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International Journal of Radiation... Jun 2024Medulloblastoma is a central nerves tumor that often occurs in pediatrics. The main radiotherapy technique for this tumor type is craniospinal irradiation (CSI), through...
INTRODUCTION
Medulloblastoma is a central nerves tumor that often occurs in pediatrics. The main radiotherapy technique for this tumor type is craniospinal irradiation (CSI), through which the whole brain and spinal cord are exposed to radiation. Due to the immaturity of healthy organs in pediatrics, radiogenic side effects such as second cancer are more severe. Accordingly, the current study aimed to evaluate the risk of secondary cancer development in healthy organs following CSI.
MATERIALS AND METHODS
Seven organs at risk (OARs) including skin, eye lens, thyroid, lung, liver, stomach, bladder, colon, and gonads were considered and the dose received by each OAR during CSI was measured inside an anthropomorphic RANDO phantom by TLDs. Then, the mean obtained dose for each organ was used to estimate the probability of secondary malignancy development according to the recommended cancer risk coefficients for specific organs.
RESULTS
The results demonstrated that the stomach and colon are at high risk of secondary malignancy occurrence, while the skin has the lowest probability of secondary cancer development. The total received dose after the treatment course by all considered organs was lower than the corresponding tolerable dose levels.
CONCLUSIONS
From the results, it can be concluded that some OARs during CSI are highly at risk of secondary cancer development. This issue may be of concern due to organ immaturity in pediatrics which can intensify the radiogenic effects of radiation exposure. Accordingly, strict shielding the OARs during craniospinal radiotherapy and/or sparing them from the radiation field through modern techniques such as hadron therapy is highly recommended.
PubMed: 38889539
DOI: 10.1080/09553002.2024.2369110 -
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 -
Advanced Science (Weinheim,... Jun 2024Medulloblastoma (MB) stands as one of the prevalent malignant brain tumors among pediatric patients. Despite its prevalence, the intricate interplay between the...
Medulloblastoma (MB) stands as one of the prevalent malignant brain tumors among pediatric patients. Despite its prevalence, the intricate interplay between the regulatory program driving malignancy in MB cells and their interactions with the microenvironment remains insufficiently understood. Leveraging the capabilities of single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq), the chromatin accessibility landscape is unveiled across 59,015 distinct MB cells. This expansive dataset encompasses cells belonging to discrete molecular subgroups, namely SHH, WNT, Group3, and Group4. Within these chromatin accessibility profiles, specific regulatory elements tied to individual subgroups are uncovered, shedding light on the distinct activities of transcription factors (TFs) that likely orchestrate the tumorigenesis process. Moreover, it is found that certain neurotransmitter receptors (NTRs) are subgroup-specific and can predict MB subgroup classification when combined with their associated transcription factors. Notably, targeting essential NTRs within tumors influences both the in vitro sphere-forming capability and the in vivo tumorigenic capacity of MB cells. These findings collectively provide fresh insights into comprehending the regulatory networks and cellular dynamics within MBs. Furthermore, the significance of the TF-NTR regulatory circuits is underscored as prospective biomarkers and viable therapeutic targets.
PubMed: 38884167
DOI: 10.1002/advs.202309554 -
Cell Death and Differentiation Jun 2024Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to...
Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin ligase HUWE1 in GNP proliferation. We show that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. Disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB.
PubMed: 38879724
DOI: 10.1038/s41418-024-01325-2 -
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 -
American Journal of Medical Genetics.... Jun 2024Gorlin syndrome can be caused by pathogenic/likely pathogenic (P/LP) variants in the tumor suppressor gene PTCH1 (9q22.1-q31), which encodes the receptor for the sonic...
Gorlin syndrome can be caused by pathogenic/likely pathogenic (P/LP) variants in the tumor suppressor gene PTCH1 (9q22.1-q31), which encodes the receptor for the sonic hedgehog (SHH) ligand. We present a 12-month-old boy clinically diagnosed with Gorlin syndrome who was found to have significantly delayed development, palmar pitting, palmar and plantar keratosis, short hands, frontal bossing, coarse face, hypertelorism, a bifid rib, misaligned and missing teeth, and SHH-activated medulloblastoma. Genetic testing, including a pediatric cancer panel and genome sequencing with peripheral blood, failed to identify any P/LP variants in PTCH1. Paired tumor/normal exome sequencing was performed, which identified a germline NM_000264.5 (PTCH1): c.361_362ins? alteration through manual review of sequencing reads. Clinical RNA sequencing further demonstrated an Alu insertion at this region (PTCH1: c.361_362insAlu), providing molecular confirmation of Gorlin syndrome. This finding exemplifies a unique mechanism for PTCH1 disruption in the germline and highlights the importance of comprehensive analysis, including manual review of DNA sequencing reads and the utility of RNA analysis to detect variant types which may not be identified by routine genetic screening techniques.
PubMed: 38864234
DOI: 10.1002/ajmg.a.63788 -
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