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ALMA observations of line emission from planet forming discs have demonstrated to be an excellent tool to probe the internal disc kinematics, often revealing subtle effects related to important dynamical processes occurring in them, such as turbulence, or the presence of planets, that can be inferred from pressure bumps perturbing the gas motion, or from the detection of the planetary wake. In particular, we have recently shown for the case of the massive disc in Elias 2-27 as how one can use such kind of observations to measure deviations from Keplerianity induced by the disc self-gravity, thus constraining the total disc mass with good accuracy and independently on mass conversion factors between the tracer used and the total mass. Here, we refine our methodology and extend it to two additional sources, GM Aur and IM Lup, for which archival line observations are available for both the 12CO and the 13CO line. For IM Lup, we are able to obtain a consistent disc mass of |$M_{\rm disc}=0.1 \, \mathrm{M}_{\odot }$|⁠ , implying a disc-star mass ratio of 0.1 (consistent with the observed spiral structure in the continuum emission) and a gas/dust ratio of ∼65 (consistent with standard assumptions), with a systematic uncertainty by a factor of ≃ 2 due to the different methods to extract the rotation curve. For GM Aur, the two lines we use provide slightly inconsistent rotation curves that cannot be attributed only to a difference in the height of the emitting layer, nor to a vertical temperature stratification. Our best-fitting disc mass measurement is |$M_{\rm disc}=0.26 \, \mathrm{M}_{\odot }$|⁠ , implying a disc-star mass ratio of ∼0.35 and a gas/dust ratio of ∼130. Given the complex kinematics in the outer disc of GM Aur and its interaction with the infalling cloud, the CO lines might not well trace the rotation curve and our results for this source should then be considered with some caution. [ABSTRACT FROM AUTHOR]

A growing body of evidence indicates that the star formation rate per unit stellar mass (sSFR) decreases with increasing mass in normal main-sequence star-forming galaxies. Many processes have been advocated as being responsible for this trend (also known as mass quenching), e.g., feedback from active galactic nuclei (AGNs), and the formation of classical bulges. In order to improve our insight into the mechanisms regulating the star formation in normal star-forming galaxies across cosmic epochs, we determine a refined star formation versus stellar mass relation in the local Universe. To this end we use the Hα narrow-band imaging followup survey (Hα3) of field galaxies selected from the HI Arecibo Legacy Fast ALFA Survey (ALFALFA) in the Coma and Local superclusters. By complementing this local determination with high-redshift measurements from the literature, we reconstruct the star formation history of main-sequence galaxies as a function of stellar mass from the present epoch up to z = 3. In agreement with previous studies, our analysis shows that quenching mechanisms occur above a threshold stellar mass Mknee that evolves with redshift as ∞(1 + z)2. Moreover, visual morphological classification of individual objects in our local sample reveals a sharp increase in the fraction of visually classified strong bars with mass, hinting that strong bars may contribute to the observed downturn in the sSFR above Mknee. We test this hypothesis using a simple but physically motivated numerical model for bar formation, finding that strong bars can rapidly quench star formation in the central few kpc of field galaxies. We conclude that strong bars contribute significantly to the red colors observed in the inner parts of massive galaxies, although additional mechanisms are likely required to quench the star formation in the outer regions of massive spiral galaxies. Intriguingly, when we extrapolate our model to higher redshifts, we successfully recover the observed redshift evolution for Mknee. Our study highlights how the formation of strong bars in massive galaxies is an important mechanism in regulating the redshift evolution of the sSFR for field main-sequence galaxies. [ABSTRACT FROM AUTHOR]

PATZ1-rearranged sarcomas are well-recognized tumors as part of the family of round cell sarcoma with EWSR1-non-ETS fusions. Whether PATZ1-rearranged central nervous system (CNS) tumors are a distinct tumor type is debatable. We thoroughly characterized a pediatric series of PATZ1-rearranged CNS tumors by chromosome microarray analysis (CMA), DNA methylation analysis, gene expression profiling and, when frozen tissue is available, optical genome mapping (OGM). The series consisted of 7 cases (M:F=1.3:1, 1-17 years, median 12). On MRI, the tumors were supratentorial in close relation to the lateral ventricles (intraventricular or iuxtaventricular), preferentially located in the occipital lobe. Two major histologic groups were identified: one (4 cases) with an overall glial appearance, indicated as "neuroepithelial" (NET) by analogy with the corresponding methylation class (MC); the other (3 cases) with a predominant spindle cell sarcoma morphology, indicated as "sarcomatous" (SM). A single distinct methylation cluster encompassing both groups was identified by multidimensional scaling analysis. Despite the epigenetic homogeneity, unsupervised clustering analysis of gene expression profiles revealed 2 distinct transcriptional subgroups correlating with the histologic phenotypes. Interestingly, genes implicated in epithelial-mesenchymal transition and extracellular matrix composition were enriched in the subgroup associated to the SM phenotype. The combined use of CMA and OGM enabled the identification of chromosome 22 chromothripsis in all cases suitable for the analyses, explaining the physical association of PATZ1 to EWSR1 or MN1. Six patients are currently disease-free (median follow-up 30 months, range 12-92). One patient of the SM group developed spinal metastases at 26 months from diagnosis and is currently receiving multimodal therapy (42 months). Our data suggest that PATZ1-CNS tumors are defined by chromosome 22 chromothripsis as causative of PATZ1 fusion, show peculiar MRI features (eg, relation to lateral ventricles, supratentorial frequently posterior site), and, although epigenetically homogenous, encompass 2 distinct histologic and transcriptional subgroups., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using fresh frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit., Methods: Analysis of patients aged 0 to 21 years, enrolled in Germany between April 2019 and February 2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing, and RNA-Seq were performed., Results: FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n = 71), BRAF V600E-mutation (n = 12), and alterations in FGFR1 (n = 14) as the most frequent alterations, among other common molecular drivers (n = 12). N = 16 cases (13%) presented rare gene fusions (eg, TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n = 27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 internal tandem duplications (n = 6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols., Conclusions: The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pediatric high-grade gliomas represent a heterogeneous group of tumors with a wide variety of molecular features. We performed whole exome sequencing and methylation profiling on matched primary and recurrent tumors from four pediatric patients with hemispheric high-grade gliomas. Genetic analysis showed the presence of some variants shared between primary and recurrent tumors, along with other variants exclusive of primary or recurrent tumors. NSD1 variants, all novel and not previously reported, were present at high frequency in our series (100%) and were all shared between the samples, independently of primary or recurrence. For every variant, in silico prediction tools estimated a high probability of altering protein function. The novel NSD1 variant (c.5924T > A; p.Leu1975His) was present in one in four cases at recurrence, and in two in four cases at primary. The novel NSD1 variant (c.5993T > A; p.Met1998Lys) was present in one in four cases both at primary and recurrence, and in one in four cases only at primary. The presence of NSD1 mutations only at recurrence may suggest that they can be sub-clonal, while the presence in both primary and recurrence implies that they can also represent early and stable events. Furthermore, their presence only in primary, but not in recurrent tumors, suggest that NSD1 mutations may also be influenced by treatment.

Background: More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol., Methods: We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses., Results: The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse., Conclusions: Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neuroblastoma (NB) is the most common extra-cranial malignancy in preschool children. To portray the genetic landscape of an overly aggressive NB leading to a rapid clinical progression of the disease, tumor DNA collected pre- and post-treatment has been analyzed. Array comparative genomic hybridization (aCGH), whole-exome sequencing (WES), and pharmacogenetics approaches, respectively, have identified relevant copy number alterations (CNAs), single nucleotide variants (SNVs), and polymorphisms (SNPs) that were then combined into an integrated analysis. Spontaneously formed 3D tumoroids obtained from the recurrent mass have also been characterized. The results prove the power of combining CNAs, SNVs, and SNPs analyses to assess clonal evolution during the disease progression by evidencing multiple clones at disease onset and dynamic genomic alterations during therapy administration. The proposed molecular and cytogenetic integrated analysis empowers the disease follow-up and the prediction of tumor recurrence.

Neuroblastoma (NB) is the most common extracranial, solid, pediatric malignancy and, despite the constant progress of treatment and development of innovative therapies, remains a complex, challenging disease causing major morbidity and mortality in children. There is significant variability in the management of neuroblastoma, partially due to the heterogeneity of the clinical and biological behavior, and partially secondary to the different approaches between treating institutions. Anesthesia takes an integral part in the multidisciplinary care of patients with NB, from diagnosis to surgery and pain control. This paper aims to review and discuss the critical steps of the perioperative and operative management of children undergoing surgery for neuroblastoma. Anesthesia and analgesia largely depend on tumor location, surgical approach, and extension of the surgical dissection. Attention should be paid to the physio-pathological changes on cardiovascular, gastrointestinal, and immune systems induced by the tumor or by chemotherapy. At the time of surgery meticulous patient preparation needs to be carried out to optimize intraoperative monitoring and minimize the risk of complications. The cross-sectional role of anesthesia in cancer care requires effective communication between all members of the multidisciplinary team.

Background: A prospective 2002-2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients' molecular features., Methods: Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68., Results: Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66-126 mo), surviving after relapse no longer than those relapsing earlier (0-5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007)., Conclusions: Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Musculoskeletal pain (MSP) conditions are a leading cause of morbidity worldwide and a common reason for ED presentation. Little is currently known about non-traumatic MSP (NTMSP) presenting to EDs. The present study described the prevalence and management practices of NTMSP in EDs., Methods: The design was a retrospective clinical audit in two hospital EDs in Western Australia covering 3 months beginning 1 January 2016. We defined NTMSP as pain of musculoskeletal origin occurring in the absence of external force or excessive physical loading. The outcomes measured included: patient, condition and hospital-episode characteristics, as well as management practices. Management practices were compared to recommended care derived from guideline recommendations. These included: assessment for red flags and psychosocial risk factors, appropriate use of diagnostic imaging, provision of patient education, administration and prescription of analgesic medication, and assessment of risk factors for opioid-related harm., Results: Eight hundred and eighty-eight patients were included in the present study. NTMSP accounted for 3.0% of all ED presentations. According to clinician documentation, red flag and psychosocial assessments were recorded in 73.3 and 10.5% of patients. Forty-one percent of patients were referred for imaging, of which 39.7% were inconsistent with guideline recommendations. Education was recorded 52.0% of the time. At least one opioid medication was administered to 55.3% of patients and there was no documented assessment of risk factors for opioid-related harm., Conclusions: NTMSP is a relatively common reason for ED presentation. Documented management practices are discordant with guideline recommendations. Strategies to improve the concordance between management and guideline recommendations are needed., (© 2019 Australasian College for Emergency Medicine.)

Type 1 neurofibromatosis (NF1) is a dominantly inherited condition predisposing to tumor development. Optic pathway glioma (OPG) is the most frequent central nervous system tumor in children with NF1, affecting approximately 15-20% of patients. The lack of well-established prognostic markers and the wide clinical variability with respect to tumor progression and visual outcome make the clinical management of these tumors challenging, with significant differences among distinct centers. We reviewed published articles on OPG diagnostic protocol, follow-up and treatment in NF1. Cohorts of NF1 children with OPG reported in the literature and patients prospectively collected in our center were analyzed with regard to clinical data, tumor anatomical site, diagnostic workflow, treatment and outcome. In addition, we discussed the recent findings on the pathophysiology of OPG development in NF1. This review provides a comprehensive overview about the clinical management of NF1-associated OPG, focusing on the most recent advances from preclinical studies with genetically engineered models and the ongoing clinical trials.

Background: Infants diagnosed with stage 4 s neuroblastoma commonly experience spontaneous disease regression, with few succumbing without response to therapy. We analyzed a large cohort of such infants enrolled in the Italian Neuroblastoma Registry to detect changes over time in presenting features, treatment and outcome., Methods: Of 3355 subjects aged 0-18 years with previously untreated neuroblastoma diagnosed between 1979 and 2013, a total of 280 infants (8.3%) had stage 4 s characteristics, 268 of whom were eligible for analyses. Three treatment eras were identified on the basis of based diagnostic and chemotherapy adopted. Group 1 patients received upfront chemotherapy; Group 2 and 3 patients underwent observation in the absence of life-threatening symptoms (LTS), except for Group 3 patients with amplified MYCN gene, who received more aggressive therapy., Results: The three groups were comparable, with few exceptions. Ten-year overall survival significantly increased from 76.9 to 89.7% and was worse for male gender, age 0-29 days and presence of selected LTS on diagnosis, elevated LDH, and abnormal biologic features. Infants who underwent primary resection ± chemotherapy did significantly better. On multivariate analysis, treatment eras and the association of hepatomegaly to dyspnea were independently associated with worse outcome., Conclusions: Our data confirm that stage 4 s neuroblastoma is curable in nearly 90% of cases. Hepatomegaly associated to dyspnea was the most important independent risk factor. The cure rate could be further increased through timely identification of patients at risk who might benefit from surgical techniques, such as intra-arterial chemoembolization and/or liver transplantation, which must be carried out in institutions with specific expertise.

Purpose: To evaluate peripapillary retinal nerve fibre layer (RNFL) thickness, measured by spectral-domain optical coherence tomography (SD-OCT), as a surrogate of visual function in a population of paediatric patients affected by optic pathway glioma (OPG) associated with neurofibromatosis type 1 (NF1)., Methods: A total of 38 paediatric patients (66 eyes) affected by MRI-proven OPG were included. Each patient underwent complete ophthalmological examination, including age-appropriate visual acuity (VA) assessment and RNFL analysis by SD-OCT. Visual acuity was classified as normal or pathologic using age-based normative data. Visual acuity was correlated to mean RNFL thickness of the whole peripapillary area and of each single analyzed sector (nasal, superior, temporal, inferior)., Results: Visual acuity was normal in 43 (65%) and pathologic in 23 (35%) eyes. Mean parapapillary RNFL thickness of each analyzed sector was significantly lower in eyes with abnormal VA (p < 0.05). The best balanced cut-off value of global RNFL thickness allowing to discriminate between eyes with normal and pathologic VA was 76.25 μm (91%, 76%, 67% and 94% of sensitivity, specificity, positive and negative predicting value, respectively). Considering best balanced cut-off values of other analyzed RNFL sectors, the superior (p = 0.0029) and the inferior (p = 0.0024) sectors reached the higher sensitivity (87% and 87%, respectively) and specificity (81% and 79%, respectively)., Conclusion: Retinal nerve fibre layer thickness is directly related to VA in children affected by NF1-related OPG, and should be considered as a potential surrogate marker of VA. Retinal nerve fibre layer thickness cut-off values can be used in paediatric patients to discriminate false-positive results obtained by VA measurement., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: The aims of patients' radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear., Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months., Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5-104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients., Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI.

SMARCB1 inactivation is a well-established trigger event in atypical teratoid/rhabdoid tumor. Recently, a role for SMARCB1 inactivation has emerged as a mechanism of clonal evolution in other tumor types, including rare brain tumors. We describe an unusual malignant intra-axial SMARCB1-deficient spindle cell desmoplastic neoplasm, occurring in a 6-year-old child with meningioangiomatosis and a long history of seizures. Striking features of the tumor were a storiform pattern and strong CD34 expression. Undifferentiated round cell areas with isolated rhabdoid cells showing high mitotic index and focal necrosis with INI1 expression loss were present. The meningioangiomatosis component showed few chromosomal imbalances, including chromosomal 22 monosomy (where SMARCB1 maps) and gain at 6q14.3. In addition to these abnormalities, the spindle cell desmoplastic neoplasm and its dedifferentiated SMARCB1-deficient component shared several other aberrations, including homozygous deletion at 9p21.3, losses at 1p, 3p, 3q, 10p, and 13q, gains and losses at 5p and 11p. In line with INI1 loss, the dedifferentiated component showed remarkably decreased levels of SMARCB1 transcript. The residual SMARCB1 allele was wildtype. Our findings suggest progression from the meningioangiomatosis to the malignant desmoplastic neoplasm through the occurrence of complex chromosomal abnormalities, and point to functional silencing of SMARCB1 in the dedifferentiation component.

Objective: To investigate the impact of childhood cancer on parents' adult attachment, social support, marital adjustment, anxiety, and depression., Methods: 30 parents of children with childhood cancer and 30 matched controls completed the following questionnaires: Experiences in Close Relationships-Revised, Dyadic Adjustment Scale-4, Multidimensional Scale of Perceived Social Support, State-Trait Anxiety Inventory - form Y, and Beck Depression Inventory., Results: Parents of children with childhood cancer had a significantly lower dyadic adjustment than controls, and higher levels of insecure-avoidant attachment, state anxiety, and depression., Conclusion: It is important for health-care personnel to take into account these parents' propensity to show increased levels of avoidant attachment during children's treatment to foster effective communication and supportive relationships between clinicians, pediatric patients, and parents.

Optic pathway glioma (OPG) represents the most common central nervous system tumor in children with Neurofibromatosis type-1 (NF1). Although overall survival is usually good, no clear prognostic factors have been identified so far. We assessed the natural history of OPG in a cohort of unselected patients affected by NF1. We retrospectively evaluated 414 consecutive patients affected by NF1 and referred to our NF1 clinic before age 6. Average follow-up was 11.9 years: 52 out of 414 patients had OPG with a total cumulative incidence of 15.4% at age 15 (Kaplan-Meier estimate) and a statistically significant difference according to sex. Brain and orbit MRI was performed in 44.7% of patients: 34.6% for screening purposes and 65.4% because of the presence of neurological, ocular or other symptoms. OPG was diagnosed in 12.5% of cases in the first group, whereas in 36.4% in the latter group (p = 0.001). Clinical management was conservative in most patients, while 8 of them underwent therapy mainly because of visual deterioration. OPG was diagnosed earlier in treated patients, but the difference was not statistically significant. Conversely, all patients who underwent screening MRI had normal visual outcome. In conclusion, OPG location does not correlate with need for treatment; female patients were more frequently affected by OPG but not more frequently treated. OPG diagnosis by screening MRI does not affect the natural history of the tumor.

Background: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III)., Methods: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone., Results: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable., Conclusions: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Less than 5% of neuroblastomas (NB) occur in adolescents and young adults (AYA), in whom the disease has an indolent and fatal course., Procedure: We studied the genomic profile and histological characteristics of 34 NBs from AYA patients enrolled in the Italian Neuroblastoma Registry (INBR) between 1979 and 2009., Results: Disease was disseminated in 20 patients and localized in 14; 30/34 tumors were classified as NB and 4/34 as nodular ganglioneuroblastoma (nGNB). Segmental Chromosome Aberrations (SCAs) were observed in 29 tumors (85%) namely 1p imbalance (58%), 17q gain (52%), 9p loss (32%), 11q loss (30%), 1q gain (17%), 7q gain (17%), 2p gain (14%), 3p loss (14%), and 4p loss (7%). MYCN amplification and MYCN gain were detected in 3 (10%) and 2 cases (7%) respectively. An anaplastic lymphoma receptor tyrosine kinase (ALK) gene mutation study on the available cases from this cohort revealed 4/25 (16%) mutated cases. In parallel, alpha thalassaemia/mental retardation syndrome X linked (ATRX) gene mutations were also sought, a novel mutation being detected in 1/21 (4,7%) cases., Conclusion: This study confirmed the low incidence of MYCN amplification in AYA and recorded a high frequency of 17q gain and 9p and 11q loss independently from the stage of the disease. The presence of 1q gain, which identifies patients with particularly aggressive disease, relapse and poor survival, was also detected. Furthermore, the frequency of ALK mutations suggests that a target-based therapy with ALK inhibitors might be effective in this subset of patients., (© 2015 Wiley Periodicals, Inc.)

To get insights on the metastatic process of human neuroblastoma (NB), the miRNA expression profile of bone marrow (BM)-infiltrating cells has been determined and compared to that of primary tumors.Twenty-two BM-infiltrating cells, 22 primary tumors, and 4 paired samples from patients with metastatic NB aged > 12 months were analyzed for the expression of 670 miRNAs by stem-loop RT-qPCR. The miRNAs whose expression was significantly different were subjected to selection criteria, and 20 selected miRNAs were tested in 10 additional BM-infiltrating cells and primary tumors. Among the miRNAs confirmed to be differentially expressed, miR-659-3p was further analyzed. Transfection of miR-659-3p mimic and inhibitor demonstrated the specific suppression and over-expression, respectively, of the miR-659-3p target gene CNOT1, a regulator of transcription of genes containing AU-rich element (ARE) sequence. Among the ARE-containing genes, miR-659-3p mimic and inhibitor specifically modified the expression of AKT3, BCL2, CYR61 and THSB2, belonging to the focal adhesion pathway. Most importantly, in BM-infiltrating cells CNOT1 expression was significantly higher, and that of AKT3, BCL2, THSB2 and CYR61 was significantly lower than in primary tumors. Thus, our study suggests a role of the focal adhesion pathway, regulated by miR-659-3p through CNOT1, in the human NB metastatic process.