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Clinical Cancer Research : An Official... Oct 2023CA19-9 synthesis is influenced by common variants in the fucosyltransferase (FUT) enzymes FUT3 and FUT2. We developed a clinical test to detect FUT variants, and...
PURPOSE
CA19-9 synthesis is influenced by common variants in the fucosyltransferase (FUT) enzymes FUT3 and FUT2. We developed a clinical test to detect FUT variants, and evaluated its diagnostic performance for pancreatic ductal adenocarcinoma (PDAC).
EXPERIMENTAL DESIGN
A representative set of controls from the Cancer of the Pancreas Screening study was identified for each FUT functional group. Diagnostic sensitivity was determined first in a testing set of 234 PDAC cases, followed by a 134-case validation set, all of whom had undergone resection with curative intent without neoadjuvant therapy. Tumor marker gene testing was performed in the Johns Hopkins Molecular Diagnostics Laboratory. CA19-9 levels were measured in the Hopkins Clinical Chemistry lab. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative ability of CA19-9 alone versus with the gene test.
RESULTS
Applying the CA19-9 standard cutoff (<36 U/mL) to all 716 subjects yielded a 68.8% sensitivity in the test set of cases, 67.2% in the validation set, at 91.4% specificity. Applying 99th percentile cutoffs according to each individual's FUT group (3, 34.9, 41.8, and 89.2, for the FUT3-null, FUT-low, FUT-intermediate, and FUT-high groups, respectively) yielded a diagnostic sensitivity for CA19-9 in the first set of cases of 66.7%, 65.7% in the validation set, at 98.9% specificity. ROC analysis for CA19-9 alone yielded an AUC of 0.84; with the tumor marker gene test, AUC improved to 0.92 (P < 0.001).
CONCLUSIONS
Using a tumor marker gene test to personalize an individual's CA19-9 reference range significantly improves diagnostic accuracy.
Topics: Humans; CA-19-9 Antigen; Reference Values; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Biomarkers, Tumor; ROC Curve
PubMed: 37566230
DOI: 10.1158/1078-0432.CCR-23-0655 -
Annals of African Medicine 2023Resection of pancreatic tissue is necessary for many pancreatic diseases. The most common form of cancer, pancreatic duct adenocarcinoma, manifests with early metastases...
INTRODUCTION
Resection of pancreatic tissue is necessary for many pancreatic diseases. The most common form of cancer, pancreatic duct adenocarcinoma, manifests with early metastases and is thought to be resistant to other currently known treatment regimens. Such tumors present a complex and difficult management and handling challenge for a surgeon. Surgical resection affords a better prognosis with a median survival of 14-20 months following resection and up to 25% 5-year survival rates. In this study, data from 75 pancreatic resections for diverse malignant pancreatic lesions will be presented.
METHODS
At a teaching institute in Central India, this ongoing longitudinal study began in 2009 and was carried on till 2018. Only 75 of the 122 patients who underwent pancreatic resection were deemed appropriate for the current study. All patients were thoroughly examined after being admitted before being given the option of surgery. There were 22 female patients and 53 male patients. The age range for the group was 34-67 years. Results from a range of different malignancies and various pancreatic resection procedures are presented in this study.
RESULTS
One of the most aggressive cancers, pancreatic adenocarcinoma, responds to surgical treatment better than other alternative techniques. Out of 75 patients in our series, 32 had pancreatic head cancer, 28 had periampullary cancer, 2 had duodenal cancer, 8 had distal cholangiocarcinoma, and 1 had mucin-producing cystadenocarcinoma. Four patients had pancreatic cancer in both the body and tail. Fifty-three men and 22 women, ages 34-67 years, Whipple's operation and distal pancreatectomy were the most frequent procedures. In our series, survival ranged from 18 to 24 months, and the 5-year survival rate was 12%, which is primarily seen with periampullary carcinoma.
CONCLUSION
The sole option for long-term survival or a cure for pancreatic cancer is surgery. Chemoradiation is ineffective as a first line of treatment. However, some reports contend that palliative chemotherapy actually improves the quality of life. The biology of the illness rules and determines the result; the kind of surgery performed had no bearing on survival, morbidity, or fatality.
CONTEXT
The above study was taken up in the context of - pancreatic tumors and pathological types, how imaging helps in deciding the plan of surgical management without biopsy. Outcomes of pancreatic resections for pancreatic cancer.
SETTINGS AND DESIGN
In a suburban hospital which is a tertiary care center, this longitudinal prospective study was conducted from 2009 to 2018.
Topics: Humans; Male; Female; Adult; Middle Aged; Aged; Pancreatectomy; Pancreatic Neoplasms; Adenocarcinoma; Longitudinal Studies; Prospective Studies; Quality of Life; Hospitals
PubMed: 38358158
DOI: 10.4103/aam.aam_165_22 -
World Journal of Gastroenterology Feb 2024Pancreatitis and pancreatic cancer (PC) stand as the most worrisome ailments affecting the pancreas. Researchers have dedicated efforts to unraveling the mechanisms... (Review)
Review
Pancreatitis and pancreatic cancer (PC) stand as the most worrisome ailments affecting the pancreas. Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases, yet their true nature continues to elude their grasp. Within this realm, oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC. Excessive accumulation of reactive oxygen species (ROS) can cause oxidative stress, and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides (NOX). NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells, activate pancreatic stellate cells, and mediate macrophage polarization. Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis, creating an oxidative microenvironment that can cause abnormal apoptosis, epithelial to mesenchymal transition and genomic instability. Therefore, understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases. In this review, we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders, aiming to provide novel insights into understanding the mechanisms underlying these diseases.
Topics: Humans; Reactive Oxygen Species; NADP; Epithelial-Mesenchymal Transition; NADPH Oxidases; Oxidative Stress; Pancreatitis
PubMed: 38414585
DOI: 10.3748/wjg.v30.i5.429 -
World Journal of Gastroenterology Jul 2023Post-acute pancreatitis diabetes (PAPD) is the second most common type of diabetes below type 2 diabetes mellitus. Due to the boom in research on this entity carried out... (Review)
Review
Post-acute pancreatitis diabetes (PAPD) is the second most common type of diabetes below type 2 diabetes mellitus. Due to the boom in research on this entity carried out during the last decade, its recognition has increased. However, much of the medical community still does not recognize it as a medium and long-term complication of acute pancreatitis (AP). Recent prospective cohort studies show that its incidence is about 23% globally and 34.5% in patients with severe AP. With the overall increase in the incidence of AP this complication will be certainly seen more frequently. Due to its high morbidity, mortality and difficult control, early detection and treatment are essential. However, its risk factors and pathophysiological mechanisms are not clearly defined. Its diagnosis should be made excluding pre-existing diabetes and applying the criteria of the American Diabetes Association after 90 d of resolution of one or more AP episodes. This review will show the evidence published so far on the incidence and prevalence, risk factors, possible pathophysiological mechanisms, clinical outcomes, clinical characteristics and preventive and corrective management of PAPD. Some important gaps needing to be clarified in forthcoming studies will also be discussed.
Topics: Humans; Pancreatitis; Diabetes Mellitus, Type 2; Acute Disease; Risk Factors
PubMed: 37576704
DOI: 10.3748/wjg.v29.i28.4405 -
Biological Research Aug 2023The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern...
BACKGROUND
The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations.
RESULTS
The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10), with a P-value close to a threshold that takes into account multiple testing.
CONCLUSIONS
Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.
Topics: Humans; Animals; Neanderthals; Diabetes Mellitus, Type 2; Polymorphism, Single Nucleotide; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms
PubMed: 37574541
DOI: 10.1186/s40659-023-00457-y -
Cell Death & Disease Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer most frequently detected at an advanced stage that limits treatment options to systemic...
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer most frequently detected at an advanced stage that limits treatment options to systemic chemotherapy, which has provided only marginal positive clinical outcomes. Currently, the first-line chemotherapeutic agent for PDAC is gemcitabine (GEM). However, the chemotherapy resistance to GEM is often overlooked in the clinical treatment of PDAC due to the lack of effective biological markers. Therefore, it is crucial to find new prognostic markers and therapeutic targets for patients with PDAC. In this study, we identified a novel regulatory mechanism in the development of resistance to GEM in PDAC. Here, we report that LINC01134 was significantly upregulated in primary tumors from PDAC patients. In vitro and in vivo functional studies revealed that LINC01134 promotes PDAC resistance to GEM through facilitating stem cell features and modulating the cell cycle. Mechanistically, LINC01134 interactes with tumor suppressor miR-497-5p in PDAC cells. Increased LINC01134 downregulates miR-140-3p to promotes the oncogenic WNT5A expression. Moreover, mA demethylase FTO participated in the upregulation of LINC01134 by maintaining LINC01134 mRNA stability through YTHDF2. Taken together, the present study suggested FTO-mediated LINC01134 stabilization to promote chemotherapy resistance to GEM through miR-140-3p/WNT5A/WNT pathway in PDAC. Our study identified new prognostic markers and new therapeutic targets for patients with PDAC.
Topics: Humans; Drug Resistance, Neoplasm; Deoxycytidine; Wnt Signaling Pathway; Carcinoma, Pancreatic Ductal; Gemcitabine; Pancreatic Neoplasms; MicroRNAs; Cell Line, Tumor; Wnt-5a Protein; Alpha-Ketoglutarate-Dependent Dioxygenase FTO
PubMed: 37914721
DOI: 10.1038/s41419-023-06244-7 -
Journal of Translational Medicine Apr 2024Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic...
Comprehensive analysis of bulk and single-cell transcriptomic data reveals a novel signature associated with endoplasmic reticulum stress, lipid metabolism, and liver metastasis in pancreatic cancer.
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy.
METHODS
Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored.
RESULTS
A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8 T cells and M1 macrophages were decreased. The number and intensity of intercellular communication were increased in the high ER stress group.
CONCLUSIONS
We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell-cell communication in the tumor microenvironment.
Topics: Humans; Endoplasmic Reticulum Stress; Pancreatic Neoplasms; Lipid Metabolism; Liver Neoplasms; Transcriptome; Single-Cell Analysis; Prognosis; Gene Expression Regulation, Neoplastic; Male; Female; Middle Aged; Gene Expression Profiling; Reproducibility of Results; Cohort Studies
PubMed: 38685045
DOI: 10.1186/s12967-024-05158-y -
Cells Dec 2023Pancreatic ductal adenocarcinoma is one of the most lethal malignant diseases, with a mortality rate being close to incidence. Due to its heterogeneity and plasticity,... (Review)
Review
Pancreatic ductal adenocarcinoma is one of the most lethal malignant diseases, with a mortality rate being close to incidence. Due to its heterogeneity and plasticity, as well as the lack of distinct symptoms in the early phases, it is very often diagnosed at an advanced stage, resulting in poor prognosis. Traditional tissue biopsies remain the gold standard for making a diagnosis, but have an obvious disadvantage in their inapplicability for frequent sampling. Blood-based biopsies represent a non-invasive method which potentially offers easy and repeated sampling, leading to the early detection and real-time monitoring of the disease and hopefully an accurate prognosis. Given the urgent need for a reliable biomarker that can estimate a patient's condition and response to an assigned treatment, blood-based biopsies are emerging as a potential new tool for improving patients' survival and surveillance. In this article, we discuss the current advances and challenges in using liquid biopsies for pancreatic cancer, focusing on circulating tumour DNA (ctDNA), extracellular vesicles (EVs), and circulating tumour cells (CTCs), and compare the performance and reliability of different biomarkers and combinations of biomarkers.
Topics: Humans; Prognosis; Reproducibility of Results; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Biomarkers; Liquid Biopsy
PubMed: 38201207
DOI: 10.3390/cells13010003 -
Pancreatology : Official Journal of the... Dec 2023Probing relevant proteomic biomarkers may facilitate effective pancreatic adenocarcinoma (PDAC) diagnosis, treatment and prevention. Here, we developed a protein-based...
BACKGROUND
Probing relevant proteomic biomarkers may facilitate effective pancreatic adenocarcinoma (PDAC) diagnosis, treatment and prevention. Here, we developed a protein-based prognostic model for PDAC by using relevant proteomic biomarkers data from The Cancer Genome Atlas (TCGA).
METHODS
We obtained PDAC's proteomic and clinical data from TCGA and used various analytical tools to identify differentially expressed proteins between normal and cancer tissues. We constructed our protein-based prognostic model and confirmed its accuracy using receiver operating characteristic curve and Kaplan-Meier survival analyses. We elucidated clinical factor-signature protein correlations by clinical correlation assessments and protein coexpression networks. We also used immunohistochemistry (protein expression assessment), Gene Set Enrichment Analysis (protein role identification) and CIBERSORT (infiltrating immune cell distribution assessment).
RESULTS
CIITA, BRAF_pS445, AR, YTHDF2, IGFBP2 and CDK1_pT14 were identified as PDAC-associated prognostic proteins. All risk scores calculated using our model provided 1-, 3-, 5-year survival probability at 70 % accuracy. The reliability of our model was validated by the GEO as well. In high- and low-risk groups, age, sex, T- and N- stage disparities were significant, and prognostic and coexpressed proteins correlated. PDAC tissues demonstrated significant CDK1_pT14 overexpression but significant BRAF_pS445, YTHDF2, and IGFBP2 underexpression. Downstream proteins of BRAF were validated by IHC. Low-risk tissues demonstrated more naïve B cells, eosinophils, activated NK cells and regulatory T cells, whereas high-risk tissues demonstrated more activated memory T cells, monocytes, neutrophils, dendritic cells and resting NK cells.
CONCLUSIONS
Our protein-based prognostic model for PDAC, along with six signature proteins, might aid in predicting PDAC prognosis and therapeutic targets.
Topics: Humans; Pancreatic Neoplasms; Prognosis; Adenocarcinoma; Proteomics; Proto-Oncogene Proteins B-raf; Reproducibility of Results; Carcinoma, Pancreatic Ductal; Biomarkers; Biomarkers, Tumor
PubMed: 37923686
DOI: 10.1016/j.pan.2023.10.021 -
Cancer Research Communications Sep 2023Cleavage of erythropoietin-producing hepatocellular ephrin receptor A2 (EphA2) triggers malignant progression and yields an N-terminal fragment (EphA2-NF) detectable in...
UNLABELLED
Cleavage of erythropoietin-producing hepatocellular ephrin receptor A2 (EphA2) triggers malignant progression and yields an N-terminal fragment (EphA2-NF) detectable in sera from patients with pancreatic ductal carcinoma. We established a quantitative automated chemiluminescence immunoassay for EphA2-NF and evaluated serum EphA2-NF levels as a biomarker to diagnose pancreatic ductal carcinoma in the test and validation cohorts. The EphA2-NF value was elevated (above the cutoff: mean ± SD) in more than half of the patients with stage I/II pancreatic ductal carcinoma. Among patients receiving standard chemotherapy for pancreatic ductal carcinoma [gemcitabine plus nab-paclitaxel (GnP)], the median survival time of patients with elevated serum EphA2-NF was half that of patients with values below the cutoff. Patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous pancreatic ductal carcinoma lesion, also show high serum EphA2 levels, which are associated with an increase in pancreatic duct size and the development of pancreatic ductal carcinoma in some cases. IHC showed loss of EphA2-NF staining in IPMN with pancreatic ductal carcinoma, but not in the normal epithelium or IPMN without pancreatic ductal carcinoma, regardless of the histologic grade. These results suggest that EphA2 cleavage is an essential event that occurs very early in pancreatic ductal carcinoma development, and that the consequent release of EphA2-NF can be detected in the serum. Thus, serum EphA2-NF could be a diagnostic biomarker for very early-stage pancreatic ductal carcinoma and pancreatic ductal carcinoma development from high-risk IPMN and as a prognostic biomarker after chemotherapy with GnP.
SIGNIFICANCE
EphA2 N-terminus deletion is involved in pancreatic ductal carcinoma development from high-risk IPMN and EphA2-NF produced by cleavage can be used as a serum biomarker to diagnose pancreatic ductal carcinoma and predict pancreatic ductal carcinoma development from high-risk IPMN.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Intraductal Neoplasms; Peptide Hydrolases; Proteolysis; Pancreatic Neoplasms
PubMed: 37712876
DOI: 10.1158/2767-9764.CRC-23-0087