Neuroendocrine Neoplasms (NEN) are increasing in incidence in England over the past two decades. Geographic and socio-economic disparities influence both incidence and survival rates. This study explores the relationship between environmental factors, access to specialised care in Centres of Excellence (CoE), and survival outcomes for NEN patients across England using Geographical Information Systems (GIS) to visualise disease distribution. Data on 19,958 NEN cases diagnosed between 2012 and 2018 were retrieved from the National Cancer Registry and Analysis Service (NCRAS) in England. GIS was used to analyse patient data, including spatial units, environmental factors, and travel times to CoE. Statistical analyses, including age-standardised rates, spatial autocorrelation, and survival analyses, were performed using QGIS, SPSS, R, and Stata software. Regional distribution showed the highest age-standardised rates (ASR) in the North-East, with lung NEN demonstrating significant spatial clustering. Environmental exposures, such as PM2.5 pollution, did not show a strong correlation with NEN distribution. Longer travel times to specialised centres were associated with worse overall survival, particularly in rural areas and among patients with higher socio-economic deprivation. Minor variations in survival rates were observed across different geographical regions when compared to London. This study highlights the uneven burden of disease across different regions in England. We have demonstrated variation in the country relating to anatomical sites and significant differences within rural or urban environments. Proximity to specialist centres was associated with better overall survival, highlighting the need for improved access to care.

This study aimed to analyze the trends and epidemiological characteristics of pancreatic cancer (PC) mortality in China from 2004 to 2021, focusing on gender, age, and regional disparities. The goal was to provide a comprehensive understanding of PC mortality and identify key risk factors to support future prevention and control strategies.

Using data from the national Disease Surveillance Point (DSP) system, which covers a large and representative sample of the Chinese population, the study examined pancreatic cancer mortality trends across different age groups, sexes, and regions. Statistical analyses, including the independent-sample t-test and age-period-cohort (APC) model, were employed to assess mortality differences and annual percentage changes from 2004 to 2021.

The study recorded a significant increase in pancreatic cancer mortality, particularly among males and older adults. Mortality was consistently higher in urban areas, but the growth rate in rural areas surpassed that of urban areas. Regional disparities were also observed, with the eastern region showing the highest mortality rates but slower increases compared to the central and western regions. Key risk factors, including aging, diabetes, smoking, and chronic pancreatitis, were identified, with gender-specific differences linked to lifestyle factors such as smoking and alcohol consumption.

Pancreatic cancer mortality in China has shown significant increases over the past 18 years, especially among males, older adults, and rural populations. The findings highlight the urgent need for targeted public health interventions to address gender- and age-specific risks, as well as healthcare access inequalities in less developed regions. Future research should focus on gathering more granular, individual-level data to better understand the complex interplay of risk factors and inform more effective prevention and treatment strategies.

The complex two-way relationship between diabetes mellitus (DM) and cancer poses a significant global health challenge. Shared mechanisms such as hyperinsulinemia, chronic inflammation, and oxidative stress create an environment that fosters cancer development, increasing the risk for certain cancers in individuals with diabetes, including pancreatic, colorectal, breast, liver, and endometrial malignancies. In this context, biomarkers emerge as essential tools, offering a means to untangle the connections between these two conditions by providing insights into early detection, diagnosis, prognosis, and treatment monitoring. For diabetic patients, biomarkers are particularly valuable as they help differentiate between changes caused by cancer and those driven by metabolic imbalances, illuminating disease evolution. This review examines the unique challenges encountered by diabetic patients with cancer, emphasizing the contributions of targeted biomarkers in identifying cancer subtypes, predicting outcomes, and guiding treatment decisions. We explore organ-specific biomarker profiles across various cancers, including pancreatic, colorectal, breast, liver, and lung, highlighting their potential to enhance diagnostic precision and enable personalized treatment strategies. Ultimately, we aim to illustrate how a deeper understanding of biomarker signatures can inform innovative clinical approaches and improve care for patients facing the dual burden of diabetes and cancer.

Patients with advanced pancreatic ductal adenocarcinoma (PDAC) generally face a poor prognosis and limited therapeutic options. This study aims to evaluate the clinical efficacy of combining PD- 1 inhibitors with chemotherapy as a first-line treatment for advanced PDAC, and to explore the correlation between various clinical parameters and treatment outcomes.This retrospective study analyzed the clinical data of 57 patients with advanced PDAC treated at the First Affiliated Hospital of Bengbu Medical University from January 2022 and June 2024. Patients were allocate into the two groups: the chemotherapy-alone group (29 cases) (CT), which received either the AG regimen or the mFOLFIRINOX regimen, and the imimmunotherapy plus chemotherapy group (28 cases) (ICT), which received the AG regimen or mFOLFIRINOX regimen in combination with PD- 1 inhibitors.The study compared progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions between the two groups. Additionally, it analyzed the correlation between various clinical indicators and their dynamic changes over time in relation to treatment outcomes. Kaplan-Meier curves were plotted for survival analysis, and log-rank tests assessed PFS and OS differences.Univariate and multivariate Cox regression analyses identified independent risk factors for prognosis, while logistic regression assessed the correlation between these factors and treatment response.The median PFS and OS in immunotherapy plus chemotherapy group were significantly superior to those in the chemotherapy-alone group (PFS: 7.3 vs. 5.8 months, P = 0.005; OS: 12 vs. 10.2 months, P = 0.031). The ORR in the group receive immunotherapy combined with chemotherapy was also significantly higher compared to the group treated with chemotherapy alone (42.86% vs. 17.24%, P = 0.03). No significant differences were observed in the incidence or severity of treatment-related adverse events (TRAEs) and immunotherapy-related adverse events (irAEs) between the CT and ICTgroups (any grade: 93.10% vs. 96.45%, P = 0.574; grade 3 or 4: 31.3% vs. 28.57%, P = 0.839). Patients without liver metastasis, without diabetes, or those who experience a increase in SOD levels following treatment may constitute an advantageous population for immune combination therapy. In conclusion, chemotherapy combined with PD- 1 inhibitors demonstrated favorable safety and tolerability, and significantly improved PFS, OS, and ORR compared to chemotherapy alone.

One percent of pancreatic adenocarcinoma (PDAC) patients are diagnosed with new onset diabetes (NOD) over the age of 50 years within 3 years. Therefore, NOD is a major factor for early diagnosis of PDAC. Research has focused on understanding the differences between NOD and type 2 diabetes, particularly in relation to PDAC. However, conflicting data exists regarding their impact on survival outcomes in PDAC patients. We performed this multi-center study to assess the prevalence and influence of NOD on clinical outcomes in patients with PDAC within a community-based hospital system.

We conducted a retrospective cohort study of 138 patients with biopsy-proven PDAC with localized/borderline disease (n=70), and metastatic disease (n=68) at three institutions from 2014 to 2021. NOD group consisted of pts diagnosed with diabetes [hemoglobin A1c (HbA1c) >6.5%] or pre-diabetes (HbA1c 5.7-6.4%) within the 3 years prior to PDAC diagnosis. Primary aim of the study was to determine the impact of NOD on clinical outcomes.

A total of 138 patients were included in the study, from which 30 met the criteria for NOD. No significant differences were noted in the demographic and clinical characteristics comparing patients based on NOD history. Comparing survival outcomes, NOD group was associated with worse overall survival (OS) in both the metastatic cohort [n=68, progression-free survival (PFS) 4.6 vs. 7.1 months, P=0.07; OS 7.1 vs. 13.2 months, P=0.01) and the resected cohort (n=40, PFS 8.4 vs. 19.3 months, P=0.04; OS 24.5 vs. 42.3 months, P=0.04). In multivariate analysis, the impact of NOD remained significant for OS and PFS in the resected cohort. Identifying common features amongst the NOD group, we found the entire cohort had a significant reduction in individual body mass index (BMI) 1 year prior to the NOD diagnosis (P=0.006).

NOD is associated with worse survival outcomes in patients with metastatic and resected PDAC. Reduction of BMI prior to diagnosis of NOD, warrants further investigation to be incorporated into the PDAC screening paradigm.

Camel milk has a unique composition that sets it apart from other types of animal milk, which has captured the interest of medical and scientific communities. Extracellular vesicles (EVs) mainly contain exosomes (Exos, 30-200 nm) and microvesicles (MVs, 200-1000 nm). Camel milk EVs, particularly Exos, which we named EVs/Exos, have arisen as a fascinating area of scientific inquiry, holding enormous potential for the future of biomedicine due to their anticancer, antibacterial, antidiabetic nephropathy, and immunostimulatory impacts. Camel milk EVs/Exos affect the antioxidant status and oxidative stress differently depending on the target cells. They boosted ROS in cancer cells but improved the antioxidant state in healthy cells. Camel milk EVs/Exos have distinct exosomal lactoferrin and kappa casein mRNAs, which could be responsible for their anticancer and immunomodulatory effects. Due to the high fat content of milk, there is a lack of established protocols for the precise isolation of EVs/Exos from milk, despite the increasing interest in this area of study. This review highlighted the techniques employed for milk EV/Exo isolation and characterization, acknowledging the challenges faced by researchers and the latest advancements in overcoming these hurdles. This review also detailed the potential of camel milk EVs/Exos in therapeutic applications. This comprehensive analysis positions camel milk EVs/Exos at the forefront of scientific inquiry, paving the way for groundbreaking discoveries in the years to come.

Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.

Pancreatic cancer (PC) is a malignant tumour with poor prognosis and high mortality, and high fasting plasma glucose (HFPG) is considered to be one of its important risk factors.

PC disease burden data were obtained from the Global Burden of Disease Study 2021 (GBD 2021) database. Annual percent change (APC), average APC (AAPC), and 95% confidence interval (95% CI) were analysed using joinpoint linkpoint regression models to assess the trend of PC burden of disease between 1990 and 2021. An age-period-cohort model was used to estimate the independent effects of age, period, and cohort on PC burden, and data on PC mortality attributable to HFPG in China from 2022 to 2032 were analysed on the basis of a Bayesian age-period-cohort model projection.

The number of Pc deaths due to HFPG continue to rise in China from 1990 to 2021, with age-standardised mortality (ASMR) and age-standardised disability-adjusted life-year rates with increasing AAPC values of 1.12% (95% CI, 0.73-1.52) and 1.00% (95% CI, 0.63-1.37), respectively. Throughout the study, we found that the overall level of PC disease burden was significantly higher in men than that in women. In age-period-cohort analyses, the age effect of PC showed an increasing and then decreasing trend, the period effect showed an overall increasing trend during the study period, and the cohort effect showed an overall slow decreasing trend. In addition, the BAPC model predicted that ASMR is expected to decline significantly in both men and women from 2022 to 2032.

It was found that PC attributable to HFPG was generally on the rise in China from 1990 to 2021 and has been on the decline in recent years, and projections suggest that the country's future PC disease burden will continue to show a downward trend. Age and period of birth are the main factors affecting the disease burden, especially in men and older age groups. Early prevention, regular screening, and research into the pathogenesis of PC have, therefore, become particularly important.

Arsenic-induced diabetes, despite being a relatively newer finding, is now a growing area of interest, owing to its multifaceted nature of development and the diversity of metabolic conditions that result from it, on top of the already complicated manifestation of arsenic toxicity. Identification and characterization of the common and differentially affected cellular metabolic pathways and their regulatory components among various arsenic and diabetes-associated complications may aid in understanding the core molecular mechanism of arsenic-induced diabetes. This study, therefore, explores the effects of arsenic on human cell lines through 14 transcriptomic datasets containing 160 individual samples using in silico tools to take a systematic, deeper look into the pathways and genes that are being altered. Among these, we especially focused on the role of transcription factors due to their diverse and multifaceted roles in biological processes, aiming to comprehensively investigate the underlying mechanism of arsenic-induced diabetes as well as associated health risks. We present a potential mechanism heavily implying the involvement of the TGF-β/SMAD3 signaling pathway leading to cell cycle alterations and the NF-κB/TNF-α, MAPK, and Ca2+ signaling pathways underlying the pathogenesis of arsenic-induced diabetes. This study also presents novel findings by suggesting potential associations of four transcription factors (NCOA3, PHF20, TFDP1, and TFDP2) with both arsenic toxicity and diabetes; five transcription factors (E2F5, ETS2, EGR1, JDP2, and TFE3) with arsenic toxicity; and one transcription factor (GATA2) with diabetes. The novel association of the transcription factors and proposed mechanism in this study may serve as a take-off point for more experimental evidence needed to understand the in vivo cellular-level diabetogenic effects of arsenic.

The online version contains supplementary material available at 10.1007/s43188-024-00255-y.

Pancreatic cancer is a rare but lethal cancer due to its biologically aggressive nature, advanced stage at the time of diagnosis, and poor response to oncologic therapies. The risk of pancreatic cancer is significantly higher to 5% in certain high-risk individuals with inherited genetic susceptibility. Screening for pancreatic cancer in these individuals from high-risk groups can help with the early detection of pancreatic cancer as well as the detection of precursor lesions leading to early surgical resection and improved overall outcomes. The advancements in radiological imaging as well as advanced endoscopic procedures has made a significant impact on the early diagnosis, surveillance, and staging of pancreatic cancer. There is also a significant advancement in the development of biomarkers for the early detection of pancreatic cancer, which has also led to the development of liquid biopsy, allowing for microRNA detection in serum and circulating tumor cells. Various societies and organizations have provided guidelines for pancreatic cancer screening and surveillance in high-risk individuals. In this review, we aim to discuss the hereditary risk factors for developing pancreatic cancer, summarize the screening recommendations by different societies, and discuss the development of novel biomarkers and areas for future research in pancreatic cancer screening for high-risk individuals.

Pancreatic adenocarcinoma is one of the most lethal types of gastrointestinal cancer despite the latest medical advances. Its incidence has continuously increased in recent years in developed countries. The location of the pancreas can result in the initial symptoms of neoplasia being overlooked, which can lead to a delayed diagnosis and a subsequent reduction in the spectrum of available therapeutic options. The role of modifiable risk factors in pancreatic cancer has been extensively studied in recent years, with smoking and alcohol consumption identified as key contributors. However, the few screening programs that have been developed focus exclusively on genetic factors, without considering the potential impact of modifiable factors on disease occurrence. Thus, fully understanding and detecting the risk factors for pancreatic cancer represents an important step in the prevention and early diagnosis of this type of neoplasia. This review reports the available evidence on different risk factors and identifies the areas that could benefit the most from additional studies.

Early detection of PDAC remains challenging due to the lack of early symptoms and the absence of reliable biomarkers. The aim of the present project was to identify miRNA and proteomics signatures discriminating PDAC patients with DM from nondiabetic PDAC patients. Proteomics analysis and miRNA array were used for protein and miRNA screening. We used Western blotting and Real-Time Quantitative Reverse Transcription polymerase chain reaction (qRT-PCR) for protein and miRNA validation. Comparisons between experimental groups with normal distributions were performed using one-way ANOVA followed by Tukey's post hoc test, and pairwise tests were performed using t-tests. p ≤ 0.05 was considered statistically significant. Protein clusters of differentiation 166 (CD166), glycoprotein CD63 (CD63), S100 calcium-binding protein A13 (S100A13), and tumor necrosis factor-β (TNF-β) were detected in the proteomics screening. The miRNA assay revealed a differential miRNA 1285 regulation. Previously described target proteins of miR-1285 cadherin-1 (CDH-1), cellular Jun (c-Jun), p53, mothers against decapentaplegic homolog 4 (Smad4), human transglutaminase 2 (TGM2) and yes-associated protein (YAP), were validated via Western blotting. miR-1285-3p was successfully validated as differentially regulated in PDAC + DM via qRT-PCR. Overall, our data suggest miRNA1285-3p, TGM2, CDH-1, CD166, and S100A13 as potential meaningful biomarker candidates to characterize patients with PDAC + DM. Data are available via ProteomeXchange with the identifier PXD053169.

Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.

Pancreatic cancer (PC) is a fatal malignant disease. It is well known that the relationship between PC and type 2 diabetes mellitus (T2DM) is a complicated bidirectional relationship. The most important factors causing increased risks of pancreatic cancer are hyperglycaemia, hyperinsulinemia, pancreatitis, and dyslipidemia. Genetics and the immune system also play an important role in the relationship between diabetes mellitus and pancreatic cancer. The primary contributors to this association involve insulin resistance and inflammatory processes within the tumour microenvironment. The combination of diabetes and obesity can contribute to PC by inducing hyperinsulinemia and influencing leptin and adiponectin levels. Given the heightened incidence of pancreatic cancer in diabetes patients compared to the general population, early screening for pancreatic cancer is recommended. Diabetes negatively impacts the survival of pancreatic cancer patients. Among patients receiving chemotherapy, it reduced their survival. The implementation of a healthy lifestyle, including weight management, serves as an initial preventive measure to mitigate the risk of disease development. The role of anti-diabetic drugs on survival is controversial; however, metformin may have a positive impact, especially in the early stages of cancer, while insulin therapy increases the risk of PC.

This study investigates temporal trends in gastrointestinal cancer-related mortality in the United States between 1999 and 2020, focusing on differences by sex, age, and race.

We investigated the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research multiple causes of death database (Years 1999-2020) for gastrointestinal cancer-related mortality with a focus on the underlying cause of death.

A total of 3 115 243 gastrointestinal cancer-related deaths occurred from 1999 to 2020. The overall age-adjusted mortality rate decreased from 46.7 per 100 000 in 1999 to 38.4 per 100 000 in 2020. The average annual percent change (AAPC) for the study period was -0.9% (95% CI: -1.0%, -0.9%, P < 0.001), with no significant difference in AAPC between the sexes but some difference between races and related to individual cancers. African Americans and Asian Americans, and Pacific Islanders experienced a greater decrease in mortality compared with Whites. Mortality rates for American Indian and Alaskan Native populations also decreased significantly from 1999 to 2020 (P < 0.001). There were significant declines in esophageal, stomach, colon, rectal, and gallbladder cancer-related mortality but increases in the small bowel, anal, pancreatic, and hepatic cancer-related mortality (P < 0.001), with variation across different sexes and racial groups.

While overall gastrointestinal cancer-related mortality declined significantly in the United States from 1999 to 2020, mortality from some cancers increased. Furthermore, differences between sexes and racial groups underscore crucial differences in gastrointestinal cancer mortality, highlighting areas for future research.

Exposure to polycyclic aromatic hydrocarbons (PAHs), byproducts of incomplete combustion, and their effects on the development of cancer are still being evaluated. Recent studies have analyzed the relationship between PAHs and tobacco or dietary intake in the form of processed foods and smoked/well-done meats. This study aims to assess the association of a blood biomarker and metabolite of PAHs, r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), dietary intake, selected metabolism SNPs, and pancreatic cancer. Demographics, food-frequency data, SNPs, treatment history, and levels of PheT in plasma were determined from 400 participants (202 cases and 198 controls) and evaluated based on pancreatic adenocarcinoma diagnosis. Demographic and dietary variables were selected based on previously published literature indicating association with pancreatic cancer. A multiple regression model combined the significant demographic and food items with SNPs. Final multivariate logistic regression significant factors (p-value < 0.05) associated with pancreatic cancer included: Type 2 Diabetes [OR = 6.26 (95% CI = 2.83, 14.46)], PheT [1.03 (1.02, 1.05)], very well-done red meat [0.90 (0.83, 0.96)], fruit/vegetable servings [1.35 (1.06, 1.73)], recessive (rs12203582) [4.11 (1.77, 9.91)], recessive (rs56679) [0.2 (0.06, 0.85)], overdominant (rs3784605) [3.14 (1.69, 6.01)], and overdominant (rs721430) [0.39 (0.19, 0.76)]. Of note, by design, the level of smoking did not differ between our cases and controls. This study does not provide strong evidence that PheT is a biomarker of pancreatic cancer susceptibility independent of dietary intake and select metabolism SNPs among a nonsmoking population.

(1) Background: Pancreatic adenocarcinoma (PAC) is one of the most lethal types of cancer. Most cases of PAC occur in the head of the pancreas. Given the proximity of the pancreatic head to the bile duct, most patients present clinically during early stages of the disease, while distally located PAC could have delayed clinical presentation. (2) Aims: To assess predictors of non-head PAC. (3) Methods: A retrospective multicenter study was conducted, including all patients who had endoscopic ultrasound (EUS) for pancreatic masses and who had histologic confirmation of PAC. (4) Results: Of the 151 patients included, 92 (60.9%) had pancreatic head cancer, and 59 (39.1%) had distal pancreatic cancer. PAC at body was the most common location in the distal PAC group (31 patients (52.5%)). Logistic regression analysis demonstrated a significant association of obesity with distal migration of PAC (OR 4.44, 95% CI 1.15-17.19, p = 0.03), while none of the other assessed parameters showed a significant association. Notably, abdominal pain was more significantly associated with distal PAC vs. head location (OR 2.85, 95% CI 1.32-6.16, p = 0.008). (5) Conclusions: Obesity shows a significant association as a clinical predictor of distal PAC. Further studies are needed to better explore this association.

Recent studies have demonstrated that CPT1A plays a critical role in tumor metabolism and progression. However, the molecular mechanisms by which CPT1A affects tumorigenicity during PAAD progression remain unclear. In the current research, the bioinformatics analysis and immunohistochemical staining results showed that CPT1A was overexpressed in PAAD tissues and that its overexpression was associated with a shorter survival time in patients with PAAD. Overexpression of CPT1A increased cell proliferation and promoted EMT and glycolytic metabolism in PAAD cells. Mechanistically, CPT1A is able to bind to Snail and facilitate PAAD progression by regulating Snail stability. In summary, our findings revealed Snail-dependent glycolysis as a crucial metabolic pathway by which CPT1A accelerates PAAD progression. Targeting the CPT1A/Snail/glycolysis axis in PAAD to suppress cell proliferation and metastatic dissemination is a new potential treatment strategy to improve the anticancer therapeutic effect and prolong patient survival.

Pancreatic adenocarcinoma (PAAD) is one of the most fatal human cancers, but effective therapies remain to be established. Cancer stem cells (CSCs) are highly resistant to anti-cancer drugs and a deeper understanding of their microenvironmental niche has been considered important to provide understanding and solutions to cancer eradication. However, as the CSC niche is composed of a wide variety of biological and physicochemical factors, the development of multidisciplinary tools that recapitulate their complex features is indispensable. Synthetic polymers have been studied as attractive biomaterials due to their tunable biofunctionalities, while hydrogelation technique further renders upon them a diversity of physical properties, making them an attractive tool for analysis of the CSC niche.

To develop innovative materials that recapitulate the CSC niche in pancreatic cancers, we performed polymer microarray analysis to identify niche-mimicking scaffolds that preferentially supported the growth of CSCs. The niche-mimicking activity of the identified polymers was further optimized by polyethylene glycol (PEG)-based hydrogelation. To reveal the biological mechanisms behind the activity of the optimized hydrogels towards CSCs, proteins binding onto the hydrogel were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the potential therapeutic targets were validated by looking at gene expression and patients' outcome in the TCGA database.

PA531, a heteropolymer composed of 2-methoxyethyl methacrylate (MEMA) and 2-(diethylamino)ethyl methacrylate (DEAEMA) (5.5:4.5) that specifically supports the growth and maintenance of CSCs was identified by polymer microarray screening using the human PAAD cell line KLM1. The polymer PA531 was converted into five hydrogels (PA531-HG1 to HG5) and developed to give an optimized scaffold with the highest CSC niche-mimicking activities. From this polymer that recapitulated CSC binding and control, the proteins fetuin-B and angiotensinogen were identified as candidate target molecules with clinical significance due to the correlation between gene expression levels and prognosis in PAAD patients and the proteins associated with the niche-mimicking polymer.

This study screened for biofunctional polymers suitable for recapitulation of the pancreatic CSC niche and one hydrogel with high niche-mimicking abilities was successfully fabricated. Two soluble factors with clinical significance were identified as potential candidates for biomarkers and therapeutic targets in pancreatic cancers. Such a biomaterial-based approach could be a new platform in drug discovery and therapy development against CSCs, via targeting of their niche.

Pancreatic cancer (PaC) is one of the most lethal tumors worldwide, difficult to diagnose, and with inadequate therapeutical chances. The most used therapy is gemcitabine, alone or in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the multidrug FOLFIRINOX. Unfortunately, PaC develops resistance early, thus reducing the already poor life expectancy of patients. The mechanisms responsible for drug resistance are not fully elucidated, and exosomes seem to be actively involved in this phenomenon, thanks to their ability to transfer molecules regulating this process from drug-resistant to drug-sensitive PaC cells. These extracellular vesicles are released by both normal and cancer cells and seem to be essential mediators of intercellular communications, especially in cancer, where they are secreted at very high numbers. This review illustrates the role of exosomes in PaC drug resistance. This manuscript first provides an overview of the pharmacological approaches used in PaC and, in the last part, focuses on the mechanisms exploited by the exosomes released by cancer cells to induce drug resistance.

Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation. Response to chemotherapy under such late circumstances is poor, resistance is frequent, and prolongation of survival is almost negligible. Early surgery has been, and still is, the only approach with a slightly better outcome. Unfortunately, the relapse percentage after surgery is still very high. In fact, early surgery clearly requires early diagnosis. Despite all the advances in diagnostic methods, the available tools for improving these results are scarce. Serum tumor markers permit a late diagnosis, but their contribution to an improved therapeutic result is very limited. On the other hand, effective screening methods for high-risk populations have not been fully developed as yet. This paper discusses the difficulties of early diagnosis, evaluates whether the available diagnostic tools are adequate, and proposes some simple and not-so-simple measures to improve it.

This narrative review summarizes the principal findings of observational studies, systematic reviews, and meta-analyses on diet and dietary patterns' role in the risk of pancreatic cancer. Etiologically pancreatic cancer is multifactorial. Evidence exists of an association between nutrients, dietary patterns, and pancreatic cancer. An extensive literature search was conducted on PubMed, Cochrane, and Google Scholar. A thorough search of articles published in English till May 2023 and related to the review was performed. The relationship between all macronutrients, micronutrients, and various dietary patterns with the risk of pancreatic cancer was assessed. It is concluded that a diet high in nutrients like red and processed meat, refined sugars, saturated and monounsaturated fats, alcohol, copper, and a Western dietary pattern can increase the likelihood of pancreatic cancer. Contrary to this, a diet consisting of fruits, vegetables, appropriate quantities of vitamins and minerals, and a Mediterranean dietary pattern is associated with a decreased risk of pancreatic cancer.

Long-standing type 2 diabetes is a known risk factor for developing pancreatic cancer, however, its influence on cancer-associated outcomes is understudied.

To examine the associations between diabetes status and pancreatic cancer outcomes.

We identified patients diagnosed with pancreatic adenocarcinoma in the national Veterans Administration System from 2010 to 2018. We classified each patient by pre-cancer diagnosis diabetes status: no diabetes, new-onset diabetes (NOD) of ≤ 3 years duration, or long-standing diabetes of > 3 years duration. We used Cox proportional hazards models to examine the association between diabetes status and survival. We adjusted the models for age, race, sex, body mass index, tobacco, and alcohol use, coronary artery disease, hypertension, chronic kidney disease, year of cancer diagnosis, and cancer stage and treatment.

We identified 6342 patients diagnosed with pancreatic adenocarcinoma. Most had long-standing diabetes (45.7%) prior to their cancer diagnosis, 14.5% had NOD, and 39.8% had no diabetes. Patients with long-standing diabetes had 10% higher mortality risk compared to patients without diabetes after adjusting for sociodemographic factors and medical comorbidities (adjusted HR 1.10; 95% CI 1.03-1.16). This difference in mortality remained statistically significant after additionally adjusting for cancer stage and receipt of potentially curative treatment (adjusted HR 1.09; 95% CI 1.02-1.15). There was no significant difference in mortality between patients with NOD compared to those without diabetes.

Long-standing but not new-onset diabetes is independently associated with increased mortality among patients with pancreatic cancer. This information has implication for prognostication and risk stratification among pancreatic cancer patients.

Gastrointestinal (GI) cancers are the second leading cause of cancer-related deaths worldwide.

The global challenges GI cancers pose are high, especially in middle- and low-income countries. Patients with these cancers present with symptoms of poor appetite, weight loss, heartburn, abdominal pain, fatigue and anaemia. Several risk factors contribute to GI cancers, including age, gender, obesity, pathogenic infections, smoking cigarettes, alcohol consumption and dietary habits. Most of these cancers are sporadic. However, some patients are at high risk due to a family history of GI cancers. Systemic diseases affect multiple organs, and their chronic occurrence elicits inflammatory responses at various sites. These diseases also contribute to GI cancers.

In this review, we discuss that untreated systemic diseases, including diabetes, hepatitis, acquired immune deficiency syndrome, ulcers and hypertension, can potentially lead to GI cancers if they remain untreated for a longer period. Systemic diseases initiate oxidative stress, inflammatory pathways and genetic manipulations, which altogether confer risks to GI cancers. Here, we describe the association between systemic diseases and their underlying mechanisms leading to GI cancers.

A growing number of epidemiological studies have suggested that diabetes mellitus may increase cancer risk and is implicated in numerous other metabolic and inflammatory disorders. The increase in proinflammatory cytokines plays a major role in insulin resistance and leads to hypoalbuminemia and micro- and macrovascular diabetes complications, including kidney disease and anemia. This study aimed to investigate the utility of carcinoembryonic antigen (CEA), C-reactive protein (CRP), serum albumin level, hemoglobin, and lactate dehydrogenase (LDH) as biomarkers for cancer risk, and the biological implications of diabetes on the evolution and prognosis of oncological patients.

We conducted a retrospective, longitudinal, observational study on a total group of 434 patients, of which 217 were diagnosed with a form of cancer and type two diabetes as a comorbidity, and the other 217 were a control group without diabetes. These patients were admitted to the oncology clinic. In subgroups, the same number of patients was considered, depending on the location of the oncological pathology. Anemia, hypoalbuminemia, elevated lactate dehydrogenase, glycated hemoglobin, and C-reactive protein levels are more pronounced in subjects with type two diabetes and cancer.

The presence of diabetes negatively affects the clinical and biological prognosis of cancer patients.

This study aims to summarize the modifiable risk factors for pancreatic ductal adenocarcinoma (PDAC) that have been known for a long time, as well as information from the most recent reports. As a cancer with a late diagnosis and poor prognosis, accurate analysis of PDAC risk factors is warranted. The incidence of this cancer continues to rise, and the five-year survival rate is the lowest with respect to other tumors. The influence of cigarette smoking, alcohol consumption, and chronic pancreatitis in increasing the risk of pancreatic ductal adenocarcinoma is continually being confirmed. There are also newly emerging reports relating to the impact of lifestyle, including physical activity, the gut and oral microbiome, and hepatotropic viruses. A precise understanding of PDAC risk factors can help to identify groups of high-risk patients, and this may contribute to population awareness and education as well as earlier diagnoses with possible better treatment outcomes.

Despite significant progress in medicine, pancreatic cancer is one of the most tardily diagnosed cancer and is consequently associated with a poor prognosis and a low survival rate. The asymptomatic clinical picture and the lack of relevant diagnostic markers for the early stages of pancreatic cancer are believed to be the major constraints behind an accurate diagnosis of this disease. Furthermore, underlying mechanisms of pancreatic cancer development are still poorly recognized. It is well accepted that diabetes increases the risk of pancreatic cancer development, however the precise mechanisms are weakly investigated. Recent studies are focused on microRNAs as a causative factor of pancreatic cancer. This review aims to provide an overview of the current knowledge of pancreatic cancer and diabetes-associated microRNAs, and their potential in diagnosis and therapy. miR-96, miR-124, miR-21, and miR-10a were identified as promising biomarkers for early pancreatic cancer prediction. miR-26a, miR-101, and miR-200b carry therapeutic potential, as they not only regulate significant biological pathways, including the TGF-β and PI3K/AKT, but their re-expression contributes to the improvement of the prognosis by reducing invasiveness or chemoresistance. In diabetes, there are also changes in the expression of microRNAs, such as in miR-145, miR-29c, and miR-143. These microRNAs are involved, among others, in insulin signaling, including IRS-1 and AKT (miR-145), glucose homeostasis (hsa-miR-21), and glucose reuptake and gluconeogenesis (miR-29c). Although, changes in the expression of the same microRNAs are observed in both pancreatic cancer and diabetes, they exert different molecular effects. For example, miR-181a is upregulated in both pancreatic cancer and diabetes mellitus, but in diabetes it contributes to insulin resistance, whereas in pancreatic cancer it promotes tumor cell migration, respectively. To conclude, dysregulated microRNAs in diabetes affect crucial cellular processes that are involved in pancreatic cancer development and progression.

Screening options for pancreatic ductal adenocarcinoma (PDAC) are limited. New-onset type 2 diabetes (NoD) is associated with subsequent diagnosis of PDAC in observational studies and may afford an opportunity for PDAC screening. We evaluated this association using a large administrative database.

Patients were identified using claims data from the OptumLabs® Data Warehouse. Adult patients with NoD diagnosis were matched 1:3 with patients without NoD using age, sex and chronic obstructive pulmonary disease (COPD) status. The event of PDAC diagnosis was compared between cohorts using the Kaplan-Meier method. Factors associated with PDAC diagnosis were evaluated with Cox's proportional hazards modeling.

We identified 640 421 patients with NoD and included 1 921 263 controls. At 3 years, significantly more PDAC events were identified in the NoD group vs control group (579 vs 505; P < 0.001). When controlling for patient factors, NoD was significantly associated with elevated risk of PDAC (HR 3.474, 95% CI 3.082-3.920, P < 0.001). Other factors significantly associated with PDAC diagnosis were increasing age, increasing age among Black patients, and COPD diagnosis (P ≤ 0.05).

NoD was independently associated with subsequent diagnosis of PDAC within 3 years. Future studies should evaluate the feasibility and benefit of PDAC screening in patients with NoD.

Nuclear magnetic resonance (NMR) metabolomics was used for identification of metabolic changes in pancreatic cancer (PC) blood plasma samples when compared to healthy controls or diabetes mellitus patients. An increased number of PC samples enabled a subdivision of the group according to individual PC stages and the construction of predictive models for finer classification of at-risk individuals recruited from patients with recently diagnosed diabetes mellitus. High-performance values of orthogonal partial least squares (OPLS) discriminant analysis were found for discrimination between individual PC stages and both control groups. The discrimination between early and metastatic stages was achieved with only 71.5% accuracy. A predictive model based on discriminant analyses between individual PC stages and the diabetes mellitus group identified 12 individuals out of 59 as at-risk of development of pathological changes in the pancreas, and four of them were classified as at moderate risk.

Insulin is the main metabolic regulator of fuel molecules in the diet, such as carbohydrates, lipids, and proteins. It does so by facilitating glucose influx from the circulation into the liver, adipose tissue, and skeletal myocytes. The outcome of which is subjected to glycogenesis in skeletal muscle and lipogenesis in adipose tissue, as well as in the liver. Therefore, insulin has an anabolic action while, on the contrary, hypoinsulinemia promotes the reverse process. Protein breakdown in myocytes is also encountered during the late stages of diabetes mellitus. The balance of the blood glucose level in physiological conditions is maintained by virtue of the interactive functions of insulin and glucagon. In insulin resistance (IR), the balance is disturbed because glucose transporters (GLUTs) of cell membranes fail to respond to this peptide hormone, meaning that glucose molecules cannot be internalized into the cells, the consequence of which is hyperglycemia. To develop the full state of diabetes mellitus, IR should be associated with the impairment of insulin release from beta-cells of the pancreas. Periodic screening of individuals of high risk, such as those with obesity, hypercholesterolemia, and pregnant nulliparous women in antenatal control, is vital, as these are important checkpoints to detect cases of insulin resistance. This is pivotal as IR can be reversed, provided it is detected in its early stages, through healthy dietary habits, regular exercise, and the use of hypoglycemic agents. In this review, we discuss the pathophysiology, etiology, diagnosis, preventive methods, and management of IR in brief.

It remains unclear how pre-existing depression, anxiety, and diabetes of different durations are associated with the risk of pancreatic cancer, its clinical characteristics, treatment modalities, and subsequent survival.

From a register-based random sample of Finns residing in Finland at the end of the period 1987-2007, 6492 patients diagnosed with primary pancreatic cancer in 2000-2014, and 32 460 controls matched for birth cohort and sex, were identified. Pre-existing depression, anxiety, and diabetes were ascertained from the records of prescribed medication purchases. Information on pancreatic cancer outcomes was obtained from the Finnish cancer register. Data were analyzed using logistic and Cox regressions.

The risk of developing pancreatic cancer was found to be associated with long-term anxiety (treatment started 36 + months before the cancer diagnosis) (odds ratio (OR): 1.13, 95% confidence interval (95%CI): 1.04-1.22) and long-term diabetes (OR 1.72, 95%CI 1.55-1.90), as well as with new-onset (treatment started 0-24 months before the cancer diagnosis) depression (OR 1.59, 95%CI 1.34-1.88), anxiety (OR 1.76, 95%CI 1.50-2.07), and diabetes (OR 3.92, 95%CI 3.44-4.48). However, the effects of these new-onset conditions were driven by cases that began treatment within 3 months before the cancer diagnosis (concomitant period). Patients with long-term depression, anxiety and diabetes and those with new-onset anxiety had a higher risk of not receiving standard treatments. Lower survival was found for pancreatic cancer patients with new-onset depression (hazards ratio (HR) 1.38, 95%CI 1.16-1.64). Survival was not associated with pre-existing anxiety or diabetes.

The associations between pancreatic cancer risk and pre-existing depression and anxiety were mostly driven by concomitant effects. Individuals with diabetes, regardless of duration, should be closely monitored for pancreatic cancer. Pancreatic cancer patients with new-onset depression should be targeted to improve their survival.

The correlation between pancreatic ductal adenocarcinoma (PDAC) and diabetes-related mechanisms support the hypothesis that early therapeutic strategies targeting diabetes can contribute to PDAC risk reduction and treatment improvement. A systematic review was conducted, using PubMed, Embase and Cochrane Library databases, to evaluate the current evidence from clinical studies qualitatively examining the efficacy of four natural products: Curcumin-Curcuma longa L.; Thymoquinone-Nigella sativa L.; Genistein-Glycine max L.; Ginkgo biloba L.; and a low-carbohydrate ketogenic diet in type 2 diabetes (T2D) and PDAC treatment. A total of 28 clinical studies were included, showing strong evidence of inter-study heterogeneity. Used as a monotherapy or in combination with chemo-radiotherapy, the studied substances did not significantly improve the treatment response of PDAC patients. However, pronounced therapeutic efficacy was confirmed in T2D. The natural products and low-carbohydrate ketogenic diet, combined with the standard drugs, have the potential to improve T2D treatment and thus potentially reduce the risk of cancer development and improve multiple biological parameters in PDAC patients.

This narrative review summarizes the main findings of observational studies (case-control and cohort) as well as systematic reviews and meta-analyses on the role of nutrients and dietary patterns on pancreatic cancer (PC) risk and elucidates possible mechanisms for the association between nutrients or specific food components and the risk of PC. A literature search of MEDLINE (PubMed), Google Scholar, ScienceDirect, and Scopus was performed. An extensive search of related articles published in the English language from 1985 to 2022 was carried out. Our search included macro- and micronutrient intake as well as dietary patterns associated with PC. In conclusion, the consumption of a diet high in nutrients such as sugar, fats, and red and processed meats can increase the risk of PC. Conversely, a high dietary intake of fresh fruit and vegetables and their associated nutrients like fiber, antioxidants, and polyphenols may prevent PC. Dietary patterns loaded with red and processed meats were also linked to an increased risk of PC, whereas dietary patterns rich in plant-based foods like vegetables, fruits, whole grains, and legumes were associated with a reduced risk of PC. Dietary fiber, fat-soluble vitamins, water-soluble vitamins, and minerals might also play a protective role against PC.

Both cancer and diabetes are complex chronic diseases that have high economic costs for society. The co-occurrence of these two diseases in people is already well known. The causal effects of diabetes on the development of several malignancies have been established, but the reverse causation of these two diseases (e.g., what type of cancer can cause T2D) has been less investigated.

Multiple Mendelian randomization (MR) methods, such as the inverse-variance weighted (IVW) method, weighted median method, MR-Egger, and MR pleiotropy residual sum and outlier test, were performed to evaluate the causal association of overall and eight site-specific cancers with diabetes risk using genome-wide association study summary data from different consortia, such as Finngen and UK biobank.

A suggestive level of evidence was observed for the causal association between lymphoid leukaemia and diabetes by using the IVW method in MR analyses (P = 0.033), indicating that lymphoid leukaemia increased diabetes risk with an odds ratio of 1.008 (95% confidence interval, 1.001-1.014). Sensitivity analyses using MR-Egger and weighted median methods showed consistent direction of the association compared with the IVW method. Overall and seven other site-specific cancers under investigation (i.e., multiple myeloma, non-Hodgkin lymphoma, and cancer of bladder, brain, stomach, lung, and pancreas) were not causally associated with diabetes risk.

The causal relationship between lymphoid leukaemia and diabetes risk points to the necessity of diabetes prevention amongst leukaemia survivors as a strategy for ameliorating the associated disease burden.

Diabetes mellitus is a global issue that has affected the lives of many people all over the world. This disorder, which is also called the mother of all diseases, possesses high pathogenicity and results in the emergence of many disorders. One of the known correlated diseases is pancreatic cancer which can be accompanied by diabetes mellitus. Therefore, finding the association between these diseases and common genes is urgent.

In this study, in order to survey the relationship between diabetes mellitus and pancreatic cancer, the common genes of these disorders were analyzed by bioinformatics tools.

For this purpose, we screened 17 shared genes from microarray data downloaded from the Gene Expression Omnibus (GEO) database. In addition, the relationship between identified genes was constructed by STRING and DAVID tools.

In total, 112 genes were identified to be differentially expressed. Among these, 17 genes were found to be common, including two genes that were down-regulated and others that were upregulated. Other analyses showed that most of the genes were enriched in Vibrio cholera infection and the mTOR signaling pathway. The biological processes of such genes included oxygen and gas transport, phagosome acidification, and GTPase activity.

In this study, 17 common genes that had not previously been considered in diabetes and pancreatic cancer were screened, which can be further considered for clinical approaches and in vitro studies.

Considering the absence of methods to find pancreatic cancer early, surveillance of high-risk groups is needed for early diagnosis.

The study aimed to investigate the effect in the incidence of pancreatic cancer and the differences between new-onset DM (NODM) and long-standing DM (LSDM) since NODM group is a representative high-risk group.

The Korean National Health Insurance Service-National Sample Cohort between 2002 and 2013 data was used. Regarding 88,396 people with DM (case group), we conducted a 1:1 propensity score matching to select a matched non-DM population (control group). To investigate the interaction between DM and the time variable distinguishing NODM and LSDM, we performed a multi-variable time-dependent Cox regression analysis.

The incidence of pancreatic cancer was higher in the DM group compared to the non-DM group (0.52% vs. 0.16%, P < 0.001). The DM group had shown different risk of pancreatic cancer development according to the duration since the DM diagnosis (NODM hazard ratio (HR): 3.81, 95% confidence interval (CI): 2.97-4.88, P < 0.001; LSDM HR: 1.53, 95% CI: 1.11-2.11, P < 0.001). When the NODM and the LSDM groups were compared, the risk of pancreatic cancer was higher in the NODM group than LSDM group (HR: 1.55, P = 0.020). In subgroup analysis, NODM group showed that men (HR = 4.42 95% CI: 3.15-6.19, P < 0.001) and patients who were in their 50 s (HR = 7.54, 95% CI: 3.24-17.56, P < 0.001) were at a higher risk of developing pancreatic cancer than matched same sex or age control group (non-DM population), respectively.

The risk of pancreatic cancer was greater in people with DM than non-DM population. Among people with DM, NODM showed a higher risk of pancreatic cancer than long standing DM.

This retrospective cohort study clarified associations between trajectories in palliative care and appetite loss among older patients with advanced unresectable pancreatic cancer and reviewed pancreatic cancer diagnosis among these populations in rural community hospitals. Patients aged >65 years and with pancreatic cancer in a rural community hospital were enrolled. The primary outcome was survival duration from the time of pancreatic cancer diagnosis. Participants were divided into those with and without appetite loss. Cumulative event-free survival rates were calculated using the Kaplan−Meier method, analyzed using the log-rank test, and stratified by factors with statistically significant between-group differences (serum albumin). The mean participant age was 84.14 (SD, 8.34) years; 31.4% were men. Significant between-group differences were noted in albumin concentration and survival duration. Kaplan−Meier curves showed a significant between-group difference in survival probability (p < 0.001). Survival duration significantly differed after stratification by albumin level (p < 0.001). Appetite loss may be a useful symptom for predicting mortality among older patients with unresectable pancreatic cancer, and hypoalbuminemia may accelerate deterioration in their conditions. Accordingly, subjective appetite loss observed by patients and families should be assessed to predict mortality, and it is advisable for physicians to promptly discuss relevant and advanced directives at appropriate timings.

Pancreatic cancer patients usually present at a late stage due to subtle clinical manifestations. One of the most predictive prognostic factors in pancreatic cancer is the pancreatic cancer stage at diagnosis; therefore, early diagnosis is essential. Until now, pancreatic cancer screening has not become a standard practice for the general population due to the low incidence. In current circumstances, targeting individuals with a high risk of pancreatic cancer may be more rational. Several screening modalities for pancreatic cancer have also become debatable topics. Therefore, this article will review current evidence and recommendations regarding pancreatic screening cancer protocol in general and in high-risk populations.

Helicobacter pylori has been implicated in the etiopathogenesis of various malignant conditions; however, there is a dearth of studies on the correlation between H. pylori infection and pancreatic cancers. Hence, this study was carried out to evaluate the association between H. pylori infection and periampullary and pancreatic cancer.

This was a single-centre, retrospective, case-control study in which all consecutive patients of periampullary or pancreatic cancer were included. The demographic details with tumour characteristics were recorded. Age and gender-matched controls were patients with other extra-abdominal benign conditions. H. pylori and the Cag A status were determined using IgG antibodies and Cag A antibodies respectively. The association between H. pylori infection and periampullary and pancreatic cancer was the primary outcome.

A total of 155 patients, 61 in the study and 94 in the control group were included. The overall prevalence of H. pylori in the study group (78.6%) was similar to that of the control group (76.5%) (p = 0.76). Although a higher trend of IgG and Cag A seropositivity was seen in the study group, the difference was not significant. The correlation of H. pylori and Cag A seropositivity showed a higher trend with site-specificity, differentiation, and nodal status. However, the difference was not significant.

There was no association between H. pylori infection and Cag A seropositivity with periampullary and pancreatic cancers. The various tumour characteristics were also not associated with H. pylori infection. Thus, routine eradication of H. pylori infection may not be recommended in periampullary and pancreatic cancers.

Pancreatic adenocarcinoma is often discovered at an advanced stage due to a lack of early symptomology, resulting in this being the fourth leading cause of cancer-related death in the USA. The relationship between diabetes mellitus and pancreatic cancer has been known for many years; however, it is not well understood. Studies have suggested that long-standing type 2 diabetes mellitus can increase the risk of pancreatic cancer by 1.5-2.0-fold. However, patients with new-onset diabetes over 50 years of age have an 8-fold higher risk of pancreatic cancer. Evidence has shown that pancreatic cancer causes diabetes, with the majority being new onset. Diabetic ketoacidosis, which occurs in long-term hyperglycemia, as an initial presentation of pancreatic adenocarcinoma is rare, and only a few cases have been reported. It is postulated that pancreatic cancer prevents insulin-producing cells of the pancreas from responding to insulin resistance. The enriching new-onset diabetes for pancreatic cancer (ENDPAC) score may be utilized as a screening tool for pancreatic carcinomas as an early diagnosis may lead to cure by surgery instead of the grave prognosis associated with it. In this case report, we discuss a 52-year-old female presenting with symptoms of diabetic ketoacidosis who was then subsequently found to have stage-4 pancreatic adenocarcinoma. We concluded that if a patient presents with new-onset diabetes, abdominal imaging with CT scans and endoscopic ultrasound may be warranted to rule out pancreatic carcinoma.

Accumulating evidence strongly suggests that hyperglycemia promotes the progression of pancreatic cancer (PC). Approximately 80% of patients with PC are intolerant to hyperglycemic conditions. In this study, we define the role of Bmi1, a stemness-related oncogene, in controlling the Warburg effect, and immune suppression under hyperglycemia conditions.

The diabetes mellitus model was established by intraperitoneal injection of streptozotocin. The role of the hyperglycemia-Bmi1-HK2 axis in glycolysis-related immunosuppression was examined in both orthotopic and xenograft in vivo models. Evaluation of immune infiltrates was carried out by flow cytometry. Human PC cell lines, SW1990, BxPC-3, and CFPAC-1, were used for mechanistic in vitro studies.

Through bioinformatics analysis, we found that hyperglycemia was strongly related to aerobic glycolysis, immunosuppression, and cancer cell stemness. High glucose condition in the tumor microenvironment promotes immune suppression by upregulating glycolysis in PC cells, which can be rescued via knockdown Bmi1 expression or after 2-deoxy-D-glucose treatment. Through gain-/loss-of-function assessments, we found that Bmi1 upregulated the expression of UPF1, which enhanced the stability of HK2 mRNA and thereby increased the expression of HK2. The role of the hyperglycemia-Bmi-HK2 pathway in the inhibition of antitumor immunity was further verified via the immune-competent and immunodeficient mice model. We also demonstrated that hyperglycemia promotes the expression of Bmi1 by elevating the intracellular acetyl-CoA levels and histone H4 acetylation levels.

Our results suggest that the previously unreported Bmi1-UPF1-HK2 pathway contributes to PC progression and immunosuppression, which may bring in new targets for developing effective therapies to treat patients with PC.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.