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International Journal of Molecular... Mar 2022The present investigation aimed to explore the intact proteome of tissues of pediatric brain tumors of different WHO grades and localizations, including medulloblastoma,...
The present investigation aimed to explore the intact proteome of tissues of pediatric brain tumors of different WHO grades and localizations, including medulloblastoma, pilocytic astrocytoma, and glioblastoma, in comparison with the available data on ependymoma, to contribute to the understanding of the molecular mechanisms underlying the onset and progression of these pathologies. Tissues have been homogenized in acidic water−acetonitrile solutions containing proteases inhibitors and analyzed by LC−high resolution MS for proteomic characterization and label-free relative quantitation. Tandem MS spectra have been analyzed by either manual inspection or software elaboration, followed by experimental/theoretical MS fragmentation data comparison by bioinformatic tools. Statistically significant differences in protein/peptide levels between the different tumor histotypes have been evaluated by ANOVA test and Tukey’s post-hoc test, considering a p-value > 0.05 as significant. Together with intact protein and peptide chains, in the range of molecular mass of 1.3−22.8 kDa, several naturally occurring fragments from major proteins, peptides, and proteoforms have been also identified, some exhibiting proper biological activities. Protein and peptide sequencing allowed for the identification of different post-translational modifications, with acetylations, oxidations, citrullinations, deamidations, and C-terminal truncations being the most frequently characterized. C-terminal truncations, lacking from two to four amino acid residues, particularly characterizing the β-thymosin peptides and ubiquitin, showed a different modulation in the diverse tumors studied. With respect to the other tumors, medulloblastoma, the most frequent malignant brain tumor of the pediatric age, was characterized by higher levels of thymosin β4 and β10 peptides, the latter and its des-IS form particularly marking this histotype. The distribution pattern of the C-terminal truncated forms was also different in glioblastoma, particularly underlying gender differences, according to the definition of male and female glioblastoma as biologically distinct diseases. Glioblastoma was also distinguished for the peculiar identification of the truncated form of the α-hemoglobin chain, lacking the C-terminal arginine, and exhibiting oxygen-binding and vasoconstrictive properties different from the intact form. The proteomic characterization of the undigested proteome, following the top-down approach, was challenging to originally investigate the post-translational events that differently characterize pediatric brain tumors. This study provides a contribution to elucidate the molecular profiles of the solid tumors most frequently affecting the pediatric age, and which are characterized by different grades of aggressiveness and localization.
Topics: Brain Neoplasms; Cerebellar Neoplasms; Child; Female; Glioblastoma; Humans; Male; Medulloblastoma; Peptides; Proteome; Proteomics
PubMed: 35328618
DOI: 10.3390/ijms23063196 -
Medicina (Kaunas, Lithuania) Jul 2019Being the fourth leading cause of cancer-related death, glial tumors are highly diverse tumor entities characterized by important heterogeneity regarding tumor... (Review)
Review
Being the fourth leading cause of cancer-related death, glial tumors are highly diverse tumor entities characterized by important heterogeneity regarding tumor malignancy and prognosis. However, despite the identification of important alterations in the genome of the glial tumors, there remains a gap in understanding the mechanisms involved in glioma malignancy. Previous research focused on decoding the genomic alterations in these tumors, but due to intricate cellular mechanisms, the genomic findings do not correlate with the functional proteins expressed at the cellular level. The development of mass spectrometry (MS) based proteomics allowed researchers to study proteins expressed at the cellular level or in serum that may provide new insights on the proteins involved in the proliferation, invasiveness, metastasis and resistance to therapy in glial tumors. The integration of data provided by genomic and proteomic approaches into clinical practice could allow for the identification of new predictive, diagnostic and prognostic biomarkers that will improve the clinical management of patients with glial tumors. This paper aims to provide an updated review of the recent proteomic findings, possible clinical applications, and future research perspectives in diffuse astrocytic and oligodendroglial tumors, pilocytic astrocytomas, and ependymomas.
Topics: Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Glioma; Humans; Mass Spectrometry; Neoplasm Staging; Neoplasms; Oligodendroglioma; Prognosis; Proteomics
PubMed: 31357616
DOI: 10.3390/medicina55080412 -
Journal of Neuro-oncology May 2023Astrocytomas and oligodendrogliomas are mainly diffuse primary brain tumors harboring a diagnostic and prognostically favorable isocitrate dehydrogenase mutation. They... (Review)
Review
PURPOSE
Astrocytomas and oligodendrogliomas are mainly diffuse primary brain tumors harboring a diagnostic and prognostically favorable isocitrate dehydrogenase mutation. They are still incurable besides growing molecular knowledge and therapy options. Circumscribed astrocytomas are also discussed here, although they represent a separate entity despite similarities in the nomenclature.
METHODS
We reviewed clinical trials, preclinical approaches as well as guideline recommendations form the major scientific Neuro-Oncology organizations for astrocytomas and oligodendrogliomas according to PRISMA guidelines.
RESULTS
After histopathological diagnosis and eventually a maximal safe resection, patients with good prognostic factors may be followed by magnetic resonance imaging (MRI). If further treatment is necessary, either after diagnosis or at progression, diffuse astrocytomas and oligodendrogliomas are mainly treated with combined radiochemotherapy or maximal safe resection followed by combined radiochemotherapy according to current guidelines based on randomized trials. Circumscribed gliomas like pilocytic astrocytomas, CNS WHO grade 1, or pleomorphic xanthoastrocytomas, CNS WHO grade 2, are often treated with surgery alone. Current approaches for therapy optimization include decision of the best chemotherapy regimen. The IDH mutation presents a rational target for small molecule inhibition and immune therapy in diffuse astrocytomas and oligodendrogliomas, while the BRAF pathway is frequently mutated and treatable in circumscribed gliomas.
CONCLUSION
Despite establishment of standard treatment approaches for gliomas that include resection, radio- and chemotherapy, there is a lack of effective treatments for progressive disease. Immune- and targeted therapies are currently investigated.
Topics: Humans; Oligodendroglioma; Astrocytoma; Glioma; Magnetic Resonance Imaging; Mutation
PubMed: 36566461
DOI: 10.1007/s11060-022-04216-z -
BMC Medical Imaging Jan 2019The purpose of this retrospective review is to determine the MR imaging features of pilocytic astrocytoma (PA) in the spinal cord to help neuroradiologists...
BACKGROUND
The purpose of this retrospective review is to determine the MR imaging features of pilocytic astrocytoma (PA) in the spinal cord to help neuroradiologists preoperatively differentiate PA from other intramedullary tumors.
METHODS
Neuro-oncology database review revealed 13 consecutive patients with a pathological spinal PA diagnosis and availability of preoperative MR imaging. Three patients had preoperative diffusion-weighted MR imaging. Demographics and conventional and diffusion MR imaging records were retrospectively evaluated.
RESULTS
Among 13 cases of spinal PA, six PAs were located in the cervical region, 4 in the cervical-thoracic region, and 3 in the thoracic region. The average length of vertebral segments involved for the tumors were 4.7 ± 4.6 segments. Six tumors had associated syringomyelia. Eight PAs were located eccentrically in the spinal cord, and eleven had well-defined margins. Eight tumors (61.5%) were intermixed cystic and solid. All were contrast-enhanced, and 53.8% of all PAs showed focal nodule enhancement of the solid components. Two PAs showed intratumoral hemorrhages, and only one demonstrated cap sign. The ADC values (n = 3) of the tumors were 1.40 ± 0.28 × 10 mm/s (min-max: 1.17-1.71 × 10 mm/s).
CONCLUSIONS
PA should be considered in the differential diagnosis of intramedullary tumors that occur in the cervical and thoracic regions. Eccentric growth pattern, well-defined margin, intermixed cystic and solid appearance, focal nodular enhancement of solid components and syringomyelia are relatively frequent features. Relatively high ADC values compared with normal-appearing spinal cord parenchyma are common in spinal PA.
Topics: Adolescent; Adult; Astrocytoma; Cervical Cord; Child; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; Female; Humans; Image Interpretation, Computer-Assisted; Male; Middle Aged; Retrospective Studies; Spinal Cord Neoplasms; Young Adult
PubMed: 30642288
DOI: 10.1186/s12880-018-0296-y -
CNS Oncology 2015
Topics: Astrocytoma; Brain Neoplasms; Humans; Wnt Signaling Pathway
PubMed: 26497968
DOI: 10.2217/cns.15.24 -
Cirugia Y Cirujanos 2017Pilocytic astrocytoma is a rare tumour, usually occurring in paediatric ages, and mainly located in the posterior fossa. It can cause hydrocephalus and intracranial... (Review)
Review
BACKGROUND
Pilocytic astrocytoma is a rare tumour, usually occurring in paediatric ages, and mainly located in the posterior fossa. It can cause hydrocephalus and intracranial hypertension and, less frequently, seizures, or a focal neurological deficit. The main imaging study by magnetic resonance imaging, which shows a tumour with solid and cystic components without peri-lesional swelling. The election treatment is surgical, and the patient is considered cured if a total resection is accomplished.
CLINICAL CASE
The case is presented of 22-year-old female patient with a supratentorial pilocytic astrocytoma and epilepsy. Histopathology reported a low grade glial proliferation, with an extensive fibrillar matrix, small cells without atypia, extensive calcifications and piloid areas consisting of bipolar fusiform cells, and some Rosenthal fibres. There were also spongiotic areas consisting of multipolar cells and associated microcysts. The final report was a pilocytic astrocytoma.
CONCLUSIONS
Pilocytic astrocytoma is more frequent in paediatric patients and in the posterior fossa. The case presented is of a young female adult with supratentorial location, making it a special case. The surgery achieved a total resection. The long-term prognosis is good, but it is necessary to perform a follow-up, particularly in adult patients because of a higher risk of recurrence.
Topics: Anticonvulsants; Astrocytoma; Cholecystitis, Acute; Craniotomy; Female; Humans; Levetiracetam; Magnetic Resonance Imaging; Neuroimaging; Piracetam; Remission Induction; Seizures; Supratentorial Neoplasms; Young Adult
PubMed: 27417707
DOI: 10.1016/j.circir.2016.05.009 -
PloS One 2021Intravoxel incoherent motion (IVIM) imaging concurrently measures diffusion and perfusion parameters and has potential applications for brain tumor classification....
INTRODUCTION
Intravoxel incoherent motion (IVIM) imaging concurrently measures diffusion and perfusion parameters and has potential applications for brain tumor classification. However, the effectiveness of IVIM for the differentiation between pilocytic astrocytoma and ependymoma has not been verified. The aim of this study was to determine the potential diagnostic role of IVIM for the distinction between ependymoma and pilocytic astrocytoma.
METHODS
Between February 2019 and October 2020, 22 children (15 males and 7 females; median age 4 years) with either ependymoma or pilocytic astrocytoma were recruited for this prospective study. IVIM parameters were fitted using 7 b-values (0-1,500 s/mm2), to develop a bi-exponential model. The diffusivity (D), perfusion fraction (f), and pseudo diffusivity (D*) were measured in both tumors and the adjacent normal-appearing parenchyma. These IVIM parameters were compared using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was employed to assess diagnostic performance.
RESULTS
The median D values for ependymoma and pilocytic astrocytoma were 0.87 and 1.25 × 10-3 mm2/s (p < 0.05), respectively, whereas the f values were 0.11% and 0.15% (p < 0.05). The ratios of the median D values for ependymoma and pilocytic astrocytoma relative to the median D values for the adjacent, normal-appearing parenchyma were 1.45 and 2.10 (p < 0.05), respectively. ROC curve analysis found that the D value had the best diagnostic performance for the differentiation between pilocytic astrocytoma and ependymoma, with an area under the ROC curve of 1.
CONCLUSION
IVIM is a beneficial, effective, non-invasive, and endogenous-contrast imaging technique. The D value derived from IVIM was the most essential factor for differentiating ependymoma from pilocytic astrocytoma.
Topics: Astrocytoma; Brain Neoplasms; Child, Preschool; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; Ependymoma; Female; Humans; Image Processing, Computer-Assisted; Male; Motion; Sensitivity and Specificity
PubMed: 33647051
DOI: 10.1371/journal.pone.0247899 -
Neurology India 2022Adult intramedullary pilocytic astrocytomas (PAs) are exceedingly rare. The aim of this study was to summarize our experiences in treating adult intramedullary PAs.
PURPOSE
Adult intramedullary pilocytic astrocytomas (PAs) are exceedingly rare. The aim of this study was to summarize our experiences in treating adult intramedullary PAs.
MATERIALS AND METHODS
We retrospectively reviewed the records of seven adult patients who underwent microsurgery for intramedullary PAs between 2010 and 2017. Magnetic resonance imaging was the standard radiological investigation. The diagnosis of PAs was based on pathology. All the follow-up data were obtained during office visits.
RESULTS
There were three males and four females with the mean age of 40.9 years. The tumors generally exhibited hypointensity on T1-weighted images (WI) and hyperintensity on T2WI. Contrast-enhanced T1WI showed heterogeneous enhancement. Gross total resection (GTR) of the tumor was achieved in four cases and subtotal resection (STR) was achieved in three cases. Two cases of STR received postoperative radiotherapy. One STR case had mildly residual tumor regrowth. At the last follow-up, neurological status was improved in six patients.
CONCLUSION
The accurate diagnosis of adult intramedullary PAs depends on pathology. GTR is the best treatment and the outcome is favorable. STR increases the risk of tumor recurrence, and regular follow-up is necessary. Due to uncertain therapeutic efficacy, radiotherapy should be considered carefully for cases of STR.
Topics: Adult; Female; Humans; Male; Astrocytoma; Magnetic Resonance Imaging; Microsurgery; Neoplasm Recurrence, Local; Neoplasm, Residual; Retrospective Studies
PubMed: 36412370
DOI: 10.4103/0028-3886.360936 -
Acta Neuropathologica Communications Aug 2020Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions...
Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX. As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Non-canonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas.
Topics: Adolescent; Adult; Aged; Astrocytoma; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Progression-Free Survival; Spinal Cord Neoplasms; Young Adult
PubMed: 32771057
DOI: 10.1186/s40478-020-00962-1 -
Neuro-oncology Jan 2015Despite 6 decades of research, only 3 drugs have been approved for astrocytomas, the most common malignant primary brain tumors. However, clinical drug development is... (Review)
Review
Despite 6 decades of research, only 3 drugs have been approved for astrocytomas, the most common malignant primary brain tumors. However, clinical drug development is accelerating with the transition from empirical, cytotoxic therapy to precision, targeted medicine. Preclinical animal model studies are critical for prioritizing drug candidates for clinical development and, ultimately, for their regulatory approval. For decades, only murine models with established tumor cell lines were available for such studies. However, these poorly represent the genomic and biological properties of human astrocytomas, and their preclinical use fails to accurately predict efficacy in clinical trials. Newer models developed over the last 2 decades, including patient-derived xenografts, genetically engineered mice, and genetically engineered cells purified from human brains, more faithfully phenocopy the genomics and biology of human astrocytomas. Harnessing the unique benefits of these models will be required to identify drug targets, define combination therapies that circumvent inherent and acquired resistance mechanisms, and develop molecular biomarkers predictive of drug response and resistance. With increasing recognition of the molecular heterogeneity of astrocytomas, employing multiple, contemporary models in preclinical drug studies promises to increase the efficiency of drug development for specific, molecularly defined subsets of tumors.
Topics: Animals; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Cell Line, Tumor; Disease Models, Animal; Drug Discovery; Glioblastoma; Humans; Mice
PubMed: 25246428
DOI: 10.1093/neuonc/nou288