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ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is the most common pancreatic malignancy comprising approximately 85% of cases. Many aspects of surgical resection of pancreatic cancer have been evaluated as to their effects on morbidity and mortality, including evaluation of anastomotic techniques, the role of extended lymphadenectomies, and the use of vascular reconstruction. Progress in the perioperative care of those undergoing pancreatic resection for PDA has resulted in improved outcomes. This review discusses the preoperative evaluation of a patient with pancreatic cancer and addresses the surgical management of these patients, with special attention to recent areas of progress and controversy.
Surgical Oncology Clinics of North America 04/2010; 19(2):335-58. · 1.12 Impact Factor
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ABSTRACT: The RON receptor mediates tumorigenic phenotypes in pancreatic cancer (PC), but no investigations currently have implicated RON signaling as a regulator of angiogenesis in PC. Angiogenesis is vital to oncogenesis, and vascular endothelial growth factor (VEGF) is the most well-characterized angiogenic protein. This study sought to determine the effect of RON stimulation on in vitro angiogenesis and VEGF production in PC cell lines.
Vascular endothelial growth factor levels from conditioned media of hepatocyte growth factor-like protein-stimulated BxPC-3 and FG cells were quantitated via enzyme-linked immunosorbent assay and likewise interrogated in the presence and absence of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase/AKT inhibitors. To determine in vitro angiogenesis, human microvascular endothelial cells were subsequently exposed to the same conditioned media to assay for microtubule formation.
RON signaling resulted in a 52% and 34% increase in VEGF levels in BxPC-3 and FG cells, respectively. Vascular endothelial growth factor secretion was inhibited with MAPK or phosphatidylinositol-3-kinase blockade in BxPC-3 cells, but only MAPK inhibition resulted in decreased VEGF production in FG cells. BxPC-3 conditioned media induced tubule formation in human microvascular endothelial cells, which was abrogated by RON inhibition.
RON signaling results in MAPK-mediated VEGF secretion by PC cells and promotion of microtubule formation. These findings suggest another mechanism by which RON signaling may promote PC progression.
Pancreas 04/2010; 39(3):301-7. · 2.39 Impact Factor
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Jocelyn Logan-Collins, Ryan M Thomas,
Peter Yu,
Dawn Jaquish,
Evangeline Mose,
Randall French,
William Stuart,
Rebecca McClaine,
Bruce Aronow,
Robert M Hoffman,
Susan E Waltz,
Andrew M Lowy
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ABSTRACT: The RON receptor tyrosine kinase is overexpressed in premalignant pancreatic intraepithelial neoplasia (PanIN) and in the majority of pancreatic cancers. In pancreatic cells, RON is an important K-Ras effector and RON ligand can enhance migration/invasion and apoptotic resistance. However, the pathobiological significance of RON overexpression in pancreatic cancers has yet to be fully established. In this study, we demonstrate that RON signaling mediates a unique transcriptional program that is conserved between cultured cells derived from murine PanIN or human pancreatic cancer cells grown as subcutaneous tumor xenografts. In both systems, RON signaling regulates expression of genes implicated in cancer-cell survival, including Bcl-2 and the transcription factors signal transducer and activator of transcription 3 (STAT 3) and c-Jun. shRNA-mediated silencing of RON in pancreatic cancer xenografts inhibited their growth, primarily by increasing susceptibility to apoptosis and by sensitizing them to gemcitabine treatment. Escape from RON silencing was associated with re-expression of RON and/or expression of phosphorylated forms of the related c-Met or epidermal growth factor receptors. These findings indicate that RON signaling mediates cell survival and in vivo resistance to gemcitabine in pancreatic cancer, and they reveal mechanisms through which pancreatic cancer cells may circumvent RON-directed therapies.
Cancer Research 02/2010; 70(3):1130-40. · 7.86 Impact Factor
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ABSTRACT: The chemokine CXCL12, together with its specific receptor, CXCR4, have been shown to mediate invasiveness and metastatic behaviour in pancreatic cancer cells. The expression of CXC12/CXCR4 has not been previously examined in pancreatic intraepithelial neoplasias (PanIN), the accepted precursor lesions to pancreatic duct cancer.
In this study we sought to characterise the expression of CXCL12 and CXCR4 during the progression of PanIN using both a murine model and human tissues.
These studies reveal that both CXCL12 and CXCR4 are expressed in PanIN and that the frequency increases during PanIN progression (0% CXCR4 expression in normal mouse and human ducts vs 100% in mouse PanIN 3 and 77% in human PanIN 3). Next we demonstrate a dose-dependent increase in the proliferation of murine PanIN cells when exposed to CXCL12. Finally, we show that expression of CXCR4 in murine PanIN cells is partially dependent on mitogen-activated protein kinase (MAPK) signalling and that the effect of CXCL12 on PanIN proliferation can be abrogated by an MAPK inhibitor.
Together these results demonstrate that CXCL12/CXCR4 expression begins in the pre-invasive stages of pancreatic neoplasia, and suggest that the presence of an autocrine loop that is at least partially regulated by MAPK signalling. Further studies that define the role of CXCR4 signalling in PanIN progression will determine if CXCR4 could serve as a novel target for chemoprevention and early stage therapy in pancreatic cancer.
Gut 08/2008; 57(11):1555-60. · 10.11 Impact Factor
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ABSTRACT: Pancreatic cancer is an aggressive disease characterized by rapid growth and early metastasis. The recepteur d'origine nantais (RON) receptor tyrosine kinase is overexpressed and/or constitutively active in several epithelial cancers, but its role in pancreatic cancer is unknown. In this study, we have characterized RON expression in both murine and human pancreatic cancer. Immunoblotting indicates that RON is expressed in pancreatic intraepithelial neoplasia (PanIN), primary, and metastatic cell lines both in the human and mouse. Immunostaining revealed that 93% of high-grade PanIN, 79% of primary, and 83% of metastatic lesions from human pancreatic tissue samples expressed RON, with minimal expression in normal ducts and low-grade PanIN (6% and 18%, respectively). Moreover, we show a dose-dependent effect of hepatocyte growth factor-like protein (HGFL), the RON-specific ligand, on pancreatic cancer cell migration and invasion, which was reversed by RON inhibition. Although stimulation with HGFL had no effect on proliferation, concurrent RON receptor blockade and gemcitabine treatment increased apoptosis of RON-expressing pancreatic cancer cells versus gemcitabine treatment alone. Finally, HGFL stimulation of pancreatic cancer cells resulted in increased expression of phospho-mitogen-activated protein kinase and phospho-Akt. Taken together, these findings suggest that RON receptor signaling may contribute to pancreatic carcinogenesis, and that further investigation is warranted to assess the potential of RON-directed therapies in this deadly disease.
Cancer Research 08/2007; 67(13):6075-82. · 7.86 Impact Factor
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ABSTRACT: An analysis of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplant Registry data shows that the greater the viral load at the time of transplantation, the more rapidly clinically evident posttransplantation hepatitis C virus (HCV) disease recurs. These data suggest that aggressive pretransplantation treatment of HCV might delay recurrent posttransplantation HCV disease and enhance posttransplantation survival. We have taken an aggressive approach to treating HCV infection pretransplantation with the use of high-dose (5 MU) daily interferon alpha(2b) in an effort to clear the virus before transplantation. A total of 27 patients with HCV-induced cirrhosis were seen and underwent transplantation at Loyola University Medical Center (Maywood, IL) between February 1997 and December 2001. There were 22 men and five women, with a mean age of 56 +/- 2 years. The majority had genotype 1 disease (67%). Of the 27 patients, 7 had a baseline platelet count <50,000/mm(3) and were excluded from interferon therapy. The remaining 20 were treated for a mean of 14 +/- 2.5 (range, 0.5 to 33.5) months before orthotopic liver transplantation (OLT). Twelve (60%) responded to the therapy with serologic clearance of HCV before OLT. The mean time from initiation of therapy to the first negative qualitative polymerase chain reaction was 4.5 +/- 1.5 (range, 0.5 to 12) months. Four of the 12 patients in whom the virus cleared did not have evidence of HCV recurrence after OLT, representing 20% of those treated and 33% of those who had HCV clearance before OLT. The duration of post-OLT freedom from HCV infection in these individuals has been 33.6 +/- 11.3 (range, 0 to 47.4) months. These data suggest that with careful supervision, cirrhotic patients can tolerate high-dose interferon. In addition, a viral clearance can be achieved in a significant number of cirrhotic patients with high-dose interferon. One third of patients, in whom the HCV cleared before OLT, did not have evidence of disease recurrence after OLT. It is thus anticipated that with early and aggressive pre-OLT HCV therapy, possibly with the use of pegylated interferon, even better results may be obtained.
Liver Transplantation 09/2003; 9(9):905-15. · 3.39 Impact Factor
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ABSTRACT: To investigate the outcome of the port-access approach for patent foramen ovale (PFO) closure and to identify the long-term risk of recurrent thromboembolic events in the paradoxical embolus subgroup after closure.
Between 1997 and 2001, 31 patients underwent PFO closure using the port-access approach. Twelve of the 31 patients underwent PFO closure secondary to at least one paradoxical embolic event leading to either transient ischemic attack or cerebral infarction. All patients were followed longitudinally with office visits and telephone interviews.
The mean age was 47 years (range 18 to 85 years). All procedures were completed successfully without conversion to median sternotomy. The mean duration of aortic occlusion and cardiopulmonary bypass for all patients (n = 31) was 32 minutes (range 17 to 55 minutes) and 72 minutes (range 40 to 124 minutes), respectively. Postoperative complications included pneumonia/pulmonary embolus (n = 1), transient atrial fibrillation (n = 3, 9.7%), and exploration for bleeding (n = 3, 9.7%). No deaths were recorded. All patients were assessed using transesophageal echocardiography, and the closure of the PFO was documented. The average length of hospital stay was 3.8 days (range 2 to 10 days) for patients with paradoxical emboli. The mean follow-up period for the paradoxical embolus subgroup was 23 months (range 4 to 45 months). One patient was lost to follow-up. Neither transient ischemic attack nor cerebral infarction recurred during follow-up.
The port-access approach to PFO closure is a safe and effective procedure, with acceptable initial experience outcome and excellent low-risk rate of recurrent thromboembolic events.
The Annals of Thoracic Surgery 11/2002; 74(4):S1326-9. · 3.74 Impact Factor
