Integrating plasma protein-centric multi-omics to identify potential therapeutic targets for pancreatic cancer.

BACKGROUND: Deciphering the role of plasma proteins in pancreatic cancer (PC) susceptibility can aid in identifying novel targets for diagnosis and treatment. METHODS: We examined the relationship between genetically determined levels of plasma proteins and PC through a systemic proteome-wide Mendelian randomization (MR) analysis utilizing cis-pQTLs from multiple centers. Rigorous sensitivity analyses, colocalization, reverse MR, replications with varying instrumental variable selections and additional datasets, as well as subsequent meta-analysis, were utilized to confirm the robustness of significant findings. The causative effect of corresponding protein-coding genes' expression and their expression pattern in single-cell types were then investigated. Enrichment analysis, between-protein interaction and causation, knock-out mice models, and mediation analysis with established PC risk factors were applied to indicate the pathogenetic pathways. These candidate targets were ultimately prioritized upon druggability and potential side effects predicted by a phenome-wide MR. RESULTS: Twenty-one PC-related circulating proteins were identified in the exploratory phase with no evidence for horizontal pleiotropy or reverse causation. Of these, 11 were confirmed in a meta-analysis integrating external validations. The causality at a transcription level was repeated for neutrophil elastase, hydroxyacylglutathione hydrolase, lipase member N, protein disulfide-isomerase A5, xyloside xylosyltransferase 1. The carbohydrate sulfotransferase 11 and histo-blood group ABO system transferase exhibited high-support genetic colocalization evidence and were found to affect PC carcinogenesis partially through modulating body mass index and type 2 diabetes, respectively. Approved drugs have been established for eight candidate targets, which could potentially be repurposed for PC therapies. The phenome-wide investigation revealed 12 proteins associated with 51 non-PC traits, and interference on protein disulfide-isomerase A5 and cystatin-D would increase the risk of other malignancies. CONCLUSIONS: By employing comprehensive methodologies, this study demonstrated a genetic predisposition linking 21 circulating proteins to PC risk. Our findings shed new light on the PC etiology and highlighted potential targets as priorities for future efforts in early diagnosis and therapeutic strategies of PC.

Optimizing prediction models for pancreatic fistula after pancreatectomy: Current status and future perspectives.

Postoperative pancreatic fistula (POPF) is a frequent complication after pancreatectomy, leading to increased morbidity and mortality. Optimizing prediction models for POPF has emerged as a critical focus in surgical research. Although over sixty models following pancreaticoduodenectomy, predominantly reliant on a variety of clinical, surgical, and radiological parameters, have been documented, their predictive accuracy remains suboptimal in external validation and across diverse populations. As models after distal pancreatectomy continue to be progressively reported, their external validation is eagerly anticipated. Conversely, POPF prediction after central pancreatectomy is in its nascent stage, warranting urgent need for further development and validation. The potential of machine learning and big data analytics offers promising prospects for enhancing the accuracy of prediction models by incorporating an extensive array of variables and optimizing algorithm performance. Moreover, there is potential for the development of personalized prediction models based on patient- or pancreas-specific factors and postoperative serum or drain fluid biomarkers to improve accuracy in identifying individuals at risk of POPF. In the future, prospective multicenter studies and the integration of novel imaging technologies, such as artificial intelligence-based radiomics, may further refine predictive models. Addressing these issues is anticipated to revolutionize risk stratification, clinical decision-making, and postoperative management in patients undergoing pancreatectomy.

Unraveling the enigma: A comprehensive review of solid pseudopapillary tumor of the pancreas.

Solid pseudopapillary tumor of the pancreas (SPTP) is a rare neoplasm predominantly observed in young females. Pathologically, CTNNB1 mutations, ß-catenin nuclear accumulation, and subsequent Wnt-signaling pathway activation are the leading molecular features. Accurate preoperative diagnosis often relies on imaging techniques and endoscopic biopsies. Surgical resection remains the mainstay treatment. Risk models, such as the Fudan Prognostic Index, show promise as predictive tools for assessing the prognosis of SPTP. Establishing three types of metachronous liver metastasis can be beneficial in tailoring individualized treatment and follow-up strategies. Despite advancements, challenges persist in understanding its etiology, establishing standardized treatments for unresectable or metastatic diseases, and developing a widely recognized grading system. This comprehensive review aims to elucidate the enigma by consolidating current knowledge on the epidemiology, clinical presentation, pathology, molecular characteristics, diagnostic methods, treatment options, and prognostic factors.

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.

External validation of fistula risk scores for postoperative pancreatic fistula after distal pancreatectomy.

BACKGROUND: Fistula risk scores such as distal fistula risk scores and DISPAIR have been recently developed to assess the risk of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. This study aimed to validate these models externally using a large-scale Chinese cohort. METHODS: The study enrolled adult patients who underwent distal pancreatectomy at a high-volume single center between January 2011 and December 2021. The clinically relevant postoperative pancreatic fistula was defined as grade B/C, according to the 2016 International Study Group of Pancreatic Surgery. Model performance was evaluated using the area under the curve. RESULTS: Among 653 eligible patients, 126 (19.3%) suffered from clinically relevant postoperative pancreatic fistulas. Independent predictors for clinically relevant postoperative pancreatic fistulas included body mass index, diabetes mellitus, pancreatic thickness at both neck and transection sites, main pancreatic duct diameter, and soft pancreas. Clinically relevant postoperative pancreatic fistula risk increased with increasing score severity. All 3 prediction models showed acceptable discrimination, with area under the curve values of preoperative distal fistula risk score at 0.723 (95% confidence interval 0.687-0.757), intraoperative distal fistula risk score at 0.737 (95% confidence interval 0.701-0.770), and DISPAIR at 0.721 (95% confidence interval 0.685-0.755). No significant differences were found among them. CONCLUSION: Distal fistula risk scores and DISPAIR are useful tools for predicting clinically relevant postoperative pancreatic fistula after distal pancreatectomy, highlighting their importance in guiding surgical approach decisions and mitigating strategies against this complication in clinical practice.

Predicting pancreatic fistula after central pancreatectomy using current fistula risk scores for pancreaticoduodenectomy and distal pancreatectomy.

BACKGROUND: The incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) after central pancreatectomy (CP) is high, yet an effective predictive method is currently lacking. This study aimed to predict CR-POPF after CP by utilizing existing fistula risk scores (FRSs) for pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: A retrospective analysis was conducted on patients undergoing CP at our institution between January 2010 and July 2022. The primary outcome was CR-POPF (grade B/C) according to the 2016 International Study Group of Pancreatic Surgery definition. To establish predictive models for CR-POPF after CP, we combined the FRSs for PD and DP using a calculation formula that considers the probability of the union of two events. As a result, we obtained twelve central FRS (C-FRS) models. The performance of each C-FRS was assessed using the area under the curves (AUC) and calibration plots. RESULTS: A total of 115 patients undergoing CP were included. Among them, 38 (33%) were male, with a median age of 53 years. CR-POPF occurred in 35 (30.4%) patients, specifically 33 (28.7%) with grade B and 2 (1.7%) with grade C. Multivariate analysis showed that body mass index (BMI) [odds ratio (OR) 1.260, 95% confidence interval (CI) 1.039-1.528, P = 0.019), pancreatic thickness at the cephalic transection site (OR 1.228, 95% CI 1.074-1.405, P = 0.003), cephalic main pancreatic duct (MPD) size (OR 41.872, 95%CI 7.614-230.265, P < 0.001), and distal MPD size (OR 0.142, 95% CI 0.036-0.561, P = 0.005) were independent predictive factors for CR-POPF. Discrimination was generally acceptable for all C-FRS models, with an AUC ranging from 0.748 (DISPAIR-a-FRS: 95% CI, 0.659-0.824) to 0.847 (Intraop-D-a-FRS: 95% CI, 0.768-0.907). The models were calibrated with adequate Brier scores ranging from 0.157 to 0.183. The performance in all subgroups was similar as that of the entire cohort. Three preoperative risk groups (low, intermediate, and high) were identified based on the clinical applicability of the Preop-D-Roberts-FRS, with corresponding incidences of CR-POPF as 0% (0/24), 30% (21/70), and 66.7% (14/21), respectively. CONCLUSION: The derived C-FRS models show potential for accurately predicting the development of CR-POPF after CP. However, further validation studies are required to determine the most effective model. In the meantime, the Preop-D-Roberts-FRS is recommended for clinical practice due to its ease of use and preoperative predictability.

Single-cell mapping reveals several immune subsets associated with liver metastasis of pancreatic ductal adenocarcinoma.

BACKGROUND: Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop promising and innovative therapeutic strategies. However, the dynamics of immune cell lineages in the TME of advanced PDAC remains elusive. METHODS: Twenty-six samples from 11 patients (including 11 primary tumor tissues, 10 blood, and 5 lymph nodes) with different stages were used to develop a multiscale immune profile. High-dimensional single-cell analysis with mass cytometry was performed to search for metastasis-correlated immune changes in the microenvironment. The findings were further validated by published single-cell RNA sequencing (scRNA-seq) data and multiplex fluorescent immunohistochemistry. FINDINGS: High-dimensional single-cell profiling revealed that the three immune-relevant sites formed a distinct immune atlas. Interestingly, the PDAC microenvironment with the potential for metastatic spread to the liver was characterized by a decreased proportion of CD103+PD-1+CD39+ T cells with cytotoxic and exhausted functional status and an increased proportion of CD73+ macrophages. Analysis of scRNA-seq data of PDAC further confirmed the identified subsets and revealed strong potential interactions via various ligand-receptor pairs between the identified T subsets and the macrophages. Moreover, stratified patients with different immune compositions correlated with clinical outcomes of PDAC. CONCLUSIONS: Our study uncovered metastasis-correlated immune changes, suggesting that ecosystem-based patient classification in PDAC will facilitate the identification of candidates likely to benefit from immunotherapy. FUNDING: This work was supported by the National Key Research and Development Program of China, the Shanghai International Science and Technology Collaboration Program, the Shanghai Sailing Program, and the Key Laboratory of diagnosis and treatment of severe hepato-pancreatic diseases of Zhejiang Province.

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer.

PURPOSE: In a phase IIb trial of nimotuzumab plus gemcitabine, substantial clinical benefits were observed in patients with locally advanced or metastatic pancreatic cancer (PC). Therefore, we conducted a phase III clinical study to verify the efficacy and safety of this combination regimen in patients with K-Ras wild-type tumors (ClinicalTrials.gov identifier: NCT02395016). PATIENTS AND METHODS: Eligible patients were randomly assigned to receive nimotuzumab (400 mg once per week) or placebo followed by gemcitabine (1,000 mg/m2 on days 1, 8, and 15, once every 4 weeks) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) and the secondary end points were progression-free survival (PFS), response rates, and safety. RESULTS: A total of 480 patients were screened; 92 patients were enrolled and 82 patients with K-Ras wild-type tumors were eligible. In the full analysis set, the median OS was 10.9 versus 8.5 months, while the restricted mean survival time (RMST) was 18.05 versus 11.14 months for the investigational versus control arm (ratio of control v investigation = 0.62 [0.40-0.97]; P = .036). Median PFS was 4.2 versus 3.6 months in the investigational versus control arm (log-rank P = .04; hazard ratio, 0.60 [0.37-0.99]) and the restricted mean PFS time was 8.08 versus 4.76 months (RMST ratio, 0.58 [0.38-0.90]; P = .036). Both OS and PFS were longer in the nimotuzumab group than in the placebo group. The objective response rates and disease control rates were 7% versus 10% and 68% versus 63% for the investigational and control groups, respectively. The incidence of adverse events were comparable between the two groups. CONCLUSION: In patients with locally advanced or metastatic K-Ras wild-type PC, nimotuzumab plus gemcitabine significantly improved OS and PFS with a good safety profile.

Thermodynamic Analysis on In Situ Underground Pyrolysis of Tar-Rich Coal: Secondary Reactions.

To develop the in situ underground pyrolysis process of tar-rich coal more scientifically, the effect of temperature and pressure on the distribution of pyrolysis products should be clarified. This paper selected the typical components in five distillates of light tar, phenol tar, naphthalene tar, washing tar, and anthracene tar as the main reaction products. 32 typical secondary reactions were constructed. Based on the thermodynamic analysis strategy, the variation of the Gibbs free energy and equilibrium constant of secondary reactions was investigated. The results showed that pressure mainly affected the reaction characteristics of molecule-increasing reactions. The Gibbs free energy value of the molecule-increasing reactions increased with increasing pressure. The trend that the reaction could proceed spontaneously gradually weakened. The initial temperature of some reactions that could proceed spontaneously would need to increase by dozens or even hundreds of degrees. Due to the influence of formation pressure, the generation of related components of light tar, naphthalene tar, washing tar, and anthracene tar would be inhibited to varying degrees in the in situ underground pyrolysis process. The secondary reactions related to phenol tar were equimolecular reactions, which were almost unaffected by stratal pressure. Axial pressure and confining pressure of different coal seam depths should be considered in the process of in situ underground pyrolysis.

CDCA8/SNAI2 Complex Activates CD44 to Promote Proliferation and Invasion of Pancreatic Ductal Adenocarcinoma.

(1) Background: Recently, cell division cycle associated 8 (CDCA8) was found to be overexpressed in pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to explore the specific mechanism of action of CDCA8 in PDAC progression. (2) Methods: All human PDAC samples and clinical data were collected from Huashan Hospital, Fudan University. All experimental studies were carried out using many in vitro and in vivo assays, including lentiviral transfection, real-time quantitative polymerase chain reaction (qPCR), western blotting, co-immunoprecipitation (Co-IP), chromatin IP (ChIP)-qPCR, dual-luciferase reporter, and in vivo imaging assays. (3) Results: Clinical data analysis of human PDAC samples revealed that CDCA8 overexpression were positively and negatively associated with tumor grade (p = 0.007) and overall survival (p = 0.045), respectively. CDCA8 knockdown inhibited PDAC proliferation and invasion in in vitro and in vivo assays. CD44 was also up-regulated by CDCA8 during PDAC progression. CDCA8 could be combined with SNAI2 to form a CDCA8/SNAI2 complex to integrate with the CD44 promoter as indicated through ChIP-qPCR and dual-luciferase reporter assays. (4) Conclusion: We showed that CDCA8-CD44 axis plays a key role in the proliferation and invasion of PDAC, which provides a potential target for treatment.

High Glucose Promotes Pancreatic Ductal Adenocarcinoma Gemcitabine Resistance and Invasion through Modulating ROS/MMP-3 Signaling Pathway.

Pancreatic ductal adenocarcinoma (PDA) is often concomitant with diabetes mellitus, which mainly manifests as an increased blood glucose level. Previous studies revealed that diabetic status reduced the survival and blunted gemcitabine sensitivity in PDA patients. This study is aimed at analyzing the mechanism of elevated gemcitabine resistance and cancer invasion ability under high glucose environment. We selected 129 patients with 22 surgical resected samples from 2015 to 2021, who underwent pancreatic surgery in Huashan Hospital. The gene expression and clinical data of PDA were obtained from The Cancer Genome Atlas (TCGA) website and were analyzed by R software. Cell viability assays and flow cytometry were applied to detect gemcitabine sensitivity and apoptosis levels in pancreatic cancer cells. Wound healing and Transwell tests were used to analyze the invasion and metastasis of cancer cells. Streptozotocin (STZ) was used to establish a hyperglycemic mouse model for the in vivo study. In this study, diabetic PDA gemcitabine users showed reduced survival compared to euglycemic PDA gemcitabine users. Clinical samples and laboratory studies revealed that MMP-3 expression was associated with glucose concentration and diabetic status. Elevated MMP-3 expression was positively related to cancer invasion and gemcitabine resistance in PDA cells and gemcitabine resistant PDA cells. Blocking MMP-3 expression inhibited gemcitabine resistance and cancer progression in cellular and animal models. MMP-3 was closely related to the expression of RRM1, a gemcitabine metabolism-related gene. Reactive oxygen species (ROS) level increased under higher glucose concentrations and was mediated by NOX4. ROS determined the MMP-3 expression in pancreatic cancer cells. Inhibiting NOX4 expression effectively suppressed MMP-3 expression, gemcitabine resistance, and cancer invasion. In conclusion, a high glucose environment induces gemcitabine resistance and cancer invasion via ROS/MMP-3 signaling pathway. MMP-3 can be a potential novel target for suppressing gemcitabine resistance and invasion in PDA.

Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth.

Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for survival from pancreatic ductal adenocarcinoma (PDAC) on glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in a nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-dependent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.

Gemcitabine-Loaded Albumin Nanoparticle Exerts An Antitumor Effect on Gemcitabine-Resistant Pancreatic Cancer Cells Induced by MDR1 and MRP1 Overexpression in Vitro.

Purpose: Gemcitabine (GEM) is the first-line chemotherapeutic drug for pancreatic cancer treatment in clinical practice. However, many reasons can reduce the efficacy of GEM, among which the high expression of ATP-binding cassette (ABC) transporters is a significant factor. In this study, we aimed to investigate the antitumor effect of gemcitabine-loaded human serum albumin nanoparticle (GEM-HSA-NP) on GEM-resistant pancreatic cancer cells induced by the high expression of ABC transporters, namely multidrug resistance protein 1/P-gp/ABCB1 (MDR1) and multidrug resistance-associated protein 1/ ABCC1 (MRP1). Methods: MDR1 and MRP1 were stably overexpressed via lentiviral transduction in the pancreatic cancer cell lines BxPC3 and PANC1. Proliferation inhibition assays, cell cycle arrest and apoptosis analyses were conducted to examine the antitumor effect of GEM-HSA-NP. In addition, intracellular ATP levels were determined to explore the potential mechanisms implicated preliminarily. Results: When administered to GEM-resistant cancer cells, GEM-HSA-NP displayed its antitumor effect by promoting the inhibition of proliferation, cell cycle arrest, and apoptosis induction. Intracellular ATP depletion, caused by the albumin component of GEM-HSA-NP was proposed to be potentially involved in the modulation of ABC transporter activity. Conclusion: GEM-HSA-NP can effectively overcome GEM-resistance induced by MDR1 and MRP1 overexpression, which highlights its potential value in a clinical setting.

Clinical significance of variant hepatic artery in pancreatic resection: A comprehensive review.

The anatomical structure of the pancreaticoduodenal region is complex and closely related to the surrounding vessels. A variant of the hepatic artery, which is not a rare finding during pancreatic surgery, is prone to intraoperative injury. Inadvertent injury to the hepatic artery may affect liver perfusion, resulting in necrosis, liver abscess, and even liver failure. The preoperative identification of hepatic artery variations, detailed planning of the surgical approach, careful intraoperative dissection, and proper management of the damaged artery are important for preventing hepatic hypoperfusion. Nevertheless, despite the potential risks, planned artery resection has become acceptable in carefully selected patients. Arterial reconstruction is sometimes essential to prevent postoperative ischemic complications and can be performed using various methods. The complexity of procedures such as pancreatectomy with en bloc celiac axis resection may be mitigated by the presence of an aberrant right hepatic artery or a common hepatic artery originating from the superior mesenteric artery. Here, we comprehensively reviewed the anatomical basis of hepatic artery variation, its incidence, and its effect on the surgical and oncological outcomes after pancreatic resection. In addition, we provide recommendations for the prevention and management of hepatic artery injury and liver hypoperfusion. Overall, the hepatic artery variant may not worsen surgical and oncological outcomes if it is accurately identified pre-operatively and appropriately managed intraoperatively.

The Role of Diabetes Mellitus in the Malignant Pancreatic Cyst Neoplasm Diagnosis and Prognosis.

Purpose: Pancreatic cyst neoplasm (PCN) is a precursor of pancreatic cancer. Previous studies reported PCN was often concurrent with diabetes. We aim to examine the association between diabetes with PCN malignancy and to detect the potential role of diabetes in PCN management and treatment. Patients and Methods: A total of 224 patients who were diagnosed with the three major types of PCN (IPMN, MCN, and SCN) and underwent surgical resection were selected. Patients were divided into three groups (normal group, new-onset diabetes group (NODM) (<4years), and long-standing diabetes group (LSDM) (>4years)) according to diabetic history and diagnostic time interval. Diabetes, fast blood glucose level, HbA1c, and insulin resistance level were measured. Malignant PCN (mPCN) radiological features (worrisome features and high-risk stigmata) were analyzed. Pathological features (PCN type, dysplasia grade, tumor stage, and tumor volume) and immunohistology of Ki67 and SMAD4 were performed. Diagnostic efficacy of each variable was determined by the ROC curve. mPCN diagnosis was the main outcome in diagnostic prediction and overall survival as the glucose controlling outcome variables. Results: Diabetes groups (NODM and LSDM) showed difference with the normal group in age, weight loss, malignancy, CA19-9 value, CEA value, Ki-67 value, tumor volume, pathological grade, and a lowered pancreatic fistula risk. NODM was related to insulin resistance, weight loss, and SMAD4 mutation. NODM (87.3%) and high insulin resistance rate (93.6%) significantly increased the sensitivity of radiological evidence-based mPCN diagnosis. Moreover, long-standing diabetes and elevated HbA1c led to reduced survival in mPCN patients than the normal PCN group. Anti-diabetic drugs showed limited influence on PCN malignancy and tumor volume. Conclusion: NODM in PCN patients was associated with malignancy, insulin resistance, weight loss, and SMAD4 mutation. Prediabetic status and NODM diagnosis enhanced the diagnostic accuracy of radiological standards (worrisome features and high-risk stigmata). Stable glucose surveillance is necessary for mPCN patients' survival.

Prevalence and prognosis of increased pancreatic enzymes in patients with COVID-19: A systematic review and meta-analysis.

INTRODUCTION: The prevalence of increased pancreatic enzymes (elevated serum amylase and/or lipase) and its relationship to clinical outcomes in patients with coronavirus disease 2019 (COVID-19) infection is not known. METHODS: A systematic review and meta-analysis of relevant studies reporting prevalence and impact of increased pancreatic enzymes (defined as an elevation in amylase and/or lipase levels above the upper limit of normal [ULN] value) in COVID-19 was undertaken. RESULTS: A total of 36,496 patients from 21 studies were included for this meta-analysis. The overall prevalence and mortality for increased pancreatic enzymes (>ULN) in COVID-19 were 25.4% (95% CI, 15.8%-36.2%) and 34.6% (95% CI, 25.5%-44.4%), respectively. The overall prevalence and mortality for increased pancreatic enzymes (>3 × ULN) were 6.1% (95% CI, 3.6%-9.2%) and 39.2% (95% CI, 18.7%-61.6%), respectively. Patients with increased pancreatic enzymes, including elevated serum lipase or amylase of either type, had worse clinical outcomes, including need for ICU admission, mechanical ventilation and mortality. DISCUSSION: Increased pancreatic enzymes is frequent and may exacerbate the consequences of COVID-19 infection.

Characterization of the genomic landscape in large-scale Chinese patients with pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with an extremely poor prognosis. Effective targets for anticancer therapy confirmed in PDAC are limited. However, the characteristics of genomics have not been fully elucidated in large-scale patients with PDAC from China. METHODS: We collected both blood and tissue samples from 1080 Chinese patients with pancreatic cancer and retrospectively investigated the genomic landscape using next-generation sequencing (NGS). FINDINGS: We found recurrent somatic mutations in KRAS (83.2%), TP53 (70.6%), CDKN2A (28.8%), SMAD4 (23.0%), ARID1A (12.8%) and CDKN2B (8.9%) in Chinese PDAC patients. Compared with primary pancreatic cancers, more genomic alterations accumulated especially cell cycle regulatory gene variants (45.4% vs 31.6%, P < 0.001) were observed in metastatic tumors. The most common mutation site of KRAS is p.G12D (43.6%) in pancreatic cancer. Patients with KRAS mutations were significantly associated with older age and mutations in the other three driver genes, while KRAS wild-type patients contained more fusion mutations and alternative mechanisms of RTK/Ras/MAPK pathway including a number of clinically targetable mutations. KRAS mutations in Chinese cohort were significantly lower than those in Western cohorts (all P < 0.05). A total of 252 (23.3%) patients with the core DNA damage response (DDR) gene mutations were detected. ATM (n =59, 5.5%) was the most frequent mutant DDR gene in patients with pancreatic cancer from China. Patients with germline DDR gene mutations were younger (P = 0.018), while patients with somatic DDR gene mutations were more likely to accumulate in metastatic lesions (P < 0.001) and had higher TMB levels (P < 0.001). In addition, patients with mutant DDR genes and patients carrying TP53 mutation were observed mutually exclusive (P < 0.001). INTERPRETATION: We demonstrated the real-world genomic characteristics of large-scale patients with pancreatic cancer from China which may have promising implications for further clinical significance and drug development. FUNDING: The funders are listed in the Acknowledgement.

The Intricate Crosstalk Between Insulin and Pancreatic Ductal Adenocarcinoma: A Review From Clinical to Molecular.

Increased insulin level (or "hyperinsulinemia") is a common phenomenon in pancreatic ductal adenocarcinoma (PDA) patients and signals poor clinical outcomes. Insulin is safe in low PDA risk population, while insulin significantly promotes PDA risk in high PDA risk population. The correlation between insulin and PDA is a reciprocal self-reinforcing relationship. On the one hand, pancreatic cancer cells synthesize multiple molecules to cause elevated peripheral insulin resistance, thus enhancing hyperinsulinemia. On the other hand, insulin promotes pancreatic cancer initiation and sustains PDA development by eliciting tumorigenic inflammation, regulating lipid and glucose metabolic reprogram, overcoming apoptosis through the crosstalk with IGF-1, stimulating cancer metastasis, and activating tumor microenvironment formation (inflammation, fibrosis, and angiogenesis). Currently, taking glucose sensitizing agents, including metformin, SGLT-2 inhibitor, and GLP-1 agonist, is an effective way of lowering insulin levels and controlling PDA development at the same time. In the future, new drugs targeting insulin-related signal pathways may pave a novel way for suppressing PDA initiation and progression.