J V Reynolds

Trinity College Dublin, Dublin, Leinster, Ireland

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Publications (153)442.24 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Contemporary clinical management of Barrett's esophagus has highlighted the lack of accurate predictive markers of disease progression to esophageal cancer. This study aims to examine alterations in mitochondrial energy metabolism profiles across the entire disease progression sequence in Barrett's esophagus. An in-vitro model was used to screen 84 genes associated with mitochondrial energy metabolism. Three energy metabolism genes (ATP12A, COX4I2, COX8C) were significantly altered across the in-vitro Barrett's disease sequence. In-vivo validations across the Barrett's sequence demonstrated differential expression of these genes. Tissue microarrays demonstrated significant alterations in both epithelial and stromal oxidative phosphorylation (ATP5B and Hsp60) and glycolytic (PKM2 and GAPDH) protein markers across the in-vivo Barrett's sequence. Levels of ATP5B in sequential follow up surveillance biopsy material segregated Barrett's non progressors and progressors to HGD and cancer. Utilizing the Seahorse XF24 flux analyzer, in-vitro Barrett's and adenocarcinoma cells exhibited altered levels of various oxidative parameters. We show for the first time that mitochondrial energy metabolism is differentially altered across the metaplasia-dysplasia-adenocarcinoma sequence and that oxidative phosphorylation profiles have predictive value in segregating Barrett's non progressors and progressors to adenocarcinoma.
    Cancer letters. 08/2014;
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    ABSTRACT: The MAGIC/UK Medical Research Council (MRC) trial set the standard of care for treatment of resectable gastric and junctional adenocarcinoma, demonstrating that perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (ECF) confers a survival benefit over surgery alone. The randomized ECF for advanced and locally advanced esophagogastric cancer (REAL-2) trial showed that, in the metastatic setting, the EOX regimen (epirubicin, oxaliplatin and capecitabine) is as effective as ECF, with a favourable toxicity profile.
    Irish Journal of Medical Science 05/2014; · 0.51 Impact Factor
  • T Moran, P Lawlor, M Brennan, N Ravi, J V Reynolds
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    ABSTRACT: Manometry is the gold standard investigation of innate or acquired motility disorders in the oesophagus. New technology in the form of high-resolution manometry (HRM) may supplant traditional water-perfused manometry and enhance standardisation of manometric interpretation and reporting. This study reports on a 10-year experience of 5,184 consecutive patients using the traditional methods, and an early experience with HRM. Of 5,184 patients assessed, 4,509 (87 %) had both pH and manometry and 675 (13 %) had manometry only. 3,523 (78 %) of the pH /manometry group had normal motility, 635 (14 %) showed ineffective motility (IM), 213 (5 %) a non-specific motility disturbance (NSMD), 42 (0.9 %) achalasia, 58 (1.3 %) nutcracker oesophagus, 22 (0.5 %) hypertensive LOS (HLOS), 8 (0.2 %) diffuse oesophageal spasm (DOS) and 8 (0.2 %) had scleroderma. For those referred solely for manometry only, 324 (48 %) had normal motility, 72 (11 %) IM, 51 (8 %) NSMD, 175 (26 %) achalasia, 16 (2 %) nutcracker oesophagus, 32 (5 %) HLOS, 1 (0.1 %) DOS and 4 (0.6 %) had scleroderma. 92 patients to date have been studied with HRM, with enhanced definition of lower oesophageal sphincter (LOS) function. For patients referred for reflux related symptoms, motility disorders are present in 22 % of the cases. Conversely, of the patients referred for dysphagia, motility disturbances are detected in 52 % of the cases sent for manometry. Our initial experience shows that HRM technology is adding a valuable dimension and clearer understanding of motility patterns in the dysphagic patient.
    Irish Journal of Medical Science 05/2014; · 0.51 Impact Factor
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    ABSTRACT: Oesophageal adenocarcinoma is an exemplar model of an obesity-associated adenocarcinoma. Altered secretion of adipokines by visceral fat is believed to play a key role in tumorigenesis. This study examined leptin receptor (ObR) and adiponectin receptor (AdipoR1 and AdipoR2) expression in oesophageal cancer, and its relationship with patient obesity status, clinicopathological data and patient survival. Tissue microarrays were constructed from paraffin-embedded oesophagectomy specimens. ObR, AdipoR1 and AdipoR2 expression was quantified by immunohistochemistry. Anthropometric data were measured at the time of diagnosis, and obesity status was assessed using visceral fat area determined by computed tomography and body mass index. Receptor expression was correlated with various clinicopathological and anthropometric variables. Patient survival was estimated using the Kaplan-Meier method, and results compared between those with low versus high receptor expression. A Cox multivariable regression model was used to assess the relationship between survival and a number of co-variables. All 125 tumours analysed expressed AdipoR1 and AdipoR2, whereas 96·8 per cent expressed ObR. There was no significant difference in tumour pathological features or patient obesity status between tumours with low versus high ObR expression. A high level of AdipoR1 expression was significantly associated with increased patient age, obesity and less advanced tumour (T) category. Expression of AdipoR2 was inversely associated with T category (P = 0·043). Low AdipoR1 expression was an independent predictor of improved overall survival (hazard ratio 0·56, 95 per cent confidence interval 0·35 to 0·90; P = 0·017). The association between adiponectin receptor expression, obesity status and tumour category and survival suggests a potential mechanism linking obesity and oesophageal cancer.
    British Journal of Surgery 03/2014; · 4.84 Impact Factor
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    ABSTRACT: Barrett's esophagus (BE) arising from chronic gastro-oesophageal reflux (GERD) is the main pathologic precursor of esophageal adenocarcinoma (EAC). The risk of progression to high-grade dysplasia (HGD) and EAC is unclear, and recent population studies from Denmark and Northern Ireland suggest that this has been overestimated in the past. No data exist from the Republic of Ireland. A detailed clinical, endoscopic, and pathologic database was established in one center as a proposed pilot for a national registry, and initial and follow-up data were abstracted by a data manager. One thousand ninety-three patients were registered, 60 patients with HGD were excluded, leaving 1033, with a median age of 59 and 2 : 1 male to female ratio, and 3599 person-years of follow-up. The overall incidence of HGD/EAC was 1.33% per year overall, 0.85% if the first year is excluded. Within the first year after index endoscopy, 18 cases of HGD or EAC were identified, and 30 following the first year. Low-grade dysplasia (LGD) on index endoscopy was associated with an incidence of progression of 6.5% per year, and 3.1% when tertiary referrals were excluded. These data provide important demographic and clinical information on the population of Irish patients with BE, with incidence rates of progression higher than recently published population-based registry series, perhaps relating to sampling and pathological assessment. Low-grade dysplasia on initial biopsy is a significant proxy marker of risk of progression.
    Diseases of the Esophagus 01/2014; · 1.64 Impact Factor
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    ABSTRACT: Neuroepithelial transforming gene 1 (NET1) mediates tumour invasion and metastasis in a number of cancers, including gastric adenocarcinoma. It is an indicator of poor prognosis in breast cancer and glioma. This study examined NET1 expression and its prognostic significance in patients with adenocarcinoma of the oesophagogastric junction (AOG). NET1 expression was measured by immunohistochemistry in a tissue microarray, constructed from biobanked tissue collected over a 10-year interval, and linked to a prospectively maintained clinical database. Using the Siewert classification for AOG, type I tumours expressed significantly higher levels of NET1, with lowest expression in type III and intermediate levels in type II (P = 0·001). In patients with AOG type III, NET1-positive patients were more likely to be female (P = 0·043), have advanced stage cancer (P = 0.035), had a higher number of transmural cancers (P = 0·006) and had a significantly higher median number of positive lymph nodes (P = 0·029). In this subgroup, NET1-positive patients had worse median overall (15 versus 23 months; P = 0·025) and disease-free (11 versus 36 per cent; P = 0·025) survival compared with NET1-negative patients. Although existing data show differences in clinical and prognostic indices across AOG subtypes, there are no studies showing differences in tumour biology. These data suggest NET1, a known mediator of an aggressive tumour phenotype in a number of gastrointestinal cancers, is expressed differentially across AOG subtypes and may be of prognostic significance in the clinical management of this condition.
    British Journal of Surgery 01/2014; 101(2):55-62. · 4.84 Impact Factor
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    ABSTRACT: Maple syrup urine disease (MSUD) has an incidence of 1:125,000 newborns in Ireland. Patients, when fasting, or in a catabolic state build up toxic metabolites leading to progressive neurological dysfunction. We describe the necessary peri-operative management of a patient with MSUD who developed symptomatic gallstones requiring a laparoscopic cholecystectomy.
    Irish medical journal 10/2013; Volume 106(9). · 0.51 Impact Factor
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    ABSTRACT: Maple syrup urine disease (MSUD) has an incidence of 1:125,000 newborns in Ireland. Patients, when fasting, or in a catabolic state build up toxic metabolites leading to progressive neurological dysfunction. We describe the necessary peri-operative management of a patient with MSUD who developed symptomatic gallstones requiring a laparoscopic cholecystectomy.
    Irish medical journal 10/2013; 106(9):277-8. · 0.51 Impact Factor
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    ABSTRACT: Esophageal adenocarcinoma (EAC) is the eighth most common cancer worldwide, and approximately 15% of patients survive 5 years. Reflux disease (GERD) and Barrett's esophagus (BE) are major risk factors for the development of EAC, and epidemiologic studies highlight a strong association with obesity. The immune, inflammatory and intracellular signaling changes resulting from chronic inflammation of the esophageal squamous epithelium are increasingly well characterized. In GERD and Barrett's, an essential role for T-cells in the initiation of inflammation in the esophagus has been identified, and a balance between T-cell responses and phenotype may play an important role in disease progression. Obesity is a chronic low-grade inflammatory state, fuelled by adipose tissue derived- inflammatory mediators such as IL-6, TNF-α and leptin, representing a novel area for targeted research. Additionally, reactive oxygen species (ROS) and receptor tyrosine kinase (RTK) activation may drive progression from esophagitis to EAC, and downstream signaling pathways employed by these molecules may be important. This review will explain the diverse range of mechanisms potentially driving and maintaining inflammation within the esophagus and explore both existing and future therapeutic strategies targeting the process.
    Cancer letters 08/2013; · 4.86 Impact Factor
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    05/2013;
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    ABSTRACT: The aim in this audit study was to identify the rate of and the reasons for unanticipated admissions in general day surgery. All day ward procedures performed during the one year period from January 2011 to January 2012 were reviewed. Of 560 procedures performed, 25 (4.4%) patients were admitted. The age range of the patients admitted was from 26 to 83 years. The average BMI of the admitted patient was 28.9 (range 24-39).The average stay in hospital was 1.7 days (range 1-3 days). The reason for admission was potentially preventable in ten (40%) patients. This included eight (80%) out of ten admissions for control of postoperative pain, nausea and vomiting. Two (20%) were admitted for surgical observation due to high risk of bleeding. Fifteen (60%) of admissions were due to a non-preventable source, including 5 with a drain inserted at a perceived difficult laparoscopic cholecystectomy, 5 for urinary retention post open inguinal hernia repair, 2 for a cardiology review and 2 for further urgent investigations because of an unexpected intraoperative finding of malignancy. The rate of un-planned admission can be reduced by controlling potentially preventable causes, however a small contribution from unexpected scenarios is inevitable.
    Irish medical journal 05/2013; 106(5):153-4. · 0.51 Impact Factor
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    ABSTRACT: BACKGROUND: For rectal cancer, an involved circumferential resection margin (CRM), defined as tumor cells within 1 mm of the CRM, is of established prognostic significance. This definition for the esophagus, however, is controversial, with the UK Royal College of Pathologists (RCP) recommending the 1 mm definition, while the College of American Pathologists (CAP) advises that only tumor cells at the cut margin (0 mm) define an incomplete (R1) resection. The aim of this study was to compare the clinical significance of both definitions in patients with pT3 tumors. METHODS: CAP- and RCP-defined CRM status in patients treated by surgery only or by multimodal therapy was recorded prospectively in a comprehensive database from May 2003 to May 2011. Kaplan-Meier survival curves were generated, and factors affecting survival were assessed by univariate and multivariate analysis. RESULTS: A total of 157 of 340 patients had pT3 esophageal tumors, with RCP-positive CRM in 60 %, and 18 % by CAP. There were no significant differences between RCP-positive CRM and negative margins for node-positive disease, local recurrence, and survival. CAP-positive CRM was associated with positive nodes (P = 0.036) and poorer survival (P = 0.023). Multivariate analysis revealed nodal invasion to be the only independent prognostic variable (P = 0.004). CONCLUSIONS: A CRM margin of <1 mm is common in pT3 esophageal tumors, a finding consistent with other reports. The <1 mm definition was not associated with node positivity, local recurrence, or survival, in contrast to actual involvement at the margin, suggesting lack of independent prognostic significance of the RCP definition and possible superiority of the CAP criteria for prospective registration of CRM.
    Annals of Surgical Oncology 03/2013; · 4.12 Impact Factor
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    ABSTRACT: Acute pancreatitis is typically associated with classical clinical and radiological features. The sensitivity of CT to diagnose acute pancreatitis depends on the severity of the attack and ranges from 77% to 92% with a specificity approaching 100%. Despite the fact this is a common disease, there are myriad clinical presentations of acute pancreatitis. We report herein an especially rare presentation where severe acute necrotising pancreatitis presented with a tender inguinoscrotal swelling with a normal pancreas on CT imaging.
    Case Reports 01/2013; 2013.
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    ABSTRACT: Adrenal metastases of oesophageal adenocarcinoma are rarely detected in the clinical setting, more frequently being found as an incidental postmortem finding in the presence of widespread metastases. With improvements in the sensitivity of radiological diagnostic modalities, the incidence of adrenal tumour detection is on the rise. We report herein a particularly rare case of primary operative management by adrenalectomy for an isolated right-sided adrenal metastasis secondary to oesophageal adenocarcinoma, with a long-term survival.
    Case Reports 01/2013; 2013.
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    ABSTRACT: Epigastric pain is a very common symptom which can be caused by a wide range of clinical conditions. A 28 year old male presented to our clinic with new onset severe epigastric pain. As part of the routine work up for pain of this nature, we proceeded to upper gastrointestinal endoscopy. A toothpick was found lodged in the antral gastric wall with a resulting inflammatory mass abutting the free edge. It was removed successfully with full resolution of symptoms, however a review of the literature shows that ingested toothpicks can cause major morbidity.
    Irish medical journal 01/2013; 106(1):23. · 0.51 Impact Factor
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    ABSTRACT: OBJECTIVES: Series from high volume oesophageal centres highlight an increasing prevalence of early malignant (EM) lesions. The advent of endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) offer alternatives to traditional surgery. The evolution of this pattern of care in a high volume centre is analysed. METHODS: Data were collected from a prospectively maintained database. 96 patients were treated with an EM lesion from 2000 to 2011. Surgery was the standard approach during the initial period (2000-2006). In 2007, with the introduction of EMR ± RFA to our Centre, a rising trend toward definitive endoscopic treatment was seen. This study details the selection of cases into treatment groups and their outcomes. RESULTS: From 2000 to 2006, 23 patients were treated with EM lesions, 96 % by surgery. Seventy-three were treated from 2007 to 2011, 55 % surgically and 45 % by EMR ± RFA. In the entire experience, there was one death from surgery and morbidity was higher in the surgery group compared with EMR ± RFA (p < 0.001). Three surgical patients (4.8 %) relapsed with HGD or cancer, and one patient with T1N1 disease died of disease recurrence. At a median of 13 months, EMR ± RFA offered 100 % disease control, 72 % had no endoscopic or histological evidence of Barrett's oesophagus and one patient represented with low grade dysplasia. CONCLUSIONS: This study highlights the changing pattern of care in the management of early oesophageal cancer. EMR ± RFA appears an acceptable alternative to surgery in carefully selected cases. However, long-term outcome analysis using these methods is required and close interdisciplinary collaboration of specialists in gastroenterology, surgery, pathology and radiology is mandatory to achieve optimum outcomes.
    Irish Journal of Medical Science 12/2012; · 0.51 Impact Factor
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    ABSTRACT: Barrett's esophagus is an increasingly common disease that  is strongly associated with reflux of stomach acid and usually  a hiatus hernia, and it strongly predisposes to esophageal  adenocarcinoma (EAC), a tumor with a very poor prognosis.  We report the first genome-wide association study on Barrett's  esophagus, comprising ,852 UK cases and 5,72 UK controls  in the discovery stage and 5,986 cases and 2,825 controls in  the replication stage. Variants at two loci were associated with  disease risk: chromosome 6p2, rs9257809 (P combined  =   4.09 × 0 −9 ; odds ratio (OR) = .2, 95% confidence interval  (CI) =.3–.28), within the major histocompatibility complex  locus, and chromosome 6q24, rs9936833 (P combined  =   2.74 × 0 −0 ; OR = .4, 95% CI = .0–.9), for which the  closest protein-coding gene is FOXF1, which is implicated in  esophageal development and structure. We found evidence that  many common variants of small effect contribute to genetic  susceptibility to Barrett's esophagus and that SNP alleles  predisposing to obesity also increase risk for Barrett's esophagus. Barrett's esophagus is one of the most common premalignant lesions in the western world. It affects over 2% of the adult population and, unlike bowel polyps, lacks any proven effective therapy 1 . In the major-ity of cases, Barrett's esophagus is associated with chronic gastro-esophageal reflux disease (GERD), including esophagitis 2,3 . Over 80% of affected individuals have a hiatus hernia in the lower esophagus that facilitates the reflux of acid and bile into the esophagus 4 . The measured annual risk of EAC in individuals with Barrett's esophagus varies widely but is approximately 0.4–1% (refs. 5–7). Notably, the incidence of EAC has been rising by 3% each year for the last 30 years; it is now the fifth most common cancer in the UK 8 . Despite modern multimodality therapy, the prog-nosis for EAC remains poor, with a 9–15% 5-year survival rate 9,10 . The etiology of Barrett's esophagus is not well characterized. Environmental factors, such as diet, are weakly associated with GERD, Barrett's esophagus and EAC, and obesity is a known risk factor for all three conditions 11 . There is also evidence implicating genetic factors: relative risks are increased by 2-to 4-fold for GERD, Barrett's esophagus and EAC when one first-degree relative is affected 12–17 . A segregation analysis of 881 pedigrees of familial Barrett's esophagus supports an incompletely dominant inheritance model with a polygenic component 18 . Extensive candidate gene and linkage searches have to date been unsuccessful in identifying genetic variants that are associated with risk of Barrett's esophagus 19 . As part of the Wellcome Trust Case Control Consortium 2 (WTCCC2) study of 15 common disorders and traits, we present the results of the first genome-wide association study of Barrett's esophagus susceptibility. Using a discovery cohort from the UK (with case samples from the Aspirin and Esomeprazole Chemoprevention Trial of Cancer in Barrett's esophagus (AspECT)) 20 and five repli-cation cohorts (including case samples from CHemoprevention Of Premalignant Intestinal Neoplasia (ChOPIN) and Esophageal Adenocarcinoma GenEtics Consortium (EAGLE) studies 9,20), we identified two variants associated with Barrett's esophagus, each with combined evidence at P < 5 × 10 −8 . The analysis workflow is outlined in Supplementary Figure 1, and characteristics of the case and con-trol samples that were included can be found in the Online Methods and Supplementary Table 1. For the discovery analysis, cases with histologically confirmed Barrett's esophagus (Online Methods) were recruited from sites across the UK (Supplementary Table 2). Population controls were taken from the WTCCC2 common set of 1958 Birth Cohort (58C) and National Blood Service (UKBS) samples as previously described 21 .
    Nature Genetics 09/2012; · 35.21 Impact Factor
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    ABSTRACT: Cancer-related inflammation is considered the 'seventh hallmark of cancer'; many studies show that tumours develop and progress within inflammatory diseases. This review focuses on Barrett's oesophagus, a common condition in which chronic inflammation and resulting alterations in the stroma can lead to carcinogenesis, specifically oesophageal adenocarcinoma. Changes that occur in the tissue microenvironment during development of this disease are discussed. Infiltration of immune cells facilitates tumour development through production of factors that promote carcinogenesis and by enabling tumours to evade the host immune response. Small molecules including cytokines, chemokines and growth factors play key roles in both inflammation and cancer by promoting proliferation, angiogenesis and carcinogenesis and by recruiting immune cells. The extracellular matrix is altered in inflammation, and provides structural support to developing tumours. Hypoxia is a common state in cancers and inflamed tissues which causes DNA damage and induces tumourigenic factors. Finally, tissue vasculature is a vital part of its microenvironment, supplying oxygen, nutrients and growth factors to rapidly dividing cells, and providing a mechanism for metastatic spread. The cells and molecules outlined here represent potential targets for treatment of this cancer, especially in its pre-cancerous, inflammatory stage
    Digestive Surgery 08/2012; 29(3):251-260. · 1.47 Impact Factor
  • J Costelloe, O Mc Cormack, J V Reynolds
    Diseases of the Esophagus 05/2012; · 1.64 Impact Factor
  • Source
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    ABSTRACT: We present a unique case of perforative appendicitis that occurred in an adult following blunt abdominal trauma. This case represents the first such reported case from Ireland. It also represents a modern practical example of Laplace's theory of the effect of increased pressure on colonic wall tension leading to localized perforation, and serves to highlight not only the importance in preoperative imaging for blunt abdominal trauma, but also the importance of considering appendiceal perforation.
    Irish medical journal 03/2012; 105(3):86-7. · 0.51 Impact Factor

Publication Stats

2k Citations
442.24 Total Impact Points

Institutions

  • 1995–2014
    • Trinity College Dublin
      • • Department of Surgery
      • • Institute of Molecular Medicine
      • • Centre for Health Sciences
      Dublin, Leinster, Ireland
  • 2000–2013
    • St. James's Hospital
      Dublin, Leinster, Ireland
  • 2001–2012
    • Saint James School Of Medicine
      Park Ridge, Illinois, United States
  • 2010
    • Dublin City University
      Dublin, Leinster, Ireland
  • 2009
    • National and Kapodistrian University of Athens
      • Division of Surgery V
      Athens, Attiki, Greece
  • 1992–1998
    • The Adelaide and Meath Hospital Ireland
      Dublin, Leinster, Ireland
  • 1993–1997
    • St. Vincent's Private Hospital
      Dublin, Leinster, Ireland
  • 1994
    • Beaumont Hospital
      Dublin, Leinster, Ireland