight and its expression was downregulated by LINC00460, whose knockdown led to a reduction in ARF1 expression. Interestingly, miR-320b downregulation partly reversed the effect of LINC00460 knockdown on the proliferation, migration, invasion and apoptosis of SW1990 cells, as well as ARF1expression. In conclusion, LINC00460 knockdown inhibited the proliferation, migration and invasion, and promotes the apoptosis of SW1990 cells via modulation of the miR-320b/ARF1 axis. Thus, LINC00460 can be perceived as a promising target in the treatment of PAAD.

Background: Circular RNAs (circRNAs) are becoming a unique member of non-coding RNAs (ncRNAs) with emerging evidence of their regulatory roles in various cancers. However, with regards to pancreatic ductal adenocarcinoma (PDAC), circRNAs biological functions remain largely unknown and worth investigation for potential therapeutic innovation., Methods: In our previous study, next-generation sequencing was used to identify differentially expressed circRNAs in 3 pairs of PDAC and adjacent normal tissues. Further validation of circRHOBTB3 expression in PDAC tissues and cell lines and gain-and-loss function experiments verified the oncogenic role of circRHOBTB3. The mechanism of circRHOBTB3 regulatory role was validated by pull-down assays, RIP, luciferase reporter assays. The autophagy response of PANC-1 and MiaPaca-2 cells were detected by mCherry-GFP-LC3B labeling and confocal microscopy, transmission electron microscopy and protein levels of LC3B or p62 via Western blot., Results: circRHOBTB3 is highly expressed in PDAC cell lines and tissues, which also promotes PDAC autophagy and then progression in vitro and in vivo. Mechanistically, circRHOBTB3 directly binds to miR-600 and subsequently acts as a miRNA-sponge to maintain the expression level of miR-600-targeted gene NACC1, which facilitates the autophagy response of PDAC cells for adaptation of proliferation via Akt/mTOR pathway. Moreover, the RNA-binding protein FUS (FUS) directly binds to pre-RHOBTB3 mRNA to mediate the biogenesis of circRHOBTB3. Clinically, circRHOBTB3, miR-600 and NACC1 expression levels are correlated with the prognosis of PDAC patients and serve as independent risk factors for PDAC patients., Conclusions: FUS-mediated circRHOBTB3 functions as a tumor activator to promote PDAC cell proliferation by modulating miR-600/NACC1/Akt/mTOR axis regulated autophagy., (© 2021. The Author(s).)

Objective: To evaluate the value of left-sided uncinate process first approach in pancreaticoduodenectomy. Methods: The clinical data of 152 patients who underwent the left-sided uncinate process first approach during pancreaticoduodenectomy at Pancreas Center, the First Affiliated Hospital of Nanjing Medical University from January 2020 to December 2020 were analyzed retrospectively. There were 64 females and 88 males,with age( M ( Q R )) of 62.0(14.7)years(range:16.0 to 84.0 years). The clinical date of 117 patients who underwent pancreaticoduodenectomy without using left-sided uncinate process first approach in the same period was selected as the control group,including 65 females and 52 males,with age of 64.0(13.0) years(range:13.0 to 84.0 years). Fisher exact probability method and t test were used to compare the data between the two groups,rank sum test was used for comparison of continuous variables between the two groups. Results: Pancreaticoduodenectomy was successfully performed in 152 patients in left-sided uncinate process first approach group. The operation time was 222.5(77.0) minutes(range:117.0 to 480.0 minutes),the time of uncinate process resection from left-side(the time from jejunum dissection to complete dissociation of the uncinate process) was 11.0(4.5) minutes(range:7.5 to 20.0 minutes),the time of pancreatic head resection (the time from jejunum dissection to pancreaticoduodenal specimen removal) was 26.0(8.5) minutes(range:20.0 to 41.0 minutes),the intraoperative blood loss was 200(150) ml(range:50 to 800 ml),and the intraoperative blood transfusion rate was 9.2% (14/152). Postoperative conditions:The postoperative hospital stay was 12 (9) d(range:6 to 55 d),the overall incidence of postoperative complications was 59.9%(91/152),and there was no perioperative death. Pathological results:The R0 resection rate of periampullary malignant tumor was 64.3%(77/112),with negative rate of uncinate process margin was 91.1%(102/112). The R0 resection rate of pancreatic ductal adenocarcinoma was 46.9%,with negative rate of uncinate process margin was 89.1%(57/64). Compared with the non-left-sided uncinate process first approach group(222.5(77.0) minutes, 9.2%(14/152)),the left-sided uncinate process first approach group had shorter operation time(246.0(94.0) minutes) ( Z =3.964, P <0.01),less intraoperative blood loss (18.8%(22/117))( Z =4.843, P <0.01),and lower intraoperative blood transfusion rate(χ²=5.248, P= 0.029). However,there were no significant differences between two groups in postoperative hospital stay( Z =1.682, P =0.093),postoperative overall complications( P =0.549),R0 resection rate of periampullary malignant tumor(χ²=2.012, P= 0.156),and negative rate of uncinate process margin(χ²=2.108, P= 0.147). Conclusions: The "left-sided uncinate process first approach" could completely resect uncinate process under a direct vision,especially when the uncinate process was behind the superior mesenteric artery or beyond the left lateral margin of the superior mesenteric artery. The "left-sided uncinate process first approach" might increase the negative rate of uncinate process margin and R0 resection rate for periampullary malignant tumor.

Objective: To investigate the value of radiomic features at contrast-enhanced CT integrated with clinic-pathologic features and body composition measures for predicting survival after upfront surgery in patients with pancreatic ductal adenocarcinoma (PDAC)., Methods: Two hundred and ninety-nine patients with PDAC who underwent surgical resection were included and allocated to training set (210 patients) and validation set (89 patients). The radiomics signature for predicting survival was constructed by using the least absolute shrinkage and selection operator Cox regression. Multivariable Cox regression analysis was used to construct a radiomics model based on radiomics signature, clinic-pathologic features and body composition measures. A clinical model without radiomics signature was also developed. Model performance was analyzed by Harrell's concordance index (C-index) and time-independent receiver operating characteristic (ROC) analysis. The Kaplan-Meier (KM) method was used for survival analysis., Results: Five independent variables were selected for the radiomics model: radiomics signature, carbohydrate antigen 19-9, skeletal muscle index, histologic grade and postoperative chemotherapy. The radiomics-based model provided better predictive performance (C-index = 0.73; all p < 0.05) than the clinical model without radiomics signature and American Joint Committee on Cancer (AJCC) TNM staging system. Patients were stratified as high-risk and low-risk group by the radiomics model. The KM analysis showed a significant difference between two groups (p < 0.05)., Conclusion: The radiovdmics-based model integrating with clinic-pathologic features and body composition measures could predict survival after surgical resection in PDAC patients., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in association with this study., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Modern pancreatic cancer surgery changed with the introduction of effective neoadjuvant therapies. Complete tumor resection is the mainstay for long-term, disease-free, and overall survival and has been a prerequisite for decreasing local recurrence. The medial resection margin in the area of the superior mesenteric vessels limits the radicalness of the resection, especially in borderline and locally advanced cases. Therefore, the periarterial soft tissue around the peripancreatic visceral arteries must be completely cleared. This procedure, namely periarterial divestment, is technically demanding but often represents an alternative to arterial resection., Objective: Here we describe the technique and our initial experience with periarterial divestment along the peripancreatic visceral arteries during pancreatic surgery. This technique, in combination with previously published resection strategies, such as artery first maneuver and mesenterico-portal venous bypass first, enables tumor resection in locally advanced pancreatic cancer., Conclusion: Periarterial divestment can prevent the need for arterial resection in borderline and locally advanced pancreatic cancer, especially after neoadjuvant therapy. The feasibility, improved safety, and oncologic equivalence of arterial divestment versus arterial resection for pancreatic cancer surgery must be evaluated by clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: 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., Methods: 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., Results: 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., Conclusions: 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.

Pancreatic cancer (PC) is one of the most malignant gastrointestinal tumors and the 5-year survival is only 9%. The expression of miRNAs in serum has been proved to be related to tumorigenesis and development of cancers. The miRNA targets and gene targets were predicted in microRNA.org, miRDB, TargetScan, and RNAInter. The expression data of STK31 (Serine/Threonine Kinase 31) and miRNAs generated from PC samples was from TCGA and the relationship of expression of STK31 and miR-543 was confirmed in PC samples from our center. Double luciferase reporter gene assay was used to demonstrate the direct binding between miR-543 and STK31. The effect of expression level of miRNAs on survival time was assessed by Kaplan-Meier curves. The Go Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of miR-543-related genes were performed. The results showed that miR-543 had a statistically significant correlation with the expression of STK31 and contained the direct binding site with STK31. The expression level of miR-543 may affect the survival of PC. The results of GO and KEGG pathway analysis showed that miR-543 might play a key role in Insulin signaling pathway. MiR-543 could be combined with STK31 and affect the expression of STK31. The expression of miR-543 could also predict the survival of patients with PC, which suggested that miR-543 might play an important role in PC. The GO and KEGG pathway analysis also displayed that miR-543 was involved in several other pathways of pancreas., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

A novel antisense lncRNA NT5E was identified in a previous microarray that was clearly up-regulated in pancreatic cancer (PC) tissues. However, its biological function remains unclear. Thus, we aimed to explore its function and clinical significance in PC. The lncNT5E expression was determined in PC specimens and cell lines. In vitro and in vivo studies detected the impact of lncNT5E depletion on PC cell proliferation, migration and invasion. Western blotting investigated the epithelial-mesenchymal transition (EMT) markers. The interaction between lncNT5E and the promoter region of SYNCRIP was detected by dual-luciferase reporter assay. The role of lncNT5E in modulating SYNCRIP was investigated in vitro. Our results showed that lncNT5E was significantly up-regulated in PC tissues and cell lines and associated with poor prognosis. LncNT5E depletion inhibited PC cell proliferation, migration, invasion and EMT in vitro and caused tumorigenesis arrest in vivo. Furthermore, SYNCRIP knockdown had effects similar to those of lncNT5E depletion. A significant positive relationship was observed between lncNT5E and SYNCRIP. Moreover, the dual-luciferase reporter assays indicated that lncNT5E depletion significantly inhibited SYNCRIP promoter activity. Importantly, the malignant phenotypes of lncNT5E depletion were rescued by overexpressing SYNCRIP. In conclusion, lncNT5E predicts poor prognosis and promotes PC progression by modulating SYNCRIP expression., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Pancreatic cancer patients are asymptomatic at early stages and leading to late diagnoses. Additionally, pancreatic cancer easily metastasizes and is resistant to radiotherapy and chemotherapy. Therefore, it is critical to understand the underlying molecular mechanisms involved in pancreatic cancer to develop more efficient diagnostic and treatment strategies. In this study, we demonstrated that circRHOT1 was overexpressed in pancreatic cancer tissues and cell lines, and it was found to directly bind to miR-125a-3p, acting as an endogenous sponge to inhibit its activity. Knockdown of circRHOT1 expression significantly inhibited proliferation as well as invasion, and it promoted apoptosis of pancreatic cancer cells via the regulation of E2F3 through the targeting of miR-125a-3p. Taken together, our results showed that circRHOT1 plays critical roles in regulating the biological functions of pancreatic cancer cells, suggesting that circRHOT1 may serve as a potential diagnostic marker and therapeutic target for patients with pancreatic cancer., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: To compare the short-term outcomes and long-term survivals of radical antegrade modular pancreatosplenectomy(RAMPS) and conventional distal pancreatectomy(CDP). Methods: A total of consecutive 304 patients including 176 male patients and 128 female patients who underwent RAMPS or CDP at Pancreas Center, the First Affiliated Hospital with Nanjing Medical University from May 2013 to June 2019 were retrospectively analyzed. The median age was 64.1 years old (range:39 to 85 years old). There were 101 patients underwent RAMPS and 203 patients underwent CDP. Measurement data with skewed distribution were presented as ( M ( Q(R) )) and comparison between groups was evaluated with the Wilcoxon rank sum test. Count data were analyzed using the χ(2) test or Fisher exact probability. Survival analyses were performed by the Kaplan-Meier method after a one to one propensity score matching(PSM) conducted to balance several variables. Results: An eighty-one to eighty-one patients were enrolled after PSM. The overall morbidity was 32.1%(26/81)and there were no in-hospital mortalities in RAMPS. The median operative time was 225(95)minutes in RAMPS, not significantly longer as compared with CDP(210(130)minutes, P= 0.916). The median greatest tumor diameter in RAMPS was 4.0(2.3)cm, not significantly larger as compared with CDP(4.5(2.2)cm, P= 0.520).There were 34.6%(28/81)patients who presented with T4 tumors by 8(th) AJCC TNM staging system in RAMPS, which was not significantly different as compared with CDP(39.5%, χ(2)=0.574, P= 0.902). The median number of examined lymph nodes was 9(9), not significantly greater in RAMPS as compared with CDP(10(11), P= 0.992). The rate of negative posterior margins using 1 mm rule in RAMPS was 70.3%(52/74), significantly higher as compared with CDP(53.6%(30/56), χ(2)=3.817, P= 0.044). The overall R0 resection rate was 44.6% (33/74) in RAMPS and 37.5% (21/56) in CDP, which was not significantly different(χ(2)=0.663, P= 0.474). The median overall survival was 16.5 months for RAMPS, 25.2 months for CDP, and there was no statistical difference between two groups( P= 0.981). The median overall survival was 16.0 months for patients with preoperative CA19-9≥300 U/ml who underwent RAMPS, 10.1 months for patients who underwent CDP, without significant difference( P= 0.082). Conclusions: RAMPS can improve the rate of negative posterior margins by 1 mm rule and probably increase R0 resection rate and the harvest of lymph nodes. RAMPS may be beneficial to some patients with preoperative CA19-9≥300 U/ml.

Background: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive pancreatic precursor lesions that can potentially develop into invasive pancreatic ductal adenocarcinoma. Currently, the International Consensus Guidelines (ICG) for IPMNs provides the basis for evaluating suspected IPMNs on computed tomography (CT) imaging. Despite using the ICG, it remains challenging to accurately predict whether IPMNs harbor high grade or invasive disease which would warrant surgical resection. A supplementary quantitative radiological tool, radiomics, may improve diagnostic accuracy of radiological evaluation of IPMNs. We hypothesized that using CT whole lesion radiomics features in conjunction with the ICG could improve the diagnostic accuracy of predicting IPMN histology., Aim: To evaluate whole lesion CT radiomic analysis of IPMNs for predicting malignant histology compared to International Consensus Guidelines., Methods: Fifty-one subjects who had pancreatic surgical resection at our institution with histology demonstrating IPMN and available preoperative CT imaging were included in this retrospective cohort. Whole lesion semi-automated segmentation was performed on each preoperative CT using Healthmyne software (Healthmyne, Madison, WI). Thirty-nine relevant radiomic features were extracted from each lesion on each available contrast phase. Univariate analysis of the 39 radiomics features was performed for each contrast phase and values were compared between malignant and benign IPMN groups using logistic regression. Conventional quantitative and qualitative CT measurements were also compared between groups, via χ 2 (categorical) and Mann Whitney U (continuous) variables., Results: Twenty-nine subjects (15 males, age 71 ± 9 years) with high grade or invasive tumor histology comprised the "malignant" cohort, while 22 subjects (11 males, age 70 ± 7 years) with low grade tumor histology were included in the "benign" cohort. Radiomic analysis showed 18/39 precontrast, 19/39 arterial phase, and 21/39 venous phase features differentiated malignant from benign IPMNs ( P < 0.05). Multivariate analysis including only ICG criteria yielded two significant variables: thickened and enhancing cyst wall and enhancing mural nodule < 5 mm with an AUC (95%CI) of 0.817 (0.709-0.926). Multivariable post contrast radiomics achieved an AUC (95%CI) of 0.87 (0.767-0.974) for a model including arterial phase radiomics features and 0.834 (0.716-0.953) for a model including venous phase radiomics features. Combined multivariable model including conventional variables and arterial phase radiomics features achieved an AUC (95%CI) of 0.93 (0.85-1.0) with a 5-fold cross validation AUC of 0.90., Conclusion: Multi-phase CT radiomics evaluation could play a role in improving predictive capability in diagnosing malignancy in IPMNs. Future larger studies may help determine the clinical significance of our findings., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

This study is to analyze differentially expressed genes (DEGs) and mutation signatures of pancreatic head cancer and pancreatic body/tail cancer. Pancreatic Adenocarcinoma (PAAD) RNA-seq data, mutation data and clinical data were downloaded and collected from The Cancer Genome Atlas (TCGA), FireHose and CBioPortal. According to the anatomic location, the patients were divided into 146 cases of pancreatic head cancer and 28 cases of pancreatic body/tail cancer. Then survival analysis was performed by Kaplan-Meier and log-rank test. Furthermore, DEGs were screened by R package Deseq2. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) were then carried out by DAVID and String. Online tool TIMER was used to analyze the immune cells infiltration. R package maftools and GenVisR were applied to analyze frequently mutated genes and mutant-allele tumor heterogeneity (MATH) of PAAD. Survival of patients with pancreatic body/tail cancer was better than those with pancreatic head cancer (median survival, 24.05 vs 19.45 months, p = 0.048). And 496 significant DEGs (|log2 FoldChange| > 1.5,false discovery rate (FDR) < 0.05) were identified, including 253 downregulated genes and 243 upregulated genes. And there were 13 Go terms (4 biological processes, 6 cellular components and 3 molecular functions) and 3 KEGG pathways (Pancreatic secretion, Fat digestion and absorption, Protein digestion and absorption) (FDR < 0.05). B cells and CD4 + T cells infiltration were more significant in pancreatic head cancer. MATH scores of pancreatic body/tail cancer were higher than pancreatic head cancer, while χ 2 test of top 10 frequently mutated genes showed little difference between them. There were prognostic and genetic differences between pancreatic head cancer and pancreatic body/tail cancer. PAAD originated from different location may have different biology natures and should not be treated with same strategy.

Background: Prognostic prediction had been widely used in various cancer entities, from early screening to end-stage patient caring. Currently, there is hardly any well-validated nomogram which exists for long-term survival prediction in pancreatic adenocarcinoma (PC) patients in a post-surgery setting. Our objectives are to identify possible prognostic factors in PC patients following radical resection and to develop a prognostic nomogram based on independent survival predictors., Methods: From 2009 to 2014, a total of 432 PC patients who underwent curative intended surgeries with complete follow-up data were included in this current retrospective long-term survival analysis. Clinicopathological data were extracted from medical records, and all missing values (percentage 0.9-8.3%) were imputed five times with the "PMM" method. Cox proportional hazards models were utilized. A nomogram was formulated based on results from the multivariate regression model so as to predict OS at 1-, 2- and 3-year as well as median OS. Validations, including discrimination and calibration, were carried out with 1000 bootstrap resamples. External validation was conducted in order to verify the accuracy of our nomogram at 1 and 2 years by utilizing the clinicopathological data of 122 PC patients who underwent curative intended surgeries in 2015 in our centre., Results: Age, abdominal pain, back pain, tumour location, preoperative neutrophil-lymphocyte ratio, preoperative CA19-9, tumour differentiation, microscopic nerve invasion, microscopic vascular invasion, T stage, lymph node ratio, M stage and adjuvant chemotherapy were all assembled into nomogram. The concordance index (C-index) of internal and external validation was 0.702 and 0.688, respectively. The C-index of the TNM staging system was 0.572 (P < 0.001 vs. nomogram)., Conclusion: Our prognostic nomogram based on clinicopathological parameters shows good performance in long-term survival prediction in PC patients following radical surgery and could play a role in further clinical utilization.

Background: Intraductal papillary mucinous neoplasms (IPMNs) are pre-malignant pancreatic cysts detected by imaging. Cyst size is one of many features evaluated on computed tomography (CT), magnetic resonance imaging (MRI), or endoscopic ultrasonography (EUS) to help guide IPMN management. Our objective was to determine which imaging modality best predicts pathological cyst size., Methods: We analyzed records for 57 IPMN cases surgically treated at Moffitt Cancer Center from 2008 to 2016 for whom pre-operative CT, MRI, and EUS IPMN cyst size and post-operative pathological cyst size values were available. Long axis cyst diameter measurements were compared to each other and corresponding pathological cyst measurements using within-subjects ANOVA, Bland-Altman analysis, and linear regression. Consensus measurements were also performed on CT and MRI images., Results: Cyst size measured via CT and MRI overestimated pathological size by 0.33 cm and 0.27 cm, respectively, whereas EUS underestimated pathological size by 0.05 cm and had the narrowest 95% limit of agreement (LOA). Among pathologically-confirmed cysts <3 cm, MRI overestimated pathological size by 0.30 cm (P = 0.049) and had the widest LOA, followed by EUS and CT. Among cysts ≥3 cm, EUS underestimated pathological size by 0.35 cm (P = 0.059) and MRI and CT overestimated pathological size by 0.23 cm and 0.51 cm, respectively., Conclusions: In this small retrospective study, EUS cyst size measurements correlated best with pathologic specimens compared to CT and MRI, especially for cysts < 3 cm. Larger prospective studies are needed to determine which imaging modalities are best to risk-stratify IPMNs and guide surgical versus. Non-surgical management., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Epigenetic modifications are involved in carcinogenesis and METTL3 is involved in RNA methylation. This study aimed to explore the role of the RNA m6A methyltransferase METTL3 in pancreatic cancer cells. The m6A modification was analyzed in human pancreatic cancer and paracancerous specimens, as well as in the normal HPDE6-C7 pancreatic cell line and the MIA-PaCa-2 and BxPC-3 pancreatic cancer cell lines. Immunohistochemistry (IHC), western blotting, and RT-qPCR were used to detect the expression of METTL3. Cell lines were transfected with siRNAs against METLL3. Proliferation, invasion, and migration were examined. The functions of METTL3 were predicted by bioinformatics analysis. In the 40 patients included, high METTL3 expression was associated with high pathological stage (P = 0.02) and high N stage (P = 0.02). Survival was better in patients with low METTL3 expression compared with those with high MTTL3 expression (P < 0.01). METTL3 and CIITA expression levels were inversely correlated (r = -0.71, P < 0.01). RNA m6A content in tumor specimens was significantly higher than that in paracancerous specimens. METTL3 protein and mRNA levels were significantly higher in tumor specimens compared with paracancerous specimens, as well as in cancerous cell lines vs. normal cells. METTL3 knockdown in MIA PaCa-2 and BxPC-3 cells decreased RNA m6A modifications. Cell proliferation, invasion, and migration were decreased by METTL3 knockdown in cancerous cell lines. A total of 673 differentially expressed genes were identified by bioinformatics: 659 were upregulated and 14 were downregulated. In conclusion, METTL3 is probably involved in pancreatic carcinogenesis. It could eventually be a prognostic marker or a treatment target., (Copyright © 2019. Published by Elsevier GmbH.)

Pancreatic cancer is one of the deadliest cancers across the world with an average 5-year survival rate of less than <6%. In this study, gemcitabine (GEM) and HIF1α-siRNA loaded GE-11 peptide conjugated liposome was successfully prepared and evaluated for its antitumor efficacy in pancreatic cancer cells. The GE11 increased the targeting specificity of liposome carrier and increased the intracellular concentrations in the cancer cells. Furthermore, synergistic combination of GEM and HIF1a-siRNA exhibited remarkable improvement in the declining of cancer cell proliferations. siRNA could effectively decrease the expression of HIF1a gene in the cancer cells. Importantly, GE-11 peptide-conjugated GEM/siRNA-loaded liposomes (GE-GML/siRNA) increased the total amount of apoptosis cells with higher proportion of cells in late apoptosis phase. GE-GML induced remarkable apoptosis of cancer cells and induced chromatin condensation and nuclear fragmentation which are considered to be typical features of apoptosis and cell death. GE-GML/siRNA showed a significant reduction in the tumour burden suggesting the superior anticancer efficacy of this formulation. GE-GML/siRNA showed four-fold reduction in tumour compared to control and two-fold reduction compared to GE-GML, respectively. Overall, present work lays foundation for the combination of GEM and HIF1a-siRNA loaded in a targeted nanocarrier system as a unique therapeutic option in pancreatic cancer treatment.

Liver-intestine cadherin (CDH17) has been known to function as a tumor stimulator and diagnostic marker for almost two decades. However, its function in highly malignant pancreatic cancer (PC) has yet to be elucidated. Using different strategies including siRNA, shRNA, and CRISPR technology, we successfully induced knockdown and knockout of CDH17 in Panc02-H7 cells and established the corresponding stable cell lines. With these cells, we demonstrated that loss of CDH17 function not only suppressed Panc02-H7 cell growth in vitro but also significantly slowed orthotopic tumor growth in vivo, resulting in the significant life extension. In vitro studies demonstrated that impairing CDH17 inhibited cell proliferation, colony formation, and motility by mechanistically modulating pro- and anti-apoptosis events in PC cells, as CDH17 suppression obviously increased expression of Bad, cytochrome C, cleaved caspase 3, and cleaved PARP, and reduced expression of Bcl-2, Survivin, and pAkt. In vivo studies showed CDH17 knockout resulted in apoptotic PC tumor death through activating caspase-3 activity. Taken together, CDH17 functions as an oncogenic molecule critical to PC growth by regulating tumor apoptosis signaling pathways and CDH17 could be targeted to develop an anti-PC therapeutic approach., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: 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., Methods: 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., Results: 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)., Conclusions: 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.

Long noncoding BRAF-activated noncoding RNA has been reported to be tightly associated with tumorigenesis and development in various types of cancers. However, the expression, biological function, and modulatory mechanism of BRAF-activated noncoding RNA in pancreatic cancer remained unclear. In the present work, we explored the carcinogenic activity and underlying mechanism of BRAF-activated noncoding RNA on pancreatic cancer in vitro . We identified that BRAF-activated noncoding RNA was upregulated in pancreatic cancer tissues and cell lines, and BRAF-activated noncoding RNA was related to tumor metastasis and stage. BRAF-activated noncoding RNA reinforces proliferation, invasion, and migration in PANC-1 and SW1990 cells. Moreover, miR-195-5p was downregulated in both PC tissues and cell lines. Our results based on luciferase reporter, RIP-Ago2 and qRT-PCR assays, showed that miR-195-5p was a direct target of BRAF-activated noncoding RNA. Furthermore, miR-195-5p inhibitor abrogated the effects of short-interfering BRAF-activated noncoding RNA on PANC-1 and SW1990 cell growth and invasion in vitro . We further identified that BRAF-activated noncoding RNA played a vital role in activating the Wnt/β-catenin pathway by sponging miR-195-5p. Collectively, our study showed that BRAF-activated noncoding RNA promotes pancreatic cancer tumorigenesis through miR-195-5p/Wnt/β-catenin axis may serve as a potential target for diagnostics and therapeutics in pancreatic cancer.

Pancreatic cancer (PC), which is one of the most lethal of malignancies and a major health burden, is associated with a dismal prognosis despite current therapeutic advances. Numerous long noncoding RNAs (lncRNA) have shown to be essential for PC tumorigenesis and progression. Nevertheless, the exact expression pattern of lnc-PCTST and its clinical significance still remain unclear. This study investigates the expression pattern of lnc-PCTST and its associated mRNA in three paired PC tissues and adjacent non-tumor tissues by Microarray-coarray approach. Briefly, our data demonstrated that lnc-PCTST expression is down-regulated in PC tissues. Also, lnc-PCTST has shown to be negatively correlated with transforming acidic coiled-coil 3 (TACC-3) expression. This expression pattern was further confirmed following qRT-PCR validation of 34 out of 48 paired cancer tissues. Furthermore, lnc-PCTST overexpression in PC cell lines inhibited cell proliferation and invasion in vitro, and tumorigenesis in vivo (using nude mice as animal model), but did not altered cell migration. Moreover, lnc-PCTST overexpression increased E-cadherin and repressed vimentin expression in vitro. Additionally, TACC-3 knockdown simulated the inhibiting effect of lnc-PCTST overexpression on PC cell lines, and the impaired proliferation, invasion effect and E-cadherin, vimentin expression on lnc-PCTST over-expressed cell lines can be rescued by overexpressed TACC-3. Significantly, the expression of lnc-PCTST was closely associated with its genomic neighboring gene TACC-3 and inhibited its promoter activity. In conclusion, lnc-PCTST is a potential tumor suppressor in PC, which inhibits cell proliferation, invasion, tumorigenesis and EMT by modulating TACC-3., (© 2018 UICC.)

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 < 0.001), male sex (p = 0.011), tumor size ≥4.0 cm (p < 0.001), alanine aminotransferase level (ALT) < 125 U/L (p < 0.001), and carbohydrate antigen (CA19-9) level ≥ 385 U/mL (p < 0.001) were independent risk factors for occult distant metastasis of PDAC. A preoperative scoring system (0-8 points) for distant metastasis on exploration was constructed using these five factors. The receiver operating characteristic curves showed that the area under the curve of this score was 0.85. A score of 6 points was suggested to be the optimal cut-off value, and the sensitivity and specificity were 85% and 69%, respectively., Conclusions: Distant metastasis is still frequently encountered on exploration for patients with potentially resectable PDAC. Younger age, male sex, larger tumor size, low ALT level and high CA19-9 level are independent predictors of unexpected distant metastasis on exploration.