Royal Devon Research Articles

Predicting response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer with serum biomarkers.

Introduction The aim of this study was to identify patient factors including serum biomarkers that may predict response to neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer staged on magnetic resonance imaging. Prediction of response may be helpful when selecting patients for a non-operative programme. Methods A retrospective review was carried out of patients undergoing neoadjuvant CRT for rectal cancer, conducted at the Royal Devon and Exeter Hospital. All patients were managed through the multidisciplinary team. Receiver operating characteristic (ROC) curve analysis was undertaken to assess the ability of biomarkers to predict response to neoadjuvant CRT. The biomarkers assessed included neutrophils, lymphocytes, monocytes, haemoglobin, platelets, C-reactive protein and carcinoembryonic antigen. Results Seventy-three patients underwent neoadjuvant CRT between January 2006 and December 2011. Nine (12.3%) of these experienced a clinical complete response and were managed with a 'watch and wait' approach. An additional ten patients (13.7%) had a pathological complete response following surgery. Using ROC curve analysis, the biomarkers with the largest area under the curve (AUC) were pre-CRT haemoglobin and post-CRT lymphocyte concentrations, producing AUC values of 0.673 and 0.618 respectively for clinical complete response. Pre-CRT haemoglobin and neutrophil concentrations produced the highest AUC values for pathological complete response at 0.591 and 0.614 respectively. Conclusions None of the assessed biomarkers offer the ability to predict response to neoadjuvant CRT in patients with rectal cancer. They cannot therefore assist in identifying complete clinical or pathological responders who could be considered for a non-operative, observational approach.

Glaucoma domiciliary service by optometrist.

Approximately 10% of UK blindness registrations are attributed to glaucoma[1]. The risk of glaucoma increases with age and it is estimated that the prevalence of chronic open angle glaucoma (COAG) is about 10% in white Europeans who are older than 70. There are an estimated 24.4 million people aged over 40 in England and around 489 000 people are currently affected by COAG. These numbers are likely to increase with increasing life expectancy[1]. With aging, there is an increase in prevalence of chronic diseases such as dementia, Alzheimer's disease and osteoarthritis, leading to severe frailty, disability and dependence for their basic needs and care[2]–[3]. The demographic profile of the South West of England shows it one third of it is population living in rural areas (31.3%) which is highest among all English regions. Also, the region's population is oldest with 4.4% people aged over 75, of whom 33% are older than 90. The life expectancy of men and women is also amongst the highest of all counties in the United Kingdom[4]. People diagnosed with COAG are managed by the hospital eye service and lifelong follow-up is normally needed so that any progression of glaucomatous damage can be detected and managed. Sight loss due to glaucoma cannot be restored, and therefore controlling the condition carefully is crucial to maintaining sight. People with severe physical and/or mental disability often reside in care homes and find journeys to hospital stressful, and in many cases not possible, even if appropriate transportation is available. Provisions of community hospitals and mobile clinic reviews has reduced the need to travel to main hospitals, however some patients are still not able to attend. To overcome this problem, a new care pathway called the glaucoma domiciliary service (GDS), managed by optometrists, a central coordinator and consultant glaucoma ophthalmologists was designed and commissioned at the Royal Devon and Exeter (RD&E) Foundation Trust. Glaucoma patients who are unable to attend normal follow-up clinics due to significant physical and/or mental disabilities are offered GDS at their residence. We present the service framework and outcome of our experience of GDS.

Effects of Exendin-4 on human adipose tissue inflammation and ECM remodelling.

BACKGROUND/OBJECTIVES:Subjects with type-2 diabetes are typically obese with dysfunctional adipose tissue (AT). Glucagon-like peptide-1 (GLP-1) analogues are routinely used to improve glycaemia. Although, they also aid weight loss that improves AT function, their direct effect on AT function is unclear. To explore GLP-1 analogues' influence on human AT's cytokine and extracellular matrix (ECM) regulation, we therefore obtained and treated omental (OMAT) and subcutaneous (SCAT) AT samples with Exendin-4, an agonist of the GLP-1 receptor (GLP-1R).SUBJECTS/METHODS:OMAT and abdominal SCAT samples obtained from women during elective surgery at the Royal Devon & Exeter Hospital (UK) were treated with increasing doses of Exendin-4. Changes in RNA expression of adipokines, inflammatory cytokines, ECM components and their regulators were assessed and protein secretion analysed by ELISA. GLP-1R protein accumulation was compared in paired AT depot samples.RESULTS:Exendin-4 induced an increase in OMAT adiponectin (P=0.02) and decrease in elastin expression (P=0.03) in parallel with reduced elastin secretion (P=0.04). In contrast to OMAT, we did not observe an effect on SCAT. There was no change in the expression of inflammatory markers (CD14, TNFA, MCP-1), collagens, TGFB1 or CTGF. GLP-1R accumulation was higher in SCAT.CONCLUSIONS:Independently of weight loss, which may bias findings of in vivo studies, GLP-1 analogues modify human OMAT physiology favourably by increasing the insulin-sensitising cytokine adiponectin. However, the reduction of elastin and no apparent effect on AT's inflammatory cytokines suggest that GLP-1 analogues may be less beneficial to AT function, especially if there is no associated weight loss.

Working internationally: challenges and opportunities.

Mel Burden, Infection Prevention and Control Nurse Specialist, Royal Devon and Exeter Hospital, shares her experiences of volunteering as a nurse in Benin and South Africa, and reflects on the professional challenges.

A novel HNF4A mutation in the antenatal clinic

A 35-year-old woman with type 1 diabetes attended the antenatal diabetes clinic at the John Radcliffe Hospital, Oxford, early in the pregnancy of her second child. She had had type 1 diabetes since the age of 13 on the background of a strong family history of type 1 diabetes in her mother, uncle and cousin. She had a normal range BMI pre-pregnancy. Her first pregnancy had been successful with the birth of a son at 37 weeks gestation, weighing 3.5 kg. It was noted in the current pregnancy that she had very tight glycaemic control and that her HbA1c had fallen from 5.9% to 5.3%, using relatively small total daily doses of insulin (Lantus 2 units per day, Novorapid 2–4 units tds), with a tendency towards hypoglycaemia. Given her clinical picture and family history, a query was raised as to her underlying diabetes type. Her GAD and ICA pancreatic auto-antibodies were checked and found to be negative, and her C-peptide level was very low at 277pmol/L, with a concurrent glucose level of 5.0 mmol/L. Monogenic diabetes had already been considered and tested for back in 1999 by the paediatric team. Results from the Department of Molecular Genetics at the Royal Devon & Exeter Hospital stated that she was negative for an HNF1A gene mutation. However, other MODY subtypes had not been tested for and so targeted next-generation sequencing of the known MODY genes on the family's saved samples was requested. No known pathogenic mutation was identified, but a novel heterozy-gous missense variant (p.Thr211Asn, NM_175914.4:c.632C > A) in the HNF4A gene was found. The patient's mother, who was diagnosed with presumed type 1 diabetes at the age of 15, was also heterozygous for the variant. The patient was certainly atypical for type 1 diabetes and the presence of the mutation in the mother would suggest that the mutation is likely to be pathogenic (although there was a 50% chance of the mother having the variant regardless). Despite good glycaemic control, the baby's abdominal circumference was greater than the 97th centile for growth on the 28-week scan. Subsequent growth is demonstrated in Figure 1. At 34 weeks, the patient developed an antepartum haemorrhage, was admitted for IV steroids (to aid fetal lung maturation), and underwent delivery by caesarean section shortly afterwards. The baby's weight was 3.8 kg, which is greater than the 99th centile for this gestational age. Ultimately, it would seem likely that this genetic variant had implications in this pregnancy. HNF4A plays a key role in determining fetal birthweight and mutations result in an increase in birthweight by an average of 800 g.1 Ten percent of HNF4A MODY patients also have transient neonatal hypoglycaemia, although this was not found in this case. Fetal growth increasing above the 75th centile, in spite of good glycaemic control in the mother, is also indicative of good evidence for pathogenicity. As with all forms of diabetes, in a variety of settings, it is important to be increasingly aware of the many different types of monogenic diabetes and their associated complications.2-4 Acknowledgements and references are available in Practical Diabetes online at www.practicaldiabetes.com. Many thanks to: Dr Rustam Rea, Prof Katherine Owen, Dr Lucy MacKillop, Dr Alistair Lumb, Dr Jonathan Levy, Sister Katy Bartlett, Miss Deborah Harrington and Miss Veronica Miller of Oxford University Hospitals Foundation Trust, and Kevin Colclough, Clinical Scientist, Royal Devon & Exeter Foundation Trust.

PWE-017 Prospective Evaluation of The Safety and Efficacy of Switching Stable Patients with Inflammatory Bowel Disease from Remicade™ to Biosimilar Infliximab (IFX)

Introduction Biosimilar IFX (CT-P13; RemsimaTM/InflectraTM) became available in the UK in February 2015 offering significant savings to the NHS. Efficacy and safety data in inflammatory bowel disease (IBD) is limited. From May 2015 IBD patients at the Royal Devon and Exeter NHSFT were switched from RemicadeTM to Biosimilar IFX. We reviewed efficacy and safety data during this switch. Methods Treatment was evaluated in IBD patients who met the following criteria: i) RemicadeTM treatment for greater than 6 months prior to switch ii) minimum follow-up data of 6 months following switch. Disease activity scores (Harvey-Bradshaw Index for Crohn’s disease [CD] and Simple Colitis Score for ulcerative colitis [UC]), CRP, drug levels and total anti-drug antibody levels were collected immediately prior to biosimilar switch and then every 16 weeks. All adverse events were recorded. Results 104 patients (54 male) met the inclusion criteria with a mean age of 43 years (range 17–71). 73 had CD, 29 had UC and 2 had IBD-unclassified. The median duration of RemicadeTM therapy prior to switch was 1137 days (95% confidence interval = 933–1290). Missing cases were excluded on a variable by variable basis. There was no significant difference in CRP (median pre-switch = 2, post-switch = 2, P = 0.81) or disease activity score (median pre-switch = 1, post-switch = 1, P = 0.44) after switching from RemicadeTM to Biosimilar IFX. 85% were in remission before compared with 81% six months following switch (P = 0.51). There was no difference in the number of people with detectable total anti-drug antibody levels (pre-switch = 29, post-switch = 27, P = 0.88) but a fall in drug levels was noted after switching (median pre-switch =5.4, post-switch = 2.8, P = 0.01). 41% had significant anti-drug antibodies pre-switch compared to 36% at 6 months post switch (P = 0.50). 11% of patients had positive anti-drug antibodies with undetectable drug levels pre-switch compared to 7% at 6 months (P = 0.35). 4 patients had adverse events within eight months of switching to biosimilar IFX; 2 minor infusion reactions and 2 anti-TNF induced skin disease. 19 patients stopped within six months of switching; 6 electively, 9 due to loss of response and 4 for other reasons. Conclusion This uncontrolled data suggests biosimilar IFX is safe and effective with no significant change observed in CRP, disease severity index and drug antibody levels six months after switch. The fall in IFX drug level after switch warrants further investigation. Disclosure of Interest K. Bennett: None Declared, G. Heap Grant/research support from: Hospira, Knapp, Abbvie, MSD, S. Hawkins: None Declared, T. Ahmad Grant/research support from: Hospira, Knapp, Abbvie, MSD

PTH-147 A More Restrictive Transfusion Policy for Upper Gastrointestinal Haemorrhage Would Save Resources Without Compromising Clinical Outcome

Introduction Upper GI bleeding (UGIB) is the most common indication for transfusion in England, comprising 14% of all transfusions. 1 Evidence has demonstrated a restrictive as opposed to liberal transfusion policy improves clinical outcome. 2 In addition to the known clinical benefits, our aim was to asssess whether a more restrictive transfusion policy would save significant resources. Methods We conducted a prospective audit of consecutive patients presenting to the Royal Devon and Exeter hospital with UGIB during a 9 week period from 7.12.12. The case notes and laboratory data were reviewed. Unstable patients, those with evidence of massive UGIB and those not receiving blood transfusion were excluded. Liberal transfusion was defined as haemoglobin >80 g/L pre-transfusion or a post transfusion haemoglobin >90 g/L. We calculated the number of additional units transfused beyond these parameters. Results 79 patients presented with an UGIB. 42 patients received a total of 170 units of red blood cells. 7 patients were transfused 1 unit, 33 patients were transfused 2 units, and 28 patients received ≥3 units. 30/42 were transfused in a liberal manner, resulting in the potentially unnecessary use of 68 additional units at a cost of £8,302. Conclusion A significant number of patients received transfusions according to our definition of a liberal transfusion strategy, usually receiving several units at a time. A restrictive transfusion policy has been proven to be safe and would also result in significant cost savings. References 1 Wallis JP, Wells AW, Chapman CE. Changing indications for red cell transfusion from 2000 to 2004 in the North of England. Transfus Med . 2006; 16 :411–417. 2 Villanueva C, Colomo A, Bosch A, Concepcion M, Hernandez-Gea V, Aracil C Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med . 2013; 368 :11–21. Disclosure of Interest None Declared

Audit of introduction of image-guided brachytherapy in the management of locally advanced carcinoma of the cervix at Royal Devon and Exeter Hospital

Audit of introduction of image-guided brachytherapy in the management of locally advanced carcinoma of the cervix at Royal Devon and Exeter Hospital

Reducing implant loss rates in breast reconstruction at the Royal Devon and Exeter Hospital: A complete audit cycle

Reducing implant loss rates in breast reconstruction at the Royal Devon and Exeter Hospital: A complete audit cycle

Developing a vascular access team.

remit of the vascular access team at the Royal Devon and Exeter NHS Foundation Trust was to reduce the rates of intravenous (IV) access-associated complications and bacteraemia by improving patient assessment and care of IV access devices. The principle drivers of Winning Ways (Chief Medical Officer, 2003) and Saving lives (Department of Health (DH), 2005) were the need to reduce infection associated with invasive devices. With central venous catheter care one of the top five high-impact interventions, the challenge is to ensure the dissemination and application of best practice. The Health and Social Care Act 2008: Code of Practice (Department of Health, 2015) states that providers must audit compliance with key policies and procedures for infection prevention. The Care Quality Commission (CQC) assesses compliance to ensure the care people receive meets essential standards of quality and safety. In 2008, the key challenges facing the team were: patient safety, high bed occupancy, costly antibiotics, procurement and education. Today the vascular access team comprises registered nurses and allied health professionals who have developed extensive specialist knowledge, skills and competence in effective patient assessment, bedside device insertion, maintenance and care. The benefits of a vascular access team are well recognised both locally and nationally (Jackson, 2007; Meyer, 2012; Walker et al, 2013; Chopra et al, 2015). Such benefits can include: ■ A reduction in device-related complications, including catheter-related bloodstream infections Developing a vascular access team

Ensuring maxillofacial paediatric anaesthetics are justified in the Royal Devon and Exeter Hospital

Ensuring maxillofacial paediatric anaesthetics are justified in the Royal Devon and Exeter Hospital

Understanding the needs of people with dementia and family carers.

This is the first in a short series that presents case study examples of the positive work achieved by trusts who participated in the Royal College of Nursing's development programme to improve dementia care in acute hospitals. When a person with dementia is in hospital, poor understanding of individual needs and preferences can contribute to a lack of person-centred care. Similarly, the needs of family carers can often be overlooked and staff do not always appreciate these needs at such a stressful time. This article illustrates how three NHS trusts have addressed these issues. To help staff get to know patients with dementia, Salford Royal NHS Foundation Trust has implemented a patient passport. Similarly, The Shrewsbury and Telford Hospital NHS Trust has implemented a carer passport that overcomes the restrictions imposed by hospital visiting hours. Royal Devon and Exeter NHS Foundation Trust also focused on carers, holding a workshop to elicit feedback on what was important to them. This was a useful means of engaging with carers and helped staff to realise that even simple changes can have a significant effect.

Current challenges to urological training in sub-Saharan Africa.

estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int 2011; 108: 1132–8 11 Grimes CE, Henry JA, Maraka J, Mkandawire NC, Cotton M. Costeffectiveness of surgery in lowand middle-income countries: a systematic review. World J Surg 2014; 38: 252–63 12 Gosselin RA, Thind A, Bellardinelli A. Cost/DALY Averted in a small hospital in Sierra Leone: what is the relative contribution of different services? World J Surg 2006; 30: 505–11 Correspondence: Nicholas J. Campain, Exeter Surgical Health Services Research Unit – Urology, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, Devon EX2 5DW, UK.

Diaphragmatic crural augmentation utilising cross-linked porcine dermal collagen biologic mesh (Permacol) in the repair of large and complex para-oesophageal herniation: a retrospective cohort study.

To evaluate the safety, efficacy and durability of selective integration of porcine dermal collagen (Permacol) biologic mesh for crural re-construction in large or complex para-oesophageal hernia surgery. Surgical repair of para-oesophageal herniation has been associated with high rates of failure. The utilisation of prosthetic mesh is controversial with complications including erosion and fistulation. Long-term outcomes for biologic mesh crural augmentation are unclear. A retrospective analysis of patients who underwent a biologic mesh (Permacol) augmented cruroplasty in the repair of large and/or complex para-oesophageal hernia was performed utilising the prospectively maintained oesophago-gastric database at the Royal Devon and Exeter Hospital between October 2004 and January 2013. This technique was selectively used for patients where the lateral extent of the diaphragmatic-crural defect prevented the fashioning of a sound, tension-free repair with sutures alone, or previous surgery had failed. Successful outcome was defined by resolution of symptoms and structural integrity of the repair. Fifty one procedures were performed on 49 patients (15 male), median age 75 (range 25-91). Post-operative morbidity included 2 (3.9%) oesophageal injuries managed conservatively, and 2 (3.9%) patients who suffered early repair breakdown requiring immediate surgical re-intervention. Four patients (8%) required endoscopic dilatation due to dysphagia, one (2%) in the early post-operative phase. The median follow-up was 36 months (range 6-105). All patients reported initial symptomatic resolution. Two patients (4%) were demonstrated to have breakdown of their repair during the follow-up period, both of whom underwent revision mesh-augmented surgery and are re-incorporated in this series. Late-onset dysphagia in two (4%) patients may be mesh-related, but no other complications were observed and a Kaplan-Meier analysis of this series predicts a symptom-free rate of approximately 94% at 5 years. The selective integration of biologic mesh to augment the crural repair in para-oesophageal hernia with extensive diaphragmatic defects appears to be safe, effective and infers the potential of long-term satisfactory outcomes.

P107. Can axillary lymph node clearance be avoided in select sentinel lymph node positive patients?

P107. Can axillary lymph node clearance be avoided in select sentinel lymph node positive patients?

P180. Audit of referrals to a family history clinic

P180. Audit of referrals to a family history clinic

P181. Integration of physical activity into breast cancer care pathway “Can-Move” programme

P181. Integration of physical activity into breast cancer care pathway “Can-Move” programme

P108. Introducing PROMs to the Royal Devon & Exeter Hospital: A service development project

P108. Introducing PROMs to the Royal Devon & Exeter Hospital: A service development project

Optimal glycaemic control and a low rate of micro and macrovascular complications in patients with HNF1A-MODY treated in a dedicated tertiary referral centre

S. Bacon 1, M.P. Kyithar1, S.R. Rizvi1, E. Donnelly 1, A. McCarthy1, M. Burke1, K. Colclough 2, S. Ellard2,3, M.M. Byrne1 1 Department of Diabetes & Endocrinology, Mater Misericordiae University Hospital, Dublin 7, Ireland. 2Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter. U.K, 3Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.

NEUROBORELLIOSIS IN SOUTH WEST ENGLAND

Lyme disease is a zoonotic infection transmitted to humans by the bite of Ixodes ticks infected with Borellia spp. Recorded incidence in the UK has increased threefold over the last decade (0.5 to 1.5 reports per 100,000)–due in part to improvement in and standardisation of serological testing but also likely with increased recognition of the wide spectrum of presentation. We assessed all Lyme serology requests between 2006 and 2011 from the Royal Devon and Exeter catchment area - one of the UK9s hotspots for Lyme disease. Testing peaked in 2008 and has since fallen. Of 206 positives, 21 attended the hospital with their illness and of those: 50% were paediatric, 56% presented with facial nerve palsy and 17% had meningitis. 72% in total had a neurological manifestation. Compared to published data from the same population in 2000–2005 Lyme incidence has doubled while the rate of hospital admission and neurological involvement has remained static, suggesting that an increased ascertainment of milder cases accounts for the increase. The breadth of neurological presentation and findings in serological, radiological and neurophysiological investigations is explored and adherence to EFNS guidance on treatment is assessed.