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Scientific Reports Jun 2024Medulloblastoma is a malignant neuroepithelial tumor of the central nervous system. Accurate prediction of prognosis is essential for therapeutic decisions in...
Medulloblastoma is a malignant neuroepithelial tumor of the central nervous system. Accurate prediction of prognosis is essential for therapeutic decisions in medulloblastoma patients. We analyzed data from 2,322 medulloblastoma patients using the SEER database and randomly divided the dataset into training and testing datasets in a 7:3 ratio. We chose three models to build, one based on neural networks (DeepSurv), one based on ensemble learning that Random Survival Forest (RSF), and a typical Cox Proportional-hazards (CoxPH) model. The DeepSurv model outperformed the RSF and classic CoxPH models with C-indexes of 0.751 and 0.763 for the training and test datasets. Additionally, the DeepSurv model showed better accuracy in predicting 1-, 3-, and 5-year survival rates (AUC: 0.767-0.793). Therefore, our prediction model based on deep learning algorithms can more accurately predict the survival rate and survival period of medulloblastoma compared to other models.
Topics: Medulloblastoma; Humans; Deep Learning; Female; Male; SEER Program; Child; Prognosis; Cerebellar Neoplasms; Adolescent; Child, Preschool; Proportional Hazards Models; Survival Rate; Adult; Young Adult; Middle Aged; Neural Networks, Computer; Infant
PubMed: 38914641
DOI: 10.1038/s41598-024-65367-9 -
European Journal of Radiology Jun 2024Survivors of medulloblastoma face a range of challenges after treatment, involving behavioural, cognitive, language and motor skills. Post-treatment outcomes are... (Review)
Review
PURPOSE
Survivors of medulloblastoma face a range of challenges after treatment, involving behavioural, cognitive, language and motor skills. Post-treatment outcomes are associated with structural changes within the brain resulting from both the tumour and the treatment. Diffusion magnetic resonance imaging (MRI) has been used to investigate the microstructure of the brain. In this review, we aim to summarise the literature on diffusion MRI in patients treated for medulloblastoma and discuss future directions on how diffusion imaging can be used to improve patient quality.
METHOD
This review summarises the current literature on medulloblastoma in children, focusing on the impact of both the tumour and its treatment on brain microstructure. We review studies where diffusion MRI has been correlated with either treatment characteristics or cognitive outcomes. We discuss the role diffusion MRI has taken in understanding the relationship between microstructural damage and cognitive and behavioural deficits.
RESULTS
We identified 35 studies that analysed diffusion MRI changes in patients treated for medulloblastoma. The majority of these studies found significant group differences in measures of brain microstructure between patients and controls, and some of these studies showed associations between microstructure and neurocognitive outcomes, which could be influenced by patient characteristics (e.g. age), treatment, radiation dose and treatment type.
CONCLUSIONS
In future, studies would benefit from being able to separate microstructural white matter damage caused by the tumour, tumour-related complications and treatment. Additionally, advanced diffusion modelling methods can be explored to understand and describe microstructural changes to white matter.
PubMed: 38901074
DOI: 10.1016/j.ejrad.2024.111562 -
Cancers May 2024Radiotherapy (RT) involving craniospinal irradiation (CSI) is important in the initial treatment of medulloblastoma. At recurrence, the re-irradiation options are...
BACKGROUND
Radiotherapy (RT) involving craniospinal irradiation (CSI) is important in the initial treatment of medulloblastoma. At recurrence, the re-irradiation options are limited and associated with severe side-effects.
METHODS
For pre-irradiated patients, patients with re-irradiation (RT2) were matched by sex, histology, time to recurrence, disease status and treatment at recurrence to patients without RT2.
RESULTS
A total of 42 pre-irradiated patients with RT2 were matched to 42 pre-irradiated controls without RT2. RT2 improved the median PFS [21.0 (CI: 15.7-28.7) vs. 12.0 (CI: 8.1-21.0) months] and OS [31.5 (CI: 27.6-64.8) vs. 20.0 (CI: 14.0-36.7) months]. Concerning long-term survival after ten years, RT2 only lead to small improvements in OS [8% (CI: 1.4-45.3) vs. 0%]. RT2 improved survival most without (re)-resection [PFS: 17.5 (CI: 9.7-41.5) vs. 8.0 (CI: 6.6-12.2)/OS: 31.5 (CI: 27.6-NA) vs. 13.3 (CI: 8.1-20.1) months]. In the RT-naïve patients, CSI at recurrence improved their median PFS [25.0 (CI: 16.8-60.6) vs. 6.6 (CI: 1.5-NA) months] and OS [40.2 (CI: 18.7-NA) vs. 12.4 (CI: 4.4-NA) months].
CONCLUSIONS
RT2 could improve the median survival in a matched cohort but offered little benefit regarding long-term survival. In RT-naïve patients, CSI greatly improved their median and long-term survival.
PubMed: 38893076
DOI: 10.3390/cancers16111955 -
The Journal of Clinical Investigation Jun 2024Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance...
Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic dataset that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor five-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB patients.
PubMed: 38885332
DOI: 10.1172/JCI171136 -
Turkish Neurosurgery Jan 2024Medulloblastomas (MBs) are the most commonly observed malignant brain tumors affecting children; they can be classified into molecular subgroups based on the 2016 and...
AIM
Medulloblastomas (MBs) are the most commonly observed malignant brain tumors affecting children; they can be classified into molecular subgroups based on the 2016 and 2021 WHO classifications, as WNT-activated, SHH-activated and TP53-wild type, SHH-activated and TP53-mutant, and non-WNT/non-SHH. However, the molecular methods to determine these subgroups are not easily accessible for routine testing as they are expensive. Here, we investigated the efficacy of immunohistochemical methods to determine molecular subgroups and prognostic predictions of MB.
MATERIAL AND METHODS
β-catenin, GAB1, YAP1, filamin A and p53 were immunohistochemically stained, and MYC and MYCN fluorescent in situ hybridization (FISH) procedures were applied to 218 cases in our series.
RESULTS
Based on the histomorphological characteristics of the cases, 67.9% were deemed classic MB; 15.6% as desmoplastic/nodular medulloblastoma (DNMB); 12.8% as large cell/anaplastic (LC/A) MB; 3.7% as medulloblastoma with extensive nodularity (MBEN). Molecular characteristics revealed that 50.5% had non-WNT/non-SHH; 33.9% had SHH-activated and TP53-wildtype; 8.7% had WNT-activated; 6.9% had SHH-activated and TP53-mutant. According to the survival curves, LC/A MBs or non-WNT/non-SHH tumors showed the worst prognosis, whereas DNMBs and WNT-activated tumors showed the best prognosis. Classic MBs or SHH-activated tumors showed a moderate course. MYCN amplification was found to act as an independent poor prognostic factor in the study.
CONCLUSION
The distribution of histological subtypes and molecular subgroups, amplification rates, and prognostic data obtained through immunohistochemical methods in our study were consistent with those reported in the literature. It was therefore hypothesized that the determination of molecular subgroups by immunohistochemical methods can be useful in daily diagnostic practice, especially in centers with limited access to molecular techniques.
PubMed: 38874255
DOI: 10.5137/1019-5149.JTN.45863-23.2 -
Scientific Reports Jun 2024The RE1 silencing transcription factor (REST) is a driver of sonic hedgehog (SHH) medulloblastoma genesis. Our previous studies showed that REST enhances cell...
The RE1 silencing transcription factor (REST) is a driver of sonic hedgehog (SHH) medulloblastoma genesis. Our previous studies showed that REST enhances cell proliferation, metastasis and vascular growth and blocks neuronal differentiation to drive progression of SHH medulloblastoma tumors. Here, we demonstrate that REST promotes autophagy, a pathway that is found to be significantly enriched in human medulloblastoma tumors relative to normal cerebella. In SHH medulloblastoma tumor xenografts, REST elevation is strongly correlated with increased expression of the hypoxia-inducible factor 1-alpha (HIF1α)-a positive regulator of autophagy, and with reduced expression of the von Hippel-Lindau (VHL) tumor suppressor protein - a component of an E3 ligase complex that ubiquitinates HIF1α. Human SHH-medulloblastoma tumors with higher REST expression exhibit nuclear localization of HIF1α, in contrast to its cytoplasmic localization in low-REST tumors. In vitro, REST knockdown promotes an increase in VHL levels and a decrease in cytoplasmic HIF1α protein levels, and autophagy flux. In contrast, REST elevation causes a decline in VHL levels, as well as its interaction with HIF1α, resulting in a reduction in HIF1α ubiquitination and an increase in autophagy flux. These data suggest that REST elevation promotes autophagy in SHH medulloblastoma cells by modulating HIF1α ubiquitination and stability in a VHL-dependent manner. Thus, our study is one of the first to connect VHL to REST-dependent control of autophagy in a subset of medulloblastomas.
Topics: Medulloblastoma; Humans; Von Hippel-Lindau Tumor Suppressor Protein; Autophagy; Hypoxia-Inducible Factor 1, alpha Subunit; Animals; Hedgehog Proteins; Cell Line, Tumor; Cerebellar Neoplasms; Mice; Down-Regulation; Gene Expression Regulation, Neoplastic; Ubiquitination; Repressor Proteins
PubMed: 38866867
DOI: 10.1038/s41598-024-63371-7 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Jun 2024To investigate the characteristics of the CD8 T cells infiltration from the 4 subtypes in medulloblastoma (MB), to analyze the relationship between CD8 T cells...
OBJECTIVE
To investigate the characteristics of the CD8 T cells infiltration from the 4 subtypes in medulloblastoma (MB), to analyze the relationship between CD8 T cells infiltration and prognosis, to study the function of C-X-C motif chemokine ligand 11 (CXCL11) and its receptor in CD8 T cells infiltration into tumors and to explore the potential mechanism, and to provide the necessary clinicopathological basis for exploring the immunotherapy of MB.
METHODS
In the study, 48 clinical MB samples (12 cases in each of 4 subtypes) were selected from the multiple medical center from 2012 to 2019. The transcriptomics analysis for the tumor of 48 clinical samples was conducted on the NanoString PanCancer IO360 Panel (NanoString Technologies). Immunohistochemistry (IHC) staining of formalin-fixed, paraffin-embedded sections from MB was carried out using CD8 primary antibody to analyze diffe-rential quantities of CD8 T cells in the MB four subtypes. Through bioinformatics analysis, the relationship between CD8T cells infiltration and prognosis of the patients and the expression differences of various chemokines in the different subtypes of MB were investigated. The expression of CXCR3 receptor on the surface of CD8T cells in MB was verified by double immunofluorescence staining, and the underlying molecular mechanism of CD8T cells infiltration into the tumor was explored.
RESULTS
The characteristic index of CD8T cells in the WNT subtype of MB was relatively high, suggesting that the number of CD8T cells in the WNT subtype was significantly higher than that in the other three subtypes, which was confirmed by CD8 immunohistochemical staining and Gene Expression Omnibus (GEO) database analysis by using R2 online data analysis platform. And the increase of CD8T cells infiltration was positively correlated with the patient survival. The expression level of CXCL11 in the WNT subtype MB was significantly higher than that of the other three subtypes. Immunofluorescence staining showed the presence of CXCL11 receptor, CXCR3, on the surface of CD8T cells, suggesting that the CD8T cells might be attracted to the MB microenvironment by CXCL11 through CXCR3.
CONCLUSION
The CD8T cells infiltrate more in the WNT subtype MB than other subtypes. The mechanism may be related to the activation of CXCL11-CXCR3 chemokine system, and the patients with more infiltration of CD8T cells in tumor have better prognosis. This finding may provide the necessary clinicopathological basis for the regulatory mechanism of CD8T cells infiltration in MB, and give a new potential therapeutic target for the future immunotherapy of MB.
Topics: Humans; CD8-Positive T-Lymphocytes; Medulloblastoma; Receptors, CXCR3; Chemokine CXCL11; Prognosis; Lymphocytes, Tumor-Infiltrating; Cerebellar Neoplasms; Male; Female
PubMed: 38864138
DOI: 10.19723/j.issn.1671-167X.2024.03.019 -
Neuro-oncology Advances 2024There is no standard treatment for the recurrence of medulloblastoma, the most common malignant childhood brain tumor, and prognosis remains dismal. In this study, we...
BACKGROUND
There is no standard treatment for the recurrence of medulloblastoma, the most common malignant childhood brain tumor, and prognosis remains dismal. In this study, we introduce a regimen that is well-tolerated and effective at inducing remission.
METHODS
The primary objectives of this study were to assess tolerability of the regimen and overall response rate (ORR). A retrospective chart review of patients with recurrent medulloblastoma, treated at two institutions with a re-induction regimen of intravenous irinotecan and cyclophosphamide with oral temozolomide and etoposide, was performed. Demographic, clinicopathologic, toxicity, and response data were collected and analyzed.
RESULTS
Nine patients were identified. Median age was 5.75 years. Therapy was well-tolerated with no therapy-limiting toxicities and no toxic deaths. Successful stem cell collection was achieved in all 5 patients in whom it was attempted. ORR after 2 cycles was 78%. Three patients had a complete response, 4 patients had a partial response, 1 patient had stable disease, and 1 patient had progressive disease. Four patients are alive with no evidence of disease (NED), 2 patients are alive with disease, 2 patients have died of disease, and 1 patient died of toxicity related to additional therapy (NED at time of death).
CONCLUSIONS
This regimen is well-tolerated and effective. Tumor response was noted in the majority of cases, allowing patients to proceed to additional treatment with no or minimal disease. Further study of this regimen in a clinical trial setting is an important next step.
PubMed: 38863988
DOI: 10.1093/noajnl/vdae070 -
NMC Case Report Journal 2024Stroke-like migraine attacks after radiation therapy (SMART) syndrome, a delayed sequela of cranial radiotherapy encountered rarely, occurs due to transient neurological...
Stroke-like migraine attacks after radiation therapy (SMART) syndrome, a delayed sequela of cranial radiotherapy encountered rarely, occurs due to transient neurological deficits coupled with migraine episodes. This case report describes an occurrence of SMART syndrome in an individual 8 years after receiving medulloblastoma treatment. The subject, a 21-year-old male, experienced abrupt aphasia and right-sided hemiparesis. Arterial spin labeling (ASL) revealed initial cerebral hypoperfusion in the left temporal and parietal regions, with no tumor resurgence or notable ischemic alterations. Two days later, the symptoms disappeared completely; nevertheless, at that time, ASL presented cerebral hyperperfusion in the same lobule. The subject experienced a pulsating headache and nausea the next day. In the context of SMART syndrome, this fluctuation in cerebral blood flow indicated by ASL is a unique finding. The significance of this case lies in the documentation of the dynamic evolution of cerebral perfusion in SMART syndrome via ASL, thereby elucidating its underlying pathophysiology. As hemiplegic migraine shows a similar cerebral perfusion pattern to SMART syndrome, we inferred an unexplored but shared pathophysiology among hemiplegic migraine and SMART syndrome. Through this successful capture of these distinct cerebral blood flow alterations, from hypoperfusion to hyperperfusion, our understanding of the pathophysiological intricacies inherent to SMART syndrome will be enhanced.
PubMed: 38863579
DOI: 10.2176/jns-nmc.2024-0037 -
Aging Jun 2024SMARCD3 has recently been shown to be an important gene affecting cancer, playing an important role in medulloblastoma and pancreatic ductal adenocarcinoma. Therefore,...
BACKGROUND
SMARCD3 has recently been shown to be an important gene affecting cancer, playing an important role in medulloblastoma and pancreatic ductal adenocarcinoma. Therefore, we conducted this research to investigate the potential involvement of SMARCD3 across cancers and to offer recommendations for future studies.
METHODS
Utilizing information on 33 malignancies in the UCSC Xena database, SMARCD3 expression and its prognostic value were assessed. The tumor microenvironment was evaluated with the "CIBERSORT" and "ESTIMATE" algorithms. SMARCD3 and immune-related genes were analyzed using the TISIDB website. The pathways related to the target genes were examined using GSEA. MSI (microsatellite instability), TMB (tumor mutational burden), and immunotherapy analysis were used to evaluate the impact of target genes on the response to immunotherapy.
RESULTS
There is heterogeneity in terms of the expression and prognostic value of SMARCD3 among various cancers, but it is a risk factor for many cancers including uterine corpus endometrial cancer (UCEC), renal clear cell carcinoma (KIRC), and gastric adenocarcinoma (STAD). GSEA revealed that SMARCD3 is related to chromatin remodeling and transcriptional activation, lipid metabolism, and the activities of various immune cells. The TMB and MSI analyses suggested that SMARCD3 affects the immune response efficiency of KIRC, LUAD and STAD. Immunotherapy analysis suggested that SMARCD3 may be a potential immunotherapy target. RT-qPCR demonstrated the variation in SMARCD3 expression in KIRC, LUAD, and STAD.
CONCLUSION
Our study revealed that SMARCD3 affects the prognosis and immunotherapy response of some tumors, providing a direction for further research on this gene.
Topics: Humans; Biomarkers, Tumor; Prognosis; Tumor Microenvironment; Immunotherapy; Neoplasms; Microsatellite Instability; Gene Expression Regulation, Neoplastic; Chromosomal Proteins, Non-Histone
PubMed: 38862250
DOI: 10.18632/aging.205921