Reginald V. Lord

St. Vincent's Hospital Sydney, Sydney, New South Wales, Australia

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Publications (133)1006.28 Total impact

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    ABSTRACT: Objective. To clarify the prognostic role of tumour protein 53 (TP53) mutations in patients with oesophageal adenocarcinoma (OAC) as there is a need for biomarkers that assist in guiding management for patients with OAC. Design. A systematic review was conducted using MEDLINE, Embase, PubMed and Current Contents Connect to identify studies published between January 1990 and February 2015 of oesophageal cancer populations (with OAC diagnoses >50% of cases) that measured tumoural TP53 status and reported hazard ratios (HR), or adequate data for estimation of HR for survival for TP53-defined subgroups. Risk of bias for HR estimates was assessed using prespecified criteria for the appraisal of relevant domains as defined by the Cochrane Prognosis Methods Group including adherence to Grading of Recommendations, Assessment, Development and Evaluation and REporting recommendations for tumor MARKer prognostic studies guidelines, as well as assay method used (direct TP53 mutation assessment vs immunohistochemistry) and adjustment for standard prognostic factors. A pooled HR and 95% CI were calculated using a random-effects model. Results. Sixteen eligible studies (11 with OAC only and 5 mixed histology cohorts) including 888 patients were identified. TP53 mutations were associated with reduced survival (HR 1.48, 95% CI 1.16 to 1.90, I2=33%). A greater prognostic effect was observed in a sensitivity analysis of those studies that reported survival for OAC- only cohorts and were assessed at low risk of bias (HR 2.11, 95% CI 1.35 to 3.31, I2=0%). Conclusions. Patients with OAC and TP53 gene mutations have reduced overall survival compared with patients without these mutations, and this effect is independent of tumour stage.
    No preview · Article · Jan 2016 · Gut
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    ABSTRACT: BACKGROUND AND AIMS: Complete endoscopic resection (CER) of Barrett's esophagus (BE) with high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EEA) is a comprehensive and precise staging tool and may produce a sustained treatment response, preventing metachronous disease. There are limited data on long-term clinical outcomes and the sustainability of dysplasia eradication after CER. We aimed to describe long-term outcomes of a primary CER strategy of BE with HGD/EEA. METHODS: Patients with biopsy-proven HGD and EEA in short-segment BE (</=3 cm in circumferential length and </=5 cm in maximal length) underwent staged CER by multiband mucosectomy or the cap method. The primary endpoint was remission of HGD or EEA (complete resection of HGD/EEA), dysplasia (complete resection of any dysplasia), and complete resection of intestinal metaplasia. RESULTS: Of 153 patients (126 HGD, 27 EEA; 83.7% male, median age of 66 years) considered suitable for CER, 138 met all inclusion criteria. CER was technically successful in all patients and was established after a median of 2 sessions. Covert synchronous EEA was found in 1 patient. At a mean follow-up of 40.7 months by intention-to-treat analysis, complete remission of HGD/EEA, dysplasia, and intestinal metaplasia was achieved in 98.5%, 89.1%, and 71.0%, respectively. In 47.1% of patients, CER changed the histological grade compared with pretreatment biopsies (28.1% downstaged and 19.0% upstaged). Esophageal dilation was performed in 36.8% in a mean of 2.5 sessions. At the end of follow-up, 96.4% of patients had no or minimal dysphagia and 90.6% of patients found CER an acceptable treatment. CONCLUSIONS: On long-term follow-up, a primary CER strategy was a highly effective, safe, and durable treatment for HGD and EEA. Despite the need for post-CER dilation in one-third of patients, the majority found it an acceptable treatment on long-term follow-up.
    No preview · Article · Jan 2016
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    ABSTRACT: Introduction: Endoscopic therapy has revolutionized the treatment of Barrett's esophagus with high-grade dysplasia (HGD) or intramucosal adenocarcinoma by allowing preservation of the esophagus in many patients who would previously have had an esophagectomy. This paradigm shift initially occurred at high-volume centers in North America and Europe but now is becoming mainstream therapy. There is a lack of uniform guidelines and algorithms for the management of these patients. Our aim was to review important concepts and pitfalls in the endoscopic management of superficial esophageal adenocarcinoma. Methods: A small group colloquium consisting of gastroenterologists, surgeons, and pathologists reviewed published data and discussed personal and institutional experiences with endotherapy for HGD and superficial esophageal adenocarcinoma. Results: The group reviewed data and provided recommendations and management algorithms for seven areas pertaining to endoscopic therapy for Barrett's HGD and superficial adenocarcinoma: (1) patient selection and evaluation; (2) imaging and biopsy techniques; (3) devices; (4) indications for resection versus ablation; (5) ER specimen handling, processing, and pathologic evaluation; (6) patient care and follow-up after endoscopic therapy; and (7) complications of endoscopic therapy and treatment options. Conclusions: Endoscopic therapy is preferred over esophagectomy for most patients with HGD or intramucosal adenocarcinoma, and may be applicable to select patients with submucosal tumors. Clear guidelines and management algorithms will aid physicians and centers embarking on endoscopic therapy and enable a standardized approach to the management of these patients that is applicable internationally.
    No preview · Article · Dec 2015 · Journal of Gastrointestinal Surgery
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    ABSTRACT: In patients with advanced heart failure, morbid obesity is a relative contraindication to heart transplantation due to higher morbidity and mortality in these patients. We performed a retrospective analysis of consecutive morbidly obese patients with advanced heart failure who underwent bariatric surgery for durable weight loss in order to meet eligibility criteria for cardiac transplantation. Seven patients (4 M/3 F, age range 31-56 years) with left ventricular ejection fraction (LVEF) ≤25 % underwent laparoscopic bariatric surgery. Median preoperative body mass index (BMI) was 42.8 kg/m(2) (range 37.5-50.8). There were no major perioperative complications in six of seven patients. Median length of hospital stay was 5 days. There was no mortality recorded during complete patient follow-up. At a median follow-up of 406 days, median BMI reduction was 12.9 kg/m(2) (p = 0.017). Postoperative LVEF improved to a median of 30 % (interquartile range (IQR) 25-53 %; p = 0.039). Two patients underwent successful cardiac transplantation. Two patients reported symptomatic improvement with little change in LV function and now successfully meet listing criteria. Three patients showed marked improvement of their LVEF and functional status, thus removing the requirement for transplantation. Bariatric surgery can achieve successful weight loss in morbidly obese patients with advanced cardiac failure, enabling successful heart transplantation. In some patients, cardiac transplantation can be avoided through surgical weight loss.
    No preview · Article · Jul 2015 · Obesity Surgery

  • No preview · Article · Apr 2015 · The Journal of Heart and Lung Transplantation
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    ABSTRACT: Background: Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett’s oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC. Methods: One hundred thirty-eight patients were studied: 45 normal oesophagus (NE), 37 BO, 16 BO with low-grade dysplasia (LGD) and 40 OAC. Results: Median tissue expression of MIC-1/GDF15 mRNA was greater than or equal to25-fold higher in BO and LGD compared to NE (P<0.001); two-fold higher in OAC vs BO (P=0.039); and 47-fold higher in OAC vs NE (P<0.001). Relative MIC-1/GDF15 tissue expression >720 discriminated between the presence of either OAC or LGD vs NE with 94% sensitivity and 71% specificity (ROC AUC 0.86, 95% CI 0.73–0.96; P<0.001). Macrophage inhibitory cytokine 1/growth differentiation factor 15 plasma values were also elevated in patients with OAC vs NE (P<0.001) or BO (P=0.015). High MIC-1/GDF15 plasma levels (greater than or equal to1140 pg ml−1) were an independent predictor of poor survival for patients with OAC (HR 3.87, 95% CI 1.01–14.75; P=0.047). Conclusions: Plasma and tissue levels of MIC-1/GDF15 are significantly elevated in patients with BO, LGD and OAC. Plasma MIC-1/GDF15 may have value in diagnosis and monitoring of Barrett’s disease.
    Full-text · Article · Mar 2015 · British Journal of Cancer
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    ABSTRACT: The identification and characterisation of differentially methylated regions (DMRs) between phenotypes in the human genome is of prime interest in epigenetics. We present a novel method, DMRcate, that fits replicated methylation measurements from the Illumina HM450K BeadChip (or 450K array) spatially across the genome using a Gaussian kernel. DMRcate identifies and ranks the most differentially methylated regions across the genome based on tunable kernel smoothing of the differential methylation (DM) signal. The method is agnostic to both genomic annotation and local change in the direction of the DM signal, removes the bias incurred from irregularly spaced methylation sites, and assigns significance to each DMR called via comparison to a null model. We show that, for both simulated and real data, the predictive performance of DMRcate is superior to those of Bumphunter and Probe Lasso, and commensurate with that of comb-p. For the real data, we validate all array-derived DMRs from the candidate methods on a suite of DMRs derived from whole-genome bisulfite sequencing called from the same DNA samples, using two separate phenotype comparisons. The agglomeration of genomically localised individual methylation sites into discrete DMRs is currently best served by a combination of DM-signal smoothing and subsequent threshold specification. The findings also suggest the design of the 450K array shows preference for CpG sites that are more likely to be differentially methylated, but its overall coverage does not adequately reflect the depth and complexity of methylation signatures afforded by sequencing. For the convenience of the research community we have created a user-friendly R software package called DMRcate, downloadable from Bioconductor and compatible with existing preprocessing packages, which allows others to apply the same DMR-finding method on 450K array data.
    Full-text · Article · Jan 2015 · Epigenetics & Chromatin
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    ABSTRACT: Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE, since most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision-making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histologic definitions of BE and early EAC; prevalence, incidence, natural history and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2015 · Journal of Gastroenterology and Hepatology

  • No preview · Article · Dec 2014 · Obesity Research & Clinical Practice
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    ABSTRACT: Bariatric surgery improves health outcomes in the obese and reduces some aspects of obesity-associated systemic inflammation. Little is known however about its effects on circulating TNF-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin level, which regulate apoptosis and are implicated in atherogenesis. Our objective was to identify whether circulating TRAIL and osteoprotegerin levels are influenced by the energy restriction and weight loss that follows bariatric surgery in obese patients with glucose disorders.
    No preview · Article · Dec 2014 · e-SPEN Journal
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    ABSTRACT: Background: Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia-dysplasia-neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett's esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). Methods: A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. Results: Median CTSE mRNA expression levels were ≥1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27-1.26, p = 0.17). Conclusions: CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues.
    Full-text · Article · Oct 2014 · Annals of Surgical Oncology
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    Nicholas J Clemons · Wayne A Phillips · Reginald V Lord
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    ABSTRACT: Esophageal adenocarcinoma develops in response to severe gastroesophageal reflux disease through the precursor lesion Barrett esophagus, in which the normal squamous epithelium is replaced by a columnar lining. The incidence of esophageal adenocarcinoma in the United States has increased by over 600% in the past 40 years and the overall survival rate remains less than 20% in the community. This review highlights some of the signaling pathways for which there is some evidence of a role in the development of esophageal adenocarcinoma. An increasingly detailed understanding of the biology of this cancer has emerged recently, revealing that in addition to the well-recognized alterations in single genes such as p53, p16, APC, and telomerase, there are interactions between the components of the reflux fluid, the homeobox gene Cdx2, and the Wnt, Notch, and Hedgehog signaling pathways.
    Preview · Article · Oct 2014 · Cancer biology & therapy
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    ABSTRACT: Background Barrett’s esophagus with high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) can be effectively treated by single-session EMR, resulting in complete Barrett’s excision (CBE). CBE provides accurate histology for staging and clinical confirmation of neoplasia eradication but is limited by a high risk of esophageal stricture formation. Objective To evaluate the effectiveness of prophylactic temporary esophageal stenting to prevent post-CBE stricture formation. Design and Setting Single-center, investigator-initiated feasibility study. Patients Circumferential, short-segment Barrett’s esophagus (≤C3≤M5) with HGD or IMC. Intervention Single-stage CBE and insertion of a fully covered metal esophageal stent at 10 days that was removed at 8 weeks. Patients were followed for a minimum of 2 surveillance endoscopies. Main Outcome Measurement Symptomatic esophageal stricture formation. Results At the end of the follow-up period, 8 patients (57.1%) required esophageal dilation for symptomatic CBE-related (n = 7) or stent-related (n = 4) strictures. A median of 3 surveillance endoscopies were performed over a median endoscopic follow-up of 17 months (range 4-25 months). Single-stage CBE successfully eliminated Barrett’s intestinal metaplasia and neoplasia in 71.4% and 92.9% of patients, respectively. Four patients were admitted to the hospital, and 4 patients had early stent removal because of pain or dysphagia. Limitations Single-center feasibility study. Conclusions In a prospective study evaluating prophylactic esophageal stent insertion after single-stage CBE, esophageal strictures formed in more than of half the study cohort, and stents were associated with significant morbidity. An alternative method to reduce stricture formation is required. (Clinical trial registration number: NCT01554280.)
    Full-text · Article · Oct 2014 · Gastrointestinal Endoscopy
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    ABSTRACT: Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.
    Full-text · Article · Oct 2014 · Nature Communications
  • Dan Falkenback · Christopher W. Lehane · Reginald V. N. Lord
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    ABSTRACT: Background Robot-assisted general surgery operations are being performed more frequently. This review investigates whether robotic assistance results in significant advantages or disadvantages for the operative treatment of gastro-oesophageal reflux disease and achalasia.Methods The electronic databases (Medline, Embase, PubMed) were searched for original English language publications for antireflux surgery and Heller's myotomy between January 1990 and December 2013.ResultsThirty-three publications included antireflux operations and 20 included Heller's myotomy. The publications indicate that the safety and effectiveness of robotic surgery is similar to that of conventional minimally invasive surgery for both operations. The six randomized trials of robot-assisted versus laparoscopic antireflux surgery showed no significant advantages but significantly higher costs for the robotic method. Gastric perforation during non-redo robotic fundoplication occurred in four trials.Conclusions No consistent advantage for robot-assisted antireflux surgery has been demonstrated, and there is an increased cost with current robotic technology. A reported advantage for robotic in reducing the perforation rate during Heller's myotomy for achalasia remains unproven. Gastric perforation during robotic fundoplication may be due to the lack of haptic feedback combined with the superhuman strength of the robot.
    No preview · Article · Aug 2014 · ANZ Journal of Surgery

  • No preview · Article · May 2014 · Gastroenterology

  • No preview · Article · May 2014 · Gastroenterology
  • Dan Falkenback · Christopher W. Lehane · Reginald V. N. Lord
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    ABSTRACT: Background Robot-assisted surgery is a technically feasible alternative to open and laparoscopic surgery, which is being more frequently used in general surgery. We undertook this review to investigate whether robotic assistance provides a significant benefit for oesophagogastric cancer surgery.Methods Electronic databases were searched for original English-language publications for robotic-assisted gastrectomy and oesophagectomy between January 1990 and October 2013.ResultsSixty-one publications were included. Thirty-five included gastrectomy, 31 included oesophagectomy and five included both operations. Several publications suggest that robot-assisted subtotal gastrectomy can be as safe and effective as an open or laparoscopic procedure, with equal outcomes with regard to the number of lymph nodes resected, overall morbidity and perioperative mortality, and length of hospital stay. Robotic assistance is associated with longer operation times but also with less blood loss in some reports. A significant benefit for robotic assistance has not been shown for the more extensive operations of oesophagectomy or total gastrectomy with D2-lymphadenectomy. There are very few oncologic data regarding local recurrence or long-term survival for any of the robotic operations.Conclusions No significant differences in morbidity, mortality or number of lymph node harvested have been shown between robot-assisted and laparoscopic gastrectomy or oesophagectomy. Robotic surgery, with its relatively short learning curve, may facilitate reproducible minimally invasive surgery in this field but operation times are reportedly longer and cost differences remain unclear. Randomized trials with oncologic outcomes and cost comparisons are needed.
    No preview · Article · May 2014 · ANZ Journal of Surgery
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    ABSTRACT: To examine the relationship between hospital volume and patient outcomes for New South Wales hospitals performing oesophagectomy and gastrectomy for oesophagogastric cancer. A retrospective, population-based cohort study of NSW residents diagnosed with a new case of invasive oesophageal or gastric cancer who underwent oesophagectomy or gastrectomy between 2001 and 2008 in NSW hospitals using linked de-identified data from the NSW Central Cancer Registry, the National Death Index and the NSW Admitted Patient Data Collection. A higher-volume hospital was defined as one performing > 6 relevant procedures per year. Odds ratios for > 21-day length of stay, 28-day unplanned readmission, 30-day mortality and 90-day mortality, and hazard ratios (HRs) for 5-year absolute and conditional survival. Oesophagectomy (908 patients) and gastrectomy (1621 patients) were undertaken in 42 and 84 hospitals, respectively, between 2001 and 2008. Median annual hospital volume ranged from 2 to 4 for oesophagectomies and ranged from 2 to 3 for gastrectomies. Controlling for known confounders, no associations between hospital volume and > 21-day length of stay and 28-day unplanned readmission were found. Overall 30-day mortality was 4.1% and 4.4% for oesophagectomy and gastrectomy, respectively. Five-year absolute survival was significantly better for patients who underwent oesophagectomy in higher-volume hospitals (adjusted HR for lower-volume hospitals, 1.28 [95% CI, 1.10-1.49]; P = 0.002) and for those with localised gastric cancer who underwent gastrectomy in higher-volume hospitals (adjusted HR for lower-volume hospitals, 1.83 [95% CI, 1.28-2.61]; P = 0.001). These data support initial surgery for oesophagogastric cancer in higher-volume hospitals.
    Full-text · Article · Apr 2014 · The Medical journal of Australia

  • No preview · Article · Jan 2014 · Gastroenterology

Publication Stats

4k Citations
1,006.28 Total Impact Points

Institutions

  • 1998-2016
    • St. Vincent's Hospital Sydney
      • Department of Upper Gastrointestinal Tract Surgery
      Sydney, New South Wales, Australia
  • 2013-2015
    • University of Notre Dame Australia
      • School of Medicine
      Fremantle, Western Australia, Australia
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2008-2014
    • University of New South Wales
      • • Faculty of Medicine
      • • Department of Surgery
      Kensington, New South Wales, Australia
    • Western Sydney University
      • School of Medicine
      Sydney, New South Wales, Australia
  • 2012
    • St. Vincent Hospital
      Green Bay, Wisconsin, United States
  • 2000-2006
    • University of Southern California
      • Department of Surgery
      Los Angeles, California, United States
    • University of California, Los Angeles
      • Department of Surgery
      Los Angeles, CA, United States
    • City University Los Angeles
      Los Ángeles, California, United States
  • 2003
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 2002
    • University of Southern Mississippi
      Mississippi, United States
  • 2000-2002
    • University of Cologne
      • Department of Vascular Surgery
      Köln, North Rhine-Westphalia, Germany
  • 2001
    • Lund University
      • Department of Surgery
      Lund, Skåne, Sweden