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Find video protocols related to scientific articles indexed in Pubmed.
Durability of Antibody Response against Hepatitis B Virus in Healthcare Workers Vaccinated as Adults.
Clin. Infect. Dis.
PUBLISHED: 11-10-2014
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?Follow-up studies of recipients of hepatitis B vaccine from endemic areas have reported loss of antibody to hepatitis B surface antigen (anti-HBs) in a high proportion of persons vaccinated at birth. In contrast, the long-term durability of antibody in persons vaccinated as adults in non-endemic areas is not well-defined.
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Pancreatic Main-Duct Involvement in Branch-Duct IPMNs: An Underestimated Risk.
Ann. Surg.
PUBLISHED: 11-08-2014
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This study aimed to analyze a large single-center population of resected intraductal papillary mucinous neoplasms (IPMN) of the pancreas with respect to risk factors of malignant transformation.
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Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study.
Gut
PUBLISHED: 09-24-2014
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Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort.
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Immunological in vivo effects of B7-H1 deficiency.
Immunol. Lett.
PUBLISHED: 08-28-2014
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B7-H1 regulatory protein, a member of the B7-H family, plays a crucial role in the modulation of immune response in healthy steady-state conditions as well as in different pathologies. B7-H1 knockout mice represent an important model to elucidate further molecular and cellular mechanisms involved, among others, in autoimmunity development and cancer progression. However, a deep immunologic characterization of this model is not complete yet. This study examined the role of B7-H1 in vivo further by direct comparison of specifically phenotyped spleen immune-cell subpopulations and their activation and naïve/memory state as well as cytokine profile in wild-type and B7-H1 knockout mice. Our results demonstrated that B7-H1 deficiency in vivo modulates several immunological parameters, including the amount and composition of Gr1(+)CD11b(+) myeloid population, the composition and activation state of the DC compartment, the frequency and status of NK and NKT cells, B-cells, naïve/memory state of CD8 T-cells and production of IL-2 and IL-10 cytokines. Moreover, we observed an increase in the PD-1 expression in the immune cells in B7-H1 knockout mice compared to the wild-type animals. Valuing the importance of B7-H1 knockout mice for their use in disease models, these data underline the role of B7-H1 in vivo also in healthy state and should be taken into account in future studies on this immunosuppressive molecule.
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Acute alcohol-induced pancreatic injury is similar with intravenous and intragastric routes of alcohol administration.
Pancreas
PUBLISHED: 08-16-2014
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Five percent of alcoholics develop an acute pancreatitis (AP). The mechanism leading to pancreatic injury is not yet understood. Microcirculatory disorders seem to play a pivotal role. The objective of this study was to compare alcoholic pancreatic injury in response to intravenous and intragastric routes of alcohol administration.
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Pharmacological cholinergic stimulation as a therapeutic tool in experimental necrotizing pancreatitis.
Pancreas
PUBLISHED: 08-16-2014
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The endogenous immune response is influenced by the stimulation of the vagal nerve. Stimulation or ablation has a direct impact on the release of pro- and anti-inflammatory mediators. In the progression of acute pancreatitis from local to systemic disease, these mediators play a pivotal role. This study evaluates the effect of pharmacologic stimulation of the cholinergic system on pancreatic damage in experimental necrotizing pancreatitis.
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Objective parameters aid the prediction of fistulas in pancreatic surgery.
Exp Ther Med
PUBLISHED: 07-07-2014
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Insufficiency of pancreatic anastomosis with leakage from the pancreatic stump and the development of fistulas account for the majority of surgical complications following pancreatic resection, which are often life threatening. The cause of pancreatic fistulas of the remnant tissue on a molecular level remains unclear. Thus, the aim of the present study was to investigate risk factors associated with postoperative pancreatic fistula (POPF) formation and to define parameters that may predict the resection outcome. Pancreatic resection margins were selected from 31 patients, including 16 individuals without and 15 patients with POPF, to analyze the degree of fibrosis, lipomatous atrophy, inflammatory activity and infiltration. Wound healing factors were assessed by luminex technology using tissue homogenates, while the distribution in situ was assessed using immunohistochemistry. Increased chronic inflammatory infiltration, a higher degree of fibrosis and a reduction in lipomatous atrophy were observed in the samples without anastomotic fistulas. Multiplex analysis of 38 wound healing factors demonstrated significantly higher levels of interleukin (IL)-6, -8 and -12, glucagon-like peptide-1 and matrix metalloproteinase (MMP)-1, -2, -3 and -12 in the group without fistulas, while lower concentrations of IL-10, IL-17 and gastric inhibitory polypeptide were observed. Therefore, the observations of the present study indicated that increased inflammatory infiltration and inflammatory activity, as well as higher concentrations of proinflammatory cytokines and higher MMP levels at the resection margins, predisposed individuals to a lower fistula incidence rate following pancreatic resection.
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Total Pancreatectomy for Primary Pancreatic Neoplasms: Renaissance of an Unpopular Operation.
Ann. Surg.
PUBLISHED: 07-01-2014
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To assess the long-term survival and quality of life in total pancreatectomies and to identify risk factors for perioperative morbidity and mortality.
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Pancreatic Adenocarcinoma: Number of Positive Nodes Allows to Distinguish Several N Categories.
Ann. Surg.
PUBLISHED: 07-01-2014
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Lymph node (LN) involvement is a major prognostic factor in pancreatic adenocarcinoma. However, the distinction N0/N1 is not sufficient to accurately predict prognosis. To improve prognostic accuracy in N1 tumors, different LN parameters have been tested. Previous studies were based on series with variable numbers of examined lymph nodes (ELN) and came to inconsistent conclusions as to the value of the number of positive lymph nodes (PLN) and the lymph node ratio (LNR).
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A systematic review of localization, surgical treatment options, and outcome of insulinoma.
Pancreas
PUBLISHED: 06-13-2014
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Insulinoma with an incidence of 0.4% is a rare pancreatic tumor. Preserving surgery is the treatment of choice. Exact localization is necessary to plan the appropriate approach. This article gives an overview on localization and surgical strategies for treatment of insulinoma.
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Prognostic impact of CA 19-9 on outcome after neoadjuvant chemoradiation in patients with locally advanced pancreatic cancer.
Ann. Surg. Oncol.
PUBLISHED: 06-11-2014
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To asses the impact of CA 19-9 and weight loss/gain on outcome after neoadjuvant chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC).
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Unresectable isolated hepatic metastases from solid pseudopapillary neoplasm of the pancreas: A case report of chemosaturation with high-dose melphalan.
Pancreatology
PUBLISHED: 05-16-2014
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Solid pseudopapillary neoplasms of the pancreas (SPN) are rare tumors. For patients with unresectable liver metastases of SPN, no standard treatment has been defined so far. Here we report a case of a 40-year-old woman with SPN and metastases confirmed to the liver, and disease progression in the liver after primary tumor resection and chemotherapy with gemcitabine and cisplatin.
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Interlude of cGMP and cGMP/protein kinase G type 1 in pancreatic adenocarcinoma cells.
Pancreas
PUBLISHED: 05-16-2014
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cAMP and cGMP signaling is important both for normal and cancer cells. This signaling is controlled by adenylyl and guanylyl cyclases and cyclic nucleotide phosphodiesterases. One of the direct targets for cGMP is protein kinase G (PKG). The main aim of this work was to investigate cGMP and PKG signaling in pancreatic adenocarcinoma (PDAC) cells.
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Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer.
Clin. Cancer Res.
PUBLISHED: 04-24-2014
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Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive collagen-rich stroma. T cells that infiltrate pancreatic cancers frequently become trapped in the stroma and do not contact tumor cells. Here, we aimed to analyze how chemokines and extracellular matrix (ECM) collagen interact in mediating T-cell infiltration in PDAC.
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Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication.
Oncotarget
PUBLISHED: 04-19-2014
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The extreme aggressiveness of pancreatic ductal adenocarcinoma (PDA) has been associated with blocked gap junctional intercellular communication (GJIC) and the presence of cancer stem cells (CSCs). We examined whether disturbed GJIC is responsible for a CSC phenotype in established and primary cancer cells and patient tissue of PDA using interdisciplinary methods based in physiology, cell and molecular biology, histology and epigenetics. Flux of fluorescent dyes and gemcitabine through gap junctions (GJs) was intact in less aggressive cells but not in highly malignant cells with morphological dysfunctional GJs. Among several connexins, only Cx43 was expressed on the cell surface of less aggressive and GJIC-competent cells, whereas Cx43 surface expression was absent in highly malignant, E-cadherin-negative and GJIC-incompetent cells. The levels of total Cx43 protein and Cx43 phosphorylated at Ser368 and Ser279/282 were high in normal tissue but low to absent in malignant tissue. si-RNA-mediated inhibition of Cx43 expression in GJIC-competent cells prevented GJIC and induced colony formation and the expression of stem cell-related factors. The bioactive substance sulforaphane enhanced Cx43 and E-cadherin levels, inhibited the CSC markers c-Met and CD133, improved the functional morphology of GJs and enhanced GJIC. Sulforaphane altered the phosphorylation of several kinases and their substrates and inhibition of GSK3, JNK and PKC prevented sulforaphane-induced CX43 expression. The sulforaphane-mediated expression of Cx43 was not correlated with enhanced Cx43 RNA expression, acetylated histone binding and Cx43 promoter de-methylation, suggesting that posttranslational phosphorylation is the dominant regulatory mechanism. Together, the absence of Cx43 prevents GJIC and enhances aggressiveness, whereas sulforaphane counteracts this process, and our findings highlight dietary co-treatment as a viable treatment option for PDA.
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Influence of interferon-? on the expression of the cancer stem cell markers in pancreatic carcinoma cells.
Exp. Cell Res.
PUBLISHED: 03-26-2014
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The cytokine interferon-? (IFN?) belongs to the group of type I interferons already used in cancer therapy. This drug possesses radio- and chemo-sensitizing, and shows anti-angiogenic properties. Cancer stem cells (CSC) are a unique population of tumor cells that initiate secondary tumors, and are responsible for metastasis formation. Patients with pancreatic ductal adenocarcinoma (PDAC) have an especially poor prognosis, with 5-year survival rates of only ~1% and median survival of 4-6 months. PDAC is characterized by the presence of CSC. In this work we demonstrate for the first time that IFN? up-regulates the expression of the CSC markers CD24, CD44 and CD133 in in vitro and in vivo models of PDAC. We showed the IFN? effects on the migration and invasion of PDAC cells, which is associated with the level of the CSC marker expression. In vivo, this drug inhibits tumor growth but promotes metastasis formation in the early stage of tumor growth. We propose that IFN? may enhance the enrichment of CSC in PDAC tumors. Additionally we also suggest that in combination therapy of solid tumors with IFN?, this drug should be given to patients prior to chemotherapy to achieve the CSC activation.
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Molecular analysis of pancreatic acinar cell cystadenomas: Evidence of a non-neoplastic nature.
Oncol Lett
PUBLISHED: 03-21-2014
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The biology of pancreatic acinar cell cystadenomas has not been clearly defined. However, a non-neoplastic process, caused by a cell differentiation failure leading to a cystic transformation, has been discussed, as well as a benign neoplastic lesion. Pancreatic acinar cell cystadenomas usually consist of thin-walled unilocular or multilocular cysts, and mural nodules have been described in two cases of a recent series. In one of these nodules, chromosomal imbalances were detected, which provided preliminary evidence for a neoplastic process. The aim of the current study was to further characterize the lesions by molecular analyses. In four cases without mural nodules, the clonality was assessed by performing mutational analyses within the highly variable displacement-loop region of the mitochondrial DNA. As a result, no closer correlation was identified between different foci within the tumors than between the tumors and adjacent normal pancreatic acinar tissue, indicating polyclonality of these lesions. Further molecular analyses revealed no mutations of the ?-catenin and K-ras genes. In addition, no immunohistochemical evidence was identified for mutations of Smad4 or p53. In conclusion, the results of the current study demonstrated that pancreatic acinar cell cystadenomas are non-neoplastic lesions, with the potential exception of those rare cases with mural nodules.
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Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival.
Mol. Carcinog.
PUBLISHED: 03-17-2014
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Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. All-trans retinoic acid (ATRA) is the major physiologically active form of vitamin A, regulating expression of many genes. Disturbances of vitamin A metabolism are prevalent in some cancer cells. The main aim of this work was to investigate deeply the components of retinoid signaling in PDAC compared to in the normal pancreas and to prove the clinical importance of retinoid receptor expression. For the study, human tumor tissues obtained from PDAC patients and murine tumors from the orthotopic Panc02 model were used for the analysis of retinoids, using high performance liquid chromatography mass spectrometry and real-time RT-PCR gene expression analysis. Survival probabilities in univariate analysis were estimated using the Kaplan-Meier method and the Cox proportional hazards model was used for the multivariate analysis. In this work, we showed for the first time that the ATRA and all-trans retinol concentration is reduced in PDAC tissue compared to their normal counterparts. The expression of RAR? and ? as well as RXR? and ? are down-regulated in PDAC tissue. This reduced expression of retinoid receptors correlates with the expression of some markers of differentiation and epithelial-to-mesenchymal transition as well as of cancer stem cell markers. Importantly, the expression of RAR? and RXR? is associated with better overall survival of PDAC patients. Thus, reduction of retinoids and their receptors is an important feature of PDAC and is associated with worse patient survival outcomes. © 2014 Wiley Periodicals, Inc.
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Monocytes activate natural killer cells via inflammasome-induced interleukin 18 in response to hepatitis C virus replication.
Gastroenterology
PUBLISHED: 03-17-2014
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Production of interferon (IFN)-? by natural killer (NK) cells is attenuated during chronic infection with hepatitis C virus (HCV). We investigated whether this is due to intrinsic or extrinsic mechanisms of NK cells.
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Triptolide reverses hypoxia-induced epithelial-mesenchymal transition and stem-like features in pancreatic cancer by NF-?B downregulation.
Int. J. Cancer
PUBLISHED: 03-12-2014
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Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies characterized by an intense tumor stroma with hypoperfused regions, a significant inflammatory response and pronounced therapy resistance. New therapeutic agents are urgently needed. The plant-derived agent triptolide also known as "thunder god vine" has a long history in traditional Chinese medicine for treatment of rheumatoid arthritis and cancer and is now in a clinical phase II trial for establishing the efficacy against a placebo. The authors mimicked the situation in patient tumors by induction of hypoxia in experimental models of pancreatic cancer stem cells (CSCs) and evaluated the therapeutic effect of triptolide. Hypoxia led to induction of colony and spheroid formation, aldehyde dehydrogenase 1 (ALDH1) and NF-?B activity, migratory potential and a switch in morphology to a fibroblastoid phenotype, as well as stem cell- and epithelial-mesenchymal transition-associated protein expression. Triptolide efficiently inhibited hypoxia-induced transcriptional signaling and downregulated epithelial-mesenchymal transition (EMT) and CSC features in established highly malignant cell lines, whereas sensitive cancer cells or nonmalignant cells were less affected. In vivo triptolide inhibited tumor take and tumor growth. In primary CSCs isolated from patient tumors, triptolide downregulated markers of CSCs, proliferation and mesenchymal cells along with upregulation of markers for apoptosis and epithelial cells. This study is the first to show that triptolide reverses EMT and CSC characteristics and therefore may be superior to current chemotherapeutics for treatment of PDA.
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Complementary induction of immunogenic cell death by oncolytic parvovirus H-1PV and gemcitabine in pancreatic cancer.
J. Virol.
PUBLISHED: 02-26-2014
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Novel therapies employing oncolytic viruses have emerged as promising anticancer modalities. The cure of particularly aggressive malignancies requires induction of immunogenic cell death (ICD), coupling oncolysis with immune responses via calreticulin, ATP, and high-mobility group box protein B1 (HMGB1) release from dying tumor cells. The present study shows that in human pancreatic cancer cells (pancreatic ductal adenocarcinoma [PDAC] cells n=4), oncolytic parvovirus H-1 (H-1PV) activated multiple interconnected death pathways but failed to induce calreticulin exposure or ATP release. In contrast, H-1PV elevated extracellular HMGB1 levels by 4.0±0.5 times (58%±9% of total content; up to 100 ng/ml) in all infected cultures, whether nondying, necrotic, or apoptotic. An alternative secretory route allowed H-1PV to overcome the failure of gemcitabine to trigger HMGB1 release, without impeding cytotoxicity or other ICD activities of the standard PDAC medication. Such broad resistance of H-1PV-induced HMGB1 release to apoptotic blockage coincided with but was uncoupled from an autocrine interleukin-1? (IL-1?) loop. That and the pattern of viral determinants maintained in gemcitabine-treated cells suggested the activation of an inflammasome/caspase 1 (CASP1) platform alongside DNA detachment and/or nuclear exclusion of HMGB1 during early stages of the viral life cycle. We concluded that H-1PV infection of PDAC cells is signaled through secretion of the alarmin HMGB1 and, besides its own oncolytic effect, might convert drug-induced apoptosis into an ICD process. A transient arrest of cells in the cyclin A1-rich S phase would suffice to support compatibility of proliferation-dependent H-1PV with cytotoxic regimens. These properties warrant incorporation of the oncolytic virus H-1PV, which is not pathogenic in humans, into multimodal anticancer treatments.
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Ribavirin improves the IFN-? response of natural killer cells to IFN-based therapy of hepatitis C virus infection.
Hepatology
PUBLISHED: 02-20-2014
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Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-?/? receptor signaling, as NK cell cytotoxicity and IFN-? production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-phosphorylation, respectively. Specifically, pSTAT1-dependent NK cell cytotoxicity increases and pSTAT4-dependent IFN-? production decreases in response to endogenous, virus-induced IFN-? and during IFN-?-based therapy. To assess whether RBV has a direct effect on NK cells and/or improves the IFN-? response of NK cells in the presence of IFN-?, we prospectively studied 22 HCV patients with and 32 patients without 4 weeks of RBV pretreatment, who all received subsequent pegylated (Peg)IFN/ribavirin combination therapy. During RBV pretreatment, both the frequency of CD56(dim) NK cells with cytotoxic effector functions and the frequency of CD56(bright) NK cells with the capacity to produce IFN-? decreased (P?=?0.049 and P?=?0.001, respectively). In vitro or in vivo exposure of NK cells to RBV improved the pSTAT4 (P?
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Influence of interferon-alpha combined with chemo (radio) therapy on immunological parameters in pancreatic adenocarcinoma.
Int J Mol Sci
PUBLISHED: 02-06-2014
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Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2?. Low doses of interferon-2? led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2? therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-? and IL-10 in the serum following the interferon-2? therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2? therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2? and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy.
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Specific CT 3D rendering of the treatment zone after Irreversible Electroporation (IRE) in a pig liver model: the "Chebyshev Center Concept" to define the maximum treatable tumor size.
BMC Med Imaging
PUBLISHED: 01-10-2014
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Size and shape of the treatment zone after Irreversible electroporation (IRE) can be difficult to depict due to the use of multiple applicators with complex spatial configuration. Exact geometrical definition of the treatment zone, however, is mandatory for acute treatment control since incomplete tumor coverage results in limited oncological outcome. In this study, the "Chebyshev Center Concept" was introduced for CT 3d rendering to assess size and position of the maximum treatable tumor at a specific safety margin.
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Outcome, complications, and mortality of an intrathoracic anastomosis in esophageal cancer in patients without a preoperative selection with a risk score.
Langenbecks Arch Surg
PUBLISHED: 01-09-2014
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Esophagectomy for esophageal cancer remains a challenge with relatively high morbidity. We analyzed outcome, complications, and mortality after abdominothoracic esophagectomy with intrathoracic anastomosis. No routine preoperative risk stratification was performed.
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Radiologic versus endoscopic evaluation of the conduit after esophageal resection: a prospective, blinded, intraindividually controlled diagnostic study.
Surg Endosc
PUBLISHED: 01-09-2014
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Anastomotic leakage is a major complication in esophageal surgery. Although contrast swallow is performed by many surgical centers before reintroduction of oral intake to exclude anastomotic leakage postoperatively, endoscopy is increasingly used in this situation and may be superior. This study compares radiographic contrast study and endoscopy for the identification of local complications after subtotal esophagectomy.
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Clinical impact of perioperative myocardial infarction after pancreatic surgery.
J. Gastrointest. Surg.
PUBLISHED: 01-02-2014
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The aim of this study was to evaluate the incidence, clinical impact and outcome of perioperative myocardial infarction (PMI) in patients undergoing pancreatic surgery.
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Chondroitin sulfate proteoglycan CSPG4 as a novel hypoxia-sensitive marker in pancreatic tumors.
PLoS ONE
PUBLISHED: 01-01-2014
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CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n?=?83) and validation (n?=?221) cohorts comprising donors (n?=?11+26) and patients with chronic pancreatitis (n?=?11+20) or neoplasms: benign (serous cystadenoma SCA, n?=?13+20), premalignant (intraductal dysplastic IPMNs, n?=?9+55), and malignant (IPMN-associated invasive carcinomas, n?=?4+14; ductal adenocarcinomas, n?=?35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n?=?139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissue(high)/sera(low)-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct epithelial lineage and contribute to cell polarity disorders. Surficial retention on tumor cells renders CSPG4 an attractive therapeutic target. Systemic 'drop and restoration' alterations accompanying IPMN and PDAC progression indicate that the interference of pancreatic diseases with local and remote shedding/release of sCSPG4 into circulation deserves broad diagnostic exploration.
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Improvement of surgical results for pancreatic cancer.
Lancet Oncol.
PUBLISHED: 10-02-2013
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Surgery is the only potential hope of cure for patients with pancreatic cancer. Advantageous tumour characteristics and complete tumour resection are the factors most relevant for a positive prognosis, so detection of premalignant or early invasive lesions, combined with safe and oncologically adequate surgery, is an important goal. The experience and volume of both the individual surgeon and hospital are of paramount importance to achieve low morbidity and adequate management of complications. Most pancreatic cancers are locally advanced or metastatic when diagnosed and need multimodal therapy. With increasing evidence on surgical and perioperative aspects of pancreatic cancer therapy, short-term and long-term outcomes of resectable and borderline resectable pancreatic cancer are improving.
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DISCOVER trial- Distal resection of the pancreas with or without coverage of the pancreatic remnant: study protocol of a randomised controlled trial.
Trials
PUBLISHED: 08-21-2013
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Distal pancreatectomy for benign and malignant tumours is the second most common surgical procedure on the pancreas. Postoperative pancreatic fistulas (POPF) represent the most significant clinical complication, causing prolongation of hospital stay and the need for additional diagnostic and therapeutic procedures. Although various techniques for preventing POPF have been evaluated, to date, there is no available technique that ensures closure of the pancreatic remnant.
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Two immune faces of pancreatic adenocarcinoma: possible implication for immunotherapy.
Cancer Immunol. Immunother.
PUBLISHED: 08-07-2013
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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms, having extremely poor prognosis with a 5-year survival rate of <1 % and a median survival of 6 months. In contrast to other malignancies, pancreatic cancer is highly resistant to chemotherapy and targeted therapy. Therefore, new treatment options are urgently needed to improve the survival of patients with PDAC. Based on our data showing that patients with higher CD8+ T cell tumour infiltration exhibited prolonged overall and disease-free survival compared to patients with lower or without CD8+ T cell tumour infiltration, we suggested that immunotherapy could be a promising treatment option for PDAC. However, clinical data from the chemoradioimmunotherapy with interferon-? (IFN) trial did not point to an improved efficiency of chemoradiation combined with IFN as compared to chemoradiotherapy alone, suggesting an important role of the immune suppression induced by PDAC and/or unspecific immune stimulation. In support of this hypothesis, we found that the PDAC patients and experimental mice had an increased number of regulatory T cells and myeloid-derived suppressor cells. These results allowed us to conclude that PDAC provokes not only an anti-tumour immune response, but also strong immune suppression. Thus, we supposed that new immunotherapeutical strategies should involve not only stimulation of the immune system of PDAC patients, but also exert control over the tumour immune suppressive milieu.
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Overcoming immunosuppression as a new immunotherapeutic approach against pancreatic cancer.
Oncoimmunology
PUBLISHED: 07-10-2013
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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of malignancy. Via a broad stimulation of the immune system, PDAC activates both antitumor immune responses and immunosuppressive mechanisms. We propose that new immunotherapeutic strategies for the management of PDAC should be designed to specifically neutralize the immunosuppressive tumor microenvironment.
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Pylorus resection in partial pancreaticoduodenectomy: impact on delayed gastric emptying.
Am. J. Surg.
PUBLISHED: 06-24-2013
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Partial pancreaticoduodenectomy (PD) is complicated by postoperative delayed gastric emptying (DGE) in up to 45% of patients. The aim of this study was to evaluate the impact of pylorus resection on DGE following PD.
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Occupational exposure to hepatitis C virus: early T-cell responses in the absence of seroconversion in a longitudinal cohort study.
J. Infect. Dis.
PUBLISHED: 06-24-2013
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Background: T-cell responses have been described in seronegative patients who test negative for hepatitis C virus (HCV) RNA despite frequent HCV exposure. However, the cross-sectional design of those studies did not clarify whether T cells were indeed induced by low-level HCV exposure without seroconversion or whether they resulted from regular acute infection with subsequent antibody loss.
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Phase I study evaluating the treatment of patients with locally advanced pancreatic cancer with carbon ion radiotherapy: the PHOENIX-01 trial.
BMC Cancer
PUBLISHED: 05-19-2013
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Treatment options for patients with locally advanced pancreatic cancer include surgery, chemotherapy as well as radiotherapy. In many cases, surgical resection is not possible, and therefore treatment alternatives have to be performed. Chemoradiation has been established as a convincing treatment alternative for locally advanced pancreatic cancer. Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 1.16 and 2.46 depending on the pancreatic cancer cell line as well as the endpoint analyzed. Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with pancreatic cancer.
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Advanced-stage pancreatic cancer: therapy options.
Nat Rev Clin Oncol
PUBLISHED: 04-30-2013
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Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, and surgical resection is a requirement for a potential cure. However, the majority of patients are diagnosed with advanced-stage disease, either metastatic (50%) or locally advanced cancer (30%). Although palliative chemotherapy is the standard of care for patients with metastatic disease, management of locally advanced adenocarcinoma is controversial. Several treatment options, including extended surgical resections, neoadjuvant therapy with subsequent resections, as well as palliative radiotherapy and/or chemotherapy, should be considered. However, there is little evidence available to support treatment options for locally advanced disease. As valid predictive biomarkers for stratification of therapy are not available today, future trials need to define the role of the different treatment options. This Review summarizes the current evidence and discusses available treatment options for both locally advanced and metastatic pancreatic adenocarcinoma.
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Gender-specific immunological effects of the phosphodiesterase 5 inhibitor sildenafil in healthy mice.
Mol. Immunol.
PUBLISHED: 04-29-2013
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Phosphodiesterase 5 (PDE5) is a pharmacological target in erectile dysfunction, pulmonary hypertension and in other indications. In tumor-bearing mice an inhibition of PDE5 with sildenafil prolongs survival of the animals through the augmentation of antitumor immunity, indicating the immunomodulatory properties of this drug. Effects of sildenafil on the immune system in healthy organisms are poorly investigated. In this work we showed that chronic application of sildenafil in healthy mice leads to opposite gender-dependent effects on NK cells, subpopulations of CD4(+) and CD8(+) T cells, activated conventional T cells, and to a decrease in Gr-1(+)CD11b(+) immature myeloid cells. Besides, sildenafil treatment decreases the serum concentration of interleukin-6. Ex vivo cultivation of isolated splenocytes with sildenafil results in an increase in CD4(+) T cells and a concomitant decrease in B cells and central memory CD8(+) T cells. Ex vivo modulatory properties of sildenafil are not gender-specific, indicating the importance of sildenafils pharmacokinetics for it immunomodulatory activity in vivo. While the PDE5 expression is equal in the splenocytes from both genders, splenocytes from female mice possess higher basal level of cGMP compared to the male ones. Moreover, cultivation of splenocytes obtained from female but not male mice with sildenafil leads to an increase in cGMP concentration, making sildenafils pharmacodynamics also responsible for gender-specific effects of the drug. Thus, this work secures conclusive evidence that the PDE5 inhibitor sildenafil possesses immunomodulatory properties and these effects are gender-specific. Immunological clinical trials are needed to prove the potential immunomodulatory effects of sildenafil in humans.
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Reactive oxygen species in the immune system.
Int. Rev. Immunol.
PUBLISHED: 04-25-2013
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Reactive oxygen species (ROS) are a group of highly reactive chemicals containing oxygen produced either exogenously or endogenously. ROS are related to a wide variety of human disorders, such as chronic inflammation, age-related diseases and cancers. Besides, ROS are also essential for various biological functions, including cell survival, cell growth, proliferation and differentiation, and immune response. At present there are a number of excellent publications including some reviews about functions of these molecules either in normal cell biology or in pathophysiology. In this work, we reviewed available information and recent advances about ROS in the main immune cell types and gave summary about functions of these highly reactive molecules both in innate immunity as conservative defense mechanisms and in essential immune cells involved in adaptive immunity, and particularly in immune suppression.
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Alcohol exacerbates LPS-induced fibrosis in subclinical acute pancreatitis.
Am. J. Pathol.
PUBLISHED: 04-05-2013
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The role of pancreatic acinar cells in initiating fibrogenic responses during the early stages of alcoholic acute pancreatitis has not been evaluated. We investigated the ability of injured acinar cells to generate pancreatic fibrosis in acute pancreatitis. Rats were fed either an ethanol-containing or control diet over 14 weeks and euthanized 3 or 24 hours after a single lipopolysaccharide injection. Profibrotic transforming growth factor-? of acinar cells and pancreatic fibrosis were assessed by immunofluorescence, histological characteristics, and electron microscopy. Human pancreatic tissues were also evaluated. Periacinar cell fibrosis and collagen were exacerbated 24 hours after endotoxemia in alcohol-fed rats. Alcohol exposure exacerbated acinar cell-specific production of transforming growth factor ? in response to lipopolysaccharide in vivo and in acinar cell-like AR42J cells in vitro. Although a morphological examination showed no visible signs of necrosis, early pancreatic fibrosis can be initiated by little or no pancreatic necrosis. Transforming growth factor ? was also significantly increased in human acinar cells from patients with acute/recurrent pancreatitis compared with chronic pancreatitis tissue. Alcohol exacerbates lipopolysaccharide-induced pancreatic fibrosis during the early onset of mild, subclinical, acute pancreatitis. We suggest that multiple, subclinical, acute pancreatitis episodes can accumulate in fibrosis during the development of chronic pancreatitis, even if there is no history of acute pancreatitis.
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Chronic pancreatitis--definition, etiology, investigation and treatment.
Dtsch Arztebl Int
PUBLISHED: 04-04-2013
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Chronic pancreatitis has an annual incidence of 23 per 100 000 population in Germany, where it accounts for about 10 000 hospital admissions per year. The disease shortens the life expectancy of its sufferers by an average of 23%. It most commonly affects men aged 20 to 40.
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Somatic mutations in exocrine pancreatic tumors: association with patient survival.
PLoS ONE
PUBLISHED: 03-04-2013
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KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P?=?0.07) with a multivariate hazard ratio (HR) of 2.19 (95%CI 1.09-4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P?=?0.03) and an associated multivariate HR 2.42 (95%CI 1.14-2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P?=?0.02) and a corresponding HR of 3.07 (95%CI 1.33-7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application.
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Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection.
Hepatology
PUBLISHED: 02-16-2013
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Hepatitis C virus (HCV) infection typically results in chronic disease with HCV outpacing antiviral immune responses. Here we asked whether innate immune responses are induced in healthcare workers who are exposed to small amounts of HCV, but do not develop systemic infection and acute liver disease. Twelve healthcare workers with accidental percutaneous exposure to HCV-infected blood were prospectively studied for up to 6 months for phenotype and function of natural killer T (NKT) and NK cells, kinetics of serum chemokines, and vigor and specificity of HCV-specific T-cell responses. Eleven healthcare workers tested negative for HCV RNA and HCV antibodies. All but one of these aviremic cases displayed NKT cell activation, increased serum chemokines levels, and NK cell responses with increased CD122, NKp44, NKp46, and NKG2A expression, cytotoxicity (as determined by TRAIL and CD107a expression), and interferon-gamma (IFN-?) production. This multifunctional NK cell response appeared a month earlier than in the one healthcare worker who developed high-level viremia, and it differed from the impaired IFN-? production, which is typical for NK cells in chronic HCV infection. The magnitude of NKT cell activation and NK cell cytotoxicity correlated with the magnitude of the subsequent HCV-specific T-cell response. T-cell responses targeted nonstructural HCV sequences that require translation of viral RNA, which suggests that transient or locally contained HCV replication occurred without detectable systemic viremia. Conclusion: Exposure to small amounts of HCV induces innate immune responses, which correlate with the subsequent HCV-specific T-cell response and may contribute to antiviral immunity. (Hepatology 2013).
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ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium.
Oncol. Rep.
PUBLISHED: 01-24-2013
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There is strong epidemiologic evidence indicating that common genetic variability could be implicated in pancreatic cancer risk and, to date, various loci have been proposed. In particular, there is increasing evidence of the involvement of ABO gene variability and pancreatic cancer risk. In a large multicentric study of 1,028 pancreatic ductal adenocarcinoma cases and 2,257 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium, we investigated the suggested association with increased risk for carriers of single nucleotide polymorphisms (SNPs) determining the A or B allele in comparison with the O allele, which encodes for a non-functional enzyme. Since glycosyltransferase activity, encoded by ABO, is higher for the A1 variant compared with the A2 variant, we investigated the hypothesis that A1 carriers were at an increased risk of pancreatic cancer. In our analysis, carriers of the A1 were indeed at greater risk of developing the disease. In addition, we investigated the possible influence that genetic variability at the ABO locus may have in pancreatic cancer survival, but we observed no effect in our population.
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Pylorus resection or pylorus preservation in partial pancreatico-duodenectomy (PROPP study): study protocol for a randomized controlled trial.
Trials
PUBLISHED: 01-22-2013
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Partial pancreatico-duodenectomy (PD) is the standard treatment for tumors of the pancreatic head. Today, preservation of the pylorus has been widely accepted as the surgical standard in this procedure. A common postoperative complication is the occurrence of delayed gastric emptying (DGE), which causes impairment of oral intake andpatients quality of life, prolongation of hospital stay and delay of further treatment (for example adjuvant chemotherapy). In a small number of two retrospective and one randomized studies, a modification by resection of the pylorus with preservation of the stomach has shown to reduce DGE incidence. The aim of the present study is to investigate the effect of pylorus resection on postoperative DGE in PD.
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Chemoradiation in patients with isolated recurrent pancreatic cancer - therapeutical efficacy and probability of re-resection.
Radiat Oncol
PUBLISHED: 01-22-2013
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In the present retrospective analysis we analysed the therapeutic outcome of a set of patients, who were treated with chemoradiation (CRT) for recurrent pancreatic cancer (RPC) in a single institution.
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Low-dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer.
Int. J. Cancer
PUBLISHED: 01-10-2013
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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms with extremely poor prognosis and a low survival rate. Immunosuppressive cell populations, e.g. regulatory T cells (Treg), appear to be important in PDAC, contributing to patients poor prognosis. Therefore, we investigated the PDAC microenvironment with a focus on conventional and regulatory T cells in view of their potential therapeutic importance. We found that tumors from the murine Panc02 orthotopic model of PDAC were infiltrated with high numbers of Treg. Remarkably, these cells exhibited the effector/memory phenotype, suggesting their enhanced suppressive activity and higher proliferation capacity. Although we observed a steady increase in transforming growth factor-? (TGF-?) levels in the tumors, treatment with a specific inhibitor of TGF-? receptor I kinase failed to abrogate Treg accumulation. A CCR4 antagonist did not affect Treg percentage in the tumor either. However, intense Treg cell division in the tumor microenvironment was demonstrated, suggesting local proliferation as a major mechanism of Treg accumulation in PDAC. Notably, this accumulation was reduced by low-dose gemcitabine administration, resulting in a modestly increased survival of PDAC mice. Our results provide an insight into mechanisms of immunosuppression in PDAC, suggesting an important role for proliferative expansion of effector/memory Treg. Low-dose gemcitabine therapy selectively depletes Treg, providing a basis for new modalities of PDAC therapy.
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European experts consensus statement on cystic tumours of the pancreas.
Dig Liver Dis
PUBLISHED: 01-08-2013
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Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.
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The hepatitis B vaccine protects re-exposed health care workers, but does not provide sterilizing immunity.
Gastroenterology
PUBLISHED: 01-03-2013
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Infection with hepatitis B virus (HBV) can be prevented by vaccination with HB surface (HBs) antigen, which induces HBs-specific antibodies and T cells. However, the duration of vaccine-induced protective immunity is poorly defined for health care workers who were vaccinated as adults.
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Serum Protein Signatures Differentiating Autoimmune Pancreatitis versus Pancreatic Cancer.
PLoS ONE
PUBLISHED: 01-01-2013
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Autoimmune pancreatitis (AIP) is defined by characteristic lymphoplasmacytic infiltrate, ductal strictures and a pancreatic enlargement or mass that can mimic pancreatic cancer (PaCa). The distinction between this benign disease and pancreatic cancer can be challenging. However, an accurate diagnosis may pre-empt the misdiagnosis of cancer, allowing the appropriate medical treatment of AIP and, consequently, decreasing the number of unnecessary pancreatic resections. Mass spectrometry (MS) and two-dimensional differential gel electrophoresis (2D-DIGE) have been applied to analyse serum protein alterations associated with AIP and PaCa, and to identify protein signatures indicative of the diseases. Patients sera were immunodepleted from the 20 most prominent serum proteins prior to further 2D-DIGE and image analysis. The identity of the most-discriminatory proteins detected, was performed by MS and ELISAs were applied to confirm their expression. Serum profiling data analysis with 2D-DIGE revealed 39 protein peaks able to discriminate between AIP and PaCa. Proteins were purified and further analysed by MALDI-TOF-MS. Peptide mass fingerprinting led to identification of eleven proteins. Among them apolipoprotein A-I, apolipoprotein A-II, transthyretin, and tetranectin were identified and found as 3.0-, 3.5-, 2-, and 1.6-fold decreased in PaCa sera, respectively, whereas haptoglobin and apolipoprotein E were found to be 3.8- and 1.6-fold elevated in PaCa sera. With the exception of haptoglobin the ELISA results of the identified proteins confirmed the 2D-DIGE image analysis characteristics. Integration of the identified serum proteins as AIP markers may have considerable potential to provide additional information for the diagnosis of AIP to choose the appropriate treatment.
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In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts.
PLoS ONE
PUBLISHED: 01-01-2013
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Pancreatic cancer is one of the leading cancer-related causes of death in the western world with an urgent need for new treatment strategies. Recently, hyperforin and nemorosone have been described as promising anti-cancer lead compounds. While hyperforin has been thoroughly investigated in vitro and in vivo, in vivo data for nemorosone are still missing. Thus, we investigated the growth-inhibitory potential of nemorosone on pancreatic cancer xenografts in NMRI nu/nu mice and determined basic pharmacokinetic parameters. Xenograft tumors were treated with nemorosone and gemcitabine, the current standard of care. Tumor sections were subjected to H&E as well as caspase 3 and Ki-67 staining. Nemorosone plasma kinetics were determined by HPLC and mass spectrometry. Induction of CYP3A4 and other metabolizing enzymes by nemorosone and hyperforin was tested on primary hepatocytes using qRT-PCR. At a dose of 50 mg/kg nemorosone per day, a significant growth-inhibitory effect was observed in pancreatic cancer xenografts. The compound was well tolerated and rapidly absorbed into the bloodstream with a half-life of approximately 30 min. Different metabolites were detected, possibly resembling CYP3A4-independent oxidation products. It is concluded that nemorosone is a potential anti-cancer lead compound with good bioavailability, little side-effects and promising growth-inhibitory effects, thus representing a valuable compound for a combination therapy approach.
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Differentiation of multiple types of pancreatico-biliary tumors by molecular analysis of clinical specimens.
J. Mol. Med.
PUBLISHED: 08-22-2011
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Timely and accurate diagnosis of pancreatic ductal adenocarcinoma (PDAC) is critical in order to provide adequate treatment to patients. However, the clinical signs and symptoms of PDAC are shared by several types of malignant or benign tumors which may be difficult to differentiate from PDAC with conventional diagnostic procedures. Among others, these include ampullary cancers, solid pseudopapillary tumors, and adenocarcinomas of the distant bile duct, as well as inflammatory masses developing in chronic pancreatitis. Here, we report an approach to accurately differentiate between these different types of pancreatic masses based on molecular analysis of biopsy material. A total of 156 bulk tissue and fine needle aspiration biopsy samples were analyzed using a dedicated diagnostic cDNA array and a composite classification algorithm developed based on linear support vector machines. All five histological subtypes of pancreatic masses were clearly separable with 100% accuracy when using all 156 individual samples for classification. Generalized performance of the classification system was tested by 10?×?10-fold cross validation (100 test runs). Correct classification into the five diagnostic groups was demonstrated for 81.5% of 1,560 test set predictions. Performance increased to 85.3% accuracy when PDAC and distant bile duct carcinomas were combined in a single diagnostic class. Importantly, overall sensitivity of detection of malignant disease was 92.2%. The molecular diagnostic approach presented here is suitable to significantly aid in the differential diagnosis of undetermined pancreatic masses. To our knowledge, this is the first study reporting accurate differentiation between several types of pancreatico-biliary tumors in a single molecular analytical procedure.
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Antioxidant therapy in acute pancreatitis: experimental and clinical evidence.
Antioxid. Redox Signal.
PUBLISHED: 08-11-2011
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Oxidative stress plays an important role in the pathogenesis of both acute and chronic pancreatitis. Although its impact is well investigated and has been studied clinically in chronic pancreatitis, it is less well defined for acute pancreatitis.
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Noninvasive indocyanine green plasma disappearance rate predicts early complications, graft failure or death after liver transplantation.
HBPD INT
PUBLISHED: 08-05-2011
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Early detection of graft malfunction or postoperative complications is essential to save patients and organs after orthotopic liver transplantation (OLT). Predictive tests for graft dysfunction are needed to enable earlier implementation of organ-saving interventions following transplantation. This study was undertaken to assess the value of indocyanine green plasma disappearance rates (ICG-PDRs) for predicting postoperative complications, graft dysfunction, and patient survival following OLT.
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Clinical profile of autoimmune pancreatitis and its histological subtypes: an international multicenter survey.
Pancreas
PUBLISHED: 07-13-2011
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The objective of this study was to clarify the clinical and pathophysiological characteristics of autoimmune pancreatitis (AIP) and its subtypes (lymphoplasmacytic sclerosing pancreatitis [LPSP] and idiopathic duct-centric pancreatitis [IDCP]) seen around the world.
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Pancreatic cancer susceptibility loci and their role in survival.
PLoS ONE
PUBLISHED: 06-27-2011
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Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease.
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Migration and chemokine receptor pattern of colitis-preventing DX5+NKT cells.
Int J Colorectal Dis
PUBLISHED: 05-30-2011
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DX5(+)NKT cells are a subpopulation of NKT cells expressing both T cell receptor and NK cell markers that show an immune-regulating function. Transferred DX5(+)NKT cells from immune competent Balb/c mice can prevent or reduce induced colitis in severe combined immunodeficient (SCID) mice. Here, we investigated the in vivo migration of DX5(+)NKT cells and their corresponding chemokine receptor patterns.
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Multidrug strategies are effective in the treatment of severe experimental pancreatitis.
Surgery
PUBLISHED: 05-28-2011
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Trypsinogen activation, oxygen radicals, cytokines, leukocyte infiltration, and pancreatic ischemia are important steps in the pathogenesis of necrotizing pancreatitis and associated systemic complications. Several drugs that inhibit those pathogenetic steps attenuated biochemical and histologic changes, while survival remained low. The aim of the present study was to evaluate the benefit of multidrug approaches compared to monotherapies on organ injury and survival in acute experimental pancreatitis in the rat model of retrograde bile injection combined with intravenous cerulein.
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Pancreatic cancer surgery in the new millennium: better prediction of outcome.
Ann. Surg.
PUBLISHED: 05-25-2011
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Surgery is the only therapy with potentially curative intention in pancreatic cancer. This analysis aimed to determine prognostic parameters in a patient cohort with resected pancreatic adenocarcinoma with a special focus on the revised R1-definition.
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Toward the blood-borne miRNome of human diseases.
Nat. Methods
PUBLISHED: 05-09-2011
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In a multicenter study, we determined the expression profiles of 863 microRNAs by array analysis of 454 blood samples from human individuals with different cancers or noncancer diseases, and validated this miRNome by quantitative real-time PCR. We detected consistently deregulated profiles for all tested diseases; pathway analysis confirmed disease association of the respective microRNAs. We observed significant correlations (P = 0.004) between the genomic location of disease-associated genetic variants and deregulated microRNAs.
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Prognostic significance of erythropoietin in pancreatic adenocarcinoma.
PLoS ONE
PUBLISHED: 04-27-2011
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Erythropoietin (Epo) administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC).
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Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor.
Cell Metab.
PUBLISHED: 04-22-2011
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Systemic bile acid (BA) homeostasis is a critical determinant of dietary fat digestion, enterohepatic function, and postprandial thermogenesis. However, major checkpoints for the dynamics and the molecular regulation of BA homeostasis remain unknown. Here we show that hypothalamic-pituitary-adrenal (HPA) axis impairment in humans and liver-specific deficiency of the glucocorticoid receptor (GR) in mice disrupts the normal changes in systemic BA distribution during the fasted-to-fed transition. Fasted mice with hepatocyte-specific GR knockdown had smaller gallbladder BA content and were more susceptible to developing cholesterol gallstones when fed a cholesterol-rich diet. Hepatic GR deficiency impaired liver BA uptake/transport via lower expression of the major hepatocyte basolateral BA transporter, Na(+)-taurocholate transport protein (Ntcp/Slc10a1), which affected dietary fat absorption and brown adipose tissue activation. Our results demonstrate a role of the HPA axis in the endocrine regulation of BA homeostasis through the liver GR control of enterohepatic BA recycling.
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Pancreas divisum: a differentiated surgical approach in symptomatic patients.
World J Surg
PUBLISHED: 04-08-2011
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Some patients with pancreas divisum (PD) develop symptoms of recurrent pancreatitis. This is probably caused by insufficient drainage of the pancreatic duct. We report the results of our follow-up of patients who underwent surgery for symptomatic pancreas divisum according to an individualized surgical approach.
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Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages.
Int. J. Oncol.
PUBLISHED: 04-04-2011
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Histone deacetylase inhibitors have been found to have potent anticancer activities, partly induced by tumour cell apoptosis. The clearance of apoptotic tumour cells is an important mechanism of antitumour immune surveillance. The aim of this study was to assess the impact of 4-phenylbutyrate (4-PB) and its immunological effects on the macrophage clearance of apoptotic pancreatic ductal adenocarcinoma (PDAC) cells. To this end, a co-culture system of human macrophages from donors and PDAC patients, and PDAC cell lines (T3M4, PANC-1 and AsPC-1) was established to study the effect of 4-PB. Apoptosis and phagocytic activity were analysed using flow cytometry, and phagocytosis was confirmed by confocal microscopy. Further, p21 expression was quantified by immunoblot analysis. 4-PB treatment (0-10 mM) resulted in a dose-dependent induction of tumour cell apoptosis in two of the cell lines (T3M4 and PANC-1), but it also induced human macrophage apoptosis. The apoptotic effect of gemcitabine on PDAC cells was further enhanced by 4-PB. Moreover, 4-PB led to a dose-dependent overexpression of the cell cycle regulator p21 in tumour cells. In co-culture, apoptotic PDAC cells were phagocytosed by donor macrophages and phagocytosis was increased through tumour cell exposure to 4-PB and/or gemcitabine, whereas phagocytosis of PANC-1 cells was reduced using macrophages of PDAC patients treated with 4-PB. The 4-PB treatment induced human macrophage expression of the pro-angiogenic IL-8 and simultaneously inhibited inflammatory cytokine release through modulation of IL-10 and TNF? after phagocytosis of apoptotic PDAC cells. In conclusion, the 4-PB treatment activated tumour cell death in PDAC cells, resulting in tumour cell phagocytosis by macrophages. The latter were characterized by an anti-inflammatory and pro-angiogenic cytokine response demonstrating adverse, tumour-promoting effects of macrophages on tumour cells. Thus, the potential of 4-PB as an anticancer agent against PDAC cannot be reliably assessed without taking into account the complex tumour microenvironment.
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CT diagnosis of recurrence after pancreatic cancer: is there a pattern?
World J. Gastroenterol.
PUBLISHED: 03-31-2011
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To investigate predilection sites of recurrence of pancreatic cancer by computed tomography (CT) in follow-up after surgery.
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Acinar cell carcinoma of the pancreas: is resection justified even in limited metastatic disease?
Am. J. Surg.
PUBLISHED: 03-27-2011
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Acinar cell carcinoma (ACC) of the pancreas is characterized by better long-term survival compared with the more common ductal adenocarcinoma, and prognosis is better in resected compared with nonresected patients. The aim of the present study was to investigate the role of surgery in ACC with limited metastatic disease.
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Randomized controlled phase I/II study to investigate immune stimulatory effects by low dose radiotherapy in primarily operable pancreatic cancer.
BMC Cancer
PUBLISHED: 02-24-2011
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The efficiencies of T cell based immunotherapies are affected by insufficient migration and activation of tumor specific effector T cells in the tumor. Accumulating evidence exists on the ability of ionizing radiation to modify the tumor microenvironment and generate inflammation. The aim of this phase I/II clinical trial is to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with pancreatic cancer.
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Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer.
Int. J. Oncol.
PUBLISHED: 02-17-2011
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The broccoli isothiocyanate, sulforaphane (SFN), was recently identified as being capable of eliminating highly therapy-resistant pancreatic carcinoma (PC) cells without inducing toxic side effects. While SFN has been shown to stimulate autophagy or self-eating, it is unclear whether this catabolic process is a pro- or anti-tumorigenic response. To investigate the role of autophagy in SFN-induced cell death, established PC cell lines were treated with SFN, and the induction of autophagy was evaluated by detecting the abundance of autophagic vesicles by electron microscopy, the increase in converted LC3-II by Western blot analysis and the autophagosome puncta of GFP-LC3 by immunofluorescence. SFN-induced autophagy was suppressed by the autophagy inhibitor chloroquine, while the autophagy inducer rapamycin did not further enhance autophagy in PC cells. Importantly, neither modulator altered SFN cytotoxicity, suggesting that SFN-induced autophagy and cell death act independently of each other. In contrast, the antioxidant N-acetyl-cysteine sustained cell viability and prevented autophagy induction after SFN exposure, indicating that both signaling pathways depend on reactive oxygen species (ROS). Our studies provide a valuable new mechanistic insight into the SFN-induced elimination of PC cells and suggest that an SFN-enriched diet potentially enhances ROS-releasing chemotherapeutic agents.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.