Clinical Characteristic and Molecular Subgroups of Thai Pediatric Medulloblastomas at Queen Sirikit National Institute of Child Health

2021 ◽  
Vol 104 (10) ◽  
pp. 1648-1657
Keyword(s):  
Child Health ◽  
Signaling Pathway ◽  
Survival Rates ◽  
Large Cell ◽  
Disease Classification ◽  
Molecular Subgroups ◽  
Molecular Subgroup ◽  
Group 4 ◽  
Group 3 ◽  
Clinical Records

Objective: To determine the correlation between clinical characteristics and molecular subgroups of medulloblastoma (MB) in Thai pediatric patients at the Queen Sirikit National Institute of Child Health (QSNICH), Thailand. Materials and Methods: MB specimens operated between 2004 and 2018 were classified by Nanostring into four molecular subgroups, including Wingless signaling pathway (WNT), Sonic Hedgehog signaling pathway (SHH), Group 3, and Group 4. For the present cases, the clinical records were retrospectively analyzed. Results: Twenty-two MB cases with complete clinical records were analyzed. Group 4 was the most common molecular subgroup (31.82%), followed by WNT (27.27%), SHH (22.73%), and Group 3 (18.18%). The histologic subtypes included 18, three, and one cases of classic MB, MB with extensive nodularity (MBEN), and large cell MB, respectively. All SHH MBs were found in infants. All MBENs belonged to SHH subgroup, and the large cell MB was Group 3. All six WNT MB cases did not experience tumor recurrence. Five-year cause specific survival rates were 100% in WNT, 60% in SHH, 57.1% in Group 4, and 0% in Group 3. Five-year recurrence-free survival rates were 100% in WNT, 42.9% in Group 4, and 0% in SHH and Group 3. Conclusion: MB is a heterogeneous disease. Classification of MB, especially at the molecular subtype, is helpful for the management and prognostication. Keywords: Medulloblastoma; Molecular subgroup

Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort

2020 ◽  
Vol 38 (18) ◽  
pp. 2028-2040 ◽  
Author(s):  
Martin Mynarek ◽  
Katja von Hoff ◽  
Torsten Pietsch ◽  
Holger Ottensmeier ◽  
Monika Warmuth-Metz ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Systemic Chemotherapy ◽  
Validation Cohort ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Large Cell ◽  
Prognostic Impact ◽  
Free Survival ◽  
Group 4 ◽  
Group 3

PURPOSE The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.

scholarly journals IMG-19. RADIOMICS AND SUPERVISED DEEP LEARNING TO PREDICT MOLECULAR SUBGROUPS IN MEDULLOBLASTOMA BASED ON WHOLE TUMOR VOLUME LABELING: A SINGLE CENTER MULTIPARAMETRIC MR ANALYSIS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii358-iii359
Author(s):  
Ioan Paul Voicu ◽  
Piero Chiacchiaretta ◽  
Massimo Caulo ◽  
Evelina Miele ◽  
Alessia Carboni ◽  
...  
Keyword(s):  
Random Forest ◽  
Intraclass Correlation ◽  
Major Axis ◽  
Molecular Classification ◽  
Molecular Subgroups ◽  
Molecular Subgroup ◽  
First Order ◽  
Group 4 ◽  
Contrast Enhanced ◽  
Group 3

Abstract PURPOSE Medulloblastoma (MB) is a complex pathology. Four molecular subgroups have been unveiled (Wingless-WNT, Sonic Hedgehog-SHH, Group 3-G3 and Group 4-G4), characterized by significant differences in patient clinical outcome. We investigated the utility of a radiomic analysis to predict molecular subgroups in patients with MB. MATERIALS AND METHODS We retrospectively evaluated 42 patients with histological diagnosis of MB, known molecular subgroup, and diagnostic MRI scan performed in our Institution on a 3 Tesla magnet. For each patient, FLAIR, ADC, T2 and contrast-enhanced MPRAGE sequences were analysed. Solid tumor volumes were segmented semiautomatically. 107 features were extracted for each sequence (Pyradiomics, Python). Features were tested for stability against labelling variations, selecting those presenting Intraclass Correlation Coefficient (ICC)&gt;0.9 across all labelling variations and all sequences. Among the remaining features, relevant features were selected with an all-relevant wrapper algorithm (Boruta, R). Remaining features were used to predict MB subgroup with a Random Forest algorithm(R). The most relevant features were ranked based on Gini index (R). RESULTS 83/107 features presented ICC &gt;0.9 for all sequences. Boruta selected 10 features. Classification analysis yielded an out-of-bag (OOB) error rate of 0.6%, (99.4% accuracy). The most relevant features for classification were “simple” first-order features such as volume, major axis or shape. CONCLUSION This radiomic study yielded robust features, which showed high accuracy in predicting the molecular MB subgroups. Random forest algorithms are ideal for multiclass classification (eg. MB subgroups) and are intrinsically suited against overfitting. The most relevant for molecular classification were first-order features.

scholarly journals MBRS-47. RAPID MOLECULAR SUBGROUPING OF MEDULLOBLASTOMA BASED ON DNA METHYLATION BY NANOPORE SEQUENCING

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii406-iii406
Author(s):  
Julien Masliah-Planchon ◽  
Elodie Girard ◽  
Philipp Euskirchen ◽  
Christine Bourneix ◽  
Delphine Lequin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Molecule ◽  
Nanopore Sequencing ◽  
Molecular Subgroup ◽  
Group Assignment ◽  
Group 4 ◽  
Methylation Assay ◽  
Tumor Group ◽  
Long Read ◽  
Group 3

Abstract Medulloblastoma (MB) can be classified into four molecular subgroups (WNT group, SHH group, group 3, and group 4). The gold standard of assignment of molecular subgroup through DNA methylation profiling uses Illumina EPIC array. However, this tool has some limitation in terms of cost and timing, in order to get the results soon enough for clinical use. We present an alternative DNA methylation assay based on nanopore sequencing efficient for rapid, cheaper, and reliable subgrouping of clinical MB samples. Low-depth whole genome with long-read single-molecule nanopore sequencing was used to simultaneously assess copy number profile and MB subgrouping based on DNA methylation. The DNA methylation data generated by Nanopore sequencing were compared to a publicly available reference cohort comprising over 2,800 brain tumors including the four subgroups of MB (Capper et al. Nature; 2018) to generate a score that estimates a confidence with a tumor group assignment. Among the 24 MB analyzed with nanopore sequencing (six WNT, nine SHH, five group 3, and four group 4), all of them were classified in the appropriate subgroup established by expression-based Nanostring subgrouping. In addition to the subgrouping, we also examine the genomic profile. Furthermore, all previously identified clinically relevant genomic rearrangements (mostly MYC and MYCN amplifications) were also detected with our assay. In conclusion, we are confirming the full reliability of nanopore sequencing as a novel rapid and cheap assay for methylation-based MB subgrouping. We now plan to implement this technology to other embryonal tumors of the central nervous system.

scholarly journals PATH-25. APPLICABILITY OF A NOMOGRAM INCLUDING CLINICAL AND MOLECULAR VARIABLES IN THE STRATIFICATION OF RISK GROUPS IN PEDIATRIC MEDULLOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi148-vi148
Author(s):  
Bruna Mançano ◽  
Rui Reis ◽  
Leticia Leal ◽  
Flavia de Paula ◽  
Carlos Almeida Jr ◽  
...  
Keyword(s):  
Survival Rates ◽  
Disease Free Survival ◽  
Risk Groups ◽  
Molecular Characteristics ◽  
Childhood And Adolescence ◽  
Tumor Subtypes ◽  
Group 4 ◽  
Pediatric Medulloblastoma ◽  
Group 3 ◽  
Multiple Variables

Abstract Medulloblastoma is the most common type of malignant brain tumor that occurs during childhood and adolescence. Currently, this pathology comprises at least four different molecular tumor subtypes (WNT, SHH, group 3 or C and group 4 or D) which have their own molecular characteristics, distinct clinical presentations and are associated with different survival rates. The purpose is to evaluate the applicability of a nomogram that includes clinical and molecular variables in pediatric medulloblastomas in the routine of the Hospital de Cancer de Barretos. The series l consists of 85 pediatric patients from 0 to 18 years old, diagnosed with medulloblastoma attended at the Hospital de Cancer de Barretos (HCB), from January 2000 to December 2017. The molecular subgroups will be performed using the Nanostring technique. This research intends to implement a nomogram that uses several variables known and involved in the treatment and prognosis of patients, this nomogram with multiple variables will show the clinical and molecular effect of each variable to predict disease-free survival and survival overall in 3 and 5 years. Thus, we will have the opportunity to analyze these characteristics in order to improve survival and reduce morbidity and consequently mortality during treatment for the different subgroups of medulloblastomas.

scholarly journals Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

2021 ◽  
Vol 39 (7) ◽  
pp. 807-821
Author(s):  
Rahul Kumar ◽  
Kyle S. Smith ◽  
Maximilian Deng ◽  
Colt Terhune ◽  
Giles W. Robinson ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Local Relapse ◽  
Genetic Alterations ◽  
Driver Genes ◽  
Methylation Array ◽  
Molecular Subgroup ◽  
Term Survival ◽  
Molecular Features ◽  
Group 4 ◽  
Group 3

PURPOSE We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

scholarly journals Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

2012 ◽  
Vol 123 (4) ◽  
pp. 473-484 ◽  
Author(s):  
Marcel Kool ◽  
Andrey Korshunov ◽  
Marc Remke ◽  
David T. W. Jones ◽  
Maria Schlanstein ◽  
...  
Keyword(s):  
Clinical Data ◽  
Meta Analysis ◽  
Molecular Subgroups ◽  
Genetic Aberrations ◽  
Group 4 ◽  
Group 3

scholarly journals MBCL-07. NON-METASTATIC MEDULLOBLASTOMA OF EARLY CHILDHOOD: RESULTS FROM THE PROSPECTIVE CLINICAL TRIAL HIT-2000 AND AN EXTENDED VALIDATION COHORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii388-iii389
Author(s):  
Martin Mynarek ◽  
Katja von Hoff ◽  
Torsten Pietsch ◽  
Holger Ottensmeier ◽  
Monika Warmuth-Metz ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Systemic Chemotherapy ◽  
Validation Cohort ◽  
Large Cell ◽  
Prognostic Impact ◽  
Free Survival ◽  
Group 4 ◽  
Dna Methylation Profiling ◽  
Group 3 ◽  
Methylation Profiling

Abstract OBJECTIVE To avoid craniospinal irradiation (CSI) in children younger than four years with non-metastatic medulloblastoma by chemotherapy, intraventricular methotrexate and risk-adapted local radiotherapy. PATIENTS AND METHODS Eighty-seven patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for non-response or progression. After 2006, local radiotherapy was introduced for non-responders or classic (CMB), anaplastic or large-cell medulloblastoma (LCA). Infantile SHH-activated medulloblastomas (SHH_INF) were subdivided by DNA-methylation profiling. Survival in SHH_INF subtypes were also assessed in a validation cohort (n=71). RESULTS Patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) (n=42) had 93% 5-year PFS, 100% 5-year OS and 93% 5-year CSI-free survival. Patients with CMB/LCA (n=45) had 37% 5y-PFS, 62% 5y-OS and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in CMB/LCA patients. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH_INF subgroup. Group 3 patients (5y-PFS 36% [n=14]) relapsed more frequently than SHH_INF (5y-PFS 93% [n=28]) or Group 4 patients (5y-PFS 83% [n=6], p&lt;0.001). SHH_INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I 73% vs. iSHH-II 83%, p=0.25, n=99). Mean IQ was 90 (radiotherapy-free survivors) vs. 74 (patients that received CSI) [p=0.012]. CONCLUSION Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH-subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in non-WNT/non-SHH CMB/LCA patients was not improved by local radiotherapy. Survival was more favorable in patients with Group 4 than in patients with Group 3 medulloblastoma.

Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters

2016 ◽  
Vol 34 (34) ◽  
pp. 4151-4160 ◽  
Author(s):  
André O. von Bueren ◽  
Rolf-Dieter Kortmann ◽  
Katja von Hoff ◽  
Carsten Friedrich ◽  
Martin Mynarek ◽  
...  
Keyword(s):  
Risk Factors ◽  
Induction Chemotherapy ◽  
Molecular Subtype ◽  
Survival Rates ◽  
Prospective Trial ◽  
Large Cell ◽  
Hazard Ratio ◽  
Mycn Amplification ◽  
Histologic Subtype ◽  
Group 3

Purpose To assess an intensified treatment in the context of clinical and biologic risk factors in metastatic medulloblastoma. Patients and Methods Patients (4 to 21 years old, diagnosed between 2001 and 2007) received induction chemotherapy, dose-escalated hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy. Subgroup status and other biologic parameters were assessed. Results In 123 eligible patients (median age, 8.2 years old; median follow-up, 5.38 years), 5-year event-free survival (EFS) and overall survival (OS) were 62% (95% CI, 52 to 72) and 74% (95% CI, 66 to 82), respectively. OS was superior compared with the precedent HIT ’91 trial. The 5-year EFS and OS were both 89% (95% CI, 67 to 100) for desmoplastic/nodular (n = 11), 61% (95% CI, 51 to 71) and 75% (95% CI, 65 to 85) for classic (n = 107), and 20% (95% CI, 0 to 55) and 40% (95% CI, 0 to 83) for large-cell/anaplastic (n = 5) medulloblastoma ( P < .001 for EFS; P = .001 for OS). Histology (hazard ratio, 0.19 for desmoplastic/nodular and 45.97 for large-cell/anaplastic medulloblastoma) and nonresponse to the first chemotherapy cycle (hazard ratio, 1.97) were independent risk factors (EFS). Among 81 (66%) patients with tumor material, 5-year EFS and OS differed between low-risk (wingless [WNT], n = 4; both 100%), high-risk ( MYCC/ MYCN amplification; n = 5, both 20%), and intermediate-risk patients (neither; n = 72, 63% and 73%, respectively). Survival rates were different between molecular subgroups (WNT, n = 4; sonic hedgehog [SHH; n = 4]; group 4 [n = 41]; group 3 with [n = 3] or without [n = 17] MYCC/MYCN amplification; P < .001). All cases showed p53 immuno-negativity. There was no association between patients with nonresponding tumors to induction chemotherapy and WNT ( P = .143) or MYCC/MYCN status ( P = .075), histologic subtype ( P = .814), or molecular subtype ( P = .383), as assessed by Fisher’s exact test. Conclusion This regimen was feasible and conferred overall favorable survival. Our data confirm the relevance of subgroup status and biologic parameters (WNT/ MYCC/ MYCN status) in a homogeneous prospective trial population, and show that metastatic group 3 patients do not uniformly have poor outcomes. Biologic subgroup, MYCC/ MYCN status, response to induction chemotherapy, and histologic subtype may serve for improved treatment stratification.

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