bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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) &gt;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

Abstract

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&lt;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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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.