Beyond image defined risk factors (IDRFs): a delphi survey highlighting definition of the surgical complexity index (SCI) in neuroblastoma.

PURPOSE: Preoperative evaluation of Image Defined Risk Factors (IDRFs) in neuroblastoma (NB) is crucial for determining suitability for upfront resection or tumor biopsy. IDRFs do not all carry the same weighting in predicting tumor complexity and surgical risk. In this study we aimed to assess and categorize a surgical complexity (Surgical Complexity Index, SCI) in NB resection. METHODS: A panel of 15 surgeons was involved in an electronic Delphi consensus survey to identify and score a set of shared items predictive and/or indicative of surgical complexity, including the number of preoperative IDRFs. A shared agreement included the achievement of at least 75% consensus focused on a single or two close risk categories. RESULTS: After 3 Delphi rounds, agreement was established on 25/27 items (92.6%). A severity score was established for each item ranging from 0 to 3 with an overall SCI range varying from a minimum score of zero to a maximum score of 29 points for any given patient. CONCLUSIONS: A consensus on a SCI to stratify the risks related to neuroblastoma tumor resection was established by the panel experts. This index will now be deployed to critically assign a better severity score to IDRFs involved in NB surgery.

Minimally invasive surgery for neuroblastic tumours: A SIOPEN multicentre study: Proposal for guidelines.

INTRODUCTION: Surgery plays a key role in the management of Neuroblastic tumours (NB), where the standard approach is open surgery, while minimally invasive surgery (MIS) may be considered an option in selected cases. The indication(s) and morbidity of MIS remain undetermined due to small number of reported studies. The aim of this study was to critically address the contemporary indications, morbidity and overall survival (OS) and propose guidelines exploring the utility of MIS for NB. MATERIALS & METHODS: A SIOPEN study where data of patients with NB who underwent MIS between 2005 and 2018, including demographics, tumour features, imaging, complications, follow up and survival, were extracted and then analysed. RESULTS: A total of 222 patients from 16 centres were identified. The majority were adrenal gland origin (54%) compared to abdominal non-adrenal and pelvic (16%) and thoracic (30%). Complete and near complete macroscopic resection (>95%) was achieved in 95%, with 10% of cases having conversion to open surgery. Complications were reported in 10% within 30 days of surgery. The presence of IDRF (30%) and/or tumour volume >75 ml were risk factors for conversion and complications in multivariate analysis. Overall mortality was 8.5%. CONCLUSIONS: MIS for NB showed that it is a secure approach allowing more than 95% resection. The presence of IDRFs was not an absolute contraindication for MIS. Conversion to open surgery and overall complication rates were low, however they become significant if tumour volume >75 mL. Based on these data, we propose new MIS guidelines for neuroblastic tumours.

Impact of neoadjuvant chemotherapy on thrombus viability in patients with Wilms tumour and caval extension: systematic review with meta-analysis.

BACKGROUND: Inferior vena cava (IVC) tumour thrombus in children with Wilms tumour is typically managed with neoadjuvant chemotherapy with the intention of achieving thrombus regression in order to minimize the risks associated with complex vascular surgery. METHODS: A systematic review of Medline and Embase databases was undertaken to identify all eligible studies with reference to thrombus viability in Wilms tumour index cases with caval/cardiac extension. A meta-analysis of proportions was utilized for pooled thrombus viability data across studies. Logistic regression was used to analyse the relationship between thrombus viability and duration of chemotherapy. RESULTS: Thirty-five eligible observational studies and case reports met inclusion criteria describing a total of 236 patients with thrombus viability data. The pooled proportion of patients with viable tumour thrombus after neoadjuvant chemotherapy was 0.53 (0.43-0.63). Logistic regression analysis of 54 patients receiving either a standard (4-6 weeks) or extended (more than 6 weeks) course of neoadjuvant chemotherapy resulted in an odds ratio of 3.14 (95 per cent c.i. 0.97 to 10.16), P = 0.056, with extended course therapy trending towards viable tumour thrombus. CONCLUSION: Preoperative chemotherapy is successful in achieving non-viability of caval and cardiac thrombi in around 50 per cent of children, without added benefit from extended cycles of neoadjuvant chemotherapy. Risks versus benefits of extirpative vascular surgery must be considered, therefore, for these high-risk patients.

Posterior urethral valves masquerading as neuropathic bladder following sacrococcygeal teratoma resection.

Neuropathic bladder may be a co-associated morbidity in newborn babies following resection of a sacrococcygeal teratoma. We report a case of a male newborn showing features of incomplete urinary voiding requiring intermittent catheterisation after operation for bladder emptying. Videourodynamic assessment excluded neuropathic bladder and posterior urethral valves were demonstrated on micturating cystography. Urology outcomes have been excellent following curative valve ablation. This report highlights the crucial importance of being aware of the rare coexistence of lower urinary tract pathology in male babies with sacrococcygeal teratoma. Routine urodynamic assessment should be considered in all children following sacrococcygeal teratoma resection.

Fetal surgery.

Fetal medicine is a super-specialty enterprise and a technology-driven field. The growth and interest in fetal surgery can be largely attributed to advances in fetal imaging and bespoke instruments for in utero intervention. Previously fatal fetal conditions are now being treated using open surgery, minimally invasive procedures, and percutaneous fetal technologies. Several fetal conditions, including myelomeningocele and twin-to-twin transfusion syndrome, have been tested rigorously in RCTs. However, as the specialty of fetal surgery grows, a robust evidence base with long-term follow-up is obligatory for every procedure. This article offers an overview of fetal surgery and antenatal intervention. As more cutting edge therapies come into clinical practice, growing public opinion and medical ethics will play a significant role in the future of this multidisciplinary specialty.

Efficacy of antireflux surgery in children with or without neurological impairment: a systematic review.

BACKGROUND: Antireflux surgery is commonly performed in children, yet evidence for its efficacy is limited. The aim of this review was to determine the effect of antireflux surgery with regard to objective measures of quality of life (QoL) and value of upper gastrointestinal investigations in neurologically normal (NN) and neurologically impaired (NI) children. METHODS: A systematic review was conducted of articles reporting children undergoing antireflux surgery in whom preoperative and postoperative objective testing was performed. Primarily, Embase, CINAHL, MEDLINE and PubMed were searched from inception to April 2019. Methodological Index for Non-randomized Studies (MINORS) criteria were used to assess article quality. RESULTS: Of 789 articles, 14 met the eligibility criteria, 12 prospective observational and 2 retrospective studies. The median MINORS score was 59·4 (i.q.r. 39 to 62·5) per cent. Seven studies reported assessment of validated QoL measures before and after antireflux surgery in 148 children. Follow-up ranged from 1 to 180 months. All studies confirmed significant improvements in QoL measures among NN and NI children at all follow-up points. Eleven studies reported on preoperative and postoperative investigations in between 416 and 440 children children. Follow-up ranged from 0·5 to 180 months. Nine studies confirmed improvements in gastro-oesophageal reflux using 24-h oesophageal pH monitoring with or without manometry, but conflicting results were identified for four studies reporting gastric emptying. No studies reported fluoroscopy or endoscopy adequately. CONCLUSION: Based on the results of studies of low-to-moderate quality, antireflux surgery improved QoL and reduced oesophageal acid exposure in NN and NI children in the short and medium term. Although antireflux surgery is a common elective operation, the lack of rigorous preoperative and postoperative evaluation(s) in the majority of patient-reported studies is striking.

ANTECEDENTES: La cirugía antirreflujo (antireflux surgery, ARS) se realiza con frecuencia en niños, aunque la evidencia sobre su eficacia es limitada. Nos propusimos determinar la eficacia de la ARS con respecto a medidas objetivas de calidad de vida (quality of life, QoL) y la utilidad de las exploraciones del tracto gastrointestinal superior en niños con funciones neurológicas normales (neurologically normal, NN) y con discapacidad neurológica (neurologically impaired, NI). MÉTODOS: Se llevó a cabo una revisión sistemática (de acuerdo con la normativa PRISMA) de artículos que describiesen series de niños sometidos a ARS en los que se realizaron pruebas objetivas preoperatorias y postoperatorias. Principalmente, se efectuó una búsqueda en EMBASE, CINAHL, Medline y Pubmed desde un comienzo hasta 04/19. La calidad de los artículos se evaluó siguiendo los criterios MINORS. RESULTADOS: De 789 artículos, 14 reunían los criterios de elegibilidad - 12 estudios observacionales prospectivos y 2 estudios retrospectivos. La mediana de la puntuación MINORS fue de 59,4 % (rango intercuartílico 23,4%). Siete estudios describieron la evaluación de medidas de QoL validadas antes y después de ARS en 148 niños. El seguimiento varió de 1 a 180 meses. Todos los estudios confirmaron mejorías significativas en medidas de QoL en los niños NN y NI en todos los puntos del seguimiento. Once estudios describieron sobre las investigaciones preoperatorias y postoperatorias en 507 niños. El seguimiento oscilaba de 0,5 a 180 meses. Nueve estudios confirmaron mejorías en el reflujo gastroesofágico utilizando la monitorización del pH esofágico de 24 horas +/- manometría, pero los resultados eran contradictorios en 3 estudios que evaluaron el vaciamiento gástrico. Ningún estudio describió de forma adecuada los datos de la fluoroscopia o endoscopia. CONCLUSIÓN: De los estudios identificados de baja o moderada calidad, en un seguimiento a corto y medio plazo, la ARS mejora la QoL y reduce la exposición del esófago al ácido en niños NN y niños NI. A pesar de que la ARS es una cirugía electiva habitual, es llamativa la falta de evaluaciones preoperatorias y postoperatorias rigurosas en la mayoría de los estudios de pacientes.

Aortopexy for the management of paediatric tracheomalacia - the Alder Hey experience.

BACKGROUND: Whilst aortopexy is an accepted and established procedure, there remains considerable heterogeneity within the literature, with inconsistencies in both the approach taken and the technique employed. Furthermore, limited data exist on both patient selection and long-term outcomes. This study aimed to report the experience of managing severe tracheomalacia by way of aortopexy in a large UK paediatric centre. METHOD: A retrospective case note review was conducted. Mean follow up was five years. RESULTS: Twenty-five patients underwent aortopexy for severe tracheomalacia caused by external vascular compression. Acute life-threatening events precipitated investigation in 72 per cent of cases. Twenty-one patients initially presented to ENT services for investigation, which comprised upper airway endoscopy and imaging with computed tomography angiography. Post-operatively, the majority of patients demonstrated complete resolution of symptoms and were discharged from all associated services. Only four patients required a tracheostomy. CONCLUSION: Aortopexy offers an effective method of treating severe tracheomalacia due to vascular compression.

Ovarian tumors in children: how common are lesion recurrence and metachronous disease? A UK CCLG Surgeons Cancer Group nationwide study.

BACKGROUND: Ovarian tumors in children are rare, mature teratoma being the most common histological entity. Robust guidelines to aid patient follow-up after resection are distinctly lacking. Although mature teratoma has a very good prognosis following complete resection, small studies have reported the occurrence of metachronous disease and recurrence to a variable degree (2.5-23% of patients). Nevertheless, there are surgeons who recommend no follow-up is required for these children after primary tumor resection. We investigated the incidence of (i) recurrence and (ii) metachronous disease in pediatric patients following ovarian tumor resection. METHODS: Retrospective multicenter study amongst UK pediatric surgical oncology centers. Females <16 years with diagnosis of ovarian tumor from 2006 to 2016 were included. Functional/neonatal ovarian cysts were excluded. RESULTS: Three hundred ten patients with ovarian tumors treated at 12 surgical oncology centers were identified. Mean age at surgery was 11 years [IQR 8-14]. Most common diagnosis were mature teratoma (57%, 177 cases), immature teratoma (10.9%, 34 cases) and serous cystadenoma (7.7%, 24 cases). 8.1% (25 cases) of all females were identified with tumor recurrence/ metachronous disease. 5.1% (9 cases) of patients with mature teratoma had recurrent/ metachronous disease. Most of these patients were diagnosed at routine clinic follow-up. CONCLUSION: Our study clearly shows that ovarian tumor recurrence(s) and metachronous disease occur, even in "benign" ovarian tumors. We recommend female pediatric patients should have robust follow-up care plans after primary diagnosis and resection of ovarian tumor(s). LEVEL OF EVIDENCE STATEMENT: This is a level II evidence study. It is a retrospective multicentre collaborative study which summarizes data from a national cohort of children.

Cellular memory of hypoxia elicits neuroblastoma metastasis and enables invasion by non-aggressive neighbouring cells.

Therapies targeting cancer metastasis are challenging owing to the complexity of the metastatic process and the high number of effectors involved. Although tumour hypoxia has previously been associated with increased aggressiveness as well as resistance to radio- and chemotherapy, the understanding of a direct link between the level and duration of hypoxia and the individual steps involved in metastasis is still missing. Using live imaging in a chick embryo model, we have demonstrated that the exposure of neuroblastoma cells to 1% oxygen for 3 days was capable of (1) enabling cell migration towards blood vessels, (2) slowing down their velocity within blood vessels to facilitate extravasation and (3) promoting cell proliferation in primary and secondary sites. We have shown that cells do not have to be hypoxic anymore to exhibit these acquired capabilities as a long-term memory of prior hypoxic exposure is kept. Furthermore, non-hypoxic cells can be influenced by neighbouring hypoxic preconditioned cells and be entrained in the metastatic progression. The acquired aggressive phenotype relies on hypoxia-inducible factor (HIF)-dependent transcription of a number of genes involved in metastasis and can be impaired by HIF inhibition. Altogether, our results demonstrate the need to consider both temporal and spatial tumour heterogeneity because cells can 'remember' an earlier environment and share their acquired phenotype with their close neighbours. As a consequence, it is necessary to monitor the correct hypoxic markers to be able to predict the consequences of the cells' history on their behaviour and their potential response to therapies.

Outcomes following prosthetic patch repair in newborns with congenital diaphragmatic hernia.

BACKGROUND: The anatomical defect in congenital diaphragmatic hernia (CDH) can usually be closed primarily but prosthetic patch repair may be required in newborns with a deficient diaphragm. High rates of patch failure and hernia recurrence (up to 50 per cent) have been reported. This study evaluated contemporary outcomes following patch repair of CDH at a UK paediatric surgical centre. METHODS: Medical records of newborns undergoing surgery for CDH between 1 February 1990 and 1 November 2010, and attending a multidisciplinary follow-up clinic, were examined. Operative details and patch utilization are reported. RESULTS: Of 118 newborns with CDH, 37 required a patch to the diaphragmatic defect. Gore-Tex® patches were used in 35 and biological Surgisis® patches in two. Eight babies additionally required an abdominal wall patch. Seven infants had an abdominal patch alone with primary diaphragm repair. A total of 102 infants (86·4 per cent) survived after surgery. Two early recurrences were both related to the use of biological patches, leading to revisional surgery with Gore-Tex® patch reconstruction. Diaphragmatic patch use was associated with a greater requirement for intensive cardiovascular and respiratory support, although there was no significant difference in mortality between patch versus primary diaphragm repair. The mortality rate was significantly higher among infants requiring abdominal wall patching (with or without a diaphragmatic patch): 40 per cent (6 of 15) versus 9·7 per cent (10 of 103) (P = 0·006). Postoperative survival rates for infants with a diaphragmatic patch alone, abdominal wall patch alone, and both abdominal and diaphragmatic patches were 86 per cent (25 of 29), 57 per cent (4 of 7) and 63 per cent (5 of 8) respectively. CONCLUSION: Prosthetic diaphragmatic hernia repair at this centre has a good outcome and low rate of recurrence (5 per cent). The recognition of an inadequate abdominal domain prenatally may additionally prove to be a useful marker for predicting increased mortality in newborns with CDH.

Use of a tissue expander as a radio-protective spacer with a latissimus dorsi flap in the management of a peripheral primitive neuroectodermal tumour (pPNET).

Peripheral primitive neuroectodermal tumours (pPNET) are aggressive neoplasms that require radical surgical resection with adjuvant chemotherapy and radiotherapy. A pPNET of the posterior chest wall was resected with wide soft tissue margins in a 14 year old male. Following tumour excision a spacer device was positioned in the retroperitoneum adjacent to the ipsilateral left kidney displacing it from the planned radiotherapy field. A pedicled latissimus dorsi myocutaneous flap was used to achieve robust soft tissue cover. Ultrasound demonstrated anteromedial displacement of the left kidney with no hydronephrosis and renal function remained normal during subsequent radiotherapy. This report highlights the usefulness of a tissue expander in providing protection for vital structures during radiotherapy.

Randomized clinical trial of glutamine-supplemented versus standard parenteral nutrition in infants with surgical gastrointestinal disease.

BACKGROUND: Addition of glutamine to parenteral nutrition in surgical infants remains controversial. The aim of this trial was to determine whether glutamine supplementation of parenteral nutrition in infants requiring surgery would reduce the time to full enteral feeding and/or decrease the incidence of sepsis and septicaemia. METHODS: A prospective double-blind multicentre randomized clinical trial was performed in surgical infants less than 3 months old who required parenteral nutrition. Patients were allocated to treatment or control groups by means of minimization. Infants received either 0·6 g per kg per day alanyl-glutamine (treatment group) or isonitrogenous isocaloric parenteral nutrition (control group) until full enteral feeding was achieved. Primary outcomes were time to full enteral feeding and incidence of sepsis. Cox regression analysis was used to compare time to full enteral feeding, and to calculate risk of sepsis/septicaemia. RESULTS: A total of 174 patients were randomized, of whom 164 completed the trial and were analysed (82 in each group). There was no difference in time to full enteral feeding or time to first enteral feeding between groups, and supplementation with glutamine had no effect on the overall incidence of sepsis or septicaemia. However, during total parenteral nutrition (before the first enteral feed), glutamine administration was associated with a significantly decreased risk of developing sepsis (hazard ratio 0·33, 95 per cent confidence interval 0·15 to 0·72; P = 0·005). CONCLUSION: Glutamine supplementation during parenteral nutrition did not reduce the incidence of sepsis in surgical infants with gastrointestinal disease. REGISTRATION NUMBER: ISRCTN83168963 (http://www.controlled-trials.com).

Exploitation of chick embryo environments to reprogram MYCN-amplified neuroblastoma cells to a benign phenotype, lacking detectable MYCN expression.

Neuroblastoma is a paediatric cancer that arises from the sympathetic ganglia (SG) or adrenal gland. Tumours that occur in patients under 18 months of age have a particularly good prognosis and frequently undergo spontaneous regression. This led to the hypothesis that developmental cues in the youngest patients may prompt belated differentiation and/or apoptosis of the tumour cells. To test our hypothesis, we have injected MYCN-amplified neuroblastoma cells into the extra embryonic veins of chick embryos at embryonic day 3 (E3) and E6 and analysed the response of these Kelly cells at E10 and E14. Amplification of the MYCN gene occurs in up to 30% of tumours and is normally associated with a very poor prognosis. Kelly cells injected at E3 follow neural crest pathways and integrate into neural locations such as SG and the enteric nervous system although never into the adrenal gland. Additionally they migrate to non-neural locations such as the heart, meninges, jaw regions and tail. The cells respond to their respective microenvironments and in SG, some cells differentiate, they show reduced cell division and crucially all cells have undetectable MYCN expression by E10. In non-neural locations, cells form more rapidly dividing clumps and continue to express MYCN. The downregulation of MYCN is dependent on continuous and direct interaction with the sympathetic ganglion environment. We propose that the MYCN-amplicon in the Kelly cells retains the ability to correctly interpret the environmental cues leading to downregulation of MYCN.

Value of liver herniation in prediction of outcome in fetal congenital diaphragmatic hernia: a systematic review and meta-analysis.

OBJECTIVES: Intrathoracic liver herniation (ILH) is being used to estimate prognosis and hence guide antenatal interventions in fetal congenital diaphragmatic hernia (CDH). However, the literature regarding its utility in this role is conflicting. This review systematically examines the currently available evidence of ILH use in fetal CDH. METHODS: MEDLINE and EMBASE databases were searched for the terms ((congenital diaphragmatic hernia) OR CDH) AND liver. Inclusion criteria were human case series of fetuses diagnosed with CDH using either ultrasound or magnetic resonance imaging. Included studies were required to have reported the antenatal liver position and the outcome (survival or not). Case reports, reviews and eventration series were excluded. Studies reporting similar cases from the same center over an overlapping time period were considered duplicates; only the larger of the studies were therefore included. Absolute totals were extracted and sums calculated. Fisher's exact test (FET) was used to compare survival rates in different groups. RESULTS: The original search retrieved 338 studies. Applying inclusion/exclusion criteria and removing duplicates left 21 case series in 20 studies. Retrieved studies differed in the definitions of liver herniation, survival and treatment modality. In total, there were 407 fetuses in the liver-up (herniated) and 303 in the liver-down (not herniated) groups. Survival rates were 45.4% and 73.9%, respectively. The difference was statistically significant (FET = 56.4, P < 0.005). Sensitivity analysis for cases that had only conventional postnatal treatment was still significant (FET = 52.8, P < 0.005). CONCLUSIONS: Liver herniation is associated with poorer prognosis in fetal CDH. Grading liver herniation or using it as part of a panel of markers may enhance the value of liver herniation as a prognostic test in fetal CDH.

Infections in gastroschisis: organisms and factors.

This study aimed to define the incidence, causative organisms and predisposing factors leading to infection related morbidity in newborns with gastroschisis. All gastroschisis patients admitted over the 5-year period (1999-2004) were retrospectively reviewed. Surveillance samples, wound, blood, urine and fecal cultures were analyzed. Duration of total parenteral nutrition, antibiotic therapy, feeding regimes and demographic data were also analyzed. Multiple logistic regression was employed using the SPSS system and p < 0.05 was considered as significant. Seventy-two neonates were identified with 53% having abnormal gut carriage mostly due to Enterobacter and Klebsiella. Wound infection occurred in 20% of cases. Abnormal gut carriage predisposed to the development of wound infection. Line sepsis occurred in 21% of neonates. Endogenous coagulase negative Staphylococcus caused 74% of septic episodes. There was no correlation between abnormal gut carriage and the development of line sepsis. Overall survival was 96%. The cause of infections in gastroschisis patients appears to be multifactorial. A multidisciplinary team can play an important role in reducing the incidence of infections. Strict aseptic protocols and auditing practice can be the invaluable tools in decreasing morbidity rates.