Kelleher F.C.,St Vincents University Hospital |
Kelleher F.C.,Peter MacCallum Cancer Center
Carcinogenesis | Year: 2011
Objective: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. Method. PubMed search (2000-2010) and literature based references. Results: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. Conclusions: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer. © The Author 2010. Published by Oxford University Press. All rights reserved.
Duffy M.J.,St Vincents University Hospital |
Duffy M.J.,University College Dublin
Tumor Biology | Year: 2013
Of all the diseases affecting humankind, cancer is one of the most difficult to treat and cure. One of the main reasons for this difficulty relates to the fact that cancer is not a single disease but consists of hundreds of different types. Furthermore, cancers exhibit considerable genetic complexity with more than 400 different genes implicated in their development. In addition, cancers display major inter- and intratumor heterogeneity. Despite these complexities, several successes have been achieved in recent years. Most of these successes relate to the specific targeting of driver genes involved in cancer development. These successes include imatinib for the treatment of chronic myeloid leukemia, anti-HER2 therapies (trastuzumab, pertuzumab, and lapatinib) to treat breast cancer, anti-EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) to treat non-small cell lung cancer, and anti-BRAF agents (vemurafenib and dabrafenib) to treat melanoma. Although the war on cancer has not yet been won, neither has it been lost. With continued basic and clinical research, cancer is being transformed into a chronic disease in which patients have increased survival rates and better quality of life. © 2013 International Society of Oncology and BioMarkers (ISOBM).
Haroon M.,Park University |
Kirby B.,St Vincents University Hospital |
FitzGerald O.,Park University
Annals of the Rheumatic Diseases | Year: 2013
Objectives The objectives of this study were to: (1) assess the prevalence of psoriatic arthritis (PsA) among Psoriasis (Ps) patients attending dermatology clinics; (2) identify clinical predictors of the development of PsA; and (3) compare the performance of three PsA screening questionnaires: Psoriatic Arthritis Screening and Evaluation (PASE), Psoriasis Epidemiology Screening Tool (PEST) and Toronto Psoriatic Arthritis Screening (ToPAS). Methods Patients were divided into two groups: Group-1, consecutive psoriasis patients attending dermatology clinics with no known diagnosis of inflammatory arthritis and Group-2, consecutive patients attending rheumatology clinics with a confirmed diagnosis of PsA. In Group-1, patients completed the screening questionnaires, followed by a full rheumatological evaluation whether or not they reported musculoskeletal symptoms. Results 200 patients were recruited with 100 in each group. In all, 84% of patients in dermatology group were using systemic therapy for their skin disease, and 99% of patients in rheumatology group were on systemic immunosuppressives. In Group-1, 29% of patients were diagnosed with PsA after rheumatological evaluation. On univariate and multivariate analyses, there was a significant positive association between Psoriasis Area and Severity Index and a new diagnosis of PsA (p=0.046). Different patterns of joint involvement were noted in patients with newly diagnosed PsA versus patients with established PsA with fewer polyarticular disease presentations (p=0.0001). In Group-1, the PEST, PASE and ToPAS assessments had sensitivities of 27.5%, 24% and 41%, and specificities of 98%, 94% and 90%, respectively. In Group-2, the sensitivities were 86%, 62% and 83%, respectively. Conclusions 29% of Ps patients attending dermatology clinics had undiagnosed PsA. Psoriasis severity was associated with a new diagnosis of PsA. Poor sensitivities for the screening questionnaires were noted due to inadequate detection of patterns of arthritis other than polyarticular disease.
Hajj-Ali R.A.,Cleveland Clinic |
Singhal A.B.,Massachusetts General Hospital |
Benseler S.,University of Toronto |
Molloy E.,St Vincents University Hospital |
Calabrese L.H.,Cleveland Clinic
The Lancet Neurology | Year: 2011
Meaningful progress in our understanding and clinical approach to primary angiitis of the CNS (PACNS) has been made in the past three decades. Increased recognition of PACNS and general advances in diagnosis of neurological disorders have led to an aggressive diagnostic approach and a proliferation of case reports providing enriched clinical and pathological descriptions. We have witnessed major advances not only in the diagnosis of PACNS but in the recognition of its mimics. Epidemiological, clinical, neuroradiagnostic, and laboratory findings have enhanced our diagnostic accuracy and recognition of PACNS mimics, however, many challenges to our understanding and management of the disease in children and adults remain. © 2011 Elsevier Ltd.
Rogers A.C.,St Vincents University Hospital
British Journal of Cancer | Year: 2016
Background:Tumour budding is a histological finding in epithelial cancers indicating an unfavourable phenotype. Previous studies have demonstrated that it is a negative prognostic indicator in colorectal cancer (CRC), and has been proposed as an additional factor to incorporate into staging protocols.Methods:A systematic review of papers until March 2016 published on Embase, Medline, PubMed, PubMed Central and Cochrane databases pertaining to tumour budding in CRC was performed. Study end points were the presence of lymph node metastases, recurrence (local and distal) and 5-year cancer-related death.Results:A total of 7821 patients from 34 papers were included, with a mean rate of tumour budding of 36.8±16.5%. Pooled analysis suggested that specimens exhibiting tumour budding were significantly associated with lymph node positivity (OR 4.94, 95% CI 3.96–6.17, P<0.00001), more likely to develop disease recurrence over the time period (OR 5.50, 95% CI 3.64–8.29, P<0.00001) and more likely to lead to cancer-related death at 5 years (OR 4.51, 95% CI 2.55–7.99, P<0.00001).Conclusions:Tumour budding in CRC is strongly predictive of lymph node metastases, recurrence and cancer-related death at 5 years, and its incorporation into the CRC staging algorithm will contribute to more effective risk stratification.British Journal of Cancer advance online publication, 6 September 2016; doi:10.1038/bjc.2016.274 www.bjcancer.com. © 2016 Cancer Research UK
Kennelly S.,Trinity College Dublin |
Collins O.,St Vincents University Hospital
Journal of Alzheimer's Disease | Year: 2012
Vascular risk factors are implicated in the pathogenesis of Alzheimer's disease (AD). There is an age-dependent relationship between blood pressure and the risk of AD. Given the potential temporal lag that can exist between the two conditions, longitudinal population studies offer the best opportunity to identify a causal relationship. Midlife hypertension increases the risk for AD, yet later-life hypertension does not appear to confer the same risk and may in fact be protective. Low diastolic blood pressure, especially in later-life, is associated with an increased risk of AD. Orthostatic hypotension and other neurocardiovascular syndromes may increase the risk for cognitive impairment and AD. Several physiopathological mechanisms may contribute to this increased risk. Dynamic blood pressure changes and impaired cerebrovascular autoregulation may result in cerebral hypoperfusion. Hypertensive patients also develop cerebral infarcts, resulting in diminished perfusion. Subsequent hypoxia driven pathways result in increased cerebral amyloid-β and phosphorylated tau protein accumulation. Treatment of elevated blood pressure with antihypertensive medications attenuates the risk of AD attributable to elevated midlife hypertension. Certain antihypertensive compounds have neuroprotective properties that may reduce the risk of AD, independent of their effects on blood pressure. © 2012 - IOS Press and the authors. All rights reserved.
Collins D.,St Vincents University Hospital |
Winter D.C.,St Vincents University Hospital
Best Practice and Research: Clinical Gastroenterology | Year: 2014
A minimally invasive approach to the management of diverticular disease has gained acceptance over the last number of years. Certainly, in the elective setting, laparoscopic sigmoid resection compares favourably with open surgery. The use of laparoscopy in the context of emergency surgery for complicated diverticular disease remains controversial however recent studies have demonstrated a defined role for laparoscopy in the acute setting. © 2013 Elsevier Ltd. All rights reserved.
Haroon M.,St Vincents University Hospital |
Gallagher P.,St Vincents University Hospital |
FitzGerald O.,St Vincents University Hospital
Annals of the Rheumatic Diseases | Year: 2014
Objectives: (1) To investigate the demographic and clinical characteristics contributing to the delay from symptom onset to the first visit to a rheumatologist; (2) to compare clinical, radiographic and patient-reported outcome measures of those who saw a rheumatologist early in their disease course with those who were diagnosed later. Methods: All psoriatic arthritis (PsA) patients, fulfilling CASPAR criteria, with an average disease duration of >10 years were invited for detailed clinical evaluation. The total lag time from symptom onset to their first rheumatological encounter was studied. The data were extracted from the referral letters and medical records. Patients were classified as early consulters or late consulters depending on whether they were seen by a rheumatologist within or beyond 6 months of symptom onset. Results: 283 PsA patients were studied. Median lag time from the disease onset to the first rheumatological assessment of the cohort was 1.00 years (IQR 0.5-2). 30% (n=86), 53% (n=149) and 71% (n=202) of the cohort were seen by a rheumatologist within 6 months, 1 and 2 years of symptom onset, respectively. PsA patients with low education status (OR 2.09, p=0.02) and Body Mass Index (OR 0.92, p=0.01) were significantly more likely to have a diagnostic delay of >2 years. On multiple stepwise regression analysis, the model predicted significant association of late consulters with the development of peripheral joint erosions (OR 4.25, p=0.001) and worse Health Assessment Questionnaire scores (OR 2.2, p=0.004). Conclusions: Even a 6-month delay from symptom onset to the first visit with a rheumatologist contributes to the development of peripheral joint erosions and worse long-term physical function. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.
Kelly E.,St Vincents University Hospital
Expert Review of Clinical Pharmacology | Year: 2014
Drugs from the two major classes of bronchodilator; umeclidinium, a long-acting muscarinic antagonist (LAMA), and vilanterol, a long-acting β2 agonist (LABA), have been combined in a single inhaler device for once-daily use in chronic obstructive pulmonary disease (COPD). These drugs have been proven safe and well tolerated in patients with COPD and show an enhanced improvement in FEV1 when compared to either drug in isolation and when compared with an established LAMA drug. In this article, we discuss the data supporting this combination inhaler and also review alternative combined LAMA/LABA options. We discuss where these agents are likely to find a place in the current therapy of COPD and where the future is likely to lead with these and other therapies. © Informa UK, Ltd.
Ryan S.,St Vincents University Hospital
Respiration; international review of thoracic diseases | Year: 2010
BACKGROUND: Sleep is associated with important adverse effects in patients with chronic obstructive pulmonary disease (COPD), such as disturbed sleep quality and gas exchange, including hypoxemia and hypercapnia. The effects of inhaled long-acting beta(2)-agonist therapy (LABA) on these disturbances are unclear. OBJECTIVES: The aim of the study was to assess the effect of inhaled salmeterol on nocturnal sleeping arterial oxygen saturation (SaO(2)) and sleep quality. METHODS: In a randomized, double-blind, placebo-controlled, crossover study of moderate/severe stable COPD patients, we compared the effects of 4 weeks of treatment with salmeterol 50 microg b.d. and matching placebo on sleeping SaO(2) and sleep quality. Overnight polysomnography (PSG) was performed at baseline, and after 4 and 8 weeks in addition to detailed pulmonary function testing. Of 15 patients included, 12 completed the trial (median age 69 years, forced expiratory volume in 1 s, FEV(1): 39%). RESULTS: Both mean SaO(2) [salmeterol vs. placebo: 92.9% (91.2, 94.7) vs. 91.0% (88.9, 94.8); p = 0.016] and the percentage of sleep spent below 90% of SaO(2) [1.8% (0.0, 10.8) vs. 25.6% (0.5, 53.5); p = 0.005] improved significantly with salmeterol. Sleep quality was similar with both salmeterol and placebo on PSG. Static lung volumes, particularly trapped gas volume, tended to improve with salmeterol. CONCLUSION: We conclude that inhaled LABA therapy improves sleeping SaO(2) without significant change in sleep quality. Copyright 2009 S. Karger AG, Basel.