Pancreatic Cancer Cases Research Articles

Disparities in pancreatic cancer among Asian-Pacific Islander and American Indian-Alaskan Native populations.

e16275 Background: Pancreatic cancer (PanCan) is the third deadliest cancer in the United States, causing 8.2% of all U.S. cancer deaths. A steady rise in incidence rates has been observed nationally, with striking variation by geographic region and across race/ethnicity. Several studies have demonstrated a disproportionate burden of PanCan incidence on non-Hispanic Black (NHB) as compared to non-Hispanic White (NHW) populations. Yet little attention has been given to the burden of disease on Asian-Pacific Islander (API) and American Indian-Alaskan Native (AI/AN) populations. Additionally, there are limited data on disparities in PanCan incidence by U.S. geographical region. This study investigates age-adjusted incidence rates and annual percent change in PanCan incidence over a 20-year period, emphasizing burden of disease among API and AI/AN persons as well as by U.S. geographic region. Methods: The National Cancer Institute’s Surveillance, Epidemiology, and End-Results (SEER) database of 22 registries was used to study newly diagnosed pancreatic cancer cases (ICD-O-3/WHO 2008) for the period 2000-2019. Incidence rates and annual percent change were age-adjusted to the 2000 U.S. standard population and calculated per 100,000 persons using SEER*Stat software. Results: The overall age-adjusted PanCan incidence rates, from lowest to highest, for AI/AN, API, NHW and NHB populations were 6.6, 9.6, 12.5 and 15.3, respectively (per 100,000 persons). When examining each registry separately, two notable outliers were observed in the state of Hawaii where API and AI/AN persons had incidence rates of 13.4 and 24.5 per 100,000 persons, respectively. For all racial/ethnic groups, except AI/AN, the annual percent change in PanCan incidence significantly rose from 2000-2019, with increases of 0.9, 0.6 and 0.3 percent per year for NHW, API and NHB persons, respectively (p < 0.05). Conclusions: A striking observation in this study was the unusually high PanCan incidence rates among API and AI/AN persons in the state of Hawaii, as compared to national rates. Moreover, a significant increase in annual percent change in PanCan incidence was observed over the study period for all racial/ethnic groups, except AI/AN. A key strength of this analysis is the examination of a large, population-based database over an extended time period. The SEER regions examined cover approximately 48% of the U.S. population and intentionally balance on racial/ethnic composition of the U.S. However, the database does not capture cancer incidence data from all U.S. states. Furthermore, this study did not examine sub-categories of API and AI/AN persons, which are groupings that may be heterogeneous with respect to disease burden over time and across U.S. regions. Future efforts will include refining the analysis into more granular racial/ethnic groups and exploring incidence rates among API and AI/AN subgroups in Hawaii.

Detection and localization of gastrointestinal cancers based on multi-dimentional signatures from a single cfDNA targeted sequencing assay.

4169 Background: Five major gastrointestinal (GI) cancers - colorectal (CRC), gastric (GC), liver (LC), esophageal (EC), and pancreatic cancer (PC) - are responsible for hundreds of thousands of mortalities annually worldwide. Unfortunately, there is a lack of cost-effective, blood-based screening method for their early detection. To address this issue, we aimed to develop GutSeer, a noninvasive, targeted methylation sequencing-based test by leveraging methylation and fragmentomic signatures carried by cell-free DNA (cfDNA). Methods: The panel of GutSeer consists of 1656 target regions which were either differentially methylated between healthy and cancer samples, or distinctively methylated in a specific GI cancer. Cancer and healthy participants were recruited and randomly divided into a training and a validation cohort. Their plasma DNA samples were analyzed to generate DNA methylation and fragmentomic features. These multi-dimensional features were integrated to build ensemble stacked machine learning models to differentiate cancer against healthy, and to determine the tissue-of-origin (TOO) of the cancer. Results: A total of 1844 cases (787 healthy, 342 LC, 239 GC, 209 EC, 180 CRC, and 87 PC cases) were recruited for this study. A cancer- vs-healthy model achieved an AUC of 0.94 and 0.95 (sensitivity of 77.7% and 77.1% under the specificity around 96%) using either methylation or fragmentomic features only, respectively. Combining both methylation and fragmentomic features further improved performances, achieving an AUC of 0.96 (sensitivity = 86.2% at a specificity of 96.7%). For individual type of cancer, GutSeer has a sensitivity of 93.3% for CRC, 81.1% for EC, 70.3% for GC, 96.5% for LC, and 86.4% for PC. An independent test using 629 benign cases as controls achieved a specificity of 87.1%. A separate TOO model was built using all features and achieved an overall accuracy of 82% for all cancer cases (66.7% for CRC, 87.0% for GC and EC combined, 89.0% for LC, and 63.2% for PC). Same as the cancer detection model, using multi-dimensional features in TOO prediction yielded higher accuracy than when models using only methylation or fragmentomics features (accuracy = 75.6% or 75.4%, respectively). When compared with whole-genome sequencing (WGS) based approaches, GutSeer showed a comparable performance in cancer detection but a higher accuracy in TOO identification, further confirming its effectiveness for detection of GI cancers. Conclusions: GutSeer, a non-invasive test integrating multi-dimensional features, was demonstrated to detect and localize the 5 main types of GI cancer with high accuracy. Our results further showed that a reasonably sized panel can perform comparably or even better than WGS-based methods in cancer detection and TOO localization, indicating GutSeer may be a low-cost solution for blood-based early screening for GI cancers.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma

IntroductionOnly a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation...

MiRNA 143 based nanobiosensor to diagnose pancreatic cancer

This work exploits miRNA 143, a biomarker to detect pancreatic cancer. Recent reports from GLOBOCAN show that cases of pancreatic cancer will increase from 557,688 in 2025 to 815,276 by 2040. Furthermore, the 5-year survival rate of patients diagnosed with pancreatic cancer is only 14%, though it can be improved to 43% if diagnosed early. This necessitates the requirement for early diagnosis which will help in providing proper treatment. However, low concentration of tumor markers at early stage makes it difficult to diagnose. MicroRNAs (miRNAs) are considered an important tool for early diagnosis of cancer, since they appear as circulating markers in blood at early stage itself. In view of this, we have developed an electrochemical sensor to detect miRNA143. The self-assembled monolayers of cysteine hydrochloride were created on gold electrode surface followed by the immobilization of citrate-capped gold nanoparticles (10–25 nm). The amino-labeled single-stranded DNA probe against miRNA143 formed covalent bonding with citrate-capped gold nanoparticles. Non-specific binding to the platform was avoided by using gelatin as a blocking agent. Further, electrochemical measurements were recorded in response to target miRNA143. Characterization of fabricated miRNA143 gold printed electrode was done through cyclic voltammetry (CV). Cyclic voltammetric curve response recorded after addition of miRNA143 spiked FBS sample onto the fabricated electrode from 9.9ag/ml to 9.9 ng/ml (1.4aM to 1.4 nM), shows decreasing redox peak height with increasing concentration. Similar behavior was observed for saturation current through chronoamperometric analysis and differential pulse voltammetric measurements. The calibration plots of peak current response, saturation current with the increasing concentrations of miRNA143 were plotted. The sensitivity of the nanosensor as calculated from DPV, Chronoamperometry and CV measurements was 201.11 µA/g/ml/cm2, 125.98 µA/g/ml/cm2 and 95.55 µA/g/ml/cm2 and respectively with lower limit of detection (LLOD) of 1.4aM. LLOD of 1.4aM makes it a promising platform for sensing miRNA 143 and as a diagnostic tool for early diagnosis of pancreatic cancer.

A deep learning algorithm to predict risk of pancreatic cancer from disease trajectories

Pancreatic cancer is an aggressive disease that typically presents late with poor outcomes, indicating a pronounced need for early detection. In this study, we applied artificial intelligence methods to clinical data from 6 million patients (24,000 pancreatic cancer cases) in Denmark (Danish National Patient Registry (DNPR)) and from 3 million patients (3,900 cases) in the United States (US Veterans Affairs (US-VA)). We trained machine learning models on the sequence of disease codes in clinical histories and tested prediction of cancer occurrence within incremental time windows (CancerRiskNet). For cancer occurrence within 36 months, the performance of the best DNPR model has area under the receiver operating characteristic (AUROC) curve = 0.88 and decreases to AUROC (3m) = 0.83 when disease events within 3 months before cancer diagnosis are excluded from training, with an estimated relative risk of 59 for 1,000 highest-risk patients older than age 50 years. Cross-application of the Danish model to US-VA data had lower performance (AUROC = 0.71), and retraining was needed to improve performance (AUROC = 0.78, AUROC (3m) = 0.76). These results improve the ability to design realistic surveillance programs for patients at elevated risk, potentially benefiting lifespan and quality of life by early detection of this aggressive cancer.

The association between red, processed and white meat consumption and risk of pancreatic cancer: a meta-analysis of prospective cohort studies.

The association between meat consumption and the risk of pancreatic cancer has not been comprehensively investigated by different types of meat. The current study was conducted to evaluate this association. PubMed and Web of Science databases were used to search for prospective cohort studies on meat consumption and pancreatic cancer risk through May 2022. A meta-analysis was performed using random-effects models to combine study-specific relative risks (RR). The quality of the included studies was evaluated using the Newcastle-Ottawa quality assessment scale. Twenty prospective cohort studies including 3,934,909 participants and 11,315 pancreatic cancer cases were identified. The pooled RR of pancreatic cancer for the highest versus lowest white meat intake category was 1.14 (95% CI: 1.03-1.27). There was no significant association between consumption of red meat and processed meat and pancreatic cancer risk in the highest versus lowest analysis. In dose-response analyses, pooled RRs were 1.14 (95% CI: 1.01-1.28) for an increase in red meat consumption of 120g per day and 1.26 (95% CI: 1.08-1.47) for an increase in white meat consumption of 100g per day, respectively. Processed meat consumption showed neither a linear nor a non-linear association with pancreatic cancer risk. Findings from this meta-analysis suggested that high consumption of red meat and white meat is associated with an increased risk of pancreatic cancer. Future prospective studies are warranted to confirm the association between meat consumption and the risk of pancreatic cancer.

Feasibility of Biliary Drainage Using a Novel Integrated Biliary Stent and Nasobiliary Drainage Catheter System for Acute Cholangitis.

Background Acute cholangitis is caused by cholestasis and bacterial infection, and if exacerbated, sepsis may occur and be fatal. Biliary drainage is recommended for acute cholangitis regardless of severity, except in some cases of mild acute cholangitis, in which antibiotics are effective. A novel integrated device comprising a biliary drainage stent and a nasobiliary drainage tube, called the UMIDAS NB stent (UMIDAS Inc., Kanagawa, Japan), was developed. In this study, we evaluated the efficacy and safety of biliary drainage using the UMIDAS NB stent outside type for acute cholangitis in clinical practice. Methods Patients with acute cholangitis with common bile duct stones or distal biliary strictures who underwent biliary drainage with the UMIDAS NB stent outside type at our institution between January 2022 and December 2022were examined retrospectively. The UMIDAS NB stent outside type was placed transpapillary using endoscopic retrograde cholangiopancreatography (ERCP). Patients with biliary drainage stent placement other than the UMIDAS NB stent outside type on the same ERCP session and patients with acute cholecystitis were excluded. Results A total of 13 patients were included in this study. The severity of cholangitis was mild in four cases, moderate in five, and severe in four. There were eight cases of common bile duct stones and five cases of pancreatic cancer. The stent diameter was 7 French scale (Fr) in five cases and 8.5 Fr in eight cases. The median procedure time was 20 minutes. Clinical success was achieved in all 13 patients (100%). No treatment-related adverse events were observed. Unintended removal of the nasobiliary drainage tube was not observed. There were no cases of biliary drainage stent dislocation with nasobiliary drainage tube removal. Conclusions Although the sample size was small, our studydemonstrated that biliary drainage with the UMIDAS NB stent outside type was effective and safe for patients with acute cholangitis who had common bile duct stones or distal biliary strictures, regardless of the severity of cholangitis.

Abstract 601: Serological responses to tumor-associated adducts in pancreatic cancer

Abstract The incidence of pancreatic cancer has increased over the past several decades and is now the fourth leading cause of cancer death in the USA. Only 8.5% of the patients live beyond 5 years after their initial diagnosis. This dismal survival rate is partly explained by the fact that most pancreatic cancer cases are detected late when treatment options are limited. Novel biomarkers are crucially needed. It has long been recognized that cancer cells abnormally accumulate chemical groups covalently linked to proteins, DNA and other molecules. Humoral responses to these “adducts” have not been thoroughly explored. To investigate these responses, we developed an ELISA platform for the detection of serum IgG reactive to 93 adducts, including post-translational modifications known to contribute to tumorigenesis, progression, and metastasis. Our panel also includes oxidation-related modification, advanced glycation end products, and certain co-enzymes that qualify as adducts based on their binding properties. Using this assay, we measured anti-adduct antibodies in the serum of adult healthy donors (N=24; age range 40-80) as well as patients with pancreatic cancer (N=31; age range 50-90). Importantly, all patient specimens were collected before any treatment. Reactivity to all adducts was analyzed using a random forest predictive model with 10,000 bootstrapped decision trees to distinguish between the two groups. Results revealed a distinctive anti-adduct IgG reactivity profile for pancreatic cancer patients when compared to controls. Applying feature selection using the Boruta algorithm identified a reduced set of 19 target adducts recognized by IgG that most efficiently discriminated between healthy donors and pancreatic cancer cases. All 19 adducts were confirmed as IgG targets in cancer patients using multiple unpaired t-tests (p≤0,05). Aside from their predictive value, we reasoned that the detection of adduct-specific antibodies in cancer patients reflected their accumulation in the tumor cells. To test this hypothesis, we assessed the level of two representative target adducts by immunofluorescence staining in tumor tissue compared to control adjacent non-tumoral tissue or healthy tonsil. Results unequivocally show higher levels of these two adducts in cancer cells compared to non-cancer cells. Taken together, these preliminary findings support our hypothesis of the development of anti-adduct antibodies in pancreatic cancer patients. Furthermore, the specific antibody signature detected in these patients is consistent with the abnormal presence of corresponding adducts in the transformed cells. Our findings pave the way for the development of diagnostic tests based on the detection of serum IgG specific to tumor-associated adducts. Citation Format: Talita Aguiar, Shunya Mashiko, Poulomi Roy, Max Dietzel, Kesava Asam, Bradley Aouizerat, Jeanine Genkinger, Helen Remotti, Emmanuel Zorn. Serological responses to tumor-associated adducts in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 601.

Abstract 1484: Identification of the critical active enhancer and regulated transcripts contributing to the refractory nature of pancreatic cancer

Abstract Background: Pancreatic adenocarcinoma (PAAD) is the most lethal human cancer, with a 5-year survival rate of less than 10%. Thus, the identification of prognostic biomarkers as well as molecular therapeutic targets should be critical. Gene expression is regulated by various factors such as transcription factors, promoters, enhancers, DNA methylation, microRNAs, etc. Among them, it has been reported that enhancers play an essential role in the development and progression of cancer. This study aims to identify the novel regulatory element of gene transcription and therapeutic targets in pancreatic cancer by analyzing enhancers. Material and Methods: We implemented NET-CAGE analysis to identify the active enhancer regions in pancreatic cancer cell lines and two immortalized normal pancreatic cell lines. As for the enhancer sequences, we conducted a motif analysis using an analytical pipeline, HOMER to capture sequence motifs enriched in the enhancers. The p-values output by HOMER were applied to identify transcription factor motifs enriched in the tumor cell lines compared to the normal cell lines. We analyzed RNA-sequencing data derived not only from 105 cases of in-house pancreatic cancer but from 178 cases of The Cancer Genome Atlas. Results: We found that the enrichment of KLF and ELF family transcription factors was observed in cancer cell lines compared to normal cell lines. ELF4 expression was significantly higher in tumor tissues than in normal tissues (Wilcoxon rank sum test, p<0.05). In survival analysis, high ELF4 expression was significantly associated with poor prognosis (Kaplan-Meier method, Log-rank test, p<0.05). Immunohistochemical staining showed ELF4 expression in the nuclei of PAAD cells, and GSEA showed a positive correlation between increased ELF4 expression and the cell cycle-related gene sets and PI3K/AKT/mTOR-related gene sets. Conclusions: The current result of the NET-CAGE enhancer analysis revealed that the KLF and ELF families might contribute to activating pancreatic cancer. As we know that KLF4 induces the pluripotency of somatic cells, KLF and ELF are considered to be cancer stemness-related genes. We are focusing on deciphering the regulatory element of the KLF and ELF to orchestrate downstream molecules of cancer stemness-related genes, which will lead to the intractability of pancreatic cancer. Citation Format: Tadashi Abe, Hideyuki Saito, Yusuke Nakano, Masahiro Hashimoto, Yuki Ando, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Ken Eto, Toru Ikegami, Koshi Mimori. Identification of the critical active enhancer and regulated transcripts contributing to the refractory nature of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1484.

Abstract 3395: Clinical impact of FGFR inhibitors on FGFR2 positive pancreatic cancer

Abstract Objectives: Here we describe the durable clinical outcomes of four FGFR2 fusion positive pancreatic cancer patients treated with FGFR inhibitors as well as a pancreatic specific analysis of FGFR alterations through our collaboration with Foundation Medicine, Inc. (FMI). Methods: We identified four patients with FGFR2 fusion positive metastatic pancreatic cancer through tumor RNAseq (OSU-SpARKFuse) which identifies gene fusions from cell free DNA (cfDNA). We assessed two tumor markers (Ca19-9 and FGFRDx, an FGFR-focused cell free DNA liquid biopsy assay) and various clinical outcomes (Best overall response, duration, and side effects to their treatments). Additionally, 10,146 tumor-tissue clinical cases of pancreatic cancers were assayed by hybrid-capture based comprehensive genomic profiling (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes, MSI, and tumor mutation burden (TMB). Results: All four patients demonstrated durable clinical responses to various FGFR inhibitors. Patient 1 harbored an FGFR2-USP33 fusion and exhibited a partial response to pemigatinib for 25 months following progression on gemcitabine/abraxane and FOLFIRI chemotherapy. Patient 2 harbored an FGFR2-INA fusion with 12 months of stable disease to pazopanib after experiencing progression from chemotherapy. Patient 3 harbored an FGFR2-INA fusion and exhibited a 12+ month on-going, partial response to pemigatinib. Patient 4 harbored an FGFR2-CEP55 fusion and demonstrated stable disease on ponatinib for 15 months, a 24-month response to gemcitabine/platinum chemotherapy, and a 7+ month on-going partial response to infigratinib. Through the genomic profiling of 10,146 tumor-tissue clinical cases of pancreatic cancer, we identified 108 FGFR fusions resulting in a prevalence of 1%. We are currently investigating co-occurring and mutually-exclusive genomic alterations, including TMB and MSI-H status, for pancreatic cancer patients harboring FGFR alterations. Conclusions: This retrospective analysis provides clinical evidence that there is a subpopulation of KRAS wild-type FGFR2 fusion positive pancreatic patients who can have beneficial and lasting responses to FGFR inhibitors further suggesting a need to investigate and expand the availability of FGFR inhibitors to more cancer types. Citation Format: Leah Stein, Julie W. Reeser, Michele R. Wing, Karthikeyan Murugesan, Anoosha Paruchuri, Zachary Risch, Eric Samorodnitsky, Emily L. Hoskins, Amy Smith, Thuy Dao, Melissa Babcook, Muhammad Imam, Aharon Freud, Sameek Roychowdhury. Clinical impact of FGFR inhibitors on FGFR2 positive pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3395.

Abstract 6102: Targeting BARD1 slows PDAC growth in vitro and in vivo and sensitizes cells to DNA damaging agents

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent malignant neoplasm of the pancreas, responsible for over 90% of pancreatic cancer cases. Despite recent therapeutic advances, the five-year overall survival rate for PDAC is only 11% and therapies remain limited. It is now known that deficiency in DNA damage repair (DDR) renders PDAC cells vulnerable to certain DNA damage agents, for example, poly (ADP-ribose) polymerase inhibitors (PARPi). Most of the DDR genes mutated in PDAC are crucial for the proper functioning of the homologous recombination repair (HRR) pathway, and loss-of-function alterations in DDR genes sensitize cells to DNA-damaging agents. Since this treatment strategy is currently limited to 5-10% of PDAC cases with known mutations in the DDR genes, it underscores a dire need to understand new therapeutic avenues and expand the PDAC patient population that could benefit from this therapeutic approach. We have recently published that BARD1 (BRCA1- Associated- Ring- Domain- 1), an obligate binding partner of BRCA1, is upregulated in PDAC cells exposed to PARPi/platinums. We found that transient inhibition of BARD1 rendered PDAC cells extremely sensitive to olaparib (PARPi)/oxaliplatin (platinum), and enhanced DNA damage. Based on these results, we created two genetic models of BARD1 inhibition and utilized these model systems to investigate if loss of BARD1 chemo-sensitizes PDAC cells to other PARPis and DNA damage agents. Doxycycline inducible shRNA and BARD1 CRISPR KO models were created to inhibit gene expression of BARD1 in PDAC cells. We first characterized these model systems to confirm the loss of BARD1 protein and mRNA expression by western blot and qRT-PCR analyses. Using colony formation and Pico green cell survival assays, we found that inhibiting BARD1 resulted in slower growth of pancreatic cancer cells in vitro. Moreover, expression of several cell cycle genes from G2-M phase was significantly decreased (p=0.05). These studies were recapitulated in a mouse xenograft subcutaneous model, where BARD1 KO and WT PDAC cells were injected subcutaneously and tumor growth was analyzed over 25-30 days. Kaplan-Meier curves were calculated and plotted using Log-rank test. We found that inhibiting BARD1 significantly (p=0.026) delayed formation of PDAC tumors in vivo. Next, we analyzed the efficacies of various DNA damaging agents when BARD1 was inhibited. Silencing or CRISPR KO of BARD1 enhanced efficacy of mitomycin C, irinotecan, as well as other PARPis, which are currently in clinical trials (rucaparib, veliparib) in vitro and lowered their IC50s. These results indicate that targeting BARD1 has the potential to benefit patients in terms of novel or improved treatments. Our ongoing and future studies will expand on these findings to understand BARD1-mediated pathway and evaluate sensitivity of multiple DNA damage agents by screening a library of > 250 compounds. Citation Format: Sohum Patel, Anoohya Arkala, Avinoam Nevler, Carolyn Coats, Charles J. Yeo, Aditi Jain. Targeting BARD1 slows PDAC growth in vitro and in vivo and sensitizes cells to DNA damaging agents. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6102.

Small Nuclear RNA 64 (snoRNA64): A novel Tumor Biomarker for Pancreatic Cancer

The pancreatic ductal adenocarcinoma (PDAC), which represents over 90% of pancreatic cancer cases, has the highest proliferative and metastatic rate in comparison to other pancreatic cancer compartments. This study is designed to determine whether small nucleolar RNA, H/ACA box 64 (snoRNA64) is associated with pancreatic cancer initiation and progression. Gene expression data from the Gene Expression Omnibus (GEO) repository have shown that snoRNA64 expression is reduced in primary and metastatic pancreatic cancer as compared to normal tissues based on statistical analysis of the in Silico analysis. Using qPCR techniques, pancreatic cancer cell lines include PK-1, PK-8, PK-4, and Mia PaCa-2 with different levels of snoRNA64, including PK-1, PK-8, PK-4, and Mia PaCa-2. The level of expression is correlated with the cell line epithelial or mesenchymal characteristics. Cell lines displaying epithelial characteristics such as PK-1, PK-8 show high levels of snoRNA64 meanwhile, cell lines displaying mesenchymal characteristics such as PK-4, Mia PaCa-2 show low levels of snoRNA64. The level of expression is correlated with the cell line epithelial or mesenchymal characteristics. After knocking down the PK-8 with high snoRNA64 expression, the epithelial markers E. cadherin (E-cad) and Cytokeratin-8 (CK-8) are decreased, while mesenchymal markers Vimentin (Vim), Cytokeratin-19 (CK-19), Metalloprotease -2 (MMP-2), and Metalloprotease-3 (MMP-3) are activated. Those changes suggest that PK-8 responding to the snoRNA64 knock down protocol and increase in mesenchymal function. Together, snoRNA64 expression may participate in epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), in which during metastasis these processes are crucial. In addition, snoRNA64 may be considered as a potential diagnostic biomarker for both early and invasive stages of PDAC. And due to its gradual expression decreases, it may be considered a barrier in tumor progression.

Characterization of pancreatic cancer with ultra-low tumor mutational burden

In pancreatic cancer (PC), Tumor mutation burden (TMB) has been reported to be lower than in other cancers, with its clinical significance remaining unclear. We analyzed the dataset of whole-exome sequencing and gene expression profiling of 93 resected PC cases. The median TMB was 0.24. The TMB was classified as High (≥ 5.0), Low (< 5.0, ≥ 1.0), or Ultra-low (< 1.0). Nineteen samples (20%) were classified as TMB-low, and 74 (80%) were classified as TMB-ultra-low; no samples were TMB-high. TMB-ultra-low PC had significantly fewer borderline resectable lesions (P = 0.028) and fewer adenosquamous carcinomas (P = 0.003) than TBM-low PC. Furthermore, the TMB-ultra-low PC showed significantly lower detection rates of driver mutations and copy number variations. Microsatellite instability was not significantly correlated with the TMB status. The TMB-ultra-low PC had a significantly better prognosis than TBM-low PC (P = 0.023). A multivariate analysis identified TMB-ultra-low PC as an independent favorable prognostic factor (hazard ratio, 2.11; P = 0.019). A gene expression analysis showed that TMB-ultra-low PC was associated with reduced TP53 inactivation (P = 0.003) and reduced chromosomal instability (P = 0.001) compared to TBM-low PC. TMB-ultra-low PC had specific gene expression signatures and a better prognosis than TMB-low PC.

Albumin-Globulin Ratio Indicates the Survival Outcome of Pancreatic Cancer Cases Who Underwent Preoperative Treatment and Curative Surgical Resection

Background The pretreatment albumin–globulin ratio (AGR) is a frequently used inflammation-associated factor that has been reported to have associations with the survival outcomes of various malignancies. Methods We retrospectively analyzed 162 patients with pancreatic cancer who underwent preoperative treatment followed by curative surgery at Nagoya University Hospital between April 2010 and December 2020. Representative nutritional status indicators of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), and albumin–globulin ratio (AGR) were calculated for each case. Results Among pretreatment blood examination parameters, only AGR (cutoff: 1.33) showed a significant difference in overall survival time (OS) and progression-free survival time (PFS) from the beginning of the preoperative treatment. Median PFS was 22.3 mo, in high AGR cases and 17.1 mo, in low AGR cases (P = 0.019). Median OS was 48.7 mo, in high AGR cases and 32.9 mo, in low AGR cases (P = 0.043). Conclusion High pretreatment AGR may be a favorable prognostic factor for pancreatic cancer patients who received preoperative multimodal therapy followed by curative cancer resection. It may imply that nutritional status and inflammation control before the multimodal treatment affect the survival outcomes of pancreatic cancer cases and needs to be optimized.

Assessment of Pancreatic Duct Dilation in Patients with Pancreatic Cancer and Chronic Pancreatitis using Ultrasonography: A Retrospective Study

Background: The present study aimed to assess the main pancreatic duct (PD) in patients with chronic pancreatitis and pancreatic cancer (PC) to determine the prevalence of dilation in both conditions. Methods and Results: A retrospective study was conducted at King Fahad Medical City in Riyadh from December 2019 to March 2020 on the use of ultrasonography to assess PD in patients with PC and CP. The sample included 73 patients: 39 (21 females and 18 males) with PC and 34 (20 males and 14 females) with CP. The diameter of the main PD was measured by ultrasonography. The mean age for PC patients was 61.17±13.96 years, and for CP patients - 42.14±17.08 years (P=0.000). The diameter of the main PD in PC was 0.52±0.22 cm, and in CP, it was 0.51±0.28 cm (P=0.865). Our results suggest that the dilation of the PD is one feature that accompanies PC and CP. In our study, there was no significant difference in the prevalence of dilation in both conditions (64.1% and 64.7%). Additionally, PC is 2.4 times more likely to be associated with diabetes mellitus than CP. Conclusion: PC occurs more commonly in the older age group, while CP occurs more commonly in the younger age group. Most cases of PC and CP were associated with dilation of the PD with no significant difference in the amount of dilation.

Helicobacter pylori Seropositivity, ABO Blood Type, and Pancreatic Cancer Risk from 5 Prospective Cohorts.

Helicobacter pylori infection may be a risk factor for pancreatic cancer, particularly infection by strains without the cytotoxin-associated gene A (CagA) virulence factor. Non-O blood type is a known risk factor for pancreatic cancer, and H. pylori gastric colonization occurs largely from bacterial adhesins binding to blood group antigens on gastric mucosa. We included 485 pancreatic cancer cases and 1,122 matched controls from 5 U.S. prospective cohorts. Prediagnostic plasma samples were assessed for H. pylori and CagA antibody titers. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for pancreatic cancer. ABO blood type was assessed using genetic polymorphisms at the ABO gene locus or self-report. Compared to H. pylori seronegative participants, those who were seropositive did not demonstrate an increased risk for pancreatic cancer (OR 0.83, 95% CI 0.65-1.06). This lack of association was similar among CagA seropositive (OR 0.75, 95% CI 0.53-1.04) and seronegative (OR 0.89, 95% CI 0.65-1.20) participants. The association was also similar when stratified by time between blood collection and cancer diagnosis (P-interaction=0.80). Consistent with prior studies, non-O blood type was associated with increased pancreatic cancer risk, but this increase in risk was similar regardless of H. pylori seropositivity (P-interaction=0.51). In this nested case-control study, history of H. pylori infection as determined by H. pylori antibody serology was not associated with pancreatic cancer risk, regardless of CagA virulence factor status. The elevated risk associated with non-O blood type was consistent in those with or without H. pylori seropositivity.

Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond.

Pancreatic enzymes assist metabolic digestion, and hormones like insulin and glucagon play a critical role in maintaining our blood sugar levels. A malignant pancreas is incapable of doing its regular functions, which results in a health catastrophe. To date, there is no effective biomarker to detect early-stage pancreatic cancer, which makes pancreatic cancer the cancer with the highest mortality rate of all cancer types. Primarily, mutations of the KRAS, CDKN2A, TP53, and SMAD4 genes are responsible for pancreatic cancer, of which mutations of the KRAS gene are present in more than 80% of pancreatic cancer cases. Accordingly, there is a desperate need to develop effective inhibitors of the proteins that are responsible for the proliferation, propagation, regulation, invasion, angiogenesis, and metastasis of pancreatic cancer. This article discusses the effectiveness and mode of action at the molecular level of a wide range of small molecule inhibitors that include pharmaceutically privileged molecules, compounds under clinical trials, and commercial drugs. Both natural and synthetic small molecule inhibitors have been counted. Anti-pancreatic cancer activity and related benefits of using single and combined therapy have been discussed separately. This article sheds light on the scenario, constraints, and future aspects of various small molecule inhibitors for treating pancreatic cancer-the most dreadful cancer so far.

Gastric intramural metastasis caused by needle tract seeding after preoperative fine needle aspiration for pancreatic body cancer subsequently resected by total pancreatectomy: a case report and literature review

BackgroundRecently, there has been an increase in the number of reports of needle tract seeding (NTS) of tumor cells after a biopsy as one of the adverse events related to endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA). In most of the previously reported cases of NTS in pancreatic cancer, distal pancreatectomy was performed as the initial surgery, following which metachronous metastasis was discovered in the gastric wall, whose localization matched the puncture route of the EUS-FNA. We report a case of early metastasis from pancreatic cancer in the gastric wall, which was postulated to be caused by NTS. Our patient underwent a total pancreatectomy (TP), and the NTS was resected synchronously.Case presentationA 70-year-old woman with a diagnosis of pancreatic head-body-tail cancer presented to our department for surgery. Transgastric EUS-FNA and biopsy established the histological diagnosis in her case. We administered neoadjuvant chemotherapy (NAC) to the patient and performed a TP. Histopathological and immunohistochemical examination subsequently confirmed the diagnosis of pT3N1aM1 pancreatic adenocarcinoma and its gastric metastasis, which was caused by NTS. It is postulated that the tumor cells of NTS had progressed to develop the metastatic lesion in the gastric wall during the NAC period. This was also resected during the initial surgery. The patient developed an early postoperative recurrence in the peritoneum 8 months after the surgery.ConclusionIn pancreatic head cancer cases, the puncture route is often included in the resection area of radical surgery, and NTS is seldom considered as a potential clinical problem. However, NTS can progress rapidly and may be associated with early recurrence of malignancy. Therefore, when transgastrointestinal puncture is performed for the diagnosis of pancreatic cancer, the treatment strategy should be established considering the potential development of NTS.

Prevalence and genomic landscape of BRAF alterations across gastrointestinal cancers.

806 Background: BRAF V600E mutations can lead to activation of the MEK/ERK pathway. The combination of dabrafenib plus trametinib was recently FDA-approved for use in these BRAF V600E altered unresectable or metastatic cancers. BRAF non-V600 alterations also increase phosphorylation of MEK and ERK and are potential candidates for MEK/ERK inhibitors. Here we examine the frequency of BRAF mutations and their genomic background across GI cancers. Methods: The Oncomap ExTra genomic profiling assay utilizes tumor-normal, whole-exome, whole-transcriptome DNA and RNA sequencing to identify somatic alterations in tumors. The assay detects single-nucleotide substitutions, indels, copy number alterations, alternative transcripts, and gene fusions. Tumor mutational burden (TMB) and microsatellite instability (MSI) are also assessed. The frequency of BRAF and other gene alterations were identified across all GI cancers. Reported BRAF alterations were limited to those linked to an FDA approved therapy, clinical trial eligibility, and those deemed significant from review of the literature. Results: A total of 1927 patients with GI cancers were assayed between April 2018 to July 2022. The BRAF gene was mutated in 85 (4.4%) patients, which included 53 (2.8%) that were V600E and 32 (1.5%) that were non-V600, representing 37.6% of BRAF mutations. Colorectal and small bowel cancers had the highest frequencies of BRAF mutations at 7.6% and 7.1% respectively, and the frequency was lower in other GI cancers (0-2.3%). In addition to BRAF V600E, other mutations occurred across the kinase domain, including D594 (0.6%), K601E (0.3%), G466 (0.3%) and G469 (0.2%). BRAF fusions were found in 1 CRC and 2 pancreatic cancer cases. BRAF mutational status (altered versus not) was significantly associated with mutations in several other genes. In addition, BRAF status was significantly associated with TMB-high and MSI-high. Conclusions: Analysis of whole-exome and whole transcriptome sequencing data found actionable BRAF mutations in 4.4% of GI cancer patients, 37.6% of whom had BRAF mutations not at V600. Several biomarkers were significantly associated with BRAF alterations. Assays that are limited to DNA sequencing, or to targeted gene panels, may not detect mutations and fusions that could aid in therapy selection and prognosis. [Table: see text]

Imaging Recommendations for Diagnosis, Staging, and Management of Pancreatic Cancer

AbstractPancreatic cancer is the fourth most prevalent cause of cancer-related death worldwide, with a fatality rate equal to its incidence rate. Pancreatic cancer is a rare malignancy with a global incidence and death ranking of 14th and 7th, respectively. Pancreatic cancer cases are divided into three categories without metastatic disease: resectable, borderline resectable, or locally advanced disease. The category is determined by the tumor's location in the pancreas and whether it is abutting or encasing the adjacent arteries and/or vein/s.The stage of disease and the location of the primary tumor determine the clinical presentation: the pancreatic head, neck, or uncinate process, the body or tail, or multifocal disease. Imaging plays a crucial role in the diagnosis and follow-up of pancreatic cancers. Various imaging modalities available for pancreatic imaging are ultrasonography (USG), contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI), and 18-fluoro-deoxy glucose positron emission tomography (FDG PET).Even though surgical resection is possible in both resectable and borderline resectable non-metastatic cases, neoadjuvant chemotherapy with or without radiotherapy has become the standard practice for borderline resectable cases as it gives a high yield of R0 resection.