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Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633–0.810). Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.

Background There are limited data available on incidence and survival of patients with choroid plexus tumors (CPT). This study provides the most current epidemiological analysis of choroid plexus tumors from 2004 to 2017 in the United States. Methods Data on 2013 patients with CPT were acquired from the Central Brain Tumor Registry of the United States in collaboration with the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute, from 2004 to 2017. CPT cases were classified by the following pathological subtypes: choroid plexus papilloma (CPP), atypical choroid plexus papilloma (aCPP), and choroid plexus carcinoma (CPC). Frequencies and age-adjusted incidence rates (AAIR) per 100 000 and rate ratios per 100 000 (IRR) were reported for age, sex, race, and ethnicity for each pathological subtype with 95% confidence intervals (95% CI). Using CDC’s National Program of Cancer Registries survival database, survival curves and hazard ratios (HRs) evaluated overall survival from 2001 to 2016. Results CPP had the highest overall incidence (AAIR: 0.034, 95% CI: 0.033–0.036), followed by CPC (AAIR: 0.008, 95% CI: 0.008–0.009) and aCPP (AAIR: 0.005, 95% CI: 0.005–0.006). Incidence was highest among children less than one year old among all subtypes (CPP AAIR: 0.278; aCPP AAIR: 0.140; CPC AAIR: 0.195), reducing as patients aged. Overall survival was worse among patients with CPC, being five times more likely to die compared to patients with CPP (HR: 5.23, 95% CI: 4.05–7.54, P Conclusions This analysis is the most current and comprehensive study in the US on the incidence and survival for CPT. Population based statistics provide critical information in understanding disease characteristics, which impact patient care and prognosis.

Secondary constitutional epimutations in LFS. A, Concordance between enrichment scores of 931 EWAS probes found significantly associated with cancer status in the discovery cohort and the validation cohort, for both the internal (left) and external (right) validation cohort. Blue = associated with cancer status and a cis-CSCE; Red = associated with cancer status but not a cis-CSCE. B, Manhattan plot of adjusted P values from meQTL association tests between the 931 EWAS probes and their most correlated rsSNP. Red line: FDR = 0.1; Blue line: FDR = 0.01; Green points: probes in cancer genes with FDR < 0.1. C, Top cis-CSCE in ETV6, TET3, MIR143, ASXL1, PARVB, and LRG1.D, Feature enrichment heatmap of the 259 significant cis-CSCE loci showing adjusted P value (p) and effect size (d). E, ROC curve of the epimutation cancer risk model on the test set. F, UMAP projection of methylation at 259 cis-CSCE for all patients, colored by cancer status. G, UMAP projection of methylation at 259 cis-CSCE for all patients, colored by clusters associated with risk. H, Kaplan–Meier survival curve demonstrating significant differences in survival probability between the three epimutation clusters.

Variants in cancer predisposition genes (class 1–2) in the wildtype and variant TP53 cohorts, annotated with cancer type, sex, LFS criteria, inheritance status, segregation, variant location, variant function, and zygosity

cisCSCE

Pedigrees and class 1–3 variants for two wildtype TP53 families that fit the classic LFS criteria. A, Pedigree of wildtype TP53 family (WT4) that fits the classic LFS criteria with four family members sequenced, two that developed cancer and two that are cancer-free. B, Pedigree of wildtype TP53 family (WT6) that fits the classic LFS criteria with six family members sequenced: five that developed cancer and one that is cancer-free.

Genomics informed risk stratification guidelines for patients with LFS with a germline TP53 variant

Supplementary Figures

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633–0.810).Significance:Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.

Germline genetic variants in LFS. A, Classification scheme for genetic variants identified from WGS. The pyramid (top) shows how genes were prioritized into four tiers from highest known cancer predisposition potential to lowest. All variants were then classified using a Cancer Variant Classification Schema (Materials and Methods) into five classes (bottom) based on pathogenicity and whether the gene fell into Tier 1–4. AD: autosomal dominant; AR: autosomal recessive; CPG: cancer predisposition gene. B, Frequency of P/LP variants in known cancer genes (class 1–3) in LFS, KiCS and 1kGP. Fisher exact test P values for comparisons between the LFS cohorts and KiCS/1kGP shown. C, Kaplan–Meier survival curve comparing patients with P/LP variants in the WNT signaling pathway (yellow), patients with at least one class 1–3 variant (red) and patients with neither WNT signaling or class 1–3 variants (blue). D, Landscape of genetic alterations in cancer genes (class 1–3) in LFS. Annotated with family, cancer type and TP53 variant status. Genetic variants are indicated as a deletion (blue), SNV or indel (red) or duplication (purple). E, The proportion of individuals in the wildtype and variant TP53 cohorts with classes 1–5 variants (Materials and Methods). F, The number of P/LP variants in cancer genes (class 1–3) in individuals that developed cancer compared with unaffected individuals, stratified by TP53 status. G, The number of P/LP variants (class 1–3) in wildtype versus variant TP53 carriers, stratified by cancer status. On the basis of the premise that variants in the WNT signaling pathway are associated with decreased cancer incidence in LFS, these variants were removed from the comparisons made in F and G.

Differential regulation of WNT signaling and LEF1 in LFS. A, Probes in the WNT signaling pathway (WNT4, SMAD3, SFRP4, SERPINF) significantly associated with cancer status. B, Probe in the body of LEF1 (cg03041109) associated with cancer status (FDR = 0.07). C, Methylation of probe in body of LEF1 (cg03041109) across members within each LFS family. Probands almost unanimously have higher LEF1 methylation than their unaffected family members. D, Plasma cfDNA methylation of the body of LEF1 (chr4:109056901-109057200), between patients with LFS and HBCs. E, Tumor methylation of the body of LEF1 (cg03041109) in CPTs, with and without a germline variant in TP53.

The LFS cohort. A, Patient cohort and characteristics (age of first cancer onset, tumor type) by TP53 status and whether profiling was performed using WGS, methylation or both. AA = adrenal adenoma; ACC = adrenocortical carcinoma; ALL = acute lymphoid leukemia; CPC = choroid plexus carcinoma; CSA = chondrosarcoma; GCT = germ cell tumor; LMS = leiomyosarcoma; MFH = malignant fibrous histiocytoma; MFS = myxofibrosarcoma; NHL = non–Hodgkin lymphoma; OS = osteosarcoma; RMS = rhabdomyosarcoma. B, Lollipop plot displaying the location and number of SNVs and indels on the canonical TP53 transcript: NM_000546, which consists of a TAD, DBD, and tetramerization domain. TP53 hotspot variants present in our cohort (175, 245, 248, 273, 282) are highlighted.

Appendix

Purpose: Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature.Methods: Gene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC).Results: A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P < 0.0001 and P < 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells.Conclusions: These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target. Clin Cancer Res; 21(6); 1457–65. ©2014 AACR.

Figure S1. Sample flow-chart describing the number of biological samples and clinical data obtained through an international multi-institutional effort and the distribution of samples in each microarray

Supplemental Methods and Supplemental Figures 1-9 Supplemental Figure 1. Overview of samples studies and 31-gene signature development Supplemental Figure. 2. Non-negative matrix factorization (NMF) analysis of the combined cohort of medulloblastoma samples (n=168) (A) Cophenetic correlation coefficient based on 2000 clustering runs for 2-10 clusters utilizing genes obtained at varying coefficients of variation; the data demonstrate that the highest cophenetic correlation coefficient was obtained at 4 clusters with 369 genes. (B) NMF consensus heatmap of 4 subgroups using the dataset containing 369 genes with high coefficient of variation. (C) Silhouette plot for identification of outliers. Outliers (n=31) were defined as samples with a silhouette width

Supplemental Tables 1-6 Supplemental Table 1. Patient and tumor characteristics Supplemental Table 2. TLDA design (45 genes) Supplemental Table 3. Information for samples evaluated using HuE Supplemental Table 4. TLDA 31-gene molecular classification of core samples Supplemental Table 5. TLDA 31-gene classification for samples without HuEx data Supplemental Table 6. TLDA 31-gene Confusion Matrix

Table S1-S3. S1Choroid plexus tumor chromosomal instability reported in literature S2-Characterization of patient and sample cohort used in analysis S3 Frequency of TP53 mutations in CPTs and characterization of mutation types. Abbreviations: CPC: choroid plexus carcinoma, CPP: choroid plexus papilloma, aCPP: atypical choroid plexus papilloma, SH3: SRC Homology 3 Domain

supplemental figure and table legend

Purpose: To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options.Experimental Design: One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes.Results: Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%–46.5% vs. 66.7%, 28.2%–87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%–71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival.Discussion: Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs. Clin Cancer Res; 21(1); 184–92. ©2014 AACR.

PURPOSE Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% ( P = .0187), respectively. In multivariable analysis, localized relapse ( P = .0073), SHH molecular subgroup ( P = .0103), CSI use after relapse ( P = .0161), and age ≥ 36 months at initial diagnosis ( P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy ( P = .007). CONCLUSION A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

PURPOSE Pediatric neuro-oncology resources are mostly unknown in Chile. We report the human and material resources available in Chilean hospitals providing pediatric neuro-oncology services. METHODS A cross-sectional survey was distributed to 17 hospitals providing pediatric neuro-oncology services (Programa Infantil Nacional de Drogas Antineoplásicas [PINDA] hospitals, 11; private, 6). RESULTS Response rate was 71% (PINDA, 8; private, 4). Pediatric neuro-oncology services were mainly provided within general hospitals (67%). Registries for pediatric CNS tumors and chemotherapy-related toxicities were available in 100% and 67% of hospitals, respectively. CNS tumors were treated by pediatric oncologists in 92% of hospitals; none were formally trained in neuro-oncology. The most used treatment protocols were the national PINDA protocols. All WHO essential medicines for childhood cancer were available in more than 80% of the hospitals except for gemcitabine, oxaliplatin, paclitaxel, and procarbazine. The median number of pediatric neurosurgeons per hospital was two (range, 2-6). General neuroradiologists were available in 83% of the centers. Pathology specimens were sent to neuropathologists (58%), adult pathologists (25%), and pediatric pathologists (17%). Intensity-modulated radiotherapy, conformal radiotherapy, and cobalt radiotherapy were used by 67%, 58%, and 42% of hospitals, respectively. Only one private hospital performed autologous hematopoietic cell transplant for children with CNS tumors. CONCLUSION A wide range of up-to-date treatment modalities are available for children with CNS tumors. Our survey highlights future directions to improve the pediatric neuro-oncology services available in Chile such as the expansion of multidisciplinary clinics, palliative care services, long-term cancer survivorship programs, dedicated clinical research support teams, establishing standardized mechanism for sending pathologic specimen for second opinion to international specialized centers, and establishing specialized neuro-oncology training program.

Persistent activation of signal transducer and activator of transcription 3 (STAT3) is frequently reported in cancers and plays important roles in tumor progression. Therefore, directly targeting persistent STAT3 signaling is an attractive cancer therapeutic strategy. The aim of this study is to test the inhibitory efficacy of novel STAT3 small molecule inhibitors, LLY17 and LLL12B, in combination with irradiation in human medulloblastoma cells. Both LLY17 and LLL12B inhibit the IL-6-induced and persistent STAT3 phosphorylation in human medulloblastoma cells. Irradiation using 4 Gy alone exhibits some inhibitory effects on medulloblastoma cell viability, and these effects are further enhanced by combining with either STAT3 inhibitor. Irradiation alone also shows certain inhibitory effects on medulloblastoma cell migration and invasion and the combination of LLY17 or LLL12B with irradiation further demonstrates greater inhibitory effects than monotherapy. STAT3 inhibitor alone or irradiation alone exhibits some suppression of medulloblastoma tumorsphere growth, and the combination of LLY17 or LLL12B and irradiation exhibits greater suppression of tumorsphere growth than monotherapy. Combining either STAT3 inhibitor with irradiation reduces the expression of STAT3 downstream targets, Cyclin D1 and Survivin, and induces apoptosis in medulloblastoma cells. These results support that combination of a potent STAT3 inhibitor such as LLY17 or LLL12B with irradiation is an effective and novel therapeutic approach for medulloblastoma.

Ependymal tumors are the third most common brain tumor under 14 years old. Even though metastatic disease is a rare event, it affects mostly young children and carries an adverse prognosis. The factors associated with dissemination and the best treatment approach have not yet been established and there is limited published data on how to manage metastatic disease, especially in patients under 3 years of age. We provide a review of the literature on clinical characteristics and radiation-sparing treatments for metastatic ependymoma in children under 3 years of age treated. The majority (73%) of the identified cases were above 12 months old and had the PF as the primary site at diagnosis. Chemotherapy-based approaches, in different regimens, were used with radiation reserved for progression or relapse. The prognosis varied among the studies, with an average of 50%-58% overall survival. This study also describes the case of a 7-month-old boy with metastatic posterior fossa (PF) ependymoma, for whom we identified a novel SPECC1L-RAF1 gene fusion using a patient-centric comprehensive molecular profiling protocol. The patient was successfully treated with intensive induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic progenitor cell rescue (AuHSCR). Currently, the patient is in continuous remission 5 years after his diagnosis, without radiation therapy. The understanding of the available therapeutic approaches may assist physicians in their management of such patients. This report also opens the perspective of newly identified molecular alterations in metastatic ependymomas that might drive more chemo-sensitive tumors.

Background The Head Start treatment protocols have focused on curing young children with brain tumors while avoiding or delaying radiotherapy through using a combination of high-dose, marrow-ablative chemotherapy and autologous hematopoietic cell transplantation (AuHCT). Late effects data from treatment on the Head Start II (HS II) protocol have previously been published for short-term follow-up (STF) at a mean of 39.7 months post-diagnosis. The current study examines long-term follow-up (LTF) outcomes from the same cohort. Methods Eighteen HS II patients diagnosed with malignant brain tumors Results There was no significant change in Full Scale IQ at LTF compared to baseline or STF. Similarly, most domains had no significant change from STF, including verbal IQ, performance IQ, academics, receptive language, learning/memory, visual-motor integration, and externalizing behaviors. Internalizing behaviors increased slightly at LTF. Clinically, most domains were within the average range, except for low average mathematics and receptive language. Additionally, performance did not significantly differ by age at diagnosis or time since diagnosis. Of note, children treated with high-dose methotrexate for disseminated disease or atypical teratoid/rhabdoid tumor displayed worse neurocognitive outcomes. Conclusions These results extend prior findings of relative stability in intellectual functioning for a LTF period. Ultimately, this study supports that treatment strategies for avoiding or delaying radiotherapy using high-dose, marrow-ablative chemotherapy and AuHCT may decrease the risk of neurocognitive and social-emotional declines in young pediatric brain tumor survivors.

Wnt-activated medulloblastoma (MB) confers an excellent prognosis. However, specific treatment strategies for patients with relapsed Wnt-MB are unknown. We report two patients with recurrent beta-catenin nucleopositive Wnt-MB successfully treated by incorporating marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (HDCx/AuHPCR). We also present a review of the literature for previously reported cases of relapsed Wnt-MB. We propose that patients with recurrent Wnt-MB may be treated using a multi-disciplinary approach that includes HDCx/AuHPCR with or without re-irradiation.

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor and an oncogene product, which plays a pivotal role in tumor progression. Therefore, targeting persistent STAT3 signaling directly is an attractive anticancer strategy. The aim of this study is to test the efficacy of a novel STAT3 small molecule inhibitor, LLL12B, in suppressing medulloblastoma cells in vitro and tumor growth in vivo. LLL12B selectively inhibited the induction of STAT3 phosphorylation by interleukin-6 but not induction of STAT1 phosphorylation by INF-γ. LLL12B also induced apoptosis in human medulloblastoma cells. In addition, LLL12B exhibited good oral bioavailability in vivo and potent suppressive activity in tumor growth of medulloblastoma cells in vivo. Besides, combining LLL12B with cisplatin showed greater inhibition of cell viability and tumorsphere formation as well as induction of apoptosis comparing to single agent treatment in medulloblastoma cells. Furthermore, LLL12B and cisplatin combination exhibited greater suppression of medulloblastoma tumor growth than monotherapy in vivo. The present study supported that LLL12B is a novel therapeutic agent for medulloblastoma and the combination of LLL12B with a chemotherapeutic agent cisplatin may be an effective approach for medulloblastoma therapy.

Medulloblastoma is the most common malignant brain tumor in children. While survival has improved in high-income countries (HIC), the outcomes for patients in low-to-middle-income countries (LMIC) are unclear. Therefore, we sought to determine the survival of children with medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 and 2013 in Peru.Between 1997 and 2013, data from 103 children older than 3 years with medulloblastoma were analyzed. Fourteen patients were excluded. The patients were split into two distinct cohorts, 1997-2008 and 2009-2013, corresponding with chemotherapy regimen changes. Event-free (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method, whereas prognostic factors were determined by univariate analysis (log-rank test).Eighty-nine patients were included; median age was 8.1 years (range: 3-13.9 years). The 5-year OS was 62% (95% CI: 53%-74%), while EFS was 57% (95% CI: 48%-69%). The variables adversely affecting survival were anaplastic histology (compared to desmoplastic; OS: HR = 3.4, p = .03), metastasis (OS: HR = 3.5, p = .01; EFS: HR = 4.3, p = .004), delay in radiation therapy of 31-60 days (compared to ≤30 days; EFS: HR = 2.1, p = .04), and treatment 2009-2013 cohort (OS: HR = 2.2, p = .02; EFS: HR = 2.0, p = .03).Outcomes for medulloblastoma at INEN were low compared with HIC. Anaplastic subtype, metastasis at diagnosis, delay in radiation therapy, and treatment in the period 2009-2013 negatively affected the outcomes in our study. Multidisciplinary teamwork, timely delivery of treatment, and partnerships with loco-regional groups and colleagues in HIC is likely beneficial.

Metastatic atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy, and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patients.We performed a meta-analysis of 1578 articles published through September 2018, including 44 studies with a total of 123 subjects. In addition, seven patients were included through chart review of patients treated at Nationwide Children's Hospital.Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant effect on survival (P = 0.0355); 3-year OS for infants less than 18 months was 21%, 18 to 36 months was 26%, and greater than 36 months was 36%. Location of the primary tumor, metastatic stage, and extent of surgical resection did not have a significant impact on OS. On univariate analysis, XRT (P0.0001), IT (P = 0.01), and AuHCR (P0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% vs 9% in those who did not). On multivariable analysis, XRT (P = 0.0006), IT (P = 0.0124), and AuHCR (P0.0001) were independently associated with reduced risk of death.Although more research is warranted to make generalizable conclusions, these results suggest that treatment regimens for patients with metastatic AT/RTs should include AuHCR, XRT, and IT.

The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.

BACKGROUND: Medulloblastoma (MB), the most malignant brain tumor of childhood has survival outcomes exceeding 80% for standard risk and 60% for high risk patients in high-income countries (HIC). These results have not been replicated in low-to-middle income countries (LMIC), where 80% of children with cancer live. METHODS: Retrospective review of 114 children (3-18 years) diagnosed with MB from 1997 to 2016 at INCA. Data on patients, disease characteristics and treatment information were retrieved from the charts and summarized descriptively. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier Method. RESULTS: The male/female ratio was 1.32 and the median age at diagnosis was 8.2 years. Headache (83%) and nausea/vomiting (78%) were the most common presenting symptoms. Overall survival (5y) was 59,1% and EFS (5y) was 58,4%. The OS for standard-risk patients was 69% and 53% for high-risk patients. Forty-five patients (35%) had metastatic disease at admission. Lower maternal education correlated with lower OS (71.3% versus 49% p=0.25). Patients who lived >40km from INCA fared better (OS= 68.2% versus 51.1% p=0.032). Almost 20% of families lived below the Brazilian minimum wage. CONCLUSIONS: The epidemiological characteristics of this series possibly explain the differences in survival that medulloblastoma patients have in Brazil. Issues related to limited health care resources, poverty, delayed diagnosis, treatment abandonment, and malnutrition are reflected in inferior survival outcomes when compared to high-income countries. Despite the difficulties encountered in an upper-middle income country, it was possible to deliver treatment with good results.

We aimed toidentify prognostic factors that may help better understand the behavior of relapsed central nervous system nongerminomatous germ cell tumors. We identified nine studies, including 101 patients; 33 patients (33%) were alive 12 months post-initial relapse. Sixty percent of patients with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level ≤25 ng/mL at initial diagnosis were survivors compared with 28% among patients with serum/CSF AFP level >25 ng/mL (P = 0.01). Seventy-one percent of patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy at relapse were survivors compared with 7% among patients who had less than CR/CCR (P < 0.0001). Forty-eight percent of patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) following relapse were survivors compared with 12% among patients who did not receive HDCx/AuHCR (P = 0.0001). Local relapse site, gross total surgical resection, and radiotherapy at relapse were not associated with improved outcomes.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of non-metastatic BGTGs, the 5- and 10-year event-free survival (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survival (OS) were 100%, and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980 to 2400 cGy/cGy[RBE]), WBI: 2340 (1800 to 3000 cGy/cGy[RBE]), WVI: 2340 cGy/cGy(RBE) (1800 to 2550 cGy/cGy[RBE]), focal: 3600 cGy (3060 to 5400 cGy). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p=0.84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p=0.0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

Background:Medulloblastoma is the most common malignant brain tumor in children. Despite improvement in overall survival rate, it still lacks an effective targeted treatment strategy. The Janus family of cytoplasmic tyrosine kinases (JAKs) and Src kinases, upstream protein kinases of signal transducer and activator of transcription 3 (STAT3), play important roles in medulloblastoma pathogenesis and therefore represent potential therapeutic targets.Methods:In this report, we examined the inhibitory efficacy of the JAK1/2 inhibitor, ruxolitinib, the JAK3 inhibitor, tofacitinib and two Src inhibitors, KX2-391 and dasatinib.Results:These small molecule drugs significantly reduce cell viability and inhibit cell migration and colony formation in human medulloblastoma cells in vitro. Src inhibitors have more potent efficacy than JAK inhibitors in inhibiting medulloblastoma cell migration ability. The Src inhibitors can inhibit both phosphorylation of STAT3 and Src while JAK inhibitors reduce JAK/STAT3 phosphorylation. We also investigated the combined effect of the Src inhibitor, dasatinib with cisplatin. The results show that dasatinib exerts synergistic effects with cisplatin in human medulloblastoma cells through the inhibition of STAT3 and Src.Conclusion:Our results suggest that the small molecule inhibitors of STAT3 upstream kinases, ruxolitinib, tofacitinib, KX2-391, and dasatinib could be novel and attractive candidate drugs for the treatment of human medulloblastoma.

Germ cell tumors (GCT) in the central nervous system (CNS) are rare tumors that occur with highest frequency in males, Asian populations, and children less than age 20 years. Due to the rarity of these tumors, their patterns of incidence are not well-described. The aim of this study is to provide the most up-to-date data on incidence and survival patterns for CNS GCT by sex, race, and age at diagnosis. The Central Brain Tumor Registry of the United States (CBTRUS) is the largest aggregation of population-based incidence data on primary brain and other CNS tumors in the United States, containing incidence data from 51 central cancer registries and representing 100% of the US population. The current study used the CBTRUS analytic file to examine incidence (IR) of CNS GCT from 2006 to 2015, as well as registry data from the Surveillance, Epidemiology, and End Results (SEER) program to examine survival. Males had greater IR than females in all CNS GCT histologies examined. Asian and Pacific Islanders had a significantly greater IR of CNS GCT than the other race categories. We confirmed that CNS GCT IR was greatest for those age 10–14 years and male. Overall survival rates were high for malignant CNS GCT, germinoma, mixed GCT, and malignant teratoma. There is significant variation in CNS GCT incidence by sex, race, and age at diagnosis. Ascertaining accurate incidence and survival rates of CNS GCT provides vital information usable in real time for clinicians, public health planners, patients, and their families.