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Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here, we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.

Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort.A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves.The nomogram, including MYCN status (P 0.0001), lactate dehydrogenase (LDH) (P = 0.0007), and presence of bone marrow metastases (P = 0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of 82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1).In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children.

Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. To better understand neuroblastoma pathogenesis, here we analyze whole-genome, whole-exome and/or transcriptome data from 702 neuroblastoma samples. Forty percent of samples harbor at least one recurrent driver gene alteration and most aberrations, including MYCN, ATRX, and TERT alterations, differ in frequency by age. MYCN alterations occur at median 2.3 years of age, TERT at 3.8 years, and ATRX at 5.6 years. COSMIC mutational signature 18, previously associated with reactive oxygen species, is the most common cause of driver point mutations in neuroblastoma, including most ALK and Ras-activating variants. Signature 18 appears early and is continuous throughout disease evolution. Signature 18 is enriched in neuroblastomas with MYCN amplification, 17q gain, and increased expression of mitochondrial ribosome and electron transport-associated genes. Recurrent FGFR1 variants in six patients, and ALK N-terminal structural alterations in five samples, identify additional patients potentially amenable to precision therapy., Genomic analysis of neuroblastoma has revealed important disease etiology. In this study, the authors assembled whole genome, exome and transcriptome data from over 700 neuroblastomas and identified molecular signatures correlated with age, and rare, potentially targetable variants overlooked in smaller cohorts.

Background Centers from Europe and United States have reported an exceedingly high number of children with a severe inflammatory syndrome in the setting of COVID-19, which has been termed multisystem inflammatory syndrome in children (MIS-C). Objectives This study aimed to analyze echocardiographic manifestations in MIS-C. Methods We retrospectively reviewed 28 MIS-C, 20 healthy controls and 20 classic Kawasaki disease (KD) patients. We reviewed echocardiographic parameters in acute phase of MIS-C and KD groups, and during subacute period in MIS-C group (interval: 5.2 ± 3 days). Results Only 1 case in MIS-C (4%) manifested coronary artery dilatation (z score=3.15) in acute phase, showing resolution during early follow up. Left ventricular (LV) systolic and diastolic function measured by deformation parameters, were worse in MIS-C compared to KD. Moreover, MIS-C patients with myocardial injury (+) were more affected than myocardial injury (-) MIS-C with respect to all functional parameters. The strongest parameters to predict myocardial injury in MIS-C were global longitudinal strain (GLS), global circumferential strain (GCS), peak left atrial strain (LAS) and peak longitudinal strain of right ventricular free wall (RVFWLS) (Odds ratio: 1.45 (1.08-1.95), 1.39 (1.04-1.88), 0.84 (0.73-0.96), 1.59 (1.09-2.34) respectively). The preserved LVEF group in MIS-C showed diastolic dysfunction. During subacute period, LVEF returned to normal (median: from 54% to 64%, p Conclusions Unlike classic KD, coronary arteries may be spared in early MIS-C, however, myocardial injury is common. Even preserved EF patients showed subtle changes in myocardial deformation, suggesting subclinical myocardial injury. During an abbreviated follow-up, there was good recovery of systolic function but persistence of diastolic dysfunction and no coronary aneurysms. Condensed abstract Multisystem inflammatory syndrome in children (MIS-C) is an illness that resembles Kawasaki Disease (KD) or toxic shock, reported in children with a recent history of COVID-19 infection. This study analyzed echocardiographic manifestations of this illness. In our cohort of 28 MIS-C patients, left ventricular systolic and diastolic function were worse than in classic KD. These functional parameters correlated with biomarkers of myocardial injury. However, coronary arteries were typically spared. The strongest predictors of myocardial injury were global longitudinal strain, right ventricular strain, and left atrial strain. During subacute period, there was good recovery of systolic function, but diastolic dysfunction persisted.

Neuroblastoma (NB) is the most common extracranial solid tumor in children and, in the high-risk group, has a 5-year mortality rate of ~50%. The high mortality rate and significant treatment-related morbidities associated with current standard of care therapies belie the critical need for more tolerable and effective treatments for this disease. While the monoclonal antibody dinutuximab has demonstrated the potential for immunotherapy to improve overall NB outcomes, the 5-year overall survival of high-risk patients has not yet substantially changed. The frequency and type of invariant natural killer T cells (iNKTs) and natural killer cells (NKs) has been associated with improved outcomes in several solid and liquid malignancies, including NB. Indeed, iNKTs and NKs inhibit tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs), kill cancer stem cells (CSCs) and neuroblasts, and robustly secrete cytokines to recruit additional immune effectors. These capabilities, and promising pre-clinical and early clinical data suggest that iNKT- and NK-based therapies may hold promise as both stand-alone and combination treatments for NB. In this review we will summarize the biologic features of iNKTs and NKs that confer advantages for NB immunotherapy, discuss the barriers imposed by the NB tumor microenvironment, and examine the current state of such therapies in pre-clinical models and clinical trials.

Pediatric histiocytic neoplasms are clonal hematopoietic disorders driven by mutations activating the mitogen-activated protein kinase (MAPK) pathway, such as BRAF-V600E. In non-BRAFV600E cases, we investigated alternative MAPK mutations and found two novel BRAF gene fusions. We investigated the distinct responsiveness of novel BRAF fusions to RAFi therapies and explored the mechanistic basis of such differential responses compared to other BRAF fusions. Two histiocytic patient tumors were analyzed using the CHOP Comprehensive Next-Gen Sequencing Solid Tumor Panel and a targeted RNA-seq panel for 106 fusion partner genes. In the two M- and L-type histiocytic neoplasms assessed, we found novel and rare BRAF gene fusions, MTAP-BRAF and MS4A6A-BRAF, respectively. Both BRAF fusions activated the MAPK/ PI3K pathways and showed homo- and hetero-dimerization with BRAF and the respective N-terminal fusion partner. In contrast to common BRAF fusions, MTAP-BRAF and MS4A6A-BRAF did not respond to PLX8394 due to a lack of disruption of active fusion homo- and hetero-dimers, which was in turn due to the untargeted, stable dimerization mediated by the N-terminal fusion partners. Conversely, we observed robust suppression with LY3009120 that bound fusion dimers and kept them in an inactivate confirmation. MEKi were found to successfully suppress fusion driven signaling and oncogenic phenotypes. Our finding that PLX8394 does not disrupt MTAP-BRAF or MS4A6A-BRAF dimerization due to contribution of N-terminal partners defines a novel paradigm for the distinct mechanisms sought by BRAF fusions in response to RAFi therapy. Overall, this study highlights the unique and differential biology hijacked by BRAF fusions in response to RAFi and further warrants detailed mechanistic classification of BRAF fusions based on their responsiveness to targeted agents.

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX–histone chaperone complex, and that induced by MYCN-mediated metabolic reprogramming, leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma., In most cancers, mutations that lead to oncogene activation and tumor suppressor inactivation synergize to promote tumorigenesis. However, in neuroblastomas, MYCN amplification and ATRX mutations are mutually exclusive and incompatible.

For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.

Artificial intelligence (AI) has emerged as a major frontier in computer science research. Although AI has broad application across many medical fields, it will have particular utility in ophthalmology and will dramatically change the diagnostic and treatment pathways for many eye conditions such as corneal ectasias, glaucoma, age-related macular degeneration and diabetic retinopathy. However, given that AI has primarily been driven as a computer science, its concepts and terminology are unfamiliar to many medical professionals. Important key terms such as machine learning and deep learning are often misunderstood and incorrectly used interchangeably. This article presents an overview of AI and new developments relevant to ophthalmology.

IMPORTANCE This study is the first to compare the extended range of vision (ERV) intraocular lens (IOL) targeted at micro-monovision to a monofocal targeted at binocular emmetropia. BACKGROUND Compares visual acuity, range of vision and spectacle independence in monofocal and ERV IOLs. DESIGN Assessor-blinded retrospective cohort study. PARTICIPANTS Eighty-eight participants (176 eyes) with bilateral IOL implants at 5+ month postoperative review. METHODS Regression analyses (general estimating equations and multiple linear regression) tested associations between IOL type (ZA9002 Tecnis 3-piece or Tecnis ZCT monofocal; and Tecnis Symfony ERV IOL) and visual acuity, adjusting for key confounders including residual astigmatism. MAIN OUTCOME MEASURES Monocular and binocular visual acuity measured with and without distance refractive correction at distance (3.00 m), intermediate (1.00 and 0.63 m) and near (0.40 m) (logMAR units); near vision reading test used British 'N' notation; self-reported spectacle independence. RESULTS There was no significant difference between ERV and monofocal groups in uncorrected binocular visual acuity at distance (P = 0.595). Binocular uncorrected visual acuity at intermediate (0.63 m: monofocal 0.24, ERV 0.09, P < 0.001) and near (0.40 m: monofocal 0.42, ERV 0.18, P < 0.001) were significantly better in the ERV group. Binocular uncorrected near vision: all the ERV group read N8 or better, compared to 36% in the monofocal group (P < 0.001); 93% of the ERV group reported spectacle independence at near compared to 33% in the monofocal group (P < 0.001). CONCLUSIONS AND RELEVANCE The ERV IOL, targeted to achieve micro-monovision, demonstrated superior range of visual acuity and spectacle independence compared to the monofocal targeted to achieve emmetropia.

Summary Background No clinical trial has been done for patients with neuroblastoma-associated opsoclonus myoclonus ataxia syndrome (OMA) and existing treatment is based on case reports and small retrospective studies. We aimed to assess OMA response to prednisone and risk-adapted chemotherapy and to establish whether the addition of intravenous immunoglobulin (IVIG) further improves response. Methods We did a randomised, open-label, phase 3 trial in 92 Children's Oncology Group institutions in North America, Australia, and New Zealand with patients younger than 8 years with biopsy-proven, newly diagnosed neuroblastoma or ganglioneuroblastoma associated with OMA. Randomisation was stratified according to the clinical stage of neuroblastoma. We randomly assigned eligible patients through use of computer generated randomisation to receive 12 cycles of IVIG (1 g/kg, day 0 and 1, cycle one; day 0, cycles two to six; day 0, cycles eight, ten, and 12; each cycle lasting 28 days) or no IVIG, in addition to prednisone (2 mg/kg per day divided twice a day for a minimum of two cycles) and neuroblastoma risk-adapted chemotherapy (cyclophosphamide 25 mg/kg for children ≤20 kg and 750 mg/m 2 for children >20 kg, day 0 for the first six cycles in patients with low-risk disease). The primary outcome was OMA response, defined as the best score of the three neurological assessments assessed at months 2, 6, and 12 with a scale developed by Mitchell and Pike; baseline versus best response scores were compared. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00033293. Findings Of the 53 patients enrolled in the study between May 15, 2004, and Feb 4, 2013, 33 (62%) were female. 44 patients had low-risk, seven had intermediate-risk, and two had high-risk neuroblastoma. 26 patients were randomly assigned to IVIG and 27 to no IVIG. One patient did not have a neurological assessment and was excluded from OMA response analysis. 21 (81%) of 26 patients in the IVIG group had an OMA response, compared with 11 [41%] of 27 in the no IVIG group (odds ratio 6·1, 95% CI 1·5–25·9, p=0·0029). Median follow-up for patients who were OMA progression-free was 6·1 years (IQR 3·6–8·7, range 1 day to 10·3 years) for both groups. For most patients, the IVIG regimen combined with cyclophosphamide or other risk-based chemotherapy was well tolerated. 28 patients reported grade 3 or higher adverse events, with the most frequent ones being anaemia, neutropenia, vomiting, infectious diseases, nystagmus, ataxia, and agitation. One patient with high-risk neuroblastoma died of a severe adenovirus infection after high-dose chemotherapy followed by autologous stem cell reconstitution. Interpretation The addition of IVIG to prednisone and risk-adapted chemotherapy improved OMA response, and this regimen constitutes a backbone on which to build additional therapy. Funding US National Cancer Institute, National Institutes of Health.

OBJECTIVE: Cognitive remediation is a promising approach to treating core cognitive deficits in adults with autism, but rigorously controlled trials of comprehensive interventions that target both social and non-social cognition over a sufficient period of time to impact functioning are lacking. This study examined the efficacy of Cognitive Enhancement Therapy (CET) for improving core cognitive and employment outcomes in adult autism. METHOD: Verbal adult outpatients with autism spectrum disorder (N = 54) were randomized to an 18-month, single-blind trial of CET, a cognitive remediation approach that integrates computer-based neurocognitive training with group-based training in social cognition, or an active Enriched Supportive Therapy (EST) comparison focused on psychoeducation and condition management. Primary outcomes were composite indexes of neurocognitive and social-cognitive change. Competitive employment was a secondary outcome. RESULTS: Intent-to-treat analyses indicated that CET produced significant differential increases in neurocognitive function relative to EST (d = .46, P = .013). Both CET and EST were associated with large social-cognitive improvements, with CET demonstrating an advantage at 9 (d = .58, p = .020), but not 18 months (d = .27, p = .298). Effects on employment indicated that participants treated with CET were significantly more likely to gain competitive employment than those in EST, OR = 6.21, p = .023, which was mediated by cognitive improvement. CONCLUSIONS: Cognitive Enhancement Therapy is a feasible and potentially effective treatment for core cognitive deficits in adult autism spectrum disorder. The treatment of cognitive impairments in this population can contribute to meaningful improvements in adult outcomes. LAY SUMMARY: Cognitive Enhancement Therapy (CET), an 18-month cognitive remediation intervention designed to improve thinking and social understanding, was found to be more effective than supportive therapy at improving mental quickness, attention, and employment in adults living with autism. Social understanding was equally improved in CET and supportive therapy. Cognitive remediation interventions are feasible and may confer significant functional benefits to adults with autism. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00902798

// Vito Alessandro Lasorsa 1,2 , Daniela Formicola 1,2 , Piero Pignataro 1,2 , Flora Cimmino 1,2 , Francesco Maria Calabrese 3 , Jaume Mora 4 , Maria Rosaria Esposito 5 , Marcella Pantile 5 , Carlo Zanon 5 , Marilena De Mariano 6 , Luca Longo 6 , Michael D. Hogarty 7 , Carmen de Torres 4 , Gian Paolo Tonini 5 , Achille Iolascon 1,2 and Mario Capasso 1,2,8 1 University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy 2 CEINGE Biotecnolgie Avanzate, Naples, Italy 3 University of Bari, Department of Biology, Bari, Italy 4 Hospital Sant Joan de Deu, Developmental Tumor Biology Laboratory and Department of Oncology, Esplugues de Llobregat, Barcelona, Spain 5 Pediatric Research Institute (IRP), Fondazione Citta della Speranza, Neuroblastoma Laboratory, Padua, Italy 6 U.O.C. Bioterapie, IRCCS AOU San Martino-IST, National Cancer Research Institute, Genoa, Italy 7 Children’s Hospital of Philadelphia, Division of Oncology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America 8 IRCCS SDN, Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy Correspondence: Mario Capasso, email: // Flora Cimmino, email: // Keywords : NGS, neuroblastoma, high risk, somatic mutation, cancer driver genes Received : December 22, 2015 Accepted : February 09, 2016 Published : March 18, 2016 Abstract The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9 , a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK . Other genes ( PTK2 , NAV3 , NAV1 , FZD1 and ATRX ), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1 , CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.