Retrospective investigation of medulloblastoma under three years of age based on methylation molecule type

Retrospective investigation of medulloblastoma under three years of age based on methylation molecule type | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Retrospective investigation of medulloblastoma under three years of age based on methylation molecule type Kaiwen Deng, Hailong Liu, Jin Feng, Li Chen, Fei Liu, Xuan Chen, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4671943/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Medulloblastoma (MB), a prevalent malignant pediatric brain tumor, typically necessitates a comprehensive treatment regimen. However, the standard treatment paradigm is often not viable for infants (< 3 years old) incomplete, which contraindicates traditional radiotherapy. This study retrospectively analyzed the efficacy of chemotherapy with deferred radiotherapy in infants. Methods The cohort consisted of 23 infants who receiving surgical resection of MB, which has been categorized into SHH, Group_3, and Group_4 subgroups and received postoperative chemotherapy. Molecular subgroups were identified using DNA methylation sequencing. This study analyzed the overall survival and recurrence rates based on molecular subgroup and evaluated the effects of treatment strategies. Results SHH accounted for 48%, Group_3 for 40%, and Group_4 for 12%. The follow-up period ranged from 1 to 131 months, with a median of 51 months. The overall survival rate was 60%, with survival rates for SHH, Group_3, and Group_4 at 66.7%, 50.0%, and 66.7%, respectively. The survival rates at 1, 3, 5, and 10 years were 92%, 80%, 48%, and 12%, respectively. Univariate and multivariate Cox regression analyses indicated that recurrence and treatment modalities significantly impacted survival times, with a hazard ratio of 10.28 for recurrence (95% CI: 1.99–53.03, p = 0.005) and 4.59 for chemotherapy alone (95% CI: 1.11–18.93, p = 0.035). The findings suggest that for infants with MB, a combined treatment approach of postoperative chemotherapy followed by delayed radiotherapy significantly improves overall survival compared to chemotherapy alone. Conclusion The findings suggest that infants with MB benefit substantially from postoperative chemotherapy followed by delayed radiotherapy. Medulloblastoma Radiotherapy Infant Chemotherapy Figures Figure 1 Figure 2 Introduction MB is one of the most malignant central nervous system tumors commonly seen in children, accounting for about 65.8% of all childhood embryonal tumors, with an incidence rate of 0.5 cases per 100,000 children aged 0–14 years.[ 1 ] MB is a highly malignant tumor with infiltrative growth and often spreads to the whole brain and spinal cord through the cerebrospinal fluid. Surgery combined with radiotherapy and chemotherapy is the main treatment for MB. Radiation therapy is an important part of the comprehensive treatment of children with MB and has significantly improved the long-term survival of children with MB, but radiation can also cause serious adverse effects in infants. Some tissues and organs, such as the brain, thyroid, and bone marrow, are sensitive to radiation, as well as affect the cognition and growth of the infants. Infants are preferably treated by surgery and chemotherapy alone due to high-risk of radiation-induced morbidity. [ 2 ][ 3 ] Patricia K. Duffner and colleagues conducted a study in 1993 in which postoperative chemotherapy was administered to infants with malignant brain tumors (including MB), resulting in a 39% response rate and suggesting that chemotherapy could effectively delay radiation therapy, thereby reducing neurotoxicity without compromising survival outcomes.[ 4 ] Another trial conducted by Stefan, et al. was conducted to treat MB under three years by intensive postoperative chemotherapy only. Chemotherapy was started two to four weeks after surgery. Children received three two-month cycles of chemotherapy, complete resection, residual tumor, and macroscopic metastases, the five-year progression-free and overall survival rates (+/-SE) were 82+/-9 percent and 93+/-6 percent, 50+/-13 percent and 56+/-14 percent, and 33+/-14 percent and 38+/-15 percent, respectively. The study suggests that young children with MB may enjoy a longer remission period after receiving postoperative chemotherapy alone.[ 5 ] In this study, we reviewed 23 cases of MB in infants diagnosed and treated at Tiantan Hospital from 2011 to 2021 and analyzed the prognosis of this cohort based on molecular typing information, pathology, molecular typing, and treatment options for the children. Methods This study was approved by the ethics committee of Beijing Tiantan Hospital, Capital Medical University. Informed consent was obtained from all participants or their parent or legal guardian. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Patient’s data These infants who had pathologically proved MB were eligible for the study by surgical resection or biopsy. Written informed consent was obtained from the parents or guardians of each child in accordance with institutional guidelines. The specimens were reviewed by two independent neuropathologists according to the 2007 WHO criteria. The tumors were subdivided into three subtypes: classic histology MB (CMB), desmoplastic/nodular MB (DNMB) and MB with extensive nodularity (MBEN), and large cell/anaplastic (LC/A) MB.[ 6 ] The children were treated with the postoperative chemotherapy. At the end of chemotherapy, if the patient’s age beyond 3, he/she was evaluated by the radiologist and the pediatric neurosurgeon for the possibility of radiotherapy; if the child was still younger than three years old at the end of the chemotherapy, the neurosurgeon and the chemotherapist evaluated the need to intensify the chemotherapy treatment until he or she turned three years of age. Delay radiotherapy In the research described, all MB treatment protocols adhered to the clinical practice guidelines provided by the National Comprehensive Cancer Network (NCCN). According to these guidelines, children under three years of age were initially treated with systemic chemotherapy following surgical resection of the tumor. Subsequently, upon reaching the age of three, radiotherapy was commenced based on the child's health status and response to treatment. This approach aims to minimize potential negative impacts on child development while maximizing survival and quality of life. DNA methylation sequencing and data processing After the sample DNA was extracted and tested, the genomic DNA was randomly interrupted to about 350bp, the interrupted DNA fragments were end-repaired, base A was added, sequencing connector was added, and the unmethylated cytosine in the DNA fragments was converted to uracil by the action of bisulfite, and then converted to thymine after PCR amplification, so that the final DNA methylation sequencing library could be obtained. The library data were sequenced on the Illumina hiseq XTen platform to obtain Raw-Data, which was filtered to remove sequencing junctions and low-quality sequences to obtain high-quality Clean Reads, which were used as the basis for data analysis. Unsupervised molecular subtyping analysis Differential methylation analysis compared tumor tissues to normal cerebellar tissues. The top 25% most variable DMRs were selected for principal component analysis (PCA). These principal components were then used for t-SNE analysis with the following parameters: theta = 0, pca = F, max_iter = 2500, perplexity = 10. Statistical Analysis Data were analyzed and graphed using RStudio statistical software. p < 0.05 was considered statistically significant. Result Table 1 Clinical and molecular characterization of the infant patients. level G3 G4 SHH p n 9 3 11 Gender (%) female 4 (44.44) 3 (100.00) 4 (36.36) 0.1428 male 5 (55.56) 0 (0.00) 7 (63.64) Age (%) 2 2 (22.22) 0 (0.00) 2 (18.18) 0.6762 3 7 (77.78) 3 (100.00) 9 (81.82) M_Stage (%) M+ 2 (22.22) 1 (33.33) 1 (9.09) 0.5476 M0 7 (77.78) 2 (66.67) 10 (90.91) Excision (%) GTR 7 (77.78) 1 (33.33) 7 (63.64) 0.3711 NTR 2 (22.22) 2 (66.67) 4 (36.36) Treatment (%) Both 5 (55.56) 2 (66.67) 10 (90.91) 0.1918 Chemotherapy 4 (44.44) 1 (33.33) 1 (9.09) Recurrence (%) 0 6 (66.67) 3 (100.00) 7 (63.64) 0.4651 1 3 (33.33) 0 (0.00) 4 (36.36) Death (%) 0 5 (55.56) 2 (66.67) 8 (72.73) 0.7237 1 4 (44.44) 1 (33.33) 3 (27.27) Histology (%) CMB 4 (44.44) 2 (66.67) 2 (18.18) 0.3770 DNMB 1 (11.11) 1 (33.33) 6 (54.55) MBEN 2 (22.22) 0 (0.00) 1 (9.09) Undefinded 2 (22.22) 0 (0.00) 2 (18.18) OS_TIME (median [IQR]) 50.892 [48.888, 66.465] 72.938 [37.093, 81.316] 67.254 [41.463, 84.240] 0.8099 A total of 23 infant with medulloblastoma were included in this study, including 12 males and 11 females. 11 samples with pathology of SHH subtype, 9 samples with G3 subtype, and 3 samples with G4 were clustered and classified by tumor samples by methylation sequencing. The follow-up time of all children was 1-131 months, and the median follow-up time was 51 months. The overall survival was 65.22%, the survival rate of SHH was 72.73%, the survival rate of G3 was 55.56%, the survival rate of G4 was 66.67%, and the survival rates of children at 1, 3, 5, and 10 years were 100.00%, 82.61%, 52.17%, and 13.04%, respectively. Clinical data of pediatric medulloblastoma patients of the 23 active cases, age was dichotomized into children aged 1–2 years and 2–3 years, with almost the same proportion of female children as male children. The distribution of molecular subtypes was statistically different among the three groups, with the highest proportion of SHH type 47.83%, G3 type 39.13% and G4 13.04%. This is accord with the typing characteristics of infant medulloblastoma. And in this study, age, sex, histologic typing, treatment, dissemination, recurrence, and survival were not statistically different among the three subtypes (Table 1 ). In histologic typing, CMB and DNMB accounted for the largest proportions of 69.47% and 34.78% respectively, and in the corresponding molecular typing, the SHH predominantly constituted DNMB and the G3 predominantly constituted CMB. (Fig. 1 ) Table 2 Cox Univariate and Multivariate Regression Analysis of Prognostic Factors in Medulloblastoma Cox univariate analysis Cox multivariate analysis Variants Hazard Ratio (95%CI) P-value Hazard Ratio (95%CI) P-value Diagnosis age 2.69 (0.43–16.71) 0.289 5.49 (0.44–68.09) 0.1847 Excision: GTR Excision: NTR 0.56 (0.11–2.75) 0.472 Gender: female Gender: male 0.71 (0.18–2.84) 0.627 Histology: CMB Histology: DNMB 0.17 (0.02–1.72) 0.133 Histology: MBEN 0.72 (0.07–7.04) 0.781 Histology: Undefinded 1.35 (0.26–7.01) 0.718 Molectype: G3 Molectype: G4 0.7 (0.08–6.45) 0.752 Molectype: SHH 0.54 (0.12–2.45) 0.423 MStage: M1 MStage: M0 1.66 (0.2-13.72) 0.638 Recurrence: 0 Recurrence: 1 10.28 (1.99–53.03) 0.005 10.69 (2.04–56.02) 0.0051 Treatment: Both Treatment: Chemotherapy 4.59 (1.11–18.93) 0.035 4.41 (0.87–22.31) 0.0726 Cox Univariate and Multivariate Regression Analysis Univariates and multivariate COX risk models were analyzed in this cohort, incorporating factors related to prognosis such as age of Diagnosis, gender, pathology type, molecular type, excision of surgical resection, treatment, whether recurrence, and whether metastasis. Among them, in the univariate analysis, the differences in whether recurrence and treatment had a significant impact on survival (P-values 0.05) (Table 2 ). The above meaningful prognostic factors were further analyzed by incorporating them into a Multivariate COX, which showed the same result as Univariates COX. the HR for recurrence (Recurrence: 1) was 10.28, 95% CI was 1.99 to 53.03, with a p-value of 0.005, and in Multivariate COX the HR was 10.69, 95% CI was 2.04 to 56.02, with a p-value of 0.0051, indicating a significant correlation to survival time. Treatment including postoperative chemotherapy alone (Chemotherapy) and postoperative chemotherapy with delayed radiotherapy (Both). The HR for Chemotherapy in Univariates COX analysis was 4.59, 95% CI was 1.11 to 18.93, with p-value was 0.035, and in Multivariate COX the HR was 4.41, 95% CI was 0.87 to 22.31, with p-value was 0.0726. This result suggests that, despite the poor prognosis of medulloblastoma in the less than 3 years of age, aggressive postoperative treatment, i.e., postoperative chemotherapy and delayed radiotherapy, rather than chemotherapy alone, has a greater benefit for overall survival. In this analysis, it is worth noting that in contrast to the results for the all-age group, it is generally believed that the SHH subtype has a poorer prognosis; however, this result was not found in this study. Survival analysis (Fig. 2 ) was performed on 23 MBs for overall survival status (a, b) and progression free survival(c, d). Overall survival analysis compared molecular type and treatment. Only the treatment had a difference in the overall survival (p = 0.022), there was no difference between molecular typing(p > 0.05). However, there is no difference among all factors being considered including histology, diagnosis age, extent of resection. The analysis shows that postoperative chemotherapy and delayed radiotherapy harvested a better OS, but not for recurrence. It is worth noting that molecular typing and the extent of resection did not make a significant difference in overall survival, and the extent of resection of MB in children is still controversial. In addition to this, it was noted that children with medulloblastoma with molecular typing of SHH are generally considered to have a worse prognosis, which was not reflected in this study. Discussion MB in infants is associated with a poor prognosis and presents significant treatment challenges, predominantly in the SHH subtype. Children in this age group have immature neurological systems, and radiotherapy not only impacts neurological development but also affects thymus gland development and bone marrow hematopoiesis. Consequently, the international consensus[ 4 ][ 5 ], on the treatment protocol for medulloblastoma in children under three years of age advocates for surgical resection as the primary treatment, supplemented by postoperative chemotherapy and delayed radiotherapy. Clinical trials have demonstrated that this treatment strategy—postoperative chemotherapy followed by delayed radiotherapy—yields better outcomes. It is noteworthy these factors traditionally considered to be of prognostic importance, such as the extent of surgical resection, molecular subtype, histological type, and age, did not exhibit a significant impact on outcomes. Consistent with the literature, our study also observed no significant differences in prognosis between total and subtotal resections. This supports the perspective offered by Thompson et al.[ 7 ]. in their systematic review and the research of Enayet et al.[ 8 ], suggesting that while current protocols categorize patients with residual tumor areas larger than 1.5 cm² as high-risk and increase craniospinal irradiation, the true prognostic significance of the extent of resection remains unclear. This strategy not only aligns with the developmental limitations of young patients but also strategically improves survival rates while potentially reducing the long-term neurotoxic effects associated with early radiotherapy. Our results advocate for a personalized treatment protocol in this vulnerable age group to minimize therapy-associated complications and enhance quality of life. Furthermore, while our study indicates improvements with the current treatment protocols, it also acknowledges limitations, such as incomplete data on the long-term quality of life and documentation of radiotherapy complications in young children. Additionally, the sample size was relatively small, which may limit the representativeness of the data. Further studies with larger cohorts are necessary to validate and refine these findings, ensuring broader applicability and precision in treatment planning. Declarations Author Contribution Conceptualization, T.J. and X.Q. and H.L.;Sample sequencing and methylation analysis, J.K. and X.C.;Patient follow-up and collection of clinical information, J.F. and L.C. and F.L. ;Writing and editing, K.D. and H.L. and T.J.;Visualization, X.C. and K.D. ;Funding Acquisition, H.L. and T.J. ; References Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2021) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014–2018. Neuro-oncology , 23 (12 Suppl 2), iii1–iii105. https://doi.org/10.1093/neuonc/noab200 Lafay-Cousin L, Smith A, Chi SN, Wells E, Madden J, Margol A, Ramaswamy V, Finlay J, Taylor MD, Dhall G, Strother D, Kieran MW, Foreman NK, Packer RJ, Bouffet E (2016) Clinical, Pathological, and Molecular Characterization of Infant Medulloblastomas Treated with Sequential High-Dose Chemotherapy. Pediatr Blood Cancer 63(9):1527–1534. https://doi.org/10.1002/pbc.26042 Mynarek, M., von Hoff, K., Pietsch, T., Ottensmeier, H., Warmuth-Metz, M., Bison,B., Pfister, S., Korshunov, A., Sharma, T., Jaeger, N., Ryzhova, M., Zheludkova, O.,Golanov, A., Rushing, E. J., Hasselblatt, M., Koch, A., Schüller, U., von Deimling,A., Sahm, F., Sill, M., … Rutkowski, S. (2020). Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort. Journal of clinical oncology: official journal of the American Society of Clinical Oncology , 38 (18), 2028–2040. https://doi.org/10.1200/JCO.19.03057 Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR (1993) Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328(24):1725–1731. https://doi.org/10.1056/NEJM199306173282401 Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352(10):978–986. https://doi.org/10.1056/NEJMoa042176 Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109. https://doi.org/10.1007/s00401-007-0243-4 Thompson EM, Bramall A, Herndon JE 2nd, Taylor MD, Ramaswamy V (2018) The clinical importance of medulloblastoma extent of resection: a systematic review. J Neurooncol 139(3):523–539. https://doi.org/10.1007/s11060-018-2906-5 Enayet AE, Nabil M, Rady MR, Yousef Y, Badawy E, Beltagy E, M. A (2021) Surgical outcome of children with medulloblastoma: a retrospective study of a 405-patient series from Children's Cancer Hospital Egypt (CCHE-57357). Child's Nerv system: ChNS : official J Int Soc Pediatr Neurosurg 37(6):1931–1940. https://doi.org/10.1007/s00381-021-05082-2 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4671943","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":330052855,"identity":"1c09e5db-00a1-44f8-b776-474968671c0f","order_by":0,"name":"Kaiwen Deng","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kaiwen","middleName":"","lastName":"Deng","suffix":""},{"id":330052856,"identity":"307645ac-c20d-4a49-857d-8337ce133717","order_by":1,"name":"Hailong Liu","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hailong","middleName":"","lastName":"Liu","suffix":""},{"id":330052857,"identity":"06a994f1-b703-41cd-8bf3-ea3f97f796be","order_by":2,"name":"Jin Feng","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"","lastName":"Feng","suffix":""},{"id":330052858,"identity":"0895fa1a-28ce-4627-9c98-5157d87a9960","order_by":3,"name":"Li Chen","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Chen","suffix":""},{"id":330052859,"identity":"4f978428-3576-4f44-9678-e3c69761951c","order_by":4,"name":"Fei Liu","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Liu","suffix":""},{"id":330052860,"identity":"cd07a850-ae64-45cd-86e9-3839659963ea","order_by":5,"name":"Xuan Chen","email":"","orcid":"","institution":"University of Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Xuan","middleName":"","lastName":"Chen","suffix":""},{"id":330052861,"identity":"f89c8352-ca21-4b33-bccf-f525452d2e5b","order_by":6,"name":"Jiankang Li","email":"","orcid":"","institution":"BGI-Shenzhen","correspondingAuthor":false,"prefix":"","firstName":"Jiankang","middleName":"","lastName":"Li","suffix":""},{"id":330052862,"identity":"7947227b-0a7d-489a-80ab-642e6e182bf8","order_by":7,"name":"Tao Jiang","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Jiang","suffix":""},{"id":330052863,"identity":"a1a6a92d-9f45-47b2-b33c-c717a31160d8","order_by":8,"name":"Xiaoguang Qiu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYDACZiBOgHE+NrAxMEiQooVxZgObBA9BLSjaeRsYCGvhO85jJvGgxsZuw/Gzh1/b7uCrs5duYHxc8Qu3FsnDPMYGCcfSkjecyUuzzj0DdJjMAWbDs324tRgc5jF8kMB2ONngQI6ZcW4byC8JbJKNPXi1GBxI+AfUcv6NmbElkVoMHyS2HbYzuJFj/JgRpqXhBz6/sBUbJPalJUjeeGPG2HuGTbLnRmKzYWMDbi185w9vk/zxzcae73yO8YefO47xs89IPviw4Q9uLQwHIFQi0Fg2YIwcA7IZGxgY2whrsQdi5g8MDDVQYXy2jIJRMApGwUgDAEdoU5LUSo9DAAAAAElFTkSuQmCC","orcid":"","institution":"Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Xiaoguang","middleName":"","lastName":"Qiu","suffix":""}],"badges":[],"createdAt":"2024-07-02 06:36:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4671943/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4671943/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":61182862,"identity":"ee56a26b-3edc-44e6-8794-819290b1307d","added_by":"auto","created_at":"2024-07-26 17:00:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65762,"visible":true,"origin":"","legend":"\u003cp\u003eSankey Diagram: Correlation Between Molecular Subtypes and Histological Types in Medulloblastoma.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4671943/v1/4dd1faa15f2a97896acf89ed.png"},{"id":61182863,"identity":"7701a630-0922-4657-aa31-67333b9e01e3","added_by":"auto","created_at":"2024-07-26 17:00:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":138636,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis (Fig 2) was performed on 23 MBs for overall survival status (a, b) and progression free survival(c, d). Overall survival analysis compared molecular type and treatment. Only the treatment had a difference in the overall survival (p=0.022), there was no difference between molecular typing(p\u0026gt;0.05). However, there is no difference among all factors being considered including histology, diagnosis age, extent of resection. The analysis shows that postoperative chemotherapy and delayed radiotherapy harvested a better OS, but not for recurrence. It is worth noting that molecular typing and the extent of resection did not make a significant difference in overall survival, and the extent of resection of MB in children is still controversial. In addition to this, it was noted that children with medulloblastoma with molecular typing of SHH are generally considered to have a worse prognosis, which was not reflected in this study.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4671943/v1/7dbd5211ba087a67c46dbf3c.png"},{"id":62278377,"identity":"e18ad415-113e-41ef-8a23-58b2224530bc","added_by":"auto","created_at":"2024-08-12 11:54:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":678315,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4671943/v1/3e06e839-c3d2-4eff-9eb6-e569953f7c19.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Retrospective investigation of medulloblastoma under three years of age based on methylation molecule type","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMB is one of the most malignant central nervous system tumors commonly seen in children, accounting for about 65.8% of all childhood embryonal tumors, with an incidence rate of 0.5 cases per 100,000 children aged 0\u0026ndash;14 years.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] MB is a highly malignant tumor with infiltrative growth and often spreads to the whole brain and spinal cord through the cerebrospinal fluid. Surgery combined with radiotherapy and chemotherapy is the main treatment for MB. Radiation therapy is an important part of the comprehensive treatment of children with MB and has significantly improved the long-term survival of children with MB, but radiation can also cause serious adverse effects in infants. Some tissues and organs, such as the brain, thyroid, and bone marrow, are sensitive to radiation, as well as affect the cognition and growth of the infants. Infants are preferably treated by surgery and chemotherapy alone due to high-risk of radiation-induced morbidity. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e\u003cp\u003ePatricia K. Duffner and colleagues conducted a study in 1993 in which postoperative chemotherapy was administered to infants with malignant brain tumors (including MB), resulting in a 39% response rate and suggesting that chemotherapy could effectively delay radiation therapy, thereby reducing neurotoxicity without compromising survival outcomes.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eAnother trial conducted by Stefan, et al. was conducted to treat MB under three years by intensive postoperative chemotherapy only. Chemotherapy was started two to four weeks after surgery. Children received three two-month cycles of chemotherapy, complete resection, residual tumor, and macroscopic metastases, the five-year progression-free and overall survival rates (+/-SE) were 82+/-9 percent and 93+/-6 percent, 50+/-13 percent and 56+/-14 percent, and 33+/-14 percent and 38+/-15 percent, respectively. The study suggests that young children with MB may enjoy a longer remission period after receiving postoperative chemotherapy alone.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eIn this study, we reviewed 23 cases of MB in infants diagnosed and treated at Tiantan Hospital from 2011 to 2021 and analyzed the prognosis of this cohort based on molecular typing information, pathology, molecular typing, and treatment options for the children.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This study was approved by the ethics committee of Beijing Tiantan Hospital, Capital Medical University. Informed consent was obtained from all participants or their parent or legal guardian. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatient\u0026rsquo;s data\u003c/h2\u003e\u003cp\u003eThese infants who had pathologically proved MB were eligible for the study by surgical resection or biopsy. Written informed consent was obtained from the parents or guardians of each child in accordance with institutional guidelines.\u003c/p\u003e\u003cp\u003eThe specimens were reviewed by two independent neuropathologists according to the 2007 WHO criteria. The tumors were subdivided into three subtypes: classic histology MB (CMB), desmoplastic/nodular MB (DNMB) and MB with extensive nodularity (MBEN), and large cell/anaplastic (LC/A) MB.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThe children were treated with the postoperative chemotherapy. At the end of chemotherapy, if the patient\u0026rsquo;s age beyond 3, he/she was evaluated by the radiologist and the pediatric neurosurgeon for the possibility of radiotherapy; if the child was still younger than three years old at the end of the chemotherapy, the neurosurgeon and the chemotherapist evaluated the need to intensify the chemotherapy treatment until he or she turned three years of age.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eDelay radiotherapy\u003c/h2\u003e\u003cp\u003e In the research described, all MB treatment protocols adhered to the clinical practice guidelines provided by the National Comprehensive Cancer Network (NCCN). According to these guidelines, children under three years of age were initially treated with systemic chemotherapy following surgical resection of the tumor. Subsequently, upon reaching the age of three, radiotherapy was commenced based on the child's health status and response to treatment. This approach aims to minimize potential negative impacts on child development while maximizing survival and quality of life.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eDNA methylation sequencing and data processing\u003c/h2\u003e\u003cp\u003eAfter the sample DNA was extracted and tested, the genomic DNA was randomly interrupted to about 350bp, the interrupted DNA fragments were end-repaired, base A was added, sequencing connector was added, and the unmethylated cytosine in the DNA fragments was converted to uracil by the action of bisulfite, and then converted to thymine after PCR amplification, so that the final DNA methylation sequencing library could be obtained. The library data were sequenced on the Illumina hiseq XTen platform to obtain Raw-Data, which was filtered to remove sequencing junctions and low-quality sequences to obtain high-quality Clean Reads, which were used as the basis for data analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eUnsupervised molecular subtyping analysis\u003c/h2\u003e\u003cp\u003eDifferential methylation analysis compared tumor tissues to normal cerebellar tissues. The top 25% most variable DMRs were selected for principal component analysis (PCA). These principal components were then used for t-SNE analysis with the following parameters: theta\u0026thinsp;=\u0026thinsp;0, pca\u0026thinsp;=\u0026thinsp;F, max_iter\u0026thinsp;=\u0026thinsp;2500, perplexity\u0026thinsp;=\u0026thinsp;10.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eData were analyzed and graphed using RStudio statistical software. p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Result","content":"\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical and molecular characterization of the infant patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003elevel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eG4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSHH\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (100.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (36.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.1428\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (55.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7 (63.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (22.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (18.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.6762\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (77.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (100.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9 (81.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eM_Stage (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (22.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (33.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (9.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.5476\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (77.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (66.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (90.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eExcision (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGTR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (77.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (33.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7 (63.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.3711\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNTR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (22.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (66.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (36.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTreatment (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBoth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (55.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (66.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (90.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.1918\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChemotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (33.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (9.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRecurrence (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (66.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (100.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7 (63.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.4651\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (33.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (36.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDeath (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (55.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (66.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8 (72.73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.7237\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (33.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (27.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHistology (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCMB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (66.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (18.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.3770\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDNMB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11.11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (33.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (54.55)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMBEN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (22.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (9.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUndefinded\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (22.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (18.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOS_TIME (median [IQR])\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50.892 [48.888, 66.465]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e72.938 [37.093, 81.316]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e67.254 [41.463, 84.240]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.8099\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eA total of 23 infant with medulloblastoma were included in this study, including 12 males and 11 females. 11 samples with pathology of SHH subtype, 9 samples with G3 subtype, and 3 samples with G4 were clustered and classified by tumor samples by methylation sequencing. The follow-up time of all children was 1-131 months, and the median follow-up time was 51 months. The overall survival was 65.22%, the survival rate of SHH was 72.73%, the survival rate of G3 was 55.56%, the survival rate of G4 was 66.67%, and the survival rates of children at 1, 3, 5, and 10 years were 100.00%, 82.61%, 52.17%, and 13.04%, respectively. Clinical data of pediatric medulloblastoma patients of the 23 active cases, age was dichotomized into children aged 1\u0026ndash;2 years and 2\u0026ndash;3 years, with almost the same proportion of female children as male children. The distribution of molecular subtypes was statistically different among the three groups, with the highest proportion of SHH type 47.83%, G3 type 39.13% and G4 13.04%. This is accord with the typing characteristics of infant medulloblastoma. And in this study, age, sex, histologic typing, treatment, dissemination, recurrence, and survival were not statistically different among the three subtypes (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In histologic typing, CMB and DNMB accounted for the largest proportions of 69.47% and 34.78% respectively, and in the corresponding molecular typing, the SHH predominantly constituted DNMB and the G3 predominantly constituted CMB. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCox Univariate and Multivariate Regression Analysis of Prognostic Factors in Medulloblastoma\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCox univariate analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCox multivariate analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariants\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHazard Ratio (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHazard Ratio (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiagnosis age\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.69 (0.43\u0026ndash;16.71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.289\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.49 (0.44\u0026ndash;68.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.1847\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExcision: GTR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExcision: NTR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.56 (0.11\u0026ndash;2.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.472\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender: female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender: male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.71 (0.18\u0026ndash;2.84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.627\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistology: CMB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistology: DNMB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.17 (0.02\u0026ndash;1.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.133\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistology: MBEN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.72 (0.07\u0026ndash;7.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.781\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistology: Undefinded\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.35 (0.26\u0026ndash;7.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.718\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMolectype: G3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMolectype: G4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.7 (0.08\u0026ndash;6.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.752\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMolectype: SHH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.54 (0.12\u0026ndash;2.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.423\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMStage: M1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMStage: M0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.66 (0.2-13.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.638\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRecurrence: 0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRecurrence: 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10.28 (1.99\u0026ndash;53.03)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10.69 (2.04\u0026ndash;56.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.0051\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment: Both\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment: Chemotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.59 (1.11\u0026ndash;18.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.035\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.41 (0.87\u0026ndash;22.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.0726\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eCox Univariate and Multivariate Regression Analysis\u003c/h2\u003e\u003cp\u003eUnivariates and multivariate COX risk models were analyzed in this cohort, incorporating factors related to prognosis such as age of Diagnosis, gender, pathology type, molecular type, excision of surgical resection, treatment, whether recurrence, and whether metastasis. Among them, in the univariate analysis, the differences in whether recurrence and treatment had a significant impact on survival (P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while gender, age of diagnosis, molecular type, and surgical resection were not related to their prognosis (P-values\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The above meaningful prognostic factors were further analyzed by incorporating them into a Multivariate COX, which showed the same result as Univariates COX. the HR for recurrence (Recurrence: 1) was 10.28, 95% CI was 1.99 to 53.03, with a p-value of 0.005, and in Multivariate COX the HR was 10.69, 95% CI was 2.04 to 56.02, with a p-value of 0.0051, indicating a significant correlation to survival time. Treatment including postoperative chemotherapy alone (Chemotherapy) and postoperative chemotherapy with delayed radiotherapy (Both). The HR for Chemotherapy in Univariates COX analysis was 4.59, 95% CI was 1.11 to 18.93, with p-value was 0.035, and in Multivariate COX the HR was 4.41, 95% CI was 0.87 to 22.31, with p-value was 0.0726. This result suggests that, despite the poor prognosis of medulloblastoma in the less than 3 years of age, aggressive postoperative treatment, i.e., postoperative chemotherapy and delayed radiotherapy, rather than chemotherapy alone, has a greater benefit for overall survival. In this analysis, it is worth noting that in contrast to the results for the all-age group, it is generally believed that the SHH subtype has a poorer prognosis; however, this result was not found in this study.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eSurvival analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) was performed on 23 MBs for overall survival status (a, b) and progression free survival(c, d). Overall survival analysis compared molecular type and treatment. Only the treatment had a difference in the overall survival (p\u0026thinsp;=\u0026thinsp;0.022), there was no difference between molecular typing(p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, there is no difference among all factors being considered including histology, diagnosis age, extent of resection. The analysis shows that postoperative chemotherapy and delayed radiotherapy harvested a better OS, but not for recurrence. It is worth noting that molecular typing and the extent of resection did not make a significant difference in overall survival, and the extent of resection of MB in children is still controversial. In addition to this, it was noted that children with medulloblastoma with molecular typing of SHH are generally considered to have a worse prognosis, which was not reflected in this study.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eMB in infants is associated with a poor prognosis and presents significant treatment challenges, predominantly in the SHH subtype. Children in this age group have immature neurological systems, and radiotherapy not only impacts neurological development but also affects thymus gland development and bone marrow hematopoiesis. Consequently, the international consensus[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], on the treatment protocol for medulloblastoma in children under three years of age advocates for surgical resection as the primary treatment, supplemented by postoperative chemotherapy and delayed radiotherapy. Clinical trials have demonstrated that this treatment strategy\u0026mdash;postoperative chemotherapy followed by delayed radiotherapy\u0026mdash;yields better outcomes.\u003c/p\u003e\u003cp\u003eIt is noteworthy these factors traditionally considered to be of prognostic importance, such as the extent of surgical resection, molecular subtype, histological type, and age, did not exhibit a significant impact on outcomes. Consistent with the literature, our study also observed no significant differences in prognosis between total and subtotal resections. This supports the perspective offered by Thompson et al.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. in their systematic review and the research of Enayet et al.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], suggesting that while current protocols categorize patients with residual tumor areas larger than 1.5 cm\u0026sup2; as high-risk and increase craniospinal irradiation, the true prognostic significance of the extent of resection remains unclear.\u003c/p\u003e\u003cp\u003eThis strategy not only aligns with the developmental limitations of young patients but also strategically improves survival rates while potentially reducing the long-term neurotoxic effects associated with early radiotherapy. Our results advocate for a personalized treatment protocol in this vulnerable age group to minimize therapy-associated complications and enhance quality of life.\u003c/p\u003e\u003cp\u003eFurthermore, while our study indicates improvements with the current treatment protocols, it also acknowledges limitations, such as incomplete data on the long-term quality of life and documentation of radiotherapy complications in young children. Additionally, the sample size was relatively small, which may limit the representativeness of the data. Further studies with larger cohorts are necessary to validate and refine these findings, ensuring broader applicability and precision in treatment planning.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization, T.J. and X.Q. and H.L.;Sample sequencing and methylation analysis, J.K. and X.C.;Patient follow-up and collection of clinical information, J.F. and L.C. and F.L. ;Writing and editing, K.D. and H.L. and T.J.;Visualization, X.C. and K.D. ;Funding Acquisition, H.L. and T.J. ;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOstrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2021) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014\u0026ndash;2018. \u003cem\u003eNeuro-oncology\u003c/em\u003e, \u003cem\u003e23\u003c/em\u003e(12 Suppl 2), iii1\u0026ndash;iii105. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/neuonc/noab200\u003c/span\u003e\u003cspan address=\"10.1093/neuonc/noab200\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLafay-Cousin L, Smith A, Chi SN, Wells E, Madden J, Margol A, Ramaswamy V, Finlay J, Taylor MD, Dhall G, Strother D, Kieran MW, Foreman NK, Packer RJ, Bouffet E (2016) Clinical, Pathological, and Molecular Characterization of Infant Medulloblastomas Treated with Sequential High-Dose Chemotherapy. Pediatr Blood Cancer 63(9):1527\u0026ndash;1534. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/pbc.26042\u003c/span\u003e\u003cspan address=\"10.1002/pbc.26042\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMynarek, M., von Hoff, K., Pietsch, T., Ottensmeier, H., Warmuth-Metz, M., Bison,B., Pfister, S., Korshunov, A., Sharma, T., Jaeger, N., Ryzhova, M., Zheludkova, O.,Golanov, A., Rushing, E. J., Hasselblatt, M., Koch, A., Sch\u0026uuml;ller, U., von Deimling,A., Sahm, F., Sill, M., \u0026hellip; Rutkowski, S. (2020). Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort. \u003cem\u003eJournal of clinical oncology: official journal of the American Society of Clinical Oncology\u003c/em\u003e, \u003cem\u003e38\u003c/em\u003e(18), 2028\u0026ndash;2040. https://doi.org/10.1200/JCO.19.03057\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDuffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR (1993) Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328(24):1725\u0026ndash;1731. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJM199306173282401\u003c/span\u003e\u003cspan address=\"10.1056/NEJM199306173282401\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352(10):978\u0026ndash;986. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa042176\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa042176\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLouis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97\u0026ndash;109. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00401-007-0243-4\u003c/span\u003e\u003cspan address=\"10.1007/s00401-007-0243-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThompson EM, Bramall A, Herndon JE 2nd, Taylor MD, Ramaswamy V (2018) The clinical importance of medulloblastoma extent of resection: a systematic review. J Neurooncol 139(3):523\u0026ndash;539. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11060-018-2906-5\u003c/span\u003e\u003cspan address=\"10.1007/s11060-018-2906-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEnayet AE, Nabil M, Rady MR, Yousef Y, Badawy E, Beltagy E, M. A (2021) Surgical outcome of children with medulloblastoma: a retrospective study of a 405-patient series from Children's Cancer Hospital Egypt (CCHE-57357). Child's Nerv system: ChNS : official J Int Soc Pediatr Neurosurg 37(6):1931\u0026ndash;1940. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00381-021-05082-2\u003c/span\u003e\u003cspan address=\"10.1007/s00381-021-05082-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Medulloblastoma, Radiotherapy, Infant, Chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-4671943/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4671943/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMedulloblastoma (MB), a prevalent malignant pediatric brain tumor, typically necessitates a comprehensive treatment regimen. However, the standard treatment paradigm is often not viable for infants (\u0026lt;\u0026thinsp;3 years old) incomplete, which contraindicates traditional radiotherapy. This study retrospectively analyzed the efficacy of chemotherapy with deferred radiotherapy in infants.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe cohort consisted of 23 infants who receiving surgical resection of MB, which has been categorized into SHH, Group_3, and Group_4 subgroups and received postoperative chemotherapy. Molecular subgroups were identified using DNA methylation sequencing. This study analyzed the overall survival and recurrence rates based on molecular subgroup and evaluated the effects of treatment strategies.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSHH accounted for 48%, Group_3 for 40%, and Group_4 for 12%. The follow-up period ranged from 1 to 131 months, with a median of 51 months. The overall survival rate was 60%, with survival rates for SHH, Group_3, and Group_4 at 66.7%, 50.0%, and 66.7%, respectively. The survival rates at 1, 3, 5, and 10 years were 92%, 80%, 48%, and 12%, respectively. Univariate and multivariate Cox regression analyses indicated that recurrence and treatment modalities significantly impacted survival times, with a hazard ratio of 10.28 for recurrence (95% CI: 1.99\u0026ndash;53.03, p\u0026thinsp;=\u0026thinsp;0.005) and 4.59 for chemotherapy alone (95% CI: 1.11\u0026ndash;18.93, p\u0026thinsp;=\u0026thinsp;0.035). The findings suggest that for infants with MB, a combined treatment approach of postoperative chemotherapy followed by delayed radiotherapy significantly improves overall survival compared to chemotherapy alone.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe findings suggest that infants with MB benefit substantially from postoperative chemotherapy followed by delayed radiotherapy.\u003c/p\u003e","manuscriptTitle":"Retrospective investigation of medulloblastoma under three years of age based on methylation molecule type","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-26 17:00:00","doi":"10.21203/rs.3.rs-4671943/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"da412981-7251-48f1-852e-b7b31aa57096","owner":[],"postedDate":"July 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-12T11:46:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-26 17:00:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4671943","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4671943","identity":"rs-4671943","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}