Evidence before this study: Acute appendicitis is the most common general surgical emergency in children. Its diagnosis remains challenging and children presenting with acute right iliac fossa (RIF) pain may be admitted for clinical observation or undergo normal appendicectomy (removal of a histologically normal appendix). A search for external validation studies of risk prediction models for acute appendicitis in children was performed on MEDLINE and Web of Science on 12 January 2017 using the search terms ["appendicitis" OR "appendectomy" OR "appendicectomy"] AND ["score" OR "model" OR "nomogram" OR "scoring"]. Studies validating prediction models aimed at differentiating acute appendicitis from all other causes of RIF pain were included. No date restrictions were applied. Validation studies were most commonly performed for the Alvarado, Appendicitis Inflammatory Response Score (AIRS), and Paediatric Appendicitis Score (PAS) models. Most validation studies were based on retrospective, single centre, or small cohorts, and findings regarding model performance were inconsistent. There was no high quality evidence to guide selection of the optimum model and threshold cutoff for identification of low-risk children in the UK and Ireland. Added value of this study: Most children admitted to hospital with RIF pain do not undergo surgery. When children do undergo appendicectomy, removal of a normal appendix (normal appendicectomy) is common, occurring in around 1 in 6 children. The Shera score is able to identify a large low-risk group of children who present with acute RIF pain but do not have acute appendicitis (specificity 44%). This low-risk group has an overall 1 in 30 risk of acute appendicitis and a 1 in 270 risk of perforated appendicitis. The Shera score is unable to achieve a sufficiently high positive predictive value to select a high-risk group who should proceed directly to surgery. Current diagnostic performance of ultrasound is also too poor to select children for surgery. Implications of all the available evidence: Routine pre-operative risk scoring could inform shared decision making by doctors, children, and parents by supporting safe selection of lowrisk patients for ambulatory management, reducing unnecessary admissions and normal appendicectomy. Hospitals should ensure seven-day-a-week availability of ultrasound for medium and high-risk patients. Ultrasound should be performed by operators trained to assess for acute appendicitis in children. For children in whom diagnostic uncertainty remains following ultrasound, magnetic resonance imaging (MRI) or low-dose computed tomography (CT) are second-line investigations.

The development of breast cancer resistance to endocrine therapy results from altered cellular plasticity leading to the emergence of a hormone independent tumour. We have previously shown that the endocrine resistant phenotype is poorly differentiated and has greater metastatic potential when compared with an endocrine sensitive phenotype. The underlying mechanism of how an ER positive, endocrine sensitive tumour can turn on these adaptive mechanisms remains unresolved. We hypothesise that cellular reprogramming can occur as a result of long-term exposure to endocrine treatment which manifests clinically as tumour recurrence. Our aim was to identify the mechanism of breast cancer cellular reprogramming in a clinical context. In this study we adopted a global approach to define transcriptional networks significantly elevated in the breast cancer metastatic setting. Using RNAseq we determined the gene expression profile of three ER positive patients who developed tumour recurrence on tamoxifen treatment. RNAseq was performed on primary tumours, axillary node metastases and subsequent distant metastases. Following bioinformatic analysis, we defined the genes that were significantly elevated in the metastatic tumours. In the metastases, genes clustered away from those in the primary and node, with 209 genes uniquely elevated in the metastatic context, suggesting altered gene expression in response to endocrine therapy. Pathway analysis of genes significantly elevated in the metastatic setting included developmental pathways (WNT signalling and TGFbeta), growth factor signalling pathways (MAPkinase), cell adhesion molecules, junction adherens and pathways in cancer. Further analysis provided a list of clinically relevant transcriptional networks which may facilitate tumour cell de-differentiation. Transcription factors including Myc, SMAD2, ESR, TCF3, CUX1 and CLOCK were identified which potentially drive reprogramming in response to endocrine treatment. We interrogated this data to identify downstream targets of this ‘de-differentiation’ network for new predictive markers of response to endocrine treatment. Bioinformatic analysis identified PAWR, an inhibitor of progenitor cell expansion as a potential SMAD2 target. In a xenograft model of endocrine resistance, PAWR expression was found to be reduced in metastatic tissue from lung, liver and bone compared with the primary tumour. In human breast cancer patients PAWR significantly associated with a good response to endocrine treatment and luminal A status (p = 0.0008), establishing PAWR as a predictor of good response to endocrine therapies. We have identified a transcriptional network which may drive a de-differentiated phenotype following endocrine treatment. Data presented here proposes a mechanism by which apparently less aggressive Luminal A type tumours may fail endocrine treatment and develop subsequent recurrence. This represents a fundamental shift in how we approach the development of resistance to endocrine therapy, establishing a number of biomarkers which will allow tracking of response to endocrine therapy or allow accurate early prediction of those who will respond to treatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-01.

Introduction High quality surgery remains the cornerstone of treating oesophago-gastric malignancy. Recent work from the Dutch Upper-gastrointestinal Cancer Audit (DUCA) have defined ten surgical and perioperative ‘textbook’ parameters that correlate with improved overall survival. The aim of this project was to examine the proportion of patients attaining ‘textbook’ outcomes for oesophagectomy and gastrectomy in our unit before and after the introduction of national key performance indicators (KPIs). Method A retrospective review of all oesophagectomies and gastrectomies from January 2010 until June 2019 was performed. Clinical, pathological, perioperative, morbidity and mortality outcomes were recorded. 10 ‘textbook’ parameters were studied pre- and post-KPI introduction. Result 269 and 284 patients underwent oesophagectomy and gastrectomy respectively, 167 pre-KPI and 386 post-KPI. There were no significant differences in age (67.6 vs 66.4 years, p=0.6), gender (71% male, 29% female vs 68% male, 22% female, p=0.48), ASA grade (p=0.6) or tumour stage (p=0.37) pre- and post-KPI. In the pre-KPI era, 28/167 (17%) patients achieved all ten textbook parameters, compared with 157/386, (41%, p=0.001) post-KPI. This compares favourably to DUCA ‘textbook’ data. There was an improvement in adequate lymphadenectomy (56% vs 83%, p=0.002), a reduction in margin positivity (21% vs 7%, p= 0.001) and peri-operative mortality (6% vs 2%, p=0.03) post-KPI. Conclusion There has been a significant improvement in perioperative outcomes in esophagectomy following the introduction of national KPIs in our unit. The number of patients achieving ‘textbook’ outcomes is comparable with international standards. The identification of textbook parameters allows further focus for future quality improvement initiatives. Take-home message National KPIs improve peri-operative outcomes in oesophago-gastric cancer.

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