A Study of Safety and Effectiveness of Evicel Fibrin Sealant as an Adjunctive Hemostat in Pediatric Surgery.

INTRODUCTION: Data on the use of fibrin sealants to control intraoperative bleeding in children are scarce. Evicel Fibrin Sealant (Ethicon Inc., Raritan, New Jersey, United States) was found safe and effective in clinical trials of adults undergoing various surgery types. We evaluated the safety and efficacy of Evicel versus Surgicel Absorbable Hemostat (Ethicon Inc.) as adjunctive topical hemostats for mild/moderate raw-surface bleeding in pediatric surgery. METHODS: A phase III randomized clinical trial was designed as required by the European Medicines Agency's Evicel Pediatric Investigation Plan: 40 pediatric subjects undergoing abdominal, retroperitoneal, pelvic, or thoracic surgery were randomized to Evicel or Surgicel, to treat intraoperative mild-to-moderate bleeding. Descriptive analyses included time-to-hemostasis and rates of treatment success (4, 7, 10 minutes), intraoperative treatment failure, rebleeding, and thromboembolic events. RESULTS: Forty of 130 screened subjects aged 0.9 to 17 years were randomized 1:1 to Evicel or Surgicel. Surgeries were predominantly open abdominal procedures. The median bleeding area was 4.0 cm2 for Evicel and 1.0 cm2 for Surgicel. The median time-to-hemostasis was 4.0 minutes for both groups. The 4-, 7-, and 10-minute treatment success rates were 80.0% versus 65.0%, 100.0% versus 80.0%, and 95.0% versus 90.0%, whereas treatment failure rates were 5.0% versus 25.0%, for Evicel and Surgicel, respectively. No deaths or thrombotic events occurred. Re-bleeding occurred in 5.0% of Evicel and 10.0% of Surgicel subjects. CONCLUSIONS: In accordance with adult clinical trials, this randomized study supports the safety and efficacy of Evicel for controlling mild-to-moderate surgical bleeding in a broad range of pediatric surgical procedures.

Sacrococcygeal teratoma: Long-term outcomes. A UK CCLG Surgeons Group Nationwide Study.

AIM: Sacrococcygeal teratoma (SCT) is a rare paediatric germ cell tumour (1:40,000). Long-term data regarding urinary tract and bowel function after SCT resection is limited to few studies. A UK Children's Cancer and Leukaemia Group (CCLG) Surgeons multicentre study aimed to critically analyse long-term functional outcomes in patients following resection of SCT. METHODS: Nationwide study of UK paediatric surgical oncology centres using a standardised data collection form. All index cases of newborn infants and children <16 years with SCT diagnosis during 2005-2015 were included. RESULTS: 165 SCT patients treated at 14 UK paediatric surgical oncology centres were included. Median age at presentation was 1 day [interquartile range, IQR: 0-25]; median age at surgery was 10 days [IQR: 4-150]. One hundred seventeen (70%) were female and 48 (30%) male. Antenatal diagnosis was made in 44% index cases. Total 59% of patients were Altman Stage I or II lesions. Follow-up data were available in 83% cases. Tumour recurrence occurred in 13 (7%) patients at median age 13 months [IQR: 8.75-30 months]. Fifty-nine (36%) of 165 patients had documented adverse bladder or bowel dysfunction. Twenty-two (37%) cases required urinary clean intermittent catheterisation (CIC) urology health care, with eight patients (14%) needing operative intervention to control management of bowel dysfunction. CONCLUSION: This UK CCLG study showed 36% of SCT patients develop bladder or bowel dysfunction after primary tumour resection. Functional assessment of bladder and bowel function is mandatory during after-care follow-up of all SCT patients. A multidisciplinary care pathway, with surgeon speciality groups including surgical oncology, paediatric urology and paediatric colorectal specialists, is strongly advised to facilitate 'best practice' monitoring of long-term health and improve patient quality of life (QoL) into adulthood.

A Novel Standard for Systematic Reporting of Neuroblastoma Surgery: The International Neuroblastoma Surgical Report Form (INSRF): A Joint Initiative by the Pediatric Oncological Cooperative Groups SIOPEN∗, COG∗∗, and GPOH∗∗∗.

OBJECTIVE: To create the first structured surgical report form for NBL with international consensus, to permit standardized documentation of all NBL-related surgical procedures and their outcomes. SUMMARY OF BACKGROUND DATA: NBL, the most common extracranial solid malignant tumor in children, covers a wide spectrum of tumors with significant differences in anatomical localization, organ or vessel involvement, and tumor biology. Complete surgical resection of the primary tumor is an important part of NBL treatment, but maybe hazardous, prone to complications and its role in high-risk disease remains debated. Various surgical guidelines exist within the protocols of the different cooperative groups, although there is no standardized operative report form to document the surgical treatment of NBL. METHODS: After analyzing the treatment protocols of the SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology pediatric cooperative groups, important variables were defined to completely describe surgical biopsy and resection of NBL and their outcomes. All variables were discussed within the Surgical Committees of SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology. Thereafter, joint meetings were organized to obtain intercontinental consensus. RESULTS: The "International Neuroblastoma Surgical Report Form" provides a structured reporting tool for all NBL surgery, in every anatomical region, documenting all Image Defined Risk Factors and structures involved, with obligatory reporting of intraoperative and 30 day-postoperative complications. CONCLUSION: The International Neuroblastoma Surgical Report Form is the first universal form for the structured and uniform reporting of NBL-related surgical procedures and their outcomes, aiming to facilitate the postoperative communication, treatment planning and analysis of surgical treatment of NBL.

Successful management of anastomotic leakage with endoscopic fibrin glue injection after primary repair of pure oesophageal atresia.

Anastomotic leakage (AL) occurs in 15% of cases of primary repair of oesophageal atresia. Urgent surgery is indicated in cases of complete anastomotic separation or severe mediastinitis. Otherwise, conservative management including keeping the patient nil per os (NPO), feeding via transanastomotic tube and prolonged parenteral nutrition, has been widely accepted as it can avoid multiple surgeries in neonates and allow oesophageal continuity to be preserved. However, complications relating to prolonged feeding tube use are common downsides to this approach and the negative impact of prolonged NPO on mastication and swallowing function cannot be ignored.In this case report, a novel approach for the treatment of AL with fibrin glue is reported, following primary repair of oesophageal atresia. It was endoscopically injected into the leakage site to enhance healing and early closure. This procedure was safely performed and achieved early establishment of oral feeding.

Lung biopsy in children: when is it useful?

AIM: To provide a further insight into the usefulness of lung biopsy in children. METHODS: Lung biopsies in children from January 2007 to December 2017 were reviewed (n=39). The histology results were categorised as: definitive diagnosis, normal lung parenchyma, inconclusive. RESULTS: Lung biopsy provided a definitive diagnosis in 25 (64%) cases. A suspected diagnosis was confirmed in 16 (41%) and a new diagnosis was found in 9 (23%) children. Histology was inconclusive in 11 (28%) cases and normal in 3 (8%). Fifteen (38%) children had treatment altered due to the biopsy result. CONCLUSION: Lung biopsy mostly confirmed the suspected diagnosis and was associated with a low procedure related morbidity (n=1) and mortality (n=0). Importantly, the biopsy result identified a pathology which altered treatment in over one third of patients. However, in a number of cases the histology was inconclusive, therefore careful patient selection is recommended to maximise diagnostic yield.

Detection of Circulating and Disseminated Neuroblastoma Cells Using the ImageStream Flow Cytometer for Use as Predictive and Pharmacodynamic Biomarkers.

PURPOSE: Circulating tumor cells (CTCs) serve as noninvasive tumor biomarkers in many types of cancer. Our aim was to detect CTCs from patients with neuroblastoma for use as predictive and pharmacodynamic biomarkers. EXPERIMENTAL DESIGN: We collected matched blood and bone marrow samples from 40 patients with neuroblastoma to detect GD2 +/CD45- neuroblastoma CTCs from blood and disseminated tumor cells (DTCs) from bone marrow using the Imagestream Imaging flow cytometer (ISx). In six cases, circulating free DNA (cfDNA) extracted from plasma isolated from the CTC sample was analyzed by high-density single-nucleotide polymorphism (SNP) arrays. RESULTS: CTCs were detected in 26 of 42 blood samples (1-264/mL) and DTCs in 25 of 35 bone marrow samples (57-291,544/mL). Higher numbers of CTCs in patients with newly diagnosed, high-risk neuroblastoma correlated with failure to obtain a complete bone marrow (BM) metastatic response after induction chemotherapy (P < 0.01). Ex vivo Nutlin-3 (MDM2 inhibitor) treatment of blood and BM increased p53 and p21 expression in CTCs and DTCs compared with DMSO controls. In five of six cases, cfDNA analyzed by SNP arrays revealed copy number abnormalities associated with neuroblastoma. CONCLUSIONS: This is the first study to show that CTCs and DTCs are detectable in neuroblastoma using the ISx, with concurrently extracted cfDNA used for copy number profiling, and may be useful as pharmacodynamic biomarkers in early-phase clinical trials. Further investigation is required to determine whether CTC numbers are predictive biomarkers of BM response to first-line induction chemotherapy.

Neuroblastoma of the Urinary Bladder in an Infant.

As it originates from neural crest cells, Neuroblastoma (NBL) can arise anywhere along the sympathetic chain. However, its occurrence in the urinary bladder (UB) is extremely rare. We present a case of an incidentally diagnosed pelvic NBL arising from the dome of the UB in a 7-month-old infant. The mass was treated with surgical excision only after being classified as a very low risk group according to the International Neuroblastoma Risk Group staging system. The patient was disease free after 5 years of follow-up. Although rare, we suggest that NBL should be considered in the differential diagnosis of UB masses in children and investigated accordingly.

Gastrointestinal complications associated with the surgical treatment of heart disease in children.

BACKGROUND/PURPOSE: The gastrointestinal system is prone to complications following heart surgery. We sought to determine the incidence and factors associated with gastrointestinal complication after cardiac surgery in children. METHODS: A retrospective review of patients aged <16years that underwent cardiac surgery between 2009 and 2013. Primary outcome was occurrence of gastrointestinal complication within 30days. Multivariable logistic regression was performed to identify variables related to occurrence of gastrointestinal complication. Patients with gastrointestinal complication were matched with controls and postoperative lengths of stay compared. RESULTS: Eight hundred eighty-one children underwent 1120 cardiac surgical procedures. At time of operation, 18% were neonates and 39% were infants. Cardiopulmonary bypass was used in 79%. Of 1120 procedures, 31 (2.8% [95% CI 2.0-3.9%]) had gastrointestinal complication. Necrotizing enterocolitis accounted for 61% of complications. Of patients with gastrointestinal complication, 87% survived to hospital discharge. Gastrointestinal complication was associated with preoperative co-morbidity (OR 2.2 [95% CI 1.02-4.8]) and univentricular disease (OR 2.5 [95% CI 1.1-5.5]). Neonates had the highest risk of gastrointestinal complication. Patients with gastrointestinal complications had longer hospital stays than controls (median difference, 13days [95% CI 3-43]). CONCLUSIONS: Serious gastrointestinal complications are uncommon but associated with longer hospital stay. Neonates with univentricular disease and preoperative comorbidity are at highest risk. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: II.

Aortopexy as treatment for tracheo-bronchomalacia in children: an 18-year single-center experience.

OBJECTIVES: To define the factors influencing the outcome of aortopexy as management of tracheo-bronchomalacia. DESIGN: A retrospective, single-center, observational, cohort study. SETTINGS: Surgical services in a tertiary care hospital. PATIENTS: One hundred five children who underwent an aortopexy for tracheo-bronchomalacia between 1990 and 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Comorbidity (categorized into three groups), surgical approach, and location of malacia were reviewed and analyzed in relation to mortality, need for a second intervention, complications, time to extubation after surgery, intensive care unit stay, and clinical improvement. Median age at surgery was 24 wks (1 wk-541 wks). Two surgical approaches were used: median sternotomy (n = 46) and left anterior parasternal (n = 59). Long-term (>2 yrs) follow-up was available for 73 patients (median = 7.0 yrs [2-18 yrs]); 73% were asymptomatic, 18% had minor symptoms, and 9% needed either ventilation or tracheostomy. The overall mortality rate was 9%, of which one-third was airway-related. Multivariable analysis revealed that major comorbidities were a significant risk factor both for mortality and the need for further procedures (re-do surgery, tracheostomy, internal stents) in contrast to surgical approach and involvement of the bronchus. Intensive care unit stay and days of ventilation after surgery were also significantly higher in patients with major comorbidities. CONCLUSIONS: Aortopexy proved to be an effective treatment for most cases of tracheo-bronchomalacia, but major comorbidity was associated with an adverse outcome. Our data suggest that aortopexy should be considered in most cases of severe tracheo-bronchomalacia.

Tracheomegaly: a complication of fetal endoscopic tracheal occlusion in the treatment of congenital diaphragmatic hernia.

BACKGROUND: Fetal endoscopic tracheal occlusion (FETO) is a promising treatment for severe congenital diaphragmatic hernia, a condition that carries significant morbidity and mortality. It is hypothesised that balloon occlusion of the fetal trachea leads to an improvement in lung growth and development. The major documented complications of FETO to date are related to preterm delivery. OBJECTIVE: To report a series of five infants who developed tracheomegaly following FETO. MATERIALS AND METHODS: Review of all children referred with tracheomegaly to the paediatric intensive care and tracheal service at two referral centres. RESULTS: Five neonates presented with features of respiratory distress shortly after birth and were subsequently found to have marked tracheomegaly. Two neonates had tracheomalacia in addition. CONCLUSION: There are no previous reports in the literature describing tracheomalacia, or more specifically, tracheomegaly, as a consequence of FETO. We propose that the particularly compliant fetal airway is at risk of mechanical damage from in utero balloon occlusion. This observation of a new problem in this cohort suggests a thorough evaluation of the trachea should be performed in children who have had FETO in utero. It may be that balloon occlusion of the trachea earlier in utero (before 26 weeks' gestation) predisposes to this condition.

Aortopexy for persistent tracheal obstruction after double aortic arch repair.

Persistent respiratory symptoms often occur after double aortic arch (DAA) repair but rarely require a second operation. We report 4 children with severe respiratory problems (failure to extubate, 2; severe respiratory distress, 2) caused by severe tracheomalacia and tracheal compression after DAA repair, treated by anterior aortopexy. Aortopexy proved effective and safe in improving symptoms and provides a simple treatment option for children with severe malacia or tracheal compression after DAA repair.

Patterns of expression of retinoic acid receptor beta 2 (RAR-beta2)-LacZ reporter gene in the embryonic foregut.

Vitamin A and its active form retinoic acid (RA) are essential for normal embryonic development. Maternal vitamin A deficiency in experimental animals is known to produce various developmental anomalies including foregut malformations and lung hypoplasia. However, there is a little known about the role of RA receptors in the developing foregut. Our aim was to study the pattern of expression of retinoic acid receptor beta 2 (RAR-beta2) in the region of the foregut during the early stages of embryonic development. Normal mouse embryos homozygous for the lacZ-fused RAR-beta2 promoter transgene were studied to detect the expression of RAR-beta2 in the embryonic foregut. Transverse and sagittal sections of the embryos were taken at the region of the foregut to observe for The normal pattern of expression of RARbeta2-LacZ between 9.5-12.5 days post conception. RAR-beta2-LacZ was expressed in the foregut tube on 9.5 and 10.5 dpc, mainly in the oesophageal part and maximally in the region of tracheo-oesophageal fold formation. This expression faded on day 11.5, and was not seen on 12.5 dpc. The change of RAR-beta2 expression between 9.5-11.5 dpc coincided with the time of tracheo-esophageal separation of the foregut. Our study has shown a possible RA-driven genetic activity during embryonic foregut development.

Midgut malrotation and associated Hirschsprung's disease: a diagnostic dilemma.

Malrotation and Hirschsprung's disease (HSD) are rarely reported together. We report our experience with three patients who presented during the neonatal period in whom the association resulted in diagnostic difficulty. In this report, we focus on the clinical presentation, diagnosis and appropriate management.

In vitro effects of adriamycin: a dose-response study.

The in vivo effects of adriamycin (ADR) on the mouse and rat embryos are well described in the literature. However, there is a lack of knowledge about the in vitro effects of ADR. The aim of this study was to investigate the effects of ADR on the developing mouse embryo and to identify a dose of ADR, which could be used for further studies of ADR effects in vitro. CD1 mouse embryos were collected at day 8.5 post conception. They were cultured in the presence of different doses of ADR (0, 125, 250, 375 and 500 microM). After 24 h, the culture was stopped and the embryos (n = 77) were scored morphologically using the Brown-Fabro scoring system and the mean score for each organ was calculated. Dose-response plots were generated and the effective dose 50 (ED50) for each organ was identified from the plots. The effects of ADR on the developing embryo were found to be dose related and there is a dose-response relationship in most of the plots. The dose-response plots were found to be parallel for some organs. A dose of 250 microM ADR was identified as the appropriate dose for further in vitro studies. The effects of ADR on the embryos were dose related and there is a dose-response relationship in most of the developing systems. The presence of parallel dose-response plots for some regions is suggestive of similar mechanism of action of ADR on these regions. A dose of 250 microM of ADR was identified for the first time in the literature and could be used for further studies of the effects of ADR on the mouse foregut in vitro.

Sacrococcygeal teratoma--a 25-year experience in a UK regional center.

BACKGROUND: Sacrococcygeal teratoma (SCT) is uncommon (1:35,000-1:40,000 newborns). We report a 25-year single-center experience with a focus on late effects. METHODS: Surgical and tumor registries identified patients with SCT between 1977 and 2001. Perinatal data, associated anomalies, operative findings, histology, and survival were recorded. Continence was assessed clinically. Urodynamics and anorectal manometry were performed as indicated. RESULTS: Thirty-three patients (28 females) were treated for SCT. Before 1988, 2 of 18 were diagnosed antenatally compared with 8 of 15 between 1988 and 2001. Ten babies were delivered by cesarean birth. Seven children presented after the neonatal period. Surgery comprised tumor excision with coccygectomy. Histology was benign in 26 (79%), malignant in 6 (18%), and immature in a single patient. Presentation beyond the newborn period was associated with malignant disease and poorer outcome. Overall survival was 94%. Neuropathic bladder or bowel disturbance was identified in 7 of 20 patients on long-term follow-up. CONCLUSIONS: Antenatal diagnosis of SCT appears to be increasing. Parental counseling should include the continence problems that may follow removal of even benign tumors. Resection by surgical oncologists and reconstruction by colorectal specialists may improve function. Follow-up by oncologists, surgeons, and urologists remains an important part of SCT management.