Real-world data for pediatric medulloblastoma: can we improve outcomes?

Sedano, Paula; Segundo, Carmen González‐San; Ingunza, L. De; Cuesta-Álvaro, Pedro; Perez‐Somarriba, Marta; Díaz-Gutiérrez, Francisco; Colino, Carmen Garrido; Lassaletta, Álvaro

doi:10.1007/s00431-020-03722-4

Cited by 8 publications

(5 citation statements)

References 35 publications

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“…In the present work, 5-year OS was 60% which is consistent with those reported in the literature (50–70%) [ 26 ]. Age showed a prognostic role where children ≤ 3 years old conferred poor survival, in accordance with findings observed by Zeltzer et al [ 27 ].…”

Section: Discussionsupporting

confidence: 93%

Prognostic value of microRNA-125a expression status in molecular groups of pediatric medulloblastoma

et al. 2023

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Purpose Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current treatment allows decent survival rates but often with life-long morbidity. Molecular classification provides a base for novel therapeutic approaches. However, these groups are heterogeneous. MicroRNA-125a has a tumor suppressor function. It is downregulated in several tumors. The expression of microRNA-125a in MB patients remains unclear. Therefore, this study was designed to evaluate the expression of microRNA-125a in molecular groups of pediatric MB patients in Egyptian population and its clinical significance. Methods Formalin-fixed, paraffin-embedded tissue blocks from 50 pediatric MB patients were retrospectively collected. Immunohistochemistry for β-catenin, GAB1, YAP1, and p53 was done for molecular classification. MicroRNA-125a expression analysis was done using qRT-PCR. Follow-up data were obtained from patients’ records. Results MicroRNA-125a expression was significantly lower in MB patients showing large cell/anaplastic (LC/A) histology and in the non-WNT/non-SHH group. Lower levels of microRNA-125a showed a tendency toward poor survival rates; however, difference was not significant. Infants and larger preoperative tumor size were significantly associated with lower survival rates. On a multivariate analysis, preoperative tumor size was an independent prognostic factor. Conclusion MicroRNA-125a expression was significantly lower in categories of pediatric MB patients with worse prognosis namely LC/A histology and the non-WNT/non-SHH group suggesting a pathogenetic role. MicroRNA-125a expression could represent a promising prognostic factor and a potential therapeutic target in the non-WNT/non-SHH group which represents the most common and the most heterogeneous group of pediatric MBs coupled with the highest rates of disseminated disease. Preoperative tumor size represents an independent prognostic factor.

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Section: Discussionsupporting

confidence: 93%

Prognostic value of microRNA-125a expression status in molecular groups of pediatric medulloblastoma

et al. 2023

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“…It grows rapidly, is difficult to resect, and spreads easily through the cerebrospinal fluid (32). With a deep understanding of MB and the progress of related clinical technology, the current therapeutic schedule for MB is postoperative radiotherapy and chemotherapy based on risk stratifications (33). Although the whole central nervous system radiotherapy may result in a series of short-term and long-term reactions, such as brain oedema, elevated intracranial pressure, hearing loss, hypothyroidism, and cognitive dysfunction, radiotherapy remains crucial in the treatment of MB (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

TOP2A correlates with poor prognosis and affects radioresistance of medulloblastoma

et al. 2022

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Radiotherapy remains the standard treatment for medulloblastoma (MB), and the radioresistance contributes to tumor recurrence and poor clinical outcomes. Nuclear DNA topoisomerase II-alpha (TOP2A) is a key catalytic enzyme that initiates DNA replication, and studies have shown that TOP2A is closely related to the therapeutic effects of radiation. In this study, we found that TOP2A was significantly upregulated in MB, and high expression of TOP2A related to poor prognosis of MB patients. Knockdown of TOP2A inhibited MB cell proliferation, migration, and invasion, whereas overexpression of TOP2A enhanced the proliferative and invasive ability of MB cells. Moreover, si-TOP2A transfection in combination with irradiation (IR) significantly reduced the tumorigenicity of MB cells, compared with those transfected with si-TOP2A alone. Cell survival curve analysis revealed that the survival fraction of MB cells was significantly reduced upon TOP2A downregulation and that si-TOP2A-transfected cells had decreased D0, Dq, and SF2 values, indicating that TOP2A knockdown suppresses the resistance to radiotherapy in MB cells. In addition, western blot analysis demonstrated that the activity of Wnt/β-catenin signaling pathway was inhibited after TOP2A downregulation alone or in combination with IR treatment, whereas overexpression of TOP2A exhibited the opposite effects. Gene set enrichment analysis also revealed that Wnt/β-catenin signaling pathway is enriched in TOP2A high-expression phenotypes. Collectively, these data indicate that high expression of TOP2A leads to poor prognosis of MB, and downregulation of TOP2A inhibits the malignant behaviour as well as the radioresistance of MB cells. The Wnt/β-catenin signaling pathway may be involved in the molecular mechanisms of TOP2A mediated reduced tumorigenicity and radioresistance of MB cells.

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“…Multimodal regimens including maximal surgical resection, radiotherapy, and chemotherapy are recommended as a standard treatment for medulloblastoma [ 3 ]. Craniospinal irradiation after surgery has been suggested to improve long-term outcome in patients with medulloblastoma [ 1 , 4 , 5 ]. However, the development of radioresistance hampers therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

RBM5-AS1 promotes radioresistance in medulloblastoma through stabilization of SIRT6 protein

Zhu

Jiang

et al. 2021

acta neuropathol commun

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Cancer stem cells (CSCs) contribute to radioresistance in medulloblastoma. Thus, identification of key regulators of medulloblastoma stemness is critical for improving radiotherapy for medulloblastoma. In the present study, we profiled CSC-related long non-coding RNAs (lncRNAs) between radioresistant and parental medulloblastoma cells. The roles of the lncRNA RBM5-AS1 in the stemness and radiosensitivity of medulloblastoma cells were investigated. We found that RBM5-AS1, a novel inducer of medulloblastoma stemness, was significantly upregulated in radioresistant medulloblastoma cells compared to parental cells. Knockdown of RBM5-AS1 diminished the viability and clonogenic survival of both radioresistant and parental medulloblastoma cells after radiation. Silencing of RBM5-AS1 significantly enhanced radiation-induced apoptosis and DNA damage. In vivo studies confirmed that depletion of RBM5-AS1 inhibited tumor growth and increased radiosensitivity in a medulloblastoma xenograft model. In contrast, overexpression of RBM5-AS1 reduced radiation-induced apoptosis and DNA damage in medulloblastoma cells. Mechanistically, RBM5-AS1 interacted with and stabilized sirtuin 6 (SIRT6) protein. Silencing of SIRT6 reduced the stemness and reinforced radiation-induced DNA damage in medulloblastoma cells. Overexpression of SIRT6 rescued medulloblastoma cells from RBM5-AS1 depletion-induced radiosensitization and DNA damage. Overall, we identify RBM5-AS1 as an inducer of stemness and radioresistance in medulloblastoma. Targeting RBM5-AS1 may represent a potential strategy to overcome the resistance to radiotherapy in this malignancy.

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Real-world data for pediatric medulloblastoma: can we improve outcomes?

Cited by 8 publications

References 35 publications

Prognostic value of microRNA-125a expression status in molecular groups of pediatric medulloblastoma

Prognostic value of microRNA-125a expression status in molecular groups of pediatric medulloblastoma

TOP2A correlates with poor prognosis and affects radioresistance of medulloblastoma

RBM5-AS1 promotes radioresistance in medulloblastoma through stabilization of SIRT6 protein

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