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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 -
Brain Research Jul 2016The Unfolded Protein Response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress in the Endoplasmic Reticulum (ER).... (Review)
Review
The Unfolded Protein Response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress in the Endoplasmic Reticulum (ER). During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply; exposure to chemotherapies) challenges, with which they must cope to survive. Primary brain tumors are relatively rare but deadly and present a significant challenge in the determination of risk factors in the population. These tumors are inherently difficult to cure because of their protected location in the brain. As such surgery, radiation and chemotherapy options carry potentially lasting patient morbidity and incomplete tumor cure. Some of these tumors, such as glioblastoma, were reported to present features of ER stress and to depend on UPR activation to sustain growth, but to date there is no clear general representation of the ER stress status in primary brain tumors. In this review, we describe the key molecular mechanisms controlling the UPR and their implication in cancers. Then we extensively review the literature reporting the status of ER stress in various primary brain tumors and discuss the potential impact of such observation on patient stratification and on the possibility of developing appropriate targeted therapies using the UPR as therapeutic target.
Topics: Animals; Brain Neoplasms; Cerebellar Neoplasms; Choroid Plexus Neoplasms; Endoplasmic Reticulum Stress; Glioblastoma; Humans; Medulloblastoma; Meningeal Neoplasms; Meningioma; Pineal Gland; Pinealoma; Signal Transduction; Unfolded Protein Response
PubMed: 27016056
DOI: 10.1016/j.brainres.2016.03.015 -
Neuroimaging Clinics of North America Nov 2016Some brain tumors results are interesting due to their rarity at presentation and overwhelming imaging characteristics, posing a diagnostic challenge in the eyes of any... (Review)
Review
Some brain tumors results are interesting due to their rarity at presentation and overwhelming imaging characteristics, posing a diagnostic challenge in the eyes of any experienced neuroradiologist. This article focuses on the most important features regarding epidemiology, location, clinical presentation, histopathology, and imaging findings of cases considered "bizarre." A review of the most recent literature dealing with these unusual tumors and pseudotumors is presented, highlighting key points related to the diagnosis, treatments, outcomes, and differential diagnosis.
Topics: Adult; Brain; Brain Diseases; Brain Neoplasms; Diagnosis, Differential; Diagnostic Imaging; Humans; Neuroimaging; Pineal Gland; Pinealoma; Vascular Malformations
PubMed: 27712799
DOI: 10.1016/j.nic.2016.06.012 -
Cancer Management and Research 2020Intracranial pineoblastomas are rare neoplasms with poor prognosis. The aim of this study was to describe the independent prognostic factors and treatment strategies for...
OBJECTIVE
Intracranial pineoblastomas are rare neoplasms with poor prognosis. The aim of this study was to describe the independent prognostic factors and treatment strategies for overall survival in pediatric and adult patients.
METHODS
Sixty-four patients were surgically treated between January 2012 and December 2018.
RESULTS
The series included 37 (57.8%) males and 27 (42.2%) females. Gross total resection was achieved in 41 (64.1%) cases, and the 1-, 3-, and 5-year rates of overall survival were 86.3, 52.3, and 36.6%, respectively. In the pediatric group (n=42), 28 patients (66.7%) were male, with the median, and the mean age was 4 and 6.2±4.7 years, respectively. After a median follow-up of 25.0 months, twenty-six patients (61.9%) died, and the 1-, 3-, and 5-year rates of overall survival were 84.9, 46.4, and 26.7%, respectively. Postoperative radiotherapy (p=0.058) and postoperative chemotherapy (p=0.183) had a positive influence on the increased overall survival. Meanwhile, postoperative radiotherapy combined with chemotherapy following surgery had a positive impact on overall survival (p=0.174, Log rank). In the adult group, the mean overall survival was 67.3±9.3 months (range, 0.8-95.3 months), and the 1-, 3-, and 5-year rates of overall survival were 89.5, 64.4, and 64.4%, respectively. In this group, no statistical association was observed between clinical factors and outcomes. However, patients who received postoperative radiotherapy (60.7 vs 57.6 month, mean survival; p=0.510, Log rank) or chemotherapy (63.0 vs 59.9 month, mean survival; p=0.404, Log rank) had better survival rates compared with those who declined.
CONCLUSION
In the pediatric group, surgery with postoperative radiotherapy and chemotherapy was a favorable factor for overall survival. In the adult group, a positive trend in overall survival was found when patients received radiation and/or chemotherapy following surgery.
PubMed: 32884348
DOI: 10.2147/CMAR.S258476 -
Clinical Radiology Jul 2023To differentiate between pineal germ cell tumour and pineoblastoma using apparent diffusion coefficient (ADC) values due to their overlapping imaging findings on...
AIM
To differentiate between pineal germ cell tumour and pineoblastoma using apparent diffusion coefficient (ADC) values due to their overlapping imaging findings on magnetic resonance imaging (MRI).
MATERIALS AND METHODS
This retrospective study was conducted on 33 patients with pineal germ cell tumours and eight patients with pineoblastoma who underwent pretreatment MRI. Twenty-seven patients (21 with pineal germ cell tumour and six with pineoblastoma) were included for ADC measurement. The minimum and mean ADC values of the tumours were measured, with normalized tumour to control ADC ratios generated. The MRI characteristics of the tumours were evaluated.
RESULTS
The mean and minimum ADC values, normalized mean and minimum ADC ratios of pineal germ cell tumours were significantly higher than those of pineoblastomas (all p<0.005). A cut-off value of 0.92 for the normalized mean ADC ratio was used to distinguish between pineal germ cell tumour and pineoblastoma and achieved an area under the curve of 0.95, sensitivity of 90.5%, specificity of 83.3%, and accuracy of 92.6%. An equal degree of contrast enhancement to the adjacent venous sinus was the only MRI characteristic that suggested the diagnosis of pineal germ cell tumour.
CONCLUSION
The ADC values could help differentiate between pineal germ cell tumour and pineoblastoma, specifically when conventional MRI findings are indeterminate.
Topics: Humans; Pinealoma; Brain Neoplasms; Retrospective Studies; Diffusion Magnetic Resonance Imaging; Diagnosis, Differential; Pineal Gland; Sensitivity and Specificity
PubMed: 37037704
DOI: 10.1016/j.crad.2023.03.008 -
Cancer Jul 2023Inhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy. This study reports the pediatric solid...
BACKGROUND
Inhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy. This study reports the pediatric solid tumor phase 2 results of the ADVL1312 trial combining irinotecan and adavosertib.
METHODS
Pediatric patients with recurrent neuroblastoma (part B), medulloblastoma/central nervous system embryonal tumors (part C), or rhabdomyosarcoma (part D) were treated with irinotecan and adavosertib orally for 5 days every 21 days. The combination was considered effective if there were at least three of 20 responses in parts B and D or six of 19 responses in part C. Tumor tissue was analyzed for alternative lengthening of telomeres and ATRX. Patient's prior tumor genomic analyses were provided.
RESULTS
The 20 patients with neuroblastoma (part B) had a median of three prior regimens and 95% had a history of prior irinotecan. There were three objective responses (9, 11, and 18 cycles) meeting the protocol defined efficacy end point. Two of the three patients with objective responses had tumors with alternative lengthening of telomeres. One patient with pineoblastoma had a partial response (11 cycles), but parts C and D did not meet the protocol defined efficacy end point. The combination was well tolerated and there were no dose limiting toxicities at cycle 1 or beyond in any parts of ADVL1312 at the recommended phase 2 dose.
CONCLUSION
This is first phase 2 clinical trial of adavosertib in pediatrics and the first with irinotecan. The combination may be of sufficient activity to consider further study of adavosertib in neuroblastoma.
Topics: Child; Humans; Irinotecan; Medulloblastoma; Neuroblastoma; Rhabdomyosarcoma; Cerebellar Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Protein-Tyrosine Kinases; Cell Cycle Proteins
PubMed: 37081608
DOI: 10.1002/cncr.34786 -
Journal of Comparative Pathology Jan 2021We report the first case of pineoblastoma in a cow. At necropsy, a soft, gelatinous greyish yellow, 4 × 3 × 2 cm mass was found midsagittally on the dorsal...
We report the first case of pineoblastoma in a cow. At necropsy, a soft, gelatinous greyish yellow, 4 × 3 × 2 cm mass was found midsagittally on the dorsal surface of the midbrain. The mass enveloped the brainstem anterior to the cerebellum, extended to the pituitary fossa and was adherent to the ventromedial aspect of the occipital lobes. Histologically, the mass was unencapsulated, with extramedullary proliferation into the lobes and meninges, but was demarcated from the adjacent brain tissue. Histological findings were consistent with a pineoblastoma, as reported in other species, and the neoplasm was strongly immunopositive for synaptophysin. Glial fibrillary acidic protein-positive spindloid astrocytic processes surrounded blood vessels and extended around neoplastic cells.
Topics: Animals; Brain Neoplasms; Cattle; Cattle Diseases; Fatal Outcome; Female; Glial Fibrillary Acidic Protein; Immunohistochemistry; Pineal Gland; Pinealoma
PubMed: 33494905
DOI: 10.1016/j.jcpa.2020.11.005 -
Surgical Pathology Clinics Jun 2020Embryonal tumors of the central nervous system (CNS) are rare, high-grade neoplasms predominantly affecting the pediatric population. Well-defined embryonal tumors... (Review)
Review
Embryonal tumors of the central nervous system (CNS) are rare, high-grade neoplasms predominantly affecting the pediatric population. Well-defined embryonal tumors include medulloblastoma, atypical teratoid/rhabdoid tumor, embryonal tumor with multilayered rosettes, C19MC-altered and embryonal tumor with multilayered rosettes, not otherwise specified, pineoblastoma, pituitary blastoma, CNS neuroblastoma, and ganglioneuroblastoma. Although their prognosis is nearly uniformly poor, the rapidly evolving understanding of their molecular biology contributes to diagnosis, prognosis, treatment, and clinical trial participation. Knowledge of current tumor stratification and diagnostic techniques will help pathologists guide care and preserve tissue for necessary or desired additional testing.
Topics: Central Nervous System Neoplasms; Cerebellar Neoplasms; Humans; Medulloblastoma; Neoplasms, Germ Cell and Embryonal; Prognosis; Rhabdoid Tumor; Teratoma
PubMed: 32389264
DOI: 10.1016/j.path.2020.01.003 -
Journal of Neuro-oncology Nov 2018Medulloblastoma, the most common primary pediatric malignant brain tumor, originates in the posterior fossa of the brain. Pineoblastoma, which originates within the...
PURPOSE
Medulloblastoma, the most common primary pediatric malignant brain tumor, originates in the posterior fossa of the brain. Pineoblastoma, which originates within the pineal gland, is a rarer malignancy that also presents in the pediatric population. Medulloblastoma and pineoblastoma exhibit overlapping clinical features and have similar histopathological characteristics. Histopathological similarities confound rapid diagnoses of these two tumor types. We have conducted a pilot feasibility study analyzing the molecular profile of archived frozen human tumor specimens using mass spectrometry imaging (MSI) to identify potential biomarkers capable of classifying and distinguishing between medulloblastoma and pineoblastoma.
METHODS
We performed matrix-assisted laser desorption ionization Fourier transform ion cyclotron resonance mass spectrometry imaging on eight medulloblastoma biopsy specimens and three pineoblastoma biopsy specimens. Multivariate statistical analyses were performed on the MSI dataset to generate classifiers that distinguish the two tumor types. Lastly, the molecules that were discriminative of tumor type were queried against the Lipid Maps database and identified.
RESULTS
In this pilot study we show that medulloblastoma and pineoblastoma can be discriminated using molecular profiles determined by MSI. The highest-ranking discriminating classifiers of medulloblastoma and pineoblastoma were glycerophosphoglycerols and sphingolipids, respectively.
CONCLUSION
We demonstrate proof-of-concept that medulloblastoma and pineoblastoma can be rapidly distinguished by using MSI lipid profiles. We identified biomarker candidates capable of distinguishing these two histopathologically similar tumor types. This work expands the current molecular knowledge of medulloblastoma and pineoblastoma by characterizing their lipidomic profiles, which may be useful for developing novel diagnostic, prognostic and therapeutic strategies.
Topics: Brain Neoplasms; Cerebellum; Child; Diagnosis, Differential; Humans; Medulloblastoma; Pilot Projects; Pineal Gland; Pinealoma; Proof of Concept Study; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 30128689
DOI: 10.1007/s11060-018-2978-2 -
Nature Communications Jul 2018Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with...
Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.
Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Brain Neoplasms; Child; Cytoskeletal Proteins; DEAD-box RNA Helicases; DNA Methylation; Exome; Gene Deletion; Gene Duplication; Genome, Human; Homozygote; Humans; Middle Aged; Muscle Proteins; Nuclear Proteins; Pineal Gland; Pinealoma; Protein Domains; Ribonuclease III; Transcriptome
PubMed: 30030436
DOI: 10.1038/s41467-018-05029-3