Outcomes of intracranial non-germinomatous germ cell tumors: a retrospective Asian multinational study on treatment strategies and prognostic factors.

PURPOSE: Non-germinomatous germ cell tumors (NGGCTs) are rare pediatric conditions. This multicenter study using Asian multinational patient data investigated treatment outcomes and prognostic factors for NGGCTs. METHODS: Medical records of 251 patients with NGGCTs treated from 1995 to 2015 were retrospectively analyzed from participating centers in Asian countries (Korea, Taiwan, Singapore, and Japan). RESULTS: The median follow up was 8.5 years (95% CI 7.8-9.9). In the total cohort, 5-year event-free survival (EFS) and overall survival (OS) rates were 78.2% and 85.4%, respectively. In 17.9% of the patients, diagnosis was determined by tumor markers alone (alpha-fetoprotein ≥ 10 ng/mL (Korea) or > 25 ng/mL (Taiwan and Singapore), and/or ß-human chorionic gonadotropin (ß-hCG) ≥ 50 mIU/mL). Patients with immature teratomas and mature teratomas comprised 12.0% and 8.4%, respectively. The 5-year EFS rate was higher in patients with histologically confirmed germinoma with elevated ß-hCG (n = 28) than those in patients with malignant NGGCTs (n = 127). Among malignant NGGCTs, patients with choriocarcinoma showed the highest 5-year OS of 87.6%, while yolk sac tumors showed the lowest OS (68.8%). For malignant NGGCT subgroups, an increase in serum ß-hCG levels by 100 mIU/mL was identified as a significant prognostic factor associated with the EFS and OS. CONCLUSION: Our result shows excellent survival outcomes of overall CNS NGGCT. However, treatment outcome varied widely across the histopathologic subgroup of NGGCT. Hence, this study suggests the necessity for accurate diagnosis by surgical biopsy and further optimization of diagnosis and treatment according to the histopathology of NGGCTs. Future clinical trials should be designed for individualized treatments for different NGGCTs subsets.

Comparison of the Relapse Ratio and Osteogenesis Between 1-Piece and 2-Piece Fronto-Orbital Distraction Osteogenesis Among Patients With Bilateral Craniosynostosis in Early Childhood.

BACKGROUND: Fronto-orbital distraction osteogenesis (FODO), used to correct bilateral coronal craniosynostosis (BCS), is grossly classified into 1-piece and 2-piece FODO. One-piece FODO osteomizes the frontal and supraorbital bones as one block by preserving the attachment between the dura mater and bone, whereas the 2-piece FODO detaches bone segments from the underlying dura mater and reshapes them. This study aimed to determine whether separating the bone-dura attachment would affect osteogenesis and the relapse of the deformity and to compare the surgical outcomes between 1-piece and 2-piece FODO. METHODS: Patients with BCS who underwent either 1-piece or 2-piece FODO between May 2008 and November 2016 were retrospectively reviewed. Patients older than 12 months who were diagnosed with syndromic or nonsyndromic craniosynostosis were included. The CT images were taken at initial presentation (T0), 1-3 years postoperatively (T1), and >4 years postoperatively (T2). These images were used to measure the frontal angle, anterior skull base ratio, and bone defect area. RESULTS: This study included 11 patients in the 1-piece group and 9 patients in the 2-piece group. The relapse ratios of the frontal angle were -2.3% ± 0.6% and -4.9% ± 2.1% in the 1-piece and 2-piece groups, respectively, showing that the 2-piece group had a significantly higher relapse ratio ( P = 0.002). At the T2 period, the 1-piece group had a significantly higher anterior skull base ratio (0.80 ± 0.10) than that in the 2-piece group (0.69 ± 0.08, P = 0.046). In addition, the bone defect area was significantly lower in the 1-piece group (T1: 4.90 ± 2.32 cm 2 , T2: 2.55 ± 1.57 cm 2 ) than in the 2-piece group (T1: 10.74 ± 5.89 cm 2 , T2: 5.35 ± 2.74 cm 2 ) both at the T1 ( P = 0.037) and T2 ( P = 0.025) periods. CONCLUSIONS: One-piece FODO can result in the preservation of the bone segments' vascularity and the enhancement of osteogenesis in the distraction gap. Moreover, 1-piece FODO is associated with lower rates of relapse of deformity and bone defects compared with 2-piece FODO. Lastly, 1-piece FODO can be performed to maximize the advantages of distraction osteogenesis and improve surgical outcomes, especially among early childhood patients with BCS.

Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types.

Neurofibromatosis type 1 (NF1) is caused by heterozygous mutation in the NF1 gene. NF1 is one of the most common human genetic diseases. However, the overall genotype-phenotype correlation has not been known, due to a wide spectrum of genotypic and phenotypic heterogeneity. Here we describe the detailed clinical and genetic features of 427 Korean NF1 patients from 389 unrelated families. Long range PCR and sequencing of genomic DNA with multiplex ligation-dependent probe amplification analysis identified 250 different NF1 mutations in 363 families (93%), including 94 novel mutations. With an emphasis on phenotypes requiring medical attention (classified and termed: NF1+), we investigated the correlation of NF1+ and mutation types. NF1+ was more prevalent in patients with truncating/splicing mutations and large deletions than in those with missense mutations (59.6%, 64.3% vs. 36.6%, p = 0.001). This difference was especially significant in the patients younger than age 19 years. The number of items in NF1+ was a higher in the former groups (0.95 ± 0.06, 1.18 ± 0.20 vs. 0.56 ± 0.10, p = 0.002). These results suggest that mutation types are associated not only with higher prevalence of severe phenotypes in NF1 but also with their earlier onset.

Tumor-infiltrating immune cell subpopulations and programmed death ligand 1 (PD-L1) expression associated with clinicopathological and prognostic parameters in ependymoma.

Ependymomas are biologically and clinically heterogeneous tumors of the central nervous system that have variable clinical outcomes. The status of the tumor immune microenvironment in ependymoma remains unclear. Immune cell subsets and programmed death ligand 1 (PD-L1) expression were measured in 178 classical ependymoma cases by immunohistochemistry using monoclonal antibodies that recognized tumor-infiltrating lymphocyte subsets (TILs; CD3, CD4, CD8, FOXP3, and CD20), tumor-associated macrophages (TAMs; CD68, CD163, AIF1), indoleamine 2,3-dioxygenase (IDO)+ cells and PD-L1-expressing tumor cells. Increases in CD3+ and CD8+ cell numbers were associated with a prolonged PFS. In contrast, increased numbers of FOXP3+ and CD68+ cells and a ratio of CD163/AIF1+ cells were significantly associated with a shorter PFS. An increase in the IDO+ cell number was associated with a significantly longer PFS. To consider the quantities of TILs, TAMs, and IDO+ cells together, the cases were clustered into 2 immune cell subgroups using a k-means clustering analysis. Immune cell subgroup A, which was defined by high CD3+, low CD68+ and high IDO+ cell counts, predicted a favorable PFS compared to subgroup B by univariate and multivariate analyses. We found six ependymoma cases expressing PD-L1. All these cases were supratentorial ependymoma, RELA fusion-positive (ST-RELA). PD-L1 expression showed no prognostic significance. This study showed that the analysis of tumor-infiltrating immune cells could aid in predicting the prognosis of ependymoma patients and in determining therapeutic strategies to target the tumor microenvironment. PD-L1 expression in the ST-RELA subgroup suggests that this marker has a potential added value for future immunotherapy treatments.

One-Piece Fronto-orbital Distraction With Midline Splitting But Without Bandeau for Metopic Craniosynostosis: Craniometric, Volumetric, and Morphologic Evaluation.

BACKGROUND: Distraction osteogenesis has gained popularity in the treatment of different types of craniosynostosis. We aimed to present the technique of 1-piece fronto-orbital distraction with midline splitting osteotomy but without bandeau for the treatment of metopic craniosynostosis, and the protocol of outcome evaluation using craniometric, volumetric, and morphologic parameters based on 3-dimensional computer simulation. METHODS: This retrospective study included 9 patients with isolated metopic craniosynostosis who underwent surgical correction with distraction osteogenesis between December 2015 and February 2018. The osteotomy was designed in the form of 1-piece fronto-orbital distraction without separation of the orbital bandeau accompanied by midline splitting osteotomy. This was followed by the application of 2 pairs of cranial distractors to produce anterolateral expansion. The 3-dimensional files from preoperative and postdistraction computed tomographic data were used for the measurement of craniometric, volumetric, and morphologic parameters. RESULTS: The postdistraction craniometric measurement revealed a 12.52% increase in the interfrontal angle. Moreover, there were increases in the bifrontal diameter, diagonal diameters, and interorbital distance. Volumetric measurements revealed an increase in the total cranial volume by 228.1 ± 110.19 cm. The anterior compartmental volume increased by 33.24%. Morphologic evaluation in the form of curvature analysis showed shrinkage of the surface area of abnormal curvature from 29.5 ± 6.71 cm preoperatively to 3.85 ± 3.66 cm after distraction. CONCLUSIONS: The technique of 1-piece fronto-orbital distraction with midline splitting osteotomy but without bandeau is an effective surgical option for the treatment of metopic craniosynostosis. The postdistraction outcomes demonstrated the correction of various forms of dysmorphology in metopic craniosynostosis.

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

Long-term endocrine effects and trends in body mass index changes in patients with childhood-onset brain tumors.

As survival rates have improved owing to advances in management strategies for pediatric brain tumors, long-term complications such as endocrine dysfunction, have emerged as a major issue. This study investigated the long-term endocrine effects of childhood-onset brain tumors in a large number of patients. This study included 151 patients with brain tumors diagnosed between January 1995 and December 2016. The following data were retrospectively reviewed: tumor location, tumor histology, endocrine abnormalities, hypothalamic involvement on brain imaging, treatment modalities, and trends in body mass index. The mean age at diagnosis of patients with sellar/suprasellar (SE/SUP-SE) tumors and supra/infratentorial (ST/IT) tumors was 9.9 ± 4.5 and 6.5 ± 4.2 years, respectively. In patient with prepubertal age at diagnosis, height standard deviation score was lower in patients with SE/SUP-SE tumors at diagnosis (P = 0.031), which was lower in patients with ST/IT tumors at the final visit (P < 0.001). The prevalence of combined pituitary hormone deficiencies was higher among patients with SE/SUP-SE tumors than in those with ST/IT tumors (81.7 vs. 36.1%, P < 0.001). Among 98 non-obese patients with SE/SUP-SE tumors, 36.7% developed obesity. The prevalence of combined pituitary hormone deficiencies and obesity was higher in patients with SE/SUP-SE tumors than in those with tumors in other locations; growth impairment was more severe in patients with ST/IT tumors.

Neurocognitive Function and Health-Related Quality of Life in Pediatric Korean Survivors of Medulloblastoma.

The neurocognitive function and quality of life of 58 Korean survivors of childhood medulloblastoma were assessed after surgery, cranial radiation and chemotherapy. All patients were evaluated with a battery of neurocognitive function tests and the Pediatric Functional Assessment of Cancer Therapy-Brain Tumor Survivors, which consists of self-report questionnaires on quality of life. The mean full-scale intelligence quotient (IQ), verbal IQ, and performance IQ scores were 90.2, 97.1, and 84.16, respectively. The mean memory quotient (MQ) score was 86.78, which was within 1 standard deviation of the average score of 100. Processing speed, attention, and executive function showed mild to moderate deficits. Intelligence, memory, executive function, visuospatial function, and simple motor function were significantly lower in the patients diagnosed before 8 years of age compared with those diagnosed after 8. The cognitive deficits in the patients diagnosed at younger ages might be related to earlier exposure to craniospinal irradiation and chemotherapy. The patient and parent proxy evaluations of attention, fine motor function, and quality of life did not differ. We found significant neurocognitive changes in a wide range of neurocognitive functional domains in Korean survivors of childhood medulloblastoma. Long-term follow-up studies of survivors of childhood medulloblastoma beginning at the time of their first diagnosis are required to better understand the deficits exhibited by survivors of childhood medulloblastoma, so that intervention strategies and treatment refinements that reduce the long-term neurocognitive decline can be developed.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.

BACKGROUND: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

Pediatric supratentorial high-grade glioma: multicenter retrospective observational study of the Korean Society for Pediatric Neuro-Oncology.

We analyzed the prognostic factors of Korean pediatric patients with supratentorial high-grade glioma (HGG). Between 1997 and 2011, 62 patients with 34 glioblastomas and 28 anaplastic gliomas were surgically operated at nine institutions. The male-to-female ratio was 33 to 29 and the median age was 12 years (range 1-18). The prognostic significance of tumor location, extent of removal, pathologic grade, treatment method, and pattern of recurrence was analyzed. The median progression-free survival (PFS) and overall survival (OS) were 9.3 (± 0.8) and 17.8 (± 1.9) months, respectively. Glioblastoma and anaplastic glioma showed OSs of 15.9 (± 1.3) and 19.6 (± 2.4) months, respectively. Based on the univariate analysis, gross total removal (GTR) and initial combined chemoradiotherapy improved PFS (p = 0.012 and p = 0.003) and OS (p = 0.030 and p = 0.013), respectively. Cerebrospinal fluid (CSF) dissemination showed poor OS (p = 0.001). Based on the multivariate analysis, GTR and initial combined chemoradiotherapy resulted in an improved PFS [(hazard ratio 0.360; 95 % CI 0.177-0.733; p = 0.005) and (hazard ratio 0.458; 95 % CI 0.230-0.911; p = 0.026), respectively]. GTR, initial combined chemoradiotherapy, and no CSF seeding resulted in an improved OS [(hazard ratio 0.417; 95 % CI 0.201-0.861; p = 0.018), (hazard ratio 0.406; 95 % CI 0.206-0.800; p = 0.009), and (hazard ratio 0.288; 95 % CI 0.148-0.563; p = 0.000), respectively]. No significant difference in PFS and OS was observed between glioblastoma and anaplastic glioma. CSF dissemination was observed in 22 patients (35.5 %) during total follow-up. Pediatric anaplastic glioma showed poor survival, similarly to glioblastoma. GTR and initial combined chemoradiotherapy were associated with improved survival.

CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity.

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

Changes in graft thickness after skull defect reconstruction with autogenous split calvarial bone graft.

The ideal material for primary reconstruction of skull defect would be the autogenous bone. However, the long-term evaluation regarding the change in bone graft thickness has not been reported. In this article, we analyzed the thickness changes of the graft according to the time period. Between March 2005 and February 2011, a total of 29 patients underwent skull reconstruction with autogenous split calvarial bone grafts. After applying exclusion criteria, computed tomographic (CT) images of 15 patients were analyzed. The donor bone was harvested in full thickness as 1 piece and then as split. One half of the bone plate was transferred to the defect site; the other half, to the donor site. Both halves were fixed with titanium plates. To compare graft thickness changes, immediate postoperative and follow-up CT scans were analyzed by a single researcher. An anatomic reference was appointed for each patient, and the thickness of the graft on the same level was measured on time-series CT images. Collected data were analyzed with a polynomial random coefficient model. The main causes of the skull defects were trauma and tumor excision. In all cases, the graft thickness was not decreased but even increased in both the donor and recipient sites. The mean graft thicknesses between 6 months and 1 year after the surgery as well as those between 2 and 3 years after the surgery were 1.24-times and 1.56-times thicker than the immediate postoperative thickness, respectively. Graft thickness turned out to be either maintained or increased over time.

Impact of One-Piece Fronto-Orbital Distraction Osteogenesis on Orbital Morphology and Strabismus Development in Unilateral Craniosynostosis.

BACKGROUND: Unicoronal craniosynostosis (UCS) is associated with orbital dysmorphologies that underlie ophthalmologic dysfunctions, such as strabismus. This study aimed to assess orbital dysmorphology in patients with UCS and how it changes after fronto-orbital distraction osteogenesis (FODO), and to analyze the features of new-onset strabismus. METHODS: A retrospective analysis was conducted on 19 patients with UCS who underwent FODO between May of 2008 and November of 2020. Ophthalmologic records and computed tomographic scans were reviewed. Seven parameters, including width, height, volume, and four-direction orbital angles were evaluated in patients with UCS and compared with those of age-matched control subjects. RESULTS: The superolateral angle and vertical angle of the ipsilateral orbit and the superomedial angle (SMA) of the contralateral orbit were more obtuse than those of the controls. Following FODO, the ipsilateral superolateral angle was decreased from 69.2 ± 5.4 degrees to 59.1 ± 4.2 degrees ( P = 0.001), and the contralateral SMA was decreased from 64.8 ± 5.8 degrees to 60.2 ± 6.0 degrees ( P = 0.003). Four of the 17 patients without strabismus in the preoperative period developed strabismus, and the horizontal type was the most common. Logistic regression analysis demonstrated a significant association between new-onset strabismus and SMA difference between both orbits (OR, 1.39; P = 0.041). CONCLUSIONS: Orbital dysmorphology in the UCS is bilateral, and the orbital roofs are dysmorphic. The bilateral orbital roofs are lifted toward the fused coronal suture and can be improved after FODO. Horizontal strabismus, such as esotropia and exotropia, is common after FODO, and superomedial orbital roof asymmetry may play a role in its development. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma.

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Retrospective analysis of treatment outcome of pediatric ependymomas in Korea: analysis of Korean multi-institutional data.

We analyzed the treatment outcomes of intracranial ependymomas in Korean children aged <18 years. Data for 96 patients were collected from five hospitals. Survival rates were calculated using the Kaplan-Meier method. Log-rank tests for univariate analyses and Cox regression model for multivariate analysis were conducted to identify prognostic factors for survival. The median age of the patients was 4 years (range, 0.3-17.9 years). The median follow-up was 55 months (range, 2-343 months). Age <3 years was an important factor for selecting adjuvant therapy after surgery. Among children aged <3 and ≥ 3 years, adjuvant radiotherapy (RT) was applied to 55 and 84 %, respectively, and adjuvant chemotherapy to 52 and 10 %, respectively. The 5 year local progression-free survival (LPFS), disease-free survival (DFS), and overall survival (OS) rates were 54, 52, and 79 %, respectively. Gross total resection was the most significant prognostic factor for all survival endpoints. Age ≥ 3 years and RT were significant prognostic factors for superior LPFS and DFS. However, the significance of age was lost in multivariate analysis for DFS. LPFS, DFS, and OS were superior in patients who started RT within 44 days after surgery (the median time) than in patients who started RT later in the patients aged ≥ 3 years. Postoperative RT was a strong prognostic factor for intracranial ependymomas. Our results suggest that early use of RT is an essential component of treatment, and should be considered in young children.

Erratum to: Retrospective analysis of treatment outcome of pediatric ependymomas in Korea: analysis of Korean multi-institutional data

The name of the 14th author was incorrect in the original publication. It is correct in this erratum (Young-Shin Ra).

Cranial compression using distractors in reverse fashion as an alternative method for correcting scaphocephaly in older patients.

BACKGROUND: Intraoperative calvarial contraction of conventional calvarial remodeling is more difficult in scaphocephaly patients who are 1 year or older in age. In our current study, gradual cranial compression with a distractor was used to correct scaphocephaly in this older age group and the surgical results were quantitatively analyzed. METHODS: Gradual cranial compression was used to treat 7 sagittal craniosynostosis patients. The mean age was 20.9 months (range, 12-32 months) and the mean follow-up period was 65 months (range, 3-81 months). Computed tomography was used to calculate the cephalic index (CI; equal to the maximum width of the head/maximum length of the head ×100), and the ratios of these indices at 3 different time periods (before, immediately after, and at 1 year postoperatively) were evaluated. RESULTS: An average cranial compression of 18 mm was found to be possible with an average CI increase from 67.9 to 73.5. The CI ratio at 1 year after surgery was found to be the highest, showing a 9.8% increase. CONCLUSION: Sagittal craniosynostosis patients are less easy to treat with conventional calvarial remodeling surgery if they are older than 1 year. Gradual cranial vault compression with distractors can be another option in these cases.

Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis.

BACKGROUND: Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. METHODS: We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. FINDINGS: We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037). INTERPRETATION: LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. FUNDING: Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.

Facial and Cranial Symmetry after One-Piece Fronto-Orbital Advancement with Distraction for Isolated Unilateral Coronal Synostosis.

BACKGROUND: The surgical correction of unilateral coronal synostosis (UCS) aims to achieve longstanding facial and cranial symmetry. The authors hypothesized that endocranial morphology correction achieved by one-piece fronto-orbital advancement with distraction osteogenesis (FODO) could alleviate facial asymmetry because endocranial morphology is thought to be its major determinant. This study aimed to quantitatively analyze the changes in supraorbital and midfacial symmetry after FODO. METHODS: The authors included 27 patients with UCS who underwent FODO between May of 2008 and November of 2019. The supraorbital, midfacial, and orbital symmetry ratios and the endocranial and midface angles were measured using computed tomography images. RESULTS: The mean follow-up period was 3.7 ± 1.9 years. The supraorbital shape became symmetric after FODO; the supraorbital distance ratio changed from 0.88 ± 0.04 to 0.98 ± 0.03 ( P < 0.001). The endocranial angulation improved from 167.5 ± 5.0 degrees to 174.4 ± 3.4 degrees ( P < 0.001) and the midface angulation decreased from 6.6 ± 2.2 degrees to 2.6 ± 1.9 degrees ( P < 0.001). In the long-term follow-up analysis (5.9 years), the endocranial angle experienced a slight relapse (-1.4% ± 0.9%) and supraorbital symmetry experienced a -2.0% ± 3.9% relapse. The midface angle continued to improve over the follow-up periods, but it was not statistically significant ( P = 0.121). CONCLUSIONS: The authors' observations indicate that FODO produced satisfactory outcomes in correcting supraorbital retrusion and midface asymmetry. In addition, FODO may allow anterior cranial base remodeling and help relieve midface and skull base angulation. Therefore, FODO can be a good therapeutic strategy for correcting supraorbital and facial asymmetry in patients with UCS. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.