Circulating cell-free DNA methylation-based multi-omics analysis allows early diagnosis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 7.2% in China. However, effective approaches for diagnosis of PDAC are limited. Tumor-originating genomic and epigenomic aberration in circulating free DNA (cfDNA) have potential as liquid biopsy biomarkers for cancer diagnosis. Our study aims to assess the feasibility of cfDNA-based liquid biopsy assay for PDAC diagnosis. In this study, we performed parallel genomic and epigenomic profiling of plasma cfDNA from Chinese PDAC patients and healthy individuals. Diagnostic models were built to distinguish PDAC patients from healthy individuals. Cancer-specific changes in cfDNA methylation landscape were identified, and a diagnostic model based on six methylation markers achieved high sensitivity (88.7% for overall cases and 78.0% for stage I patients) and specificity (96.8%), outperforming the mutation-based model significantly. Moreover, the combination of the methylation-based model with carbohydrate antigen 19-9 (CA19-9) levels further improved the performance (sensitivity: 95.7% for overall cases and 95.5% for stage I patients; specificity: 93.3%). In conclusion, our findings suggest that both methylation-based and integrated liquid biopsy assays hold promise as non-invasive tools for detection of PDAC.

Efficacy of nab­paclitaxel vs. Gemcitabine in combination with S­1 for advanced pancreatic cancer: A multicenter phase II randomized trial.

Patients with advanced pancreatic cancer (PC) need a cost-effective treatment regimen. The present study was designed to compare the efficacy and safety of nab-paclitaxel plus S-1 (AS) and gemcitabine plus S-1 (GS) regimens in patients with chemotherapy-naïve advanced PC. In this open-label, multicenter, randomized study named AvGmPC, eligible patients with chemotherapy-naïve advanced PC were randomly assigned (1:1) to receive AS (125 mg/m2 nab-paclitaxel, days 1 and 8; 80-120 mg S-1, days 1-14) or GS (1,000 mg/m2 gemcitabine, days 1 and 8; 80-120 mg S-1, days 1-14). The treatment was administered every 3 weeks until intolerable toxicity or disease progression occurred. The primary endpoint was progression-free survival (PFS). Between December 2018 and March 2022, 101 of 106 randomized patients were treated and evaluated for analysis (AS, n=49; GS, n=52). As of the data cutoff, the median follow-up time was 11.37 months [95% confidence interval (CI), 9.31-13.24]. The median PFS was 7.16 months (95% CI, 5.19-12.32) for patients treated with AS and 6.41 months (95% CI, 3.72-8.84) for patients treated with GS (HR=0.78; 95% CI, 0.51-1.21; P=0.264). The AS regimen showed a slightly improved overall survival (OS; 13.27 vs. 10.64 months) and a significantly improved ORR (44.90 vs. 15.38%; P=0.001) compared with the GS regimen. In the subgroup analyses, PFS and OS benefits were observed in patients treated with the AS regimen who had KRAS gene mutations and high C-reactive protein (CRP) levels (≥5 mg/l). The most common grade ≥3 adverse events were neutropenia, anemia and alopecia in the two groups. Thrombocytopenia occurred more frequently in the GS group than in the AS group. While the study did not meet the primary endpoint, the response benefit observed for AS may be suggestive of meaningful clinical activity in this population. In particular, promising survival benefits were observed in the subsets of patients with KRAS gene mutations and high CRP levels, which is encouraging and warrants further investigation. This trial was retrospectively registered as ChiCTR1900024588 on July 18, 2019.

Serum Interleukin-6 as a Biomarker for Early Prediction of Post-Operative Infectious Complications After Elective Pancreatectomy.

Background: To investigate whether interleukin (IL)-6 could predict the post-operative complications of elective pancreatectomy early. Patients and Methods: Overall, 122 patients who underwent elective pancreatectomy from June 2020 to May 2021 in our hospital were enrolled. Interleukin-6 was measured on the day before and at six hours after surgery, and on post-operative day one, three, and five. The associations between IL-6 level and post-operative complications were analyzed, and the predictive value of IL-6 for complications was assessed. Results: Sixty-three patients developed post-operative complications. Higher IL-6 was observed in patients with post-operative complications on post-operative day one, post-operative day three, and post-operative day five, with odd ratios of 1.43, 1.68, and 2.54 (p = 0.01, p = 0.01, and p = 0.01), respectively. These trends were also observed in patients with infectious complications preoperatively, on post-operative day one, post-operative day three, and post-operative day five, with ORs of 2.46, 1.95, 2.01, and 2.49 (p = 0.00, 0.00, 0.01, 0.00) respectively. Multivariate regression revealed that IL-6 is the only predictor for infectious complications on post-operative day one (p = 0.016). Based on the optimal cutoffs, pre-operative IL-6, IL-6 on post-operative day one and post-operative day three for predicting infectious complications yielded area under the curve (AUC) of 0.73, 0.70, and 0.70, with high negative predictive value of 82.7%, 92.2%, and of 91.3%, respectively. Conclusions: This study validated the early predictive value of IL-6 on infectious complications after pancreatectomy. Because of the performance of serum IL-6 in predicting infectious complications and high NPV, we endorse that IL-6 could be a potential biomarker for early prediction and antibiotic optimization after pancreatectomy.

NEDD8-Activating Enzyme Inhibitor MLN4924 Inhibits Both the Tumor Stroma and Angiogenesis in Pancreatic Cancer via Gli1 and REDD1.

PURPOSE: Pancreatic cancer is characterized by a dense desmoplasia stroma, which hinders efficient drug delivery and plays a critical role in tumor progression and metastasis. MLN4924 is a first-in-class NEDD8-activating enzyme inhibitor that exhibits anti-tumor activities toward pancreatic cancer, and given the comprehensive effects that MLN4924 could have, we ask what impact MLN4924 would have on the stroma of pancreatic cancer and its underlying mechanisms. METHODS: Primary pancreatic stellate cells (PSCs) and human HMEC-1 cells were treated with MLN4924 in vitro. The proliferation and extracellular matrix protein levels of PSCs were tested, and their relationship with transcription factor Gli1 in PSCs was investigated. The angiogenic phenotypes of HMEC-1 cells were evaluated using capillary-like tube formation assay, and their relationship with REDD1 in HMEC-1 cells was investigated. RESULTS: In this study, we found that MLN4924 inhibited the proliferation of pancreatic stellate cells and their secretion of collagen and CXCL-1, and the collagen secretion inhibiting effect of MLN4924 was related with transcription factor Gli1. MLN4924 inhibited multiple angiogenic phenotypes of HMEC-1 cells, and mTOR agonist partially relieved the inhibition of MLN4924 on HEMCs. MLN4924 increased the expression of REDD1 and REDD1 knockdown promoted the angiogenic phenotypes of HMEC-1 cells. CONCLUSIONS: Our study suggests that MLN4924 inhibits both the tumor stroma and angiogenesis in pancreatic cancer, and the inhibition effect is related with Gli1 in pancreatic stellate cells and REDD1 in vascular endothelial cells, respectively.

Circulating cytokines allow for identification of malignant intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are the precursor lesions of pancreatic cancers, requiring active surgical intervention during cancer development. However, the current criteria for predicting malignant IPMNs remain challenging and limited. Hence, this study aimed to assess the discriminatory performance of circulating cytokines, including TNF-α, IL-2R, IL-6, and IL-8, then build a novel predictive model to improve the diagnostic accuracy. METHOD: A total of 131 retrospective (from March 2016 to December 2019) and 53 prospective (from March 2020 to January 2021) patients who were histologically confirmed as IPMNs were consecutively collected and analyzed. RESULT: The circulating levels of TNF-α, IL-2R, IL-6, and IL-8 were significantly elevated in malignant IPMNs, and were verified as independent factors for malignant IPMNs (p < 0.05). Then, a novel score, the circulating cytokine score (CCS), was calculated and demonstrated as an independent predictive indicator with a higher area under the curve (AUC) than each cytokine alone (p < 0.001). Besides the CCS, two high-risk stigmata features, the presence of solid component (PSC), and main pancreatic duct (MPD) dilation ≥10 mm were also demonstrated as independent indicators for predicting malignant IPMNs. Finally, a novel nomogram incorporating the CCS and these two high-risk stigmata features presented a remarkable diagnostic performance, both in the training and validation cohorts with AUCs of 0.928 and 0.873, respectively. CONCLUSION: The CCS can be considered a novel independent predictive indicator for malignant IPMNs. Additionally, the formulated nomogram model integrating the CCS, PSC, and MPD ≥10 mm can be a valuable and promising tool for predicting the malignant transformation of IPMNs during long-term follow-ups to assist in timely and accurate surgical decisions.

GFAT1 is highly expressed in cancer stem cells of pancreatic cancer.

Background: Cancer stem cells (CSCs) play pivotal roles in the growth, invasion, metastasis, and chemoresistance of pancreatic cancer (PC). The current characterization of CSCs in PC is not complete. Glutamine-fructose-6-phosphate transaminase 1 (GFAT1) is a key enzyme that regulates the hexosamine pathway (HP), in which it not only controls glucose influx but also catalyzes the reaction to form glucosamine 6-phosphate. Recently, it was reported that GFAT1 is highly expressed in PC. However, the relevance of this high expression of GFAT1, especially its association with cancer stemness, has not been well defined and is thus addressed in the current study. Methods: GFAT1 levels were determined in PC from a public database and assessed by bioinformatics tools. GFAT1 expression in CD133+ and CD44+ CSCs in PC was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunostaining on cytospun cells after flow cytometry-based cell sorting. GFAT1+ cells were separated from GFAT1- cells by transfection of PC cell lines with a designed plasmid that expressed red fluorescent protein (RFP) under a GFAT1 promoter. Tumor sphere formation, tumor growth, tumor cell invasion, cell migration, and the resistance to gemcitabine-induced apoptosis were determined in GFAT1+ vs. GFAT1- PC cells. Results: GFAT1 levels were significantly upregulated in PC compared to the adjacent non-PC tissue. There were significantly more GFAT1+ cells in the CD133+ population than in the CD133- population, and similarly, there were significantly more GFAT1+ cells in the CD44+ population than in the CD44- population. Compared to GFAT1- PC cells, GFAT1+ PC cells generated significantly more tumor spheres in culture, appeared to be more invasive and migratory, and were significantly more resistant to gemcitabine-induced cell apoptosis. Conclusions: GFAT1 is highly expressed in CSCs among PC cells and may be crucial for PC growth, metastasis, and chemoresistance.

Prognostic Effect of Age in Resected Pancreatic Cancer Patients: A Propensity Score Matching Analysis.

Background: While the elderly population account for an indispensable proportion in pancreatic ductal adenocarcinoma (PDAC), these patients are underrepresented in clinical trials. Whether surgery offered the same benefit for elderly patients as that for younger cohort and which factors affected long-term outcome of elderly population remained unclear. Aims: This study aims to evaluate long-term prognosis of elderly PDAC patients (≥70 years old) after surgery and to investigate potential prognostic factors. Methods: This retrospective study included PDAC patients receiving radical resection from January 2012 to July 2019 in Zhongshan Hospital Fudan University. Patients were divided into young (<70) and old groups (≥70). Propensity score matching (PSM) was conducted to eliminate the confounding factors. We investigated potential prognostic factors via Cox proportional hazards model and Kaplan-Meier estimator. Nomogram model and forest plot were constructed to illustrate the prognostic value of age. Results: A total of 552 PDAC patients who received radical resection were included in this research. Elderly patients showed poorer nutritional status and were less likely to received adjuvant treatment. After matching, although age [hazard ratio (HR)=1.025, 95%CI 0.997-1.054; p=0.083] was not statistically significant in the multivariate cox regression analysis, further survival analysis showed that patients in the old group had poorer overall survival (OS) when compared with young group (p=0.039). Furthermore, reception of adjuvant chemotherapy (HR=0.411, 95%CI 0.201-0.837; p=0.014) was the only independent prognostic factor among elderly patients and could significantly improve OS. Subgroup analysis indicated that age had better prognostic value in PDAC patients with good preoperative nutritional status and relative low tumor burden. Finally, a prognostic prediction model contained age, reception of adjuvant chemotherapy, American Joint Committee on Cancer (AJCC) 8th T and N stage was constructed and presented in nomogram, whose Harrell's concordance index was 0.7478 (95%CI, 0.6960-0.7996). The calibration curves at 1 and 3 years indicated an optimal conformity between actual and nomogram-predicted survival probability in the PDAC patient who received surgery. Conclusion: The elderly PDAC patients were associated with worse OS survival after radical resection, and the noticeable negative effect of age was observed among PDAC patients with better preoperative nutritional status and less aggressive tumor biology. Adjuvant chemotherapy was essential to improve survival outcome of elderly PDAC patients following radical resection.

PYCR1: A Potential Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor with an extremely poor prognosis in digestive tumors. Pyrroline-5-carboxylate reductase 1 (PYCR1) plays an important role in tumor development. Therefore, we aimed to explore the effect of PYCR1 on the growth of PDAC cells. Methods: Tumor tissues and adjacent normal pancreatic tissues were collected from 89 patients with PDAC. And immunohistochemistry (IHC) was used to analyze the expression level of PYCR1 in both. RNA interference was used to inhibit the expression of PYCR1 in PANC- 1 and AsPC-1 cells. After infection, the expression of PYCR1 protein was detected by Western blot. The proliferation and growth of PDAC cells were detected by Celigo analysis, MTT, and clone formation assay. Cell apoptosis was analyzed by flow cytometry. Furthermore, the effect of PYCR1 interference on tumor growth was evaluated in vivo through injecting tumor cells subcutaneously into nude mice. Results: The expression of PYCR1 in pancreatic cancer tissues was significantly higher than in paired adjacent normal pancreatic tissues (P <0.01). In vitro, the downregulation of PYCR1 expression significantly inhibited the cell proliferation and colony formation, and increased apoptosis in PANC-1 cells and AsPC-1 cells compared with the shCtrl group (P <0.01). And in vivo, PYCR1 interference also significantly inhibited tumor growth both in the tumor volume and weight. Conclusion: PYCR1 interference was able to inhibit cell proliferation and promote cell apoptosis of pancreatic cancer. The PYCR1 may serve as a potential therapeutic and prognostic biomarker for the treatment of pancreatic cancer.

Gene expression profiling reveals the genomic changes caused by MLN4924 and the sensitizing effects of NAPEPLD knockdown in pancreatic cancer.

MLN4924 inhibits the proteolytic degradation of Cullin-Ring E3 ligase (CRL) substrates and exhibits antitumor activity toward various malignancies, including pancreatic cancer. MLN4924 suppresses tumor growth by altering various key regulator proteins; however, its impact on gene expression in tumors remains unknown. In this study, the genomic changes caused by MLN4924 in pancreatic cancer were examined by gene chip analysis and ingenuity pathway analysis. Eleven pathways were significantly altered (5 activated and 6 inhibited), 45 functions were significantly changed (21 activated and 24 inhibited), and the most activated upstream factor was predicted to be TNF. Of 691 differentially expressed genes, NAPEPLD knockdown showed synergism with MLN4924, as determined by real-time quantitative PCR and high content screening. NAPEPLD knockdown enhanced the effect of MLN4924 on inhibiting proliferation and inducing apoptosis in vitro. In a pancreatic cancer nude mouse model, MLN4924 inhibited tumor growth more significantly in the NAPEPLD knockdown group than in the control group. NAPEPLD expression was higher in pancreatic cancer tissues than in the normal pancreas but was not associated with prognosis. These findings indicate that MLN4924 causes extensive genomic changes in pancreatic cancer cells, and targeting NAPEPLD may increase the efficacy of MLN4924.

Prognostic value of tumor-associated N1/N2 neutrophil plasticity in patients following radical resection of pancreas ductal adenocarcinoma.

BACKGROUND: As an integral part of the tumor microenvironment (TME), tumor-associated neutrophils play a crucial role in tumor development. The objective of this study was to investigate the plasticity of tumor-associated N1 and N2 neutrophils in the TME of pancreatic ductal adenocarcinoma (PDAC), along with its impact on survival and association with immune infiltrations. METHODS: The primary and validation cohorts including 90 radical resection patients from September 2012 to May 2016 and 29 radical resection patients from September 2018 to October 2019, respectively, with complete survival data, were enrolled. Immunofluorescence staining was used to identify tumor-associated N1 and N2 neutrophils, and the N1/N2 ratio was used to evaluate N1 and N2 plasticity. Thereafter, the association between tumor-associated N1/N2 neutrophil plasticity, clinical features, and immune infiltrations was investigated. RESULTS: There was a significant increase in tumor-associated N2 neutrophils compared with tumor-associated N1 neutrophils. Low N1/N2 ratios were associated with the poorer differentiation of tumors, easier lymph node metastases, and a higher TNM stage. The median overall survival (OS) and recurrence-free survival (RFS) of the high tumor-associated N1 neutrophil group were significantly longer than those of the low group, while the tumor-associated N2 neutrophils played an opposite role. The multivariable analysis revealed that a high N1/N2 ratio was a significant prognostic indicator for OS and RFS. In addition, tumor-associated N1/N2 neutrophils showed an opposite correlation with tumor-infiltrating CD8+ T cells and Tregs. CONCLUSION: The plasticity of tumor-associated N1/N2 neutrophils was identified as a crucial prognostic indicator that might reflect the TME and immune escape in patients with PDAC. On further investigation and validation, our findings may be used to further stratify patients with varying prognoses to optimize treatment.

Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer.

Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, its biological function in PDAC remains unclear. Here, we demonstrated that circulating and tumoral LPS was significantly increased by intestinal leakage in the orthotopic murine PDAC model, and LPS administration promoted T cell infiltration but exhaustion paradoxically in the subcutaneous murine PDAC model. By bioinformatic analysis, Toll-like receptor 4 (TLR4), LPS receptor, was further found to enrich in immune tolerance signaling in PDAC tissues. Then, a significant positive correlation was found between TLR4 and programmed death ligand-1 (PD-L1) in clinical PDAC tissues, as well as serum LPS and tumoral PD-L1. Meanwhile, LPS stimulation in vitro and in vivo obviously upregulated tumor PD-L1 expression, and effectively promoted cancer cells resistance to T cell cytotoxicity. Mechanistically, the activation of TLR4/MyD88/AKT/NF-κB cascade was found to participate in LPS mediated PD-L1 transcription via binding to its promoter regions, which was enhanced by crosstalk between NF-κB and AKT pathways. Finally, PD-L1 blockade could significantly reverse LPS-induced immune escape, and synergized with LPS treatment. Taken together, LPS can remodel tumor microenvironment, and synergize with PD-L1 blockade to suppress tumor growth, which may be a promising comprehensive strategy for PDAC.

Co-treatment With Everolimus, an mTOR-Specific Antagonist, or Downregulation of ELK1 Enhances the Sensitivity of Pancreatic Cancer Cells to Genistein.

Genistein is a natural isoflavone with pharmacological or potentially anti-tumor properties. However, the resistance of cancer cells to genistein remains a major obstacle. This study focused on the mechanism implicated in the resistance of pancreatic cancer (PC) cells to genistein and the mechanism of action. First, key molecules and signaling pathways related to genistein resistance in PC cells were explored using bioinformatics tools. DEP domain containing MTOR interacting protein (DEPTOR), a typical inhibitor of the mammalian target of rapamycin (mTOR) signaling, was predicted to be poorly expressed in the genistein-resistant PC cells. Thereafter, genistein-resistant PC cells (Panc-1 and PaCa) were constructed. Altered expression of DEPTOR was introduced in cells, and everolimus (ELM), an mTOR-specific antagonist, was administrated in cells as well to examine their roles in genistein resistance. The cell apoptosis was examined in vitro and in vivo in mouse xenograft tumors. The upstream regulator of DEPTOR was predicted via bioinformatic tools. The bioinformatic analyses showed that the PI3K/AKT/mTOR signaling pathway was activated in the setting of DEPTOR downregulation in genistein-resistant PC cells. DEPTOR overexpression reduced the 50% inhibiting concentration (IC50) of genistein in PC cells and suppressed mTOR phosphorylation, and it increased caspase-3 activity, LDH release and apoptosis in PC cells. ELM treatment enhanced the sensitivity of PC cells to genistein in vitro and it strengthened the tumor-eliminating role of genistein in mice. ETS transcription factor ELK1 (ELK1), a transcription factor that negatively regulated DEPTOR transcription, was suppressed by genistein. Upregulation of ELK1 suppressed DEPTOR transcription and reduced the genistein sensitivity of cells, and it also blocked the genistein-sensitizing roles of ELM in PC cells. In conclusion, this study demonstrated that ELK1 reduces DEPTOR transcription, leading to mTOR phosphorylation and the drug resistance of PC cells.

Prediction of pancreatic fistula after pancreatectomy by virtual touch tissue imaging and quantification (VTIQ) technology.

OBJECTIVES: The aim of this study was to quantitatively evaluate the stiffness of pancreatic parenchyma and solid focal pancreatic lesions (FPLs) by virtual touch tissue imaging and quantification (VTIQ) technique and to investigate the potential usefulness of VTIQ method in the prediction of post-operative pancreatic fistula (POPF) after pancreatectomy. METHODS: In this prospective study, patients who scheduled to undergo pancreatectomy were initially enrolled and received VTIQ assessment within one week before surgery. VTIQ elastography (Siemens ACUSON Sequoia, 5C-1 transducer) was used to measure the shear wave velocity (SWV) value of FPLs and the body part pancreatic parenchyma. The palpation stiffness of pancreas was qualitatively evaluated during operation by surgeons. POPF was finally diagnosed and graded through a three-weeks post-operative follow-up according to international study group of pancreatic fistula (ISGPF). SWV values were compared between POPF positive and negative group. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic efficacy of SWV value in predicting POPF. RESULTS: From December 2020 to June 2021, 44 patients were finally enrolled in this study, among which, 26 patients were identified to develop POPF after pancreatectomy. The SWV value of pancreatic parenchyma in POPF positive group was significantly lower than that in POPF negative group (P = 0.001). However, there was no significant difference in palpation stiffness between the two groups (P = 0.124). Besides, neither the SWV value of FPL nor the SWV ratio between FPL to surrounding pancreatic parenchyma differ significantly between POPF positive and negative group (P > 0.05). Taking SWV value of pancreatic parenchyma >1.10 m/s as a cut-off value for predicting POPF, area under the receiver operating characteristic curve (AUROC) was 0.864 with 72.2% sensitivity, 92.3% specificity, 86.7% positive predictive value (PPV) and 82.8% negative predictive value (NPV), respectively. CONCLUSIONS: VTIQ technique might be a potential non-invasive imaging method to predict POPF before pancreatectomy in future clinical practice.

A randomised, multicentre trial of somatostatin to prevent clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy.

BACKGROUND: Prophylactic somatostatin to reduce the incidence of clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy remains controversial. We assessed the preventive efficacy of somatostatin on clinically relevant postoperative pancreatic fistula in intermediate-risk patients who underwent pancreaticoduodenectomy at pancreatic centres in China. METHODS: In this multicentre, prospective, randomised controlled trial, we used the updated postoperative pancreatic fistula classification criteria and cases were confirmed by an independent data monitoring committee to improve comparability between centres. The primary endpoint was the rate of clinically relevant postoperative pancreatic fistula within 30 days after pancreaticoduodenectomy. RESULTS: Eligible patients (randomised, n = 205; final analysis, n = 199) were randomised to receive postoperative intravenous somatostatin (250 µg/h over 120 h; n = 99) or conventional therapy (n = 100). The primary endpoint was significantly lower in the somatostatin vs control group (n = 13 vs n = 25; 13% vs 25%, P = 0.032). There were no significant differences for biochemical leak (P = 0.289), biliary fistula (P = 0.986), abdominal infection (P = 0.829), chylous fistula (P = 0.748), late postoperative haemorrhage (P = 0.237), mean length of hospital stay (P = 0.512), medical costs (P = 0.917), reoperation rate (P > 0.99), or 30 days' readmission rate (P = 0.361). The somatostatin group had a higher rate of delayed gastric emptying vs control (n = 33 vs n = 21; 33% vs 21%, P = 0.050). CONCLUSIONS: Prophylactic somatostatin treatment reduced clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy. TRIAL REGISTRATION: NCT03349424.

DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.

Pancreatic cancer is a highly malignant tumour of the digestive tract which is difficult to diagnose and treat. Approximately 90% of cases arise from ductal adenocarcinoma of the glandular epithelium. The morbidity and mortality of the disease have increased significantly in recent years. Its 5-year survival rate is <1% and has one of the worst prognoses amongst malignant tumours. Pancreatic cancer has a low rate of early-stage diagnosis, high surgical mortality and low cure rate. Selenium compounds produced by selenoamino acid metabolism may promote a large amount of oxidative stress and subsequent unfolded reactions and endoplasmic reticulum stress by consuming the NADPH in cells, and eventually lead to apoptosis, necrosis or necrotic cell death. In this study, we first identified DIAPH3 as a highly expressed protein in the tissues of patients with pancreatic cancer, and confirmed that DIAPH3 promoted the proliferation, anchorage-independent growth and invasion of pancreatic cancer cells using overexpression and interference experiments. Secondly, bioinformatics data mining showed that the potential proteins interacted with DIAPH3 were involved in selenoamino acid metabolism regulation. Selenium may be incorporated into selenoprotein synthesis such as TrxR1 and GPX4, which direct reduction of hydroperoxides or resist ferroptosis, respectively. Our following validation confirmed that DIAPH3 promoted selenium content and interacted with the selenoprotein RPL6, a ribosome protein subunit involved in selenoamino acid metabolism. In addition, we verified that DIAPH3 could down-regulate cellular ROS level via up-regulating TrxR1 expression. Finally, nude mice xenograft model experimental results demonstrate DIAPH3 knock down could decrease tumour growth and TrxR1 expression and ROS levels in vivo. Collectively, our observations indicate DIAPH3 could promote pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.

Prognostic value of preoperative glucose to lymphocyte ratio in patients with resected pancreatic cancer.

BACKGROUND: Inflammatory factors and fasting blood glucose were verified to be associated with the prognosis of pancreatic ductal adenocarcinoma. The goal of this study is to confirm the prognostic role of preoperative blood glucose to lymphocyte ratio for patients with resected pancreatic ductal adenocarcinoma. METHODS: A total of 259 pancreatic ductal adenocarcinoma patients were enrolled and randomly divided into training cohort and validation cohort. The training cohort was used to generate an optimal cutoff value and the validation cohort was used to further validate the model. RESULTS: A total of 259 patients were incorporated in this study and randomly divided into the training cohort (n = 130, 1/2 of 259) and the validation cohort (129, 1/2 of 259). The optimal cutoff value of glucose to lymphocyte ratio was calculated to be 3.47 for overall survival. Cox regression analysis found that preoperative blood glucose to lymphocyte ratio was independent risk factor (p = 0.040) for overall survival. Prognostic values of glucose to lymphocyte ratio on overall survival were observed in younger male patients with pancreatic body and tail cancer, American Joint Committee on Cancer 8th N1 stage, without microvascular and peripancreatic fat invasion, and Carbohydrate antigen 19-9 higher than 200 U/ml. A prognostic prediction model of overall survival was designed and presented in nomogram. CONCLUSION: Preoperative blood glucose to lymphocyte ratio is an independent biomarker to predict the overall survival for pancreatic ductal adenocarcinoma patients who underwent curative resection.

Comprehensive Analysis of Immunoinhibitors Identifies LGALS9 and TGFBR1 as Potential Prognostic Biomarkers for Pancreatic Cancer.

Pancreatic cancer (PC) is one of the most deadly cancers worldwide. To uncover the unknown novel biomarker used to indicate early diagnosis and prognosis in the molecular therapeutic field of PC is extremely of importance. Accumulative evidences indicated that aberrant expression or activation of immunoinhibitors is a common phenomenon in malignances, and significant associations have been noted between immunoinhibitors and tumorigenesis or progression in a wide range of cancers. However, the expression patterns and exact roles of immunoinhibitors contributing to tumorigenesis and progression of pancreatic cancer (PC) have not yet been elucidated clearly. In this study, we investigated the distinct expression and prognostic value of immunoinhibitors in patients with PC by analyzing a series of databases, including TISIDB, GEPIA, cBioPortal, and Kaplan-Meier plotter database. The mRNA expression levels of IDO1, CSF1R, VTCN1, KDR, LGALS9, TGFBR1, TGFB1, IL10RB, and PVRL2 were found to be significantly upregulated in patients with PC. Aberrant expression of TGFBR1, VTCN1, and LGALS9 was found to be associated with the worse outcomes of patients with PC. Bioinformatics analysis demonstrated that LGALS9 was involved in regulating the type I interferon signaling pathway, interferon-gamma-mediated signaling pathway, RIG-I-like receptor signaling pathway, NF-kappa B signaling pathway, cytosolic DNA-sensing pathway, and TNF signaling pathway. And TGFB1 was related to mesoderm formation, cell matrix adhesion, TGF-beta signaling pathway, and Hippo signaling pathway. These results suggested that LGALS9 and TGFBR1 might serve as potential prognostic biomarkers and targets for PC.

Clinical Analysis of Acinar Cell Carcinoma of the Pancreas: A Single-Center Experience of 45 Consecutive Cases.

BACKGROUNDS: Acinar cell carcinoma of the pancreas is a rare malignancy, and its features remain unclear. We aimed to analyze the clinical characteristics, treatment and prognosis of acinar cell carcinoma with our institutional case series. METHODS: Patients diagnosed with acinar cell carcinoma in our hospital between 2005 and 2019 were reviewed. Investigations on clinicopathological features, treatment details and long-term survival were performed. RESULTS: A total of 45 pathologically confirmed acinar cell carcinomas were identified. The median age at diagnosis was 58 years with a male-to-female ratio of 3.1:1. There were 24 (53.3%) localized, 5 (11.1%) locally advanced and 16 (35.6%) metastatic cases, with a pancreatic head-to-body/tail ratio of 1:1.4 for all the primary lesions. In the localized group, there were 10 pancreatoduodenectomy, 12 distal pancreatectomy, 1 total pancreatectomy, and 1 distal pancreatectomy combined with proximal gastrectomy. Among the locally advanced and metastatic cases, 13 patients received chemotherapy, 1 received concurrent radiochemotherapy, 1 underwent synchronous resection of primary tumor and liver metastasis, 1 underwent palliative operation, 1 underwent exploratory laparotomy, and 4 required no treatment. The median overall survival of this series was 18.9 months with a 5-year survival rate of 19.6%. Moreover, the resected acinar cell carcinoma patients were associated with prolonged survival compared with the unresected cases (36.6 vs. 8.5 months, P < 0.001). CONCLUSIONS: Surgical resection could improve the long-term survival of acinar cell carcinoma patients, which might also improve the prognosis of selected metastatic cases. Large-scale studies are needed to further clarify the biological behavior and clinical features, and to seek the optimal treatments.

HEATR1 Deficiency Promotes Chemoresistance via Upregulating ZNF185 and Downregulating SMAD4 in Pancreatic Cancer.

OBJECTIVE: To discover the correlated gene with HEATR1 in regulating chemoresistance of gemcitabine. METHODS: Gene chip analysis was performed to find out differential genes between HEATR1-KD and control groups. The top 20 genes were subjected to high-content screening, and functional assay was implemented. Gene expression profiling was carried out to find the downstream target. Immunohistochemistry and survival analysis were performed. RESULTS: ZNF185 fold change (4.5285) was the most significant between the HEATR1-KD and control groups. Knocking down ZNF185 could promote the chemosensitivity, apoptosis, and proliferative inhibition, with SMAD4 significantly upregulated. Patients with high HEATR1 and SMAD4 or low ZNF185 exhibited better survival. CONCLUSION: HEATR1, ZNF185, and SMAD4 could affect the chemosensitivity of gemcitabine and may be the indicators of gemcitabine selection in the chemotherapy of pancreatic cancer.

Preoperative radiotherapy improves overall survival of pT4 pancreatic ductal adenocarcinoma patients after surgical resection.

OBJECTIVE: The aim of delivering radiotherapy for pancreatic ductal adenocarcinoma patients was to sterilize vessel margin, increase R0 resection rate and delay local progression. Whether preoperative radiotherapy could prolong overall survival of surgical candidates remained unknown. METHODS: Pancreatic ductal adenocarcinoma patients receiving radical resection from surveillance, epidemiology and end result database were enrolled. Propensity score matching was conducted to balance difference in baseline characteristics, and survival analyses were performed to compare overall survival between preoperative radiotherapy and upfront resection groups. Cox proportional hazard regression model and subgroup analyses were utilized to identify prognostic factors. RESULTS: A total of 11 665 and 597 pancreatic ductal adenocarcinoma patients receiving upfront resection and preoperative radiotherapy followed by resection from 2004 to 2016 were identified, respectively, while baseline characteristics were distinct between groups. After propensity score matching, preoperative radiotherapy was not associated with better overall survival (upfront resection vs preoperative radiotherapy, 26 vs 27 months). Subgroup analyses showed that preoperative radiotherapy was a protective factor in pT4 (hazard ratio = 0.64, 95% confidence interval: 0.47-0.88) but a negative predictor in pT1 (hazard ratio = 1.79, 95% confidence interval: 1.08-2.97) patient populations. Survival analyses showed that preoperative radiotherapy improved overall survival of patients with pT4 stage (upfront resection vs preoperative radiotherapy, 19 vs 25 months) and involvement of celiac axis, superior mesenteric artery and aorta (upfront resection vs preoperative radiotherapy, 20 vs 27 months), while preoperative radiotherapy was associated with worse overall survival in patients with pT1 tumor (upfront resection vs preoperative radiotherapy, 39 vs 24 months). CONCLUSION: Preoperative radiotherapy could improve survival of resected pancreatic ductal adenocarcinoma patients with pT4 stage or with celiac axis, superior mesenteric artery and aorta invasion.