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Nature Methods Aug 2018Brain tumors are among the most lethal and devastating cancers. Their study is limited by genetic heterogeneity and the incompleteness of available laboratory models....
Brain tumors are among the most lethal and devastating cancers. Their study is limited by genetic heterogeneity and the incompleteness of available laboratory models. Three-dimensional organoid culture models offer innovative possibilities for the modeling of human disease. Here we establish a 3D in vitro model called a neoplastic cerebral organoid (neoCOR), in which we recapitulate brain tumorigenesis by introducing oncogenic mutations in cerebral organoids via transposon- and CRISPR-Cas9-mediated mutagenesis. By screening clinically relevant mutations identified in cancer genome projects, we defined mutation combinations that result in glioblastoma-like and central nervous system primitive neuroectodermal tumor (CNS-PNET)-like neoplasms. We demonstrate that neoCORs are suitable for use in investigations of aspects of tumor biology such as invasiveness, and for evaluation of drug effects in the context of specific DNA aberrations. NeoCORs will provide a valuable complement to the current basic and preclinical models used to study brain tumor biology.
Topics: Animals; Brain Neoplasms; Disease Models, Animal; Genes, myc; Genetic Engineering; Glioblastoma; Heterografts; Human Embryonic Stem Cells; Humans; Male; Mice; Mice, Nude; Mutation; Neuroectodermal Tumors, Primitive; Oncogenes; Organoids; Transcriptome; Xenograft Model Antitumor Assays
PubMed: 30038414
DOI: 10.1038/s41592-018-0070-7 -
Pediatric Blood & Cancer Aug 2021Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial.
BACKGROUND
Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients receiving temozolomide (TMZ) and irinotecan with that of patients receiving TMZ, irinotecan, and bevacizumab for recurrent MB/central nervous system (CNS) primitive neuroectodermal tumor (PNET).
METHODS
Patients with relapsed/refractory MB or CNS PNET were randomly assigned to receive TMZ (150 mg/m /day PO on days 1-5) and irinotecan (50 mg/m /day IV on days 1-5) with or without bevacizumab (10 mg/kg IV on days 1 and 15).
RESULTS
One hundred five patients were eligible and treated on study. Median OS was 13 months in the standard arm and 19 months with the addition of bevacizumab; median event-free survival (EFS) was 6 months in the standard arm and 9 months with the addition of bevacizumab. The hazard ratio for death from the stratified relative-risk regression model is 0.63. Overall, 23 patients completed 12 courses of planned protocol therapy, 23% (12/52) in the experimental arm with bevacizumab versus 21% (11/53) in the standard arm. Toxicity profiles were comparable in both treatment arms. The estimate of the incidence of feasibility events associated with the bevacizumab arm is three of 52 (5.8%) (95% CI 1.2-16%). Events included myelosuppression, electrolyte abnormalities, diarrhea, and elevated transaminases. One intracranial hemorrhage event was observed in each arm.
CONCLUSION
The addition of bevacizumab to TMZ/irinotecan significantly reduced the risk of death in children with recurrent MB. The combination was relatively well tolerated in this heavily pretreated cohort. The three-drug regimen demonstrated a sufficient risk reduction to warrant further investigation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Child; Humans; Irinotecan; Medulloblastoma; Neuroectodermal Tumors, Primitive; Temozolomide
PubMed: 33844469
DOI: 10.1002/pbc.29031 -
Annals of Oncology : Official Journal... Sep 2013Renal Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is extremely rare. Clinical symptoms are nonspecific presenting abdominal pain, palpable mass, and...
BACKGROUND
Renal Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is extremely rare. Clinical symptoms are nonspecific presenting abdominal pain, palpable mass, and hematuria. Owing to advanced technology demonstrating the ES-specific EWS/ETS translocation, this differential diagnosis has become feasible.
PATIENTS AND METHODS
The German database of GPOH Ewing's sarcoma trials from 1980 to 2009 was searched for kidney as primary site. Twenty-four patients were identified and analyzed. The median time of observation was 3.71 years (range 0.27-8.75 years). Additionally, we carried out a Medline search for renal ES/PNET.
RESULTS
The median age was 24.9 years (range 11-60 years). In 37.5%, patients presented with primary metastases. Tumor thrombi in the adjacent renal vessels occurred in 56.2%. In 90.9%, rearrangements of t(11;22) were found. All patients received a combined chemotherapy according to the EURO-E.W.I.N.G.99 protocol. In accordance, local control consisted predominantly of combined modality surgery and radiation (47%). At 3 years, overall survival (OS) was 0.80 (SE = 0.09), and event-free survival (EFS) 0.66 (SE = 0.11).
CONCLUSIONS
ES/PNET should be considered in the differential diagnosis of renal tumors. Patients with renal ES/PNET respond to and benefit from conventional ES treatment according to ES study protocols. Therefore, an accurate diagnostic approach and a guideline-adapted therapy should be facilitated.
Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Clinical Trials as Topic; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Kidney; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neuroectodermal Tumors, Primitive; Sarcoma, Ewing; Survival; Young Adult
PubMed: 23761687
DOI: 10.1093/annonc/mdt215 -
Archives of Pathology & Laboratory... Feb 2012Intraocular medulloepithelioma is a congenital tumor of the ciliary epithelium that typically presents during the first decade of life. The histologic diagnosis is based... (Review)
Review
Intraocular medulloepithelioma is a congenital tumor of the ciliary epithelium that typically presents during the first decade of life. The histologic diagnosis is based on characteristic ribbons of pseudostratified neuroepithelium admixed with loose mesenchymal tissue rich in hyaluronic acid, vaguely resembling developing retina and vitreous. More than a third of medulloepitheliomas contain heteroplastic tissue, which in some cases makes up most of the tumor. Malignant medulloepitheliomas consist of a proliferation of neuroblasts, which in areas can be indistinguishable from retinoblastoma. Unlike its highly malignant counterpart in the central nervous system, intraocular medulloepithelioma has a good prognosis as long as tumor has not spread beyond the eye. Definitive diagnosis and eye-conserving therapy is possible with fine-needle aspiration biopsy. The histologic differential diagnosis of medulloepithelioma is broad, ranging from retinoblastoma and sarcoma to ciliary epithelial adenoma and adenocarcinoma.
Topics: Diagnosis, Differential; Eye; Eye Neoplasms; Humans; Neuroectodermal Tumors, Primitive; Prognosis; Retinoblastoma
PubMed: 22288972
DOI: 10.5858/arpa.2010-0669-RS -
Indian Journal of Pathology &... May 2022Embryonal tumors are a heterogenous group of neoplasms mostly defined by recurrent genetic driver events. They have been, previously, broadly classified as either... (Review)
Review
Embryonal tumors are a heterogenous group of neoplasms mostly defined by recurrent genetic driver events. They have been, previously, broadly classified as either medulloblastoma or supratentorial primitive neuroectodermal tumors (PNETs). However, the application of DNA methylation/gene expression profiling in large series of neoplasms histologically defined as PNET, revealed tumors, which showed genetic events associated with glial tumors. These findings led to the definitive removal of the term "PNET" in the 2016 World Health Organization (WHO) classification of CNS tumors. Moreover, further studies on a large scale of methylation profiling have allowed the identification of new molecular-defined entities and have largely influenced the 5 edition of the WHO classification of CNS tumors (WHO CNS5) for both medulloblastomas and other CNS embryonal tumors. The importance of molecular characteristics in CNS embryonal tumors is well represented by the identification of different molecular groups and subgroups in medulloblastoma. So, in the CNS5, the emerged group 3 and group 4 belong to the classification, and the four molecular and morphologic types are now combined into a unique section. Among other embryonal tumors, two new recognized entities are introduced in CNS5: CNS neuroblastoma, FOXR2-activated, and CNS tumor with BCOR internal tandem duplication (ITD). Embryonal tumor with multilayered rosettes (ETMR), already present in the previous classification now has a revised nomenclature as a result of the new DICER1 alteration, additional to the formerly known C19MC. Regarding atypical teratoid/rhabdoid tumor (AT/RT), three molecular subgroups are recognized in CNS5. The combination of histopathological and molecular features reflects the complexity of all these tumors and gives critical information in terms of prognosis and therapy. This encourages the use of a layered diagnostic report with the integrated diagnosis at the top, succeeded by layers including the histological, molecular, and other essential details.
Topics: Brain Neoplasms; Central Nervous System Neoplasms; Cerebellar Neoplasms; DEAD-box RNA Helicases; Forkhead Transcription Factors; Humans; Medulloblastoma; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive; Ribonuclease III; World Health Organization
PubMed: 35562137
DOI: 10.4103/ijpm.ijpm_1049_21 -
Frontiers in Endocrinology 2023Reprogramming of cellular metabolism is now a hallmark of tumorigenesis. In recent years, research on pancreatic neuroendocrine tumors (pNETs) has focused on genetic and... (Review)
Review
INTRODUCTION
Reprogramming of cellular metabolism is now a hallmark of tumorigenesis. In recent years, research on pancreatic neuroendocrine tumors (pNETs) has focused on genetic and epigenetic modifications and related signaling pathways, but few studies have been devoted to characterizing the metabolic profile of these tumors. In this review, we thoroughly investigate the metabolic pathways in pNETs by analyzing the transcriptomic and metabolomic data available in the literature.
METHODOLOGY
We retrieved and downloaded gene expression profiles from all publicly available gene set enrichments (GSE43797, GSE73338, and GSE117851) to compare the differences in expressed genes based on both the stage and MEN1 mutational status. In addition, we conducted a systematic review of metabolomic data in NETs.
RESULTS
By combining transcriptomic and metabolomic approaches, we have identified a distinctive metabolism in pNETs compared with controls without pNETs. Our analysis showed dysregulations in the one-carbon, glutathione, and polyamine metabolisms, fatty acid biosynthesis, and branched-chain amino acid catabolism, which supply the tricarboxylic acid cycle. These targets are implicated in pNET cell proliferation and metastasis and could also have a prognostic impact. When analyzing the profiles of patients with or without metastasis, or with or without MEN1 mutation, we observed only a few differences due to the scarcity of published clinical data in the existing research. Consequently, further studies are now necessary to validate our data and investigate these potential targets as biomarkers or therapeutic solutions, with a specific focus on pNETs.
Topics: Humans; Pancreatic Neoplasms; Neuroendocrine Tumors; Prognosis; Epigenesis, Genetic; Neuroectodermal Tumors, Primitive
PubMed: 37908747
DOI: 10.3389/fendo.2023.1248575 -
Journal of Child Neurology Oct 2008Embryonal tumors are the most common brain tumors in infants less than 36 months. Histologically characterized as undifferentiated small, round cell tumors with... (Review)
Review
Embryonal tumors are the most common brain tumors in infants less than 36 months. Histologically characterized as undifferentiated small, round cell tumors with divergent patterns of differentiation, these include medulloblastoma, the most common form of embryonal tumor, as well as supratentorial primitive neuroectodermal tumor, medulloepithelioma, ependymoblastoma, medullomyoblastoma, melanotic medulloblastoma, and atypical teratoid/rhabdoid tumor. All are similarly aggressive and have a tendency to disseminate throughout the central nervous system. Because of efforts to avoid craniospinal irradiation in an attempt to lessen treatment-related neurotoxicity, management of these tumors in infants is unique. Outcomes remain similarly poor among all the tumor types and, therefore, identification of specific molecular targets that have prognostic and therapeutic implications is crucial. The molecular and clinical aspects of the 3 most common aggressive infantile embryonal tumors, medulloblastoma, supratentorial primitive neuroectodermal tumor, and atypical teratoid/rhabdoid tumor, are the focus of this review.
Topics: Biomarkers, Tumor; Brain Neoplasms; Humans; Infant; Infant, Newborn; Medulloblastoma; Neoplasm Metastasis; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors; Rhabdoid Tumor
PubMed: 18952586
DOI: 10.1177/0883073808321769 -
The British Journal of Ophthalmology Oct 1988Sixteen cases of medulloepithelioma are described. Clinical data and follow-up were available on 15. Four patients underwent iridocyclectomy initially; all later needed... (Review)
Review
Sixteen cases of medulloepithelioma are described. Clinical data and follow-up were available on 15. Four patients underwent iridocyclectomy initially; all later needed enucleation and one had an orbital recurrence. The remaining 12 patients underwent primary enucleation. All 15 patients with follow-up are alive with no evidence of tumour recurrence. It is suggested that enucleation be performed for all but the most localised tumour. Rubeosis was noted in 13 of the 16 eyes, and this may assist in making the diagnosis. The World Health Organisation histological classification of medulloepithelioma was applied, but some problems were encountered, particularly where the presence of heteroplastic brain tissue was used as a criterion for teratoid tumour and where rosettes were used as a criterion for malignancy.
Topics: Adolescent; Child; Child, Preschool; Ciliary Body; Eye Enucleation; Female; Humans; Infant; Male; Middle Aged; Neuroectodermal Tumors, Primitive, Peripheral; Uveal Neoplasms
PubMed: 3056510
DOI: 10.1136/bjo.72.10.764 -
Acta Neuropathologica Sep 2020Embryonal tumor with Multilayered Rosettes (ETMR) is a relatively rare but typically deadly type of brain tumor that occurs mostly in infants. Since the discovery of the... (Review)
Review
Embryonal tumor with Multilayered Rosettes (ETMR) is a relatively rare but typically deadly type of brain tumor that occurs mostly in infants. Since the discovery of the characteristic chromosome 19 miRNA cluster (C19MC) amplification a decade ago, the methods for diagnosing this entity have improved and many new insights in the molecular landscape of ETMRs have been acquired. All ETMRs, despite their highly heterogeneous histology, are characterized by specific high expression of the RNA-binding protein LIN28A, which is, therefore, often used as a diagnostic marker for these tumors. ETMRs have few recurrent genetic aberrations, mainly affecting the miRNA pathway and including amplification of C19MC (embryonal tumor with multilayered rosettes, C19MC-altered) and mutually exclusive biallelic DICER1 mutations of which the first hit is typically inherited through the germline (embryonal tumor with multilayered rosettes, DICER1-altered). Identification of downstream pathways affected by the deregulated miRNA machinery has led to several proposed potential therapeutical vulnerabilities including targeting the WNT, SHH, or mTOR pathways, MYCN or chromosomal instability. However, despite those findings, treatment outcomes have only marginally improved, since the initial description of this tumor entity. Many patients do not survive longer than a year after diagnosis and the 5-year overall survival rate is still lower than 30%. Thus, there is an urgent need to translate the new insights in ETMR biology into more effective treatments. Here, we present an overview of clinical and molecular characteristics of ETMRs and the current progress on potential targeted therapies.
Topics: Biomarkers, Tumor; Brain Neoplasms; Gene Expression Profiling; Humans; Infant; MicroRNAs; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive
PubMed: 32601913
DOI: 10.1007/s00401-020-02182-2 -
Archives of Pathology & Laboratory... Jun 2012Primitive neuroectodermal tumors exist as a part of the Ewing sarcoma/primitive neuroectodermal tumor family. These tumors most commonly arise in the chest wall and... (Review)
Review
Primitive neuroectodermal tumors exist as a part of the Ewing sarcoma/primitive neuroectodermal tumor family. These tumors most commonly arise in the chest wall and paraspinal regions; cases with a renal origin are rare entities, but have become increasingly reported in recent years. Although such cases occur across a wide age distribution, the average age for a patient with a renal primitive neuroectodermal tumor is the mid- to late 20s, with both males and females susceptible. Histologically, these tumors are characterized by pseudorosettes. Immunohistochemically, CD99 is an important diagnostic marker. Clinically, these are aggressive tumors, with an average 5-year disease-free survival rate of only 45% to 55%. Given that renal primitive neuroectodermal tumor bears many similarities to other renal tumors, it is important to review the histologic features, immunostaining profile, and genetic abnormalities that can be used for its correct diagnosis.
Topics: Biomarkers, Tumor; Diagnosis, Differential; Humans; Kidney; Kidney Neoplasms; Neuroectodermal Tumors, Primitive
PubMed: 22646279
DOI: 10.5858/arpa.2011-0104-RS