International Journal of Molecular Sciences

Research

Jump to: Review

1399 KiB

Open AccessArticle

The Impact of SMAD4 Loss on Outcome in Patients with Advanced Pancreatic Cancer Treated with Systemic Chemotherapy

by Steffen Ormanns, Michael Haas, Anna Remold, Stephan Kruger, Stefan Holdenrieder, Thomas Kirchner, Volker Heinemann and Stefan Boeck

Int. J. Mol. Sci. 2017, 18(5), 1094; https://doi.org/10.3390/ijms18051094 - 19 May 2017

Cited by 20 | Viewed by 6302

Abstract

The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and [...] Read more.

The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and outcome in PC patients receiving palliative chemotherapy. Using immunohistochemistry, we examined SMAD4 expression in tumor tissue of 143 aPC pts treated within completed prospective clinical and biomarker trials. In uni- and multivariate analyses, SMAD4 expression status was correlated to clinicopathological patient characteristics and outcome. At chemotherapy initiation, 128 pts had metastatic PC; most pts (n = 99) received a gemcitabine-based regimen. SMAD4 loss was detected in 92 pts (64%); patient characteristics such as gender, age, tumor grading, disease stage or number of metastatic sites had no significant impact on tumoral SMAD4 status. In univariate analyses, SMAD4 loss had no impact on overall survival (hazard ratio (HR) 1.008, p = 0.656); however, we observed a prolonged progression-free survival (HR 1.565, p = 0.038) in pts with tumoral SMAD4 loss. This finding was confirmed in multivariate analyses (HR 1.790, p = 0.040), but only for gemcitabine-treated pts. In contrast to previous studies in resectable PC, loss of SMAD4 expression was not associated with a negative outcome in patients with advanced PC receiving systemic chemotherapy. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

1941 KiB

Open AccessArticle

Molecular Ghrelin System in the Pancreatic Acinar Cells: The Role of the Polypeptide, Caerulein and Sensory Nerves

by Joanna Bonior, Piotr Ceranowicz, Ryszard Gajdosz, Beata Kuśnierz-Cabala, Piotr Pierzchalski, Zygmunt Warzecha, Artur Dembiński, Michał Pędziwiatr, Michalina Kot, Anna Leja-Szpak, Katarzyna Nawrot-Porąbka, Paweł Link-Lenczowski, Rafał Olszanecki, Krzysztof Bartuś and Jolanta Jaworek

Int. J. Mol. Sci. 2017, 18(5), 929; https://doi.org/10.3390/ijms18050929 - 2 May 2017

Cited by 11 | Viewed by 4907

Abstract

Ghrelin (GHRL) is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Experimental studies showed that GHRL protects the stomach and pancreas against acute damage, but the effect of GHRL on pancreatic acinar cells was still undetermined. Aim: To investigate the effect [...] Read more.

Ghrelin (GHRL) is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Experimental studies showed that GHRL protects the stomach and pancreas against acute damage, but the effect of GHRL on pancreatic acinar cells was still undetermined. Aim: To investigate the effect of GHRL and caerulein on the functional ghrelin system in pancreatic acinar cells taking into account the role of sensory nerves (SN). Methods: Experiments were carried out on isolated pancreatic acinar cells and AR42J cells. Before acinar cells isolation, GHRL was administered intraperitoneally at a dose of 50 µg/kg to rats with intact SN or with capsaicin deactivation of SN (CDSN). After isolation, pancreatic acinar cells were incubated in caerulein-free or caerulein containing solution. AR42J cells were incubated under basal conditions and stimulated with caerulein, GHRL or a combination of the above. Results: Incubation of isolated acinar cells with caerulein inhibited GHS-R and GHRL expression at the level of mRNA and protein in those cells. Either in rats with intact SN or with CDSN, administration of GHRL before isolation of acinar cells increased expression of GHRL and GHS-R in those cells and reversed the caerulein-induced reduction in expression of those parameters. Similar upregulation of GHS-R and GHRL was observed after administration of GHRL in AR42J cells. Conclusions: GHRL stimulates its own expression and expression of its receptor in isolated pancreatic acinar cells and AR42J cells on the positive feedback pathway. This mechanism seems to participate in the pancreatoprotective effect of GHRL in the course of acute pancreatitis. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

2940 KiB

Open AccessArticle

Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats

by Zygmunt Warzecha, Paweł Sendur, Piotr Ceranowicz, Jakub Cieszkowski, Marcin Dembiński, Ryszard Sendur, Joanna Bonior, Jolanta Jaworek, Tadeusz Ambroży, Rafał Olszanecki, Beata Kuśnierz-Cabala, Kaczmarzyk Tomasz, Romana Tomaszewska and Artur Dembiński

Int. J. Mol. Sci. 2017, 18(4), 882; https://doi.org/10.3390/ijms18040882 - 21 Apr 2017

Cited by 24 | Viewed by 5427 | Correction

Abstract

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic [...] Read more.

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

1576 KiB

Open AccessArticle

High Glucose Accelerates Cell Proliferation and Increases the Secretion and mRNA Expression of Osteopontin in Human Pancreatic Duct Epithelial Cells

by Miho Ito, Naohiko Makino, Akiko Matsuda, Yushi Ikeda, Yasuharu Kakizaki, Yoshihiko Saito, Yoshiyuki Ueno and Sumio Kawata

Int. J. Mol. Sci. 2017, 18(4), 807; https://doi.org/10.3390/ijms18040807 - 12 Apr 2017

Cited by 23 | Viewed by 5624

Abstract

Background: The incidence of pancreatic cancer is increasing year-by-year in Japan. Among the diseases that complicate pancreatic cancer, diabetes is the most common. Recently, it has become evident that patients suffering from diabetes and obesity show increased expression of osteopontin (OPN). The purpose [...] Read more.

Background: The incidence of pancreatic cancer is increasing year-by-year in Japan. Among the diseases that complicate pancreatic cancer, diabetes is the most common. Recently, it has become evident that patients suffering from diabetes and obesity show increased expression of osteopontin (OPN). The purpose of this study was to investigate the effect of high glucose and high insulin culture conditions on a human pancreatic duct epithelial cell line (HPDE-6), focusing particularly on OPN expression. Methods: HPDE-6 were cultured under various conditions, employing several combinations of glucose (normal, 6 mM high, 30 mM, and 60 mM) and insulin (0.1 nM, 1 nM) concentration. Results: HPDE-6 cell proliferation was significantly accelerated under high glucose culture conditions in comparison to samples in 6 mM glucose, and was more prominent under high insulin conditions. At the same time, the expression of OPN mRNA was also increased significantly. In comparison with 6 mM glucose, the expression of 8-OHdG DNA was increased in high glucose culture. Conclusion: HPDE-6 cells show accelerated proliferation and increased OPN expression when cultured under high glucose and high insulin conditions. Furthermore, the cells show increased oxidative stress in the presence of high glucose. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

1478 KiB

Open AccessArticle

Serum Metabolomic Profiles for Human Pancreatic Cancer Discrimination

by Takao Itoi, Masahiro Sugimoto, Junko Umeda, Atsushi Sofuni, Takayoshi Tsuchiya, Shujiro Tsuji, Reina Tanaka, Ryosuke Tonozuka, Mitsuyoshi Honjo, Fuminori Moriyasu, Kazuhiko Kasuya, Yuichi Nagakawa, Yuta Abe, Kimihiro Takano, Shigeyuki Kawachi, Motohide Shimazu, Tomoyoshi Soga, Masaru Tomita and Makoto Sunamura

Int. J. Mol. Sci. 2017, 18(4), 767; https://doi.org/10.3390/ijms18040767 - 4 Apr 2017

Cited by 21 | Viewed by 5517

Abstract

This study evaluated the clinical use of serum metabolomics to discriminate malignant cancers including pancreatic cancer (PC) from malignant diseases, such as biliary tract cancer (BTC), intraductal papillary mucinous carcinoma (IPMC), and various benign pancreaticobiliary diseases. Capillary electrophoresismass spectrometry was used to analyze [...] Read more.

This study evaluated the clinical use of serum metabolomics to discriminate malignant cancers including pancreatic cancer (PC) from malignant diseases, such as biliary tract cancer (BTC), intraductal papillary mucinous carcinoma (IPMC), and various benign pancreaticobiliary diseases. Capillary electrophoresismass spectrometry was used to analyze charged metabolites. We repeatedly analyzed serum samples (n = 41) of different storage durations to identify metabolites showing high quantitative reproducibility, and subsequently analyzed all samples (n = 140). Overall, 189 metabolites were quantified and 66 metabolites had a 20% coefficient of variation and, of these, 24 metabolites showed significant differences among control, benign, and malignant groups (p < 0.05; Steel–Dwass test). Four multiple logistic regression models (MLR) were developed and one MLR model clearly discriminated all disease patients from healthy controls with an area under receiver operating characteristic curve (AUC) of 0.970 (95% confidential interval (CI), 0.946–0.994, p < 0.0001). Another model to discriminate PC from BTC and IPMC yielded AUC = 0.831 (95% CI, 0.650–1.01, p = 0.0020) with higher accuracy compared with tumor markers including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), pancreatic cancer-associated antigen (DUPAN2) and s-pancreas-1 antigen (SPAN1). Changes in metabolomic profiles might be used to screen for malignant cancers as well as to differentiate between PC and other malignant diseases. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

1199 KiB

Open AccessArticle

Serum Concentrations of Angiopoietin-2 and Soluble fms-Like Tyrosine Kinase 1 (sFlt-1) Are Associated with Coagulopathy among Patients with Acute Pancreatitis

by Paulina Dumnicka, Beata Kuśnierz-Cabala, Mateusz Sporek, Małgorzata Mazur-Laskowska, Krzysztof Gil, Marek Kuźniewski, Piotr Ceranowicz, Zygmunt Warzecha, Artur Dembiński, Joanna Bonior and Ryszard Drożdż

Int. J. Mol. Sci. 2017, 18(4), 753; https://doi.org/10.3390/ijms18040753 - 2 Apr 2017

Cited by 36 | Viewed by 4482

Abstract

In severe acute pancreatitis (SAP), systemic inflammation leads to endothelial dysfunction and activation of coagulation. Thrombotic disorders in acute pancreatitis (AP) include disseminated intravascular coagulation (DIC). Recently, angiopoietin-2 and soluble fms-like tyrosine kinase 1 (sFlt-1) were proposed as markers of endothelial dysfunction in [...] Read more.

In severe acute pancreatitis (SAP), systemic inflammation leads to endothelial dysfunction and activation of coagulation. Thrombotic disorders in acute pancreatitis (AP) include disseminated intravascular coagulation (DIC). Recently, angiopoietin-2 and soluble fms-like tyrosine kinase 1 (sFlt-1) were proposed as markers of endothelial dysfunction in acute states. Our aim was to assess the frequency of coagulation abnormalities in the early phase of AP and evaluate the relationships between serum angiopoietin-2 and sFlt-1 and severity of coagulopathy. Sixty-nine adult patients with AP were recruited: five with SAP, 15 with moderately severe AP (MSAP) and 49 with mild AP. Six patients were diagnosed with DIC according to International Society on Thrombosis and Haemostasis (ISTH) score. All patients had at least one abnormal result of routine tests of hemostasis (low platelet count, prolonged clotting times, decreased fibrinogen, and increased D-dimer). The severity of coagulopathy correlated with AP severity according to 2012 Atlanta criteria, bedside index of severity in AP and duration of hospital stay. D-dimers correlated independently with C-reactive protein and studied markers of endothelial dysfunction. Angiopoietin-2, D-dimer, and ISTH score were best predictors of SAP, while sFlt-1 was good predictor of MSAP plus SAP. In clinical practice, routine tests of hemostasis may assist prognosis of AP. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

595 KiB

Open AccessArticle

The Neutrophil/Lymphocyte Ratio at Diagnosis Is Significantly Associated with Survival in Metastatic Pancreatic Cancer Patients

by Matteo Piciucchi, Serena Stigliano, Livia Archibugi, Giulia Zerboni, Marianna Signoretti, Viola Barucca, Roberto Valente, Gianfranco Delle Fave and Gabriele Capurso

Int. J. Mol. Sci. 2017, 18(4), 730; https://doi.org/10.3390/ijms18040730 - 29 Mar 2017

Cited by 57 | Viewed by 5422

Abstract

Different inflammation-based scores such as the neutrophil/lymphocyte ratio (NLR), the Odonera Prognostic Nutritional Index (PNI), the Glasgow Prognostic Score, the platelet/lymphocyte ratio, and the C-reactive protein/albumin ratio have been found to be significantly associated with pancreatic cancer (PDAC) prognosis. However, most studies have [...] Read more.

Different inflammation-based scores such as the neutrophil/lymphocyte ratio (NLR), the Odonera Prognostic Nutritional Index (PNI), the Glasgow Prognostic Score, the platelet/lymphocyte ratio, and the C-reactive protein/albumin ratio have been found to be significantly associated with pancreatic cancer (PDAC) prognosis. However, most studies have investigated patients undergoing surgery, and few of them have compared these scores. We aimed at evaluating the association between inflammatory-based scores and PDAC prognosis. In a single center cohort study, inflammatory-based scores were assessed at diagnosis and their prognostic relevance as well as that of clinic-pathological variables were evaluated through multiple logistic regression and survival probability analysis. In 206 patients, age, male sex, tumor size, presence of distant metastasis, access to chemotherapy, and an NLR > 5 but not other scores were associated with overall survival (OS) at multivariate analysis. Patients with an NLR < 5 had a median survival of 12 months compared to 4 months in those with an NLR > 5. In the 81 patients with distant metastasis at diagnosis, an NLR > 5 resulted in the only variable significantly associated with survival. Among patients with metastatic disease who received chemotherapy, the median survival was 3 months in patients with an NLR > 5 and 7 months in those with an NLR < 5. The NLR might drive therapeutic options in PDAC patients, especially in the setting of metastatic disease. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

4311 KiB

Open AccessArticle

Endogenously Expressed IL-4Rα Promotes the Malignant Phenotype of Human Pancreatic Cancer In Vitro and In Vivo

by Benno Traub, Lie Sun, Yongsu Ma, Pengfei Xu, Johannes Lemke, Stephan Paschke, Doris Henne-Bruns, Uwe Knippschild and Marko Kornmann

Int. J. Mol. Sci. 2017, 18(4), 716; https://doi.org/10.3390/ijms18040716 - 28 Mar 2017

Cited by 17 | Viewed by 4838

Abstract

Exogenous interleukin-4 (IL-4) has been demonstrated to affect the growth of different human malignancies including pancreatic cancer cells. The aim of our study was to determine the role of endogenously expressed IL-4-receptor-α-chain (IL-4Rα) in pancreatic cancer cells. IL-4Rα-suppression was achieved by generating Capan-1 [...] Read more.

Exogenous interleukin-4 (IL-4) has been demonstrated to affect the growth of different human malignancies including pancreatic cancer cells. The aim of our study was to determine the role of endogenously expressed IL-4-receptor-α-chain (IL-4Rα) in pancreatic cancer cells. IL-4Rα-suppression was achieved by generating Capan-1 cells stably expressing shRNA targeting IL-4Rα. The malignant phenotype was characterized by assessing growth properties, directional and non-directional cell movement in vitro and tumor growth in vivo. Signaling pathways were analyzed upon IL-4 and IL-13 stimulation of wildtype (WT) and control-transfected cells compared to IL-4Rα-knockdown cells. Silencing of IL-4Rα resulted in reduced anchorage-dependent cell growth (p < 0.05) and reduced anchorage-independent colony size (p < 0.001) in vitro. Moreover, cell movement and migration was inhibited. IL-4 and IL-13 stimulation of Capan-1-WT cells induced activation of similar pathways like stimulation with Insulin-like growth factor (IGF)-I. This activation was reduced after IL-4Rα downregulation while IGF-I signaling seemed to be enhanced in knockdown-clones. Importantly, IL-4Rα silencing also significantly suppressed tumor growth in vivo. The present study indicates that endogenously expressed IL-4 and IL-4Rα contribute to the malignant phenotype of pancreatic cancer cells by activating diverse pro-oncogenic signaling pathways. Addressing these pathways may contribute to the treatment of the disease. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

3281 KiB

Open AccessArticle

Detection of Circulating Tumor Cells Using Negative Enrichment Immunofluorescence and an In Situ Hybridization System in Pancreatic Cancer

by Yu Xu, Tai Qin, Jing Li, Xiuchao Wang, Chuntao Gao, Chao Xu, Jihui Hao, Jingcheng Liu, Song Gao and He Ren

Int. J. Mol. Sci. 2017, 18(4), 622; https://doi.org/10.3390/ijms18040622 - 23 Mar 2017

Cited by 51 | Viewed by 7484

Abstract

Pancreatic cancer (PC) is the most lethal type of gastrointestinal cancer, and early detection and monitoring is an urgent problem. Circulating tumor cells (CTCs) are emerging as a non-invasive biomarker for tumor detection. However, the low sensitivity is a main problem in the [...] Read more.

Pancreatic cancer (PC) is the most lethal type of gastrointestinal cancer, and early detection and monitoring is an urgent problem. Circulating tumor cells (CTCs) are emerging as a non-invasive biomarker for tumor detection. However, the low sensitivity is a main problem in the traditional CellSearch System for detecting CTCs, especially in patients with PC. In this study, we used negative enrichment (NE), immunofluorescence and in situ hybridization (FISH) of chromosome 8 (NE-iFISH) to capture and identify CTCs in PC patients. We showed that the NE-iFISH system exhibited a dramatically high detection rate of CTCs in PC patients (90%). The diagnostic rate of PC reached 97.5% when combining CTCs ≥ 2 and carbohydrate antigen 19-9 (CA19-9) > 37 µmol/L. The 1-year survival in the group of CTCs < 3 was significantly higher than that of CTCs ≥ 3 (p = 0.043). In addition, we analyzed the role of chromosomal instability in CTCs detection. The group of triploid (three hybridization signals of chromosome 8) CTCs ≥ 3 showed a shorter 1-year survival (p = 0.0279) and overall survival (p = 0.0188) than the group with triploid CTCs < 3. Importantly, the triploid CTC number but not the overall CTC counts could be a predictor of chemo-sensitivity. Moreover, circulating tumor microembolus (CTMs) were found in stage IV patients, and were positively related to the poor response to chemotherapy. In conclusion, the NE-iFISH system significantly improved the positive detection rate of CTCs and triploid CTC could be used to predict prognosis or the response to the chemotherapy of PC patients. CTM is a potential indicator of the chemotherapeutic effect in advanced PC patients. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

391 KiB

Open AccessArticle

Determination of VEGFR-2 (KDR) 604A>G Polymorphism in Pancreatic Disorders

by Vlad Pădureanu, Mihail Virgil Boldeanu, Ioana Streaţă, Mihai Gabriel Cucu, Isabela Siloşi, Lidia Boldeanu, Maria Bogdan, Anca Ştefania Enescu, Maria Forţofoiu, Aurelia Enescu, Elena Mădălina Dumitrescu, Dragoş Alexandru, Valeriu Marian Şurlin, Mircea Cătălin Forţofoiu, Ileana Octavia Petrescu, Florin Petrescu, Mihai Ioana, Marius Eugen Ciurea and Adrian Săftoiu

Int. J. Mol. Sci. 2017, 18(2), 439; https://doi.org/10.3390/ijms18020439 - 17 Feb 2017

Cited by 11 | Viewed by 4580

Abstract

Pancreatic disorders have a high prevalence worldwide. Despite the fact that screening methods became more effective and the knowledge we have nowadays about pancreatic diseases has enhanced, their incidence remains high. Our purpose was to determine whether single nucleotide polymorphism (SNP) of VEGFR-2/KDR [...] Read more.

Pancreatic disorders have a high prevalence worldwide. Despite the fact that screening methods became more effective and the knowledge we have nowadays about pancreatic diseases has enhanced, their incidence remains high. Our purpose was to determine whether single nucleotide polymorphism (SNP) of VEGFR-2/KDR (vascular endothelial growth factor receptor 2/kinase insert domain receptor) influences susceptibility to develop pancreatic pathology. Genomic DNA was extracted from blood samples collected from patients diagnosed with acute pancreatitis (n = 110), chronic pancreatitis (n = 25), pancreatic cancer (n = 82) and healthy controls (n = 232). VEGFR-2 (KDR) 604A>G (rs2071559) polymorphism frequency was determined with TaqMan allelic discrimination assays. Statistical assessment was performed by associating genetic polymorphism with clinical and pathological data. In both pancreatic disorders and healthy control groups the polymorphism we studied was in Hardy-Weinberg equilibrium. Association between increased risk for pancreatic disorders and studied polymorphism was statistically significant. KDR 604AG and AG + GG genotypes were more prevalent in acute pancreatitis and pancreatic cancer patients than in controls. These genotypes influence disease development in a low rate. No association was found between chronic pancreatitis and KDR 604AG and AG + GG genotypes. In Romanian cohort, we found an association between the KDR 604A→G polymorphism and acute pancreatitis and pancreatic cancer. Carriers of the -604G variant allele were more frequent among acute pancreatitis and pancreatic cancer than among controls, suggesting that KDR 604G allele may confer an increased risk for these diseases. In the future, more extensive studies on larger groups are necessary, in order to clarify the role of VEGFR2 polymorphisms in pancreatic pathology. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

1294 KiB

Open AccessArticle

The Diagnostic Usefulness of Serum Total Bile Acid Concentrations in the Early Phase of Acute Pancreatitis of Varied Etiologies

by Aleksandra Maleszka, Paulina Dumnicka, Aleksandra Matuszyk, Michał Pędziwiatr, Małgorzata Mazur-Laskowska, Mateusz Sporek, Piotr Ceranowicz, Rafał Olszanecki, Marek Kuźniewski and Beata Kuśnierz-Cabala

Int. J. Mol. Sci. 2017, 18(1), 106; https://doi.org/10.3390/ijms18010106 - 6 Jan 2017

Cited by 11 | Viewed by 5310

Abstract

The most common causes of acute pancreatitis (AP) are biliary tract diseases with cholestasis and alcohol consumption. In 10%–15% of patients, etiology determination is difficult. Identification of the etiology allows for the implementation of adequate treatment. The aim of this study was to [...] Read more.

The most common causes of acute pancreatitis (AP) are biliary tract diseases with cholestasis and alcohol consumption. In 10%–15% of patients, etiology determination is difficult. Identification of the etiology allows for the implementation of adequate treatment. The aim of this study was to assess the utility of the serum concentrations of total bile acids (TBA) to diagnose AP etiology in the early phase of the disease. We included 66 patients with AP, admitted within the first 24 h from the onset of symptoms. TBA were measured in serum at 24, 48, and 72 h from the onset of AP, using an automated fifth generation assay. The bilirubin-to-TBA ratio (B/TBA) was calculated. TBA was highest on the first day of AP and decreased subsequently. In patients with biliary etiology, serum TBA was significantly higher compared to those with alcoholic and other etiologies. B/TBA was significantly higher in patients with alcoholic etiology. At admission, the cut-off values of 4.7 µmol/L for TBA and 4.22 for the B/TBA ratio allowed for a differentiation between biliary and other etiologies of AP with a diagnostic accuracy of 85 and 83%. Both TBA and B/TBA may help in the diagnosis of AP etiology in the early phase of AP. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

1057 KiB

Open AccessArticle

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

by Andrea Párniczky, Eszter Hegyi, Anna Zsófia Tóth, Ákos Szücs, Andrea Szentesi, Áron Vincze, Ferenc Izbéki, Balázs Csaba Németh, Péter Hegyi and Miklós Sahin-Tóth

Int. J. Mol. Sci. 2016, 17(12), 2148; https://doi.org/10.3390/ijms17122148 - 20 Dec 2016

Cited by 12 | Viewed by 5575

Abstract

Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 [...] Read more.

Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% for CELA3A p.G241A and 1.5% for CELA3B p.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T in CELA3B showed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39–0.89, p = 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

4384 KiB

Open AccessArticle

Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer

by Tanja Grimmig, Romana Moench, Jennifer Kreckel, Stephanie Haack, Felix Rueckert, Roberta Rehder, Sudipta Tripathi, Carmen Ribas, Anil Chandraker, Christoph T. Germer, Martin Gasser and Ana Maria Waaga-Gasser

Int. J. Mol. Sci. 2016, 17(12), 2060; https://doi.org/10.3390/ijms17122060 - 8 Dec 2016

Cited by 54 | Viewed by 6740

Abstract

Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of [...] Read more.

Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

1149 KiB

Open AccessArticle

Serum Soluble Fms-Like Tyrosine Kinase 1 (sFlt-1) Predicts the Severity of Acute Pancreatitis

by Paulina Dumnicka, Mateusz Sporek, Małgorzata Mazur-Laskowska, Piotr Ceranowicz, Marek Kuźniewski, Ryszard Drożdż, Tadeusz Ambroży, Rafał Olszanecki and Beata Kuśnierz-Cabala

Int. J. Mol. Sci. 2016, 17(12), 2038; https://doi.org/10.3390/ijms17122038 - 6 Dec 2016

Cited by 25 | Viewed by 5171

Abstract

Organ failure is the most important determinant of the severity of acute pancreatitis (AP). Soluble fms-like tyrosine kinase 1 (sFlt-1) is positively associated with organ failure in sepsis. Our aim was to evaluate the diagnostic utility of automated sFlt-1 measurements for early prediction [...] Read more.

Organ failure is the most important determinant of the severity of acute pancreatitis (AP). Soluble fms-like tyrosine kinase 1 (sFlt-1) is positively associated with organ failure in sepsis. Our aim was to evaluate the diagnostic utility of automated sFlt-1 measurements for early prediction of AP severity. Adult patients (66) with AP were recruited, including 46 with mild (MAP), 15 with moderately-severe (MSAP) and 5 with severe AP (SAP). Serum and urine samples were collected twice. Serum sFlt-1 was measured with automated electrochemiluminescence immunoassay. Serum concentrations of sFlt-1 were significantly higher in patients with MSAP and SAP as compared to MAP. SAP patients had the highest concentrations. At 24 and 48 h, sFlt-1 positively correlated with inflammatory markers (leukocyte count, C-reactive protein), kidney function (creatinine, urea, cystatin C, serum and urine neutrophil gelatinase-associated lipocalin, urine albumin/creatinine ratio), D-dimer and angiopoietin-2. sFlt-1 positively correlated with the bedside index of severity in AP (BISAP) score and the duration of hospital stay. Serum sFlt-1 above 139 pg/mL predicted more severe AP (MSAP + SAP). In the early phase of AP, sFlt-1 is positively associated with the severity of AP and predicts organ failure, in particular kidney failure. Serum sFlt-1 may be a practical way to improve early assessment of AP severity. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

3179 KiB

Open AccessArticle

Meta-Analysis of Early Nutrition: The Benefits of Enteral Feeding Compared to a Nil Per Os Diet Not Only in Severe, but Also in Mild and Moderate Acute Pancreatitis

by Katalin Márta, Nelli Farkas, Imre Szabó, Anita Illés, Áron Vincze, Gabriella Pár, Patrícia Sarlós, Judit Bajor, Ákos Szűcs, József Czimmer, Dóra Mosztbacher, Andrea Párniczky, Kata Szemes, Dániel Pécsi and Péter Hegyi

Int. J. Mol. Sci. 2016, 17(10), 1691; https://doi.org/10.3390/ijms17101691 - 20 Oct 2016

Cited by 23 | Viewed by 10195

Abstract

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed [...] Read more.

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann–Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

3057 KiB

Open AccessArticle

Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis

by Zygmunt Warzecha, Paweł Sendur, Piotr Ceranowicz, Marcin Dembiński, Jakub Cieszkowski, Beata Kuśnierz-Cabala, Rafał Olszanecki, Romana Tomaszewska, Tadeusz Ambroży and Artur Dembiński

Int. J. Mol. Sci. 2016, 17(10), 1709; https://doi.org/10.3390/ijms17101709 - 12 Oct 2016

Cited by 25 | Viewed by 5258 | Correction

Abstract

Coagulation is recognized as a key player in inflammatory and autoimmune diseases. The aim of the current research was to examine the effect of pretreatment with acenocoumarol on the development of acute pancreatitis (AP) evoked by cerulein. Methods: AP was induced in rats [...] Read more.

Coagulation is recognized as a key player in inflammatory and autoimmune diseases. The aim of the current research was to examine the effect of pretreatment with acenocoumarol on the development of acute pancreatitis (AP) evoked by cerulein. Methods: AP was induced in rats by cerulein administered intraperitoneally. Acenocoumarol (50, 100 or 150 µg/kg/dose/day) or saline were given once daily for seven days before AP induction. Results: In rats with AP, pretreatment with acenocoumarol administered at the dose of 50 or 100 µg/kg/dose/day improved pancreatic histology, reducing the degree of edema and inflammatory infiltration, and vacuolization of acinar cells. Moreover, pretreatment with acenocoumarol given at the dose of 50 or 100 µg/kg/dose/day reduced the AP-evoked increase in pancreatic weight, serum activity of amylase and lipase, and serum concentration of pro-inflammatory interleukin-1β, as well as ameliorated pancreatic DNA synthesis and pancreatic blood flow. In contrast, acenocoumarol given at the dose of 150 μg/kg/dose did not exhibit any protective effect against cerulein-induced pancreatitis. Conclusion: Low doses of acenocoumarol, given before induction of AP by cerulein, inhibit the development of that inflammation. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

1970 KiB

Open AccessArticle

The Prognostic and Predictive Role of Epidermal Growth Factor Receptor in Surgical Resected Pancreatic Cancer

by Meng Guo, Guopei Luo, Chen Liu, He Cheng, Yu Lu, Kaizhou Jin, Zuqiang Liu, Jiang Long, Liang Liu, Jin Xu, Dan Huang, Quanxing Ni and Xianjun Yu

Int. J. Mol. Sci. 2016, 17(7), 1090; https://doi.org/10.3390/ijms17071090 - 8 Jul 2016

Cited by 17 | Viewed by 5356

Abstract

The data regarding the prognostic significance of EGFR (epidermal growth factor receptor) expression and adjuvant therapy in patients with resected pancreatic cancer are insufficient. We retrospectively investigated EGFR status in 357 resected PDAC (pancreatic duct adenocarcinoma) patients using tissue immunohistochemistry and validated the [...] Read more.

The data regarding the prognostic significance of EGFR (epidermal growth factor receptor) expression and adjuvant therapy in patients with resected pancreatic cancer are insufficient. We retrospectively investigated EGFR status in 357 resected PDAC (pancreatic duct adenocarcinoma) patients using tissue immunohistochemistry and validated the possible role of EGFR expression in predicting prognosis. The analysis was based on excluding the multiple confounding parameters. A negative association was found between overall EGFR status and postoperative survival (p = 0.986). Remarkably, adjuvant chemotherapy and radiotherapy were significantly associated with favorable postoperative survival, which prolonged median overall survival (OS) for 5.8 and 10.2 months (p = 0.009 and p = 0.006, respectively). Kaplan–Meier analysis showed that adjuvant chemotherapy correlated with an obvious survival benefit in the EGFR-positive subgroup rather than in the EGFR-negative subgroup. In the subgroup analyses, chemotherapy was highly associated with increased postoperative survival in the EGFR-positive subgroup (p = 0.002), and radiotherapy had a significant survival benefit in the EGFR-negative subgroup (p = 0.029). This study demonstrated that EGFR expression is not correlated with outcome in resected pancreatic cancer patients. Adjuvant chemotherapy and radiotherapy were significantly associated with improved survival in contrary EGFR expressing subgroup. Further studies of EGFR as a potential target for pancreatic cancer treatment are warranted. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

Review

Jump to: Research

1532 KiB

Open AccessReview

Neoadjuvant Therapy of Pancreatic Cancer: Definitions and Benefits

by Stefan Heinrich and Hauke Lang

Int. J. Mol. Sci. 2017, 18(8), 1622; https://doi.org/10.3390/ijms18081622 - 26 Jul 2017

Cited by 107 | Viewed by 11437

Abstract

The standard treatment of resectable pancreatic cancer is surgery followed by adjuvant chemotherapy. Due to the complication rate of pancreatic surgery and the high rate of primary irresectability, neoadjuvant concepts are increasingly used for pancreatic cancer. Neoadjuvant therapy is better tolerated than adjuvant [...] Read more.

The standard treatment of resectable pancreatic cancer is surgery followed by adjuvant chemotherapy. Due to the complication rate of pancreatic surgery and the high rate of primary irresectability, neoadjuvant concepts are increasingly used for pancreatic cancer. Neoadjuvant therapy is better tolerated than adjuvant and might decrease the surgical complication rate from pancreatic surgery. In contrast to neoadjuvant chemoradiation, the nutritional status improves during neoadjuvant chemotherapy. Also, the survival of patients who develop postoperative complications after neoadjuvant therapy is comparable to those without complications whereas the survival of patients who underwent upfront surgery and then develop surgical complications is impaired. Moreover, large data base analyses suggest a down-sizing effect and improvement of overall survival by neoadjuvant therapy. Neoadjuvant chemotherapy appears to be equally efficient in converting irresectable in resectable disease and more efficient with regard to systemic tumor progression and overall survival compared to neoadjuvant chemoradiation therapy. Despite these convincing findings from mostly small phase II trials, neoadjuvant therapy has not yet proven superiority over upfront surgery in randomized trials. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

1523 KiB

Open AccessReview

Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies

by Aleksandra Adamska, Alice Domenichini and Marco Falasca

Int. J. Mol. Sci. 2017, 18(7), 1338; https://doi.org/10.3390/ijms18071338 - 22 Jun 2017

Cited by 412 | Viewed by 18027

Abstract

Pancreatic ductal adenocarcinoma (PDAC), which constitutes 90% of pancreatic cancers, is the fourth leading cause of cancer-related deaths in the world. Due to the broad heterogeneity of genetic mutations and dense stromal environment, PDAC belongs to one of the most chemoresistant cancers. Most [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), which constitutes 90% of pancreatic cancers, is the fourth leading cause of cancer-related deaths in the world. Due to the broad heterogeneity of genetic mutations and dense stromal environment, PDAC belongs to one of the most chemoresistant cancers. Most of the available treatments are palliative, with the objective of relieving disease-related symptoms and prolonging survival. Currently, available therapeutic options are surgery, radiation, chemotherapy, immunotherapy, and use of targeted drugs. However, thus far, therapies targeting cancer-associated molecular pathways have not given satisfactory results; this is due in part to the rapid upregulation of compensatory alternative pathways as well as dense desmoplastic reaction. In this review, we summarize currently available therapies and clinical trials, directed towards a plethora of pathways and components dysregulated during PDAC carcinogenesis. Emerging trends towards targeted therapies as the most promising approach will also be discussed. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

506 KiB

Open AccessReview

Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes

by Marie Rouanet, Marine Lebrin, Fabian Gross, Barbara Bournet, Pierre Cordelier and Louis Buscail

Int. J. Mol. Sci. 2017, 18(6), 1231; https://doi.org/10.3390/ijms18061231 - 8 Jun 2017

Cited by 34 | Viewed by 10201

Abstract

A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments [...] Read more.

A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

710 KiB

Open AccessReview

Genomic Variations in Pancreatic Cancer and Potential Opportunities for Development of New Approaches for Diagnosis and Treatment

by Shuangshuang Lu, Tasqeen Ahmed, Pan Du and Yaohe Wang

Int. J. Mol. Sci. 2017, 18(6), 1201; https://doi.org/10.3390/ijms18061201 - 5 Jun 2017

Cited by 13 | Viewed by 5814

Abstract

Human pancreatic cancer has a very poor prognosis with an overall five-year survival rate of less than 5% and an average median survival time of six months. This is largely due to metastatic disease, which is already present in the majority of patients [...] Read more.

Human pancreatic cancer has a very poor prognosis with an overall five-year survival rate of less than 5% and an average median survival time of six months. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Although our understanding of the molecular events underlying multi-step carcinogenesis in pancreatic cancer has steadily increased, translation into more effective therapeutic approaches has been inefficient in recent decades. Therefore, it is imperative that novel and targeted approaches are designed to facilitate the early detection and treatment of pancreatic cancer. Presently, there are numerous ongoing studies investigating the types of genomic variations in pancreatic cancer and their impact on tumor initiation and growth, as well as prognosis. This has led to the development of therapeutics to target these genetic variations for clinical benefit. Thus far, there have been minimal clinical successes directly targeting these genomic alterations; however research is ongoing to ultimately discover an innovative approach to tackle this devastating disease. This review will discuss the genomic variations in pancreatic cancer, and the resulting potential diagnostic and therapeutic implications. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

1726 KiB

Open AccessReview

Targeting the Epidermal Growth Factor Receptor in Addition to Chemotherapy in Patients with Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

by Jaseela Chiramel, Alison C. Backen, Rille Pihlak, Angela Lamarca, Melissa Frizziero, Noor-ul-Ain Tariq, Richard A. Hubner, Juan W. Valle, Eitan Amir and Mairéad G. McNamara

Int. J. Mol. Sci. 2017, 18(5), 909; https://doi.org/10.3390/ijms18050909 - 26 Apr 2017

Cited by 21 | Viewed by 5190

Abstract

Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced [...] Read more.

Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, p = 0.15) or overall survival (HR: 0.94, p = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, p = 0.007), and grade (G)3/4 rash (OR: 4.82, p = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = −0.69, p < 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

709 KiB

Open AccessReview

Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward

by Mohammad Aslam Khan, Shafquat Azim, Haseeb Zubair, Arun Bhardwaj, Girijesh Kumar Patel, Moh’d Khushman, Seema Singh and Ajay Pratap Singh

Int. J. Mol. Sci. 2017, 18(4), 779; https://doi.org/10.3390/ijms18040779 - 6 Apr 2017

Cited by 49 | Viewed by 10443

Abstract

Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is [...] Read more.

Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

490 KiB

Open AccessReview

Novel Diagnostic and Predictive Biomarkers in Pancreatic Adenocarcinoma

by John C. Chang and Madappa Kundranda

Int. J. Mol. Sci. 2017, 18(3), 667; https://doi.org/10.3390/ijms18030667 - 20 Mar 2017

Cited by 109 | Viewed by 8567

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts have been dedicated to finding the appropriate serum and imaging biomarkers to help early detection and predict response to treatment of PDAC. Carbohydrate antigen 19-9 (CA 19-9) has been the most validated serum marker and has the highest positive predictive value as a stand-alone marker. When combined with carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA 125), CA 19-9 can help predict the outcome of patients to surgery and chemotherapy. A slew of novel serum markers including multimarker panels as well as genetic and epigenetic materials have potential for early detection of pancreatic cancer, although these remain to be validated in larger trials. Imaging studies may not correlate with elevated serum markers. Critical features for determining PDAC include the presence of a mass, dilated pancreatic duct, and a duct cut-off sign. Features that are indicative of early metastasis includes neurovascular bundle involvement, duodenal invasion, and greater post contrast enhancement. 18-F-fluorodeoxyglucose (18-FDG) radiotracer uptake and changes following treatment may predict patient overall survival following treatment. Similarly, pretreatment apparent diffusion coefficient (ADC) values may predict prognosis with lower ADC lesions having worse outcome. Although these markers have provided significant improvement in the care of pancreatic cancer patients, further advancements can be made with perhaps better combination of markers or discovery of unique marker(s) to pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

823 KiB

Open AccessReview

The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma

by Daisuke Kudo, Akiko Suto and Kenichi Hakamada

Int. J. Mol. Sci. 2017, 18(3), 600; https://doi.org/10.3390/ijms18030600 - 9 Mar 2017

Cited by 31 | Viewed by 5933

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases to affect humans, regardless of whether patients receive multimodal therapy (including surgery, radiotherapy, and chemotherapy). This resistance to intervention is currently considered to be caused by the desmoplastic change of the extracellular [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases to affect humans, regardless of whether patients receive multimodal therapy (including surgery, radiotherapy, and chemotherapy). This resistance to intervention is currently considered to be caused by the desmoplastic change of the extracellular matrix (ECM) in PDAC tissues, which is characterized by the accumulation of cancer-associated fibroblasts, collagen, proteoglycan, and hyaluronan. Among these ECM components, hyaluronan has attracted interest because various studies have indicated that hyaluronan-rich PDAC is correlated with the progressive properties of cancer cells, both in experimental and clinical settings. Hence, the reduction of hyaluronan in cancer tissue may represent a novel therapeutic approach for PDAC. 4-methylumbelliferone (4-MU) is a derivative of coumarin that was reported to suppress the synthesis of hyaluronan in cultured human skin fibroblasts in 1995. As an additional study, our group firstly reported that 4-MU reduced the hyaluronan synthesis of mouse melanoma cells and exerted anti-cancer activity. Subsequently, we have showed that 4-MU inhibited liver metastasis in mice inoculated with human pancreatic cancer cells. Thereafter, 4-MU has been accepted as an effective agent for hyaluronan research and is expected to have clinical applications. This review provides an overview of the interaction between PDAC and hyaluronan, the properties of 4-MU as a suppressor of the synthesis of hyaluronan, and the perspectives of PDAC treatment targeting hyaluronan. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Figure 1

293 KiB

Open AccessReview

The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications

by Paulina Dumnicka, Dawid Maduzia, Piotr Ceranowicz, Rafał Olszanecki, Ryszard Drożdż and Beata Kuśnierz-Cabala

Int. J. Mol. Sci. 2017, 18(2), 354; https://doi.org/10.3390/ijms18020354 - 8 Feb 2017

Cited by 132 | Viewed by 9197

Abstract

Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation [...] Read more.

Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

4198 KiB

Open AccessReview

Pancreatic Neuroendocrine Neoplasms: Basic Biology, Current Treatment Strategies and Prospects for the Future

by Akihiro Ohmoto, Hirofumi Rokutan and Shinichi Yachida

Int. J. Mol. Sci. 2017, 18(1), 143; https://doi.org/10.3390/ijms18010143 - 13 Jan 2017

Cited by 48 | Viewed by 9558

Abstract

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1%–2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2; and neuroendocrine carcinoma: NEC) on the basis of the Ki-67 proliferation index [...] Read more.

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1%–2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2; and neuroendocrine carcinoma: NEC) on the basis of the Ki-67 proliferation index and the mitotic count according to the 2010 World Health Organization (WHO) classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic background together with preclinical studies to develop new agents, including those already under investigation for small cell lung cancer (SCLC), will be needed to improve the prognosis. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

815 KiB

Open AccessReview

Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications

by Brittany R. Silverman and Jiaqi Shi

Int. J. Mol. Sci. 2016, 17(12), 2138; https://doi.org/10.3390/ijms17122138 - 19 Dec 2016

Cited by 26 | Viewed by 8078

Abstract

Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. Emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. Some of these mutations are driver mutations in cancer development. Several most [...] Read more.

Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. Emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. Some of these mutations are driver mutations in cancer development. Several most important mechanisms of epigenetic regulations include DNA methylation, histone modifications (methylation, acetylation, and ubiquitination), chromatin remodeling, and non-coding ribonucleic acids (RNAs). These modifications can alter chromatin structure and promoter accessibility, and thus lead to aberrant gene expression. However, exactly how these alterations affect epigenetic reprogramming in pancreatic cancer cells and in different stages of tumor development is still not clear. This mini-review summarizes the current knowledge of epigenetic alterations in pancreatic cancer development and progression, and discusses the clinical applications of epigenetic regulators as diagnostic biomarkers and therapeutic targets in pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Pancreatic Disorders

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issue

Published Papers (28 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI