Metachronous pancreatic cancer originating from disseminated founder pancreatic intraductal neoplasias.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 330-330
Author(s):  
Yusuke Ono ◽  
Hidenori Karasaki ◽  
Koji Imai ◽  
Junpei Sasajima ◽  
Shin-ichi Chiba ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Pancreatic Head ◽  
Digital Pcr ◽  
Ductal Adenocarcinoma ◽  
Tumor Evolution ◽  
Low Grade ◽  
Kras Mutations ◽  
Current Case ◽  
Remnant Pancreas ◽  
Intraepithelial Lesions

330 Background: Clonal populations originated from benign-looking “founder cells” may spread widely within pancreas instead of being localized in situ before frank pancreatic ductal adenocarcinoma (PDA) can be detected. Metachronous PDA is not common event, and we here sought to define potent origin of multiple PDAs developed in a woman by using advanced genetics technologies. Methods: In addition to precise pathological assessment, genetic approaches such as deep sequencing of multiplex PCR amplicons of cancer-associated genes (Ion Torrent PGM platform) and digital PCR were employed. Results: Curative resection of pancreatic head tumor was performed; however, “recurrent” lesions in the remnant pancreas were found 3.5-years later and total pancreatectomy was subsequently performed. The metachronous lesions were morphologically similar to the primary PDA. All 3 PDAs were shown to possess rare somatic mutations in KRAS (p.T58I and p.Q61H). Curiously, identical KRAS mutations were found in low-grade “intraepithelial” lesions, which localized in normal area of the pancreas and one of them possessed p53mutation, which was also found in the PDAs. Conclusions: Rare KRAS haplotype was identified in the metachronous PDAs in the current case. Surprisingly, the identical somatic mutations were also found in independent low-grade “intraepithelial” lesions with and without additional mutation in p53. The footprint of the tumor evolution marked by mutational profiling supports a human correlate to the mouse models of “dissemination” occurring at the earliest stages of pancreatic neoplasia.

scholarly journals A New Surgical Technique of Pancreaticoduodenectomy with Splenic Artery Resection for Ductal Adenocarcinoma of the Pancreatic Head and/or Body Invading Splenic Artery: Impact of the Balance between Surgical Radicality and QOL to Avoid Total Pancreatectomy

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Ryosuke Desaki ◽  
Shugo Mizuno ◽  
Akihiro Tanemura ◽  
Masashi Kishiwada ◽  
Yasuhiro Murata ◽  
...  
Keyword(s):  
Surgical Technique ◽  
Splenic Artery ◽  
Insulin Dose ◽  
Survival Rates ◽  
Pancreatic Head ◽  
Ductal Adenocarcinoma ◽  
Curative Intent ◽  
Remnant Pancreas ◽  
Artery Resection ◽  
New Surgical Technique

For pancreatic ductal adenocarcinoma (PDAC) of the head and/or body invading the splenic artery (SA), we developed a new surgical technique of proximal subtotal pancreatectomy with splenic artery and vein resection, so-called pancreaticoduodenectomy with splenic artery resection (PD-SAR). We retrospectively reviewed a total of 84 patients with curative intent pancreaticoduodenectomy (PD) for PDAC of the head and/or body. These 84 patients were classified into the two groups: conventional PD (n=66) and PD-SAR (n=18). Most patients were treated by preoperative chemoradiotherapy (CRT). Postoperative MDCT clearly demonstrated enhancement of the remnant pancreas at 1 and 6 months in all patients examined. Overall survival rates were very similar between PD and PD-SAR (3-year OS: 23.7% versus 23.1%,P=0.538), despite the fact that the tumor size and the percentages of UICC-T4 determined before treatment were higher in PD-SAR. Total daily insulin dose was significantly higher in PD-SAR than in PD at 1 month, while showing no significant differences between the two groups thereafter. PD-SAR with preoperative CRT seems to be promising surgical strategy for PDAC of head and/or body with invasion of the splenic artery, in regard to the balance between operative radicality and postoperative QOL.

scholarly journals Utility of “liquid biopsy” using pancreatic juice for early detection of pancreatic cancer

2018 ◽  
Vol 06 (12) ◽  
pp. E1454-E1461 ◽  
Author(s):  
Tetsuhiro Okada ◽  
Hirotoshi Iwano ◽  
Yusuke Ono ◽  
Hidenori Karasaki ◽  
Takayuki Sato ◽  
...  
Keyword(s):  
Pancreatic Duct ◽  
Pancreatic Juice ◽  
Liquid Biopsy ◽  
Early Stage ◽  
Ductal Adenocarcinoma ◽  
Histological Evaluation ◽  
Resected Specimen ◽  
Driver Gene ◽  
Low Grade ◽  
Kras Mutations

Abstract Background Despite advances in the diagnosis of pancreatic ductal adenocarcinoma (PDA), histological evaluation of small and poorly defined masses in the pancreas is uncomfortable and unsafe. Methods We herein report a case of early stage PDA, in which multiple KRAS mutations were detected in the pancreatic juice preoperatively. A small hypoechoic area adjacent to the portal vein was detected through endoscopic ultrasound in the pancreatic body. KRAS mutations were evaluated using plasma, and the pancreatic juice by digital PCR. Results Pancreatic duct biopsy and pancreatic juice cytology were performed with no evidence of malignancy; however, KRAS mutations, KRAS G12V and G12D, were detected in the pancreatic juice. Histological assessment of the resected specimen demonstrated a solid tumor with desmoplastic reaction accompanied by carcinoma in situ in the main pancreatic duct where KRAS G12V mutation was identified. More detailed analysis demonstrated KRAS G12D mutation in the cluster of low grade pancreatic intraepithelial neoplasia, implying that the lesion developed independently. Conclusions Our study indicates the potential of “endoscopic liquid biopsy” to capture the driver gene for PDA diagnosis.

scholarly journals A Functional Spatial Analysis Platform for Discovery of Immunological Interactions Predictive of Low-Grade to High-Grade Transition of Pancreatic Intraductal Papillary Mucinous Neoplasms

2018 ◽  
Vol 17 ◽  
pp. 117693511878288 ◽  
Author(s):  
Souptik Barua ◽  
Luisa Solis ◽  
Edwin Roger Parra ◽  
Naohiro Uraoka ◽  
Mei Jiang ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Subsequent Development ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Cellular Interactions ◽  
Spatial Interactions ◽  
Intraductal Papillary Mucinous Neoplasms ◽  
Remnant Pancreas ◽  
Mucinous Neoplasms

Intraductal papillary mucinous neoplasms (IPMNs), critical precursors of the devastating tumor pancreatic ductal adenocarcinoma (PDAC), are poorly understood in the pancreatic cancer community. Researchers have shown that IPMN patients with high-grade dysplasia have a greater risk of subsequent development of PDAC in the remnant pancreas than do patients with low-grade dysplasia. In this study, we built a computational prediction model that encapsulates the spatial cellular interactions in IPMNs that play key roles in the transformation of low-grade IPMN cysts to high-grade cysts en route to PDAC. Using multiplex immunofluorescent images of IPMN cysts, we adopted algorithms from spatial statistics and functional data analysis to create metrics that summarize the spatial interactions in IPMNs. We showed that an ensemble of models learned using these spatial metrics can robustly predict, with high accuracy, (1) the dysplasia grade (low vs high grade) and (2) the risk of a low-grade cyst progressing to a high-grade cyst. We obtained high classification accuracies on both tasks, with areas under the curve of 0.81 (95% confidence interval: 0.71-0.9) for task 1 and 0.81 (95% confidence interval: 0.7-0.94) for task 2. To the best of our knowledge, this is the first application of an ensemble machine learning approach for discovering critical cellular spatial interactions in IPMNs using imaging data. We envision that our work can be used as a risk assessment tool for patients diagnosed with IPMNs and facilitate greater understanding and investigation of the cellular interactions that cause transition of IPMNs to PDAC.

Clonal hematopoiesis mutations in plasma cfDNA RAS/BRAF genotyping of metastatic colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15083-e15083
Author(s):  
Beili Wang ◽  
Fei Huang ◽  
Minna Shen ◽  
Shengchao Wu ◽  
Qian Yu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Somatic Mutations ◽  
Digital Pcr ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Clonal Hematopoiesis ◽  
Tumor Tissues ◽  
Next Generation Sequencing Ngs ◽  
Tumor Somatic Mutations

e15083 Background: Clonal hematopoiesis (CH) leads to blood-derived somatic mutations in KRAS, NRAS and BRAF. Our aim is to identify the prevalence of CH-derived mutations in these three genes in metastatic colorectal cancer (mCRC) patients and reveal the practical clinical implication of these mutations on plasma genotyping. Methods: We analyzed KRAS, NRAS and BRAF genotypes in plasma and matched tumor tissues of 236 mCRC patients through next-generation sequencing (NGS) and polymerase chain reaction. Suspected CH mutations were defined as those only detected in plasma with variant allelic frequencies (AFs) of <5% and were confirmed by paired peripheral blood cells (PBCs) using droplet digital PCR (ddPCR). The hemopoietic lineage harboring a CH-derived mutation was analyzed through flow cytometry. Results: We identified suspected CH mutations in twenty patients (8.4%, 20/236). Three of these patients (1.27%, 3/236) had a CH-derived KRAS mutation, which was confirmed present in paired PBCs. Two of them had a KRAS G12X and the third had a KRAS Q61H. We did not detect CH-derived NRAS or BRAF mutations in our cohort. All three patients harboring a CH-derived mutation previously received chemotherapy treatment. In a selected CH-derived KRAS G12X case, the mutation was enriched in lymphocytes and persisted in plasma cell-free DNA (cfDNA) over the course of 4 months of therapy. Conclusions: In summary, we confirmed the existence of CH-derived KRAS mutations in a small proportion of mCRC patients. This should be noted to prevent misclassification as tumor somatic mutations when performing cfDNA sequencing in the absence of genotyping matched PBCs.

scholarly journals Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

2013 ◽  
Vol 98 (2) ◽  
pp. E364-E369 ◽  
Author(s):  
Nishant Agrawal ◽  
Yuchen Jiao ◽  
Mark Sausen ◽  
Rebecca Leary ◽  
Chetan Bettegowda ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Somatic Mutations ◽  
Medullary Thyroid Cancer ◽  
Driver Mutations ◽  
High Confidence ◽  
Kras Mutations ◽  
Protein Coding ◽  
Medullary Thyroid ◽  
Oncogenic Mutations ◽  
Independent Cohort

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

scholarly journals Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1090
Author(s):  
Hassan Sadozai ◽  
Animesh Acharjee ◽  
Thomas Gruber ◽  
Beat Gloor ◽  
Eva Karamitopoulou
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Disease Progression ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Budding ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Mesenchymal Transition

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

scholarly journals High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1656 ◽  
Author(s):  
Etienne Buscail ◽  
Catherine Alix-Panabières ◽  
Pascaline Quincy ◽  
Thomas Cauvin ◽  
Alexandre Chauvet ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Liquid Biopsy ◽  
Neoadjuvant Treatment ◽  
Digital Pcr ◽  
Portal Blood ◽  
Ductal Adenocarcinoma ◽  
Clinical Value ◽  
Liquid Biopsies

Purpose: Expediting the diagnosis of pancreatic ductal adenocarcinoma (PDAC) would benefit care management, especially for the start of treatments requiring histological evidence. This study evaluated the combined diagnostic performance of circulating biomarkers obtained by peripheral and portal blood liquid biopsy in patients with resectable PDAC. Experimental design: Liquid biopsies were performed in a prospective translational clinical trial (PANC-CTC #NCT03032913) including 22 patients with resectable PDAC and 28 noncancer controls from February to November 2017. Circulating tumor cells (CTCs) were detected using the CellSearch® method or after RosetteSep® enrichment combined with CRISPR/Cas9-improved KRAS mutant alleles quantification by droplet digital PCR. CD63 bead-coupled Glypican-1 (GPC1)-positive exosomes were quantified by flow cytometry. Results: Liquid biopsies were positive in 7/22 (32%), 13/22 (59%), and 14/22 (64%) patients with CellSearch® or RosetteSep®-based CTC detection or GPC1-positive exosomes, respectively, in peripheral and/or portal blood. Liquid biopsy performance was improved in portal blood only with CellSearch®, reaching 45% of PDAC identification (5/11) versus 10% (2/22) in peripheral blood. Importantly, combining CTC and GPC1-positive-exosome detection displayed 100% of sensitivity and 80% of specificity, with a negative predictive value of 100%. High levels of GPC1+-exosomes and/or CTC presence were significantly correlated with progression-free survival and with overall survival when CTC clusters were found. Conclusion: This study is the first to evaluate combined CTC and exosome detection to diagnose resectable pancreatic cancers. Liquid biopsy combining several biomarkers could provide a rapid, reliable, noninvasive decision-making tool in early, potentially curable pancreatic cancer. Moreover, the prognostic value could select patients eligible for neoadjuvant treatment before surgery. This exploratory study deserves further validation.

scholarly journals Detection of KRAS Mutations in Circulating Tumor DNA by Digital PCR in Early Stages of Pancreatic Cancer

2016 ◽  
Vol 62 (11) ◽  
pp. 1482-1491 ◽  
Author(s):  
Nora Brychta ◽  
Thomas Krahn ◽  
Oliver von Ahsen
Keyword(s):  
Pancreatic Cancer ◽  
Early Stage ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Surgical Removal ◽  
Plasma Samples ◽  
Kras Mutations ◽  
Detection Rates ◽  
Early Stages ◽  
Tumor Dna

Abstract BACKGROUND Since surgical removal remains the only cure for pancreatic cancer, early detection is of utmost importance. Circulating biomarkers have potential as diagnostic tool for pancreatic cancer, which typically causes clinical symptoms only in advanced stage. Because of their high prevalence in pancreatic cancer, KRAS proto-oncogene, GTPase [KRAS (previous name: Kirsten rat sarcoma viral oncogene homolog)] mutations may be used to identify tumor-derived circulating plasma DNA. Here we tested the diagnostic sensitivity of chip based digital PCR for the detection of KRAS mutations in circulating tumor DNA (ctDNA) in early stage pancreatic cancer. METHODS We analyzed matched plasma (2 mL) and tumor samples from 50 patients with pancreatic cancer. Early stages (I and II) were predominant (41/50) in this cohort. DNA was extracted from tumor and plasma samples and tested for the common codon 12 mutations G12D, G12V, and G12C by chip-based digital PCR. RESULTS We identified KRAS mutations in 72% of the tumors. 44% of the tumors were positive for G12D, 20% for G12V, and 10% for G12C. One tumor was positive for G12D and G12V. Analysis of the mutations in matched plasma samples revealed detection rates of 36% for G12D, 50% for G12V, and 0% for G12C. The detection appeared to be correlated with total number of tumor cells in the primary tumor. No KRAS mutations were detected in 20 samples of healthy control plasma. CONCLUSIONS Our results support further evaluation of tumor specific mutations as early diagnostic biomarkers using plasma samples as liquid biopsy.

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