Bristol Children's Hospital Research Articles

Routine Whole Genome Sequencing Offers a More Comprehensive Assessment of IG/TCR Gene Rearrangements for MRD Targets in Acute Lymphoblastic Leukemia - Data from the First 62 Cases from the NHS England Genomic Medicine Service

Introduction Minimal residual disease (MRD) monitoring is fundamental for risk stratification and treatment in acute lymphoblastic leukemia (ALL). Sensitive molecular assay requires presentation samples to be screened for immunoglobulin and T-cell receptor (IG/TCR) gene rearrangements. Previously samples were screened by PCR, heteroduplex analysis and Sanger sequencing to identify clone defining IG/TCR gene rearrangements. Subsequently these sequences were used to develop qPCR assays for MRD follow-up monitoring. More recently, targeted IG/TCR high-throughput sequencing (HTS) has been used with similar panels to identify gene rearrangements. Both these methods have limitations, in that only rearrangements covered by the panels are detected, and the techniques are labour intensive and expensive. Whole genome sequencing (WGS) has potential to discover all IG/TCR rearrangements in a single assay giving greater potential to detect markers for follow up MRD monitoring. In England all patients with ALL are eligible for WGS at diagnosis via the National Health Service, Genomic Medicine Service (NHS GMS). Methods Sixty-two patients, presenting with ALL at either Great Ormond Street Hospital or Bristol Children's Hospital, had short-read WGS via the NHS GMS performed concurrently with standard of care (SOC) targeted HTS to identify IG/TCR rearrangements. A bespoke bioinformatic pipeline was developed to identify IG/TCR rearrangements in the WGS samples. SOC targeted HTS analysis was performed using the open source Vidjil bioinformatic software. A cut-off of 5% (clone proportion of total clonotypes) was used to define an acceptable disease-specific clone for monitoring. Results All 62 samples had a greater number of rearrangements detected by WGS than targeted HTS. The mean number of clones >5% detected was 2.7 by targeted HTS and 3.1 by WGS. For rearrangements identified by targeted HTS at a 5% cut-off, 97% (185 out of 190) were identified by WGS. All targets were identified by WGS using a 10% cut-off (Table 1).Despite the lower depth of coverage of the WGS assay, it retrieved 89% of sequences seen in SOC down to a level of 1%, as well as additional re-arrangements not seen by the SOC assay (Figure 1). As well as additional rearrangements being discovered by WGS, we observed novel rearrangements (dd3/ja rearrangements) not previously identified using a targeted approach. To establish if the additional sequences identified by WGS were clinically applicable as MRD targets, we designed allele specific oligonucleotides for a representative 32 rearrangements for testing by qPCR. Over half (n=16) were able to be used to track MRD in follow-up samples. New primer/probe sets were designed for the novel dd3/ja rearrangements identified by WGS, these were also tested by qPCR and performed well enough to be clinically applicable for MRD monitoring. Conclusions WGS approach outperformed targeted HTS, identifying more IG/TCR rearrangements suitable for molecular MRD monitoring in all patients. This is of particularly benefit in cases where targeted HTS only identifies 1 or 2 potential MRD targets. WGS also has the advantage of identifying other key gene rearrangements (BCR-ABL, KMT2A, SIL-TAL, IKZF1) that make excellent targets for MRD monitoring. Beyond this, WGS delivers all diagnostic information, germline and additional somatic findings that aid diagnosis. For ALL, in one test WGS can now replace all molecular diagnostics. In England all patients with leukemia are eligible for centralised WGS. With continued improvements in turnaround times, and reducing costs, we propose that WGS should be the new diagnostic standard for pediatric ALL

Effects of endothelin receptor antagonism in an experimental model of renal transplantation

s / International Journal of Surgery 23 (2015) S15eS134 S21 Conclusion: Our results indicate the existence of a mitochondrial stress environment with a lasting negative impact on residual kidney-function at day 30 likely reflecting a renal-tubular dysfunction in the remaining kidney. Further biochemical analyses are ongoing to confirm the nature of this dysfunction allowing the targeting of timely interventions. 0598: EFFECTS OF ENDOTHELIN RECEPTOR ANTAGONISM IN AN EXPERIMENTAL MODEL OF RENAL TRANSPLANTATION K. Shah, S. Hosgood, M. Patel, M. Nicholson. University of Leicester, UK Aim: Uncontrolled Donation after Circulatory Death (uDCD) donors provide a large potential source of kidneys but there is reluctance to use them due to prolonged warm ischaemic times. Endothelin-1, a potent vasoconstrictor, is a major contributor to ischaemic injury. This study aimed to investigate the benefit of endothelin receptor blockade in an experimental model of uDCD transplantation. Methods: Porcine kidneys underwent 60 minutes warm ischaemia and 2 hours cold ischaemia followed by 3 hours of reperfusion with autologous blood without (control, n 1⁄4 6) and with (n 1⁄4 6) 500mg BQ-123, a selective ETA endothelin receptor antagonist. Markers of renal function and injury were analysed. Results: Renal blood flow was significantly higher in the experimental group at 15e30 minutes of reperfusion (29.6e37.7 vs. 13.1e18.2 ml/min/ 100 g, p 1⁄4 0.02), after which, although higher throughout, statistical significance was lost. Urine output, creatinine clearance and oxygen consumption were also higher in the experimental group throughout but statistical significance was only seen in the 1st hour urine output (83 vs. 32 ml/hr, p 1⁄4 0.01). Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels were not different between the groups. Conclusion: Kidneys can recover from warm ischaemic injury. BQ-123 appeared to improve perfusion and function initially but did not have a sustained effect or significant overall benefit. Association of Surgeons of Great Britain & Ireland Short Paper Session 0002: SURGICAL AND TRANSCATHETER CLOSURE OF CONGENITAL CORONARY FISTULAE: OUTCOMES FROM A NATIONAL AUDIT D. Fudulu, D. Dorobantu, M. Caputo, S. Stoica. Bristol Children's Hospital, UK Aim: To report short and long term outcomes after surgical and transcatheter correction of congenital coronary fistulas (CCF). Methods: Using data from the UK Central Cardiac Audit Database we performed a retrospective analysis of all patients undergoing surgical or transcatheter correction of CCF between 2000 and 2012. Results: Out of 81 patients (48.2% Male, 51.8% Female), 34 (42%) underwent surgical repair and 47 (58%) had transcatheter procedures. The median ages were 12.6 years for surgery (range, 0.08e68.2) and 7.8 years (range, 0.01e77.8) in the catheterization group. Mean follow-up times were: 5.3 years (range, 0e13.0) for the surgical group and 4.6 years (range, 0e12.7) for the catheter group. Therewas no 30-daymortality in the entire cohort. One-year mortality for the surgical group was 7.41 % vs. 2.94 % for the catheter group (p 1⁄4 0.58). In the catheter group 4 patients (8.51%) required one or more reinterventions, compared to no reinterventions in the surgical cohort (p 1⁄4 0.13). Conclusions: CCF repair via transcatheter or surgical approach is attainable with no early mortality and good medium-term results. Careful patient selection would have to be partly responsible for these excellent national results Reintervention is overall infrequent and it appears to be higher after transcatheter embolisation. 0418: TRANS-VAGINAL DUPLEX ULTRASOUND FOR DETECTING PELVIC VEIN INCOMPETENCE IN WOMEN: A PILOT STUDY V. Hansrani, D. Kotecha, K. Norse, C. McCollum. University of Manchester, UK Aim: Pelvic vein incompetence (PVI) is diagnosed by reflux venography. This is invasive, nephrotoxic and involves ionizing radiation in young women. Trans-vaginal duplex ultrasound (TVU) is a non-invasive and entirely safe alternative. We compared TVUwith reflux venography for the detection of PVI. Methods: Womenwith clinical suspicion of PVI who attended for TVU and reflux venography were included in this study (n 1⁄4 20). Sensitivity, specificity, positive and negative predictive value (PPV, NPV) were calculated for TVU with reflux venography as the ‘gold standard’. Results: 40-paired TVU and reflux venography images were analysed from 20women, mean (range) age 45 (25e55). PVI was detected in all 20 images with TVU and 19 of 20 (95%) images with reflux venography. The sensitivity and PPV of TVU to detect PVI was 100% and 95% respectively. TVU identified left ovarian vein incompetence with a sensitivity and specificity of 78.6% and 66.7%; right ovarian vein incompetence with sensitivity and specificity of 71.4% and 100%; left internal iliac vein incompetence with sensitivity and specificity of 91.7% and 100%, and right internal iliac vein incompetence sensitivity and specificity of 70% and 90% respectively. Conclusion: TVU is accurate and safe alternative to reflux venography in diagnosing of PVI. 0719: LIVING KIDNEY DONATION IN THE ELDERLY: THE UK EXPERIENCE R. Tamburrini, Z. Ahmed, A. Shafi, N. Kessaris, N. Mamode. Guy's Hospital,

Quality of life impacts from rotavirus gastroenteritis on children and their families in the UK

AimsRotavirus vaccines (RV) are safe and effective but demand significant investment of healthcare resource. In countries with low mortality due to rotavirus, a key component to assessing cost-effectiveness is quantifying the Health Related Quality of Life (HRQoL) lost due to rotavirus acute gastroenteritis (RVAGE). MethodsFamilies with children less than six years old with gastroenteritis were recruited from attendees to Bristol Children's Hospital Emergency Department. Stools were tested for viral causes of gastroenteritis. Children's HRQoL was assessed at presentation using Health Utilities Index 2 (HUI2) with visual analogue scale (VAS). The effect of the child's illness on the HRQoL of up to two adult carers was assessed using EQ-5D-5L. Families completed a daily symptom diary to assess time to recovery and within-family transmission. Results127 families consented to take part, 84(65%) had rotavirus as the cause of illness. At the time of attendance, mean paediatric HRQoL with RVAGE was 0.74(HUI2) and 0.42(VAS). Primary/secondary carer's HRQoL was 0.68/0.80 (EQ5D) or 0.70/0.79 (VAS). The mean number of QALYs lost due to RVAGE was 3.1–3.5 per thousand children and 7.7–8.7 per thousand family units.In 52% of RVAGE families at least one other member developed a secondary case of gastroenteritis. For working parents, 69% missed work, for a mean of 2.8 days (95% CI 2.3–3.4). ConclusionsWe have found the HRQoL loss associated with RVAGE in children and their carers to be significantly higher than estimates used for all RV medical attendances in UK cost-effectiveness calculations.

Restructuring services to reduce waiting times and prevent complications

PurposeInguinal hernias are a common problem amongst neonates, and a potential source of significant morbidity through incarceration of the hernia. Expedited surgical repair can prevent incarceration and reduce complications. The department at Bristol Children's Hospital aimed to minimise waiting times for surgery thereby reducing incarceration and complication rates. This paper aims to examine how this was done.Design/methodology/approachBristol Children's Hospital provides local and regional (tertiary referral) services. Retrospective audit of waiting times from referral to surgery was performed against the departmental standard of four weeks. Data were collected on frequency of incarceration and any complications. Following service restructure, second cycle audit was performed to assess the impact of change.FindingsFirst cycle audit (n=74) found median waiting time 20 days, (Mean 28.4 days, Range 0‐138 days). A total of 28 per cent of patients waited longer than the target four weeks from referral. Incarceration occurred in 13 per cent of patients awaiting surgery. Two patients (2.7 per cent) experienced complications. Following service restructuring second cycle audit (n=28) found waiting times were significantly reduced (median two days, mean 7.0, p<0.0001). Only 7 per cent of patients waited over four weeks for surgery. There were no incarcerations or complications.Practical implicationsThis study demonstrates a successful model of service for management of neonatal inguinal hernias which could be adopted at children's hospitals throughout the UK.Originality/valueThis study highlights a successful audit process, in which the extent of a problem is quantified and analysed, strategies for improvement are identified and implemented, and second cycle audit confirms the impact of change and an improved service.

Near infrared spectroscopy in paediatric cardiac surgery - a review of local experience and national survey

Introduction: Many centres have adopted Near infrared spectroscopy (NIRS) as a standard of care for adult cardiac surgery, despite limited evidence [1]. A search of the literature on the use of NIRS in paediatric cardiac surgery reveals mostly case reports and no randomised controlled trials. NIRS has been used for selected cases at Bristol Children's Hospital (BCH) for 2 years. We sought to establish firstly, whether there was evidence that NIRS had guided perioperative management at BCH by auditing current practice and, secondly, whether NIRS was used routinely in the other UK paediatric cardiac centres. Methods: For the first phase of the project, downloaded NIRS data, anaesthetic and bypass records covering a 10-week period at BCH were collated retrospectively. Periods of significant cerebral desaturation were mapped to contemporaneous notes and recordings to determine whether they related to specific perioperative events. In the second phase, a 10-question survey was e-mailed to a paediatric cardiac anaesthetist at all UK paediatric cardiac centres. A reminder email was sent 10 days later, if required and a second anaesthetist was contacted after a further week if there was still no response. Anaesthetists were asked questions concerning their peri- and-postoperative use of NIRS, how reliant they were on it, what indicators they used to signify cerebral hypoxia and whether they have used NIRS to guide therapy. Results: NIRS at Bristol Children's Hospital Twenty eight sets of records were analysed and, of these, two provided clear evidence of NIRS guiding perioperative management. In the first, concerning a 19-month-old, a Glenn shunt was performed on bypass, following a non-bypass attempt, aborted due to poor cerebral oxygen saturations. The second concerned low cerebral tissue saturation due to temporary obstruction of the superior vena cava by the cannula after commencing bypass in a 3-year-old. National Survey: We received 11 completed surveys from 13 centres. NIRS is used in 6/11 (55%) centres and, of these, three use it for all cases. Of the four that don't use NIRS, two plan to in the near future. All of those using NIRS routinely stated they would now be uncomfortable undertaking a case without it. Concerning those with experience of NIRS (7), cerebral hypoxia is determined by either a percentage drop (3), absolute values (1) or a combination (3). The cerebral saturation % for concern given ranged from 30% to 55%. All centres with NIRS also used it postoperatively (although half did so only occasionally) and 6/7 of those with experience of NIRS were aware of situations where NIRS had significantly altered patient management. Discussion: There is a large disparity in the use of NIRS in paediatric cardiac surgery in the UK with around half of the centres surveyed using it. Furthermore, of those that do use NIRS, there is a lack of consensus between centres on the most accurate mechanisms and thresholds used to identify cerebral hypoxia. This is probably related to the lack of clarity in the literature of the benefits of NIRS in this patient group. Our local review illustrated two instances, over 10 weeks, where NIRS was valuable in directing patient management. Furthermore, the vast majority of those surveyed with experience of NIRS had also used it to guide management at some point. There are some limitations to this study. Our local note review was retrospective and relied on accurate reporting by the anaesthetist at the time. If anything, however, this would result in the under-reporting of events. We acknowledge that we only surveyed one anaesthetist in each centre and their answers may not reflect those of all of their colleagues. There were also two centres that we were unable to get a reply from. Conclusion: We have found two local examples of perioperative management guided by NIRS. We have further identified, through the survey, evidence of the inconsistency and deficiency of standard in the use of NIRS in the UK. Conflict of interest: The authors declare no conflict of interest in this study.

Problems in diagnosis and management of goitre in childhood and adolescence.

This study is a retrospective review of 17 patients aged 16 and under with a total of 18 goitres, who were investigated and treated at Bristol Children's Hospital and Bristol Royal Infirmary between 1967 and 1994. There were five neoplasms, comprising follicular adenoma (three) and papillary carcinoma (two). Other benign causes of goitre included nodular goitre (four), non-toxic hyperplasia (three) and chronic lymphocytic thyroiditis (three). The authors suggest some guidelines to help in the diagnosis and management of goitre in young patients, as a consequence of significant difficulties encountered in 12 of the 17 patients in this series.

Lifestyle behaviours of young adult survivors of childhood cancer.

This cross-sectional study collected baseline data on the health behaviours of a large population of survivors of childhood cancer in the UK, aged 18–30 years, compared with those of sex- and age-matched controls. Data from 178 young adult survivors of childhood cancer, diagnosed and treated at Bristol Children's Hospital, 184 peers from the survivors' GP practices and 67 siblings were collected by postal questionnaire. Conditional logistic regression analysis showed that, for matched sets of survivors and controls, survivors of a variety of childhood cancers reported lower levels of alcohol consumption (P=0.005), lower levels of cigarette smoking (P=0.027) and lower levels of recreational drug use (P=0.001) than controls. Analysis of matched sets of survivors and siblings showed similar trends but no significant differences. A health behaviour index for each participant was constructed from the data collected on five key health behaviours which influence future health status. Comparison of the means for each case group showed that survivors of childhood cancer were leading healthier lives than controls or siblings. This finding was expressed most clearly as the difference in the means of the health behaviour index for each case group, derived from five health behaviours (one-way ANOVA, P<0.001).British Journal of Cancer (2002) 87, 1204–1209. doi:10.1038/sj.bjc.6600632 www.bjcancer.com© 2002 Cancer Research UK

Ultrasound Diagnosis of Infantile Hypertrophic Pyloric Stenosis: Determinants of Pyloric Length and the Effect of Prematurity

AIM: To evaluate the determinants of sonographic measurements of pyloric length and muscle thickness in infants with hypertrophic pyloric stenosis (HPS) and to determine whether infants born prematurely have proportionately smaller measurements. MATERIALS AND METHODS: A retrospective review was carried out of 190 infants operated on for HPS at Bristol Children's Hospital over a 5-year period. Sonographic measurements of pyloric length and muscle thickness were related to age, history of prematurity, weight, sex and family history of HPS. RESULTS: Pyloric length in infants with HPS was significantly greater in those born at term compared to those born prematurely (18·6mm [SD 2·2] vs 17·3mm [SD 3·1], P=0·043); this was explainable by body weight, with length increasing by 1·13mm (SE 0·35) per kilogram (P=0·002). There was no significant relationship with measured muscle thickness. CONCLUSION: Sonographic measurement of pyloric length is strongly correlated with the weight of the infant, irrespective of other factors. The relationship of length and weight may be useful in confirming the presence of HPS in small and premature infants Haider, N. et al. (2002). Clinical Radiology57, 136–139.

Early surgery compared with watchful waiting for glue ear and effect on language development in preschool children: a randomised trial

Otitis media with effusion (OME) is the most common cause of hearing loss in children and is generally treated by elective surgery. We compared in children with persistent OME the effect on speech and language development of immediate surgery (ventilation-tube insertion) and watchful waiting before surgery. We did a randomised controlled trial with masked outcome assessment in Bristol Children's Hospital, Bristol, UK. We included 186 children born between April 1, 1991, and Dec 31, 1992, who had confirmed bilateral OME and bilateral hearing impairment of 25-70 dB of at least 3 months' duration. Children were randomly assigned surgery within 6 weeks (n=92), or 9 months of watchful waiting (n=90), after which bilateral tube insertion was done if required. We assessed hearing loss, expressive language, and verbal comprehension at 9 months and 18 months. At 9 months, standardised scores for expressive language and verbal comprehension differed between groups with marginal significance after adjustment for baseline differences (p=0.04 and p=0.028, respectively). At 9 months, verbal comprehension and expressive language skills in the watchful-waiting group were 3.24 months behind those in the early-surgery group. The watchful-waiting group was delayed on these two measures compared with their age-expected levels. 18 months after randomisation, 85% of children in the watchful-waiting group had received surgery and groups did not differ significantly. There is some benefit from ventilation-tube insertion for expressive language and verbal comprehension but the timing of surgery is not critical.

Peroperative 123I-MIBG scan using a sterile probe for staging and resection of neuroblastoma in children

Two children with neuroblastoma were treated at Bristol Children's Hospital. One had primary resection of a right adrenal tumor; the other had resection of a secondary lymph node located in the left supraclavicular fossa. In both cases, the patients received 123I-meta-iodobenzylguanidine (MIBG) preoperatively, and a sterlizable, hand-held Cadmium-Telluride (CdTe) solid-state detector was used for localization of the tumor. The surgical procedure was facilitated significantly by this peroperative radioisotope-guided technique.

Causes of death in a paediatric oncology unit.

The records of 101 patients (64 males and 37 females) registered at Bristol Children's Hospital who died between January 1986 and December 1989 were reviewed to determine the cause of death. Nineteen patients (19%) died without obtaining remission and 6 (6%) in first remission. Seventy-six (75%) died after relapse; three during re-induction and two in second remission. The causes of death were active disease in 85 patients (84%), active disease and infection (4%), active disease and other factors (4%), infection only (3%), toxic cardiomyopathy (2%), graft versus host disease (2%), and second malignancy (1%).

A drug identification chart for the asthma clinic

In a disease such as asthma, where the patient may be supervised from both the GP's surgery and a hospital clinic, there are likely to be problems in the physician appreciating the complete therapy the patient is actually receiving. Accordingly, the indicated drug identification chart was designed and its use in the asthma clinic at Bristol Children's Hospital examined.

Peak expiratory flow rate and malnutrition

Journal Article Peak expiratory flow rate and malnutrition Get access F. Carswell, F. Carswell ∗ Departments of Child Health and Parasitology, University of Dar-es-Salaam, TanzaniaDept. of Child Health, Bristol Children's Hospital, Bristol, UK ∗Correspondence to: Dr. F. Carswell, Children's Hospital, St. Michael's Hill, Bristol, UK. Search for other works by this author on: Oxford Academic PubMed Google Scholar J. Hellier, J. Hellier Departments of Child Health and Parasitology, University of Dar-es-Salaam, TanzaniaDept. of Child Health, Bristol Children's Hospital, Bristol, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar P.S.E.G. Harland, P.S.E.G. Harland Departments of Child Health and Parasitology, University of Dar-es-Salaam, TanzaniaDept. of Child Health, Bristol Children's Hospital, Bristol, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar R.H. Meakins R.H. Meakins Departments of Child Health and Parasitology, University of Dar-es-Salaam, TanzaniaDept. of Child Health, Bristol Children's Hospital, Bristol, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 74, Issue 6, 1980, Page 814, https://doi.org/10.1016/0035-9203(80)90212-6 Published: 01 January 1980 Article history Published: 01 January 1980 Accepted: 19 February 1980

(11) Dyskeratosis. For diagnosis.

British Journal of DermatologyVolume 89, Issue s9 p. 53-54 (11) Dyskeratosis. For diagnosis. Dr R.P. Warin, Dr R.P. Warin Bristol Children's Hospital, BristolSearch for more papers by this author Dr R.P. Warin, Dr R.P. Warin Bristol Children's Hospital, BristolSearch for more papers by this author First published: July 1973 https://doi.org/10.1111/j.1365-2133.1973.tb03444.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume89, Issues9July 1973Pages 53-54 RelatedInformation

Cerebral Palsy in Childhood.

In writing this book, the author attempts to analyse the various etiological factors contributing to occurrence of cerebral palsy in childhood. In order to make a total clinical assessment of the child with cerebral palsy, she also evaluates the associated clinical defects, such as sensory loss or hearing deficit, in addition to the neuromuscular involvement. The data in the book are based on a group of 301 children seen at the Cerebral Palsy Assessment Clinic of the Bristol Children's Hospital, Bristol, England. These children were examined by a team of workers whose purpose was to evaluate each child for educability and proper placement. The average number of children with cerebral palsy who reached the age of 5 years in the period 1930-1951 was 1.90 per 1000 live births in Bristol. Cases of cerebral palsy are discussed under the headings of ( a ) paraplegia, ( b ) monoplegia, ( c ) hemiplegia, ( d ) quadriplegia, ( e ) athetosis,