scholarly journals Omega-3 Fatty Acids Prevent Early Pancreatic Carcinogenesis via Repression of the AKT Pathway

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1289 ◽  
Author(s):  
Yongzeng Ding ◽  
Bhargava Mullapudi ◽  
Carolina Torres ◽  
Emman Mascariñas ◽  
Georgina Mancinelli ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Fatty Acids ◽  
Early Stage ◽  
Disease Incidence ◽  
Tumor Formation ◽  
Early Stage Disease ◽  
Vast Number ◽  
Pancreatic Carcinogenesis ◽  
Ω3 Fatty Acids ◽  
Phosphorylated Akt

Pancreatic cancer remains a daunting foe despite a vast number of accumulating molecular analyses regarding the mutation and expression status of a variety of genes. Indeed, most pancreatic cancer cases uniformly present with a mutation in the KRAS allele leading to enhanced RAS activation. Yet our understanding of the many epigenetic/environmental factors contributing to disease incidence and progression is waning. Epidemiologic data suggest that diet may be a key factor in pancreatic cancer development and potentially a means of chemoprevention at earlier stages. While diets high in ω3 fatty acids are typically associated with tumor suppression, diets high in ω6 fatty acids have been linked to increased tumor development. Thus, to better understand the contribution of these polyunsaturated fatty acids to pancreatic carcinogenesis, we modeled early stage disease by targeting mutant KRAS to the exocrine pancreas and administered diets rich in these fatty acids to assess tumor formation and altered cell-signaling pathways. We discovered that, consistent with previous reports, the ω3-enriched diet led to reduced lesion penetrance via repression of proliferation associated with reduced phosphorylated AKT (pAKT), whereas the ω6-enriched diet accelerated tumor formation. These data provide a plausible mechanism underlying previously observed effects of fatty acids and suggest that administration of ω3 fatty acids can reduce the pro-survival, pro-growth functions of pAKT. Indeed, counseling subjects at risk to increase their intake of foods containing higher amounts of ω3 fatty acids could aid in the prevention of pancreatic cancer.

scholarly journals Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Gulfem D. Guler ◽  
Yuhong Ning ◽  
Chin-Jen Ku ◽  
Tierney Phillips ◽  
Erin McCarthy ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Early Stage ◽  
Ductal Adenocarcinoma ◽  
Cell Free Dna ◽  
Early Stage Disease ◽  
Non Invasive ◽  
Cancer Pathogenesis ◽  
Free Dna ◽  
Stage Disease ◽  
Circulating Cell Free Dna

Abstract Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n = 64) in comparison with a non-cancer cohort (n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis (YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92–0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.

scholarly journals Circulating Cell-Free Tumour DNA for Early Detection of Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3704
Author(s):  
Jedrzej J. Jaworski ◽  
Robert D. Morgan ◽  
Shivan Sivakumar
Keyword(s):  
Pancreatic Cancer ◽  
Early Detection ◽  
Early Stage ◽  
Lower Sensitivity ◽  
Detection Rates ◽  
Early Stage Disease ◽  
Genetic Sequencing ◽  
Number Of Factors ◽  
Stage Disease ◽  
Invasive Method

Pancreatic cancer is a lethal disease, with mortality rates negatively associated with the stage at which the disease is detected. Early detection is therefore critical to improving survival outcomes. A recent focus of research for early detection is the use of circulating cell-free tumour DNA (ctDNA). The detection of ctDNA offers potential as a relatively non-invasive method of diagnosing pancreatic cancer by using genetic sequencing technology to detect tumour-specific mutational signatures in blood samples before symptoms manifest. These technologies are limited by a number of factors that lower sensitivity and specificity, including low levels of detectable ctDNA in early stage disease and contamination with non-cancer circulating cell-free DNA. However, genetic and epigenetic analysis of ctDNA in combination with other standard diagnostic tests may improve early detection rates. In this review, we evaluate the genetic and epigenetic methods under investigation in diagnosing pancreatic cancer and provide a perspective for future developments.

Quality of life and satisfaction with care in a contemporary cohort of pancreatic cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21623-e21623 ◽  
Author(s):  
Omar Abdel-Rahman ◽  
Daniel John Renouf ◽  
David F. Schaeffer ◽  
Winson Y. Cheung
Keyword(s):  
Quality Of Life ◽  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Positive Impact ◽  
Early Stage ◽  
Care Delivery ◽  
Pancreatic Head ◽  
Cancer Center ◽  
Early Stage Disease

e21623 Background: Pancreatic cancer patients face significant disease- and treatment-related morbidity while management is frequently complex. With recent advances in radiation and surgery and the introduction of new systemic therapy regimens, understanding these patients’ quality of life (QOL) and their satisfaction with the care that they currently receive is essential to inform the design of future care delivery models. Methods: Pancreas Centre BC was established in British Columbia in 2012 to promote efficient triage, rapid access to multidisciplinary care, and early involvement of palliative care, if necessary. Consecutive pancreatic cancer patients who were referred to and seen at Pancreas Centre BC completed the EORTC-QLQ C30 and PAN26 questionnaires before and after surgery as well as surveys focused on the levels of satisfaction with their disease management. Using independent samples t-tests, we correlated clinical characteristics with QOL and satisfaction scores. Results: In total, 167 patients were included: median age was 63 years, 45% were men, and 70% were ECOG 0/1. The majority had early stage disease (78%), pancreatic head tumors (53%), adenocarcinoma histology (68%), and adjuvant gemcitabine (75%). Baseline mean QOL scores were 63, 90, 83, 58 and 92 (out of 100) in the overall, physical, emotional, cognitive and social domains, respectively. Advanced age ( > 70 years), weight loss ( > 10 kg), and poor ECOG were independently associated with lower overall QOL rating (all p > 0.05). Surgery had a positive impact on all functional domains where we observed a mean improvement in QOL scores ranging from 8 to 17 points (all p > 0.05). In terms of satisfaction, 94% of patients rated their overall care as good to excellent. Likewise, 80% of patients were very or mostly satisfied with the amount of information they received and 84% of patients rated the healthcare information they received as very or mostly helpful. Conclusions: Despite the morbidity of pancreatic cancer, patients referred to and seen at a tertiary pancreatic cancer center reported good QOL and satisfaction levels, suggesting that the centralization of pancreatic cancer care may be an effective model to address the high priority needs of this population

Significant upstaging of patients with stage I pancreatic cancer from clinical to pathologic staging.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 349-349
Author(s):  
Heather Stuart ◽  
Caroline Ripat ◽  
Basem Azab ◽  
Danny Yakoub ◽  
Dido Franceschi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Early Stage ◽  
Clinical Stage ◽  
Stage I ◽  
Clinical Staging ◽  
Early Stage Disease ◽  
Risk Of Mortality ◽  
Stage Disease ◽  
Pathologic Staging ◽  
Group 2

349 Background: Clinical staging of patients with pancreatic cancer is essential to determine if neo-adjuvant treatment, surgery or palliative treatment is required. Patients with early stage disease often receive upfront surgery, where as patients with more advanced disease often receive neo-adjuvant therapy. Therefore the accuracy of clinical staging significantly influences management decisions. This study investigates the correlation between clinical and pathologic staging for patients with stage I pancreatic cancer. Methods: A retrospective review of patients with pancreatic cancer in National Cancer Data Base from 1998-2006 was preformed. The clinical stage of patients with presumed stage I disease was compared to the postoperative pathologic stage. Cox proportional hazard ratio model and regression analysis were used to determine factors associated with mortality and upstaging, respectively. Results: 1697 patients with clinical stage I pancreatic cancer were divided into two groups. Group 1 was comprised of patients who were stage I postoperatively and Group 2 was comprised of patients that were upstaged to either stage II, III or IV postoperatively. There were 704 (41%) in group 1 and 993 (59%) in group 2. Within group 2, 595 (60%) were stage II, 321 (32%) were stage III and 77 (8%) were stage IV. Patients that were upstaged after surgery had an increased risk of mortality (HR 1.414, p < 0.001), whereas patients that received adjuvant chemotherapy had a decreased risk of mortality (HR 0.799, p < 0.001). Compared to Grade 1 tumors, Grade 2 and 3 tumors on biopsy were most likely to be upstaged on final pathology (p < 0.001). Conclusions: Patients with stage I pancreatic cancer are often candidates for upfront surgery, however this study demonstrates that a large number are upstaged on postoperative staging. Recognizing this may lead clinicians to administer neo-adjuvant treatment in a greater number of patients with early stage disease in order to optimize survival.

scholarly journals NFATc4 RegulatesSox9Gene Expression in Acinar Cell Plasticity and Pancreatic Cancer Initiation

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Elisabeth Hessmann ◽  
Jin-San Zhang ◽  
Nai-Ming Chen ◽  
Marie Hasselluhn ◽  
Geou-Yarh Liou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Initial Step ◽  
Pancreatic Tissue ◽  
Tumor Formation ◽  
Egfr Signaling ◽  
Pancreatic Carcinogenesis ◽  
Acinar To Ductal Metaplasia ◽  
Epidermal Growth ◽  
Stress Signals ◽  
Signaling Activation

Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC) development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation-induced signaling activation of the epidermal growth factor (EGFR) or induction of Sox9 expression, are required for tumor formation. Herein, we aimed to dissect the mechanism that links EGFR signaling to Sox9 gene expression during acinar-to-ductal metaplasia in pancreatic tissue adaptation and PDAC initiation. We show that the inflammatory transcription factor NFATc4 is highly induced and localizes in the nucleus in response to inflammation-induced EGFR signaling. Moreover, we demonstrate that NFATc4 drives acinar-to-ductal conversion and PDAC initiation through direct transcriptional induction ofSox9. Therefore, strategies designed to disrupt NFATc4 induction might be beneficial in the prevention or therapy of PDAC.

scholarly journals KRAS, A Prime Mediator in Pancreatic Lipid Synthesis through Extra Mitochondrial Glutamine and Citrate Metabolism

2021 ◽  
Vol 22 (10) ◽  
pp. 5070
Author(s):  
Isaac James Muyinda ◽  
Jae Gwang Park ◽  
Eun Jung Jang ◽  
Byong Chul Yoo
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Metabolic Pathways ◽  
Early Stage ◽  
Lipid Synthesis ◽  
Metabolic Reprogramming ◽  
Treatment Modalities ◽  
Early Stage Disease ◽  
Pancreatic Cancer Cells ◽  
Citrate Metabolism

Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven pancreatic cancer is very lethal, with a five-year survival rate of <9%, irrespective of therapeutic advances. Different treatment modalities including chemotherapy, radiotherapy, and immunotherapy demonstrated only marginal efficacies because of pancreatic tumor specificities. Surgery at the early stage of the disease remains the only curative option, although only in 20% of patients with early stage disease. Clinical trials targeting the main oncogenic driver, KRAS, have largely been unsuccessful. Recently, global metabolic reprogramming has been identified in patients with pancreatic cancer and oncogenic KRAS mouse models. The newly reprogrammed metabolic pathways and oncometabolites affect the tumorigenic environment. The development of methods modulating metabolic reprogramming in pancreatic cancer cells might constitute a new approach to its therapy. In this review, we describe the major metabolic pathways providing acetyl-CoA and NADPH essential to sustain lipid synthesis and cell proliferation in pancreatic cancer cells.

scholarly journals Benefit of Cisplatin With Definitive Radiotherapy in Older Women With Cervical Cancer

2019 ◽  
Vol 17 (8) ◽  
pp. 969-975
Author(s):  
Michael Xiang ◽  
Elizabeth A. Kidd
Keyword(s):  
Cervical Cancer ◽  
Propensity Score ◽  
Older Women ◽  
Competing Risks ◽  
Propensity Score Analysis ◽  
Early Stage ◽  
Disease Incidence ◽  
Early Stage Disease ◽  
Definitive Radiotherapy ◽  
Score Analysis

Background: Cisplatin with definitive radiotherapy (RT) is considered the standard of care for cervical cancer; however, older women are frequently undertreated and have worse outcomes compared with younger patients. Because women aged ≥65 years have been disproportionately underrepresented in clinical trials, uncertainties exist regarding how much they benefit from the addition of cisplatin to RT. Patients and Methods: Women aged ≥65 years with nonmetastatic cervical cancer treated with definitive external-beam RT and brachytherapy were identified in the SEER-Medicare database. Death attributable to cervical cancer (cancer-specific mortality [CSM]) was evaluated against competing risks of death using Gray’s test. Propensity score analysis and the Fine-Gray multivariable regression model were used to adjust for baseline differences, including comorbidity. Results: The total cohort comprised 826 patients, of whom 531 (64%) received cisplatin, 233 (28%) were FIGO stage I, 374 (45%) were stage II, and 219 (27%) were stage III–IVA. Older age and chronic kidney disease significantly predicted omission of cisplatin. Virtually all cisplatin dosing was weekly, with a median of 5 cycles. Death from cervical cancer was significantly lower with cisplatin than without (5-year CSM, 31% vs 39%; P=.02; adjusted hazard ratio, 0.72; P=.02), which persisted in propensity score analysis. Receiving ≥5 cycles was required for benefit, as no difference in CSM was seen in patients receiving 1 to 4 cycles versus no cisplatin. Subgroup analyses revealed that the benefit of cisplatin persisted in women aged ≥75 years and those with early-stage disease. Incidence of cytopenia, nausea/vomiting, and hypovolemia increased in patients treated with cisplatin. Conclusions: Administration of cisplatin with definitive RT in women aged ≥65 years was associated with a significant benefit in the incidence of death attributable to cervical cancer, despite competing risks for mortality in an older population. Receiving at least 5 cycles of weekly cisplatin was required for benefit.

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