Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism-The UK Perspective.

Context: In focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic ß-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery. Objective: We describe surgical and nonsurgical outcomes of focal CHI in a national cohort. Methods: Patients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018. Results: Of 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose. Conclusion: Despite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management.

Case report: contradictory genetics and imaging in focal congenital hyperinsulinism reinforces the need for pancreatic biopsy.

BACKGROUND: Congenital Hyperinsulinism (CHI) is an important cause of severe hypoglycaemia in infancy due to excessive, dysregulated insulin secretion. In focal CHI, a localised lesion within the pancreas hypersecretes insulin and, importantly, hypoglycaemia resolution is possible through limited surgical resection of the lesion. Diagnosis of focal CHI is based on a crucial combination of compatible genetics and specialised imaging. Specifically, a focal lesion arises due to a paternal mutation in one of the ATP-sensitive potassium channel genes, KCNJ11 or ABCC8, in combination with post-zygotic loss of maternal heterozygosity within the affected pancreatic tissue. 6-[18F]Fluoro-L-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET)/computed tomography (CT) imaging is used to detect and localise the lesion prior to surgery. However, its accuracy is imperfect and needs recognition in individual case management. CASE PRESENTATION: We report the case of an infant with hypoglycaemia due to CHI and a paternally inherited KCNJ11 mutation, c.286G > A (p.Ala96Thr), leading to a high probability of focal CHI. However,18F-DOPA PET/CT scanning demonstrated diffuse uptake and failed to conclusively identify a focal lesion. Due to unresponsiveness to medical therapy and ongoing significant hypoglycaemia, surgery was undertaken and a small 4.9 × 1.7 mm focal lesion was discovered at the pancreatic neck. This is the second case where this particular KCNJ11 mutation has been incorrectly associated with diffuse 18F-DOPA uptake, in contrast to the correct diagnosis of focal CHI confirmed by pancreatic biopsy. CONCLUSIONS: Identifying discrepancies between genetic and imaging investigations is crucial as this may negatively impact upon the diagnosis and surgical treatment of focal CHI. This case highlights the need for pancreatic biopsy when a strong suspicion of focal CHI is present even if 18F-DOPA imaging fails to demonstrate a discrete lesion.

Operative management of pediatric ovarian tumors and the challenge of fertility-preservation: Results from the UK CCLG Surgeons Cancer Group Nationwide Study.

BACKGROUND: Ovarian tumors in the pediatric age group are rare. A significant number of children with ovarian mass lesions present "out of hours "as surgical emergencies, and surgical management does not always involve a surgical oncologist. This multicenter study reports how the mode of clinical presentation may influence (i) operation (conventional open vs minimally invasive surgery (MIS)) and (ii) examines if young females presenting as surgical emergency(s) are more likely to undergo total oophorectomy or ovarian sparing surgery. 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 cystadenoma (12%, 36 cases). Seventy percent (217) of cases were performed as open procedures. Thirty percent (94) of children underwent MIS. Tumors were significantly smaller in children who underwent MIS. Median tumor size in the laparoscopic group was 6 cm compared to 11 cm in the open group (p < 0.00001). Children who underwent MIS were significantly more likely to have ovary sparing surgery. CONCLUSION: This UK nationwide study demonstrates that ovary-sparing surgery and minimally invasive surgery are still infrequently deployed by pediatric surgeons in the UK. Patients with smaller tumors were more likely to undergo MIS, and more frequently underwent ovary-sparing surgery. In view of the implications on fertility and hormonal health caused by unilateral oophorectomy, it is time to review this current practise and agree consensus guidelines to reduce rates of unnecessary oophorectomy. 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.

Manchester Arena bombing: lessons learnt from a mass casualty incident.

On 22 May 2017 Salman Abedi detonated an improvised explosive device in the Manchester Arena resulting in 23 deaths (including the attacker). This was the deadliest terrorist attack on UK soil since the 2005 London bombings, but was only one of five mass casualty terrorist attacks in the UK in 2017. Preparation for mass casualty incidents (MCI) is obligatory, involving such methods as multiagency tabletop exercises, mock hospital exercises, as well as simulation and training for clinicians in managing the injuries that would be anticipated in such an event. Even in the best prepared units, such an incident will pose significant challenges due to the unpredictable nature of these events with respect to timing and number of casualties. Following an MCI, local and national reviews are undertaken to assess the effectiveness of the response, but also to identify areas where lessons can be learnt and to disseminate these to allow inclusion in future planning. We present the experience following a mass casualty terrorist incident along with a number of lessons learnt from this event.

Paediatric Horner's syndrome: is investigation for underlying malignancy always required?

OBJECTIVE: Horner's syndrome (HS) is characterised by a triad of ocular miosis, ptosis and anhidrosis. HS may be a subtle sign of occult pathology in otherwise asymptomatic children, neuroblastoma (NBL) being the the most common associated malignant tumour. Despite such knowledge, the incidence of underlying malignancy in children with HS remains unclear and robust evidence to guide best clinical practice is sparse. We performed a systematic review of the literature with the aim of identifying the incidence of NBL in children with HS of unknown aetiology, and establishing if screening for NBL should be routinely performed in this patient population. METHODS: Systematic review of the literature (PubMed and Ovid/Medline database, 1961-2018). RESULTS: The initial search identified 334 manuscripts, of which 8 studies were included in the final analysis. All reports were single-centre retrospective studies without control groups and included a total of 152 patients (age range 0-20 years). All studies investigated patients with HS but without previously established diagnosis. In the studies included, 17 out of a total of 152 patients were diagnosed with a space-occupying lesion. 12 out of the 152 patients were subsequently detected with NBL. CONCLUSION: HS in children may be the first sign of occult malignancy. We report the first systematic review that comprehensively investigates the incidence of malignancy in this unique patient cohort. We show that HS of unknown aetiology in children warrants further investigation(s) to exclude an underlying space-occupying lesion. This should include cross-sectional imaging of the brain, neck and thorax, plus urinary catecholamines for prompt diagnosis and treatment.

Outcome and prognostic factors in pediatric malignant peripheral nerve sheath tumors: An analysis of the European Pediatric Soft Tissue Sarcoma Group (EpSSG) NRSTS-2005 prospective study.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are rare tumors of childhood. The role of standard chemotherapy in unresectable MPNST is still unclear. We report the outcome and prognostic factors in the EpSSG risk-adapted prospective study for localized pediatric MPNST. METHODS: Patients were stratified into four treatment groups defined by surgical resection, tumor size, and tumor grade (G): (a) surgery-only group-resected tumors G1; (b) adjuvant radiotherapy group-R0/R1, G2 tumors; (c) adjuvant chemotherapy group-R0/R1, G3 tumors; and (d) neoadjuvant chemotherapy group-R2 resected tumors and/or nodal involvement. Chemotherapy consisted of four courses of ifosfamide-doxorubicin and two courses of ifosfamide concomitant with radiotherapy (50.4-54 Gy). RESULTS: Overall, the study included 51 patients. The 5-year event-free survival (EFS) and overall survival (OS) were 52.9% (95% confidence interval, 38.1-65.8) and 62.1% (46.7-74.3), respectively. The 5-year EFS was 92% (56.6-98.9) for treatment group 1 (N = 13), 33% (0.9-77.4) for treatment group 2 (N = 4), 29% (4.1-61.2) for treatment group 3 (N = 7), and 42% (23.1-60.1) for treatment group 4 (N = 27). Response rate to chemotherapy (partial response + complete response) in patients with measurable disease was 46%. The presence of neurofibromatosis type 1 (NF1; 51% of patients) was an independent poor prognostic factor for OS and EFS. CONCLUSION: The outcome for patients with resectable MPNST was excellent. Standard ifosfamide-doxorubicin for unresectable MPNST rendered the best reported outcome. Children with NF1 disease seem to have worse prognosis.

Transanastomotic tubes reduce the cost of nutritional support in neonates with congenital duodenal obstruction.

PURPOSE: To determine the impact of intra-operative Trans-anastomotic Tube (TAT) placement on the cost of post-operative nutrition in infants with congenital duodenal obstruction (CDO). METHODS: A retrospective analysis of patients undergoing corrective surgery for CDO, with birth-weight over 1.5 kg over a 10-year period. Data are presented as median (inter-quartile range) and analysed with Mann-Whitney U test and Fisher's exact test as appropriate. RESULTS: 59 patients were included. There was no difference between TAT and non-TAT groups for baseline characteristics, age at operation and abnormality. In the TAT group there was a significant reduction in the duration of post-operative parenteral nutrition (PN) [6 (0-11) vs 12 (8-19) days, p = 0.006], the cost of PN [£750 (0-1375) vs £1500 (1000-2375), p = 0.006] and the total cost of nutrition [£765.26 (38.36-1404) vs £1387.52 (1008.23-2363.08), p = 0.015], thereby demonstrating a median cost saving of £622.26 per patient. 14% experienced TAT displacement but no other TAT complications were encountered. CONCLUSION: The use of a TAT is a safe and effective way to reduce the duration of PN required in patients with CDO. This infers a significant cost saving per patient, a factor that cannot be overlooked in this period of austerity.

Clinical Diversity in Focal Congenital Hyperinsulinism in Infancy Correlates With Histological Heterogeneity of Islet Cell Lesions.

Background: Congenital Hyperinsulinism (CHI) is an important cause of severe and persistent hypoglycaemia in infancy and childhood. The focal form (CHI-F) of CHI can be potentially cured by pancreatic lesionectomy. While diagnostic characteristics of CHI-F pancreatic histopathology are well-recognized, correlation with clinical phenotype has not been established. Aims: We aimed to correlate the diversity in clinical profiles of patients with islet cell organization in CHI-F pancreatic tissue. Methods: Clinical datasets were obtained from 25 patients with CHI-F due to ABCC8/KCNJ11 mutations. 18F-DOPA PET-CT was used to localize focal lesions prior to surgery. Immunohistochemistry was used to support protein expression studies. Results: In 28% (n = 7) of patient tissues focal lesions were amorphous and projected into adjoining normal pancreatic tissue without clear delineation from normal tissue. In these cases, severe hypoglycaemia was detected within, on average, 2.8 ± 0.8 (range 1-7) days following birth. By contrast, in 72% (n = 18) of tissues focal lesions were encapsulated within a defined matrix capsule. In this group, the onset of severe hypoglycaemia was generally delayed; on average 46.6 ± 14.3 (range 1-180) days following birth. For patients with encapsulated lesions and later-onset hypoglycaemia, we found that surgical procedures were curative and less complex. Conclusion: CHI-F is associated with heterogeneity in the organization of focal lesions, which correlates well with clinical presentation and surgical outcomes.

Controversies in the management of ovarian tumours in prepubertal children - A BAPS and UK CCLG Surgeons Cancer Group National Survey.

BACKGROUND: No clear treatment and follow-up protocols have been established for prepubertal patients with ovarian tumours. The lack of adequate prospective data in the literature includes all aspects of their management. A significant number of children with ovarian masses present out of hours as a surgical emergency and are initially managed by paediatric surgeons without special interest in surgical oncology. Clear guidance on the management of such tumours is therefore fundamental. We hypothesised that - owing to the lack of clear guidelines - the current approach to prepubertal ovarian tumours amongst paediatric surgeons is highly heterogenous. METHODS: An eleven-item multiple choice questionnaire was distributed amongst all BAPS consultant paediatric surgeons in the UK and simultaneously to all paediatric surgical oncology members of the UK Children's Cancer and Leukaemia Group in order to survey the management of ovarian masses in children. We aimed to compare the management approaches in both groups. RESULTS: 63 consultants participated in the survey; 49% with a special interest in surgical oncology, 48% with different subspecialty interests. The majority of participants (56%) performed 1-5 operations on ovarian tumours per year. Preoperative imaging of choice for the oncology surgeons was US and MRI (77.3%) versus 41.4% in the group of surgeons with different special interests. Surgeons with different special interests were more likely to request Ca125 as a preoperative tumour marker (62.1% vs 32.3%). 19.3% of oncology surgeons, and 27.6% of surgeons with other special interest stated they would never remove an ovarian tumour via the laparoscopic approach. Follow-up practise was highly variable amongst survey participants in both surgeon groups regarding frequency, duration and further investigations during follow-up. Almost 50% of participants follow their patients up according to personal practice protocols. CONCLUSION: This first national survey on the management of prepubertal ovarian tumours demonstrates great heterogeneity in the current approach amongst UK paediatric surgeons. Better evidence is needed to formulate clear guidance for the management of such tumours. We propose instigation of a multicentre registry for ovarian tumours to generate prospective data and clarify guidance for the future. LEVEL OF EVIDENCE STATEMENT: This is a level II evidence study. In itself it is a retrospective study, with the literature review including one large, high-quality prospective cohort study, and further prospective cohort studies of ordinary quality.

Mortality and morbidity in oesophageal atresia.

BACKGROUND: Several classification systems exist to predict mortality in oesophageal atresia, the most widely quoted of these being over 20 years old. No classification system exists to predict morbidity. We sought to test whether these classification systems remain relevant and to determine whether they can be useful to predict morbidity. In addition, we aimed to identify independent risk factors for predicting mortality and morbidity. METHODS: Neonates presenting with oesophageal atresia over a 20-year period (1990-2010) were retrospectively reviewed. Discriminative statistical analysis compared the performance of current classification systems. Stepwise logistic regression analysis of the influence of perioperative risk factors on mortality and duration of ventilatory support and intensive care unit stay were performed. RESULTS: All classification systems predicted mortality in this series of 248 neonates. Birth weight, cardiac anomalies and pre-operative pneumonia were independent risk factors for predicting mortality in oesophageal atresia. The Waterston classification is the most useful classification for predicting post-operative morbidity in terms of length of hospital stay and time spent ventilated. CONCLUSION: Despite advances in the neonatal care of the very low birth weight infant and those with congenital cardiac disease, these conditions remain relevant in predicting mortality and morbidity in oesophageal atresia.

Atypical Forms of Congenital Hyperinsulinism in Infancy Are Associated With Mosaic Patterns of Immature Islet Cells.

Objectives: We aimed to characterize mosaic populations of pancreatic islet cells from patients with atypical congenital hyperinsulinism in infancy (CHI-A) and the expression profile of NKX2.2, a key transcription factor expressed in ß-cells but suppressed in δ-cells in the mature pancreas. Patients/Methods: Tissue was isolated from three patients with CHI-A following subtotal pancreatectomy. CHI-A was diagnosed on the basis of islet mosaicism and the absence of histopathological hallmarks of focal and diffuse CHI (CHI-D). Immunohistochemistry was used to identify and quantify the proportions of insulin-secreting ß-cells and somatostatin-secreting δ-cells in atypical islets, and results were compared with CHI-D (n = 3) and age-matched control tissues (n = 3). Results: In CHI-A tissue, islets had a heterogeneous profile. In resting/quiescent islets, identified by a condensed cytoplasm and nuclear crowding, ß-cells were reduced to <50% of the total cell numbers in n = 65/70 islets, whereas δ-cell numbers were increased with 85% of islets (n = 49/57) containing >20% δ-cells. In comparison, all islets in control tissue (n = 72) and 99% of CHI-D islets (n = 72) were composed of >50% ß-cells, and >20% δ-cells were found only in 12% of CHI-D (n = 8/66) and 5% of control islets (n = 3/60). Active islets in CHI-A tissue contained proportions of ß-cells and δ-cells similar to those of control and CHI-D islets. Finally, when compared with active islets, quiescent islets had a twofold higher prevalence of somatostatin/NKX2.2+ coexpressed cells. Conclusions: Marked increases in NKX2.2 expression combined with increased numbers of δ-cells strongly imply that an immature δ-cell profile contributed to the pathobiology of CHI-A.

Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease.

OBJECTIVES: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation. METHODS: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly. RESULTS: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation. CONCLUSIONS: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.

Non-cross-linked porcine acellular dermal matrix (Strattice Tissue Matrix) in pediatric reconstructive surgery.

BACKGROUND: A variety of prosthetic materials are used in the pediatric population for abdominal and chest wall reconstruction. Pediatric experience of non-cross-linked porcine acellular dermal matrix is limited to patients following liver transplantation. We review our outcomes in patients in whom this matrix was used. METHODS: A retrospective analysis of patients who underwent abdominal and chest wall reconstruction with a non-cross-linked porcine acellular dermal matrix (Strattice TM) was performed to assess clinical outcomes. RESULTS: The tissue matrix was used in thirteen patients over a three-year period. Eleven had abdominal wall reconstruction and two underwent chest wall reconstruction. Seven procedures were contaminated at the time of surgery. Median age at insertion was 8.1years (5days-18years) with a median weight of 20.6kg (1.9kg-99kg). The tissue matrix failed in one patient with no unanticipated adverse events. CONCLUSION: Future growth and need for reoperation requires special consideration in pediatric patients undergoing abdominal or thoracic wall reconstruction. Non-cross-linked porcine acellular dermal matrix can be safely used for abdominal and chest wall reconstruction in the pediatric population with a number of advantages over previously utilized materials. In our study, children have a favorable risk profile as compared to published adult series.

Nematode infection mimicking paratesticular malignancy.

Paratesticular swellings pose a diagnostic dilemma due to concerns over malignancy. We present a case of paratesticular swelling in a 13-year-old boy as a result of Dirofilaria immitis infection. The boy presented with a 2-month history of right testicular discomfort associated with an irregular mass within the scrotum.

Granular hemostat deposits mimicking disseminated malignancy.

Hemostatic matrices are a part of the surgeon's armamentarium against profuse intraoperative bleeding. Granular deposits may form after the use of a liquid hemostat which can be mistaken for tumor recurrence or metastatic disease in the setting of neoplasia. We present two cases that highlight the importance of full knowledge of product usage during previous operations and the need for histological examination of these lesions.

Laparoscopic orchidopexy in boys with prune belly syndrome--outcome and technical considerations.

BACKGROUND AND PURPOSE: Cryptorchidism is an ubiquitous feature in prune belly syndrome (PBS). Laparoscopic orchidopexy allows dissection of the spermatic cord with minimal morbidity. We discuss the technical difficulties and outcome of three boys with PBS who underwent two-stage laparoscopic Fowler-Stephens orchidopexy (F-SO). PATIENTS AND METHODS: Three boys, ages 1, 2, and 4, underwent laparoscopic F-SO. All boys had viable testes that were found within 3 cm of the deep inguinal ring. The testicular vessels were either ligated bilaterally with 4/0 polyglactin or monopolar diathermy was used and the vessels divided. Bilateral second-stage F-SO was performed within 6 months in two boys and limited to one side in the third boy. One boy awaits the contralateral second stage. RESULTS: All three boys have adequately sized gonads. Based on our experience, the port incisions should be smaller than routine practice to prevent air leak in PBS. Although the intra-abdominal pressure of 12 mm Hg did not vary from our normal practice, a high flow rate is necessary after initial insufflation (6 L/min) to compensate for inevitable gas leaks because the abdominal wall is so thin. Risk of diathermy injury to the thin abdominal wall and the vessels is significant. Laparoscopy enables easy visualization of the ureter, testes, and testicular vessels and permits complete dissection of testicular vessels. It is easier to maintain integrity of spermatic vessels. CONCLUSION: Use of radially expanding trocars, small incisions, and high gas flow rates permit this procedure to be performed safely with good outcome and cosmetic results in this challenging group of boys.

Laparostomy closure in stage 4S neuroblastoma.

Laparostomy in children is a rare procedure, and there is little in the literature as to the best method for closure in children with an open abdomen. We describe 2 cases with stage 4S neuroblastoma that required emergency decompressive laparostomy. Both cases highlight advantages and disadvantages with known techniques for achieving skin and fascia closure. We believe this to be the first report of a combination of extracellular matrix mesh and vacuum therapy for successful fascial and skin closure in stage 4S neuroblastoma.

Negative exploration for pyloric stenosis--is it preventable?

BACKGROUND: The diagnosis of infantile hypertrophic pyloric stenosis (IHPS), although traditionally clinical, is now increasingly dependent on radiological corroboration. The rate of negative exploration in IHPS has been reported as 4%. The purpose of our study was to look at elements of supportive clinical evidence leading to positive diagnosis, and to review these with respect to misdiagnosed cases undergoing negative exploration. METHODS: All infants undergoing surgical exploration for IHPS between January 2000 and December 2004 were retrospectively analysed with regard to clinical symptoms, examination findings, investigations and operative findings. RESULTS: During the study period, 343 explorations were performed with a presumptive diagnosis of IHPS. Of these, 205 infants (60%) had a positive test feed, 269 (78%) had a positive ultrasound scan and 175 (55%) were alkalotic (pH >or=7.45 and/or base excess >or=2.5). The positive predictive value for an ultrasound (US) diagnosis was 99.1% for canal length >or=14 mm, and 98.7% for muscle thickness >or=4 mm. Four infants (1.1%) underwent a negative surgical exploration; Ultrasound was positive in 3, and negative in 1(who underwent surgery on the basis of a positive upper GI contrast). One US reported as positive had a muscle thickness <4 mm. Two false positive US were performed at peripheral hospitals. One infant had a false positive test feed following a positive ultrasound diagnosis. Two infants had negative test feeds. CONCLUSION: A 1% rate of negative exploration in IHPS compares favourably with other studies. However potential causes of error were identified in all 4 cases. Confident diagnosis comprises a combination of positive test feed and an 'in house US' in an alkalotic infant. UGI contrast study should not be used in isolation to diagnose IHPS. If the test feed is negative, strict diagnostic measurements should be observed on US and the pyloric 'tumour' palpated on table under anaesthetic before exploration.