Risk Factor For Pancreatic Cancer Research Articles

Clinical risk factors for pancreatic cancer: protocol for an umbrella review

IntroductionIdentifying cancer earlier can help save lives. An increasingly popular approach to diagnosing cancer earlier is in the development of risk prediction models to be applied to the electronic healthcare...

9334 Pancreatic Adenocarcinoma Presenting As Diabetic Ketoacidosis

Abstract Disclosure: J. Alvarez: None. M.H. Horani: None. Background: Pancreatic adenocarcinoma is often diagnosed at an advanced stage due to late onset of clinical features including poor appetite, weight loss, weakness, epigastric pain, and rarely impaired glucose tolerance. In patients who present with impaired glucose tolerance or diabetic ketoacidosis without prior history of diabetes, pancreatic adenocarcinoma should be considered. Clinical Case: Patient is a 45-year woman with depression, HTN, irritable bowel syndrome who was found unresponsive by family and presented to the ED for acute encephalopathy. On exam, she was obtunded, tachypneic, with fruity-smelling breath and dry mucous membranes. Initial labs showed glucose of 950 mg/dL (70-99 mg/dL), lipase 539 U/L (8-78 U/L), lactic acid 4 mmol/L 0.5-2 mmol/L), ketone-BHB 170.75 mg/dL (0-2.81 mg/dL), A1c 16.5%. She had no prior history or family history of diabetes. She was admitted to hospital for DKA management.CXR to evaluate dyspnea showed bilateral opacities so CT chest/abdomen/pelvis without contrast was ordered. This showed bilateral multilobar pneumonia, trace pleural effusions, 6.7 x 3.8 cm lobulated fluid collection along pancreatic tail, 12.1 x 6.6 x 4.4 cm RLQ cystic lesion and 4.4 cm lesion vs loculation along the right pelvic sidewall.Initially, GI recommended repeat imaging of the pancreas in 4-6 weeks. OBGYN was consulted for pelvic masses and recommended IR-guided biopsy of right pelvic mass which showed rare mildly atypical mucinous epithelium present, cystic mucinous neoplasm cannot be excluded.CEA and CA125 tumor markers returned elevated. These biopsies showed adenocarcinoma (solid component) and rare atypical mucinous epithelium consistent with cystic mucinous neoplasm (cystic fluid). Patient was deemed medically stable for discharge with recommended follow-up to appropriate specialists. Following discharge, she was officially diagnosed with Stage III (cT4, cN0, cM0) pancreatic adenocarcinoma and started on appropriate chemotherapeutic regimen. Discussion: The current understanding is long-standing type 2 diabetes mellitus as a risk factor for pancreatic cancer based on previous studies.The inverse relationship of pancreatic cancer causing new onset diabetes is more rare, but if cancer is suspected in these patients it could potentially help in the diagnosis of early stage adenocarcinoma. Other case reports have suggested implementation of the enriching new-onset diabetes for pancreatic cancer (ENDPAC) score in addition to CT and EUS as screening for pancreatic cancer may help with earlier diagnosis.

8297 Risk Of Pancreatic Cancer In Patients With Diabetes Mellitus And Pancreatitis: A Nationwide Nested Case-Control Study

Abstract Disclosure: Y. Kim: None. H. Kim: None. M. Yu: None. C. Nam: None. E. Kang: None. Background: Despite diabetes mellitus and pancreatitis being known risk factors for pancreatic cancer, but because of their low incidence, patients with these conditions are not included in pancreatic cancer screening. This study aimed to determine the high-risk subgroup of patients with diabetes and pancreatitis that would benefit from pancreatic cancer screening. Methods: A nested case-control study was conducted using data from the national health information database of the Korean National Health Insurance Service. Patients were categorized into the following groups: type 2 diabetes only (T2D-only), pancreatitis only (PAN-only), type 2 diabetes followed by pancreatitis (T2D-PAN), post-pancreatitis DM (PPDM), and no diabetes and no pancreatitis (NDNP). Conditional logistic regression was used to determine significant associations of each group with pancreatic cancer development risk. Results: The risk of pancreatic cancer was significantly higher in the T2D-PAN (adjusted odds ratio [AOR], 4.96; 95% confidence interval [CI], 4.48-5.49) and PPDM (AOR, 4.71; 95% CI, 4.12-5.37) groups than in the NDNP group. Furthermore, the T2D-PAN and PPDM groups had a significantly higher risk of pancreatic cancer than the T2D-only and PAN-only groups. Compared to patients in the NDNP group, patients with PPDM using insulin had a 9-fold increased risk (AOR, 9.84; 95% CI, 6.77-14.29), and patients with T2D-PAN using insulin had a 6-fold increased risk (AOR, 6.62; 95% CI, 5.33-8.20). Conclusion: Patients with both diabetes and pancreatitis had a higher risk of pancreatic cancer than those with either alone, regardless of the order of occurrence, and insulin use was associated with an additional increase in pancreatic cancer risk. These results suggest that these subgroups of patients could be considered to benefit from pancreatic cancer screening. Presentation: 6/2/2024

Adipose tissue-derived extracellular vesicles from obese mice suppressed splenocyte-mediated pancreatic cancer cell death.

Obesity is a risk factor for pancreatic cancer and negatively contributes to the immune system. However, the mechanisms by which obesity mediates these actions are still poorly understood. Recent studies have demonstrated that extracellular vesicles (EVs) are key mediators of communication between cells and may influence various aspects of cancer progression. We aim to explore the influence of EVs derived from adipose tissue of obese mice on cytokine production within the interactions between cancer cells and immune cells. We isolated EVs from the adipose tissue of both C57BL6/J mice and Ob/Ob mice. Subsequently, we treated EVs with Panc02 cells, the murine ductal pancreatic cancer cell line, which were co-cultured with splenocytes. Viability and SMAD4 gene expression were examined in Panc02 cells, and cytokine concentrations of IL-6, IL-4, IL-12, and IL-12p70 were measured in the cultured medium. Interestingly, we observed a significant reduction in splenocyte-mediated Panc02 cell death when treated with EVs derived from the adipose tissue of Ob/Ob mice, compared to those from C57BL6/J mice. Additionally, EVs from Ob/Ob mice-derived adipose tissue significantly increased the levels of IL-4, IL-2, and IL-12p70 in the culture media of Panc02 cells co-cultured with splenocytes, compared to EVs from C57BL6/J mice-derived adipose tissue. Adipose tissue-derived EVs from obese mice suppressed splenocyte-mediated Panc02 cell death and upregulated IL-4, IL-2, and IL-12p70 in cultured medium.

Clinical significance of intraductal papillary mucinous neoplasms incidentally detected in patients with extrapancreatic gastrointestinal malignancies with a focus on pancreatic cancer development

BackgroundIntraductal papillary mucinous neoplasm is occasionally detected in the preoperative images of patients with gastrointestinal malignancies. Despite numerous studies examining the incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasm, limited data exist on the prevalence of intraductal papillary mucinous neoplasm in those with gastrointestinal malignancies. Given that intraductal papillary mucinous neoplasm is a known risk factor for pancreatic cancer, this study aimed to evaluate the prevalence of intraductal papillary mucinous neoplasm in patients who underwent radical surgery for extrapancreatic gastrointestinal malignancies and its impact on pancreatic cancer development. MethodsWe retrospectively reviewed the preoperative computed tomography images of patients who underwent radical surgery for gastrointestinal malignancies between January 2017 and December 2021 for the presence of intraductal papillary mucinous neoplasm. Patients were divided into intraductal papillary mucinous neoplasm and non–intraductal papillary mucinous neoplasm groups, and clinicopathologic features and long-term outcomes, including pancreatic cancer development, were compared between groups. ResultsA total of 814 patients who underwent radical surgery for extrapancreatic gastrointestinal malignancies were included. Among them, 81 patients (10.0%) had intraductal papillary mucinous neoplasm. The median observation period was 39 (0–79) months. Notably, pancreatic cancer developed in 5 patients with intraductal papillary mucinous neoplasm and 1 without. The 5-year cumulative incidences of pancreatic cancer were 8.8% and 0.2% in the intraductal papillary mucinous neoplasm and non–intraductal papillary mucinous neoplasm groups, respectively (P < .001). ConclusionIntraductal papillary mucinous neoplasm is frequently detected in the preoperative images of patients with gastrointestinal malignancies and is associated with a significantly higher risk of developing pancreatic cancer. Consequently, long-term surveillance for pancreatic cancer is crucial in patients with intraductal papillary mucinous neoplasm, particularly those with extrapancreatic gastrointestinal malignancies.

The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice.

In pancreatic cancer, the tumor microenvironment (TME) accounts for up to 90% of the tumor mass. Pancreatitis, characterized by the increased infiltration of macrophages into the pancreas, is a known risk factor for pancreatic cancer. The NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor regulates responses to oxidative stress and can promote cancer and chemoresistance. NRF2 also attenuates inflammation through the regulation of macrophage-specific genes. Heme oxygenase 1 (HO-1) is expressed by anti-inflammatory macrophages to degrade heme, and its expression is dependent on NRF2 translocation to the nucleus. In macrophages stimulated with conditioned media from pancreatic cancer cells, HO-1 protein levels increased, which correlated with higher NRF2 expression in the nuclear fraction. Significant differences in macrophage infiltration and HO-1 expression were detected in LSL-KrasG12D/+; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice and wildtype mice with pancreatitis. Since epigenetic modulation is a mechanism used by tumors to regulate the TME, using small molecules as epigenetic modulators to activate immune recognition is therapeutically desirable. When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis.

Abstract A061: DKK3 in pancreatic cancer – Elucidating the roles of a double-edged sword

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly challenging disease with a poor prognosis due to lack of diagnostic biomarkers and high tumor heterogeneity. Therefore, it is crucial to meticulously examine the intricate molecular mechanisms in PDAC. We previously identified DKK3 (Dickkopf-3) as a novel factor promoting organ regeneration during pancreatitis and established a previously unknown link between DKK3 and the Wnt and Hedgehog signaling. Given that pancreatitis is a significant risk factor for pancreatic cancer, we were motivated to investigate the potential role of DKK3 in PDAC development. We utilized PDAC mouse models driven by LSL-KrasG12D/+; Ptf1aCre/+ with wildtype, homozygous/heterozygous DKK3 deletion in both epithelial and stromal compartment while employing in vitro and ex vivo systems to examine the stage and compartment-specific roles of the same. Through a comprehensive and time-resolved analysis of tumor characteristics, we discovered that the loss of DKK3 led to rapid oncogenic transformation, marked by a significant increase in metaplasia and desmoplasia starting at an early stage (10 weeks). Ex vivo acinar-to-ductal metaplasia assay and rescue experiments with wildtype and DKK3-null acinar cells revealed that secreted DKK3 operates as a tumor suppressive roadblock in PDAC-initiating steps. This advanced preneoplastic stage translated into accelerated progression toward invasive tumors at 36 weeks, a shortened overall survival, and a higher liver metastasis incidence in the DKK3-null animals at the endpoint. Interestingly, transcriptomic analyses further validated our observation and revealed the involvement PI3-AKT signaling pathway as an underlying mechanism. Further characterization of isolated tumor cells confirmed our observations, revealing prominent mesenchymal features and enhanced migratory capacities upon loss of DKK3. Interestingly, DKK3-null PDACs exhibited a pronounced stroma remodeling with a myofibroblastic cancer-associated fibroblast-enriched environment, as well as an immunosuppressive stroma with abundant regulatory T cells and cytotoxic T cell depletion, as substantiated by coculture experiments. Intriguingly, while displaying similar phenotypic features to DKK3-null tumors, Dkk3+/- heterozygotes exhibited the most aggressive outcome. To further dissect this finding, we conducted a set of in silico approaches and immunostainings revealing persistent stromal DKK3 expression in DKK3- proficient PDACs. This suggested a possible dual role of DKK3 that could operate either as a friend or a foe depending on its spatiotemporal expression in PDAC. In line, in vitro systems demonstrated a distinct oncogenic effect of DKK3 on endpoint tumor cells, particularly promoting malignant cell migration. In summary, we propose that epithelial DKK3 exerts cell-autonomous tumor suppressive functions during the onset of PDAC, while stromal DKK3 acts as an oncogenic cue driving cancer progression. These findings highlight DKK3 as a promising biomarker and a novel therapeutic target for PDAC tumors. Citation Format: Dharini Srinivasan, Frank Arnold, Elodie Roger, Anna Härle, Michael K Melzer, Chantal Allgöwer, Patrick C Hermann, Lukas Perkhofer, Johann Gout, Alexander Kleger. DKK3 in pancreatic cancer – Elucidating the roles of a double-edged sword [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A061.

Acute pancreatitis as a risk factor of chronic pancreatitis and pancreatic cancer. An overview.

This is an overview of relation between acute and chronic pancreatitis and between acute pancreatitis and pancreatic cancer. Acute pancreatitis and recurrent acute pancreatitis are an etiological factor of chronic pancreatitis. Population-based studies have calculated the risk of acute recurrent pancreatitis after the first attack of acute pancreatitis to be 20% and development of chronic pancreatitis after first attack of acute pancreatitis is 10%. An important risk factor is tobacco smoking. Acute and chronic pancreatitis are risk factors for pancreatic cancer. The risk of acute pancreatitis is related to the number of recurrences of acute pancreatitis, but not the etiology of acute pancreatitis. Acute pancreatitis, as well as chronic pancreatitis, are risk factors for pancreatic cancer. After an attack of acute pancreatitis or recurrent acute pancreatitis a patient should be regarded as a high risk.

Occupational and environmental risk factors for pancreatic cancer: A retrospective cohort study at a hospital in central Taiwan

Occupational and environmental risk factors for pancreatic cancer: A retrospective cohort study at a hospital in central Taiwan

Pancreatic Cancer: A Review of Risk Factors.

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.

Pancreatic cancer risk in diabetic patients using the Japanese Regional Insurance Claims

Pancreatic cancer presents a critical health issue characterized by low survival rates. Identifying risk factors in specific populations, such as those with diabetes, is crucial for early detection and improved outcomes. This study aimed to identify risk factors for pancreatic cancer in diabetic patients using a longitudinal cohort from the Shizuoka Kokuho database, spanning April 2012 to September 2021. Diabetic patients were identified and monitored for the onset of pancreatic cancer. Factors analyzed included age, sex, the Elixhauser comorbidity index, and specific comorbidities. Statistical analyses involved univariate and multivariate Cox proportional hazards regression. The study identified 212,775 as diabetic patients and 1755 developed pancreatic cancer during the period. The annual incidence rate of pancreatic cancer in this group was 166.7 cases per 100,000 person-years. The study identified older age, male sex, a history of liver disease, chronic pancreatitis, and pancreatic cystic lesions as significant risk factors for pancreatic cancer in diabetic patients. The study also highlighted the absence of a significant association between diabetes type or diabetic complications and the onset of pancreatic cancer. These findings may aid in the early diagnosis of pancreatic cancer in diabetic patients and may inform revisions in screening practices in diabetic patients.

Relationship of pancreatitis to pancreatic cancer: from population-based observations to preclinical and mechanistic insights

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, accounting for 95% of pancreatic cancer cases, with a 5-year survival rate of around 10%. The relationship between pancreatitis and pancreatic cancer has been noted within the medical community. Recent epidemiological data and findings from experimental mouse models have underscored pancreatitis as a critical risk factor for pancreatic cancer. Therefore, exploring the mechanisms underlying the transition from pancreatitis to pancreatic cancer is crucial for improving early detection and treatment strategies for pancreatic cancer. In this review, we conducted a comprehensive search of the PubMed database and discussed relevant original studies, focusing on three key areas: findings from population- and animal-based studies, the role of pancreatic epithelial cell-intrinsic factors, and the impact of immune cells and cytokines. Additionally, we offered our prospectives on possible future research directions.

Genome-Wide Analysis to Assess if Heavy Alcohol Consumption Modifies the Association between SNPs and Pancreatic Cancer Risk.

Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10-8 in the meta-analysis; Pinteraction = 2.1 × 10-9 in the case-control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.

Incidence and risk factors of pancreatic cancer during 15 years follow-up in the Golestan Cohort Study in Iran

Incidence and risk factors of pancreatic cancer during 15 years follow-up in the Golestan Cohort Study in Iran

Pancreatic cancer in Saudi Arabia (2005–2020): increasing trend

Pancreatic cancer, a highly fatal malignancy, has shown a global rise in the incidence and mortality rates. However, these rates vary significantly across different regions worldwide. This study aims to assess the incidence and mortality of pancreatic cancer in Saudi Arabia. We collected the data from 16 annual cancer incidence reports in Saudi Arabia for the study period (2005–2020) and from the WHO's IARC Global Cancer Observatory website. Although the burden of pancreatic cancer in Saudi Arabia is relatively lower compared to global rates, the disease incidence has shown a steady increase over the study period, in addition to regional variations within the country. The disease predominantly affects the elderly population, aged 50 years and above in both genders, with males exhibiting higher rates than females. Further studies are required to identify the potential risk factors for pancreatic cancer in the Saudi population.

Frailty Assessment for Risk Stratification in Pancreatic Surgery – Results of a Single-Center Cohort Study

Abstract Background Large cohort studies found an increase in frailty with age. Age is a known risk factor for pancreatic cancer. Seventy percent of new diagnoses are made in patients aged more than 65 years. Pancreatic resections represent the only hope for cure but are associated with high morbidity. The definition “fit for pancreatic surgery”, currently mainly based on age and comorbidities, is continuously challenged. Aims The aim of this study is to analyze the impact of frailty on postoperative outcomes after pancreatic resections. Methods Data of consecutive patients undergoing pancreatic resections between January 2015 and July 2022 were retrospectively analyzed. Postoperative complications were graded by the Clavien-Dindo Classification, Comprehensive Complication Index (CCI) and complications specific to pancreatic resections as recommended and published by the International Study Group of Pancreatic Surgery. The modified frailty index (mFI) was defined by 11 variables. An mFI score above 0.27 was set to define frailty. Results A pancreatic resection was performed in 159 patients, of which 23 (15%) were classified as frail. Pancreatoduodenectomies were similarly distributed in both groups. Frail patients were older (median of 74 vs. 69 years). Male gender was associated with frailty (83%, p=0.001)., Moreover, frailty was associated with an increased rate of preoperative biliary drainage. Although intensive care stay was increased in the frail group (median 3 vs. 0 days; p=0.01), total length of hospital stay was not affected. Frailty was associated with severe complications as defined by a comprehensive complication index &amp;gt;50 (35% vs. 10%; p=0.003), an increased rate of severe type C pancreatic fistula (13% vs. 2%, p=0.04), and a higher 90-day mortality (13% vs. 2%, p=0.04). Conclusion Assessment of frailty should be used for preoperative risk stratification since frailty is associated with a higher morbidity and mortality after pancreatic resections.

Detection of Pancreatic Cancer and Nutritional Support in Chronic Pancreatitis

Chronic pancreatitis (CP) is a significant risk factor for pancreatic cancer and there had been a great deal of interest in surveillance and detection of pancreatic cancer. According to presence of genetic mutation, CP can be classified into hereditary CP and sporadic CP. CP with PRSS1 gene mutation showed a high incidence of pancreatic cancer justifying screening and surveillance for those older than 40 years. But CP with other mutations and sporadic CP have relatively low incidence of pancreatic cancer and surveillance is not recommended. While computed tomography or magnetic resonance imaging is widely used for screening, endoscopic ultrasound is not recommended because of parenchymal inflammation, fibrosis, and calcification associated with CP. However, when a patient with CP has multiple risk factors for pancreatic cancer, risk of pancreatic cancer increases significantly. Patients with CP have increased risk of pancreatic cancer at five years after diagnosis; individualized screening and surveillance based on symptoms and specific circumstances should be considered. Patients with CP have a high risk of malnutrition and malnutrition is quite common. Clinicians should assess nutritional status and implement nutritional support. Nutritional support must include both macronutrients and micronutrients. Given the high risk of osteoporosis and osteopathy in CP, clinicians should consider early diagnosis, prevention, and treatment. Consultation with nutritional support team is highly recommended.

The Use of Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus Does Not Increase the Risk of Pancreatic Cancer: A U.S.-Based Cohort Study.

GLP-1 RAs are widely used for T2DM treatment due to their cardiorenal and metabolic benefits. This study examines the risk of pancreatic cancer with GLP-1 RA use in patients with T2DM. We analyzed TriNetX's deidentified research database using the U.S. Collaborative Network comprising 62 healthcare organizations across the U.S.A. Patients with T2DM were split into two cohorts: one receiving GLP-1 RAs, and one not receiving GLP-1 RAs. We excluded patients with known risk factors for pancreatic cancer, including pancreatic cysts, a personal or family history of BRCA1, BRCA2, CDKN2A, KRAS, MEN1, MLH1, MSH2, NOTCH1, PALB2, PMS2, and PRSS1S genes, family history of pancreatic cancer, and VHL syndrome. Using a 1:1 propensity score-matching model based on baseline characteristics and comorbidities, we created comparable cohorts. We then compared the rate of pancreatic cancer between the two cohorts at a 7-year interval. Out of 7,146,015 identified patients with T2DM, 10.3% were on a GLP-1 RA and 89.7% were not. Post-PSM, 721,110 patients were in each group. Patients on GLP-1 RAs had a 0.1% risk compared to a 0.2% risk of pancreatic cancer in the 7-year timeframe. The use of GLP-1 RAs in patients with type 2 diabetes mellitus (T2DM) does not appear to substantially elevate the risk of pancreatic cancer; in fact, it may potentially exert a protective effect.

Pancreatic cancer: from early detection to personalized treatment approaches.

Pancreatic cancer is notorious for its persistently poor prognosis and health outcomes, so some of the questions that may be begged are "Why is it mostly diagnosed at end stage?", "What could we possibly do with the advancing technology in today's world to detect early pancreatic cancer and intervene?", and "Are there any implementation of the existing novel imaging technologies?". Well, to start with, this is in part because the majority of patients presented would already have reached a locally advanced or metastatic stage at the time of diagnosis due to its highly aggressive characteristics and lack of symptoms. Due to this striking disparity in survival, advancements in early detection and intervention are likely to significantly increase patients' survival. Presently, screening is frequently used in high-risk individuals in order to obtain an early pancreatic cancer diagnosis. Having a thorough understanding of the pathogenesis and risk factors of pancreatic cancer may enable us to identify individuals at high risk, diagnose the disease early, and begin treatment promptly. In this review, the authors outline the clinical hurdles to early pancreatic cancer detection, describe high-risk populations, and discuss current screening initiatives for high-risk individuals. The ultimate goal of this current review is to study the roles of both traditional and novel imaging modalities for early pancreatic cancer detection. A lot of the novel imaging techniques mentioned seem promising, but they need to be put to the test on a large scale and may need to be combined with other non-invasive biomarkers before they can be widely used.

Abstract 2184: A high-fat diet accelerates early-stage murine pancreatic carcinogenesis by influencing, in part, mesenteric adipose tissue metabolism

Abstract Increased adiposity represents a modifiable risk factor of pancreatic cancer. Multiple preclinical studies have shown that a high-fat and high-sugar diets on the acceleration of pancreatic carcinogenesis, in the context of obesity. However, the impact of diets resembling the omega-6 to omega-3 fatty acid (FA) ratio in a Western-style diet, remains unclear. Furthermore, the role of the mesenteric adipose tissue (MAT) in pancreatic carcinogenesis is poorly characterized. Thus, we aimed to determine the impact of a high-fat diet with a ratio of 9 parts omega-6 FA to each omega-3 FA, on early stages of pancreatic carcinogenesis in a genetically engineered LSL- KrasLSL-G12D; Ptf1aCre/+ (KC) model of pancreatic cancer, with an emphasis on evaluating the contribution of the MAT within the pancreatic microenvironment. For this purpose, cohorts of male and female KC mice (6-8 males and females per diet group) were randomly assigned to either a control diet (CD) group (9:1 of omega-6 FAs to omega-3 FAs) or a high-fat diet (HFD) group (9:1 of omega-6 FAs to omega-3 FAs) and fed their respective diets until three months of age. After eight weeks on their diets, HFD-fed mice had significantly increased body weight, fat mass, and elevated serum leptin levels. Furthermore, HFD-fed mice had increased acinar-to-ductal metaplasia, associated with increased PCNA expression, ERK and STAT3 phosphorylation and elevated pro-tumorigenic immune cell expression compared to CD-fed mice. Although no significant differences in MAT weight or adipocyte size were observed after 8 weeks between the groups, metabolomics analysis of the MAT revealed that HFD-fed mice had significant upregulation of many key metabolites linked to proliferative and inflammatory pathways. For instance, HFD-fed female KC mice had significant differences in α-linolenic acid metabolism and the biosynthesis of unsaturated fatty acids, while male mice had significant differences in arginine biosynthesis, amino acid metabolism, linoleic acid metabolism, and α-linolenic acid metabolism. HFD-fed female mice had a significant increase in α-linolenic acid and linoleic acid in MAT, concurrent with a reduction in inosine 5-monophosphate and α-tocopherol compared to female CD-fed mice. HFD-fed male mice displayed a more pronounced difference in metabolites, including an increase in α-linolenic acid, linoleic acid, malic acid, glutamine, isoleucine, and several other amino acids, with a concurrent reduction in lauric acid and palmitoleic acid compared to male CD-fed mice. In summary, a HFD accelerates pancreatic carcinogenesis through multifaceted mechanisms, including effects on the tumor and surrounding adipose depots. A HFD increases affects MAT metabolism in a sex-dependent manner, that might ultimately promote early-stage progression of pancreatic carcinogenesis. Citation Format: Aya Ead, Joanna Wirkus, Gerardo G. Mackenzie. A high-fat diet accelerates early-stage murine pancreatic carcinogenesis by influencing, in part, mesenteric adipose tissue metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2184.