Publications by authors named "Stephen J Wigmore"

166 Publications

Remote diagnosis of surgical-site infection using a mobile digital intervention: a randomised controlled trial in emergency surgery patients.

NPJ Digit Med 2021 Nov 18;4(1):160. Epub 2021 Nov 18.

Department of Clinical Surgery, University of Edinburgh, 51 Little France Crescent, Edinburgh, UK.

Surgical site infections (SSI) cause substantial morbidity and pose a burden to acute healthcare services after surgery. We aimed to investigate whether a smartphone-delivered wound assessment tool can expedite diagnosis and treatment of SSI after emergency abdominal surgery. This single-blinded randomised control trial (NCT02704897) enroled adult emergency abdominal surgery patients in two tertiary care hospitals. Patients were randomised (1:1) to routine postoperative care or additional access to a smartphone-delivered wound assessment tool for 30-days postoperatively. Patient-reported SSI symptoms and wound photographs were requested on postoperative days 3, 7, and 15. The primary outcome was time-to-diagnosis of SSI (Centers for Disease Control definition). 492 patients were randomised (smartphone intervention: 223; routine care: 269). There was no significant difference in the 30-day SSI rate between trial arms: 21 (9.4%) in smartphone vs 20 (7.4%, p = 0.513) in routine care. Among the smartphone group, 32.3% (n = 72) did not utilise the tool. There was no significant difference in time-to-diagnosis of SSI for patients receiving the intervention (-2.5 days, 95% CI: -6.6-1.6, p = 0.225). However, patients in the smartphone group had 3.7-times higher odds of diagnosis within 7 postoperative days (95% CI: 1.02-13.51, p = 0.043). The smartphone group had significantly reduced community care attendance (OR: 0.57, 95% CI: 0.34-0.94, p = 0.030), similar hospital attendance (OR: 0.76, 95% CI: 0.28-1.96, p = 0.577), and significantly better experiences in accessing care (OR: 2.02, 95% CI: 1.17-3.53, p = 0.013). Smartphone-delivered wound follow-up is feasible following emergency abdominal surgery. This can facilitate triage to the appropriate level of assessment required, allowing earlier postoperative diagnosis of SSI.
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http://dx.doi.org/10.1038/s41746-021-00526-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602321PMC
November 2021

Hepatectomy after bile duct injury: a systematic review.

HPB (Oxford) 2021 Oct 5. Epub 2021 Oct 5.

University Department of Clinical Surgery, University of Edinburgh, Little France Crescent, Edinburgh, UK. Electronic address:

Background: Bile duct injury (BDI) after cholecystectomy can lead to recurrent cholangitis, even after biliary reconstruction. This necessitates hepatectomy in a minority of patients. A systematic review was conducted, summarizing the pattern of biliary injury sustained in this group and their outcomes after hepatectomy.

Methods: A literature search included the MEDLINE, EMBASE, PubMed and Cochrane libraries. Retrospective cohort studies describing outcomes for hepatectomy after BDI, and the nature of the antecedent BDI, published between 1999 and 2019, were selected.

Results: Eight articles described a cohort of 2110 patients with BDI. Of these, 84 underwent hepatectomy. Complex vasculo-biliary injuries had been sustained in most cases. The mean time to hepatectomy was between 26 and 224 months after BDI. A right hepatectomy was performed in 67-89% of cases. Post hepatectomy, intra-abdominal infection (range 0-50%) and bile leaks (range 0-45%) occurred variably. Mortality occurred in three series. Nineteen percent of patients (16 of 84) developed recurrent symptoms at follow up.

Conclusion: Hepatectomy after bile duct injury is an uncommon procedure and represents a salvage strategy when vasculo-biliary injury happens. Liver resection leads to resolution of symptoms in the majority of the cases however postoperative bile leaks and intra-abdominal infection are common.
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http://dx.doi.org/10.1016/j.hpb.2021.09.012DOI Listing
October 2021

Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility.

Hepatology 2021 Oct 15. Epub 2021 Oct 15.

Centre for Medical Informatics, Usher Institute, University of Edinburgh.

Background & Aims: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants, representing new targets for gallstone research and treatment.

Approach & Results: We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1,089 cases, 5,228 controls) and conducted a GWA meta-analysis (43,639 cases,506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (P < 5 * 10 ), of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared to the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations.

Conclusions: This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.
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http://dx.doi.org/10.1002/hep.32199DOI Listing
October 2021

Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience.

HPB (Oxford) 2021 11 19;23(11):1656-1665. Epub 2021 Mar 19.

Addenbrookes Hospital, Hills Rd, Cambridge, CB2 0QQ, UK. Electronic address:

Introduction: The SARS-CoV-2 pandemic presented healthcare providers with an extreme challenge to provide cancer services. The impact upon the diagnostic and treatment capacity to treat pancreatic cancer is unclear. This study aimed to identify national variation in treatment pathways during the pandemic.

Methods: A survey was distributed to all United Kingdom pancreatic specialist centres, to assess diagnostic, therapeutic and interventional services availability, and alterations in treatment pathways. A repeating methodology enabled assessment over time as the pandemic evolved.

Results: Responses were received from all 29 centres. Over the first six weeks of the pandemic, less than a quarter of centres had normal availability of diagnostic pathways and a fifth of centres had no capacity whatsoever to undertake surgery. As the pandemic progressed services have gradually improved though most centres remain constrained to some degree. One third of centres changed their standard resectable pathway from surgery-first to neoadjuvant chemotherapy. Elderly patients, and those with COPD were less likely to be offered treatment during the pandemic.

Conclusion: The COVID-19 pandemic has affected the capacity of the NHS to provide diagnostic and staging investigations for pancreatic cancer. The impact of revised treatment pathways has yet to be realised.
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http://dx.doi.org/10.1016/j.hpb.2021.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973054PMC
November 2021

Genome-Wide Association Study of NAFLD Using Electronic Health Records.

Hepatol Commun 2021 Sep 17. Epub 2021 Sep 17.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Edingburgh, Scotland.

Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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http://dx.doi.org/10.1002/hep4.1805DOI Listing
September 2021

Intra-observer agreements in multidisciplinary team assessments of pancreatic cancer patients.

J Surg Oncol 2021 Dec 7;124(8):1402-1408. Epub 2021 Sep 7.

Department of Surgery, HPB Research Unit, Aarhus University Hospital, Aarhus, Denmark.

Background And Methods: Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (<50%), moderate (50%-75%), and high (>75%) agreement.

Results: Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors.

Conclusions: We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment.
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http://dx.doi.org/10.1002/jso.26670DOI Listing
December 2021

Clinical Outcomes of Ablation Compared with Resection for Single Hepatocellular Carcinoma Lesions, as a Primary Treatment or Bridging to Liver Transplantation: A Retrospective Comparative Study.

Ann Transplant 2021 Jul 30;26:e931980. Epub 2021 Jul 30.

Department of Hepato-Pancreato-Biliary (HPB)/Transplant Surgery, The University of Edinburgh Clinical Surgery, Edinburgh, United Kingdom.

BACKGROUND Ablative therapies (AT) are widely utilized as bridging treatment for liver transplantation (LT) candidates with hepatocellular carcinoma (HCC) who are on the transplant waiting list to minimize dropout rate. We aimed to investigate whether AT could be considered a primary treatment modality for LT candidates with single, small HCC lesions. MATERIAL AND METHODS We retrospectively investigated the outcomes of patients with AT for single HCC lesions as primary treatment or bridging to LT between 2010 and 2017, compared with surgical resection (SR) during the same time period as control. Univariate and multivariate survival analyses were performed. Matched analysis, after propensity score matching (PSM), was performed to minimize the selection bias confounding effect on outcomes. RESULTS Of 162 patients identified, 92 received AT and 70 had SR. PSM identified 38 paired matches in each group. Overall survival (OS) and disease-free survival (DFS) before matching showed comparable outcomes for each treatment after 1, 3, and 5 years. Multivariate analysis using Cox regression models adjusting the study confounders showed lesion size (>30 mm), not treatment received, was associated with worse DFS (hazard ratio, 2.21 [95% confidence interval, 1.14-4.28]). In the matched groups, OS and DFS were equivalent and consistent with the whole-cohort survival outcomes. Explant histopathology of patients having AT as a bridge to LT showed complete pathological response in 85.7% of patients. CONCLUSIONS This study supports the use of AT with curative intent for single ≤3-cm HCCs, particularly in LT candidates, with salvage transplantation kept as a backup in case of recurrence.
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http://dx.doi.org/10.12659/AOT.931980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330445PMC
July 2021

Equality, diversity and inclusion in HPB surgery.

HPB (Oxford) 2021 Jun 22;23(6):813-814. Epub 2021 Mar 22.

Past President IHPBA, Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa.

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http://dx.doi.org/10.1016/j.hpb.2021.03.008DOI Listing
June 2021

Social Media for the Hepato-Pancreato-Biliary community (#SoMe4HPB): connecting a specialized online group for scientific and clinical knowledge dissemination.

HPB (Oxford) 2021 Sep 19;23(9):1448-1455. Epub 2021 Mar 19.

Department of Gastrointestinal Surgery, Stavanger University Hospital, POB 8100, N-4068, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Background: Social media has an increasingly important role in scientific communication, clinical discussions and knowledge distribution. While several surgical disciplines have taken to internet for increased connectivity, there is currently little knowledge about the social media activity in the field of hepatopancreatobiliary surgery. We aimed to evaluate the implementation and use of a specific HPB hashtag and Twitter handle.

Methods: The hashtag and Twitter handle (#SoMe4HPB; @hpb_so) were initiated on February 2019. We evaluated the response during the initial 15 months by applying NodeXL to trace activity.

Results: The Twitter handle had 1388 followers (by May 7, 2020) and had generated 855 tweets and retweets. A total of 1120 mentions of 182 accounts were recorded in original tweets by @hpb_so. The largest global reach was recorded in December 2019 (254.000 people). Pancreatic cancer was the subject of 15% of all posts, liver malignancies of 12% of all posts and minimally invasive surgery of 8%.

Conclusion: The Social Media for the Hepato-Pancreato-Biliary community (#SoMe4HPB) and its associated Twitter handle @hpb_so had a well-built inception followed by a progressive development connecting individuals interested in HPB Surgery internationally. The involvement of more actors is required in order to fully attain its scientific dissemination role.
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http://dx.doi.org/10.1016/j.hpb.2021.01.017DOI Listing
September 2021

Author's Reply: Prehabilitation Before Major Abdominal Surgery.

World J Surg 2021 03 5;45(3):911-912. Epub 2021 Jan 5.

Department of General Surgery, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK.

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http://dx.doi.org/10.1007/s00268-020-05889-1DOI Listing
March 2021

Identifying cell-enriched miRNAs in kidney injury and repair.

JCI Insight 2020 12 17;5(24). Epub 2020 Dec 17.

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Small noncoding RNAs, miRNAs (miRNAs), are emerging as important modulators in the pathogenesis of kidney disease, with potential as biomarkers of kidney disease onset, progression, or therapeutic efficacy. Bulk tissue small RNA-sequencing (sRNA-Seq) and microarrays are widely used to identify dysregulated miRNA expression but are limited by the lack of precision regarding the cellular origin of the miRNA. In this study, we performed cell-specific sRNA-Seq on tubular cells, endothelial cells, PDGFR-β+ cells, and macrophages isolated from injured and repairing kidneys in the murine reversible unilateral ureteric obstruction model. We devised an unbiased bioinformatics pipeline to define the miRNA enrichment within these cell populations, constructing a miRNA catalog of injury and repair. Our analysis revealed that a significant proportion of cell-specific miRNAs in healthy animals were no longer specific following injury. We then applied this knowledge of the relative cell specificity of miRNAs to deconvolute bulk miRNA expression profiles in the renal cortex in murine models and human kidney disease. Finally, we used our data-driven approach to rationally select macrophage-enriched miR-16-5p and miR-18a-5p and demonstrate that they are promising urinary biomarkers of acute kidney injury in renal transplant recipients.
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http://dx.doi.org/10.1172/jci.insight.140399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819746PMC
December 2020

Steroid-Free Versus Steroid-Containing Immunosuppression for Liver Transplant Recipients.

Clin Liver Dis (Hoboken) 2020 Nov 10;16(5):191-195. Epub 2020 Dec 10.

Department of Medicine-Gastroenterology & Hepatology and Preventive Medicine Northwestern University Feinberg School of Medicine Chicago IL.

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http://dx.doi.org/10.1002/cld.992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727845PMC
November 2020

TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.

J Hepatol 2021 04 19;74(4):860-872. Epub 2020 Nov 19.

Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK. Electronic address:

Background & Aims: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA.

Methods: The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis.

Results: Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206 macrophages. Pharmacological blocking of the TWEAK downstream target chemokine monocyte chemoattractant protein 1 (MCP-1 or CCL2) significantly reduced CCA xenograft growth, while TWEAK overexpression drove cancer-associated fibroblast proliferation and collagen deposition in the tumour niche. Genetic Fn14 ablation significantly reduced inflammatory, fibrogenic and ductular responses during carcinogenic TAA-mediated injury.

Conclusion: These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth.

Lay Summary: Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation.
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http://dx.doi.org/10.1016/j.jhep.2020.11.018DOI Listing
April 2021

Comment on "Pancreatectomy With Arterial Resection for Pancreatic Adenocarcinoma: How Can It Be Done Safely and With Which Outcomes?"

Ann Surg 2021 Dec;274(6):e814-e815

Department of HPB and Liver Transplant Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1097/SLA.0000000000004536DOI Listing
December 2021

How surgeons should behave on social media.

Surgery (Oxf) 2020 Oct 30;38(10):623-626. Epub 2020 Aug 30.

is a Clinical Lecturer and Honorary Specialty Registrar in Surgery at the Royal Infirmary of Edinburgh, UK. Conflicts of interest: none declared.

This article documents the rise in popularity of social media use by surgeons for personal and professional use. It considers some of the important issues around privacy, patient confidentiality and professionalism and discusses some of the common pitfalls of using social media as a surgeon.
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http://dx.doi.org/10.1016/j.mpsur.2020.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456585PMC
October 2020

The Future Role of Machine Learning in Clinical Transplantation.

Transplantation 2021 04;105(4):723-735

Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.

The use of artificial intelligence and machine learning (ML) has revolutionized our daily lives and will soon be instrumental in healthcare delivery. The rise of ML is due to multiple factors: increasing access to massive datasets, exponential increases in processing power, and key algorithmic developments that allow ML models to tackle increasingly challenging questions. Progressively more transplantation research is exploring the potential utility of ML models throughout the patient journey, although this has not yet widely transitioned into the clinical domain. In this review, we explore common approaches used in ML in solid organ clinical transplantation and consider opportunities for ML to help clinicians and patients. We discuss ways in which ML can aid leverage of large complex datasets, generate cutting-edge prediction models, perform clinical image analysis, discover novel markers in molecular data, and fuse datasets to generate novel insights in modern transplantation practice. We focus on key areas in transplantation in which ML is driving progress, explore the future potential roles of ML, and discuss the challenges and limitations of these powerful tools.
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http://dx.doi.org/10.1097/TP.0000000000003424DOI Listing
April 2021

Synchronous colorectal liver metastases: timing of resection and patterns of referral.

Hepatobiliary Surg Nutr 2020 Apr;9(2):242-243

Department of Clinical Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.21037/hbsn.2019.10.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188541PMC
April 2020

Adipose depot gene expression and intelectin-1 in the metabolic response to cancer and cachexia.

J Cachexia Sarcopenia Muscle 2020 08 31;11(4):1141-1153. Epub 2020 Mar 31.

Clinical Surgery, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK.

Background: Cancer cachexia is a poorly understood metabolic consequence of cancer. During cachexia, different adipose depots demonstrate differential wasting rates. Animal models suggest adipose tissue may be a key driver of muscle wasting through fat-muscle crosstalk, but human studies in this area are lacking. We performed global gene expression profiling of visceral (VAT) and subcutaneous (SAT) adipose from weight stable and cachectic cancer patients and healthy controls.

Methods: Cachexia was defined as >2% weight loss plus low computed tomography-muscularity. Biopsies of SAT and VAT were taken from patients undergoing resection for oesophago-gastric cancer, and healthy controls (n = 16 and 8 respectively). RNA was isolated and reverse transcribed. cDNA was hybridised to the Affymetrix Clariom S microarray and data analysed using R/Bioconductor. Differential expression of genes was assessed using empirical Bayes and moderated-t-statistic approaches. Category enrichment analysis was used with a tissue-specific background to examine the biological context of differentially expressed genes. Selected differentially regulated genes were validated by qPCR. Enzyme-linked immunosorbent assay (ELISA) for intelectin-1 was performed on all VAT samples. The previously-described cohort plus 12 additional patients from each group also had plasma I = intelectin-1 ELISA carried out.

Results: In VAT vs. SAT comparisons, there were 2101, 1722, and 1659 significantly regulated genes in the cachectic, weight stable, and control groups, respectively. There were 2200 significantly regulated genes from VAT in cachectic patients compared with controls. Genes involving inflammation were enriched in cancer and control VAT vs. SAT, although different genes contributed to enrichment in each group. Energy metabolism, fat browning (e.g. uncoupling protein 1), and adipogenesis genes were down-regulated in cancer VAT (P = 0.043, P = 5.4 × 10 and P = 1 × 10 respectively). The gene showing the largest difference in expression was ITLN1, the gene that encodes for intelectin-1 (false discovery rate-corrected P = 0.0001), a novel adipocytokine associated with weight loss in other contexts.

Conclusions: SAT and VAT have unique gene expression signatures in cancer and cachexia. VAT is metabolically active in cancer, and intelectin-1 may be a target for therapeutic manipulation. VAT may play a fundamental role in cachexia, but the down-regulation of energy metabolism genes implies a limited role for fat browning in cachectic patients, in contrast to pre-clinical models.
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http://dx.doi.org/10.1002/jcsm.12568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432578PMC
August 2020

Meta-analysis and Meta-regression of Survival After Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma.

Ann Surg 2021 02;273(2):240-250

Department of Clinical Surgery, University of Edinburgh, Little France Crescent, Edinburgh, UK.

Objective: To systematically review studies reporting survival data following neoadjuvant chemoradiation and orthotopic liver transplantation (NCR-OLT) for unresectable perihilar cholangiocarcinoma (pCC).

Background: Despite survival improvements for other cancers, the prognosis of pCC remains dismal. Since publication of the Mayo protocol in 2000, increasing numbers of series globally are reporting outcomes after NCR-OLT.

Methods: MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from January 2000 to February 2019. A meta-analysis of proportions was conducted, pooling 1, 3-, and 5-year overall survival and recurrence rates following NCR-OLT across centers. Per protocol and intention to treat data were interrogated. Meta-regression was used to evaluate PSC as a confounder affecting survival.

Results: Twenty studies comprising 428 patients were eligible for analysis. No RCTs were retrieved; the majority of studies were noncomparative cohort studies. The pooled 1, 3-, and 5-year overall survival rates following OLT without neoadjuvant therapy were 71.2% (95% CI 62.2%-79.4%), 48.0% (95% CI 35.0%-60.9%), and 31.6% (95% CI 23.1%-40.7%). These improved to 82.8% (95% CI 73.0%-90.8%), 65.5% (95% CI 48.7%-80.5%), and 65.1% (95% CI 55.1%-74.5%) if neoadjuvant chemoradiation was completed. Pooled recurrence after 3 years was 24.1% (95% CI 17.9%-30.9%) with neoadjuvant chemoradiation, 51.7% (95% CI 33.8%-69.4%) without.

Conclusions: In unresectable pCC, NCR-OLT confers long-term survival in highly selected patients able to complete neoadjuvant chemoradiation followed by transplantation. PSC patients appear to have the most favorable outcomes. A high recurrence rate is of concern when considering extending national graft selection policy to pCC.
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http://dx.doi.org/10.1097/SLA.0000000000003801DOI Listing
February 2021

Laparoscopic liver resection in cirrhotics: feasibility and short-term outcomes compared to non-cirrhotics.

ANZ J Surg 2020 06 18;90(6):1104-1107. Epub 2020 Feb 18.

Department of HPB/Transplant Surgery, Royal Infirmary of Edinburgh, The University of Edinburgh, Edinburgh, UK.

Background: Laparoscopic liver resection (LLR) is increasingly common worldwide but its suitability in patients with cirrhosis is not clearly defined. There are minimal data in the western literature on this topic and previous work has compared LLR to open hepatectomy rather than to LLR in non-cirrhotic patients. This study compared short-term outcomes of LLR in cirrhotic patients to LLR in non-cirrhotic patients.

Methods: Retrospective review of minor LLR at the Royal Infirmary of Edinburgh from January 2006 to January 2018 was conducted. Patients were stratified by whether they had cirrhosis - defined as per radiological appearances and liver function tests. Variables of interest included baseline clinicopathological information with short-term outcomes (length of stay and complications) regarded as the primary outcome of interest.

Results: Out of 1207 liver resections in the study period, there were 120 LLR with 30 patients having cirrhosis. Patients with cirrhosis were more likely to be male and have higher median American Society of Anesthesiologists scores (3 versus 2; P < 0.01). The most common operation was left lateral sectionectomy (n = 67). There was no difference in duration of surgery (cirrhosis 88 min versus no cirrhosis 99 min; P = 0.64) and patients in the cirrhosis arm had no conversions to open (0% versus 12%; P = 0.06). There was no difference in complications (12% versus 13%; P = 0.75) or median length of stay (4 versus 4 days; P = 0.14) and no difference in survival between both groups.

Conclusion: With careful patient selection, LLR is feasible in patients with cirrhosis and provides comparable outcomes to non-cirrhotic patients undergoing LLR.
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http://dx.doi.org/10.1111/ans.15745DOI Listing
June 2020

Novel Organ Perfusion and Preservation Strategies in Transplantation - Where Are We Going in the United Kingdom?

Transplantation 2020 09;104(9):1813-1824

Department of Transplant Surgery, Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, United Kingdom.

This review article focuses on current clinical outcomes with novel perfusion strategies in organ transplantation. Broadly, these approaches can be divided into in situ regional perfusion in the donor and ex situ machine perfusion of individual organs. In both settings, hypothermic and normothermic techniques are in clinical use. Evidence from full text articles, abstracts, and data presented at scientific meetings has been considered. Animal studies have been excluded. The review focuses on kidney, liver, pancreas, heart, and lungs. The level of evidence ranges from quasi-experimental work in human pancreas to multiple meta-analyses of Randomized Controlled Trials for hypothermic machine perfusion of kidneys. The data in this review were presented to experts in organ perfusion and preservation at the National Health Service Blood and Transplant Preservation and Perfusion Future Strategy Summit in London in October 2018. The outcomes of the meeting are discussed in the review after due consideration of the available evidence base.
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http://dx.doi.org/10.1097/TP.0000000000003106DOI Listing
September 2020

Neuromuscular junctions are stable in patients with cancer cachexia.

J Clin Invest 2020 03;130(3):1461-1465

Biomedical Sciences, Edinburgh Medical School, Edinburgh, United Kingdom.

Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular junction (NMJ) may play a key role in cachexia, but this has yet to be investigated in human patients. Here, high-resolution morphological analyses were undertaken on NMJs of rectus abdominis obtained from patients undergoing upper GI cancer surgery compared with controls (N = 30; n = 1,165 NMJs). Cancer patients included those with cachexia and weight-stable disease. Despite the low skeletal muscle index and significant muscle fiber atrophy (P < 0.0001) in patients with cachexia, NMJ morphology was fully conserved. No significant differences were observed in any of the pre- and postsynaptic variables measured. We conclude that NMJs remain structurally intact in rectus abdominis in both cancer and cachexia, suggesting that denervation of skeletal muscle is not a major driver of pathogenesis. The absence of NMJ pathology is in stark contrast to what is found in related conditions, such as age-related sarcopenia, and supports the hypothesis that intrinsic changes within skeletal muscle, independent of any changes in motor neurons, represent the primary locus of neuromuscular pathology in cancer cachexia.
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http://dx.doi.org/10.1172/JCI128411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269586PMC
March 2020

Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis.

Cell Rep 2019 11;29(7):1832-1847.e8

Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh EH16 4TJ, UK. Electronic address:

Iterative liver injury results in progressive fibrosis disrupting hepatic architecture, regeneration potential, and liver function. Hepatic stellate cells (HSCs) are a major source of pathological matrix during fibrosis and are thought to be a functionally homogeneous population. Here, we use single-cell RNA sequencing to deconvolve the hepatic mesenchyme in healthy and fibrotic mouse liver, revealing spatial zonation of HSCs across the hepatic lobule. Furthermore, we show that HSCs partition into topographically diametric lobule regions, designated portal vein-associated HSCs (PaHSCs) and central vein-associated HSCs (CaHSCs). Importantly we uncover functional zonation, identifying CaHSCs as the dominant pathogenic collagen-producing cells in a mouse model of centrilobular fibrosis. Finally, we identify LPAR1 as a therapeutic target on collagen-producing CaHSCs, demonstrating that blockade of LPAR1 inhibits liver fibrosis in a rodent NASH model. Taken together, our work illustrates the power of single-cell transcriptomics to resolve the key collagen-producing cells driving liver fibrosis with high precision.
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http://dx.doi.org/10.1016/j.celrep.2019.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856722PMC
November 2019

Plasma Metabolomics Identifies Lipid and Amino Acid Markers of Weight Loss in Patients with Upper Gastrointestinal Cancer.

Cancers (Basel) 2019 Oct 19;11(10). Epub 2019 Oct 19.

Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.

Cachexia is a multifactorial wasting syndrome associated with high morbidity and mortality in patients with cancer. Diagnosis can be difficult and, in the clinical situation, usually relies upon reported weight loss. The 'omics' technologies allow us the opportunity to study the end points of many biological processes. Among these, blood-based metabolomics is a promising method to investigate the pathophysiology of human cancer cachexia and identify candidate biomarkers. In this study, we performed liquid chromatography mass spectrometry (LC/MS)-based metabolomics to investigate the metabolic profile of cancer-associated weight loss. Non-selected patients undergoing surgery with curative intent for upper gastrointestinal cancer were recruited. Fasting plasma samples were taken at induction of anaesthesia. LC/MS analysis showed that 6 metabolites were highly discriminative of weight loss. Specifically, a combination profile of LysoPC 18.2, L-Proline, Hexadecanoic acid, Octadecanoic acid, Phenylalanine and LysoPC 16:1 showed close correlation for eight weight-losing samples (≥5% weight loss) and nine weight-stable samples (<5%weight loss) between predicted and actual weight change (r = 0.976, = 0.0014). Overall, 40 metabolites were associated with ≥5% weight loss. This study provides biological validation of the consensus definition of cancer cachexia (Fearon et al.) and provides feasible candidate markers for further investigation in early diagnosis and the assessment of therapeutic intervention.
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http://dx.doi.org/10.3390/cancers11101594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826420PMC
October 2019

Can a smartphone-delivered tool facilitate the assessment of surgical site infection and result in earlier treatment? Tracking wound infection with smartphone technology (TWIST): protocol for a randomised controlled trial in emergency surgery patients.

BMJ Open 2019 10 3;9(10):e029620. Epub 2019 Oct 3.

Department of Clinical Surgery, University of Edinburgh, 51 Little France Crescent, Edinburgh, UK.

Introduction: National data suggest that surgical site infection (SSI) complicates 2%-10% of general surgery cases, although the patient-reported incidence is much higher. SSIs cause significant patient morbidity and represent a significant burden on acute healthcare services, in a cohort predominantly suitable for outpatient management. Over three-quarters of UK adults now own smartphones, which could be harnessed to improve access to care. We aim to investigate if a smartphone-delivered wound assessment tool results in earlier treatment.

Methods And Analysis: This is a randomised controlled trial aiming to recruit 500 patients across National Health Service (NHS) hospitals. All emergency abdominal surgery patients over the age of 16 who own smartphones will be considered eligible, with the exclusion of those with significant visual impairment. Participants will be randomised in a 1:1 ratio between standard postoperative care and the intervention - use of the smartphone tool in addition to standard postoperative care. The main outcome measure will be time-to-diagnosis of SSI with secondary outcome measures considering use of emergency department and general practitioner services and patient experience. Follow-up will be conducted by clinicians blinded to group allocation. Analysis of time-to-diagnosis will be by comparison of means using an independent two sample t-test.

Ethics And Dissemination: This is the first randomised controlled trial on the use of a smartphone-delivered wound assessment tool to facilitate the assessment of SSI and the impact on time-to-diagnosis. The intervention is being used in addition to standard postoperative care. The study design and protocol were reviewed and approved by Southeast Scotland Research and Ethics Committee (REC Ref: 16/SS/0072 24/05/2016). Study findings will be presented at academic conferences, published in peer-reviewed journals and are expected in 2020. A written lay summary will be available to study participants on request.

Trial Registration Number: NCT02704897; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-029620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797297PMC
October 2019

The harms of early cessation of trials on systematic reviews.

Lancet Gastroenterol Hepatol 2019 09;4(9):667

Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(19)30192-XDOI Listing
September 2019

Improved Survival in Liver Transplant Patients Receiving Prolonged-release Tacrolimus-based Immunosuppression in the European Liver Transplant Registry (ELTR): An Extension Study.

Transplantation 2019 09;103(9):1844-1862

Department of Surgery and Liver Transplantation, Fundeni Clinical Institute, University of Medicine "Carol Davila", Bucharest, Romania.

Background: We compared, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release tacrolimus (IR-T)-based immunosuppression. This retrospective analysis comprises up to 8-year data collected between 2008 and 2016, in an extension of our previously published study.

Methods: Patients with <1 month follow-up were excluded; patients were propensity score matched for baseline characteristics. Efficacy measures included: univariate/multivariate analyses of risk factors influencing graft/patient survival up to 8 years posttransplantation, and graft/patient survival up to 4 years with PR-T versus IR-T. Overall, 13 088 patients were included from 44 European centers; propensity score-matched analyses comprised 3006 patients (PR-T: n = 1002; IR-T: n = 2004).

Results: In multivariate analyses, IR-T-based immunosuppression was associated with reduced graft survival (risk ratio, 1.49; P = 0.0038) and patient survival (risk ratio, 1.40; P = 0.0215). There was improvement with PR-T versus IR-T in graft survival (83% versus 77% at 4 y, respectively; P = 0.005) and patient survival (85% versus 80%; P = 0.017). Patients converted from IR-T to PR-T after 1 month had a higher graft survival rate than patients receiving IR-T at last follow-up (P < 0.001), or started and maintained on PR-T (P = 0.019). One graft loss in 4 years was avoided for every 14.3 patients treated with PR-T versus IR-T.

Conclusions: PR-T-based immunosuppression might improve long-term outcomes in liver transplant recipients than IR-T-based immunosuppression.
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http://dx.doi.org/10.1097/TP.0000000000002700DOI Listing
September 2019

Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study.

J Hepatol 2019 08 7;71(2):313-322. Epub 2019 May 7.

Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.

Background & Aims: Little is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors.

Methods: We analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival.

Results: Among 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH - an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p <0.001). NASH was not significantly associated with survival of patients (hazard ratio [HR] 1.02, p = 0.713) or grafts (HR 0.99; p = 0.815) after accounting for available recipient and donor variables. Infection (24.0%) and cardio/cerebrovascular complications (5.3%) were the commonest causes of death in patients with NASH without HCC. Increasing recipient age (61-65 years: HR 2.07, p <0.001; >65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (<18.5 kg/m: HR 4.29, p = 0.048) or high (>40 kg/m: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors.

Conclusions: The number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications.

Lay Summary: The prevalence of non-alcoholic fatty liver disease has increased dramatically in parallel with the worldwide increase in obesity and diabetes. Its progressive form, non-alcoholic steatohepatitis, is a growing indication for liver transplantation in Europe, with good overall outcomes reported. However, careful risk factor assessment is required to maintain favourable post-transplant outcomes in patients with non-alcoholic steatohepatitis.
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http://dx.doi.org/10.1016/j.jhep.2019.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656693PMC
August 2019

Gallstone Disease and the Risk of Cardiovascular Disease.

Sci Rep 2019 04 9;9(1):5830. Epub 2019 Apr 9.

Department of Clinical Surgery, The University of Edinburgh, Edinburgh, EH16 4SA, UK.

Gallstone disease (GD) is one of the most common presentations to surgical units worldwide and shares several risk factors with cardiovascular disease (CVD). CVD remains the most common cause of death worldwide and results in considerable economic burden. Recent observational studies have demonstrated an association between GD and CVD with some studies demonstrating a stronger association with cholecystectomy. We present the findings of a meta-analysis assessing the relationship between GD and CVD. A total of fourteen cohort studies with over 1.2 million participants were included. The pooled hazard ratio (HR, 95% confidence interval [CI]) for association with GD from a random-effects model is 1.23 (95%CI: 1.16-1.30) for fatal and non-fatal CVD events. The association was present in females and males. Three studies report the relationship between cholecystectomy and CVD with a pooled HR of 1.41 (95%CI: 1.21-1.64) which compares to a HR of 1.30 (95%CI: 1.07-1.58) when cholecystectomy is excluded although confounding may influence this result. Our meta-analysis demonstrates a significant relationship between GD and CVD events which is present in both sexes. Further research is needed to assess the influence of cholecystectomy on this association.
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http://dx.doi.org/10.1038/s41598-019-42327-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456597PMC
April 2019
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