Marker For Pancreatic Cancer Research Articles

High Expression of CHST11 Correlates with Poor Prognosis and Tumor Immune Infiltration of Pancreatic Cancer.

Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and its prognosis is poor. It has been reported that carbohydrate sulfotransferase 11 (CHST11) is associated with tumor progression in various cancers but rarely reported in PC. The aim of this study was to comprehensively investigate the clinical value of CHST11 in PC. CHST11 gene expression analysis was conducted by The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and Human Protein Atlas (HPA) databases. Survival analysis and receiver operating characteristic (ROC) curves were performed to evaluate the prognostic significance of CHST11 based on TCGA and International Cancer Genome Consortium (ICGC) databases. Additionally, functional enrichment analysis was also performed. Moreover, single-sample Gene Set Enrichment Analysis (ssGSEA) and ESTIMATE algorithm were used to assess immune infiltration. Finally, the relationship between CHST11 expression and immune checkpoint gene levels was estimated by Spearman's correlation analysis. CHST11 was highly expressed in PC tissues compared with normal tissues, and the expression of CHST11 was related to T stage, N stage, and histological grade. The survival time of PC patients with CHST11 low-expression was significantly better than those with CHST11 high-expression. The areas under the ROC curve corresponding to 1-, 3-, and 5-year survival in the TCGA dataset were 0.573, 0.671, and 0.740, respectively, and those in the ICGC dataset were 0.588, 0.602, and 0.626, respectively. Functional enrichment analysis showed that CHST11 may be involved in the regulation of immune function. Finally, the level of CHST11 was significantly correlated with 22 types of tumor-infiltrating immune cells, immune and stromal scores, and 7 immune checkpoint genes. High-expression of CHST11 was correlated with poor prognosis and tumor immune infiltration in PC. Moreover, CHST11 may act as a novel prognostic marker and potential therapeutic target of PC.

Risk factors and prognostic index model for pancreatic cancer.

Pancreatic cancer is a highly malignant tumor with poor prognosis. Chronic inflammation contributes to the progression of pancreatic cancer. However, few studies have examined the prognostic role of inflammatory markers in this cancer. Our study sought to analyze the prognostic risk factors of and construct a prognostic index (PI) model using inflammatory markers for pancreatic cancer. Forty-eight patients diagnosed with pancreatic cancer at our hospital were selected for this retrospective analysis. Data on the general clinical characteristics, tumor-related features, blood index factors, and treatment methods were collected. The Cox proportional-hazards model was used to analyze the factors affecting the prognosis, and the Kaplan-Meier analysis was used to draw the survival curve. The median overall survival time was 14.5 months, and the 1-, 2-, and 3-year survival rates were 20.83% (10/48), 6.25% (3/48), and 4.17% (2/48), respectively. The univariate analysis showed that tumor grade, vascular invasion, adjacent tissue invasion, lymph node metastasis, tumor-node-metastasis (TNM) stage, the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the lymphocyte-monocyte ratio (LMR) were significantly correlated with the median survival of pancreatic cancer patients (P<0.05). The Cox regression equation showed that tumor grade III-IV (X1), vascular invasion (X2), TNM stage III-IV (X3), a NLR >3.8 (X4), and a PLR >182.1 (X5) were independent risk factors affecting the prognosis of patients with pancreatic cancer (all P<0.05). The prognostic model for pancreatic cancer can be expressed as: PI =3.521X1+4.157X2+1.282X3+2.441X4+6.015X5. Patients with tumor grade I-II, non-vascular invasion, TNM stage I-II, a NLR ≤3.8, and a PLR ≤182.1 exhibited a higher 1-year survival rate. The areas under the receiver operating characteristic (ROC) curves for the NLR >3.8 and the PLR >182.1 were 0.778 and 0.713, respectively. Tumor grade, vascular invasion, TNM staging, the NLR, and the PLR are independent risk factors affecting the prognosis of pancreatic cancer patients. The NLR and PLR have good clinical value in predicting the survival outcomes of pancreatic cancer patients.

Correlation of CA 19-9 with HbA1c in prediabetic and diabetic groups

Introduction and Aim: Carbohydrate antigen19-9 (CA 19-9) is a marker of pancreatic cancer. In diabetics, pancreatic beta cell dysfunction can lead to elevated serum CA19-9 level. This study was designed for estimation of CA19-9 in diabetes and its correlation with glucose levels and glycosylated hemoglobin. Materials and Methods: The includes diabetic, pre diabetic with no history of malignancies and healthy normal subjects (n=50 each). Ca19-9 was estimated using ELISA, HbA1c by D10-Biorad variant turbo and the Lipid profile in Roche COBAs 6000 auto analyzer. Statistical analysis was done by Statistical Package for Social Sciences software version17 (SPSS 17). P &lt;0.05 was considered significant. Results: Serum CA19-9 level was high in diabetics compared to normal, (p=0.38) however it was decreased in pre diabetic group (P=0.06). There was significant difference in comparison of CA19-9 levels between pre diabetic and diabetics(p=0.001). A significant increase in triglycerides was observed both in diabetics (p&lt;0.01) and pre-diabetics(p=0.04). There was a significant positive correlation of CA19-9 with TC/HDL (p=0.022) and non-HDL(p) in control group. Conclusion: CA19-9 levels can be influenced by glycemic status, hence assessment of pancreatic cancer in diabetic patients must be interpreted carefully in consideration with CA19-9 levels. CA19-9 level was decreased in prediabetics when compared to normal and diabetics. This is a novel finding, the cause for which must ascertained, and this will open further avenues for research.

IDO1/TDO dual inhibitor RY103 targets Kyn-AhR pathway and exhibits preclinical efficacy on pancreatic cancer.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn) in kynurenine pathway (KP) is involved in the immunosuppression in pancreatic cancer (PC), but the value of IDO1 as an independent prognostic marker for PC is uncertain. Moreover, the correlation between tryptophan 2,3-dioxygenase (TDO), an isozyme of IDO1, and PC is largely unknown. Using TCGA database, the correlation between IDO1 and/or TDO expression and PC patients' survival was analyzed. The expressions of IDO1 and TDO in PC cells and PC mice were examined. The effects of IDO1, TDO or dual inhibition on IDO1 and TDO effector pathway (Aryl hydrocarbon receptor, AhR) and on migration and invasion of PC cells were investigated. The block effect of IDO1/TDO dual inhibitor RY103 on KP was evaluated. The preclinical efficacy of RY103 and its immunomodulatory effect on KPIC orthotopic PC mice and Pan02 tumor-bearing mice were explored. Results showed that IDO1/TDO co-expression is an independent prognostic marker for PC. RY103 can significantly block KP and target Kyn-AhR pathway to blunt the migration and invasion of PC cells, exhibit preclinical efficacy and ameliorate IDO1/TDO-mediated immunosuppression in PC mice.

S100A2 Is a Prognostic Biomarker Involved in Immune Infiltration and Predict Immunotherapy Response in Pancreatic Cancer.

Pancreatic cancer (PC) is a highly fatal and aggressive disease with its incidence and mortality quite discouraging. It is of great significance to construct an effective prognostic signature of PC and find the novel biomarker for the optimization of the clinical decision-making. Due to the crucial role of immunity in tumor development, a prognostic model based on nine immune-related genes was constructed, which was proved to be effective in The Cancer Genome Atlas (TCGA) training set, TCGA testing set, TCGA entire set, GSE78229 set, and GSE62452 set. Furthermore, S100A2 (S100 Calcium Binding Protein A2) was identified as the gene occupying the most paramount position in risk model. Gene set enrichment analysis (GSEA), ESTIMATE and CIBERSORT algorithm revealed that S100A2 was closely associated with the immune status in PC microenvironment, mainly related to lower proportion of CD8+T cells and activated NK cells and higher proportion of M0 macrophages. Meanwhile, patients with high S100A2 expression might get more benefit from immunotherapy according to immunophenoscore algorithm. Afterwards, our independent cohort was also used to demonstrate S100A2 was an unfavorable marker of PC, as well as its remarkably positive correlation with the expression of PD-L1. In conclusion, our results demonstrate S100A2 might be responsible for the preservation of immune-suppressive status in PC microenvironment, which was identified with significant potentiality in predicting prognosis and immunotherapy response in PC patients.

Early Diagnostic Ability of Human Complement Factor B in Pancreatic Cancer Is Partly Linked to Its Potential Tumor-Promoting Role

Although plasma complement factor B (CFB, NX_P00751), both alone and in combination with CA19-9 (i.e., the ComB-CAN), previously exhibited a reliable diagnostic ability for pancreatic cancer (PC), its detectability of the early stages and the cancer detection mechanism remained elusive. We first evaluated the diagnostic accuracy of ComB-CAN using plasma samples from healthy donors (HDs), patients with chronic pancreatitis (CP), and patients with different PC stages (I/II vs III/IV). An analysis of the area under the curve (AUC) by PanelComposer using logistic regression revealed that ComB-CAN has a superior diagnostic ability for early-stage PC (97.1.% [95% confidence interval (CI): (97.1-97.2)]) compared with CFB (94.3% [95% CI: 94.2-94.4]) or CA19-9 alone (34.3% [95% CI: 34.1-34.4]). In the comparisons of all stages of patients with PC vs CP and HDs, the AUC values of ComB-CAN, CFB, and CA19-9 were 0.983 (95% CI: 0.983-0.983), 0.950 (95% CI: 0.950-0.951), and 0.873 (95% CI: 0.873-0.874), respectively. We then investigated the molecular mechanism underlying the detection of early-stage PC by using stable cell lines of CFB knockdown and CFB overexpression. A global transcriptomic analysis coupled to cell invasion assays of both CFB-modulated cell lines suggested that CFB plays a tumor-promoting role in PC, which likely initiates the PI3K-AKT cancer signaling pathway. Thus our study establishes ComB-CAN as a reliable early diagnostic marker for PC that can be clinically applied for early PC screening in the general public.

Analysis of KRAS Mutation Subtype in Tissue DNA and Cell-Free DNA Using Droplet Digital PCR and the Function of Cell-Free DNA as a Recurrence Predictive Marker in Pancreatic Cancer.

KRAS mutation is a major regulator in the tumor progression of pancreatic cancer. Here, we compared the frequency and mutation burden of KRAS mutation subtypes with paired tumor tissue and blood in patients and examined their clinical significance. DNA from tumor tissues and cell-free DNA (cfDNA) from preoperative blood were obtained from 70 patients with pancreatic cancer. Subtypes and mutation burdens of KRAS G12D and G12V mutations were evaluated using droplet digital PCR. Comparing the presence of mutations in tissue, accumulative and simultaneous mutations of G12D or G12V were identified of 67 (95.7%), and 48 patients (68.6%). Conversely, in blood, they were only identified in 18 (25.7%) and four (5.7%) patients; respectively. Next, comparing the mutation burden in tissue, the mutation burden varied from less than 0.1 to more than five, whereas that of cfDNA in blood was mostly between one and five, as cases with a mutation burden lower than 0.1 and higher than five were rare. Finally, the presence of the G12V mutation alone in cfDNA and the combination of the G12V mutation with elevated CA 19-9 levels were associated with poor recurrence-free survival. These fundamental data on the KRAS mutation subtypes and their clinical significance could support their potential as predictive markers for postoperative recurrence.

Peripheral blood monocytes predict clinical prognosis and support tumor invasiveness through NF-κB-dependent upregulation of Snail in pancreatic cancer.

BackgroundThe tumor inflammatory microenvironment plays a vital role in the initiation and progression of pancreatic cancer (PC). Both the lymphocyte-to-monocyte ratio (LMR) and preoperative peripheral blood monocytes are related to the prognosis of PC patients. However, the direct effect of monocytes on PC cells is not fully understood. The current study aimed to assess the effect of monocytes on PC and explore its potential mechanism.MethodsThe cutoff value of peripheral blood monocytes was evaluated by the receiver operating characteristic (ROC) curve. Transwell migration and invasion assays were used to detect the mobility of PC cells. The cytokines derived from monocytes were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Western blotting was utilized to assess the expression of epithelial-mesenchymal transition (EMT) related markers. The expression level of Snail in PC tissue was determined by immunohistochemical (IHC) staining.ResultsA high monocyte count was inversely correlated with lymph node status and 5-year overall survival in PC. The PC cells underwent a cellular morphology change and increased cell motility after coculture with THP-1 monocytes. The THP-1 monocytes secreted various proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1α), which activated the nuclear factor-κB (NF-κB) signaling pathway leading to the upregulation of Snail and thereby promoting the EMT of PC cells. The expression level of Snail correlated significantly with the density of peripheral blood monocytes, and their level status was significantly associated with 5-year overall survival.ConclusionsThese findings indicated that elevated monocytes counts were a poor prognostic marker in PC, and monocytes could directly induce the EMT process of PC cells by upregulating Snail expression through the NF-κB signaling pathway.

Characterization of the GATA Transcription Factor Family and Exploration of Their Relevance to Immune Infiltration and Tumor Microenvironment in Pancreatic Cancer.

BackgroundPancreatic cancer (PC) presents a phenomenal disease burden worldwide. The GATA transcription factor family is associated with a variety of human malignancies. However, the relation between GATA family members (GATAs) and PC has not been elucidated.MethodsThis study integrates large-scale bioinformatics database resources to analyze the expression patterns of GATAs in PC patients and explore their underlying function mechanism and relevance to immune infiltration and other different cell types in the tumor microenvironment in pancreatic cancer. First, the expression pattern of GATAs in pancreatic cancer was detected by the Oncomine database and the Gene Expression Profile Interaction Analysis (GEPIA2) database and verified through other datasets in the R2 platform. Then, we used the cBioPortal database and the Human Protein Atlas to assess the correlation between GATAs and clinicopathological features of PC. Then, survival analyses were performed to identify candidate prognostic factors in the GATA family in PC patients. Further, we performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction (PPI) network, immune-infiltration correlation analysis, and cell type analysis of the tumor microenvironment at the single-cell level to explain the function of GATAs in pancreatic cancer.ResultsWe found that GATA3 and GATA6 were highly expressed in pancreatic cancer, and the expression levels of GATA4 and GATA6 correlated with the pathological stage, differentiation grade, and molecular subtype of pancreatic cancer. The survival analysis revealed that lower GATA4 of PC patients was associated with better outcomes, and higher GATA6 might be associated with longer OS. In addition, GATA3 was associated with immune cell infiltration of PC, and GATA6 was mainly distributed in the epithelial cells with ductal phenotype.ConclusionThis work tentatively identified GATA3, GATA4, and GATA6 in the GATA family associated with pancreatic cancer. GATA4 may serve as a prognostic factor for PC patients, and GATA6 may act as a subtype marker for PC. In addition, GATA3 may reflect the immune-infiltration status of PC.

Simple prognostic markers for optimal treatment of patients with unresectable pancreatic cancer.

Most patients with pancreatic cancer are ineligible for curative resection at diagnosis, resulting in poor prognosis. This study aimed to evaluate the prognostic factors in patients with unresectable pancreatic cancer.We retrospectively collected clinical data from 196 patients with unresectable pancreatic cancer who received palliative chemotherapy (N = 153) or palliative care alone (N = 43) from January 2011 to December 2013. Patients’ background data and overall survival were analyzed using the Cox proportional hazard regression model.In patients receiving palliative chemotherapy (gemcitabine-based regimen, 88.2%) and palliative care alone, the median (range) ages were 68 (43–91) and 78 (53–90) years, and metastatic diseases were present in 80% (N = 123) and 86% (N = 37), respectively. Multivariate analysis in the palliative chemotherapy patients showed that liver metastasis (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.58–3.20, P < .001), neutrophil-to-lymphocyte ratio (>4.5 vs ≤4.5; HR 3.45, 95% CI 2.22–5.36, P < .001), and cancer antigen 19-9 (CA19-9) (≥900 vs <900 U/mL; HR 1.45, 95% CI 1.02–2.05, P = .036) were independent prognostic factors. In those receiving palliative care alone, lung (HR 3.27, 95% Cl 1.46-7.35, p = 0.004) and peritoneum (HR 2.50, 95% CI 1.20–5.18, P = .014) metastases and the C-reactive protein-to-albumin ratio (≥1.3 vs <1.3; HR 3.33, 95% Cl 1.51–7.35, P = .003) were independent prognostic factors. Furthermore, patients with multiple factors had worse prognosis in both groups. Median survival time of palliative chemotherapy patients with risk factors 0, 1, 2, and 3 were 13.1 (95% CI 8.0–16.9), 9.4 (95% CI 7.9–10.1), 6.6 (95% CI 4.9–7.8), and 2.5 (95% CI 1.7–4.0) months, respectively. Similarly, median survival time was 5.7 (95% CI 1.3 -8.0), 2.1 (95% CI 1.5–3.9), and 1.3 (95% CI 0.6–1.7) months, respectively, for palliative care alone patients with risk factor 0, 1, and 2 to 3.Prognostic markers for pancreatic cancer were neutrophil-to-lymphocyte ratio, liver metastasis, and CA19-9 in patients undergoing palliative chemotherapy and C-reactive protein-to-albumin ratio and lung/peritoneum metastases in patients undergoing palliative care alone. These simple markers should be considered when explaining the prognosis and therapeutic options to patients.

The Scavenger Receptor MARCO Expressed by Tumor-Associated Macrophages Are Highly Associated With Poor Pancreatic Cancer Prognosis.

Macrophage-targeting therapies have become attractive strategies for immunotherapy. Deficiency of MARCO significantly inhibits tumor progression and metastasis in murine models of pancreatic cancer. However, the role of MARCO in patients with pancreatic cancer remains unclear. In the present study, we analyzed tumor-associated macrophage (TAM)-related changes using the Cancer Genome Atlas database. We observed a significant enrichment of M2 macrophages in pancreatic cancer tissues. We found that several pro-tumor markers are increased in cancer tissues, including CD163, CD206, SIRPα, LILRB1, SIGLEC10, AXL, MERTK, and MARCO. Crucially, MARCO is highly or exclusively expressed in pancreatic cancer across many types of solid tumors, suggesting its significant role in pancreatic cancer. Next, we investigated the expression of MARCO in relation to the macrophage marker CD163 in a treatment-naïve pancreatic cancer cohort after surgery (n = 65). MARCO and CD163 were analyzed using immunohistochemistry. We observed increased expression of CD163 and MARCO in pancreatic cancer tissues compared with paracancerous tissues. Furthermore, we observed a large variation in CD163 and MARCO expression in pancreatic cancer tissues among cases, suggesting the heterogeneous expression of these two markers among patients. Correlation to clinical data indicated a strong trend toward worse survival for patients with high CD163 and MARCO macrophage infiltration. Moreover, high CD163 and MARCO expression negatively affected the disease-free survival and overall survival rates of patients with pancreatic cancer. Univariate and multivariate analysis revealed that CD163 and MARCO expression was an independent indicator of pancreatic cancer prognosis. In conclusion, high CD163 and MARCO expression in cancer tissues is a negative prognostic marker for pancreatic cancer after surgery. Furthermore, anti-MARCO may be a novel therapy that is worth studying in depth.

ANXA1 Contained in EVs Regulates Macrophage Polarization in Tumor Microenvironment and Promotes Pancreatic Cancer Progression and Metastasis.

The tumor microenvironment (TME) is a dynamic system where nontumor and cancer cells intercommunicate through soluble factors and extracellular vesicles (EVs). The TME in pancreatic cancer (PC) is critical for its aggressiveness and the annexin A1 (ANXA1) has been identified as one of the oncogenic elements. Previously, we demonstrated that the autocrine/paracrine activities of extracellular ANXA1 depend on its presence in EVs. Here, we show that the complex ANXA1/EVs modulates the macrophage polarization further contributing to cancer progression. The EVs isolated from wild type (WT) and ANXA1 knock-out MIA PaCa-2 cells have been administrated to THP-1 macrophages finding that ANXA1 is crucial for the acquisition of a protumor M2 phenotype. The M2 macrophages activate endothelial cells and fibroblasts to induce angiogenesis and matrix degradation, respectively. We have also found a significantly increased presence of M2 macrophage in mice tumor and liver metastasis sections previously obtained by orthotopic xenografts with WT cells. Taken together, our data interestingly suggest the relevance of ANXA1 as potential diagnostic/prognostic and/or therapeutic PC marker.

Serum Carboxypeptidase Activity and Genotype-Stratified CA19-9 to Detect Early-Stage Pancreatic Cancer

Serum diagnostic markers of early-stage pancreatic ductal adenocarcinoma (PDAC) are needed, especially for stage I disease. As tumors grow and cause pancreatic atrophy, markers derived from pancreatic parenchyma such as serum carboxypeptidase A (CPA) activity lose diagnostic performance. We evaluated, with CA19-9, serum CPA as a marker of early pancreatic cancer. Serum CPA activity levels were measured in 345 controls undergoing pancreatic surveillance, divided into 2 sets, set 1 being used to establish a reference range. Variants within the CPA1 locus were sought for their association with pancreatic CPA1 expression to determine if such variants associated with serum CPA levels. A total of 190 patients with resectable PDAC were evaluated. Among controls, those having 1 or more minor alleles of CPA1 variants rs6955723 or rs2284682 had significantly higher serum CPA levels than did those without (P= .001). None of the PDAC cases with pancreatic atrophy had an elevated CPA. Among 122 PDAC cases without atrophy, defining serum CPA diagnostic cutoffs by a subject's CPA1 variants yielded a diagnostic sensitivity of 18% at 99% specificity (95% confidence interval [CI], 11.7-26) (vs 11.1% sensitivity using a uniform diagnostic cutoff); combining CPA with variant-stratified CA19-9 yielded a sensitivity of 68.0% (95% CI, 59.0-76.2) vs 63.1% (95% CI, 53.9- 71.7) for CA19-9 alone; and among stage I PDAC cases, diagnostic sensitivity was 51.9% (95% CI, 31.9-71.3) vs 37.0% (95% CI, 19.4-57.6) for CA19-9 alone. In the validation control set, the variant-stratified diagnostic cutoff yielded a specificity of 98.2%. Serum CPA activity has diagnostic utility before the emergence of pancreatic atrophy as a marker of localized PDAC, including stage I disease.

Peptide Signatures for Prognostic Markers of Pancreatic Cancer by MALDI Mass Spectrometry Imaging.

Simple SummaryPancreatic cancer remains one of the most lethal tumor entities worldwide given its overall 5-year survival after diagnosis of 9%. Thus, further understanding of molecular changes to improve individual prognostic assessment as well as diagnostic and therapeutic advancement is crucial. The aim of this study was to investigate the feasibility of Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify specific peptide signatures linked to established prognostic parameters of pancreatic cancer. In a patient cohort of 18 patients with exocrine pancreatic cancer after tumor resection, MALDI imaging analysis additional to histopathological assessment was performed. Applying this method to tissue sections of the tumors, we were able to identify discriminative peptide signatures corresponding to nine proteins for the prognostic histopathological features lymphatic vessel invasion, lymph node metastasis and angioinvasion. This demonstrates the technical feasibility of MALDI-MSI to identify peptide signatures with prognostic value through the workflows used in this study.Despite the overall poor prognosis of pancreatic cancer there is heterogeneity in clinical courses of tumors not assessed by conventional risk stratification. This yields the need of additional markers for proper assessment of prognosis and multimodal clinical management. We provide a proof of concept study evaluating the feasibility of Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify specific peptide signatures linked to prognostic parameters of pancreatic cancer. On 18 patients with exocrine pancreatic cancer after tumor resection, MALDI imaging analysis was performed additional to histopathological assessment. Principal component analysis (PCA) was used to explore discrimination of peptide signatures of prognostic histopathological features and receiver operator characteristic (ROC) to identify which specific m/z values are the most discriminative between the prognostic subgroups of patients. Out of 557 aligned m/z values discriminate peptide signatures for the prognostic histopathological features lymphatic vessel invasion (pL, 16 m/z values, eight proteins), nodal metastasis (pN, two m/z values, one protein) and angioinvasion (pV, 4 m/z values, two proteins) were identified. These results yield proof of concept that MALDI-MSI of pancreatic cancer tissue is feasible to identify peptide signatures of prognostic relevance and can augment risk assessment.

A Serum Marker for Early Pancreatic Cancer With a Possible Link to Diabetes.

Pancreatic cancer (PC) has a grim prognosis, and an early diagnostic biomarker has been highly desired. The molecular link between diabetes and PC has not been well established. Bioinformatics screening was performed for a serum PC marker. Experiments in cell lines (5 PC and 1 normal cell lines), mouse models, and human tissue staining (37 PC and 10 normal cases) were performed to test asprosin production from PC. Asprosin's diagnostic performance was tested with serums from multi-center cohorts (347 PC, 209 normal, and 55 additional diabetic patients) and evaluated according to PC status, stages, and diabetic status, which was compared with that of CA19-9. Asprosin, a diabetes-related hormone, was found from the bioinformatics screening, and its production from PC was confirmed. Serum asprosin levels from multi-center cohorts yielded an age-adjusted diagnostic area under the curve (AUC) of 0.987 (95% confidence interval [CI] = 0.961 to 0.997), superior to that of CA19-9 (AUC = 0.876, 95% CI = 0.847 to 0.905), and a cut-off of 7.18 ng/mL, at which the validation set exhibited a sensitivity of 0.957 and a specificity of 0.924. Importantly, the performance was maintained in early-stage and non-metastatic PC, consistent with the tissue staining. A slightly lower performance against additional diabetic patients (n = 55) was restored by combining asprosin and CA19-9 (AUC = 0.985, 95% CI = 0.975 to 0.995). Asprosin is presented as an early-stage PC serum marker that may provide clues for PC-induced diabetes. Larger prospective clinical studies are warranted to solidify its utility.

S1691 Smoke but No Fire: A Case of Massive CA 19-9 Elevation From NSAID Use

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed medication for pain and inflammation, but are a leading cause of drug-induced liver injury (DILI). What is not well documented is ibuprofen-induced elevated carbohydrate antigen (CA) 19-9, which raises concern for pancreatic cancer. This case demonstrates liver injury and markedly elevated CA 19-9 in the 1000s, which resolved with cessation of ibuprofen use in the setting of negative endoscopic ultrasound (EUS) with fine needle aspiration (FNA). Case Description/Methods: 45 year old male with no history of liver or biliary disease presented with painless jaundice. Status post hemorrhoidectomy with daily ibuprofen use (400mg, 8 tablets) for pain. New-onset upper extremity pruritus with 13 lbs. unintentional weight loss. Upon evaluation, patient had AST 217 U/L, ALT 157 U/L, alkaline phosphatase (ALP) 964 U/L, and bilirubin 13.6 mg/dL without leukocytosis, platelet dysfunction, coagulopathy, or systemic symptoms. Right upper quadrant ultrasound did not demonstrate any obstruction. Screening CA 19-9 of 1046 U/mL prompted diagnostic EUS-FNA of pancreas, which was normal. Interval liver function tests and CA 19-9 demonstrated marked downtrend with cessation of ibuprofen use—AST 25 U/L, ALT 21 U/L, ALP 152 U/L, bilirubin 2 mg/dL, and CA 19-9 84 U/mL. Discussion: NSAIDs-induced DILI has an estimated incidence of 1-23 cases per 100,000 patient-years. Ibuprofen makes up ∼10% of DILI cases in developed countries. Time to onset is 12 days. Serum CA 19-9 is the only validated tumor marker for pancreatic cancer, which has an annual incidence of 3.9 per 100,000. Higher CA 19-9 serum levels with cut off of 90 U/mL have a sensitivity of 86% and specificity of 39% for malignancy. Our patient had a CA 19-9 >1000 U/mL with weight loss, which required evaluation with EUS-FNA to rule out malignancy. Elevated CA 19-9 secondary to ibuprofen has only been noted on a single center retrospective study as a statistically significant incidence of 7.1% of 581 patients, p = 0.034 when compared to controls. However, the underlying mechanism has not been defined on literature review. Thus, this case is a rare presentation of elevated CA 19-9 secondary to ibuprofen instead of something more sinister as a pancreatic malignancy. Thorough evaluation is necessary to provide reassurance that this is a transient process that will resolve with cessation of the offending agent.Figure 1.: On non enhanced images pancreas appear enlarged and hypodense with irregular margins.

Evaluation of biomarkers, genetic mutations, and epigenetic modifications in early diagnosis of pancreatic cancer.

BACKGROUNDPancreatic cancer (PC) is one of the deadliest malignancies with an alarming mortality rate. Despite significant advancement in diagnostics and therapeutics, early diagnosis remains elusive causing poor prognosis, marred by mutations and epigenetic modifications in key genes which contribute to disease progression. AIMTo evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley. METHODSA total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9 (CA 19-9), tissue polypeptide specific antigen (TPS), carcinoembryonic antigen (CEA), vascular endothelial growth factor-A (VEGF-A), and epidermal growth factor receptor (EGFR). Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma (KRAS), Breast cancer type 2 (BRCA-2), and deleted in pancreatic cancer-4 (DPC-4) genes. However, epigenetic modifications (methylation of CpG islands) were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A (p16; CDKN2A), MutL homolog 1 (hMLH1), and Ras association domain-containing protein 1(RASSF1A) genes.RESULTSWe found significantly elevated levels of biological markers CA 19-9 (P ≤ 0.05), TPS (P ≤ 0.05), CEA (P ≤ 0.001), and VEGF (P ≤ 0.001). Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12 (16 subjects, P ≤ 0.05), and 13 (12 subjects, P ≤ 0.05). However, we did not find a mutation in DPC-4 (1203G > T) and BRCA-2 (617delT) genes. Furthermore, epigenetic modification revealed that CpG methylation in 21 (P ≤ 0.05) and 4 subjects in the promoter regions of the p16 and hMLH1 gene, respectively.CONCLUSIONIn conclusion, CA 19-9, TPS, CEA, and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC. Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC. Additionally, methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.

Plasma-Derived Exosome MiR-19b Acts as a Diagnostic Marker for Pancreatic Cancer.

BackgroundDiagnosis of pancreatic cancer (Pca) is challenging. This study investigated the value of plasma-derived exosome miR-19b (Exo-miR-19b) in diagnosing patients with Pca.MethodsPlasma was collected from 62 patients with Pca, 30 patients with other pancreatic tumor (OPT), 23 patients with chronic pancreatitis (CP), and 53 healthy volunteers. MiR-19b levels in plasma-derived exosomes were detected.ResultsPlasma-derived Exo-miR-19b levels normalized using miR-1228 were significantly lower in Pca patients than in patients with OPT, CP patients, and healthy volunteers. The diagnostic values of Exo-miR-19b normalized using miR-1228 were superior to those of serum cancer antigen 19-9 (CA19-9) in differentiating Pca patients from healthy volunteers (area under the curve (AUC): 0.942 vs. 0.813, p = 0.0054), potentially better than those of CA19-9 in differentiating Pca patients from CP patients (AUC: 0.898 vs. 0.792, p = 0.0720), and equivalent to those of CA19-9 in differentiating Pca patients from patients with OPT (AUC: 0.810 vs. 0.793, p = 0.8206). When normalized using Caenorhabditis elegans miR-39 (cel-miR-39), Exo-miR-19b levels in Pca patients were significantly higher than those in patients with OPT, CP patients, and healthy volunteers. The diagnostic values of Exo-miR-19b normalized using cel-miR-39 were equivalent to those of CA19-9 in differentiating Pca patients from healthy volunteers (AUC: 0.781 vs. 0.813, p = 0.6118) and CP patients (AUC: 0.672 vs. 0.792, p = 0.1235), while they were inferior to those of CA19-9 in differentiating Pca patients from patients with OPT (AUC: 0.631 vs. 0.793, p = 0.0353).ConclusionPlasma-derived Exo-miR-19b is a promising diagnostic marker for Pca. The diagnostic value of plasma-derived Exo-miR-19b normalized using miR-1228 is superior to that of serum CA19-9 in differentiating patients with Pca from healthy volunteers.

Некролитическая мигрирующая эритема как диагностический маркер рака поджелудочной железы

К паранеопластическим синдромам относят заболевания, возникающие вследствие развития злокачественного новообразования и проявляющиеся симптомами, отдаленными от локализации самой опухоли и ее метастазов. Паранеопластические дерматозы – это многочисленная группа различных кожных проявлений, указывающих на возможность наличия опухоли, в том числе на ранней бессимптомной стадии развития. Одним из таких дерматозов является некролитическая мигрирующая эритема – патология кожи, имеющая ассоциацию с глюкагономой – альфа-клеточной опухолью поджелудочной железы, продуцирующей глюкагон. Представленное в статье описание клинического случая поможет улучшить понимание общности патогенетических аспектов между новообразованием и дерматозом, повысить онкологическую настороженность смежных специалистов и организовать эффективное междисциплинарное взаимодействие, улучшив качество жизни больных с опухоль-ассоциированными дерматозами. Paraneoplastic syndromes include diseases that arise as a result of the development of a malignant neoplasm, manifested by symptoms that are remote from the localization of the tumor itself and its metastases. Paraneoplastic dermatoses are a large group of various skin manifestations that indicate the possibility of the presence of a tumor, including at an early asymptomatic stage of development. One of these dermatoses is necrolytic migrating erythema, a skin pathology associated with glucagonoma, an alpha – cell tumor of the pancreas that produces glucagon. The description of the clinical case presented in the article will help to improve the understanding of the common pathogenetic aspects between neoplasm and dermatosis, increase the oncological alertness of related specialists and organize effective interdisciplinary interaction, as a result, improving the quality of life of patients with tumor-associated dermatoses.

Graphene-Assisted Electrochemical Sensor for Detection of Pancreatic Cancer Markers.

Pancreatic cancer is a highly lethal gastrointestinal malignancy. Most patients are already in the middle to advanced stages of pancreatic cancer at the time of diagnosis and cannot be treated completely. As a single-atom planar two-dimensional crystal, graphene’s unusual electronic structure, specific electronic properties and excellent electron transport capacity make it uniquely advantageous in the field of electrochemical sensing. In this mini-review, we summarize the potential application of graphene in pancreatic cancer detection. K-Ras gene, CEA and MicroRNA are important in the early diagnosis of pancreatic cancer.