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Objective: Metabolic risks play a key role in the progression of pancreatic cancer. This study aimed to present global, regional and national data on mortality and disability-adjusted life-year (DALY) for pancreatic cancer attributable to metabolic risk and to forecast mortality to 2030 using data from the Global Burden of Disease (GBD)., Methods: Data on mortality and DALYs due to pancreatic cancer attributable to metabolic risks were obtained from GBD 2019. Metabolic risks include high fasting plasma glucose (FPG) and high body mass index (BMI). Total numbers and age-standardized rates per 100,000 people for mortality and DALYs were reported by age, sex, region and country/territory from 1990 to 2019. The "Bayes age-period-cohort" method was used for projections of mortality to 2030., Results: Globally, there was a 3.5-fold increase in the number of pancreatic cancer deaths attributable to metabolic risk, from 22,091 in 1990 to 77,215 in 2019. High-income North America and Central Europe had the highest age-standardized mortality rates (ASMRs) of pancreatic cancer attributable to high FPG and high BMI in 2019, respectively. From 1990 to 2019, the global ASMR of pancreatic cancer attributable to high FPG and high BMI increased. Countries with high healthcare access quality had much higher age-standardized DALY rates. In the next 10 years, the ASMR of pancreatic cancer attributable to high FPG and high BMI will continue to increase., Conclusion: Pancreatic cancer mortality and DALYs attributable to metabolic factors remain high, particularly in high-income regions or countries. Studies on the metabolic mechanism of pancreatic cancer and effective treatment strategies are needed., (© 2024. The Author(s).)

This study aims to summarize and visually analyze the current research status in pancreatic cancer immunotherapy during the past two decades by bibliometrics and explore the current research hotspots and future development directions. The literature related to pancreatic cancer immunotherapy from 2002 to 2021 was downloaded from the core database of the Web of Science. VOSviewer and CiteSpace software were used to visualize the included literature. A total of 2528 articles were included. In the past two decades, publications in the pancreatic cancer immunotherapy field have increased almost annually. As the country with the largest publications, the United States has various research institutions dedicated to pancreatic cancer immunotherapy. Jaffee EM and Zheng L from Johns Hopkins University and Vonderheide RH from the University of Pennsylvania have published the most articles in this field. The current research hotspots of pancreatic cancer immunotherapy include the tumor microenvironment, immune cells, immune checkpoint blockade, and combination therapy. The study of novel immunotherapies and combination therapy may become the primary focus of future research on pancreatic cancer immunotherapy. More prospective clinical studies with high evidence levels should be conducted.

Background: Pancreatic cancer poses a serious medical problem worldwide. Countries in the Western Pacific Region are facing public health challenges from cancer. This study assesses the time trends of pancreatic cancer mortality in the Western Pacific Region from 1990 to 2019 and predicts its trend to 2044., Methods: Mortality data were obtained from the Global Health Data Exchange. We used an age-period-cohort model to estimate age, period and birth cohort effects on pancreatic cancer mortality from 1990 to 2019 by calculating net drift, local drift, age-specific rate, period rate ratio, and cohort rate ratio. We also predict pancreatic cancer mortality to 2044 in Western Pacific countries., Results: Overall, there were 178,276 (95% uncertain interval: 157,771 to 198,636) pancreatic cancer deaths in the Western Pacific Region in 2019, accounting for 33.6% of all deaths due to pancreatic cancer worldwide. There were significant increases in pancreatic cancer disability-adjusted life years between 1990 and 2019 in the Western Pacific Region, mainly due to population growth and aging. Pancreatic cancer mortality increased with age. The period effect showed an increasing trend of mortality for both sexes over the study period. Compared to the reference period (2000 to 2004), the rate ratio was elevated in both males and females in the period of 2015 to 2019. There was an overall increasing rate ratio from early birth cohorts to recent cohorts. Deaths may continue to increase in the next 25 years in the ten countries, while most countries have seen their age-standardized rate forecasts fall., Conclusion: The mortality of pancreatic cancer is still high in the Western Pacific Region. Countries/territories should focus on pancreatic cancer prevention and early cancer screening in high-risk populations. Specific public health methods and policies aimed at reducing risk factors for pancreatic cancer are also needed., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Tumor-associated macrophage 2 (TAM2) abundantly infiltrates pancreatic ductal adenocarcinoma (PAAD), and its interaction with malignant cells is involved in the regulation of tumor metabolism. In this study, we explored the metabolic heterogeneity involved in TAM2 by constructing TAM2-associated metabolic subtypes in PAAD., Materials and Methods: PAAD samples were classified into molecular subtypes with different metabolic characteristics based on a multi-omics analysis strategy. 20 PAAD tissues and 10 normal pancreatic tissues were collected for proteomic and metabolomic analyses. RNA sequencing data from the TCGA-PAAD cohort were used for transcriptomic analyses. Immunohistochemistry was used to assess TAM2 infiltration in PAAD tissues., Results: The results of transcriptomics and immunohistochemistry showed that TAM2 infiltration levels were upregulated in PAAD and were associated with poor patient prognosis. The results of proteomics and metabolomics indicated that multiple metabolic processes were aberrantly regulated in PAAD and that this dysregulation was linked to the level of TAM2 infiltration. WGCNA confirmed pyruvate and glycolysis/gluconeogenesis as co-expressed metabolic pathways of TAM2 in PAAD. Based on transcriptomic data, we classified the PAAD samples into four TAM2-associated metabolic subtypes (quiescent, pyruvate, glycolysis/gluconeogenesis and mixed). Metabolic subtypes were each characterized in terms of clinical prognosis, tumor microenvironment, immune cell infiltration, chemotherapeutic drug sensitivity, and functional mechanisms., Conclusion: Our study confirmed that the metabolic remodeling of pyruvate and glycolysis/gluconeogenesis in PAAD was closely related to TAM2. Molecular subtypes based on TAM2-associated metabolic pathways provided new insights into prognosis prediction and therapy for PAAD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Du, Jiang, Dong, Li, Tang, Yi, Zhou and Zhang.)

Tumor-associated macrophages M2 (TAM2), which are highly prevalent infiltrating immune cells in the stroma of pancreatic cancer (PC), have been found to induce an immunosuppressive tumor microenvironment, thus enhancing tumor initiation and progression. However, the immune therapy response and prognostic significance of regulatory genes associated with TAM2 in PC are currently unknown. Based on TCGA transcriptomic data and single-cell sequencing data from the GEO database, we identified TAM2-driven genes using the WGCNA algorithm. Molecular subtypes based on TAM2-driven genes were clustered using the ConsensusClusterPlus algorithm. The study constructed a prognostic model based on TAM2-driven genes through Lasso-COX regression analysis. A total of 178 samples obtained by accessing TCGA were accurately categorized into two molecular subtypes, including the high-TAM2 infiltration (HMI) cluster and the low-TAM2 infiltration (LMI) cluster. The HMI cluster exhibits a poor prognosis, a malignant tumor phenotype, immune-suppressive immune cell infiltration, resistance to immunotherapy, and a high number of genetic mutations, while the LMI cluster is the opposite. The prognostic model composed of six hub genes from TAM2-driven genes exhibits a high degree of accuracy in predicting the prognosis of patients with PC and serves as an independent risk factor. The induction of TAM2 was employed as a means of verifying these six gene expressions, revealing the significant up-regulation of BCAT1, BST2, and MERTK in TAM2 cells. In summary, the immunophenotype and prognostic model based on TAM2-driven genes offers a foundation for the clinical management of PC. The core TAM2-driven genes, including BCAT1, BST2, and MERTK, are involved in regulating tumor progression and TAM2 polarization, which are potential targets for PC therapy.

Background: The dilemma of pancreatic cancer treatment has become a global challenge. For this reason, effective, feasible, and new medical methods are currently much-needed. Betulinic acid (BA) has been valued as a potential therapy for pancreatic cancer. However, the mechanism by which BA exerts an inhibitory effect on the development of pancreatic cancer remains elusive., Methods: A rat model and two cell models of pancreatic cancer were established, and the effect of BA on pancreatic cancer was verified in vivo and in vitro by using MTT, Transwell, flow cytometry, RT-PCR, Elisa and immunohistochemistry. At the same time, miR-365 inhibitors were introduced to test whether BA played a role in mediating miR-365., Results: BA can significantly inhibit the proliferation and invasion of pancreatic cancer cells and promote apoptosis. In vivo experiments, BA can significantly lower the number of cancer cells and tumor volume in the rat model of pancreatic cancer. In vitro , it was found that BA inhibited the protein level and phosphorylation level of AKT/STAT3 by mediating the expression of miR365/BTG2/IL-6. Like BA, miR-365 inhibitors also significantly inhibited cell viability and invasion ability, and inhibited the protein level and phosphorylation level of AKT/STAT3 by changing the expression of BTG2/IL-6, and their combination had a synergistic effect., Conclusion: BA inhibits AKT/STAT3 expression and phosphorylation by modulating miR-365/BTG2/IL-6 expression, and BA inhibits the progression of pancreatic cancer through the aforementioned mechanism., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2023 Li et al.)

Background: Pancreatic cancer (PAAD) is a malignant tumor with a poor prognosis and lacks sensitive biomarkers for diagnosis and targeted therapy. Cuproptosis, a recently proposed form of cell death based on cellular copper ion concentration, plays a key role in cancer biology. This study is aimed at constructing a risk model for predicting the prognosis of PAAD patients based on cuproptosis-related genes., Methods: Pancreatic-related data from UCSC-TCGA and UCSC-GTEx databases were extracted for analysis, and TCGA-PAAD samples were randomly divided into the training and validation groups. Pearson correlation analysis was used to obtain cuproptosis-related genes coexpressed with 19 copper death genes. Univariate Cox and Lasso regression analyses were used to obtain cuproptosis-related prognostic genes. Multivariate Cox regression analysis was used to construct the final prognostic risk model. The risk score curve, Kaplan-Meier survival curves, and ROC curve were used to evaluate the predictive ability of the Cox risk model. Finally, the functional annotation of the risk model was obtained through enrichment analysis., Results: The Cox risk model has an eight prognostic cuproptosis-related gene signature. Kaplan-Meier survival curves demonstrated that the high-risk group had a shorter survival time. The ROC curve of the risk score was well created to predict one-, three-, and five-year survival rates, and AUC of the risk score was higher than other clinical characteristics. Cox regression analysis revealed that the risk score has an independent prognostic value for PAAD. GSEA reveals specific tumor pathways associated with the risk model (Myc targets v1, mTORC1 signaling, and E2F targets)., Conclusions: We constructed a prognostic model containing eight cuproptosis-related genes (AKR1B10, KLHL29, PROM2, PIP5K1C, KIF18B, AMIGO2, MRPL3, and PI4KB) that can accurately predict the prognosis of PAAD patients. The results will provide new perspectives for individualized outcome prediction and new therapy development for PAAD patients., Competing Interests: All authors declare that there is no conflict of interest., (Copyright © 2023 Yan Du et al.)

Objective: Pancreatic cancer poses a serious medical problem worldwide. Studies have reported the relationship between smoking and cancer. This study aimed to evaluate the burden of pancreatic cancer attributable to smoking and its global, regional and national trends, patterns and alterations from 1990 to 2019., Methods: Data were extracted from the Global Health Data Exchange query tool, including deaths, disability-adjusted life-years (DALYs) and age-standardized rates (ASRs). Measures were stratified by sex, age, region, country/territory and sociodemographic index (SDI). We used Joinpoint regression to determine the secular trend of ASRs by calculating the average annual percentage change (AAPC)., Results: In 2019, smoking risk-related deaths and DALYs accounted for 21.3% and 21.1% of global pancreatic cancer, respectively. There were 113,384 (95% UI 98,830 to 128,466) deaths of smoking-attributable pancreatic cancer worldwide in 2019, of which 64.1% were in males. The disease burden was higher in males than in females. High-income regions or large population regions had the higher disease burden. East Asia carried the highest number of smoking-attributable pancreatic cancer deaths and DALYs. The Caribbean had the fastest increasing rate (AAPC = 3.849, 95% CI 3.310 to 4.391) of age-standardized death rate over the past 30 years. In 2019, China had the highest number of deaths, which was followed by the USA and Japan. There was a trend of increasing ASDR along with increases in SDI., Conclusion: Variations existed in the smoking risk-related pancreatic cancer burden among different sexes, age groups, regions and countries/territories. The burden of smoking-attributable pancreatic cancer should be considered an important health issue. Future strategies should include comprehensive policies to control tobacco use.

Aim: The aim of this study is to identify cuproptosis-related lncRNAs and construct a prognostic model for pancreatic cancer patients for clinical use., Methods: The expression profile of lncRNAs was downloaded from The Cancer Genome Atlas database, and cuproptosis-related lncRNAs were identified. The prognostic cuproptosis-related lncRNAs were obtained and used to establish and validate a prognostic risk score model in pancreatic cancer., Results: In total, 181 cuproptosis-related lncRNAs were obtained. The prognostic risk score model was constructed based on five lncRNAs (AC025257.1, TRAM2-AS1, AC091057.1, LINC01963, and MALAT1). Patients were assigned to two groups according to the median risk score. Kaplan-Meier survival curves showed that the difference in the prognosis between the high- and low-risk groups was statistically significant. Multivariate Cox analysis showed that our risk score was an independent risk factor for pancreatic cancer patients. Receiver operator characteristic curves revealed that the cuproptosis-related lncRNA model can effectively predict the prognosis of pancreatic cancer. The principal component analysis showed a difference between the high- and low-risk groups intuitively. Functional enrichment analysis showed that different genes were involved in cancer-related pathways in patients in the high- and low-risk groups., Conclusion: The risk model based on five prognostic cuproptosis-related lncRNAs can well predict the prognosis of pancreatic cancer patients. Cuproptosis-related lncRNAs could be potential biomarkers for pancreatic cancer diagnosis and treatment., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2022 Wenkai Jiang et al.)

The signal transducer and activator of transcription (STAT) is a family of intracellular cytoplasmic transcription factors involved in many biological functions in mammalian signal transduction. Among them, STAT3 is involved in cell proliferation, differentiation, apoptosis, and inflammatory responses. Despite the advances in the treatment of pancreatic cancer in the past decade, the prognosis for patients with pancreatic cancer remains poor. STAT3 has been shown to play a pro-cancer role in a variety of cancers, and inhibitors of STAT3 are used in pre-clinical and clinical studies. We reviewed the relationship between STAT3 and pancreatic cancer and the latest results on the use of STAT3 inhibitors in pancreatic cancer, with the aim of providing insights and ideas around STAT3 inhibitors for a new generation of chemotherapeutic modalities for pancreatic cancer.

Background: Antihypertensive medications may have some impacts on cancer. The influence of antihypertensive medications, including angiotensin converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs) and diuretics, on patients with pancreatic cancer (PC) remains controversial. This meta-analysis was conducted to investigate whether antihypertensive medications had a negative effect on the prognosis of patients with PC., Methods: The PubMed, Embase, Web of Science and the Cochrane Library databases were searched up to 30 November 2021. The Newcastle-Ottawa scale was used to evaluate the quality of each study. This meta-analysis was registered with PROSPERO (CRD42021279169) and was carried out by using RevMan 5.3., Results: Twelve studies with 120,549 patients were included in this study. ACEIs/ARBs [HR = 0.89, 95% CI (0.70-1.14)], CCB (HR = 0.69, 95% CI (0.47-0.99)], beta-blockers [HR = 0.95, 95% CI (0.84-1.07)] and diuretics [HR = 1.08, 95% CI (0.91-1.29)] use had no effects on overall survival among patients with PC (all P ≥ 0.05)., Conclusion: Antihypertensive medication will not have a negative effect on overall survival in patients with PC. PC patients with hypertension should continue to use antihypertensive medications to reduce the morbidity and mortality of cardiovascular events.

Abstract: Despite great progress in the treatment of pancreatic cancer under the efforts of researchers, the survival time of patients with pancreatic cancer is shorter than that of patients with other cancers. Thus, we have a great need for innovative therapeutic methods, including research and development of new drugs and innovation of administration methods. Exosomes are a type of extracellular vesicles wrapped by a lipid bilayer. Thanks to the low clearance ratio and strong specificity of exosomes in circulation, together with in-depth research on the surface protein of exosomes and a targeted modification method, there is a strong potential to apply exosomes in the transfer and even targeted delivery of chemotherapeutics, RNA, and natural products. Particularly, exosomes carrying microRNA show good application prospects in cancer therapy. This article is intended to summarize the progress of research relating to the treatment of pancreatic cancer via exosomal microRNAs., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)