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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 -
Annals of Surgery Oct 2023We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts.
A Combined DNA/RNA-based Next-Generation Sequencing Platform to Improve the Classification of Pancreatic Cysts and Early Detection of Pancreatic Cancer Arising From Pancreatic Cysts.
OBJECTIVE
We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts.
BACKGROUND AND AIMS
Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results.
METHODS
An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data.
RESULTS
Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity.
CONCLUSIONS
PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.
Topics: Humans; RNA; Early Detection of Cancer; Pancreatic Cyst; Pancreatic Neoplasms; DNA; High-Throughput Nucleotide Sequencing
PubMed: 37212422
DOI: 10.1097/SLA.0000000000005904 -
Journal of Translational Medicine Dec 2023Pancreatic cancer is an aggressive malignancy with high mortality, and cancer cell stemness and related drug resistance are considered important contributors to its poor...
OBJECTIVE
Pancreatic cancer is an aggressive malignancy with high mortality, and cancer cell stemness and related drug resistance are considered important contributors to its poor prognosis. The objective of this study was to identify regulatory targets associated with the maintenance of pancreatic cancer stemness.
MATERIALS AND METHODS
Pancreatic tumor samples were collected from patients at Sun Yat-sen University Cancer Center, followed by immunofluorescence analysis. Pancreatic cancer cell lines with Interleukin-20 receptor subunit beta (IL20RB) overexpression and knockdown were established, and clonal formation, spheroid formation and side population cell analysis were conducted. The effects of IL20RB knockdown on the tumor-forming ability of pancreatic cancer cells and chemotherapy resistance in vivo were explored.
RESULTS
IL20RB expression was significantly upregulated in pancreatic cancer tissues, and was correlated with unfavorable prognosis. The IL20RB receptor promotes stemness and chemoresistance in both in vitro and in vivo models of pancreatic cancer. Mechanistically, IL20RB enhances the stemness and chemoresistance of pancreatic cancer by promoting STAT3 phosphorylation, an effect that can be counteracted by a STAT3 phosphorylation inhibitors. Additionally, Interleukin-19 derived from the microenvironment is identified as the primary ligand for IL20RB in mediating these effects.
CONCLUSION
Our findings demonstrate that IL20RB plays a crucial role in promoting stemness in pancreatic cancer. This discovery provides a potential therapeutic target for this lethal disease.
Topics: Humans; Cell Line, Tumor; Drug Resistance, Neoplasm; Signal Transduction; Pancreatic Neoplasms; Prognosis; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 38098005
DOI: 10.1186/s12967-023-04800-5 -
The Oncologist Jul 2023Pancreatic cancer is one of the few cancer types in the US with incidence and death rates continuing to rise. As the disease threatens to become the second leading cause... (Review)
Review
Pancreatic cancer is one of the few cancer types in the US with incidence and death rates continuing to rise. As the disease threatens to become the second leading cause of cancer-related deaths in the country, it is imperative to review the best practices currently available to extend and improve patient lives. To provide a roadmap for healthcare professionals detecting, diagnosing, and caring for patients with pancreatic cancer as a supplement to national guidelines focused on recommended treatment regimens, the Pancreatic Cancer Action Network (PanCAN)'s Scientific and Medical Affairs staff and expert Scientific and Medical Advisory Board have created a series of position statements. The statements are based upon scientific evidence and clinical observations published in the literature and research conducted through PanCAN's internal programs and initiatives. This review summarizes the rationale and sources for these position statements related to diagnosis, treatment, and care for pancreatic cancer and provides information about resources to make these recommendations accessible to patients and their medical teams. Pancreatic cancer is a complex and extremely challenging disease. Beyond treatment recommendations outlined in national guidelines, steps can be taken to help patients feel better and live longer. Under the framework of the "Right Track" model-right team, right tests, right treatments, data sharing-PanCAN's position statements can provide supplementary guidance to healthcare professionals for the short- and long-term management of patients with the disease.
Topics: Humans; Pancreatic Neoplasms
PubMed: 37043728
DOI: 10.1093/oncolo/oyad080 -
Virchows Archiv : An International... Feb 2024Neoplasias of the hepatopancreatobiliary tract are growing in numbers, have the poorest prognosis of all major cancer entities, and thus represent a rising clinical... (Review)
Review
Neoplasias of the hepatopancreatobiliary tract are growing in numbers, have the poorest prognosis of all major cancer entities, and thus represent a rising clinical problem. Their molecular diagnostic has dramatically improved, contributing to tumor subtyping, definition of malignancy, and uncovering cases with hereditary predisposition. Most of all, predictive molecular testing allows to identify cases amenable to treatment with the rising number of approved targeted drugs, immune-oncological treatment, and clinical trials. In this review, the current state of molecular testing and its contribution to clinical decision-making are outlined.
Topics: Humans; Pathology, Molecular; Pancreatic Neoplasms; Genetic Predisposition to Disease; Molecular Diagnostic Techniques; Medical Oncology
PubMed: 38429607
DOI: 10.1007/s00428-024-03744-5 -
Pharmacological Research Aug 2023Pancreatic cancer (PC) is a serious gastrointestinal tract disease for which the 5-year survival rate is less than 10%, even in developed countries such as the USA. The...
Pancreatic cancer (PC) is a serious gastrointestinal tract disease for which the 5-year survival rate is less than 10%, even in developed countries such as the USA. The genomic profile alterations and dysregulated biological mechanisms commonly occur in PC. Macroautophagy/autophagy is a cell death process that is maintained at a basal level in physiological conditions, whereas its level often changes during tumorigenesis. The function of autophagy in human cancers is dual and can be oncogenic and onco-suppressor. Autophagy is a potent controller of tumorigenesis in PC. The supportive autophagy in PC escalates the growth rate of PC cells and its suppression can mediate cell death. Autophagy also determines the metastasis of PC cells, and it can control the EMT in affecting migration. Moreover, starvation and hypoxia can stimulate glycolysis, and glycolysis induction can be mediated by autophagy in enhancing tumorigenesis in PC. Furthermore, protective autophagy stimulates drug resistance and gemcitabine resistance in PC cells, and its inhibition can enhance radiosensitivity. Autophagy can degrade MHC-I to mediate immune evasion and also regulates polarization of macrophages in the tumor microenvironment. Modulation of autophagy activity is provided by silibinin, ursolic acid, chrysin and huaier in the treatment of PC. Non-coding RNAs are also controllers of autophagy in PC and its inhibition can improve therapy response in patients. Moreover, mitophagy shows dysregulation in PC, which can enhance the proliferation of PC cells. Therefore, a bioinformatics analysis demonstrates the dysregulation of autophagy-related proteins and genes in PC as biomarkers.
Topics: Humans; Cell Line, Tumor; Pancreatic Neoplasms; Autophagy; Carcinogenesis; Tumor Microenvironment
PubMed: 37336429
DOI: 10.1016/j.phrs.2023.106822 -
BMC Microbiology Jan 2024Studying the effects of the microbiome on the development of different types of cancer has recently received increasing research attention. In this context, the... (Review)
Review
Studying the effects of the microbiome on the development of different types of cancer has recently received increasing research attention. In this context, the microbial content of organs of the gastrointestinal tract has been proposed to play a potential role in the development of pancreatic cancer (PC). Proposed mechanisms for the pathogenesis of PC include persistent inflammation caused by microbiota leading to an impairment of antitumor immune surveillance and altered cellular processes in the tumor microenvironment. The limited available diagnostic markers that can currently be used for screening suggest the importance of microbial composition as a non-invasive biomarker that can be used in clinical settings. Samples including saliva, stool, and blood can be analyzed by 16 s rRNA sequencing to determine the relative abundance of specific bacteria. Studies have shown the potentially beneficial effects of prebiotics, probiotics, antibiotics, fecal microbial transplantation, and bacteriophage therapy in altering microbial diversity, and subsequently improving treatment outcomes. In this review, we summarize the potential impact of the microbiome in the pathogenesis of PC, and the role these microorganisms might play as biomarkers in the diagnosis and determining the prognosis of patients. We also discuss novel treatment methods being used to minimize or prevent the progression of dysbiosis by modulating the microbial composition. Emerging evidence is supportive of applying these findings to improve current therapeutic strategies employed in the treatment of PC.
Topics: Humans; Pancreatic Neoplasms; Biomarkers; Microbiota; Anti-Bacterial Agents; Dysbiosis; Tumor Microenvironment
PubMed: 38183010
DOI: 10.1186/s12866-023-03166-4 -
Journal of Gastrointestinal and Liver... Dec 2023Endoscopic ultrasound (EUS) guided biliary drainage (BD) is an accepted salvage procedure in patients with distal malignant biliary obstruction (DMBO) when endoscopic... (Review)
Review
Endoscopic ultrasound (EUS) guided biliary drainage (BD) is an accepted salvage procedure in patients with distal malignant biliary obstruction (DMBO) when endoscopic retrograde cholangiopancreatography (ERCP) is unsuccessful. The potential advantages of EUS-BD include gastric or duodenal biliary access, utilization of novel biliary stents and stent placement away from the area of stenosis, resulting in longer stent patency. These features make EUS-BD very appealing as a primary procedure for biliary drainage. There is a growing body of evidence supporting the utilization of EUS as a primary drainage procedure instead of ERCP, with comparable outcomes.
Topics: Humans; Endosonography; Pancreatic Neoplasms; Duodenum; Cholangiopancreatography, Endoscopic Retrograde; Stents; Drainage; Cholestasis; Ultrasonography, Interventional
PubMed: 38147611
DOI: 10.15403/jgld-4922 -
Scientific Reports Oct 2023Pancreatic ductal adenocarcinoma (PDAC) is associated with a very poor prognosis. Therefore, there has been a focus on identifying new biomarkers for its early diagnosis...
Pancreatic ductal adenocarcinoma (PDAC) is associated with a very poor prognosis. Therefore, there has been a focus on identifying new biomarkers for its early diagnosis and the prediction of patient survival. Genome-wide RNA and microRNA sequencing, bioinformatics and Machine Learning approaches to identify differentially expressed genes (DEGs), followed by validation in an additional cohort of PDAC patients has been undertaken. To identify DEGs, genome RNA sequencing and clinical data from pancreatic cancer patients were extracted from The Cancer Genome Atlas Database (TCGA). We used Kaplan-Meier analysis of survival curves was used to assess prognostic biomarkers. Ensemble learning, Random Forest (RF), Max Voting, Adaboost, Gradient boosting machines (GBM), and Extreme Gradient Boosting (XGB) techniques were used, and Gradient boosting machines (GBM) were selected with 100% accuracy for analysis. Moreover, protein-protein interaction (PPI), molecular pathways, concomitant expression of DEGs, and correlations between DEGs and clinical data were analyzed. We have evaluated candidate genes, miRNAs, and a combination of these obtained from machine learning algorithms and survival analysis. The results of Machine learning identified 23 genes with negative regulation, five genes with positive regulation, seven microRNAs with negative regulation, and 20 microRNAs with positive regulation in PDAC. Key genes BMF, FRMD4A, ADAP2, PPP1R17, and CACNG3 had the highest coefficient in the advanced stages of the disease. In addition, the survival analysis showed decreased expression of hsa.miR.642a, hsa.mir.363, CD22, BTNL9, and CTSW and overexpression of hsa.miR.153.1, hsa.miR.539, hsa.miR.412 reduced survival rate. CTSW was identified as a novel genetic marker and this was validated using RT-PCR. Machine learning algorithms may be used to Identify key dysregulated genes/miRNAs involved in the disease pathogenesis can be used to detect patients in earlier stages. Our data also demonstrated the prognostic and diagnostic value of CTSW in PDAC.
Topics: Humans; Cathepsin W; Down-Regulation; MicroRNAs; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Prognosis; Biomarkers; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor
PubMed: 37794108
DOI: 10.1038/s41598-023-42928-y -
World Journal of Surgical Oncology Aug 2023Invasive pancreatic cystic neoplasms (iPCNs) are an uncommon and biologically heterogeneous group of malignant neoplasms. We aimed to investigate the clinicopathological...
PURPOSES
Invasive pancreatic cystic neoplasms (iPCNs) are an uncommon and biologically heterogeneous group of malignant neoplasms. We aimed to investigate the clinicopathological characteristics of iPCN patients and to develop nomograms for individual survival prediction after radical surgery.
METHODS
Data of patients diagnosed with iPCN and pancreatic ductal adenocarcinoma (PDAC) between 2000 and 2018 from the SEER database were retrieved. The differences in clinical outcomes were evaluated using the Kaplan-Meier analysis. Nomograms were proposed based on the Cox regression model and internally validated by C-index, area under the curve (AUC) value, and calibration plot.
RESULTS
A total of 7777 iPCN patients and 154,336 PDAC patients were enrolled. Most neoplasms were advanced, with 63.1% at stage IV. The 3-year overall survival (OS) and cancer-specific survival (CSS) rates in surgical patients were as follows: 45.7% and 50.1% for invasive intraductal papillary mucinous neoplasm (IPMN), 54.8% and 59.3% for invasive mucinous cystic neoplasm (MCN), 97.8% and 98.2% for invasive solid pseudopapillary neoplasm (SPN), 88.9% and 88.9% for invasive serous cystic neoplasm (SCN), and 27.3% and 30.5% for PDAC. Subgroup analyses showed no clinical benefit from chemotherapy or radiotherapy in lymph node-negative iPCN patients who underwent surgery. The following variables associated with OS and CSS were identified: age, race, chemotherapy, radiotherapy, histologic type, pathological grade, regional nodes examined, and T, N, and M stage. The nomograms had good discrimination and calibration by internal validation, with an AUC value of 0.800 for 3-year OS and 0.814 for 3-year CSS.
CONCLUSION
Our study showed that the prognosis of iPCN patients was significantly better than PDAC patients. The proposed nomograms demonstrated substantially better discrimination and calibration.
Topics: Humans; Retrospective Studies; Pancreas; Pancreatic Neoplasms; Neoplasms, Cystic, Mucinous, and Serous; Carcinoma, Pancreatic Ductal
PubMed: 37612715
DOI: 10.1186/s12957-023-03145-z