scholarly journals Microbial Dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer

2018 ◽  
Author(s):  
Roberto Mendez ◽  
Kousik Kesh ◽  
Nivedita Arora ◽  
Leá Di Martino ◽  
Florencia McAllister ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Survival Rate ◽  
Early Detection ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Ductal Adenocarcinoma ◽  
Metabolic Reconstruction ◽  
Microbiome Analysis ◽  
Early Stages ◽  
Kpc Mice

AbstractPurposeThe lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated to the abysmal survival rate in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high-risk for PDAC.Experimental DesignA combination of 16s pyrosequencing and whole-genome sequencing of gut microbiota was used in a spontaneous genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUmanN2 pipeline. Serum polyamine levels were measured from murine and patient samples using standard methods.ResultsResults showed a progressive Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentration. Therefore, at the early stages of tumorigenesis, the gut microbial composition changes in a way to release metabolites that foster host tumorigenesis, thereby fulfilling the ‘vicious cycle hypothesis’ of the role of the microbiome in health and disease states.ConclusionsOur results provide a potential, precise, non-invasive tool for early detection of PDAC, which will result in improved outcomes.SynopsisGut microbiota changes during early stages of pancreatic ductal adenocarcinoma (PDAC) progression and contributes towards host polyamine pool. Both changes can be used as an early predictive marker for PDAC.Translational RelevancePancreatic carcinogenesis progresses through pre-cancerous PanIN lesions to invasive cancer. Even though these morphological changes are histologically distinct, imaging techniques are not able to distinguish the pre-invasive PanINs from normal pancreas, making detection of a tumor at a precancerous stage impossible. Thus, majority of cases (85–90%) present with advanced pancreatic cancer at the time of diagnosis. This contributes to the dismal survival rate in this disease. Our study of gut microbiome analysis on KPC mice during tumor progression followed by metabolic reconstruction and experimental validation in human samples indicate that gut-microbiome analysis along with an analysis of the microbial metabolites can be developed as potential biomarkers for detection of PDAC at early stages when histological changes are not yet grossly apparent.

scholarly journals Microbial dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer

2019 ◽  
Vol 41 (5) ◽  
pp. 561-570 ◽  
Author(s):  
Roberto Mendez ◽  
Kousik Kesh ◽  
Nivedita Arora ◽  
Leá Di Martino ◽  
Florencia McAllister ◽  
...  
Keyword(s):  
Early Detection ◽  
Survival Rates ◽  
Elevated Serum ◽  
Fecal Microbiota ◽  
Genetically Engineered ◽  
Polyamine Metabolism ◽  
Ductal Adenocarcinoma ◽  
Metabolic Reconstruction ◽  
Early Stages ◽  
16S Rrna Pyrosequencing

Abstract The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated with the abysmal survival rates in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. We used a combination of 16s rRNA pyrosequencing and whole-genome sequencing of gut fecal microbiota in a genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUMAnN2 pipeline. Serum polyamine levels were measured from murine and patient samples using chromogenic assay. Our results showed a Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentrations. Therefore, at the early stages of tumorigenesis, there is a strong correlation between microbial changes and release of metabolites that foster host tumorigenesis, thereby fulfilling the ‘vicious cycle hypothesis’ of the role of microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which may result in improved outcomes.

scholarly journals The Screening and Early Detection of Pancreatic Cancer: Who, When, and How?

2020 ◽  
Vol 25 (2) ◽  
pp. 65-71
Author(s):  
Jae Hyuck Chang
Keyword(s):  
Pancreatic Cancer ◽  
Chronic Pancreatitis ◽  
General Population ◽  
Early Detection ◽  
Imaging Modality ◽  
Ductal Adenocarcinoma ◽  
Average Risk ◽  
Cystic Lesions ◽  
Low Prevalence ◽  
New Onset

More than 80% of patients with pancreatic ductal adenocarcinoma (PDA) present with symptomatic, surgically unresectable disease. If a “stage shift” from the current 20% resectable proportion to greater by early detection can be achieved, it will unequivocally lead to improved survival in this otherwise dismal disease. Although the goal of early detection of PDA is laudable, the relatively low prevalence PDA renders general population screening infeasible. To avoid the perils of overdiagnosis and to focus early detection efforts on individuals deemed to be at higher-than-average risk, we need to define those subsets of individuals, such as familial kindred and patients with precursor cystic lesions, chronic pancreatitis, and new-onset diabetes. The next step is to determine when and how often to conduct surveillance in the atrisk individuals and the modalities (biomarkers and imaging) that will be used in the surveillance and diagnostic settings, respectively. Nonetheless, vast challenges still remain in terms of validated blood-based biomarkers, imaging modality, and when and how often the surveillance.

scholarly journals Omics Approaches in Pancreatic Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1052
Author(s):  
Iranzu González-Boja ◽  
Antonio Viúdez ◽  
Saioa Goñi ◽  
Enrique Santamaria ◽  
Estefania Carrasco-García ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Survival Rate ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Curative Intent ◽  
Pancreatic Cancers ◽  
Wide Range ◽  
Prevention And Treatment ◽  
Shed Light

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.

Development of Pancreatic Cancer: Targets for Early Detection and Treatment

2016 ◽  
Vol 34 (5) ◽  
pp. 525-531 ◽  
Author(s):  
Markus M. Lerch ◽  
Julia Mayerle ◽  
Ujjwal Mahajan ◽  
Matthias Sendler ◽  
F. Ulrich Weiss ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Chronic Pancreatitis ◽  
Early Detection ◽  
Tyrosine Kinases ◽  
Histone Deacetylases ◽  
Hedgehog Signaling ◽  
Pharmaceutical Preparations ◽  
Chemotherapeutic Agents ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Tools

Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death worldwide and compared to other malignancies its share in cancer mortality is expected to rise further. This is due to a lack of sensitive diagnostic tools that would permit earlier detection in a potentially curable stage and the very slow progress in finding effective drug treatments for pancreatic cancer. Key Messages: Aside from genetic predispositions and environmental agents, chronic pancreatitis is by far the greatest risk factor for PDAC. It also shares several etiological factors with pancreatic cancer and represents its most challenging differential diagnosis. Biomarkers that can distinguish between chronic pancreatitis and PDAC may therefore be suitable for the latter's early detection. Moreover, targeting the natural history of chronic pancreatitis would be one approach to prevent PDAC. Targeting tumor-cell signaling directly by interfering with receptor tyrosine kinases has shown some efficacy, although the results in clinical trials were less encouraging than for other cancers. Other compounds developed have targeted the formation of extracellular matrix around the tumor, the proteolytic activity in the tumor environment, histone deacetylases, hedgehog signaling and heat shock proteins, but none has yet found its way into routine patient care. Attempts to individualize treatment according to the tumor's somatic mutation profile are novel but so far impractical. Conclusions: Progress in the treatment of pancreatic cancer has been exceedingly slow and mostly dependent on improved pharmaceutical preparations or combinations of established chemotherapeutic agents. The promise of major breakthroughs implied in targeting tumor signal transduction events has so far not materialized.

Early Detection and Biomarkers in Pancreatic Cancer

2007 ◽  
Vol 5 (10) ◽  
pp. 1034-1041 ◽  
Author(s):  
David E. Misek ◽  
Tasneem H. Patwa ◽  
David M. Lubman ◽  
Diane M. Simeone
Keyword(s):  
Pancreatic Cancer ◽  
Early Detection ◽  
Cancer Control ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Protein Biomarkers ◽  
Recent Developments ◽  
New Biomarkers ◽  
Low Sensitivity ◽  
Sensitivity Specificity

Major advances in cancer control will be greatly aided by early detection for diagnosing and treating cancer in its preinvasive state before metastasis. Unfortunately, for pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related death in the United States, effective early detection and screening are currently not available and tumors are typically diagnosed at a late stage, frequently after metastasis. Partly because of low sensitivity/specificity, existing biomarkers such as CA19-9 are not adequate as early detection markers of pancreatic cancer. Thus, a great need exists for new biomarkers for pancreatic cancer. This article focuses on recent developments in the identification of new serum protein biomarkers that are useful in the early detection of PDAC.

scholarly journals Gemcitabine plus Nab-paclitaxel as a second-line treatment following FOLFIRINOX failure in advanced pancreatic cancer: a multicenter, single-arm, open-label, phase 2 trial

2021 ◽  
Vol 13 ◽  
pp. 175883592110561
Author(s):  
Gunn Huh ◽  
Hee Seung Lee ◽  
Jin Ho Choi ◽  
Sang Hyub Lee ◽  
Woo Hyun Paik ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Survival Rate ◽  
Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Second Line ◽  
Phase 2 ◽  
First Line ◽  
Open Label ◽  
Phase 2 Trial ◽  
Open Label Phase

Background: The aim of this study was to evaluate the efficacy and safety of gemcitabine plus nab-paclitaxel (GnP) as second-line chemotherapy following first-line FOLFIRINOX treatment failure in advanced pancreatic cancer. Methods: This was a multicenter, single-arm, open-label, phase 2 trial done at three tertiary centers in South Korea from May 2018 to December 2019. Eligible patients were aged 20 years or older, had histologically confirmed advanced pancreatic ductal adenocarcinoma, and disease progression after receiving first-line FOLFIRINOX. Patients received a second-line GnP regimen as intravenous nab-paclitaxel at a dose of 125 mg/m2 and gemcitabine at a dose of 1000 mg/m2, on days 1, 8, and 15 every 4 weeks until disease progression or unacceptable toxicity. The primary outcome was survival rate at 6 months and the secondary outcomes were median progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events. This study is registered with Clinicaltrials.gov. (NCT03401827) Results: Forty patients were enrolled in the study. The survival rate at 6 months was 72.5% [95% confidence interval (CI), 59.9–87.7], achieving superiority over prespecified assumed 6-month OS rate of 20% for best supportive care only ( p < 0.001). The median PFS and OS were 5.8 months (95% CI, 4.3–8.7) and 9.9 months (95% CI, 7.5–12.4), respectively. DCR was 87.5% with six partial responses and 29 stable diseases. Grade 3 or higher treatment-related adverse events occurred in 25 (62.5%) patients with the most common being thrombocytopenia, anemia, neutropenia, peripheral neuropathy, and peripheral edema. Conclusion: GnP demonstrated favorable efficacy with acceptable toxicity in patients with advanced pancreatic ductal adenocarcinoma after FOLFIRINOX failure.

scholarly journals Solid Pseudopapillary Neoplasm of the Pancreas: Unfolding an Intriguing Condition

2021 ◽  
pp. 1-12
Author(s):  
Manuel António Alves Cruz ◽  
Pedro Moutinho-Ribeiro ◽  
Pedro Costa-Moreira ◽  
Guilherme Macedo
Keyword(s):  
Pancreatic Cancer ◽  
Survival Rate ◽  
Malignant Neoplasm ◽  
World Health ◽  
Ductal Adenocarcinoma ◽  
Malignant Neoplasms ◽  
Low Grade ◽  
Solid Pseudopapillary Neoplasm ◽  
Imaging Characteristics ◽  
Health Organization

Pancreatic cancer is one of the most lethal malignant neoplasms, with a 1-year survival rate after diagnosis of 24%, and a 5-year survival rate of only 9%. While this illustrates the behavior of its main histologic type – ductal adenocarcinoma, there are other histologic subtypes of pancreatic cancer that can harbor excellent prognosis. Solid pseudopapillary neoplasm, described as a rare low-grade malignant neoplasm by the World Health Organization, is the best example of that, having an overall 5-year survival rate of about 97%. Not only the prognosis, but everything about this entity is unique: its histogenesis, epidemiology, presentation, imaging characteristics, cytology features, immunohistochemical profile, and treatment. This explains the urge to improve our understanding about this entity and thus our ability to accurately recognize and manage it. Having this in mind, this article aims to summarize the most relevant topics regarding this entity.

scholarly journals Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion

Gut ◽  
2019 ◽  
Vol 69 (1) ◽  
pp. 122-132 ◽  
Author(s):  
Hong Jiang ◽  
Xiuting Liu ◽  
Brett L Knolhoff ◽  
Samarth Hegde ◽  
Kyung Bae Lee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Models ◽  
Transforming Growth Factor ◽  
Inhibitor Therapy ◽  
Janus Kinase ◽  
Gene Set Enrichment Analysis ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Kpc Mice ◽  
Stat3 Signalling

ObjectiveWe investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time.DesignPancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRasG12D/wt; p53flox/wt) treated with FAK inhibitor were analysed for the activation of a compensatory survival pathway in resistant tumours. We identified pathways involved in the regulation of signal transducer and activator of transcription 3 (STAT3) signalling on FAK inhibition by gene set enrichment analysis and verified these outcomes by RNA interference studies. We also tested combinatorial approaches targeting FAK and STAT3 in syngeneic transplantable mouse models of PDAC and KPC mice.ResultsIn KPC mice, the expression levels of phosphorylated STAT3 (pSTAT3) were increased in PDAC cells as they progressed on FAK inhibitor therapy. This progression corresponded to decreased collagen density, lowered numbers of SMA+ fibroblasts and downregulation of the transforming growth factor beta (TGF-β)/SMAD signalling pathway in FAK inhibitor-treated PDAC tumours. Furthermore, TGF-β production by fibroblasts in vitro drives repression of STAT3 signalling and enhanced responsiveness to FAK inhibitor therapy. Knockdown of SMAD3 in pancreatic cancer cells abolished the inhibitory effects of TGF-β on pSTAT3. We further found that tumour-intrinsic STAT3 regulates the durability of the antiproliferative activity of FAK inhibitor, and combinatorial targeting of FAK and Janus kinase/STAT3 act synergistically to suppress pancreatic cancer progression in mouse models.ConclusionStromal depletion by FAK inhibitor therapy leads to eventual treatment resistance through the activation of STAT3 signalling. These data suggest that, similar to tumour-targeted therapies, resistance mechanisms to therapies targeting stromal desmoplasia may be critical to treatment durability.

scholarly journals Impact of Adjuvant Chemoradiotherapy on Survival of Resected Pancreatic Adenocarcinoma Cancer: A Surveillance, Epidemiology and End Results (SEER) Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaomao Shi ◽  
Jin Peng ◽  
Huangang Jiang ◽  
Yu Gao ◽  
Wenbo Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Survival Rate ◽  
Lymph Nodes ◽  
Clinical Characteristics ◽  
Cox Regression ◽  
Ductal Adenocarcinoma ◽  
Adjuvant Chemoradiotherapy ◽  
Propensity Matching ◽  
Rate Selection ◽  
End Results

BackgroundThe benefits of postoperative adjuvant chemoradiotherapy (CRT) for pancreatic cancer remain controversial. The purpose of this study is to determine if adjuvant CRT can improve the overall survival of postoperative pancreatic cancer patients compared to adjuvant chemotherapy (CT).MethodsPatients with resected pancreas adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results (SEER) database (2004–2016). Multivariate Cox regression was used to determine the factors related to survival rate. Selection bias was reduced to a minimum through propensity matching analysis. Subgroup analyses by clinical characteristics were performed.ResultsThis study identified 10,097 patients who received adjuvant CT (n = 5,454) or adjuvant CRT (n = 4,643). On multivariate analysis, age, sex, tumor size, site, grade, stage, T stage, and lymph node metastasis were independent risk factors for OS. The basic clinical characteristics were well balanced after propensity matching. After propensity matching, CRT can improve the survival rate compared with CT [median OS: 22 months vs 23 months (HR, 0.928; 95% CI, 0.881–0.977; P = 0.004)]. Subgroup analysis indicated that the survival benefit of adjuvant chemoradiotherapy was more significant in patients with female (HR, 0.860; 95% CI, 0.798–0.926; P = 0.005 for interaction) or T3 (HR, 0.905; 95% CI, 0.855–0.957; P = 0.04 for interaction) or lymph nodes positive (HR, 0.883; 95% CI, 0.832–0.938; P = 0.005 for interaction).ConclusionAdjuvant CRT was associated with improved survival compared with adjuvant CT in patients with resection of pancreatic ductal adenocarcinoma. The benefit was more significant in patients with female or T3 or lymph nodes positive.

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