scholarly journals Pharmacokinetics of preoperative intraperitoneal 5-FU in patients with pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Mikael Öman ◽  
Yvonne Wettergren ◽  
Elisabeth Odin ◽  
Sofia Westermark ◽  
Peter Naredi ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Tissue ◽  
Membrane Transporters ◽  
Postoperative Treatment ◽  
Ductal Adenocarcinoma ◽  
Clinical Protocol ◽  
Expression Of Genes ◽  
Pancreatic Tumour ◽  
Genes Encoding

Abstract Purpose The aim was to investigate the pharmacokinetics of preoperatively administered intraperitoneal (IP) 5-FU in patients with resectable pancreatic ductal adenocarcinoma (PDAC) by analyzing levels of 5-FU and target metabolites in peritoneal fluid, plasma, liver, lymph nodes, pancreatic tumour, and pancreatic tissue. These results were correlated to expression of genes encoding enzymes of the 5-FU pathway and cell membrane transporters of 5-FU and FdUMP. Methods Twenty-two patients with PDAC were treated with IP 5-FU before surgery. The postoperative treatment followed a routine clinical protocol. 5-FU and its metabolites were analyzed by LC–MS/MS. The expression of genes encoding enzymes and transporters in the 5-FU pathway was analyzed by qPCR. Results After IP treatment, 5-FU could be detected in plasma, lymph nodes, liver, pancreatic tumour, and pancreatic tissue. The highest 5-FU concentration was found in the liver, also expressing high levels of the 5-FU transporter OAT2. 5-FU was converted to active FdUMP in all tissues and the highest concentration was measured in lymph nodes, liver and pancreatic tumour (18.5, 6.1 and 6.7 pmol/g, respectively). There was a correlation between the FdUMP and dUr levels in lymph nodes (r = 0.70, p = 0.0076). In tumours, there was an association between OAT2 expression and FdUMP concentration. Conclusion The study shows uptake of IP 5-FU and drug metabolism to active FdUMP in pancreatic tumour, liver, and lymph nodes. Extended studies are warranted to evaluate the IP route for 5-FU administration in PDAC patients.

Utility of CT Radiomics Features in Differentiation of Pancreatic Ductal Adenocarcinoma From Normal Pancreatic Tissue

2019 ◽  
Vol 213 (2) ◽  
pp. 349-357 ◽  
Author(s):  
Linda C. Chu ◽  
Seyoun Park ◽  
Satomi Kawamoto ◽  
Daniel F. Fouladi ◽  
Shahab Shayesteh ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Tissue ◽  
Ductal Adenocarcinoma ◽  
Normal Pancreatic Tissue

Establishment of tolerance to commensal bacteria requires a complex microbiota and is accompanied by decreased intestinal chemokine expression

2012 ◽  
Vol 302 (1) ◽  
pp. G55-G65 ◽  
Author(s):  
L. N. Fink ◽  
S. B. Metzdorff ◽  
L. H. Zeuthen ◽  
C. Nellemann ◽  
M. B. Kristensen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lymph Nodes ◽  
Ex Vivo ◽  
Gene Expression Pattern ◽  
Mesenteric Lymph Nodes ◽  
Microbial Detection ◽  
E Coli ◽  
Germ Free ◽  
Expression Of Genes ◽  
Genes Encoding

Intricate regulation of tolerance to the intestinal commensal microbiota acquired at birth is critical. We hypothesized that epithelial cell tolerance toward early gram-positive and gram-negative colonizing bacteria is established immediately after birth, as has previously been shown for endotoxin. Gene expression in the intestine of mouse pups born to dams that were either colonized with a conventional microbiota or monocolonized ( Lactobacillus acidophilus or Eschericia coli ) or germ free was examined on day 1 and day 6 after birth. Intestinal epithelial cells from all groups of pups were stimulated ex vivo with L. acidophilus and E. coli to assess tolerance establishment. Intestine from pups exposed to a conventional microbiota displayed lower expression of Ccl2, Ccl3, Cxcl1, Cxcl2, and Tslp than germ-free mice, whereas genes encoding proteins in Toll-like receptor signaling pathways and cytokines were upregulated. When comparing pups on day 1 and day 6 after birth, a specific change in gene expression pattern was evident in all groups of mice. Tolerance to ex vivo stimulation with E. coli was only established in conventional animals. Colonization of the intestine was reflected in the spleen displaying downregulation of Cxcl2 compared with germ-free animals on day 1 after birth. Colonization reduced the expression of genes involved in antigen presentation in the intestine-draining mesenteric lymph nodes, but not in the popliteal lymph nodes, as evidenced by gene expression on day 23 after birth. We propose that microbial detection systems in the intestine are upregulated by colonization with a diverse microbiota, whereas expression of proinflammatory chemokines is reduced to avoid excess recruitment of immune cells to the maturing intestine.

scholarly journals The clinical relevance of the Hippo pathway in pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Richard Drexler ◽  
Mirco Küchler ◽  
Kim C. Wagner ◽  
Tim Reese ◽  
Bernd Feyerabend ◽  
...  
Keyword(s):  
Cancer Research ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Clinical Relevance ◽  
Hippo Pathway ◽  
Ductal Adenocarcinoma ◽  
Proliferative Potential ◽  
The Past ◽  
Pancreatic Tumour ◽  
The Hippo Pathway ◽  
Disease Free

Abstract Purpose The Hippo pathway has broadened in cancer research in the past decade and revealed itself to be an important driver for tumorigenesis and metastatic spread. In this study, we investigated the clinical relevance of the Hippo pathway with regard to metastatic invasion, patients’ outcome and histopathological features. Methods Protein expression of components of the Hippo pathway were analyzed by immunohistochemistry (IHC) using paraffin-embedded tissue from 103 patients who had been diagnosed with pancreatic ductal adenocarcinoma and had undergone surgery. Results were correlated with clinicopathological data, disease-free and overall survival. Results Immunohistochemistry studies in pancreatic tumour tissues revealed a significant upregulation of MST1, MST2, pLATS, pYAP and 14-3-3, representing the active Hippo pathway, in non-metastasized patients (p < 0.01). In turn, the pathway is more inactive in metastasized patients and relating liver metastases as LATS1, LATS2, YAP, transcriptional factors TEAD2 and TEAD3 were upregulated in these patients (p < 0.01). A higher pYAP expression was associated with a favorable OS and DFS. Conclusion The Hippo pathway is inactive in metastasized patients releasing the pro-metastatic and proliferative potential of the pathway. Furthermore, our study underlines the prognostic relevance of the Hippo pathway as a shift in the balance towards the inactive pathway predicts an unfavorable OS and DFS.

scholarly journals Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors

2016 ◽  
Vol 397 (9) ◽  
pp. 871-881 ◽  
Author(s):  
Anthony J. O’Donoghue ◽  
Sam L. Ivry ◽  
Chaity Chaudhury ◽  
Daniel R. Hostetter ◽  
Douglas Hanahan ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immunoblot Analysis ◽  
Pancreatic Tissue ◽  
Tumor Burden ◽  
Ductal Adenocarcinoma ◽  
Aspartyl Protease ◽  
Altered Expression ◽  
Cathepsin E ◽  
Stage Disease ◽  
End Stage

Abstract The cathepsin family of lysosomal proteases is increasingly being recognized for their altered expression in cancer and role in facilitating tumor progression. The aspartyl protease cathepsin E is overexpressed in several cancers and has been investigated as a biomarker for pancreatic ductal adenocarcinoma (PDAC). Here we show that cathepsin E expression in mouse PDAC tumors is increased by more than 400-fold when compared to healthy pancreatic tissue. Cathepsin E accumulates over the course of disease progression and accounts for more than 3% of the tumor protein in mice with end-stage disease. Through immunoblot analysis we determined that only procathepsin E exists in mouse PDAC tumors and cell lines derived from these tumors. By decreasing the pH, this procathepsion E is converted to the mature form, resulting in an increase in proteolytic activity. Although active site inhibitors can bind procathepsin E, treatment of PDAC mice with the aspartyl protease inhibitor ritonavir did not decrease tumor burden. Lastly, we used multiplex substrate profiling by mass spectrometry to identify two synthetic peptides that are hydrolyzed by procathepsin E near neutral pH. This work represents a comprehensive analysis of procathepsin E in PDAC and could facilitate the development of improved biomarkers for disease detection.

scholarly journals Dysregulation of miRNAs Targeting the IGF-1R Pathway in Pancreatic Ductal Adenocarcinoma

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1856
Author(s):  
Maria Dobre ◽  
Vlad Herlea ◽  
Cătălina Vlăduţ ◽  
Mihai Ciocîrlan ◽  
Vasile Daniel Balaban ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathway ◽  
Treatment Options ◽  
Therapy Resistance ◽  
Pancreatic Disease ◽  
Pancreatic Tissue ◽  
Ductal Adenocarcinoma ◽  
Normal Tissues ◽  
Pdac Tissue

Background: Pancreatic ductal adenocarcinoma (PDAC), the most prevalent neoplastic lethal pancreatic disease, has a poor prognosis and an increasing incidence. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is considered to be a contributing factor to the progression, metastasis, and therapy resistance of PDAC. Currently available treatment options for PDAC are limited, but microRNAs (miRNAs) may represent a new therapeutic strategy for targeting genes involved in the IGF-1R signaling pathway. Method: We investigated the expression levels of 21 miRNAs involved in the IGF-1R signaling pathway in pancreatic tissue from 38 patients with PDAC and 11 controls (five patients with chronic pancreatitis and six patients with normal pancreatic tissue). Results: We found 19 differentially expressed miRNAs between the PDAC cases and the controls. In particular, miR-100-5p, miR-145-5p, miR-29c-3p, miR-9-5p, and miR-195-5p were exclusively downregulated in PDAC tissue but not in chronic pancreatitis or normal pancreatic tissues; both control types presented similar levels. We also identified miR-29a-3p, miR-29b-3p, and miR-7-5p as downregulated miRNAs in PDAC tissues as compared with normal tissues but not with pancreatitis tissues. Conclusions: We identified a panel of miRNAs that could represent putative therapeutic targets for the development of new miRNA-based therapies for PDAC.

scholarly journals Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Daniel J. Tan ◽  
Mithun Mitra ◽  
Alec M. Chiu ◽  
Hilary A. Coller
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Intron Retention ◽  
Interaction Network ◽  
Intron Loss ◽  
Ductal Adenocarcinoma ◽  
Genes Encoding ◽  
Highly Correlated

AbstractPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate of <8%. Unsupervised clustering of 76 PDAC patients based on intron retention (IR) events resulted in two clusters of tumors (IR-1 and IR-2). While gene expression-based clusters are not predictive of patient outcome in this cohort, the clusters we developed based on intron retention were associated with differences in progression-free interval. IR levels are lower and clinical outcome is worse in IR-1 compared with IR-2. Oncogenes were significantly enriched in the set of 262 differentially retained introns between the two IR clusters. Higher IR levels in IR-2 correlate with higher gene expression, consistent with detention of intron-containing transcripts in the nucleus in IR-2. Out of 258 genes encoding RNA-binding proteins (RBP) that were differentially expressed between IR-1 and IR-2, the motifs for seven RBPs were significantly enriched in the 262-intron set, and the expression of 25 RBPs were highly correlated with retention levels of 139 introns. Network analysis suggested that retention of introns in IR-2 could result from disruption of an RBP protein−protein interaction network previously linked to efficient intron removal. Finally, IR-based clusters developed for the majority of the 20 cancer types surveyed had two clusters with asymmetrical distributions of IR events like PDAC, with one cluster containing mostly intron loss events. Taken together, our findings suggest IR may be an important biomarker for subclassifying tumors.

scholarly journals Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

2019 ◽  
Author(s):  
Soledad A. Camolotto ◽  
Veronika K. Belova ◽  
Luke Torre-Healy ◽  
Jeffery M. Vahrenkamp ◽  
Kristofer C. Berrett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Subtype ◽  
Ductal Adenocarcinoma ◽  
Reciprocal Regulation ◽  
Expression Of Genes ◽  
Response To Chemotherapy ◽  
Expression Program

AbstractPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: Classical and Basal-like. The Classical subtype is characterized by a more favorable prognosis and better response to chemotherapy than the Basal-like subtype. The Classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor HNF4α. Using in vitro and in vivo PDAC models, we show that HNF4α restrains tumor growth and drives tumor cells toward an epithelial identity. Gene expression analysis from murine models and human tumors shows that HNF4α activates expression of genes associated with the Classical subtype. Although HNF4α loss is not sufficient for complete conversion to the Basal-like subtype gene expression profile, HNF4α directly represses SIX4 and SIX1, mesodermal lineage specifiers expressed in the Basal-like subtype. Finally, HNF4α-negative PDAC cells rely on expression of SIX4 and SIX1 for proliferation in vitro and in vivo. Overall, our data show that HNF4α regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the Classical gene expression program and repression of SIX4 and SIX1, which may represent novel dependencies of the Basal-like subtype.

Impact of Acute Inflammation on the Survival Outcomes of Patients with Resected Pancreatic Ductal Adenocarcinoma

2021 ◽  
pp. 1-9
Author(s):  
Mohamed Rabie Saad ◽  
Ho-Seong Han ◽  
Yoo-Seok Yoon ◽  
Jai Young Cho ◽  
Jun Suh Lee ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Predictive Factors ◽  
Acute Inflammation ◽  
Acute Cholangitis ◽  
Microvascular Invasion ◽  
Ductal Adenocarcinoma ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Positive Lymph Nodes

<b><i>Introduction:</i></b> The impact of acute inflammation on cancer progression is still not well elucidated. Pancreatic head cancer is occasionally associated with acute cholangitis. C-reactive protein (CRP) is a biomarker that indicates presence of acute inflammation. <b><i>Methods:</i></b> We reviewed the patients’ data with pancreatic ductal adenocarcinoma (PDAC) who underwent pancreaticoduodenectomy between 2004 and 2018. <b><i>Results:</i></b> Two hundred ninety-one patients were included. Median preoperative CRP was 0.45 mg/dL (0–18.9). Median follow-up duration was 22 months (4–152). The 1-, 3-, and 5-year overall survival (OS) rates were 76.4%, 32.2%, and 22.9%, respectively. Recurrence occurred in 168 cases (57.7%). The 1-, 3-, and 5-year disease-free survival (DFS) rates were 53.9%, 27.1%, and 21.9%, respectively. The median OS was higher in normal CRP patients (27 months) than those with elevated CRP (18 months) (log-rank 0.038). The median DFS was higher in normal CRP patients (17 months) than those with elevated CRP (9 months) (log-rank &#x3c; 0.001). Predictive factors for OS included BMI, CRP, adjuvant therapy, positive lymph nodes, and microvascular invasion. Predictive factors for DFS included CRP, positive lymph nodes, and microvascular invasion. <b><i>Conclusion:</i></b> Preoperative CRP was an independent poor prognostic factor for OS and DFS of patients with resected PDAC.

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