Complication rate after gastrostomy placement in children can be reduced by simple surgical steps.

AIM: To evaluate if the incidence of postoperative complications after gastrostomy placement is correlated to perioperative parameters or patient characteristics. METHODS: In this prospective observational study, children <18 years of age planned to receive a gastrostomy at partaking clinics between 2014 and 2019 were invited. Pre-, peri- and postoperative variables were collected and followed up 3 months postoperatively. RESULTS: Five hundred and eighty-two patients were included (median age: 26 months, median weight: 10.8 kg), mainly laparoscopic (52.0%) and push-PEG (30.2%) technique used. The incidence of complications was lower in the group of patients receiving a gastrostomy tube that was 2 mm longer than the gastrostomy canal (p < 0.001-0.025), and a thickness of 12 Fr (p < 0.001-0.009). These findings were confirmed by multivariate analysis also including operative technique, age and weight. Patients with oncological disease had significantly higher incidence of pain and infection but the lowest incidence of granulomas (p < 0.001-0.01). CONCLUSION: This study indicates that a 12 Fr gastrostomy tube that is 2 mm longer than the gastrostomy canal is correlated with the lowest incidence of postoperative complications the first 3 months after surgery. Oncological patients had the lowest incidence of granulomas which probably is related to chemotherapy.

Resolving the biological paradox of aneurysm formation in children with tuberous sclerosis complex.

Aortic aneurysms are rare manifestations in children with tuberous sclerosis complex (TSC) with life threating implications. Although an association between TSC, aortic and other aneurysms has been recognized, mechanistic insights explaining the pathophysiology behind aneurysm development and genetic aberrations in TSC have so far been lacking. Here, we summarize existing knowledge on aneurysms in TSC and present a case of a 2-year-old boy with an infrarenal aortic aneurysm, successfully treated with open aortic reconstruction. Histologic examination of the excised aneurysm wall showed distortion of vessel wall structure with loss of elastin and a pathologic accumulation of smooth muscle cells. Until now, these pathologic features have puzzled researchers as proliferating smooth muscle cells would rather be expected to preserve vessel wall integrity. Recent reports exploring the biological consequences of the dysregulated intracellular signaling pathways in patients with TSC provide plausible explanations to this paradox, which may support the development of future therapeutic strategies.

A dynamic mutational landscape associated with an inter-regionally diverse immune response in malignant rhabdoid tumour.

Malignant rhabdoid tumour (MRT) is a childhood neoplasm of high malignancy characterised by biallelic mutation and/or loss of the epigenetic master regulator SMARCB1, accompanied by no or few other oncogenic drivers. In spite of their generally low mutational burden, an intratumoural T-cell response has been reported in a subset of MRTs, indicating that immune checkpoint inhibition may be considered a viable therapy option for some patients. We assess here the evolution over time and space of predicted neoantigens and indicators of immune checkpoint status in two MRT patients who progressed under treatment. Both patients showed an accumulation of novel clonal and subclonal mutations, including predicted neoantigens, in metastases compared to their inferred ancestral clones in the primary tumours. The first patient had peritoneal metastases from an MRT of the liver. Clonal deconvolution revealed polyclonal seeding from the primary tumour to a single metastatic site, followed by a local subclonal burst of mutations. The second patient had a renal MRT with multiple pulmonary metastases, each of which could be traced back to a single genetically unique founder cell, with formation of novel subclones in two metastases. Both patients showed a regionally heterogeneous landscape of predicted neoantigens and of tumour-infiltrating lymphocytes expressing CD8 and PD1. In both patients, some tumour regions fulfilled established criteria for PD-L1 positivity (> 1% of tumour cells), while others did not. This suggests that even in a tumour type like MRT, with a single driver mutation, there can be heterogeneity in neoantigen repertoire, immune response, and biomarkers for checkpoint blockade among sampled locations. This must be taken into account when assessing progressed MRT patients for checkpoint inhibition therapy. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism.

Mosaic genome-wide paternal uniparental disomy (GW-pUPD) is a rarely recognised disorder. The phenotypic manifestations of multilocus imprinting defects (MLIDs) remain unclear. We report of an apparently non-syndromic infant with severe congenital hyperinsulinism (CHI) and diffuse pancreatic labelling by 18F*-DOPA-PET/CT leading to near-total pancreatectomy. The histology was atypical with pronounced proliferation of endocrine cells comprising >70% of the pancreatic tissue and a small pancreatoblastoma. Routine genetic analysis for CHI was normal in the blood and resected pancreatic tissue. At two years' age, Beckwith-Wiedemann Syndrome (BWS) stigmata emerged, and at five years a liver tumour with focal nodular hyperplasia and an adrenal tumour were resected. pUPD was detected in 11p15 and next in the entire chromosome 11 with microsatellite markers. Quantitative fluorescent PCR with amplification of chromosome-specific DNA sequences for chromosomes 13, 18, 21 and X indicated GW-pUPD. A next generation sequencing panel with 303 SNPs on 21 chromosomes showed pUPD in both blood and pancreatic tissue. The mosaic distribution of GW-pUPD ranged from 31 to 35% in blood and buccal swap to 74% in the resected pancreas, 80% in a non-tumour liver biopsy, and 100% in the liver focal nodular hyperplasia and adrenal tumour. MLID features included transient conjugated hyperbilirubinaemia and lack of macrosomia from BWS (pUPD6); and behavioural and psychomotor manifestations of Angelman Syndrome (pUPD15) on follow-up. In conclusion, atypical pancreatic histology in apparently non-syndromic severe CHI patients may be the first clue to BWS and multi-syndromal CHI from GW-pUPD. Variations in the degree of mosaicism between tissues explained the phenotype.

Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma.

Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.Significance: These findings underpin the complexity of PDX modeling as a means to advance translational applications against neuroblastoma. Cancer Res; 78(20); 5958-69. ©2018 AACR.

Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer.

A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored1-5. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns.

Outcomes of biliary atresia in the Nordic countries - a multicenter study of 158 patients during 2005-2016.

BACKGROUND/PURPOSE: Biliary atresia is the most common reason for newborn cholestasis and pediatric liver transplantation. Even after normalization of serum bilirubin after portoenterostomy, most patients require liver transplantation by adulthood due to expanding fibrosis. We addressed contemporary outcomes of biliary atresia in the Nordic countries. METHODS: Data on center and patients characteristics, diagnostic practices, surgical treatment, adjuvant medical therapy after portoenterostomy, follow-up and outcomes were collected from all the Nordic centers involved with biliary atresia care during 2005-2016. RESULTS: Of the 154 patients, 148 underwent portoenterostomy mostly by assigned surgical teams at median age of 64 (interquartile range 37-79) days, and 95 patients (64%) normalized their serum bilirubin concentration while living with native liver. Postoperative adjuvant medical therapy, including steroids, ursodeoxycholic acid and antibiotics was given to 137 (93%) patients. Clearance of jaundice associated with young age at surgery and favorable anatomic type of biliary atresia, whereas annual center caseload >3 patients and diagnostic protocol without routine liver biopsy predicted early performance of portoenterostomy. The cumulative 5-year native liver and overall survival estimate was 53% (95% CI 45-62) and 88% (95% CI 83-94), respectively. Portoenterostomy age <65days and annual center caseload >3 patients were predictive for long-term native liver survival, while normalization of serum bilirubin after portoenterostomy was the major predictor of both native liver and overall 5-year survival. CONCLUSIONS: The outcomes of biliary atresia in the Nordic countries compared well with previous European studies. Further improvement should be pursued by active measures to reduce patient age at portoenterostomy. RETROSPECTIVE PROGNOSIS STUDY: Level II.

Neuroblastoma patient-derived orthotopic xenografts reflect the microenvironmental hallmarks of aggressive patient tumours.

Treatment of high-risk childhood neuroblastoma is a clinical challenge which has been hampered by a lack of reliable neuroblastoma mouse models for preclinical drug testing. We have previously established invasive and metastasising patient-derived orthotopic xenografts (PDXs) from high-risk neuroblastomas that retained the genotypes and phenotypes of patient tumours. Given the important role of the tumour microenvironment in tumour progression, metastasis, and treatment responses, here we analysed the tumour microenvironment of five neuroblastoma PDXs in detail. The PDXs resembled their parent tumours and retained important stromal hallmarks of aggressive lesions including rich blood and lymphatic vascularisation, pericyte coverage, high numbers of cancer-associated fibroblasts, tumour-associated macrophages, and extracellular matrix components. Patient-derived tumour endothelial cells occasionally formed blood vessels in PDXs; however, tumour stroma was, overall, of murine origin. Lymphoid cells and lymphatic endothelial cells were found in athymic nude mice but not in NSG mice; thus, the choice of mouse strain dictates tumour microenvironmental components. The murine tumour microenvironment of orthotopic neuroblastoma PDXs reflects important hallmarks of aggressive and metastatic clinical neuroblastomas. Neuroblastoma PDXs are clinically relevant models for preclinical drug testing.

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.

Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.

Neuroblastoma patient-derived orthotopic xenografts retain metastatic patterns and geno- and phenotypes of patient tumours.

Neuroblastoma is a childhood tumour with heterogeneous characteristics and children with metastatic disease often have a poor outcome. Here we describe the establishment of neuroblastoma patient-derived xenografts (PDXs) by orthotopic implantation of viably cryopreserved or fresh tumour explants of patients with high risk neuroblastoma into immunodeficient mice. In vivo tumour growth was monitored by magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography. Neuroblastoma PDXs retained the undifferentiated histology and proliferative capacity of their corresponding patient tumours. The PDXs expressed neuroblastoma markers neural cell adhesion molecule, chromogranin A, synaptophysin and tyrosine hydroxylase. Whole genome genotyping array analyses demonstrated that PDXs retained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p and gain of chromosome 17q. Thus, neuroblastoma PDXs recapitulate the hallmarks of high-risk neuroblastoma in patients. PDX-derived cells were cultured in serum-free medium where they formed free-floating neurospheres, expressed neuroblastoma gene markers MYCN, CHGA, TH, SYP and NPY, and retained tumour-initiating and metastatic capacity in vivo. PDXs showed much higher degree of infiltrative growth and distant metastasis as compared to neuroblastoma SK-N-BE(2)c cell line-derived orthotopic tumours. Importantly, the PDXs presented with bone marrow involvement, a clinical feature of aggressive neuroblastoma. Thus, neuroblastoma PDXs serve as clinically relevant models for studying and targeting high-risk metastatic neuroblastoma.

Pre- and postoperative vomiting in children undergoing video-assisted gastrostomy tube placement.

Background. The aim of this study was to determine the incidence of pre- and postoperative vomiting in children undergoing a Video-Assisted Gastrostomy (VAG) operation. Patients and Methods. 180 children underwent a VAG operation and were subdivided into groups based on their underlying diagnosis. An anamnesis with respect to vomiting was taken from each of the children's parents before the operation. After the VAG operation, all patients were followed prospectively at one and six months after surgery. All complications including vomiting were documented according to a standardized protocol. Results. Vomiting occurred preoperatively in 51 children (28%). One month after surgery the incidence was 43 (24%) in the same group of children and six months after it was found in 40 (22%). There was a difference in vomiting frequency both pre- and postoperatively between the children in the groups with different diagnoses included in the study. No difference was noted in pre- and postoperative vomiting frequency within each specific diagnosis group. Conclusion. The preoperative vomiting symptoms persisted after the VAG operation. Neurologically impaired children had a higher incidence of vomiting than patients with other diagnoses, a well-known fact, probably due to their underlying diagnosis and not the VAG operation. This information is useful in preoperative counselling.

Robot-assisted radical cystoprostatectomy in a small child with rhabdomyosarcoma: a case report.

We report the first case of a robot-assisted radical cystoprostatectomy in a 22-month-old boy with embryonal rhabdomyosarcoma in his urinary bladder. Treatment according to international protocol CWS-2002 P (Cooperative Weichteilsarkom Studie) was given prior to surgery. The da Vinci S Surgical System from Intuitive Surgical (Sunnyvale, CA, USA) was used to laparoscopically remove the urinary bladder and prostate radically. The surgical procedure performed and the postoperative course were uneventful. This technique is safe and feasible also in small children. It seems to have advantages over open surgery and no disadvantages. We recommend this technique for further use.

Complications of video-assisted gastrostomy in children with or without a ventriculoperitoneal shunt.

The aim of the study was to test the hypothesis that the presence of a ventriculoperitoneal shunt (VPS) influences the frequency of postoperative complications after video-assisted gastrostomy (VAG) in children. When using a power of 80%, a critical value for significance of 5% and an assumed population-based standard deviation of 0.4, it will be required to have a sample size of at least 14 children to show that a difference of 0.6 is significant when using Student's t test for paired samples. Thus, 15 consecutive children with VPSs were included in the present study. All the children had nutritional problems and underwent a VAG operation at a tertiary care university hospital. After the operation, the children were prospectively followed up. Specially trained nurses documented all complications according to a protocol. For the purpose of comparison, we had a control group of neurologically disabled children without VPSs, matched for age and operated with VAG. The children did not present with any serious postoperative intra-abdominal complications or central nervous system infection. There was no significant difference in the frequency of minor complications between the studied group and the control group. This study did not reveal that children with VPSs who undergo a VAG button placement are at high risk for infection and subsequent shunt malfunction. They did not have more postoperative problems than a matched control group of neurologically disabled children.

Complications of video-assisted gastrostomy in children with malignancies or neurological diseases.

AIM: To test the hypothesis whether the administration of cytostatic drugs close to surgery in children with malignancies influences the rate of postoperative complications. METHOD: Included in the study were 27 children with malignancies and a control group of 27 neurologically impaired children. All the children had nutritional problems and underwent a video-assisted gastrostomy (VAG) operation during the period 1997-2002. The children were postoperatively followed up. All complications were documented according to a protocol by a specially trained nurse and correlated to the time elapsed from completion of the last preoperative or the first postoperative cytostatic drug treatment. The complications in the two groups were compared. RESULTS: The children with malignant diseases did not have more postoperative complications of the VAG than those having neurological defects. There was no correlation to complications regarding timing of the operation and administration of cytostatic drugs. CONCLUSION: This study revealed no aggravated influence of cytostatic drug treatment on early postoperative problems of VAG. The timing of cytostatic drug administration in relation to the surgical intervention did not influence the frequency of postoperative complications.

Video-assisted gastrostomy in infants less than 1 year.

The objectives of this study were to report our experience with the laparoscopic video-assisted gastrostomy technique in infants operated during their first year of life. A total of 53 infants (35 males, 18 females) aged 6 +/- 3 months, varying from 3 weeks to 11 months, underwent video-assisted gastrostomy. They were prospectively followed up. Included are infants with neurological dysfunction, chromosomal anomalies, metabolic disorders, cardiac anomalies or respiratory insufficiency. All the infants were operated under general and local anaesthesia. Gastrostomy tube feeding began within 4 h after the operation. The infants were followed with a scheduled control at 1 and 6 months postoperatively documenting complications and weight gain. The main outcome measure was the number and type of complications as well as weight gain using the age-adjusted Z-score of weight to normalize the data relative to a reference population. The weight before and 6 months after the video-assisted gastrostomy was 5.5 +/- 1.6 and 8.5 +/- 1.6 kg, respectively. The Z-score increased significantly (P < 0.001) from -2.7+/-1.5 to -1.7 +/- 1.0. This illustrates the postoperative weight gain and catch-up. Short and long-term complications included minor local wound infection, leakage around the gastrostomy tube and granuloma, but no severe complications. Our results encourage the use of video-assisted gastrostomy as a safe technique to provide a route for long-term nutritional support even in infants less than 1 year.

Closure after gastrostomy button.

A gastrostomy device is removed from the gastrostoma when no longer needed. The aim of the study was to test the hypothesis of whether it is possible for the surgeon to decide which stoma has to be closed with a gastroraphy and which to leave for a spontaneous closure within a reasonable period of time. Out of a cohort of 321 patients, who had been operated with a video-assisted gastrostomy, we included all the 48 patients having had their gastrostomy button removed. These patients were carefully followed and the closure of the gastrostoma was registered. According to the institutional routine we waited at least 3 months after the removal of the gastrostomy device before suggesting to the child's guardians an operative closure of the stoma. In 26 patients the stoma closed within 3 months, whereas in 22 patients a surgical gastroraphy was performed. We found no differences between the two groups regarding the patients' diagnoses, the duration of the gastrostoma use or patient's age at the time of removal of the gastrostomy device. This study rejected the hypothesis of predictability of the gastrostoma closure. Thus, we recommend a routine expectance after the removal of a gastrostomy device for at least 1 month. If no spontaneous closure occurs, then a gastroraphy should be performed.

Omentum herniation at a 2-mm trocar site.

An infant underwent laparoscopy using a 2-mm trocar for the video optic to achieve a gastrostomy. Two days postoperatively, a trocar-site herniation of the omentum was noted and measured. This suggests that the operating surgeon should consider a secure closure of the wound even after a 2-mm trocar is used in infants.