MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression.

The Hippo signaling axis is a tumor suppressor pathway that is activated by various extra-pathway factors to regulate cell differentiation and organ development. Recent studies have reported that autophosphorylation of the core kinase cassette stimulates activation of the Hippo signaling cascade. Here, we demonstrate that protein arginine methyltransferase 5 (PRMT5) contributes to inactivation of the Hippo signaling pathway in pancreatic cancer. We show that the Hippo pathway initiator serine/threonine kinase 3 (STK3, also known as MST2) of Hippo signaling pathway can be symmetrically di-methylated by PRMT5 at arginine-461 (R461) and arginine-467 (R467) in its SARAH domain. Methylation suppresses MST2 autophosphorylation and kinase activity by blocking its homodimerization, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also show that the specific PRMT5 inhibitor GSK3326595 re-activates the dysregulated Hippo signaling pathway and inhibits the growth of human pancreatic cancer xenografts in immunodeficient mice, thus suggesting potential clinical application of PRMT5 inhibitors in pancreatic cancer.

Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression.

Aberrant expression of programmed death ligand-1 (PD-L1) in tumor cells promotes cancer progression by suppressing cancer immunity. The retinoblastoma protein RB is a tumor suppressor known to regulate the cell cycle, DNA damage response, and differentiation. Here, we demonstrate that RB interacts with nuclear factor κB (NF-κB) protein p65 and that their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine-252 (S249/T252) phosphorylation of RB. RNA-seq analysis shows a subset of NF-κB pathway genes including PD-L1 are selectively upregulated by RB knockdown or CDK4/6 inhibitor. S249/T252-phosphorylated RB inversely correlates with PD-L1 expression in patient samples. Expression of a RB-derived S249/T252 phosphorylation-mimetic peptide suppresses radiotherapy-induced upregulation of PD-L1 and augments therapeutic efficacy of radiation in vivo. Our findings reveal a previously unrecognized tumor suppressor function of hyperphosphorylated RB in suppressing NF-κB activity and PD-L1 expression and suggest that the RB-NF-κB axis can be exploited to overcome cancer immune evasion triggered by conventional or targeted therapies.

DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4.

The bromodomain and extra-terminal domain (BET) protein BRD4 is emerging as a promising anticancer therapeutic target. However, resistance to BET inhibitors often occurs, and it has been linked to aberrant degradation of BRD4 protein in cancer. Here, we demonstrate that the deubiquitinase DUB3 binds to BRD4 and promotes its deubiquitination and stabilization. Expression of DUB3 is transcriptionally repressed by the NCOR2-HDAC10 complex. The NCOR2 gene is frequently deleted in castration-resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells. DUB3-proficient prostate cancer cells are resistant to the BET inhibitor JQ1 in vitro and in mice, but this effect is diminished by DUB3 inhibitory agents such as CDK4/6 inhibitor in a RB-independent manner. Our findings identify a previously unrecognized mechanism causing BRD4 upregulation and drug resistance, suggesting that DUB3 is a viable therapeutic target to overcome BET inhibitor resistance in cancer.

High glucose-upregulated PD-L1 expression through RAS signaling-driven downregulation of PTRH1 leads to suppression of T cell cytotoxic function in tumor environment.

BACKGROUND: Nearly 80% of patients with pancreatic cancer suffer from glucose intolerance or diabetes. Pancreatic cancer complicated by diabetes has a more immunosuppressive tumor microenvironment (TME) and is associated with a worse prognosis. The relationship between glucose metabolism and programmed cell death-Ligand 1 (PD-L1) is close and complex. It is important to explore the regulation of high glucose on PD-L1 expression in pancreatic cancer and its effect on infiltrating immune effectors in the tumor microenvironment. METHODS: Diabetic murine models (C57BL/6) were used to reveal different immune landscape in euglycemic and hyperglycemic pancreatic tumor microenvironment. Bioinformatics, WB, iRIP [Improved RNA Binding Protein (RBP) Immunoprecipitation]-seq were used to confirm the potential regulating role of peptidyl-tRNA hydrolase 1 homolog (PTRH1) on the stability of the PD-L1 mRNA. Postoperative specimens were used to identify the expression of PD-L1 and PTRH1 in pancreatic cancer. Co-culturing T cells with pancreatic cancer cells to explore the immunosuppressive effect of pancreatic tumor cells. RESULTS: Our results revealed that a high dose of glucose enhanced the stability of the PD-L1 mRNA in pancreatic tumor cells by downregulating PTRH1 through RAS signaling pathway activation following epidermal growth factor receptor (EGFR) stimulation. PTRH1 overexpression significantly suppressed PD-L1 expression in pancreatic cells and improved the proportion and cytotoxic function of CD8+ T cells in the pancreatic TME of diabetic mice. CONCLUSIONS: PTRH1, an RBP, plays a key role in the regulation of PD-L1 by high glucose and is closely related to anti-tumor immunity in the pancreatic TME.

Utility of Dark-Blood Dual-Energy CT Images for Predicting Vascular Involvement and R0 Resection in Patients With Pancreatic Cancer.

BACKGROUND. Current CT criteria for assessing vascular involvement by pancreatic ductal adenocarcinoma (PDAC) use circumferential contact as an indirect indicator. Dark-blood images derived from dual-energy CT (DECT) provide high lumen-to-wall contrast and may aid assessment. OBJECTIVE. The purpose of this study was to compare the diagnostic performance of 55-keV virtual monoenergetic images (VMIs) assessed using NCCN criteria with that of dark-blood images assessed using wall-based criteria for predicting vascular involvement and surgical resection that achieves microscopically negative margins (i.e., R0 resection) in patients with PDAC who undergo contrast-enhanced DECT. METHODS. This retrospective study included 109 patients (mean age, 62.6 ± 8.8 [SD] years; 66 men, 43 women) with histologically confirmed PDAC who underwent pancreatic parenchymal and portal venous phase DECT within 4 weeks before surgery (including PDAC resection in 73 patients) between July 2020 and June 2022. Dark-blood images were derived using a two-material decomposition algorithm. Two radiologists independently reviewed 55-keV VMIs and dark-blood images in separate sessions to evaluate celiac artery, common hepatic artery, superior mesenteric artery, portal vein, and superior mesenteric vein involvement; a third radiologist resolved discrepancies. On 55-keV VMIs, vessel relationships were classified as no contact, abutment (≤ 180° contact), or encasement (> 180° contact). On dark-blood images, vessel walls were categorized as intact circumferentially, irregular, or discontinuous. Tumor resectability status was classified on the basis of vessel relationships. Surgical observation served as the reference for vascular involvement. Margin status was determined for resected tumors. RESULTS. Across the five vessels, for predicting vascular involvement, abutment or encasement on 55-keV VMIs had sensitivity of 100.0% (all vessels) and specificity of 66.2-92.9%, and an irregular or discontinuous wall on dark-blood images had sensitivity of 80.0-100.0% and specificity of 88.2-98.0%. Specificity was higher for an irregular or discontinuous wall than for abutment or encasement for all vessels (all p < .05); sensitivity was not different for any vessel (all p > .05). Resectable disease classified by dark-blood images, compared with resectable disease classified by 55-keV VMIs, showed no difference in sensitivity (89.5% vs 78.9%, p = .33) but showed higher specificity (75.9% vs 59.3%, p = .01) for predicting R0 resection. CONCLUSION. Dark-blood images showed higher diagnostic performance than 55-keV VMIs for predicting vascular involvement and R0 resection in patients with PDAC. CLINICAL IMPACT. Dark-blood images may aid decisions regarding neoadjuvant therapy and surgical planning for PDAC.

miR-222-3p-containing macrophage-derived extracellular vesicles confer gemcitabine resistance via TSC1-mediated mTOR/AKT/PI3K pathway in pancreatic cancer.

Gemcitabine resistance limits the efficacy of chemotherapy and maintains a challenge for treatment outcomes. Therefore, we aimed to clarify the downstream mechanisms underlying the role of miR-222-3p delivered by M2 macrophage-derived extracellular vesicles (M2 MDEs) in the chemoresistance of pancreatic cancer (PCa). We separated the mouse macrophages and polarized them to M2 phenotypes, from which the EVs were derived. miR-222-3p was highly expressed in M2 MDEs. M2 MDEs were internalized by PCa cells. miR-222-3p overexpressing M2 MDEs were treated with gemcitabine and co-cultured with PCa cells for in vitro experiments. Co-culture with M2 MDEs enriched with miR-222-3p suppressed the sensitivity to gemcitabine, accompanied by diminished apoptosis and promoted proliferation. Furthermore, the M2 MDEs and PCa cells were injected to mice with gemcitabine exposure for in vivo substantiation. The delivery of miR-222-3p inhibitor by M2 MDEs suppressed tumor growth and elevated sensitivity of cancer cells to gemcitabine. Moreover, miR-222-3p was indicated to target and suppress TSC1 expression, while miR-222-3p activated the PI3K/AKT/mTOR pathway. Together, miR-222-3p-containing M2 MDEs enhance chemoresistance in PCa through TSC1 inhibition and activation of the PI3K/AKT/mTOR pathway.

Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling.

BACKGROUND: Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. METHODS: The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEMsen) and GEM-resistant (GEMres) pancreatic cancer cells. RESULTS: We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEMsen and GEMres cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEMres cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEMres cells than that in GEMsen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEMres tumors, Evr significantly decreased the volume of GEMres tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. CONCLUSIONS: Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.

Practice Patterns and Perioperative Outcomes of Laparoscopic Pancreaticoduodenectomy in China: A Retrospective Multicenter Analysis of 1029 Patients.

OBJECTIVE: The aim of the study was to analyze the outcomes of patients who have undergone laparoscopic pancreaticoduodenectomy (LPD) in China. SUMMARY BACKGROUND DATA: LPD is being increasingly used worldwide, but an extensive, detailed, systematic, multicenter analysis of the procedure has not been performed. METHODS: We retrospectively reviewed 1029 consecutive patients who had undergone LPD between January 2010 and August 2016 in China. Univariate and multivariate analyses of patient demographics, changes in outcome over time, technical learning curves, and the relationship between hospital or surgeon volume and patient outcomes were performed. RESULTS: Among the 1029 patients, 61 (5.93%) required conversion to laparotomy. The median operation time (OT) was 441.34 minutes, and the major complications occurred in 511 patients (49.66%). There were 21 deaths (2.43%) within 30 days, and a total of 61 (5.93%) within 90 days. Discounting the effects of the early learning phase, critical parameters improved significantly with surgeons' experience with the procedure. Univariate and multivariate analyses revealed that the pancreatic anastomosis technique, preoperative biliary drainage method, and total bilirubin were linked to several outcome measures, including OT, estimated intraoperative blood loss, and mortality. Multicenter analyses of the learning curve revealed 3 phases, with proficiency thresholds at 40 and 104 cases. Higher hospital, department, and surgeon volume, as well as surgeon experience with minimally invasive surgery, were associated with a lower risk of surgical failure. CONCLUSIONS: LPD is technically safe and feasible, with acceptable rates of morbidity and mortality. Nonetheless, long learning curves, low-volume hospitals, and surgical inexperience are associated with higher rates of complications and mortality.

Predictive nomogram for postoperative pancreatic fistula following pancreaticoduodenectomy: a retrospective study.

BACKGROUND: Postoperative pancreatic fistula (POPF) represents the most common complication following pancreaticoduodenectomy (PD). Predictive models are needed to select patients with a high risk of POPF. This study was aimed to establish an effective predictive nomogram for POPF following PD. METHODS: Consecutive patients who had undergone PD between January 2016 and May 2020 at a single institution were analysed retrospectively. A predictive nomogram was established based on a training cohort, and Lasso regression and multivariable logistic regression analysis were used to evaluate predictors. The predictive abilities of the predicting model were assessed for internal validation by the area under the receiver operating characteristic curve (AUC) and calibration plot using bootstrap resampling. The performance of the nomogram was compared with that of the currently used a-FRS model. RESULTS: A total of 459 patients were divided into a training cohort (n = 302) and a validation cohort (n = 157). No significant difference was observed between the two groups with respect to clinicopathological characteristics. The POPF rate was 16.56%. The risk factors of POPF POPF were albumin difference, drain amylase value on postoperative day 1, pancreas texture, and BMI, which were all selected into a nomogram. Nomogram application revealed good discrimination (AUC = 0.87, 95% CI: 0.81-0.94, P <  0.001) as well as calibration abilities in the validation cohort. The predictive value of the nomogram was better than that of the a-FRS model (AUC: 0.87 vs 0.62, P <  0.001). CONCLUSIONS: This predictive nomogram could be used to evaluate the individual risk of POPF in patients following PD, and albumin difference is a new, accessible predictor of POPF after PD. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Register ( ChiCTR2000034435 ).

TRIM47 accelerates aerobic glycolysis and tumor progression through regulating ubiquitination of FBP1 in pancreatic cancer.

Increasing studies demonstrated that ubiquitination plays a vital role in the pathogenesis of pancreatic cancer, and targeting regulation of the ubiquitination process is a potential means for cancer treatment. However, the role of tripartite motif 47 (TRIM47) in pancreatic cancer is still unclear. Here, significantly upregulated TRIM47 and decreased FBP1 expressions were found in pancreatic cancer patient tissues and pointed to a lower survival rate. In addition, we show that TRIM47 was upregulated in pancreatic cancer cells and promoted cell proliferation in vitro and in vivo. Mechanistic investigations showed that TRIM47 promoted the aerobic glycolysis of pancreatic cancer cells, which was largely dependent on the direct binding to and ubiquitination of fructose-1, 6-biphosphatase (FBP1). Furthermore, the promotion of TRIM47 on the Warburg effect and pancreatic cancer progression was abolished by the overexpression of FBP1. Therefore, targeting TRIM47/FBP1 axis might provide a novel strategy to suppress the development of pancreatic cancer.

Albumin Difference as a New Predictor of Postoperative Complications following Pancreatectomy.

BACKGROUND: Postoperative complications after pancreatectomy are a challenging problem due to their high incidence and serious consequences. The majority of studies have focused on a specific complication, but data on predictors of overall postoperative complications (OPCs) are limited. METHODS: The data of patients who underwent pancreatectomy at a single institute between 2017 and 2019 were analyzed retrospectively. Univariate and multivariate logistic regression were used to investigate predictors of the outcomes of interest. The Clavien-Dindo classification and comprehensive complication index (CCI) were used to assess postoperative complications and the severity of postoperative complications. The relationship between predictors and the CCI was evaluated by linear regression. RESULTS: A total of 490 patients were divided into a training group (n = 339) and a validation group (n = 151). The rate of OPCs was 44.25%. Fluid transfusion and albumin difference (AD) were predictors of OPCs. AD showed a good discrimination (AUC = 0.70) and good calibration in the validation cohort. AD was associated with complications, including pancreatic fistula, intra-abdominal hemorrhage, intra-abdominal infection, delayed gastric emptying, and re-intervention, and was positively correlated with complication severity. Intraoperative blood loss and preoperative albumin were independent predictors of AD. CONCLUSIONS: AD, a variable that reflects dynamic physiological changes is a new and accessible predictor of OPCs following pancreatectomy.

Long noncoding RNA ITGB2-AS1 promotes growth and metastasis through miR-4319/RAF1 axis in pancreatic ductal adenocarcinoma.

Long noncoding RNA (lncRNA) has been considered as potentially critical regulators in pancreatic ductal adenocarcinoma (PDAC). In this study, we prospectively investigate the effect and mechanism of lncRNA integrin subunit beta 2-anti-sense RNA 1 (ITGB2-AS1) on regulation of PDAC progression. The expression of ITGB2-AS1 and its target were analyzed by quantitative real-time polymerase chain reaction and in situ hybridization. 3-(4,5-Dimethylthiazol-z-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, wound healing, and transwell assays were used to investigate the influence of ITGB2-AS1 on cell proliferation, cell cycle, migration, and invasion, respectively. The interaction between ITGB2-AS1 and its target was determined via luciferase activity assay and RNA immunoprecipitation. The subcutaneous xenotransplanted tumor model was established and employed to detect the tumorigenic function of ITGB2-AS1, which was evaluated by western blot analysis, immunohistochemistry, and hematoxylin and eosin staining. The results showed that ITGB2-AS1 was elevated in both PDAC tumor tissues and cell lines, predicting a poor prognosis in PDAC patients. Knocking down of ITGB2-AS1 suppressed PDAC cell proliferation, invasion, and migration but induced cell apoptosis in vitro. Moreover, ITGB2-AS1 could target and inhibit the expression of miR-4319 and miR-4319-targeted and -suppressed serine/threonine kinase RAF1. ITGB2-AS1 promoted PDAC progression via inhibition of miR-4319. Interference of ITGB2-AS1 could suppress in vivo tumorigenic ability of PDAC via downregulation of RAF1. In conclusion, ITGB2-AS1 promoted PDAC progression via sponging miR-4319 to upregulate RAF1, suggesting the potential therapeutic target ability of ITGB2-AS1 in PDAC.

The prognostic value of modified Glasgow Prognostic Score in pancreatic cancer: a meta-analysis.

BACKGROUND: Several studies were conducted to explore the prognostic value of modified Glasgow Prognostic Score (mGPS) in pancreatic cancer, which reported contradictory results. The purpose of this meta-analysis was to summarize and further investigate the correlation between mGPS and overall survival (OS) in pancreatic cancer. METHODS: A systematic literature search was performed in PubMed, EMBASE, ISI Web of Science, Cochrane library databases and OVID to identify eligible studies published from Jan 1, 2011 to June 20, 2020. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were used to detect the prognostic significance of mGPS in patients with pancreatic cancer. RESULTS: A total of 222 non-repetitive studies were identified, and 20 related studies that explored the association between survival outcomes and mGPS in pancreatic cancer patients were finally enrolled in this meta-analysis. The results showed a significant correlation between high level of mGPS and poor OS (HR = 1.50, 95% CI 1.20-1.89, P < 0.0001). Similar results were observed in the subgroup analyses based on the treatment regimen and research region. CONCLUSIONS: Our study suggested the close association between poor prognosis and high level of mGPS, which will be helpful for future clinical applications in patients with pancreatic cancer.

A new scoring system can be applied to predict the organ failure related events in acute pancreatitis accurately and rapidly.

AIM: To establish a new scoring system to predict the organ failure (OF)-related events in acute pancreatitis (AP) with high accuracy and rapidity. BACKGROUND: AP is a complicated immunological response that leads to multiple organ failure，but no single scoring system has so far effectively predicted the severity of OF-related events in AP. METHODS: The research utilized a retrospective study including 1076 AP patients to establish the new scoring system and a prospective study of another 138 patients to verify it. All the laboratory parameters were measured at admission (within 72 h of disease onset). Dunnett'T3 test, univariate and multivariate ordinal logistic regressions were performed. ROC curves were drawn to calculate the cut-off value of the chosen factors and to validate the predictive value of the system. RESULTS: Lactate dehydrogenase (LDH), creatinine (Cr), albumin (ALB) and calcium (Ca2+) made up the new system. The Area Under the Curve (AUC) of the system for OF was 0.904, and for persistent organ failure (POF) was 0.893 while that for death cases was 0.969. As a result, patients who scored 'zero' seemed to recover soon, who received a score '1-4' might have transient organ failure (TOF) but not POF. When the score was over 5, it was probable that patients would suffer POF, and even die if it exceeded 9. The test of the new scoring system proved it conducted well. CONCLUSION: The new scoring system can accurately and promptly predict the OF-related events in AP.

Albumin difference as a new predictor of pancreatic fistula following distal pancreatectomy: a retrospective study of 211 consecutive patients.

PURPOSE: The level of albumin declines after surgery, and whether the difference between preoperative and postoperative albumin levels on postoperative day 1 has an effect on the development of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) is unclear. Our aim was to evaluate the effect of albumin difference on POPF. METHODS: A retrospective analysis of consecutive patients who had undergone DP between January 2016 and October 2018 at a single institution was conducted. Patient demographic data and perioperative data were analysed using univariate and multivariate models. Pancreatic fistula was defined by the 2016 International Study Group of Pancreatic Surgery criteria. All patients were followed for up to 90 days. RESULTS: A total of 211 consecutive patients were identified. The POPF rate was 15.64%, and no 90-day mortality was observed. Five predictors were independently associated with POPF: albumin difference (OR 6.60, 95% CI 2.36-18.45, P < 0.001), pancreatic texture (OR 4.15, 95% CI 1.62-10.63, P = 0.003), operative time (OR 3.13, 95% CI 1.19-8.24, P = 0.021), intraoperative fluid transfusion (OR 4.85, 95% CI 1.70-13.79, P = 0.003), and cardiovascular disease (OR 5.38, 95% CI 1.99-14.55, P = 0.001). CONCLUSIONS: Although DP can be performed with a low rate of mortality, POPF remains a common complication. Albumin difference is a new, accessible predictor for POPF following DP.

The product value of serum albumin and prothrombin time activity could be a useful biomarker for severity prediction in AP: An ordinal retrospective study.

AIM: To appraise the predictive function of 'the product value of serum albumin and prothrombin time activity' (PAA) on admission for the organ failure related events of acute pancreatitis (AP). BACKGROUND: 789 patients with AP were included in this retrospective study. 468 patients generated transient organ failure (TOF). 242 were diagnosed with persistent organ failure (POF), of which 63 patients died. STUDY: All the values of laboratory parameters were measured upon admission to hospital. Dunnett'T3 test, Uni- and multi-variate ordinal logistic regression were used. ROC curve was utilized to evaluate the ultimate predictive values. RESULTS: Among the patients with 4 different levels of severity of acute pancreatitis, PAA observably reduced as the disease aggravated (32.20 vs 29.56 vs 23.54 vs 17.89). PAA was also an independent risk factor for the aggravation of AP (OR: 0.873, 95% CI: 0.848, 0.899; p < 0.01). The Area Under the Curve (AUC) of PAA for OF was 0.828 (0.783, 0.872), 0.828 for POF (0.790, 0.865) and 0.905 for death cases (0.862, 0.948). CONCLUSION: The product value of serum albumin and prothrombin time activity is a good predictor of the severity, especially the events related to organ failure of acute pancreatitis.

Tumor location as an indicator of survival in T1 resectable pancreatic ductal adenocarcinoma: a propensity score-matched analysis.

BACKGROUND: The latest 8th edition of the AJCC staging system emphasizes the importance of tumor size however, the clinical significance of the combination of tumor location with tumor size remains unknown. METHODS: We conducted this study to investigate the prognostic role of tumor location in T1 resectable pancreatic ductal adenocarcinoma (PDAC). Resectable PDAC patients from Surveillance, Epidemiology, and End Results (SEER) database (2004-2014) were selected for the propensity score matching analysis. We used matched cohort to analyze the relationship between clinicopathologic features and survival of patients. RESULT: Eight thousand, four hundred nine patients were included in the propensity score matching analysis and 4571 patients were selected for final analysis. In T1 patients, the patients with pancreatic head tumor had worse prognosis compared to the patients with body/tail tumors. Multivariate analysis result showed that pancreatic body/tail location was an independent indicator for better chances of survival in T1 PDAC patients (hazard ratio, 0.69; 95%CI, 0.52-0.93; P = 0.01). The modified staging system was more efficient than the AJCC 8th staging system. CONCLUSION: Modified staging system exhibited a good assessment of the survival rate. The tumor location is a good prognostic indicator for T1 resectable PDAC patients. Modification of T1 subgroup according to tumor location exhibited favorable survival prediction effects.

Reciprocal loop of hypoxia-inducible factor-1α (HIF-1α) and metastasis-associated protein 2 (MTA2) contributes to the progression of pancreatic carcinoma by suppressing E-cadherin transcription.

Metastasis-associated protein 2 (MTA2) is overexpressed in certain malignancies, and plays important roles in tumour metastasis and progression. The present study highlights the function of MTA2 in pancreatic carcinoma through its role as a deacetylator of hypoxia-inducible factor-1α (HIF-1α) and a cotranscriptional factor for E-cadherin expression. We found that overexpression of MTA2 promoted, and knockdown of MTA2 inhibited, the invasion and proliferation of pancreatic carcinoma cells both in vitro and in xenograft models in vivo. We also found that MTA2 is transcriptionally upregulated by HIF-1α through a hypoxia response element (HRE) of the MTA2 promoter in response to hypoxia. Reciprocally, MTA2 deacetylates HIF-1α and enhances its stability through interacting with histone deacetylase 1 (HDAC1). Consequently, HIF-1α recruits MTA2 and HDAC1 to the HRE of the E-cadherin promoter, by which E-cadherin transcription is repressed. In agreement with these experimental results, MTA2 is positively associated with HIF-1α, but inversely correlated with E-cadherin, in pancreatic carcinoma samples. Moreover, data from The Cancer Genome Atlas on 172 pancreatic carcinomas indicate an association between high expression of MTA2 and short overall survival. Taken together, our study identifies MTA2 as a critical hub and potential therapeutic target to inhibit the progression and metastasis of pancreatic carcinoma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Intra-Ampullary Papillary-Tubular Neoplasm: A Population-Based Analysis.

BACKGROUND Intra-ampullary papillary-tubular neoplasm (IAPN) is recognized as a precancerous lesion with a great tendency to evolve into pancreatic cancer. The Surveillance, Epidemiology, and End Results (SEER) database is now large enough to study unusual cancers. Based on pathologic and epidemiologic characteristics of IAPN available in SEER, important clinicopathological correlations can be made. MATERIAL AND METHODS Cases of IAPN and other intraductal papillary mucinous neoplasms of the bile duct (OBIPMN) diagnosed between 1973 and 2014 were searched in the SEER database. The analysis was carried out with respect to patient clinical characteristics, tumor characteristics, incidence, and survival. RESULTS In total, 685 patients with IAPN were identified compared with 2465 patients with OBIPMN in the same period. The incidence rate of IAPN was decreased, with a 4.882% annual percent change. The patient characteristics of IAPN were quite different from OBIPMN in many characteristics, including age, gender, marital status, and survival. Compared with OBIPMN, the tumor characteristics of IAPN indicated that more patients were diagnosed at an earlier stage in multiple stage systems such as pathological grade (P<0.001), sixth American Joint Committee on Cancer stage (P<0.001), TNM stage (P<0.001), and SEER historic stage (P<0.001). In the survival analysis, the cancer-specific survival of IAPN was significantly better than OBIPMN (P<0.001) and the cancer-specific survival get worse at higher stages (P<0.001). Moreover, the 5-year cancer-specific survival rate of IAPN was also significantly better than that of OBIPMN (36.5% versus 25.4%, P<0.001). Finally, the multivariate analysis showed a correlation between cancer-specific survival and age of diagnosis and N stage (P<0.001). CONCLUSIONS Analysis of the SEER database clearly demonstrated that IAPN was a precancerous lesion tend to be diagnosed earlier compared with OBIPMN, which contributed to the better prognosis, and surgery was suggested if possible.

A Population-Based Study of the Incidence and Survival of Anorectal Gastrointestinal Stromal Tumor.

BACKGROUND Gastrointestinal stromal tumor (GIST) is the most common type of primary gastrointestinal mesenchymal tumor, but GISTs arising in the anus and rectum are rare. This study aimed to undertake a population-based analysis of the incidence, patient demographics, and survival of patients with anorectal GIST compared with patients with GIST arising from other sites based on the Surveillance, Epidemiology, and End Results (SEER) Program database. MATERIAL AND METHODS The SEER database was used to identify all patients diagnosed with GIST and patients diagnosed with anorectal GIST from 2000 to 2015. The incidence of GIST, baseline clinical and demographic data, tumor stage, and patient survival data were analyzed, including overall survival (OS) and cancer-specific survival (CSS). RESULTS A total of 277 patients with anorectal GIST were identified, with an incidence of 0.018 per 100,000. The incidence of GIST arising from other sites was 0.719 per 100,000. The median age at diagnosis for anorectal GIST was 57.5 years (range, 26-92 years), median tumor size was 6.55 cm (range, 0.6-20 cm), and surgery, but not chemotherapy, improved OS and CSS. Patients with anorectal GIST had a mean 1-year, 3-year, 5-year, and 10year OS of 91.1%, 82.5%, 75.2%, and 58.5%, respectively. Patients with GIST arising at other sites had a mean 1-year, 3-year, 5-year, and 10-year OS of 88.3%, 76.4%, 66.5%, and 46.8%, respectively. CONCLUSIONS Anorectal GIST is a rare tumor that has a better outcome compared with GISTs arising at other sites in the gastrointestinal tract.