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Data in Brief Oct 2020Methylation profiling is widely used to study tumor biology and perform cluster analysis, particularly in brain cancer research where tissue biopsies are scarce. We have...
Methylation profiling is widely used to study tumor biology and perform cluster analysis, particularly in brain cancer research where tissue biopsies are scarce. We have recently reported on the development of novel mouse models for germ line mutations in pineoblastoma (, 2020). Here, we present unpublished methylation profiling of 8 Rb-deleted/p53-deleted pineoblastoma from our mouse model as well as 3 normal cerebellum tissues as control. The primary dataset can be accessed via SRA (PRJNA638504). These methylation data can be used to perform inter- and intra-species comparisons with other brain cancers as well as with specific subtypes of pineoblastoma, and to investigate potential epigenetic mechanisms and pathways underlying Rb-deficient pineoblastoma-genesis..
PubMed: 32923545
DOI: 10.1016/j.dib.2020.106229 -
Pediatric Neurosurgery 2023Embryonal tumors are highly malignant cancers of the central nervous system, with a relatively high incidence in infants and young children. Even with intensive... (Review)
Review
BACKGROUND
Embryonal tumors are highly malignant cancers of the central nervous system, with a relatively high incidence in infants and young children. Even with intensive multimodal treatment, the prognosis of many types is guarded, and treatment-related toxicity is significant. Recent advances in molecular diagnostics allowed the discovery of novel entities and inter-tumor subgroups, with opportunities for improved risk-stratification and treatment approaches.
SUMMARY
Medulloblastomas separate into four distinct subgroups with distinct clinicopathologic characteristics, and data from recent clinical trials for newly diagnosed medulloblastoma support subgroup-specific treatment approaches. Atypical teratoid rhabdoid tumor (ATRT), embryonal tumor with multilayered rosettes (ETMR), and pineoblastoma, as well as other rare embryonal tumors, can be distinguished from histologically similar tumors by virtue of characteristic molecular findings, with DNA methylation analysis providing a strong adjunct in indeterminate cases. Methylation analysis can also allow further subgrouping of ATRT and pineoblastoma. Despite the dire need to improve outcomes for patients with these tumors, their rarity and lack of actionable targets lead to a paucity of clinical trials and novel therapeutics.
KEY MESSAGES
(1) Embryonal tumors can be accurately diagnosed with pediatric-specific sequencing techniques. (2) Medulloblastoma risk stratification and treatment decisions should take into account molecular subgroups. (3) There is a dire need for a novel collaborative clinical trial design to improve outcomes is rare pediatric embryonal tumors.
Topics: Child, Preschool; Humans; Infant; Brain Neoplasms; Central Nervous System Neoplasms; Cerebellar Neoplasms; Medulloblastoma; Neoplasms, Germ Cell and Embryonal; Pineal Gland; Pinealoma; Rhabdoid Tumor; Clinical Trials as Topic
PubMed: 37245504
DOI: 10.1159/000531256 -
Neuro-oncology Advances 2022Pineoblastoma is a rare brain tumor usually diagnosed in children. Given its rarity, no pineoblastoma-specific trials have been conducted. Studies have included...
BACKGROUND
Pineoblastoma is a rare brain tumor usually diagnosed in children. Given its rarity, no pineoblastoma-specific trials have been conducted. Studies have included pineoblastoma accruing for other embryonal tumors over the past 30 years. These included only occasional children with pineoblastoma, making clinical features difficult to interpret and determinants of outcome difficult to ascertain.
PATIENTS AND METHODS
Centrally or independently reviewed series with treatment and survival data from North American and Australian cases were pooled. To investigate associations between variables, Fisher's exact tests, Wilcoxon-Mann-Whitney tests, and Spearman correlations were used. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analyses.
RESULTS
We describe a pooled cohort of 178 pineoblastoma cases from Children's Oncology Group (n = 82) and institutional series (n = 96) over 30 years. Children <3 years of age have significantly worse survival compared to older children, with 5-year progression-free survival (PFS) and overall survival (OS) estimates of 13.5 ± 5.1% and 16.2 ± 5.3%, respectively, compared with 60.8 ± 5.6% and 67.3 ± 5.0% for ≥3 years old (both < .0001). Multivariable analysis showed male sex was associated with worse PFS in children <3 years of age (hazard ratio [HR] 3.93, 95% CI 1.80-8.55; = .0006), suggestive of sex-specific risks needing future validation. For children ≥3 years of age, disseminated disease at diagnosis was significantly associated with an inferior 5-year PFS of 39.2 ± 9.7% (HR 2.88, 95% CI 1.52-5.45; = .0012) and 5-year OS of 49.8 ± 9.1% (HR 2.87, 95% CI 1.49-5.53; = .0016).
CONCLUSION
Given the rarity of this tumor, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.
PubMed: 35664557
DOI: 10.1093/noajnl/vdac056 -
Clinical Cancer Research : An Official... Jul 2017Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the... (Review)
Review
Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in and account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop. .
Topics: Anaplastic Lymphoma Kinase; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; Neuroblastoma; Neuroimaging; Pinealoma; Receptor Protein-Tyrosine Kinases; Retinoblastoma; Retinoblastoma Binding Proteins; Transcription Factors; Ubiquitin-Protein Ligases
PubMed: 28674118
DOI: 10.1158/1078-0432.CCR-17-0652 -
Ochsner Journal 2019The pineal gland, a small, pinecone-shaped organ deep within the brain, is responsible for producing melatonin. The gland consists of pineal parenchymal cells and glial... (Review)
Review
The pineal gland, a small, pinecone-shaped organ deep within the brain, is responsible for producing melatonin. The gland consists of pineal parenchymal cells and glial cells that can form neoplasms. Pineal region neoplasms can also arise from germ cells and adjacent structures. This review focuses on detection of serum and cerebrospinal fluid (CSF) biomarkers of germ cell tumors and pineal parenchymal cell tumors, as these types comprise most neoplasms specific to the pineal region. For this review, we searched PubMed using the following keywords: biomarkers, germ cell tumor, germinoma, melatonin, pineal, pineal gland, pineal neoplasm, pinealoma, pineal parenchymal cell tumor, pineal region, and pineal tumor. We limited our search to full-text English articles and identified other relevant sources from the reference lists of identified articles. Serum and CSF biomarker assays have a role in cases of suspected pineal germ cell or parenchymal neoplasms. Biomarkers including alpha-fetoprotein, beta-human chorionic gonadotropin, and placental alkaline phosphatase inform diagnosis and treatment and are important for monitoring germ cell tumor response to treatment. No biomarkers are currently available that inform diagnosis or treatment of pineal parenchymal tumors, although melatonin assays may have a role in monitoring response to treatment. Serum and CSF biomarkers in conjunction with clinical and radiographic evidence of a pineal region mass can inform the decision whether to undertake stereotactic biopsy or surgical excision or whether to proceed straight to medical treatment.
PubMed: 30983898
DOI: 10.31486/toj.18.0110 -
Journal of Neurosurgery. Pediatrics Sep 2022DICER1-mutant malignant brain neoplasms are very rare tumors, and published data have relied on case reports or small case series. In this review, the authors aimed to... (Review)
Review
OBJECTIVE
DICER1-mutant malignant brain neoplasms are very rare tumors, and published data have relied on case reports or small case series. In this review, the authors aimed to systematically summarize the types and distribution patterns of DICER1 mutations, clinicopathological characteristics, and prognostic outcomes of these tumors.
METHODS
The authors searched PubMed and Web of Science for relevant studies. They included studies if they provided individual patient data of primary malignant brain tumors carrying DICER1 mutations.
RESULTS
The authors found 16 studies consisting of 9 embryonal tumors with multilayered rosettes (ETMRs), 30 pineoblastomas, 52 primary intracranial sarcomas, and 27 pituitary blastomas. Pineoblastoma, ETMR, and pituitary blastoma were more likely to carry DICER1 germline mutations, while only a small subset of primary intracranial sarcomas harbored these mutations (p < 0.001). Nearly 80% of tumors with germline mutations also had another somatic mutation in DICER1. ETMR and primary intracranial sarcoma were associated with an increased risk for tumor progression and relapse compared with pituitary blastoma and pineoblastoma (p = 0.0025), but overall survival (OS) was not significantly different. Gross-total resection (GTR) and radiotherapy administration were associated with prolonged OS.
CONCLUSIONS
ETMR, pineoblastoma, primary intracranial sarcoma, and pituitary blastoma should be considered rare phenotypes of the DICER1 syndrome, and families should be counseled and screened for associated tumors. ETMR and primary intracranial sarcoma had a higher risk of relapse. GTR and radiotherapy appeared to improve the OS of patients with DICER1-mutant malignant intracranial tumors.
PubMed: 35901678
DOI: 10.3171/2022.6.PEDS22119 -
Neuro-oncology Advances 2022The management of pineal parenchymal tumors remains controversial.
Survival and associated predictors for patients with pineoblastoma or pineal parenchymal tumors of intermediate differentiation older than 3 years: Insights from the National Cancer Database.
BACKGROUND
The management of pineal parenchymal tumors remains controversial.
METHODS
The 2004-2017 National Cancer Database was queried for cases (age >3 years) with histologically confirmed pineal parenchymal tumors of intermediate differentiation (PPTID, n = 90) or pineoblastoma (n = 106).
RESULTS
Within the PPTID group, median age was 41 years; 49% were males. Five- and 10-year survival were 83% and 78%, respectively. Adjuvant radiation and chemotherapy were administered in 64% and 17% patients, respectively. The effect of radiation with or without chemotherapy (HR 1.15, = .81, and HR 1.31, = .72, respectively), and extent of resection (HR = 1.07, = .93) was not significant. Within the pineoblastoma group, median age was 25 years; 51% were males. Five- and 10-year survival were 66% and 42%, respectively. Adjuvant radiation and chemotherapy were administered in 72% and 51%, respectively. In multivariable analysis, patients with pineoblastoma who received both radiation and chemotherapy (n = 39) had significantly lower hazard of death (HR 0.35, 95% CI 0.14-0.85, = .02) compared to those who received radiation alone (n = 20) or no adjuvant treatment (n = 19). Finally, females in the pineoblastoma group were found to have a lower hazard of death compared to males (HR 0.24, 95% CI 0.10-0.58, = .001); this comparison trended toward statistical significance in the PPTID subgroup (HR 0.40, 95% CI 0.14-1.08, = .07).
CONCLUSIONS
Survival rates were higher in patients with PPTID vs patients with pineoblastoma. Adjuvant chemoradiation was associated with improved survival in pineoblastoma and females had lower hazards of death. Further research should identify specific patient profiles and molecular subgroups more likely to benefit from multimodality therapy.
PubMed: 35611271
DOI: 10.1093/noajnl/vdac057 -
Acta Neuropathologica Feb 2020Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation...
Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B-like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B-like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.
Topics: Adolescent; Age Factors; Brain Neoplasms; Child; Child, Preschool; Cohort Studies; DNA Methylation; Female; Humans; Male; Pineal Gland; Pinealoma; Proto-Oncogene Mas; Risk Factors; Survival Rate; Young Adult
PubMed: 31802236
DOI: 10.1007/s00401-019-02106-9 -
Chinese Medical Journal Feb 2023
Topics: Humans; Child; Child, Preschool; Pinealoma; Prognosis; Brain Neoplasms; Pineal Gland
PubMed: 36989486
DOI: 10.1097/CM9.0000000000002063 -
Nature Communications Apr 2020Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of...
Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.
Topics: Animals; Autophagosomes; Autophagy; Cluster Analysis; Disease Models, Animal; Gene Deletion; Germ-Line Mutation; Humans; Integrases; Kaplan-Meier Estimate; Lysosomes; Mice; Neoplasm Metastasis; Nortriptyline; Pinealoma; Retinoblastoma Protein; Tumor Suppressor Protein p53
PubMed: 32286280
DOI: 10.1038/s41467-020-15585-2