bluuebunny/crossref_metadata_2025 huggingface dataset:
O6: EARLY ANASTOMOTIC BILIARY COMPLICATIONS AFTER LIVER TRANSPLANTATION
Authors: Tingle SJ , Thompson ER , Ali SS , Ibrahim IK , Irwin E , Sen G , White SA , Manas DM , Wilson CH
Published: April 2021

Introduction

Biliary leaks and anastomotic strictures are common early biliary complications (EBC) following liver transplantation. However, their impact on outcomes remains controversial and poorly described.

Method

The NHS registry on adult liver transplantation between 2006 and 2017 was retrospectively reviewed (n=8304). Multiple imputations were performed to account for missing data. Adjusted regression models were used to assess predictors of EBC, and their impact on outcomes. 35 potential variables were included, and backwards stepwise selection enabled unbiased selection of variables for inclusion in final models.

Result

EBC occurred in 9.6% of patients. Adjusted cox regression revealed that EBCs have a significant and independent impact on graft survival (Leak HR=1.325; P=0.021, Stricture HR=1.514; P=0.002, Leak plus stricture HR=1.533; P=0.034) and patient survival (Leak HR=1.218; P=0.131, Stricture HR=1.578; P<0.001, Leak plus stricture HR=1.507; P=0.044). Patients with EBC had longer median hospital stay (23 versus 15 days; P<0.001) and increased chance for readmission within the first year (56% versus 32%; P<0.001). On adjusted logistic regression the following were identified as independent risk factors for development of EBC: donation following circulatory death (OR=1.280; P=0.009), accessory hepatic artery (OR=1.324; P=0.005), vascular anastomosis time in minutes (OR=1.005; P=0.032) and ethnicity ‘other’ (OR=1.838; P=0.011).

Conclusion

EBCs prolong hospital stay, increase readmission rates and are independent risk factors for diminished graft survival and increased mortality in liver transplantation. We have identified factors that increase the likelihood of EBC occurrence; further research into interventions to prevent EBCs in these at-risk groups is vital to improve liver transplantation outcomes.

Take-home message

Using a large registry database we have shown that early anastomotic biliary complications are independent risk factors for decreased graft survival and increased mortality after liver transplantation. Research into interventions to prevent biliary complications in high risk groups are essential to improve liver transplant outcomes.
O7: APPARENT PATHOLOGICAL COMPLETE RESPONSE TO NEOADJUVANT THERAPY LEADS TO SELECTION OF TREATMENT RESISTANT CANCER STEM CELLS IN OESOPHAGEAL ADENOCARCINOMA
Authors: Walker RC , Harrington J , Grace B , Lloyd M , Byrne JP , Kelly JJ , Noble F , Rose-Zerilli MJ , Underwood TJ
Published: April 2021

Introduction

In oesophageal adenocarcinoma with an apparent pathological complete response (pCR) to neoadjuvant therapy (NAT) there remains debate as to whether oesophagectomy is required. Single Cell RNA sequencing (scRNAseq) enables identification and characterisation of cell populations at higher resolution than diagnostic techniques.

Method

ScRNAseq was used to determine transcriptomic profiles of cell populations in 24 OAC tumours and 13 matched normal samples. Five were also analysed using bulk RNA sequencing and high-precision mass spectrometry proteomics. Immunohistochemistry (IHC) was used to validate pCR. Paired scRNAseq analysis of pre-and post-treatment specimens from three further patients was used to compare transcriptomic profiles before and after NAT. Cancer cells (CCs) were assigned a cancer stem cell (CSC) score curated from published gene sets.

Result

We analysed a total of 22,738 single cells forming 29 different cell phenotypes. In two samples with apparent pCR, IHC staining, bulk RNA sequencing and proteomics of post-treatment samples failed to identify CCs. ScRNAseq, conversely, revealed persistent CCs (12/978 and 45/774). Transcriptomic analysis identified upregulation of stem cell markers and high CSC scores in these cells.

Conclusion

We have shown that CCs persist beneath the lower detection limit of standard approaches in apparent pCR. These cells express marker genes and expression programs consistent with CSCs. CSCs are a critical subpopulation that drive tumour initiation, growth, invasion, metastasis and resistance to therapy. These gene expression programs are not enriched in non-responders and straight to surgery samples. Oesophagus sparing treatment algorithms in pCR may subject patients to unnecessary risk of progression.

Take-home message

Cancer cells remain within tumours after apparent complete pathological response. These cells express stem cell markers associated with resistance to therapy and cancer progression.
O10: METFORMIN TREATMENT IMPROVES LYMPHOCYTE METABOLISM IN A MOUSE MODEL OF MAJOR SURGERY
Authors: Jones TF , Gutierrez A , Arroyo del , Henson SM , Ackland GL
Published: April 2021

Introduction

Lymphopaenia is common after major surgery and associated with poor outcome. T-lymphocytes restrain damaging innate inflammation. Major surgery impairs T-lymphocyte metabolism in humans, which promotes lymphopaenia. Metformin is known to improve mitochondrial bioenergetics in models of inflammation. Firstly, we hypothesised that a mouse model of major surgery would demonstrate impaired T-lymphocyte metabolism and secondly, that metformin treatment in vivo would reverse the phenotype.

Method

Male C57Bl/6 mice aged between 8 and 12 weeks were housed in a specific pathogen free environment with free access to food and water. Animals were dosed with either vehicle (phosphate buffered saline, 20 ml/kg) or metformin (250 mg/kg) daily via intraperitoneal injection for four days prior to and after surgery. A partial hepatectomy was performed under isofluorane anaesthesia. Naive littermates were used as controls. All experiments were performed according to the Animals (Scientific Procedures) Act 1986. Splenic T-lymphocytes were isolated by negative selection using magnetic beads. Mitochondrial bioenergetics were measured using a Seahorse Extracellular Flux analyser. Parametric statistical analysis was performed and a p-value < 0.05 was chosen to represent significance.

Result

T-lymphocytes demonstrated reduced spare respiratory capacity (SRC, 285 vs 497 %, p=0.004) after surgery compared to naive controls. Metformin treatment in vivo reversed this observation and SRC was comparable to naive (437 vs 497 %, p=0.34). Metformin treatment in vitro increased spare respiratory capacity in T-lymphocytes from mice after surgery compared to naive (change from untreated, 187 vs 91 %, p=0.03).

Conclusion

Perioperative metformin treatment improved T-lymphocyte metabolism in a mouse model of major surgery.

Take-home message

Metformin is a potential treatment for the lymphocyte metabolic dysfunction observed after surgery.
O11: MYOFERLIN: A NOVEL BIOMARKER OF RADIOSENSITIVITY IN LOCALLY ADVANCED RECTAL CANCER
Authors: Fowler H , Sutton P , Bowden D , Parsons J , Vimalachandran D
Published: April 2021

Introduction

Our proteomic data has validated that high levels of the protein myoferlin confers poorer response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Myoferlin plays a role in membrane repair and VEGF signal transduction, and is associated with worse prognosis in numerous other epithelial cancers. We aim to assess the impact of myoferlin on the radiosensitivity of rectal cancer.

Method

Clonogenic assays were performed using immortalised colorectal cancer cells (HCT116,HT29,LIM,MDST8) to assess survival at escalating radiation doses following knockdown with myoferlin siRNA or a small molecular inhibitor(WJ460). 3D models (spheroids) were used to examine the effect of WJ460 on tumour growth.

Result

Quantification of myoferlin using immunoblotting demonstrated that MDST8 and LIM were higher expressors than HCT116 and HT29. Higher levels correlated with increasing radio-resistance as calculated by colony formation efficiency (CFE). Using clonogenic assays, cells treated with myoferlin siRNA or WJ460 demonstrated increased radiosensitivity compared to controls across all radiation doses, most significantly at 4Gy. Treatment of spheroids with WJ460 significantly reduced growth compared to controls at all radiation doses (p<0.05), with WJ460 limiting growth considerably more than treatment with the current gold standard 5-FU. HCT116 spheroid volume day 15; WJ460 4.96um3,5-FU 6.74um3,DMSO 24.9um3.

Conclusion

Inhibition of myoferlin is associated with increased radiosensitivity of colorectal cancer cells, and treatment with a small molecular inhibitor significantly reduces growth in spheroid models. Further work is required further validate its potential use as a biomarker in locally advanced rectal cancer.

Take-home message

We have found that myoferlin is a protein associated with poor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Manipulation of this protein sensitises the cancer cells to radiotherapy.
O14: RANDOM FOREST MODELS FOR PREDICTING SURVIVAL AFTER OESOPHAGECTOMY
Authors: Rahman SA , Walker RC , Crosby T , Maynard N , Cromwell DA , Underwood TJ
Published: April 2021

Introduction

For patients with oesophageal cancer, producing accurate prediction models for survival after oesophagectomy has proved challenging. We investigated whether Random Survival Forests (RSF), a novel machine learning method, could produce an accurate prognostic model for overall survival after oesophagectomy.

Method

The study used data from the National Oesophago-Gastric Cancer Audit and included patients diagnosed with oesophageal adenocarcinoma or squamous cell carcinoma between 2012 and 2018 in England and Wales and who underwent a curative oesophagectomy with adequate lymphadenectomy (15 LN) and survived to discharge (n=6198). Missing data was handled using multiple imputation and the data was split into training and validation cohorts. 13 variables were selected for inclusion using Random Forest variable importance and used to train the final model. The same variables were used to develop a traditional Cox regression model.

Result

Median survival was 53 months in both cohorts. The final RSF model had good discrimination in the validation cohort with a C-index of 0.757(0.755-0.759), exceeding the Cox model; 0.748(0.746-0.750). At 3 years post-surgery, overall survival was 56.2%. The RSF yielded a mean predicted survival of 55.8%(IQR 29.5%-81.7%) compared to 55.4%(40.0%-77.7%) for the Cox model. The most important variables were lymph node involvement and pT/ypT stage, however other variables including neoadjuvant treatment completion and surgical complications were also found to be important.

Conculsion

A Random Forest survival model provided better performance in predicting survival after curative oesophagectomy. This will allow more personalised predictions to be delivered clinicians and patients.

Take-home message

Random Forest survival models can accurately predict post-operative prognosis after oesophagectomy.
O21: GENOME-WIDE ASSOCIATION STUDY OF VARICOSE VEINS IN 810,625 INDIVIDUALS IDENTIFIES 45 GENETIC RISK LOCI
Authors: Ahmed WUR , Wiberg A , Ng M , Furniss D
Published: April 2021

Introduction

Varicose veins (VV) impact a third of the UK adult population; 10% of patients develop lipodermatosclerosis and ulceration. VV often requires surgical management, however, there is a high-risk of recurrence. VV is a complex disease, where genetic and non-genetic components contribute to overall phenotypic expression. The genetic architecture of VV is poorly understood; we aimed to uncover its genetic basis.

Method

We conducted hitherto the largest genome-wide association study of VV. In stage one, using UK Biobank, we compared 22,473 VV patients and 379,183 controls. In stage two, replication and meta-analysis were performed in an independent cohort of 113,041 VV cases and 295,928 controls from 23&Me (California, USA). In-silico analysis was conducted in FUMA, MAGMA, and XGR.

Result

109 genome-wide significant (P≤ 5×10-8) loci were identified in UK Biobank, 45 of which successfully replicated in the 23&Me cohort. Twenty-seven loci have not been previously reported. FUMA positionally-mapped 128 genes at the replicated loci, with 84 having a combined annotation-dependent depletion score (CADD) >12.37, suggesting functional, deleterious variants. MAGMA analysis implicated pathways involved in cardiovascular system development (P=1.57×10-08) and tube morphogenesis (P=9.35×10-08). Furthermore, XGR revealed enriched pathways in downstream signalling in naive CD8+ T cells (P=0.0017), and encoding structural and core extracellular glycoproteins (both P=0.007).

Conclusion

We identified 45 variants conferring risk of VV, which provide insights into disease biology. Implicated genes are enriched in pathways involved in vascular development, immune cell activity and extracellular matrix function, and provide new targets for therapeutic development.

Take-home message

Unravelling the genetic architecture of varicose veins may facilitate our understanding of the disease and guide therapeutic approaches.
O23: CHARACTERISING PATIENT-DERIVED COLORECTAL CANCER TISSUE-ORIGINATED ORGANOIDAL SPHEROIDS FOR HIGH-THROUGHPUT MICROFLUIDIC APPLICATIONS
Authors: Khot MI , Levenstein M , Coppo R , Kondo J , Inoue M , Kapur N , Jayne DG
Published: April 2021

Introduction

Three-dimensional (3D) cell models have gained reputation as better representations of in vivo cancers as compared to monolayered cultures. Recently, patient tumour tissue-derived organoids have advanced the scope of complex in vitro models, by allowing patient-specific tumour cultures to be generated for developing new medicines and patient-tailored treatments. Integrating 3D cell and organoid culturing into microfluidics, can streamline traditional protocols and allow complex and precise high-throughput experiments to be performed with ease.

Method

Patient-derived colorectal cancer tissue-originated organoidal spheroids (CTOS) cultures were acquired from Kyoto University, Japan. CTOS were cultured in Matrigel and stem-cell media. CTOS were treated with 5-fluorouracil and cytotoxicity evaluated via fluorescent imaging and ATP assay. CTOS were embedded, sectioned and subjected to H&E staining and immunofluorescence for ABCG2 and Ki67 proteins. HT29 colorectal cancer spheroids were produced on microfluidic devices using cell suspensions and subjected to 5-fluorouracil treatment via fluid flow. Cytotoxicity was evaluated through fluorescent imaging and LDH assay.

Result

5-fluorouracil dose-dependent reduction in cell viability was observed in CTOS cultures (p<0.01). Colorectal CTOS cultures retained the histology, tissue architecture and protein expression of the colonic epithelial structure. Uniform 3D HT29 spheroids were generated in the microfluidic devices. 5-fluorouracil treatment of spheroids and cytotoxic analysis was achieved conveniently through fluid flow.

Conclusion

Patient-derived CTOS are better complex models of in vivo cancers than 3D cell models and can improve the clinical translation of novel treatments. Microfluidics can streamline high-throughput screening and reduce the practical difficulties of conventional organoid and 3D cell culturing.

Take-home message

Organoids are the most advanced in vitro models of clinical cancers. Microfluidics can streamline and improve traditional laboratory experiments.
O26: SIGMA RECEPTORS IN BREAST CANCER – EXAMINING THEIR LIGAND MEDIATED MECHANISMS OF CANCER CELL DEATH AND POTENTIAL FOR CLINICAL DIAGNOSTICS
Authors: Borde P , Cosgrove N , Safrany ST , Young LS
Published: April 2021

Introduction

Sigma receptors (SRs) are regularly overexpressed in cancer however their functions remain unknown. Certain Sigma1-receptor (Sig1R) ligands trigger death in breast cancer (BCa) cells but not in non-cancerous breast cells (NCB). In stressed cells, Sig1R is vital to the pro-survival unfolded protein response (UPR). Cancer cells depend on UPR signalling for survival, investigating Sig1R mediated mechanisms in BCa vs. NCB might uncover novel and targetable weaknesses in cancer.

Method

UPR activation by Sig1R antagonist IPAG was examined in BCa cells by Western blotting. Sig1R and UPR marker localizations were examined by immunofluorescence. SR gene expression between 141 matched breast tumour tissue and tumour adjacent normal samples was compared using RNAseq data from The Cancer Genome Atlas (TCGA). Merged microarray datasets were used to compare SR expression in 399 primary breast tumours with relapse (BCaR) vs. 352 without relapse (BCaNR).

Result

Relative to non-cancerous human mammary epithelial cells, Sig1R expression was lowest in MCF7s and highest in MDA-MB-468s. IPAG induced differential temporal activation of all three branches of the UPR in MCF7 and tamoxifen-resistant, low Sig1R expressing cell line LY2. TCGA RNAseq data highlighted SR overexpression in BCa particularly in the basal subtype. Microarray data showed both oestrogen receptor (ER)+ and ER- BCaR primaries had elevated SIGMAR1 compared to BCaNR primaries of the same respective ER status.

Conclusion

BCa cells are dependent on Sig1R mediated signalling. Sig1R expression might indicate the propensity of breast tumours to relapse. Thus, Sig1R represents a potential target in BCa, particularly for aggressive subtypes.

Take-home message

The Sigma-1 receptor (Sig1R) has a vital but unknown pro-survival function in cancer; Sig1R ligands cause death in cancer cells while sparing non-cancerous ones. Characterizing Sig1R mediated signalling may reveal novel, selective therapeutic targets in cancer.
O28: M6A DEMETHYLASE FTO A POTENTIAL TARGET IN BRAIN METASTATIC BREAST CANCER
Authors: Keelan S , Charmsaz S , Purcell S , Varešlija D , Cocchiglia S , Bane F , Hill A , Young L
Published: April 2021

Introduction

Brain metastasis (BrM) occurs in 10-30% of patients with advanced breast cancer (BC). BrM is increasing in incidence and confers a poor prognosis. We aimed to investigate the contribution of global epi-transcriptomic alterations in N6-methyladenosine (m6A) RNA-methylation as a therapeutic target in brain metastatic breast cancer.

Method

In preliminary studies we have demonstrated m6A demethylase – FTO as the main contributor to the progression of ER+ breast cancer. Furthermore an association between FTO and reduced disease-free-survival (n=870, p=0.018) was observed. Here we conducted an epigenetic inhibitor screen using two therapeutic agents, ethyl-ester-meclofenamic acid (MA2) and FB23-2 on matched 2D cell line, 3D organoid cultures and patient-derived xenografts (PDX) explant models of brain metastasis.

Result

Upon integration of mapped global RNA methylation landscape with matched proteomic analysis, we observed genome-wide RNA hypo-methylation of key pluripotency genes, including SOX2 and KLF4, as key players underlying tumour progression to the brain.  Genetic and pharmacological inhibition of FTO in novel ex vivo models of BrM significantly reduced protein expression levels of KLF4 and SOX2. Moreover, pharmacological inhibition of FTO with MA2 and FB23-2, inhibited cell proliferation in endocrine-resistant BC and patient BrM cells. We translate our findings to the clinic by demonstrating the efficacy of anti-FTO therapies in several unique PDX and 3D organoid BrM models.

Conclusion

Our results reveal epi-transcriptional remodelling events as a key mechanism in BrM. This study establishes an early role for targeting RNA methylation in the management of disease progression and presents FTO as a potential therapeutic target in BrM.

Take-home message

This study establishes an early role for targeting RNA methylation in the management of disease progression and presents FTO as a potential therapeutic target in brain metastatic breast cancer.
O30: EVALUATION OF AXILLARY LYMPH NODE METASTATIC BURDEN BY PREOPERATIVE ULTRASOUND
Authors: Keelan S , Sorensen J , Downey E , Hegarty A , Nelson T , Duke D , Power C , Hill A
Published: April 2021

Introduction

Sentinel lymph node biopsy (SLNB) is the gold standard for determining axillary nodal status. There is growing interest in using preoperative axillary ultrasound (AUS) as a non-invasive means of assessing the axilla. However, AUS has limited sensitivity and is subject to operator dependency. This study aimed to quantify axillary nodal burden in preoperative AUS.

Method

This retrospective study used an institutional database of all primary invasive breast carcinomas from 2006–2019. Those with pathologically proven axillary metastatic disease were included. Patients were considered in two groups, low nodal burden/LNB(1-2LN) and high nodal burden/HNB(≥3LN) based on total positive lymph node count(SLNB+ALND). Preoperative AUS reports were assessed to determine those suspicious for axillary metastasis.

Result

Of the 347 patients (n=349 axillae), 77.9% had LNB and 22.1% had HNB. In patients with LNB, 228(83.8%) had a normal AUS versus 44(16.2%) suspicious AUS. In those with HNB 60(77.9%) had normal AUS findings versus 17(22.1%) suspicious findings. On multivariate analysis Nottingham Grade-3 was associated with suspicious AUS findings (p=0.02). However, receptor status, SLN macro-metastasis and extra-nodal extension were not associated with abnormal AUS.

Conclusion

As the surgical approach to the axilla becomes increasingly conservative, detection of axillary involvement by non-invasive means is an area of increasing research. In this cohort, AUS did not reliably identify patients with axillary metastasis. These results highlight the challenges in accurately assessing the axilla using preoperative AUS, which may result in axillary undertreatment if used as an alternative to surgical staging.

Take-home message

As the surgical approach to the axilla becomes increasingly conservative, detection of axillary involvement by non-invasive means is an area of increasing research. This study highlights the challenges in accurately assessing the axilla using preoperative AUS, which may result in axillary undertreatment if used as an alternative to surgical staging.
O31: CORRELATION BETWEEN THYROID FINE NEEDLE ASPIRATION CYTOLOGY (FNAC) SCORES AND CANCER INCIDENCE ON FINAL HISTOPATHOLOGY – A MULTI-CENTRE RETROSPECTIVE ANALYSIS
Authors: Iwegbulem O , Razzaq Z , Crowley F , Majeed M , Cagney D , McCarthy J , Diaz A , Sheehan P , Redmond HP
Published: April 2021

Introduction

Fine Needle Aspiration Cytology (FNAC) is the best diagnostic tool for evaluating thyroid nodules pre-operatively. The Bethesda System for Reporting Thyroid Cyto-pathology (TBSRTC) in America and THY classification in Europe are standardized reporting systems for thyroid FNAC specimens using six categories. As compared to the first edition in 2009, a second edition of TBSRTC published in 2017 has revised risk of malignancy (ROM) for these categories, with focus on atypia of unknown significance (Thy3A) upgraded to 10-30% from previously 5-15%, and suspicion for follicular neoplasm (Thy3F) 25-40% from previous 15-30%.

Method

A three-year audit of thyroid surgeries performed in two high volume thyroid institutions from January 2016 to September 2019, was performed retrospectively. The FNAs were performed by thyroid specialist radiologists with a cytopathology technician in attendance for rapid on-site evaluation and reported as per TBSRTC and Thy classification, by a Consultant Cyto-pathologist from a single institution.

Result

A total of 702 patients were examined. There were 552 patients who had corresponding FNAC prior to surgery (mean age 53.6 years, females 79%). The rates of malignancy were, Thy1: 9.3%, Thy2: 4.6%, Thy3A: 10.8%, Thy3F: 28.7%, Thy4: 82.3% and Thy5: 100%. The main types of thyroid malignancy were Papillary (73.6%), Follicular (14.1%), Medullary (4%), Anaplastic (4.7%) and others (3.6%).

Conclusion

Pre-operative diagnosis of thyroid nodules using TBSRTC was comparable and the criteria helped avoid misinterpretation of results. Our results were comparable with the risk of malignancy in 2009 edition of TBSRTC, as compared to the 2017 revision.

Take-home message

Pre-operative diagnosis of thyroid nodules using The Bethesda System for Reporting Thyroid Cyto-pathology (TBSRTC) was comparable and the criteria helped avoid misinterpretation of results. Our results were comparable with the risk of malignancy in 2009 edition of TBSRTC, as compared to the 2017 revision.
O33: PROSPECTIVE RISK ASSESSMENT ALONE DOES NOT IMPROVE 30-DAY MORTALITY IN EMERGENCY LAPAROTOMY PATIENTS
Authors: Vavilov S , Pockney P
Published: April 2021

Introduction

Emergency laparotomy still carries a high mortality risk. According to the latest National Emergency Laparotomy Audit (NELA) report, half of the patients without pre-operative risk scoring had a higher observed than predicted mortality. Data from Perth, Australia also suggests that pre-operative scoring improves mortality. The aim of this study was to determine if a prospective risk assessment has an independent favourable effect on outcomes.

Method

A retrospective review of all emergency abdominal surgeries meeting NELA inclusion criteria undertaken at four different-sized Australian surgical centres was performed between April 2015 and December 2018. A predicted and observed mortality was assessed in prospectively and retrospectively risk-stratified patients.

Result

There were 852 patients charts reviewed during the study period. Patient demographics included 404 males (47.4%), mean age: 69 years, median American Society of Anaesthesiologists score: 3, mean length of stay: 14.0 days and mean ICU length of stay: 1.8 days. There were 72 patients who died within 30 days (8.5%). Median preoperative P-POSSUM score was 6.9%, median preoperative NELA score – 5.2%. A total of 27/133 (20.3%) patients who were scored prospectively died within 30 days; 45/719 (6.3%) retrospectively scored patients died within 30 days. Neither of these rates was very different from the predicted.

Conclusion

30-day mortality in emergency laparotomy patients in Hunter New England region, Australia, compares favourably with the latest mortality figures reported by NELA. However, contrary to other publications, prospective scoring alone did not have any beneficial effect on 30-day mortality in our cohort

Take-home message

Patients undergoing emergency abdominal surgery require preoperative risk assessment to improve outcomes. However, just the fact of assigning a risk score preoperatively alone does not help to improve mortality.
O35: THE MANAGEMENT OF PATENT DUCTUS ARTERIOSUS IN LOW BIRTH WEIGHT AND PREMATURE NEONATES: WHO, WHAT, WHEN AND HOW?
Authors: Asif A , Parry A
Published: April 2021

Objectives

The management of patent ductus arteriosus (PDA) in neonates is a contentious issue with variations between many centres. Does timing PDA management prophylactically, fare better than waiting for haemodynamic compromise? Are medical approaches safer and more effecitve than an interventional approach? How should medical or surgical interventions be approached? Should clinicians intervene at all? This review aims to navigate through the current literature.

Method

Keywords "Patent ductus arteriosus", "neonate", "premature", "preterm" and "low birth weight" were searched on PubMed, the Cochrane Library and Medline. Referenced articles were also included. Outcome measures such as time to closure, rate of closure, morbidity and mortality were observed.

Result

Studies observing conservative management showed that PDAs close spontaneously in up to 73%. Complication rates in conservative management compared to indomethacin use were similar, with conservative measures taking longer to reach closure. Indomethacin was shown to have better outcomes when used prophylactically compared to symptomatic cases. However, paracetamol and oral ibuprofen was shown to be safer than indomethacin in symptomatic patients with less renal and gastrointestinal effects. Successful medical management was demonstrated to be dependent on ductal diameter and gestational age. Outcomes following prophylactic surgery were similar to those undergoing conservative management. Morbidity and mortality were similar in those undergoing percutaneous occlusion and open ligation.

Conclusion

Many studies were observational, retrospective, single-centre studies and had not reported important outcome measures. Robust evidence from randomised, multi-centre studies are needed, as well as studies comparing treatment disciplines. Future studies should look to report long-term outcome measures.

Take-home message

Despite the range of studies meta-analyses available, there is a lack of robust and definitive evidence out there to suggest when and how to approach a PDA in premature/low-birthweight neonates which is reflected in the heterogeneity of management options for PDA patients between different centres. Observational studies show that conservative management, management using paracetamol and an interventional approach (either thoracotomy or endovascular) are all viable options, however the lack of randomised, interventional studies fail to show which method is superior.
O37: SYSTEMATIC REVIEW AND PROPORTIONAL META-ANALYSIS OF SURVIVAL FOLLOWING NEOADJUVANT CHEMORADIATION AND LIVER TRANSPLANTATION IN UNRESECTABLE HILAR CHOLANGIOCARCINOMA
Authors: Cambridge WA , Guest RV
Published: April 2021

Introduction

Despite improvements in survival for other tumour types, the prognosis of hilar cholangiocarcinoma (CC) continues to be extremely poor. Since publication of the Mayo protocol in 2000, an increasing number of case series around the world have reported excellent outcomes after neoadjuvant chemoradiation followed by liver transplantation (NCR-LT) in unresectable hilar CC.

Method

MEDLINE, EMBASE, Scopus and Web of Science databases were searched and data extracted from relevant studies. A proportional meta-analysis was conducted to pool 1, 3- and 5-year survival and disease recurrence rates following NCR-LT.

Result

Twenty studies comprising 428 patients were eligible for final analysis. The pooled 1, 3- and 5-year overall survival rates following LT 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 rates 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) following administration of a neoadjuvant chemoradiation protocol. The pooled recurrence rate was 51.7% (95% CI 33.8 - 69.4) in patients who did not undergo neoadjuvant treatment and 24.1% (95% CI 17.9 - 30.9) in those who did.

Conclusion

In unresectable hilar CC, NCR-LT confers long-term survival in selected patients able to complete neoadjuvant chemoradiation followed by transplantation. Patients with primary sclerosing cholangitis have the most favourable survival outcomes. A high disease recurrence rate is of concern when considering extending national graft allocation schemes. CC - Cholangiocarcinoma, NCR-LT - Neoadjuvant Chemoradiation & Liver Transplantation

Take-home message

In selected patients, the treatment of unresectable hilar cholangiocarcinoma with neoadjuvant chemoradiation and liver transplantation results in 5-year overall survival rates greater than 50%. Patients with hilar cholangiocarcinoma and concomitant primary sclerosing cholangitis have the most favourable outcomes post-transplantation.
O39: THE HISTOPATHOLOGICAL AND MOLECULAR FEATURES OF BREAST CARCINOMA WITH HIGH-GRADE TUMOUR BUDDING
Authors: Lloyd A , Ryan E , Boland M , Medani S , Elwahab Abd , Malone C , Sweeney K , Barry K , McLaughlin R , Lowery A , Kerin M
Published: April 2021

Background

Tumour budding (TB) is an adverse histological feature in many cancers. It is thought to represent epithelial-to-mesenchymal transition, a key step in the metastatic process. The role of TB in breast carcinoma (BC) remains unclear.

Aim

To investigate the relationship between TB and other histological and molecular features of BC.

Method

A systematic search was performed to identify studies that compared features of BC based on the presence or absence of high-grade TB. Dichotomous variables were pooled as odds ratios (OR) using the Cochran–Mantel–Haenszel method. Quality assessment of the included studies was performed using the Newcastle-Ottawa scale (NOS).

Result

Seven studies with a total of 1040 patients (high grade TB n=519, 49.9%; low grade TB n=521, 50.1%) were included. A moderate- to high-risk of bias was noted. The median NOS was 7 (range 6-8). High-grade TB was significantly associated with lymph node involvement (OR 2.28, 95% c.i. 1.74 to 2.98, P<0.001) and lymphovascular invasion (OR 3.08, 95% c.i. 2.13 to 4.47, P<0.001). Regarding molecular subtypes, there was an increased likelihood of high-grade TB in oestrogen- (OR 1.66, 95% c.i. 1.21 to 2.29, P=0.002) and progesterone-receptor positive (OR 1.68, 95% c.i. 1.10 to 2.59, P=0.02) tumours. In contrast triple negative breast cancer had a reduced incidence of high-grade TB (OR 0.46, 95% c.i. 0.30 to 0.72, P=0.0006).

Conclusion

High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC.

Take-home message

High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC.
O41: JOURNAL RANKING METHODS AND THEIR APPLICATION IN GENERAL SURGERY - A SYSTEMATIC REVIEW
Authors: Arshad SR , Gallivan ER , Skinner H , Kerry J , Burke JR , Young AL
Published: April 2021

Introduction

Bibliometrics enable the objective assessment of a journals quality and prestige, making them vital to academic surgical integrity. This paper systematically reviews the evidence for current journal-ranking platforms.

Method

An initial systematic search identified published journal bibliometrics on 5th November 2019. Studies assessing journal bibliometrics were identified through a second systematic search through OVID Medline database (PROSPERO:159689) on 18th November 2019. Non-English papers and those solely referring to author and institutional ranking methods were excluded. A coding framework was developed to assess strengths and limitations of journal bibliometrics.

Result

The systematic search returned 2480 articles. All abstracts were reviewed leaving 474 for full assessment. 306 papers were included in the final synthesis. 12 journal bibliometrics were identified. SCImago Journal Rank (SJR) was deemed the most robust journal ranking method. Impact Factor (IF) is the most commonly used but has clear limitations. Altmetrics are likely to become more important. Ranking the Top 25 general surgical journals using SJR and IF results in clear discordance.

Conclusion

Impact Factor is susceptible to manipulation by journals putting its reliability into question. This has huge implications for academic surgery, the appraisal of evidence and its downstream assessment for inclusion into clinical guidelines and practice. SJR is more robust and it is recommended that this ranking method is adopted by the academic surgical community going forward.

Take-home message

The widely used Impact Factor can be manipulated by journals, which has implications for academic surgery and evidence-based medicine. SCImago Journal Rank is more robust and should be adopted by the academic surgical community.
O42: THE ROLE OF TOURNIQUETS IN TRANSTIBIAL AMPUTATION FOR PERIPHERAL VASCULAR DISEASE: A SYSTEMATIC REVIEW & META-ANALYSIS
Authors: Cagney D , Byrne J , Fulton GJ , Manning BJ , Redmond HP
Published: April 2021

Introduction

The use of lower limb tourniquets is traditionally discouraged in severe atherosclerotic disease. However, blood loss and increased transfusion requirements are associated with post-operative morbidity in patients undergoing major lower limb amputation. The aim of this systematic review is to summarise and pool the available data to determine the impact of tourniquet application when performing trans-tibial amputation for peripheral vascular disease.

Method

This systematic review was conducted according to PRISMA guidelines. A systematic search of Medline, Embase and Cochrane Library was undertaken for articles which compared the use of a tourniquet versus no tourniquet in patients undergoing trans-tibial amputation for peripheral vascular disease. The main outcomes included intra-operative blood loss, post-operative transfusion requirement, need for revision surgery and 30-day mortality.

Result

Four studies met the inclusion criteria for quantitative analysis with a total of 267 patients. A tourniquet was used in 130 patients. Both groups were matched for age, gender, co-morbidities and pre-operative haemoglobin. In patients undergoing trans-tibial amputation, tourniquets were associated with significantly lower intra-operative blood loss (Mean difference= -147.6mls; P=0.03) and lower transfusion requirements (pooled odds ratio (OR), 0.12, p=0.03). The need for stump revision (OR, 0.7; p=0.48), proceeding to transfemoral amputation within 30 days (OR, 0.67; p=0.25) and 30-day mortality (OR, 0.65; p=0.41) all favoured tourniquet use but the differences were not found to be significant.

Conclusion

Tourniquets can reduce intra-operative blood loss and transfusion requirements in patients undergoing trans-tibial amputation without increasing ischaemic complications and need for revision surgery.

Take-home message

Tourniquets are safe to use in trans-tibial amputation for severe peripheral vascular disease and can reduce intra-operative blood loss without increasing ischaemic complications.
O48: MYOFERLIN: A NOVEL PREDICTIVE BIOMARKER AND THERAPEUTIC TARGET IN ADVANCED COLORECTAL CANCER
Authors: Fowler H , Sutton P , Bowden D , Parsons J , Vimalachandran D
Published: April 2021

Introduction

Myoferlin is a protein involved in cell proliferation, migration and angiogenesis, which are essential in tumour metastasis. Its expression correlates with a poorer prognosis in various epithelial cancers, but has yet to be associated with survival in colorectal cancer. We aim to investigate myoferlin's role in cell migration, and the development of metastases in our patients with rectal cancer.

Method

Tissue Microarrays (TMAs) of matched tumour and lymph node samples from 111 patients with rectal cancer were stained for myoferlin. Expression profiles were examined and correlated with clinical outcomes. Wound healing assays were used to assess the rate of migration in immortalised colorectal cells (HCT116, HT29) following myoferlin knockdown with siRNA.

Result

Our TMAs demonstrated that high myoferlin expression in rectal tumour samples was associated with metastatic spread to local lymph nodes (p<0.05). Positive lymph nodes had significantly higher levels of myoferlin than non-involved lymph nodes (p<0.001). The positive predictive value (PPV) of a highly expressing lymph node containing metastatic spread was 100%, negative predictive value (NPV) 88.41%, 95% CI [80.81, 93.24]. Wound healing assays demonstrated a decreased ability of cells to migrate following myoferlin knockdown with siRNA, compared to controls (p<0.05).

Conclusion

Our results demonstrate that high myoferlin expression is associated with metastatic spread to local lymph nodes, and increased migration and proliferation of cells. It is a predictor of poor clinical outcomes, and therefore warrants further investigation as a potential therapeutic target in both locally advanced and metastatic rectal cancer.

Take-home message

We have demonstrated that the protein myoferlin is associated with metastatic spread of rectal cancer to local lymph nodes. Therefore it is a potential predictive biomarker and therapeutic target in advanced rectal cancer.
O57: GREATER USE OF NON-TECHNOLOGICAL SIMULATION METHODS IMPROVES SKILL ACQUISITION IN SURGICAL TEACHING
Authors: Hill A , Thomas M , Williams D
Published: April 2021

Introduction

Studies that have reviewed technologies including haptic feedback and virtual reality indicate the usefulness of simulation. However, these technologies are not universally available. Less technologically innovative simulation methods that utilise the learning environment, equipment and presentation can still effectively support surgical teaching. A review was undertaken to assess the effect of these lower fidelity simulation methods on surgical skill acquisition.

Method

Two courses enrolled 12 and 14 respectively, with trainees ranging in seniority from Foundation Year 1 to Core Trainee Year 2. Four basic surgical skills (suturing, hand tying, local anaesthetic and surgical instruments) were taught in 20 and 30 minute stations. These skills were used to assess trainee confidence before and after teaching, using a 5 point qualitative data collection scale ranging from Not Very to Very Confident. The faculty received a pre-course lecture on teaching methods to ensure standardisation.

Result

Mean confidence increased following participation in simulation teaching; 1st course demonstrated a post-teaching increase of 42%, 2nd a 60% increase. Individual skill confidence increased more following simulation-based course in hand tying (57% p=0.002, v 89% p=0.00007), local anaesthetic (30% p=0.001, v 41% p=0.005) and surgical instruments (44% p=0.005, v 89% p=0.0001). Suturing was not associated with increased mean confidence, but median confidence score increased more (33% p=0.005, v 60% p=0.0001).

Conclusion

Greater incorporation of simulation in training is generally associated with increased confidence with surgical skills. This is likely due to better contextualisation, leading to improved understanding of the place of the skills in the clinical setting.

Take-home message

Greater incorporation of simulation techniques, not necessarily of a technological nature, leads to increased confidence with surgical skills.
O62: INTRA-OPERATIVE ADJUNCTS IN MINIMALLY INVASIVE RADIO-GUIDED PARATHYROIDECTOMY AT A SPECIALIST ENDOCRINE SURGERY CENTRE
Authors: Razzaq Z , Majeed M , Hanrahan M , Cagney D , O' Leary DP , Redmond HP
Published: April 2021

Introduction

Primary Hyperparathyroidism (PH) is common cause of hypercalcaemia (0.3% of the population). Minimally invasive radio-guided parathyroidectomy (MIRP) has been made possible due to advancements in pre-operative imaging i.e. sestamibi scans allowing localisation of areas of parathyroid hyperactivity.

Method

Due to the disagreement in the literature regarding which intra operative adjunct is best used in MIRP surgery to decrease recurrence, the rationale for this study is to examine and compare the performance of these adjuncts in consecutive patients i.e. 1. Intra operative PTH assay (IOPTHA) 2. Tc-99m radio-guidance using a gamma probe and the 20% rule 3. Frozen section analysis.

Result

45 MIRP procedures were carried out between 01/07/2018 and 30/10/2019. 77.8% were females; mean age was 62 years (range 30 - 79). Final pathology showed that in 43 of the cases parathyroid tissue was correctly removed; thyroid tissue was identified for the other 2 cases. 20% rule was positive in 43 out of the 45 cases and negative in 2 (sensitivity 100%, specificity 100%). A drop in IOPTHA greater than 50% was found in 41 out of the 45 cases but not in 4 (sensitivity 93.9%, specificity 100%). Frozen section was 100% concordant with final pathology (45/45). AUC analysis showed no significant difference in the performance of these tests (p = 0.15) but was around 1 for 20% rule and Frozen section.

Conclusion

When radio-guidance and frozen sections are added to IOPTHA, the success rate of parathyroidectomy is markedly improved. Using them together will greatly reduce recurrent hyperparathyroidism.

Take-home message

When radio-guidance and frozen sections are added to Intra-operative PTH assays in Minimally Invasive Radio-Guided Parathyroidectomy, the success rate of parathyroidectomy is markedly improved. Using them together as in our study will greatly reduce the incidence of recurrent hyperparathyroidism and thus recurrent surgery.
O66: FLOW CYTOMETRIC AND RNA SEQUENCED UNCOUPLING OF TUMOUR-INFILTRATING LYMPHOCYTE CHECKPOINT EXPRESSION AND MISMATCH REPAIR STATUS IN COLORECTAL CANCER
Authors: Zaborowski A , Harmon C , Duquette D , Dyck L , Lynch L , Winter D
Published: April 2021

Introduction

Selection criteria for immunotherapy with checkpoint blockade in colorectal cancer are currently based on mismatch repair status. However, intra-tumoral T cell response varies among patients with the same MMR status. Inhibitory checkpoint expression on tumour-infiltrating lymphocytes in microsatellite stable and unstable CRC is unknown.

Method

Flow cytometric analysis and single-cell RNA sequencing, using the 10x genomic platform, were performed ex vivo on tumour and uninvolved colonic tissue samples from patients undergoing surgical resection for colorectal cancer. Inhibitory checkpoint expression (PD-1) and functional status of isolated populations of TILs were analysed.

Result

Conventional and unconventional tissue-resident T cells were enriched in tumour samples compared to uninvolved healthy colonic tissue. Upregulation of PD-1 expression on TILs was observed in all patients, however the % upregulation varied among those with the same MMR status. A proportion of MSS tumours were found to have high levels of PD-1 expression, while a subset of MSI tumours had low PD-1 expression. Functional studies of cytotoxicity demonstrated varying TIL production of IFNg, TNFa and amphiregulin in patients with the same MMR status.

Conclusion

TIL profile (infiltration pattern, checkpoint expression and functional status) differs among patients with the same MMR status. A subset of ‘hot’ immunogenic MSS tumours exist that may respond to checkpoint blockade. Characterisation of TIL profile represents a more accurate method of selecting patients likely to derive benefit. Abbrev. CRC Colorectal cancer, MMR Mismatch repair, TIL Tumour-infiltrating lymphocytes, MSS Microsatellite stable, MSI Microsatellite unstable, IFNg Interferon-gamma, TNFa Tumour necrosis factor alpha

Take-home message

A subset of immunogenic microsatellite stable colorectal tumours exist that may respond to checkpoint blockade. Mismatch repair status alone does not accurately predict response to immunotherapy.
O69: THE SENTINEL LYMPH NODE TECHNIQUE IN THE ENDOMETRIAL CANCER
Authors: Bouaziz H , Sghaier S , Slimane M , Zabaar L , Bouzaiene H , Rahal K
Published: April 2021

Introduction

The sentinel lymph node (SLN) concept represents advancement in the management of the endometrial cancer (EC).

We aim to assess the performance of the SLN procedure; its positive predictive value (PPV) and negative predictive value (NPV); in stage I of EC (FIGO2009).

Method

A prospective study is conducted in our institution. We perform a double detection of the SLN (radiolabel Tc 99 microsulfur colloid and a color method using patent blue) followed by pelvic lymphadenectomy with or without paraaortic lymphadenectomy. A pelvic MRI is performed to determine myometrial invasion and nodal status. The injection of Tc 99m colloid occurs the day prior to surgery. The injection into the stroma of the cervix at the 3 and 9 o'clock positions was performed by an oncologist surgeon with the assistance of a nuclear medicine physician. Preoperative lymphoscintigraphy was obtained after 90-120 minutes. We inject into the cervical stroma 2cc of patent blue similar to the Tc99 injection. A gamma detecting probe is used to locate radioactive lymph nodes. The SLNs identified then are labelled as radioactive and/or blue. No frozen-section analysis was performed.

Results

For the pathological analysis of the SLN, Haematoxylin Eosin is used. If there is no metastasis detected, an ultra staging protocol using different anti-cytokeratines is conducted. Studies have shown that this approach is possible having satisfactory results when conducted by dedicated surgical, radiology and pathology team. We look forward to our outcomes to illustrate those results.

Take-home message

Sentinel lymph node is a good alternative for gynecological cancer