Prognosis Of Medulloblastoma Research Articles

CNSC-33. GROUP3 MEDULLOBLASTOMA WITH BONE MARROW AND ABDOMINAL CAVITY METASTASIS:A CASE REPORT

Abstract Medulloblastoma is an infratentorial primitive neuro-ectodermal tumour, which is commonly occurring in childhood. It often spreads through the cerebrospinal fluid pathways with a very low rate of systemic metastases. Extra-central nervous system metastases have a poor prognosis in medulloblastoma. Here, we reported a case of Group3 medulloblastoma with bone marrow and abdominal cavity metastasis. A 10-year-old girl complained of headache, dizziness, vomiting and nausea. Magnetic resonance imaging(MRI) of the brain showed a large mass in the fourth ventricle and obstructive hydrocephalus. The surgery was performed to remove the mass and ventriculoabdominnal shunt was performed for obstructive hydrocephalus. Histological verification was proven classic medulloblastoma and next-generation sequencing confirmed molecular group of Gruop3 with MYC amplication. Radiotherapy was subsequently performed one month after the surgery. During the radiotherapy, brain MRI showed metastasis on the surface of the brain, which confer a poor prognosis. After the radiotherapy According to the therapeutic schedule, She would accept chemotherapy one month after the radiotherapy. But She suffered severe bone marrow suppression manifested as anaemia and thrombocytopenia, which can not be improved by medication and blood transfusion. A bone marrow aspiration was subsequently performed, and bone marrow smear showed large numbers of tumor cells at high magnification and was lack of normal hematopoietic cells. The girl was deteriorating rapidly with jaundice, ascites, hepatosplenomegaly and pancreatitis after the bone marrow aspiration. We found a lot of tumor cells in the bleeding tendency ascites and finally confirmed bone marrow and abdominal cavity metastasis concurrently. Eventually, She died less than a month after the metastasis and the overall survival was only 6 months. This typical case demonstrated severe bone marrow suppression of unknown origin should caused alarm and be performed bone marrow aspiration as soon as possible. The prognosis of medulloblastoma with extra-central nervous system metastases is poor and people may die in months.

Systematic transcriptomic analysis of childhood medulloblastoma identifies N6- methyladenosine-dependent lncRNA signatures associated with molecular subtype, immune cell infiltration, and prognosis.

Medulloblastoma, the most common malignant pediatric brain tumor, is classified into four main molecular subgroups, but group 3 and group 4 tumors are difficult to subclassify and have a poor prognosis. Rapid point-of-care diagnostic and prognostic assays are needed to improve medulloblastoma risk stratification and management. N6-methyladenosine (m6A) is a common RNA modification and long non-coding RNAs (lncRNAs) play a central role in tumor progression, but their impact on gene expression and associated clinical outcomes in medulloblastoma are unknown. Here we analyzed 469 medulloblastoma tumor transcriptomes to identify lncRNAs co-expressed with m6A regulators. Using LASSO-Cox analysis, we identified a five-gene m6A-associated lncRNA signature (M6LSig) significantly associated with overall survival, which was combined in a prognostic clinical nomogram. Using expression of the 67 m6A-associated lncRNAs, a subgroup classification model was generated using the XGBoost machine learning algorithm, which had a classification accuracy > 90%, including for group 3 and 4 samples. All M6LSig genes were significantly correlated with at least one immune cell type abundance in the tumor microenvironment, and the risk score was positively correlated with CD4 + naïve T cell abundance and negatively correlated with follicular helper T cells and eosinophils. Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

Systematic transcriptomic analysis of childhood medulloblastoma identifies N6-methyladenosine-dependent lncRNA signatures associated with molecular subtype, immune cell infiltration, and prognosis

Medulloblastoma, the most common malignant pediatric brain tumor, is classified into four main molecular subgroups, but group 3 and group 4 tumors are difficult to subclassify and have a poor prognosis. Rapid point-of-care diagnostic and prognostic assays are needed to improve medulloblastoma risk stratification and management. N6-methyladenosine (m6A) is a common RNA modification and long non-coding RNAs (lncRNAs) play a central role in tumor progression, but their impact on gene expression and associated clinical outcomes in medulloblastoma are unknown. Here we analyzed 469 medulloblastoma tumor transcriptomes to identify lncRNAs co-expressed with m6A regulators. Using LASSO-Cox analysis, we identified a five-gene m6A-associated lncRNA signature (M6LSig) significantly associated with overall survival, which was combined in a prognostic clinical nomogram. Using expression of the 67 m6A-associated lncRNAs, a subgroup classification model was generated using the XGBoost machine learning algorithm, which had a classification accuracy > 90%, including for group 3 and 4 samples. All M6LSig genes were significantly correlated with at least one immune cell type abundance in the tumor microenvironment, and the risk score was positively correlated with CD4+ naïve T cell abundance and negatively correlated with follicular helper T cells and eosinophils. Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

MDB-68. DISCOVERING DRUG SENSITIVITIES IN MEDULLOBLASTOMA USING PATIENT- AND PDX-DERIVED TUMOROIDS

Abstract BACKGROUND Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor types and is subdivided into four major types: WNT, SHH, Group 3 and Group 4. Treatment, including resection, cranio-spinal radiotherapy, and chemotherapy, often leads to undesirable long-term side effects. MB prognosis depends on type, subtype, and genetic alterations, reflecting the high level of heterogeneity observed in these tumors and indicating that specific patient populations with particularly poor prognosis require alternative treatment approaches. Therefore, preclinical models are essential for recapitulating MB heterogeneity and developing subtype-specific treatments. METHODS Long-term in vitro MB tumoroid models were developed from patient and PDX tumors and molecularly characterized using DNA methylation and transcriptomic analyses. High-throughput single drug screening (225 compounds) and combination screening were performed to identify (subtype-specific) drug sensitivities. RESULTS Fifteen tumoroid lines were established from TP53-mutated SHH (n=6), Group 3 (G3) MYC-amplified (n=4) and non-amplified (n=5) patient (n=6) and PDX (n=9) tumors. DNA methylation analyses confirmed the maintenance of molecular identity in these tumoroids after long-term culture (>5 passages). Transcriptome analyses reveal a more proliferative, progenitor-like phenotype in these tumoroids compared to patient/PDX tumors. Hight-throughput drug screens identified both common and type-specific drug sensitivities within MB. Notably, drugs targeting CDK7, CDK12, CHECK1, BCL2L, and HDAC demonstrated efficacy in both G3 and TP53-mutated SHH-MB, while TOP1/2 and MDM2 inhibitors were specific for G3-MB. Currently, these drugs are being further investigated to select the most effective synergistic drug combinations for in vivo validation in PDX models. CONCLUSIONS Thus far, we have established already fifteen MB tumoroid models representing SHH-MB and G3-MB and identified several drug targets, including cell cycle kinases and HDACs. Tumoroids closely resemble patient tumors, based on methylome and transcriptome, enhancing their relevance for drug discovery applications in a high-throughput fashion and for prioritizing new treatment strategies for MB patients in clinical trials.

A Nomogram Model for Predicting Prognosis of Patients with Medulloblastoma.

To identify the prognostic factors associated with cancer-specific survival in medulloblastoma (MB), and to use them for establishing a nomogram model to predict cancer-specific survival. In total, 268 patients with MB were included; they were rigorously respectively screened from the Surveillance, Epidemiology, and End Results database from 1988 to 2015 and statistically analyzed in R language. This study focused on cancer-specific death and used the cox regression analysis for variable filtering. The model was calibrated using C-index, area under the curve (AUC), and calibration curve. As per our findings, it was determined that extension (localized: hazard ratio [HR]=0.5899, p=0.00963; further extension: indicator) and treatment modality (radiation after surgery chemotherapy sequence unknown: HR=0.3646, p=0.00192; no surgery: indicator) were statistically significant in the prognosis of MB and were finally utilized to construct a nomogram model for predicting the condition. The AUC values were 0.649, 0.629, and 0.64 at 2, 3, and 5 years, respectively. Tumor extension and treatment modality were independent prognostic factors for MB.

Mitochondrial subtype MB-G3 contains potential novel biomarkers and therapeutic targets associated with prognosis of medulloblastoma

BackgroundMedulloblastoma is the most common malignant brain tumor in children. There are four groups, each with different causal mutations, affected pathways and prognosis. Here, we investigated the role of mitochondria in medulloblastoma and whether there are differences between the different groups.MethodsWe compared the gene expression levels in the four different medulloblastoma groups (MB-WNT, MB-SHH, MB-G3 and MB-G4), with the focus on genes associated with mitochondria. We used several tools including Salmon, Tximeta, DESeq2, BiomaRt, STRING, Ggplot2, EnhancedVolcano, Venny 2.1 and Metscape.ResultsA total of 668 genes were differentially expressed and the most abundant genes were associated with cell division pathway followed by modulation of chemical synaptic transmission. We also identified several genes (ABAT, SOX9, ALDH5A, FOXM1, ABL1, NHLH1, NEUROD1 and NEUROD2) known to play vital role in medulloblastoma. Comparative expression analysis revealed OXPHOS complex-associated proteins of mitochondria. The most significantly expressed genes in the MB-SHH and MB-G4 groups were AHCYL1 and SFXN5 while PAICS was significantly upregulated in MB-WNT group. Notably, MB-G3 contained the most downregulated genes from the OXPHOS complexes, except COX6B2 which was strongly upregulated.ConclusionsWe show the importance of mitochondria and compare their role in the four different medulloblastoma groups.

The Role of the Dysregulation of Long Non-Coding and Circular RNA Expression in Medulloblastoma: A Systematic Review.

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Although recent multi-omic studies have led to advances in MB classification, there is still room for improvement with regard to treatment response and survival. Therefore, identification of new and less invasive biomarkers is needed to refine the diagnostic process and to develop more personalized treatment strategies. In this context, non-coding RNAs (ncRNAs) could be useful biomarkers for MB. In this article, we reviewed the role of two types of ncRNAs, long non-coding (lncRNAs) and circular RNAs (circRNAs), as biomarkers for the diagnosis, subgroup classification, and prognosis of MB. We also reviewed potential candidates with specific functions and mechanisms of action in the disease. We performed a search in PubMed and Scopus using the terms ("long non coding RNAs" OR "lncRNAs") and ("circular RNAs" OR "circRNAs") AND "medulloblastoma" to identify biomarker discovery or functional studies evaluating the effects of these ncRNAs in MB. A total of 26 articles met the inclusion criteria. Among the lncRNAs, the tumorigenic effects of the upregulated lnc-IRX3-80 and lnc-LRRC47-78 were the most studied in MB. Among the circRNAs, the upregulation of circSKA3 and its functional impact in MB cell lines were the most consistent results, so this circRNA could be considered a potential biomarker in MB. Additional validation is required for many deregulated lncRNAs and circRNAs; therefore, further studies are warranted.

Multiparametric MRI-Based Radiomics Signature with Machine Learning for Preoperative Prediction of Prognosis Stratification in Pediatric Medulloblastoma

Despite advances in risk-stratified treatment strategies for children with medulloblastoma (MB), the prognosis for MB with short-term recurrence is extremely poor, and there is still a lack of evaluation of short-term recurrence risk or short-term survival. This study aimed to construct and validate a radiomics model for predicting the outcome of MB based on preoperative multiparametric magnetic resonance images (MRIs) and to provide an objective for clinical decision-making. The clinical and imaging data of 64 patients with MB admitted to Shenzhen Children's Hospital from December 2012 to December 2021 and confirmed by pathology were retrospectively collected. According to the 18-month progression-free survival, the cases were classified into a good prognosis group and a poor prognosis group, and all cases were divided into training group (70%) and validation group (30%) randomly. Radiomics features were extracted from MRI of each child. The consistency test, t-test, and the least absolute shrinkage and selection operator were used for feature selection. The support vector machine (SVM) and receiver operator characteristic were used to evaluate the distinguishing ability of the selected features to the prognostic groups. RAD score was calculated based on the selected features. The clinical characteristics and RAD score were included in the multivariate logistic regression, and prediction models were constructed by screening out independent influences. The radiomics nomogram was constructed, and its clinical significance was evaluated. A total of 1930 radiomic features were extracted from the images of each patient, and 11 features were included in the construction of radiomics score after selected. The area under the curve (AUC) values of the SVM model in the training and validation groups were 0.946 and 0.797, respectively. The radiomics nomogram was constructed based on the training cohort, and the AUC values in the training group and the validation group were 0.926 and 0.835, respectively. The results of clinical decision curve analysis showed that a good net benefit could be obtained from the nomogram. The radiomics nomogram established based on MRI can be used as a noninvasive predictive tool to evaluate the prognosis of children with MB, which is expected to help neurosurgeons better conduct preoperative planning and patient follow-up management.

The Association Between Socioeconomic Factors at Diagnosis and Survival in Medulloblastoma: A Propensity Score-Matched Analysis and Population-Based Study.

Medulloblastoma(MB) is the most common malignant brain tumor of childhood. The associations between socioeconomic statuses (SES) and survival outcomes of medulloblastoma remain unclear. The aim of this study was to develop a nomogram to predict medulloblastoma specific death (MBSD) and overall survival (OS) in patients with medulloblastoma, taking into account socioeconomic factors in patients with medulloblastoma. We included patients diagnosed with MB between 1975 and 2016 from the Surveillance, Epidemiology, and End Results database. Propensity Score Matching (PSM) was performed to reduce selection bias. Multivariate cox proportional hazards model was used to assess SES impact and clinically relevant variables of medulloblastoma specific death and overall survival. Independent prognostic factors determined by multivariate analysis were used to construct nomograms. A total of 2660 patients were enrolled after matching. Study showed unemployed rate (MBSD, high level vs. low level, P = 0.020) (OS, high level vs. low level, P = 0.017), and marital status (OS, married vs unmarried/unknown, P = 0.029) were important factors affecting prognosis of medulloblastoma in male. Meanwhile, median household income (MBSD, quartile 1 vs. quartile 3, P = 0.047) (OS, quartile 1 vs. quartile 2, P = 0.017) (OS, quartile 1 vs. quartile 3, P = 0.014), residence (MBSD, urban vs. rural, P = 0.041), and insurance status (MBSD, insured vs. uninsured/unknown, P = 0.002)(OS, insured vs. uninsured/unknown, P = 0.001) were significant factors affecting prognosis of medulloblastoma in female. Through the calibration plot and C-index test, our nomogram was also of predictive significance. The unique features of MB have provided a scenario for analysis of the impact of racial, ethnic, gender, and socioeconomic factors. The current findings have important public health implications for achieving the goal of a healthy population. Given the known morbidity rates, long-term psychological, financial and medical burdens that these children and their families must bear, it is critical to identify and address these gaps.

Timing is everything: A connection between medulloblastoma prognosis and foetal cerebellar development.

The childhood brain tumour medulloblastoma is typically classified into multiple discrete molecular subgroups with characteristic DNA methylation and expression patterns. Several of these subgroups are used as, or proposed to be, an effective basis for treatment stratification. Here, we highlight the close connection between the findings described in a recent series of studies which, together, strongly imply a continuous association between survival outcome, the transcriptional profile of a Group3/Group4 (i.e. non-WNT/non-SHH) medulloblastoma and the specific point during early foetal cerebellar development at which initial pathogenic disruption took place. This has important implications for future efforts to model the disease by incorporating driving molecular features into their specific developmental context. This further suggests that instead of relying upon discrete DNA methylation subgroups, using expression biomarkers as the basis of a continuous risk predictor may produce a more effective risk stratification of patients with Group3/Group4 medulloblastoma.

Analysis of the personalized treatment and the relevant prognostic factors in children with medulloblastoma

<b>Purpose:</b> The present study summarized cases of children (<i>n</i> = 32) with medulloblastoma (MB) who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis. <b>Methods:</b> According to the risk stratification criteria, the cases were divided into the following four risk groups: low, standard, high, and very high. The 5-year overall survival (OS) and progression-free survival (PFS) rates were summarized. Further, the effects on the prognosis of tumor size, tumor stage, degree of resection, treatment mode, metastatic recurrence, molecular typing, and risk stratification were analyzed. <b>Results:</b> In the present study, following surgery, 3 cases abandoned radiotherapy (RT) and chemotherapy (CHT), 7 cases (<3 years of age) received only CHT, and 22 cases received combined RT and CHT. Total and near-total tumor resections were performed in 29 cases (90.6%). Subtotal resections were performed in 3 cases, and there were no surgery-related deaths. The average follow-up duration was 47 months. The average 5-year PFS and OS rates were 57.3% ± 7.2% and 68.7% ± 8.6%, respectively. The OS and PFS rates were significantly correlated with tumor-risk stratification, molecular staging, tumor stage, treatment mode, and recurrence after surgery (<i>p</i> < 0.01). The degree of tumor resection, pathological type, and the presence of preoperative implantation were secondary factors affecting the prognosis (<i>p</i> < 0.05). Age was correlated with the PFS rate. There was no correlation between age/tumor location/tumor size and prognosis (<i>p</i> > 0.05). Favorable prognostic factors in the low- and standard-risk groups were stage M0, wingless-type MB, postoperative RT combined with CHT, no postoperative recurrence, age ≥3 years, and total tumor resection. <b>Conclusions:</b> Personalized treatment strategies based on the risk stratification of MB and postoperative stratified comprehensive treatment could help improve the prognosis for MB.

TOP2A correlates with poor prognosis and affects radioresistance of medulloblastoma.

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.

Tumor-Associated Macrophages Correlate With Prognosis in Medulloblastoma.

PurposeMacrophage polarization plays an essential role in the tumor microenvironment of brain tumors. However, the role of tumor-associated macrophages (TAMs) in medulloblastoma still remains controversial. Thus, we investigated the distribution of macrophages in medulloblastoma tissues and analyzed the association of TAM recruitment and medulloblastoma patients’ outcomes.MethodsWe obtained a total of 71 paraffin sections from patients with medulloblastoma, and detected the activated phenotype (M1/M2) by monoclonal antibodies for CD68, HLA-DR and CD163 with multiple fluorescence immunohistochemistry method. The number of polarized macrophages was quantified using the InForm software. Outcomes were analyzed according to clinical data and quantified macrophage data.ResultsThe study revealed that TAMs were significantly higher in sonic hedgehog (SHH) medulloblastoma than in other subgroups, and M1 macrophages in metastatic group were significantly higher than those in non-metastatic group. A Kaplan-Meier survival analysis and multivariate Cox regression model showed the correlation of high percentage of total macrophages (P = 0.038, HR = 0.241) and M1 macrophages (P = 0.034, HR = 0.333) with good 5-year progression-free survival (PFS); however, M2 macrophages had no correlation with survival of medulloblastoma patients (P> 0.05).ConclusionHigh percentage of total macrophages and M1 macrophages are correlated with good outcome of medulloblastoma patients. TAMs might be a target of therapy.

Dynamic susceptibility contrast and diffusion-weighted MRI in posterior fossa pilocytic astrocytoma and medulloblastoma.

The utility of perfusion MRI in distinguishing between pilocytic astrocytoma (PA) and medulloblastoma (MB) is unclear. This study aimed to evaluate the diagnostic and prognostic performance of dynamic susceptibility contrast (DSC)-MRI parameters and apparent diffusion coefficient (ADC) values between PA and MB. Between January 2012 and August 2021, 49 (median, 7 years [range, 1-28 years]; 28 females) and 35 (median, 8 years [1-24 years]; 12 females) patients with pathologically confirmed PA and MB, respectively, were included. The normalized relative cerebral blood volume and flow (nrCBV and nrCBF) and mean and minimal normalized ADC (nADCmean and nADCmin) values were calculated using volume-of-interest analyses. Diagnostic performance and Pearson's correlation with progression-free survival were also evaluated. The MB group showed a significantly higher nrCBV and nrCBF (nrCBV: 1.69 [0.93-4.23] vs. 0.95 [range, 0.37-2.28], p = .0032; nrCBF: 1.62 [0.93-3.16] vs. 1.07 [0.46-2.26], p = .0084) and significantly lower nADCmean and nADCmin (nADCmean: 0.97 [0.70-1.68] vs. 2.21 [1.44-2.80], p < .001; nADCmin: 0.50 [0.19-0.89] vs. 1.42 [0.89-2.20], p < .001) than the PA group. All parameters exhibited good diagnostic ability (accuracy >0.80) with nADCmin achieving the highest score (accuracy = 1). A moderate correlation was found between nADCmean and progression-free survival for MB (r = 0.44, p = .0084). DSC-MRI parameters and ADC values were useful for distinguishing between PA and MB. A lower ADC indicated an unfavorable MB prognosis, but the DSC-MRI parameters did not correlate with progression-free survival in either group.

Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis

Medulloblastoma is the most common embryonic brain tumor in children. We investigated a cohort of 52 Asian medulloblastoma patients aged between 0 and 19 years old, who received surgical resections and post-resection treatments in the Taipei Medical University Hospital and the Taipei Veterans General Hospital. Genome-wide RNA sequencing was performed on fresh-frozen surgical tissues. These data were analyzed using the CIBERSORTx immune deconvolution software. Two external clinical and molecular datasets from United States (n = 62) and Canada (n = 763) were used to evaluate the transferability of the gene-signature scores across ethnic populations. The abundance of 13 genes, including DLL1, are significantly associated with overall survival (All Cox regression P < 0.001). A gene-signature score was derived from the deep transcriptome, capable of indicating patients’ subsequent tumor recurrence (Hazard Ratio [HR] 1.645, confidence interval [CI] 1.337–2.025, P < 0.001) and mortality (HR 2.720, CI 1.798–4.112, P < 0.001). After the adjustment of baseline clinical factors, the score remains indicative of recurrence-free survival (HR 1.604, CI 1.292–1.992, P < 0.001) and overall survival (HR 2.781, CI 1.762–4.390, P < 0.001). Patients stratified by this score manifest not only distinct prognosis but also different molecular characteristics: Notch signaling ligands and receptors are comparatively overexpressed in patients with poorer prognosis, while tumor infiltrating natural killer cells are more abundant in patients with better prognosis. Additionally, immunohistochemical staining showed the DLL1 protein, a major ligand in the Notch signaling pathway, and the NCAM1 protein, a representative biomarker of natural killer cells, are present in the surgical tissues of patients of four molecular subgroups, WNT, SHH, Group 3 and Group 4. NCAM1 RNA level is also positively associated with the mutation burden in tumor (P = 0.023). The gene-signature score is validated successfully in the Canadian cohort (P = 0.009) as well as its three molecular subgroups (SHH, Group 3 and Group 4; P = 0.047, 0.018 and 0.040 respectively). In conclusion, pediatric medullablastoma patients can be stratified by gene-signature scores with distinct prognosis and molecular characteristics. Ligands and receptors of the Notch signaling pathway are overexpressed in the patient stratum with poorer prognosis. Tumor infiltrating natural killer cells are more abundant in the patient stratum with better prognosis.

Effects of different molecular subtypes and tumor biology on the prognosis of medulloblastoma.

Medulloblastoma is one ofthe most common malignant brain tumors in the pediatric population. Recent studies identified four distinct medulloblastoma subgroups with different molecular alterations and pathways, and natural courses and outcomes. To evaluate the results of surgical and medical treatments of patients with medulloblastoma and compare them among the medulloblastoma subgroups. The clinical and radiological features, medical and surgical management and treatment outcomes and their correlation with molecular subgroups of 58 patients treated for medulloblastoma in the last 20years were evaluated. Fifty-eight patients, of whom 35 were male and 23 were female, were evaluated. The median age was 6years (range, 1-19years). The most common symptoms were nausea and vomiting (60%). Forty-three percent of the patients had headache and 40% had ataxia. Previous pathology reports revealed that 43 (74%), eight (14%), five (8%), and two (3%) had classic, desmoplastic, desmoplastic/nodular, and anaplastic morphologies, respectively. After the subgroup analyses, five patients (12%) were attributed to the wingless subgroup (WNT) group; 14 (32.5%), to the sonic hedgehog subgroup (SHH) group; and 24 (56%), to the non-WNT non-SHH group. On the basis of immunohistochemical analysis results, 15 patients could not be attributed to any subgroups. The clinical risk groups (average vs high-risk) and age at diagnosis (≥ 3years vs < 3years of age) were significant for 5-year event free survival (86% vs 43%, p:0.011 and 59% vs 36%, p:0.039). There was no significant difference in survival or event free survival according to molecular subtypes in this cohort. In corporation of molecular features to the clinicopathologic classification leads to risk-adapted treatment. Although the molecular subgroups did not affect outcome significantly in this study, more studies with larger numbers of patients are needed to understand the tumor pathophysiology of medulloblastoma and design the future medical practice.

Risk Factors Associated with Post-therapeutic Outcome for Medulloblastoma: An Experience from Indonesia.

Context:The prognosis of medulloblastoma is better in patients who underwent complete treatment consisting of surgery, radiotherapy, and chemotherapy. However, the realization of such multidiscipline management is quite challenging in developing countries, including Indonesia. Until now, no study on the management of medulloblastoma has ever been conducted in Indonesia.Aims:The authors aimed to study the characteristics, management, and mortality outcome of medulloblastoma patients in Dr. Cipto Mangunkusumo National Referral Hospital, Jakarta, Indonesia.Subjects and Methods:This study was based on medical record and registry of 44 medulloblastoma patients who underwent tumor removal in Dr. Cipto Mangunkusumo National Referral Hospital, Jakarta, Indonesia, between 2011 and 2018.Statistical Analysis Used:Cox regression analysis was utilized to determine the relationship between patients' demography, tumor characteristics, and treatment, with mortality.Results:The incidence of mortality was 84.1% and median months' survival time (95% confidence interval [CI]) was 13 (8.67–17.32). Gross total removal (GTR) was performed in 43.2% of all tumor removal surgery. Only 50% of all patients completed radiotherapy, and 6.8% concluded multimodalities treatment (surgery, radiotherapy, and chemotherapy). Significant statistical association between age, gender, and extent of resection with mortality was identified (HR [95% CI] for age: 0.44 [0.22–0.88], gender: 0.001 [0.000–0.27; REF: female], and biopsy: 31.52 [1.09–910.56; REF: GTR]).Conclusions:The survival rate of medulloblastoma in Indonesia is inferior to that previously reported in other studies. There is no unusual characteristic contributing to neoteric risk factor. The authors surmise that insufficient multidisciplinary management for the disease, consisting of suboptimal tumor resection, the absence of risk stratification, and incomplete postsurgical treatment (radiotherapy and chemotherapy) resulted in such outcome.

Pediatric Medulloblastoma: A Study from Western Region of Saudi Arabia

Objective: Medulloblastoma is the most common malignant brain tumors in children worldwide. It is little known about the characteristics associated with medulloblastoma and the outcome in Saudi Arabia. Therefore, the study was conducted to understand the current status and what should be done for future. Methods: A retrospective chart review of all children (<14 years) who have been diagnosed and managed with medulloblastoma at King Faisal specialist hospital and research center (KFSHRC) in Jeddah, Saudi Arabia from 2011 to 2017. Important epidemiological and clinical Data have been collected and analyzed through descriptive statistics to understand the clinical characteristics and treatment outcomes. In addition, Kaplan-Meier survival analysis was conducted to generate EFS and OS. Results: The obtained results of OS of 73.7% with suggested that lower age (Age ≤ 3), high risk, positive metastasis at presentation, partial resection remained vital and contributed to lower overall survival rate among the patients with P value as follow: (P: 3 years (P<0.001) was the major factor for better survival. Conclusion: As per the observation, the estimated outcome of total cohort was OS 73.7% and EFS 54.8% which are comparable to the developed countries. The age of > 3 years and the complete surgical excision are emerging as the most significant factors affecting OS (80.5%, 88.7%) and EFS (61.2%, 70%). Average risk and negative metastasis had significant OS with p value of 0.04, 0.02 respectively. This study provides an important clue in understanding the importance of the demographic, clinical, and treatment modalities in understanding the prognosis of medulloblastoma. This report will serve as an important resource from Kingdom of Saudi Arabia regarding medulloblastoma survival.

QOL-44. ASSESSMENT OF NEUROCOGNITIVE FUNCTION AND MRI PARAMETERS IN LONG-TERM SURVIVORS WITH POSTERIOR FOSSA TUMORS: A COMPARISON BETWEEN MEDULLOBLASTOMAS TREATED BY REDUCED-DOSE CRANIOSPINAL IRRADIATION AND OTHER TUMORS

BACKGROUNDChildren with medulloblastoma cannot avoid chemoradiotherapy including craniospinal radiation, although prognosis of medulloblastoma has improved and previous studies have reported a significant risk of intellectual disturbance by these treatments. We retrospectively analysed neurocognitive functions, clinical MRI parameters of patients with posterior fossa tumors, especially medulloblastomas.MATERIALS AND METHODSTwenty-two patients (12 medulloblastomas, 5 ependymomas, 5 astrocytomas) treated in our institution were enrolled in this study. Mean age was 7.8 years and 6.5 years, percentage of hydrocephalus at onset was 66.7% and 60%, respectively in medulloblastoma group and in other tumor group (ependymoma and astrocytoma). Postoperative chemoradiotherapy including reduced-dose craniospinal irradiation (18Gy) was done for medulloblastoma group and local radiation or operation only was done for other group. Version 3 or 4 of Wechsler Intelligent Scale for Children (WISC) was used by neurocognitive function analysis. Ventricular size, white matter volume and other parameters were also was estimated based on MRI. Follow-up duration was 6–17 years (mean: 10.5 years).RESULTSEvaluations of neurocognitive functions based on WISC pointed out lower performance IQ than verbal IQ in long term survivor of both group, especially working memory (P=0.05). Both hydrocephalus and cranial nerve complications was influenced lower scores of WISC, but age at onset did not influence WISC scores. Comparison between both group showed there was no significant difference about cognitive function and white matter volume.

Production of a SCID mouse model of medulloblastoma to explore the therapeutic value of targeting tumor driver genes.

Tumor driver genes are genes where structural or sequence mutations confer a selective advantage for cancer cells. The individualized targeting of tumor driver genes has become a topic of interest for tumor treatment. The prognosis for medulloblastoma (MB), a common type of malignant intracranial tumor found in children, is poor. The tumor driver genes and the corresponding targeted drugs remain to be studied. The present study analyzed tumor driver genes from tumor tissue and peripheral blood from one patient with nodular desmoplastic MB with Sonic Hedgehog activation and screened targeted drugs for the tumor driver genes. Additionally, MB tissue was successfully implanted into the SCID mouse which were then used for subsequent drug screening. The present study explored novel treatments for MB from the perspective of tumor driver genes, and may provide new ideas for choosing individualized targeted therapies for patients with MB.