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ObjectivesPaediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs.DesignA multicentre, international, collaborative cohort study.Setting91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020.ParticipantsPatients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin’s lymphoma, Hodgkin lymphoma, Wilms’ tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer.Main outcome measureAll-cause mortality at 30 days and 90 days.Results1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (pConclusionsThe COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally.

// Eric J. Rellinger 1, 6 , Chandrasekhar Padmanabhan 1 , Jingbo Qiao 1, 6 , Brian T. Craig 1, 6 , Hanbing An 1 , Jing Zhu 1 , Hernan Correa 2 , Alex G. Waterson 3 , Craig W. Lindsley 3 , R. Daniel Beauchamp 1, 4, 5 and Dai H. Chung 1, 4, 6 1 Section of Surgical Sciences, Department of Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 2 Department of Pathology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 3 Department of Pharmacology and Vanderbilt Institute of Chemical Biology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 4 Department of Cancer Biology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 5 Department of Cell and Developmental Biology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 6 Department of Pediatric Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville, USA Correspondence to: Dai H. Chung, email: dai.chung@vanderbilt.edu R. Daniel Beauchamp, email: daniel.beauchamp@vanderbilt.edu Keywords: ML327, neuroblastoma, MYCN, neural crest, epithelial-to-mesenchymal transition Received: April 13, 2017 Accepted: July 03, 2017 Published: July 20, 2017 ABSTRACT Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. MYCN -amplification is a feature of ~30% of neuroblastoma tumors and portends a poor prognosis. Neural crest precursors undergo epithelial-to-mesenchymal transition (EMT) to gain migratory potential and populate the sympathoadrenal axis. Neuroblastomas are posited to arise due to a blockade of neural crest differentiation. We have recently reported effects of a novel MET inducing compound ML327 ( N -(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide) in colon cancer cells. Herein, we hypothesized that forced epithelial differentiation using ML327 would promote neuroblastoma differentiation. In this study, we demonstrate that ML327 in neuroblastoma cells induces a gene signature consistent with both epithelial and neuronal differentiation features with adaptation of an elongated phenotype. These features accompany induction of cell death and G1 cell cycle arrest with blockage of anchorage-independent growth and neurosphere formation. Furthermore, pretreatment with ML327 results in persistent defects in proliferative potential and tumor-initiating capacity, validating the pro-differentiating effects of our compound. Intriguingly, we have identified destabilization of MYC signaling as an early and consistent feature of ML327 treatment that is observed in both MYCN -amplified and MYCN -single copy neuroblastoma cell lines. Moreover, ML327 blocked MYCN mRNA levels and tumor progression in established MYCN -amplified xenografts. As such, ML327 may have potential efficacy, alone or in conjunction with existing therapeutic strategies against neuroblastoma. Future identification of the specific intracellular target of ML327 may inform future drug discovery efforts and enhance our understanding of MYC regulation.

Omphalitis is an infrequent neonatal infection of the umbilicus. Necrotizing infections are a rare complication of omphalitis that requires prompt antibiotic therapy, surgical debridement, and supportive care. Here, we present a rare case of Clostridium sordellii necrotizing omphalitis that progressed to severe toxemia characterized by refractory hypotension, massive capillary leak, leukemoid reaction, and absence of fever. These clinical features are common in C. sordellii infections and harbor a poor prognosis with only one reported survivor (out of 12) of C. sordellii omphalitis reported in the literature. Early antibiotic and surgical intervention remain the mainstay of care as no early detection assays or antitoxins are commercially available.

Computed tomography (CT) has become a standard adjunct in the evaluation of patients with trauma. However, utility of imaging at the referring hospital remains controversial. We study the effect of CT scans at referring hospitals on in-hospital mortality at a receiving trauma center.A retrospective cohort study was performed with adult patients with severe trauma transferred to a level I trauma center from regional nontrauma hospitals between 2012 and 2017. Baseline characteristics were compared with Student's t-test and Pearson's chi-squared testing. The primary endpoint was in-hospital mortality. Cox regression, controlling for transfer time, was used to evaluate the effect of imaging on mortality.Three thousand four hundred and fifteen adult patients with trauma were included: 1135 (33.2%) received a pretransfer CT scan, whereas 2280 (66.8%) did not. Patients who received a pretransfer CT scan were more likely to be older, female, white, have a higher Charlson Comorbidity Index, less severely injured, have a blunt mechanism, and be transferred by ground. There was no difference in distance (58.3 miles versus 57.0 miles, P = 0.34), but transfer times were significantly increased for those who received pretransfer scans (288 versus 213 min, P 0.005). The adjusted model controlling for multiple variables has a hazard ratio of 0.533 (95% confidence interval 0.42-0.68, P 0.005).There is a survival advantage for patients who receive pretransfer CT scans despite having significantly longer transport times. We suggest that this decreased mortality associated with pretransfer imaging may reflect improving trends in referring physician transfer decisions.

Cell division cycle 42 (CDC42), a small GTPase of the Rho-subfamily, regulates diverse cellular functions including proliferation, cytoskeletal rearrangement and even promotes malignant transformation. Here, we found that increased expression of CDC42 correlated with undifferentiated neuroblastoma as compared to a more benign phenotype. CDC42 inhibition decreased cell growth and soft agar colony formation, and increased cell death in BE(2)-C and BE(2)-M17 cell lines, but not in SK-N-AS. In addition, silencing of CDC42 decreased expression of N-myc in BE(2)-C and BE(2)-M17 cells. Our findings suggest that CDC42 may play a role in the regulation of aggressive neuroblastoma behavior.

Laparoscopy and thoracoscopy are effective and beneficial approaches for many abdominal and thoracic surgical procedures in children of all ages. Safe application of minimally invasive surgery in pediatric patients requires an understanding of the effects of carbon dioxide insufflation. Insufflation causes two major physiological consequences—increased intra-abdominal or intrathoracic pressure and CO2 absorption—which in turn produce a variety of physiologic sequelae. Cardiac index, mean arterial pressure, and aortic blood flow decrease during abdominal insufflation, and increased intra-abdominal pressure can lead to impaired pulmonary mechanics. Increased minute ventilation must be achieved during minimally invasive surgery, especially in neonates, to prevent hypercarbia and subsequent acidosis. Newborns are very sensitive to ventilation/perfusion mismatch if single-lung ventilation is employed during thoracoscopy. Reversible anuria and oliguria occur with laparoscopy, although this effect is less common after infancy. Effects on inflammatory cytokines and cellular infiltrates appear to be less significant in laparoscopic versus open operations in children. This chapter details the physiologic effects of laparoscopy and thoracoscopy on individual organ systems and discusses general preoperative and postoperative considerations for minimally invasive surgery in children.

Background The MYC family of proteins promotes neuroblastoma tumorigenesis at least in part through the induction of aerobic glycolysis by promoting the transcription of key glycolytic enzymes, such as LDHA. FX11 is a selective inhibitor of LDHA that has demonstrated preclinical efficacy in adult cancers. Herein, we hypothesized that FX11 would inhibit aerobic glycolysis and block growth of neuroblastoma cells. Methods We surveyed 3 MYCN–single copy and 5 MYCN-amplified neuroblastoma cell lines to correlate C-MYC/N-MYC protein levels with LDHA expression. Cell viability was measured with FX11 using a tetrazolium-based assay. Cell cycle analysis using propidium iodide with flow cytometry was performed to evaluate for growth arrest. Immunoblotting demonstrated PARP and Caspase 3 cleavage as evidence of apoptosis. Results LDHA is frequently expressed in both MYCN--amplified and MYCN-single copy cell lines. N-MYC and C-MYC protein levels did not correlate with LDHA protein expression. FX11 inhibits aerobic glycolysis and growth in three MYCN-amplified and one MYCN–single copy neuroblastoma cell lines. FX11 induces modest G1 cell cycle arrest with selective induction of apoptosis. Conclusion Small molecule LDHA inhibition is capable of blocking aerobic glycolysis and growth of neuroblastoma cell lines in vitro and merits further in vivo evaluation of its preclinical efficacy in neuroblastomas.

Neuroblastoma arises from the neural crest, the precursor cells of the sympathoadrenal axis, and differentiation status is a key prognostic factor used for clinical risk group stratification and treatment strategies. Neuroblastoma tumor-initiating cells have been successfully isolated from patient tumor samples and bone marrow using sphere culture, which is well established to promote growth of neural crest stem cells. However, accurate quantification of sphere-forming frequency of commonly used neuroblastoma cell lines has not been reported. Here, we show that MYCN-amplified neuroblastoma cell lines form spheres more frequently than non-MYCN-amplified cell lines. We also show that sphere formation is directly sensitive to cellular differentiation status. 13-cis-retinoic acid is a clinically used differentiating agent that induces a neuronal phenotype in neuroblastoma cells. Induced differentiation nearly completely blocked sphere formation. Furthermore, sphere formation was specifically FGF-responsive and did not respond to increasing doses of EGF. Taken together, these data suggest that sphere formation is an accurate method of quantifying the stemness phenotype in neuroblastoma.

Background/Purpose Patients with hypoplastic left heart syndrome (HLHS) experience a higher risk for complications from gastroesophageal reflux, prompting frequent need for fundoplication. Patients between stage I and II palliation ("interstage") are at particularly high operative risk because of the parallel nature of their pulmonary and systemic blood flow. Laparoscopic approach for fundoplication is common for pediatric patients. However, its safety in interstage HLHS is relatively unknown. We examined the perioperative physiologic burden of a laparoscopic fundoplication in HLHS patients. Methods All patients who underwent open or laparoscopic fundoplication during the interstage period at our institution since 2006 were reviewed. Perioperative physiologic data, echocardiographic findings, survival, and complications were collected from the anesthetic record and patient chart. Results Nineteen patients with HLHS had laparoscopic fundoplication, 13 (68%) during the interstage period, compared to 64 performed by the open approach. Ten (77%) of 13 interstage patients had perioperative hemodynamic instability. Incidence of instability between open and laparoscopic groups was not different. One laparoscopic patient required ECMO support for shunt thrombosis. Conclusions Despite a high incidence of hemodynamic instability, overall outcomes are consistent with those reported in the literature for this high-risk patient population. Laparoscopic approach for fundoplication during the interstage period appears to be a relatively safe option for these patients.

Previous studies have reported decreased continence in patients undergoing transanal endorectal pull-through (TERP) for Hirschsprung's disease compared to the older transabdominal approach (TAA). To address this, we examined long-term stooling outcomes in a large, multicenter cohort of patients undergoing either TERP or TAA.Data were collected from 5 large pediatric institutions. Patient families were surveyed using a stooling score system (0-40, best to worst total score). Inclusion criteria included patients older than 3 years and those who had more than 6 months of recovery after pull-through. Those with total colonic aganglionosis were excluded. Statistical analysis included univariate and multivariate linear regression (significance, P.05).Two hundred eighty-one patients underwent TERP (192) or TAA (89). Interviews were completed in 149 (104 [52%] TERP vs 45 [52%] TAA). The TAA group had a significantly greater number of daily bowel movements for each respective postoperative year and experienced more early complications (3% vs 1% with1 complication; P = .061) and late complications (19% vs 4% with1 complication; P.001). Although the TAA group had a higher mean enterocolitis score (3.3 +/- 0.4 vs 1.8 +/- 0.2; P.001), this was not borne out by multivariate regression analysis (P = .276). Parental survey showed that there were no significant differences between procedures in mean total, continence, or stooling pattern scores.Transanal endorectal pull-through was associated with fewer complications and fewer episodes of enterocolitis. In contrast to prior studies, TERP patients did not have a higher rate of incontinence. These results support use of TERP as an excellent surgical approach for children with Hirschsprung's disease.

Foregut duplications occur at various locations throughout the upper gastrointestinal tract, including the thoracic cavity. Thoracic foregut duplications are typically intimately associated with the esophagus and therefore are located in either the posterior mediastinum or in pleural cavity. Here we report a case of foregut duplication of the middle mediastinum, intimately associated with the pericardium and great vessels that contained gastric mucosa, ciliated respiratory epithelium, bronchial-type epithelium, pancreatic tissue and hepatocytes. The literature of mediastinal foregut duplications is also reviewed.