Impact of one-piece fronto-orbital distraction osteogenesis on orbital morphology and the development of strabismus in patients with 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 2008 and November 2020. Ophthalmologic records and computed tomography were reviewed. Seven parameters, including width, height, volume, and 4-direction orbital angles were evaluated in patients with UCS and compared with those of age-matched control subjects. RESULTS: The superolateral angle (SLA) and vertical angle (VA) 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 SLA 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 superomedial angle difference between both orbits (p=0.041, odds ratio: 1.39). 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.

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.

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.

Clinical Features and Prognosis of Diffuse Midline Glioma: A Series of 24 Cases.

BACKGROUND: Diffuse midline glioma (DMG) which occurs in midline structures and characterized by harboring K27M mutation in genes encoding the histone 3 protein is classified as World Health Organization (WHO) grade IV regardless of histological findings and has a poor prognosis. Nevertheless, because of its relatively rare incidence compared with other high-grade gliomas, a comprehensive description encompassing clinical features and genomic profiles of DMG is still lacking. METHODS: In this study, we analyzed data of 24 patients who were diagnosed as DMG which was confirmed by surgical specimens in both pediatric and adult patients. We described the clinical outcomes of patients with DMG and their genomic profiles through a retrospective analysis of 24 patients with DMG. RESULTS: The clinical characteristics of the 24 patients with DMG were analyzed. Ten patients (41%) underwent tumor resection and 14 patients (59%) underwent tumor biopsy. The median overall survival was 10.4 months (95% confidence interval [CI], 8.4 to 12.5) and progression free survival was 3.9 months (95% CI, 2.6 to 5.2). Fifteen patients (62%) were accompanied by hydrocephalus. None of the patient, tumor, or treatment factors had any significant associated with survival. In both immunohistochemistry staining (n=24) and targeted next generation sequencing (n=15), TP53 mutation was the most common genetic mutation (25% and 46%, respectively) found in the patients except alterations in histone 3 protein. CONCLUSION: Although surgical treatment of patient with DMG does not affect the overall survival prognosis, it can help improve the patient's accompanying neurological symptoms in some limited cases. Hydrocephalus is often accompanied with DMG and treatment for hydrocephalus is often also required. Multidisciplinary therapeutic approach is needed.

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.

Accelerated cranial distraction protocol for one-piece fronto-orbital distraction osteogenesis without bandeau in patients with craniosynostosis.

This study aimed to compare the bony relapse ratios of standard and accelerated distraction protocols (ADP) in one-piece fronto-orbital distraction osteogenesis (DO). Patients with unilateral or bilateral coronal synostoses who underwent one-piece fronto-orbital DO were included. The accelerated cranial distraction protocol included a 3-day latency period and a distraction rate of 1-2 mm/day, followed by a 4-week consolidation period. Intracranial volume was measured using computed tomography (CT) before the surgery, at the end of the consolidation period, and 1 year after the removal of distractors. The intracranial volume changes and relapse ratios were calculated. This study included 32 patients; of these, 16 were included in each of the ADP and standard protocol (SP) groups. The mean ages were 1.4 years and 1.6 years in the ADP and SP groups, respectively (p = 0.895). In the ADP and SP groups, the expanded volumes were 270.9 ± 90.3 cm3 and 284.6 ± 149.7 cm3 (p = 0.91) and the growth-corrected expanded volumes were 162.1 ± 67.5 cm3 and 177.1 ± 105.2 cm3, respectively (p = 0.867). The relapse and growth-corrected relapse ratios showed no significant differences between the two groups, suggesting similar stability between the two protocols. The relapse ratios were 7.1 ± 4.8% and 7.3 ± 5.0% (p = 0.91) and the growth-corrected relapse ratios were -3.0 ± 3.3% and -2.4 ± 2.7%, respectively (p = 0.498). Within the limitations of the study, it seems that the ADP can shorten the distraction period without compromising stability. This may contribute to resolving the disadvantages and highlighting the advantages of DO.

One-piece fronto-orbital distraction osteogenesis without bandeau in patients with coronal craniosynostosis: A five-year follow-up retrospective study of 45 consecutive patients.

This study aimed to review the surgical outcomes, complications, and long-term relapses in patients with unilateral or bilateral coronal craniosynostosis, who underwent one-piece fronto-orbital distraction osteogenesis (FODO) without bandeau. The cephalic index, frontal angle, and supraorbital symmetry ratio were measured on the initial and follow-up computed tomography images. Esthetic outcomes were evaluated using the Whitaker classification. 45 patients were included in this study. The average follow-up interval was 5.4 ± 1.1 years (range 2.5-8.5 years). In patients with bilateral coronal craniosynostosis, the frontal angle decreased with a relapse ratio of -2.8 ± 4.3% during long-term follow-up compared with that during short-term follow-up (p = 0.028). In patients with unilateral coronal craniosynostosis, the supraorbital symmetry ratio decreased slightly, with a relapse ratio of -3.8 ± 2.6% during long-term follow-up (p = 0.017). Complications included dural tears during osteotomy (n = 2), early distractor removal (n = 2), and wound problems (n = 3). Within the limitations of the study it seems that one-piece fronto-orbital distraction osteogenesis (FODO) generates successful and sustainable results even in the long term. Therefore, this treatment option should be considered for patients with unilateral and bilateral coronal craniosynostoses whenever appropriate.

Outcomes of intracranial germinoma-A retrospective multinational Asian study on effect of clinical presentation and differential treatment strategies.

BACKGROUND: This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes. METHODS: A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken. RESULTS: From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had ß-human chorionic gonadotropin values <50 mIU/mL. The 5/10-year overall survival (OS) and recurrence-free survival (RFS) rates were 97.2%/96.2% and 89.9%/86.9%, respectively. RFS was predicted by the radiotherapy (RT) field, with focal RT having the worst outcome, whereas chemotherapy usage had no impact on survival. Among patients who received chemotherapy, response to chemotherapy did not predict survival outcomes. In M0 patients, primary basal ganglia tumors predicted a worse RFS. In patients with bifocal tumors, an extended field RT was associated with better outcomes. In multivariable analysis, only RT fields were associated with RFS. In relapsed patients, salvage rates were high at 85.7%. Additionally, patients who received salvage RT had a better outcome (91.6% vs. 66.7%). CONCLUSIONS: Survival outcomes of patients with germinoma were excellent. Thus, the focus of treatment for intracranial germinoma should be on survivorship. Further studies are warranted to find the optimal intensity and volume of radiation, including the role of chemotherapy in the survival of patients with intracranial germinomas, considering age, primary tumor location, and extent of disease.

Complete posterior cranial vault distraction osteogenesis to correct Chiari malformation type I associated with craniosynostosis.

OBJECTIVE: Posterior vault distraction osteogenesis (PVDO) is an effective tool to increase intracranial volume and expand the posterior cranial fossa. During PVDO, the authors extended osteotomy posterior to the foramen magnum to fully expand the posterior cranial fossa. The aim of this study was to investigate the efficacy of complete PVDO in posterior fossa expansion and treatment of Chiari malformation type I (CM-I) in patients with craniosynostosis. METHODS: Patients with craniosynostosis who had undergone complete PVDO between January 2012 and May 2020 were reviewed retrospectively. A coronal osteotomy extending to the foramen magnum was performed and the foramen magnum was decompressed by removing its posterior rim with a 1-mm Kerrison rongeur. Four distractor devices were placed and the vector of distraction was controlled from the posterior to the inferior-posterior direction, depending on the deformity. Changes in the intracranial volume, posterior cranial fossa area, and cerebellar tonsillar descent were measured after complete PVDO by using CT and MRI. RESULTS: A total of 11 patients with craniosynostosis and concurrent CM-I were included in the study. The mean age was 34.6 ± 24.0 months (continuous variables are expressed as the mean ± SD throughout). One patient had sleep apnea, which was consistent with CM-I, and another patient had a headache, which was nonspecific. The intracranial volume increased from 1179.6 ± 180.2 cm3 to 1440.6 ± 251.5 cm3 (p = 0.003; 24.5% increase compared to the preoperative volume). The posterior skull base area increased from 44.9 ± 19.3 cm2 to 72.7 ± 18.1 cm2 (p = 0.004). Cerebellar tonsillar descent decreased in all 11 patients after complete PVDO (preoperative: 10.8 ± 3.7 mm, postoperative: 2.7 ± 3.0 mm; p = 0.003). Among the 11 patients, 5 showed complete resolution of cerebellar tonsillar herniation. CONCLUSIONS: Complete PVDO can more efficiently expand the posterior cranial fossa, unlike conventional methods. Moreover, it helps to relieve cerebellar tonsillar herniation. Complete PVDO is a powerful tool to increase the intracranial and posterior fossa volumes in patients with craniosynostosis and concurrent CM-I.

Multicentric Spinal Pilocytic Astrocytoma Presenting with Syringomyelia.

Pilocytic spinal cord astrocytomas make up 21% of intramedullary tumors. Only 20% of those tumors are associated with syringomyelia. To our knowledge, this is the first report of an adult presenting with multiple spinal pilocytic astrocytomas associated with syringomyelia. We report a case of a 27-year-old woman who had neck and arm pain for months. She underwent cervical magnetic resonance imaging (MRI) that demonstrated a syrinx from C2 and extending to C6. A coronal view of the MRI showed multiple mural nodules. Total excision of multicentric nodules within a cyst was performed with an uneventful intraoperative and postoperative period and the patient was discharged home with moderate right-hand numbness.

Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.

PURPOSE: Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years. MATERIALS AND METHODS: A search of medical records from seven centers was performed between January 2005 and December 2016. RESULTS: Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01). CONCLUSION: Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

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.

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.

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

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.

Pediatric Glioma at the Optic Pathway and Thalamus.

Gliomas are the most common pediatric tumors of the central nervous system. In this review, we discuss the clinical features, treatment paradigms, and evolving concepts related to two types of pediatric gliomas affecting two main locations: the optic pathway and thalamus. In particular, we discuss recently revised pathologic classification, which adopting molecular parameter. We believe that our review contribute to the readers' better understanding of pediatric glioma because pediatric glioma differs in many ways from adult glioma according to the newest advances in molecular characterization of this tumor. A better understanding of current and evolving issues in pediatric glioma is needed to ensure effective management decision.

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.

Long-Term Results Following Surgical Resection of Chordomas in the Craniocervical Junction and the Upper Cervical Spine: Review of 12 Consecutive Cases.

BACKGROUND: Since chordoma is refractory to chemotherapy and conventional radiotherapy, radical surgical resection is mandatory. However, it is surgically demanding in the craniocervical junction (CCJ) and upper cervical spine. OBJECTIVE: To analyze long-term surgical results of cervical chordomas. METHODS: We retrospectively reviewed 12 consecutive patients who underwent surgical treatment for CCJ or upper cervical chordomas from 2001 to 2009 in 2 academic institutions. We analyzed the progression-free survival and overall survival and compared the results between gross total resection (GTR) cases and partial resection (PR). Complications were analyzed by comparing primary and recurrent tumor. We also delineated the type of radiotherapy. RESULTS: Of the 12 patients, 5 underwent GTR and 7 underwent PR. GTR of the tumor was achieved by intralesional piecemeal removal. No recurrence occurred in the GTR group. PR group had 6 cases of regrowth (85.7%). Ten patients (83.3%) underwent any kind of radiation therapy. There were 3 (60%) patients in the GTR group and 7 (100%) in the PR group. Compared to PR, GTR revealed a better 3-yr progression-free survival rate (100% vs 14.3%) as well as a better 3-yr overall survival rate (100% vs 71.4%). Surgical complication rate (40% for GTR vs 42.9% for PR) was not significantly different between the groups. The surgical complication rates of primary and revision surgery were 25% and 75%, respectively. Complication associated with radiation occurred in 2 patients. CONCLUSION: Gross total intralesional piecemeal resection with perioperative radiation therapy is an acceptable strategy for CCJ and the upper cervical chordoma management.