Certolizumab pegol for the treatment of patients with moderate-to-severe chronic plaque psoriasis: pooled analysis of week 16 data from three randomized controlled trials.

BACKGROUND: Certolizumab pegol, an Fc-free, PEGylated, anti-tumour necrosis factor (TNF) biologic, has demonstrated favourable results in three ongoing, phase 3, randomized, double-blinded, placebo-controlled trials in adults with psoriasis. OBJECTIVE: Data were pooled from the ongoing trials to investigate efficacy in selected subgroups and add precision to estimates of treatment effects during the initial 16 weeks of treatment. METHODS: In each trial, patients ≥18 years with moderate-to-severe chronic plaque psoriasis for ≥6 months were randomized to receive certolizumab 400 mg, certolizumab 200 mg or placebo every 2 weeks for 16 weeks. Coprimary endpoints for the pooled analysis were responder rates at Week 16, defined as ≥75% reduction in psoriasis area and severity index (PASI 75) and physician global assessment (PGA) of 0/1 ('clear'/'almost clear' with ≥2-category improvement). Safety was assessed by treatment-emergent adverse events. RESULTS: A total of 850 patients treated with certolizumab 400 mg (N = 342), certolizumab 200 mg (N = 351) or placebo (N = 157) were included in the pooled analysis. At Week 16, PASI 75 and PGA 0/1 responder rates were 80.1% and 63.7% in the certolizumab 400 mg group, 74.5% and 54.6% in the certolizumab 200 mg group, and 7.5% and 2.8% in the placebo group (P < 0.0001 for each dose versus placebo). In patients with and without prior biologic therapy, both doses of certolizumab resulted in substantially higher responder rates versus placebo. The incidence of adverse events was generally similar between the 400 mg and placebo groups, and somewhat lower in the 200 mg group versus placebo. No new safety signals were identified. CONCLUSION: Certolizumab pegol 400 mg or 200 mg every 2 weeks for 16 weeks was associated with statistically significant and clinically meaningful improvements in signs and symptoms of psoriasis in patients with and without prior biologic therapy, and a safety profile consistent with the anti-TNF class in psoriasis.

Safety, pharmacokinetics, and pharmacodynamics of RSLV-132, an RNase-Fc fusion protein in systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study.

Blood-borne RNA circulating in association with autoantibodies is a potent stimulator of interferon production and immune system activation. RSLV-132 is a novel fully human biologic Fc fusion protein that is comprised of human RNase fused to the Fc domain of human IgG1. The drug is designed to remain in circulation and digest extracellular RNA with the aim of preventing activation of the immune system via Toll-like receptors and the interferon pathway. The present study describes the first clinical study of nuclease therapy in 32 subjects with systemic lupus erythematosus. The drug was well tolerated with a very favorable safety profile. The approximately 19-day serum half-life potentially supports once monthly dosing. There were no subjects in the study that developed anti-RSLV-132 antibodies. Decreases in B-cell activating factor correlated with decreases in disease activity in a subset of patients.

The management of bilious vomiting in the neonate.

Bilious vomiting is synonymous with intestinal obstruction, be it functional or anatomical. In the neonate it may be due to congenital malformations of the gastrointestinal tract or develop due to acquired conditions, particularly intestinal complications associated with prematurity. This review considers the congenital malformations that may present with bilious vomiting and explores the diagnostic dilemmas faced in the preterm infant. The difficult issue of the need to exclude malrotation in term infants with bilious vomiting and the consequences of time-critical transfer is discussed.

Testicular atrophy following paediatric primary orchidopexy: A prospective study.

BACKGROUND: With the Nordic consensus statement advocating orchidopexy at an earlier age, the present study sought to investigate the outcomes of primary paediatric orchidopexy at a tertiary UK centre. OBJECTIVE: To prospectively assess testicular atrophy following primary orchidopexy for undescended testes in a paediatric population. Secondary outcomes were complication rates and whether outcomes were dependent on grade of operating surgeon. STUDY DESIGN: Prospective data regarding age at operation, classification of the undescended testis, length of follow-up, and subjective comparison of intraoperative and postoperative testicular volumes compared with the contralateral testis were collected. Testicular atrophy was defined as >50% loss of testicular volume or a postoperative testicular volume <25% of the volume of the contralateral testis. Patients were excluded for incomplete data and follow-up <6 months. RESULTS: Data for 234 patients were analysed. Testicular atrophy occurred in 2.6% of cases. There was no reported testicular re-ascent. All secondary acquired cases underwent a previous ipsilateral hernia repair. There was no significant difference in outcomes comparing the grade of surgeon (consultant n = 8, trainee/staff-grade surgeon n = 7-8). There was a trend towards postoperative catch-up growth in approximately one fifth of cases. DISCUSSION: Previous studies have reported a testicular atrophy rate of 5%. The present study reported a similar rate of 2.6%. In agreement with a previous publication, it was also found that testicular atrophy was not dependent on the grade of operating surgeon. The mechanism for testicular catch-up growth is not well understood. Animal studies have supported the hypothesis that increased temperature has a detrimental effect on testicular volume. However, follow-up in the present cohort was short (median 6.9 months), making interpretation of this finding difficult. It is acknowledged that clinical palpation alone to determine testicular volume potentially introduces intra-observer and inter-observer error. However, prospective studies using ultrasound to determine testicular volumes following orchidopexy have reported catch-up growth. CONCLUSION: This study represented one of the larger collections of prospective assessments of outcomes following primary orchidopexy. It was acknowledged that subjectively assessing testicular volume is not ideal; however, the data correlated with similar studies.

An unlikely cause of severe malnutrition in a 3-year-old girl with previous gastroschisis.

A 3-year-old girl with previous gastroschisis associated with jejunal and colonic atresia presented with severe oedema, abdominal pain and diarrhoea. Clinically she was malnourished. Serum albumin and concentrations of micronutrients were low. A barium meal examination showed jejunal dilation. A stricture was suspected and the patient was taken to theatre where an 8 cm length of bowel was resected including a jejunal stricture at the point of previous atresia repair. Inside the proximal dilated jejunum was a large trichobezoar (hairball), thought to be acting as a ball valve inside the bowel. This girl made a rapid recovery after surgery. Her nutritional state improved, symptoms resolved and serum biochemistry normalised. She remains well at follow-up with normal blood results, normal albumin and no diarrhoea.

Congenital lung malformations: an ongoing controversy.

INTRODUCTION: Congenital lung malformations are rare lesions that are most commonly diagnosed antenatally. Management of such lesions, particularly those that are asymptomatic, remains controversial. We undertook a survey to ascertain current practice of surgeons in the UK and Ireland. METHODS: All consultant members of the British Association of Paediatric Surgeons were asked to complete a survey on congenital lung malformations with respect to antenatal management, symptomatic and asymptomatic lesions, and operative techniques. RESULTS: Responses were received from 20 paediatric surgical centres and highlighted the ongoing variability in management of such lesions, particularly those that are asymptomatic. Twenty per cent of surgeons never resect an asymptomatic lesion and twenty-four per cent always do. The remainder intervene selectively, with size being the most commonly stated indication. Most resections are undertaken via thoracotomy although 35% of surgeons use thoracoscopy for some procedures. CONCLUSIONS: National data based on congenital anomaly registers are needed to determine the natural history of these malformations and to guide future management.

Contemporary management and outcomes for infants born with oesophageal atresia.

BACKGROUND: Reports on the management and outcome of rare conditions, such as oesophageal atresia, are frequently limited to case series reporting single-centre experience over many years. The aim of this study was to identify all infants born with oesophageal atresia in the UK and Ireland to describe current clinical practice and outcomes. METHODS: This was a prospective multicentre cohort study of all infants born with oesophageal atresia and/or tracheo-oesophageal fistula in 2008-2009 in the UK and Ireland to record current clinical management and early outcomes. RESULTS: A total of 151 infants admitted to 28 paediatric surgical units were identified. Some aspects of perioperative management were universal, including oesophageal decompression, operative technique and the use of transanastomotic tubes. However, there were a number of areas where clinical practice varied considerably, including the routine use of perioperative chest drains, postoperative contrast studies and antireflux medication, with each of these being employed in 30-50 per cent of patients. There was a trend towards routine postoperative ventilation. CONCLUSION: The prospective methodology used in this study can help identify practices that all surgeons employ and also those that few surgeons use. Areas of clinical equipoise can be recognized and avenues for further research identified.

Scope and feasibility of operating on the neonatal intensive care unit: 312 cases in 10 years.

PURPOSE: To report the scope, feasibility and learning experience of operating on neonates on the neonatal intensive care unit (NICU). METHODS: (1) Review of all NICU operations performed by general neonatal surgeons over 10 years; (2) 6-month prospective comparison of procedures performed in NICU or operating room; (3) structured interviews with five surgeons with 1-13 years experience of operating on NICU. RESULTS: 312 operations were performed in 249 infants. Median birth weight was 1,494 g (range 415-4,365), gestational age 29 weeks (22-42), and age at operation 25 days (0-163). Nearly half (147) were laparotomy for acute abdominal pathology in preterm, very low birth-weight infants There were no surgical adverse events related to location of surgery. Surgeon satisfaction with operating on NICU for this population was high (5/5). Several factors contribute to making this process a success. CONCLUSIONS: This is the largest reported series of general neonatal surgical procedures performed on NICU. Operating on NICU is feasible and safe, and a full range of neonatal operations can be performed. It removes risks associated with neonatal transfer and is likely to reduce physiological instability. We recommend this approach for all ventilated neonates and urge neonatal surgeons to operate at the cotside of unstable infants.

Meconium obstruction of prematurity.

Meconium obstruction of prematurity is an entity primarily affecting very low birthweight or extremely low birthweight babies causing low intestinal obstruction. Its presence may at best delay establishment of enteral feeding and compromise nutrition and at worst lead to mechanical obstruction requiring surgery or to intestinal perforation. There are considerable challenges in the recognition, diagnosis and management of this condition. Awareness of the disease and understanding of its pathogenesis may lead to early detection of affected babies and allow proactive measures to decrease the associated morbidity and mortality.

Trans-anastomotic tubes reduce the need for central venous access and parenteral nutrition in infants with congenital duodenal obstruction.

PURPOSE: To determine the effect of trans-anastomotic tube (TAT) feeding on outcome following repair of congenital duodenal obstruction (CDO). METHODS: Retrospective comparative study of all infants with CDO over 10 years. Data are median (range). Mann-Whitney U test and Fisher's exact test were used. RESULTS: Of 55 infants with CDO (48 atresia, 7 stenosis), 17 were managed with a TAT, 38 without. Enteral feeds were commenced earlier in infants with a TAT compared to those without (TAT 2 days post-repair [1-4] vs. no-TAT 3 days post-repair [1-7]; p = 0.006). Infants with a TAT achieved full enteral feeds significantly sooner than those without (TAT 6 days post-repair [2-12] vs. no-TAT 9 days post-repair [3-36]; p = 0.005). Significantly fewer infants in the TAT group required central venous catheter (CVC) placement and parenteral nutrition (PN) than in the no-TAT group (TAT 2/17 vs. no-TAT 28/38, p < 0.0001). There were six CVC-related complications (5 infections, 1 PN extravasation) and four TATs became displaced and were removed before achieving full enteral feeds. One infant with a TAT with trisomy 21 and undiagnosed Hirschsprung disease developed an anastomotic leak and jejunal perforation requiring re-operation. CONCLUSIONS: A TAT significantly shortens time to full enteral feeds in infants with CDO significantly reducing the need for central venous access and PN.

An audit of transfers for neonatal surgical care in England in 2007.

OBJECTIVE: To audit the access to specialist services for infants requiring transfer for surgical care in the neonatal networks in England in 2007. METHODS: Data on neonates transferred for surgical care from January to December 2007 were obtained from the National Neonatal Audit Programme database. Information on origin and destination of transfer was used to assess what proportion of infants required transfer to another network or, in the six network centres without a surgical service, to a more distant surgical centre than appropriate. RESULTS: Information was available from 18 of the 24 neonatal networks and identified 484 infants transferred for surgery for whom complete data were available. Ninety-one infants (18.8%) were transferred out of network or to a more distant centre than appropriate. This compares with 3.6% for all network patients and far exceeds the maximum figure of 5% recommended by the National Audit Office. Only one network was able to use a single surgical centre for transfers, and the median number of surgical units accessed in the year was 3 (range 1-8). CONCLUSIONS: Neonates requiring surgical care in England often need transfer beyond the local network. The reasons for this need further investigation by a prospective audit of access to neonatal surgical care.

Neonatal spontaneous colonic perforation due to cystic fibrosis.

We report two cases of spontaneous colonic perforation associated with cystic fibrosis (CF) in the neonatal period. Both presented with an acute abdomen soon after birth and required laparotomy and stoma formation. Colonic perforation as an initial presentation of CF is reviewed and management options are discussed.

Recurrent neonatal gastro-intestinal problems after spontaneous intestinal perforation.

To identify intestinal complications during the neonatal period following spontaneous isolated intestinal perforation (SIP). A retrospective case notes review was undertaken of all patients with a diagnosis of SIP, confirmed at laparotomy or post-mortem, admitted between January 2000 and January 2005. Patients with confirmed gastric perforation were excluded as were patients with proven necrotising enterocolitis (NEC) or suspected, but not confirmed, SIP. Seventeen patients, median gestation 27 weeks and median birth weight 780 g, were treated by drain alone (1), drain and later laparotomy (4) or primary laparotomy (12). Eight patients required enterostomy formation at primary laparotomy (1 jejunostomy, 1 colostomy and 6 ileostomy). Five babies died in the neonatal period and three later in the first year. Nine patients (53%) had ten subsequent episodes of intestinal pathology requiring surgical intervention between 5 and 136 days later comprising early recurrent isolated perforation (2), NEC (3), milk curd obstruction with or without perforation (3) and adhesion obstruction (2). Secondary surgery involved laparotomy in eight patients, five of whom required formation or re-formation of a stoma, and palliative drain insertion in one patient. Recurrent intestinal pathology requiring surgical intervention during the neonatal period occurred in 53% of babies with SIP. Surgeons and neonatologists should be aware that this group of patients are prone to further intestinal pathology.

A technique to demonstrate external haemorrhoids.

Although uncommon in children, haemorrhoids are one of the causes of a protruding anal lesion and may be confused with rectal prolapse or prolapse of a rectal polyp. The lesions may not be obvious when the child is anaesthetised because of lack of straining. This may prevent accurate diagnosis and impede identification of the lesion if surgery is being attempted. The authors report 3 cases where a 20 F Foley catheter with 30 ml balloon was inserted rectally and gentle traction applied to reproduce the raised venous pressure generated during straining. On each occasion external haemorrhoids could be demonstrated as the underlying pathology.

The effect of antenatal diagnosis on the management of small bowel atresia.

The aim of this study was to determine whether babies with small bowel atresia (SBA) diagnosed antenatally followed a different course from those diagnosed postnatally. We reviewed the records of neonates admitted to a single institution between 1985 and 2000 with a diagnosis of SBA. Thirty-nine neonates presented with SBA, with antenatal diagnosis (AND) being made in 12 (31%). There was no difference between the AND and postnatal diagnosis (PND) groups in terms of gestational age at birth, but the AND group had a lower mean birth weight. The babies in the AND group were operated on more quickly than those in the PND group. Ten out of 12 (83%) AND patients required parenteral nutrition compared with 12 out of 27 (44%) in the PND group, and the AND group had a significantly longer mean length of stay and spent a longer time on parenteral nutrition than the PND group.

Exclusion of androgen insensitivity syndrome in girls with inguinal hernias: current surgical practice.

To review the current approach of paediatric surgeons to the exclusion of androgen insensitivity syndrome (CAIS) in girls with inguinal hernias (IH), a questionnaire was sent to all specialist paediatric surgeons in the United Kingdom and Ireland asking if they exclude CAIS, how they exclude it, and what they say to parents preoperatively. In all, 32 surgeons responded (29%); 41% made no attempt to exclude CAIS because they thought the incidence was too low to justify exclusion; 19(59%) excluded CAIS at the time of surgery by assessment of the internal genitalia. Only 1 performed karyotyping primarily, and then only for bilateral IH. Although most would proceed to karyotyping if the primary assessment suggested CAIS, some would not. Of those who exclude CAIS, only 1 mentions CAIS preoperatively, 6 others mention gonadal inspection, and 12/19 (63%) make no comment. Thirty-one surgeons agreed to take part in a prospective study to define the incidence of CAIS in girls with IH. It is concluded that surgeons who exclude CAIS in girls with IH adopt different assessment methods, some of which may be unreliable. However, many do not attempt to exclude CAIS, believing the incidence to be too low. As the health and medicolegal consequences of failing to exclude CAIS may be considerable, surgeons should consider changing their practice. A prospective study should be undertaken to determine the incidence of CAIS in girls with IH.

The ascending testis: is late orchidopexy due to failure of screening or late ascent?

It is widely recommended that infant boys with undescended testes (UDT) should be referred for surgical opinion before the age of 18 months. To attempt to identify the reasons why the mean age at orchidopexy in our institution was as high as 5.5 years, a retrospective review of the screening history, examinations, and management of boys over the age of 3 years at the time of orchidopexy was undertaken by reference to community, general practitioner, and hospital records. In 36 children where hospital and community records giving information prior to referral were available, the UDT had previously been documented on at least one occasion as descended in 24 children or retractile in 10. In 1 child there was delayed referral, and in another, there was operative delay. It is concluded that there is either frequent failure of the Child Health Surveillance screening programme, or that late ascent of a testis previously sited in the scrotum is a common occurrence. We recommend further prospective studies to clarify this latter phenomenon.

Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) treated with etanercept (Enbrel) in controlled studies of 3 to 6 months' duration had rapid and sustained improvement of their disease, with minimal safety issues. In this study, we examine safety and clinical benefit after longer term treatment with etanercept. METHODS: All adult patients with RA with a previously inadequate response to one or more disease modifying antirheumatic drugs, and who received at least one dose of etanercept as monotherapy in controlled or open label clinical trials were evaluated for safety and clinical benefit. Adverse event rates were compared as was evidence of continued benefit over time. RESULTS: Etanercept continued to be safe and well tolerated in 628 adult patients treated for a median of 25 mo (maximum 43 mo; 1109 patient-years). Nine percent of patients withdrew due to lack of efficacy and 7% due to adverse events. Most adverse events were mild, and no statistically significant increases in frequency of events were seen when patients received etanercept over longer periods of time. Clinical benefit was maintained with longterm therapy. A 100% improvement in individual disease activity measures was achieved by 17% to 28% of the patients. Fifty-five percent of patients who were taking corticosteroids (mean dose at baseline 6.6 mg/day) decreased or discontinued corticosteroid therapy while maintaining control of their arthritis symptoms. CONCLUSION: Etanercept continued to be safe and well tolerated, and its clinical benefit was sustained for a median of 25 mo and for as long as 43 mo in patients with RA.

Gastric tube graft interposition as an oesophageal substitute.

BACKGROUND: Use and techniques of oesophageal replacement for long gap oesophageal atresia are still evolving. Gastric tube graft interposition as an oesophageal substitute was evaluated on an animal model. METHODS: Twenty-three postweaned, 28-day-old-piglets were used as the experimental animals. Isoperistaltic gastric tube interposition based on the right gastroepiploic vessels was performed at 28 days of life. Postoperative evaluation included weekly measurement of weight, clinical assessment for gastrointestinal and respiratory complications and deglutition difficulties. Haemoglobin, serum ferritin, albumin, globulins, total proteins and red cell folate were assayed. Pigs were killed and analysed histopathologically following a maximum observation period of 149 days. RESULTS: Growth of the pigs was normal. Deglutition was not impaired in 16 pigs (89%). Minor leak was diagnosed in three pigs (17%), which was successfully managed conservatively. Anastomotic stricture was seen in two pigs (11%). Graft necrosis was not seen. Gross histology showed the absence of hypertrophy, redundancy and kinking of the interposed gastric tube graft. Microscopically non-erosive oesophagitis was seen in three pigs (17%), ulcerative oesophagitis was seen in two pigs (11%) and submucosal fibrosis was seen in seven pigs (39%). Dysplasia or Barrett's oesophagitis was not observed at the end of animal growth. CONCLUSIONS: Gastric tube graft interposition is an immediate ideal oesophageal substitute due to fewer complications, probable absence of gastro-oesophageal reflux in the majority by histology, and absence of dilatation and redundancy of the interpose tube. The oesophageal substitute adequately met the nutritional needs for growth and development in the animal model.