Comparison of toxicity following single versus tandem autologous transplant regimens for pediatric medulloblastoma.

BACKGROUND: Medulloblastoma outcomes have improved with craniospinal irradiation and chemotherapy, but such therapy has resulted in poor neurocognitive outcomes for young patients. Chemotherapy-only regimens with autologous transplant have been implemented with the intention of avoiding radiation. It is not yet known whether single or tandem transplantation is superior with respect to efficacy and/or safety. METHODS: We performed a retrospective review of children with medulloblastoma treated at Dana-Farber Cancer Institute from 1996 to 2016 who received either single or tandem autologous transplantation after completion of induction chemotherapy. We compared safety and outcome data between the two groups. RESULTS: Among 23 patients, 12 received tandem transplants. Median follow-up was 6.4 years (IQR = 0.8-10.5). There was no statistically significant difference in 5-year EFS or OS between the single (70.7 ± 14%, 80.2 ± 13%) and tandem transplant groups (57.1 ± 15%, 79.6 ± 13%). Seven tandem transplant patients received subsequent radiation while only four required radiation in the single transplant group (p = .41). In the single transplant regimen, patients experienced longer antibiotic duration (p = .03) and LOS (p = .01) and a trend toward increased number of transfusions (p = .06). Four cases of veno-occlusive disease were reported in the single transplant group (p = .04). CONCLUSIONS: Outcomes were similar between regimens, but the single transplant regimen had more hepatic complications. These data suggest that tandem transplant regimens may have reduced toxicity compared to the single transplant regimen with similar outcome measures.

Long-term safety of growth hormone replacement therapy after childhood medulloblastoma and PNET: it is time to set aside old concerns.

To assess the long-term safety of administering growth hormone (GH) in patients with GH deficiency due to treatment for childhood medulloblastoma and primitive neuroectodermal tumor (PNET). Data were retrospectively retrieved on children receiving GH supplementation, assessing their disease-free and overall survival outcomes and risk of secondary malignancies using Kaplan-Meier and Cox models. Overall 65 children were consecutively collected from May 1981 to April 2013. All patients had undergone craniospinal irradiation (total dose 18-39 Gy), and subsequently received GH for a median (interquartile range, IQR) of 81 (50.6-114.9) months. At a median (IQR) of 122.4 months (74.4-149.5) after the end of their adjuvant cancer treatment, two patients (3 %) experienced recurrent disease and 8 (12.3 %) developed secondary malignancies, all but one of them (an osteosarcoma) related to radiation exposure and occurring within the radiation fields. There was no apparent correlation between the administration of GH replacement therapy (or its duration) and primary tumor relapse or the onset of secondary malignancies [HR: 1.01 (95 % CI: 0.98, 1.03) for every additional 12 months of GH supplementation; p = 0.36). At univariate analysis, the large cell or anaplastic medulloblastoma subtype, metastases and myeloablative chemotherapy correlated with a higher risk of secondary malignancies (p < 0.1), but multivariate analysis failed to identify any factors independently associated with this risk. Our data supports once more the safety of long-term GH replacement therapy in children treated for medulloblastoma/PNET, previously reported in larger data sets. The neurooncology community now need to warrant large-scale meta-analyses or international prospective trials in order to consolidate our knowledge of factors other than GH, such as genetic predisposition, high-grade/metastatic disease, high-dose chemotherapy and era of treatment, in promoting the occurrence of secondary malignancies.

MBMethPred: a computational framework for the accurate classification of childhood medulloblastoma subgroups using data integration and AI-based approaches.

Childhood medulloblastoma is a malignant form of brain tumor that is widely classified into four subgroups based on molecular and genetic characteristics. Accurate classification of these subgroups is crucial for appropriate treatment, monitoring plans, and targeted therapies. However, misclassification between groups 3 and 4 is common. To address this issue, an AI-based R package called MBMethPred was developed based on DNA methylation and gene expression profiles of 763 medulloblastoma samples to classify subgroups using machine learning and neural network models. The developed prediction models achieved a classification accuracy of over 96% for subgroup classification by using 399 CpGs as prediction biomarkers. We also assessed the prognostic relevance of prediction biomarkers using survival analysis. Furthermore, we identified subgroup-specific drivers of medulloblastoma using functional enrichment analysis, Shapley values, and gene network analysis. In particular, the genes involved in the nervous system development process have the potential to separate medulloblastoma subgroups with 99% accuracy. Notably, our analysis identified 16 genes that were specifically significant for subgroup classification, including EP300, CXCR4, WNT4, ZIC4, MEIS1, SLC8A1, NFASC, ASCL2, KIF5C, SYNGAP1, SEMA4F, ROR1, DPYSL4, ARTN, RTN4RL1, and TLX2. Our findings contribute to enhanced survival outcomes for patients with medulloblastoma. Continued research and validation efforts are needed to further refine and expand the utility of our approach in other cancer types, advancing personalized medicine in pediatric oncology.

CoMB-Deep: Composite Deep Learning-Based Pipeline for Classifying Childhood Medulloblastoma and Its Classes.

Childhood medulloblastoma (MB) is a threatening malignant tumor affecting children all over the globe. It is believed to be the foremost common pediatric brain tumor causing death. Early and accurate classification of childhood MB and its classes are of great importance to help doctors choose the suitable treatment and observation plan, avoid tumor progression, and lower death rates. The current gold standard for diagnosing MB is the histopathology of biopsy samples. However, manual analysis of such images is complicated, costly, time-consuming, and highly dependent on the expertise and skills of pathologists, which might cause inaccurate results. This study aims to introduce a reliable computer-assisted pipeline called CoMB-Deep to automatically classify MB and its classes with high accuracy from histopathological images. This key challenge of the study is the lack of childhood MB datasets, especially its four categories (defined by the WHO) and the inadequate related studies. All relevant works were based on either deep learning (DL) or textural analysis feature extractions. Also, such studies employed distinct features to accomplish the classification procedure. Besides, most of them only extracted spatial features. Nevertheless, CoMB-Deep blends the advantages of textural analysis feature extraction techniques and DL approaches. The CoMB-Deep consists of a composite of DL techniques. Initially, it extracts deep spatial features from 10 convolutional neural networks (CNNs). It then performs a feature fusion step using discrete wavelet transform (DWT), a texture analysis method capable of reducing the dimension of fused features. Next, the CoMB-Deep explores the best combination of fused features, enhancing the performance of the classification process using two search strategies. Afterward, it employs two feature selection techniques on the fused feature sets selected in the previous step. A bi-directional long-short term memory (Bi-LSTM) network; a DL-based approach that is utilized for the classification phase. CoMB-Deep maintains two classification categories: binary category for distinguishing between the abnormal and normal cases and multi-class category to identify the subclasses of MB. The results of the CoMB-Deep for both classification categories prove that it is reliable. The results also indicate that the feature sets selected using both search strategies have enhanced the performance of Bi-LSTM compared to individual spatial deep features. CoMB-Deep is compared to related studies to verify its competitiveness, and this comparison confirmed its robustness and outperformance. Hence, CoMB-Deep can help pathologists perform accurate diagnoses, reduce misdiagnosis risks that could occur with manual diagnosis, accelerate the classification procedure, and decrease diagnosis costs.

miR-196B-5P and miR-200B-3P Are Differentially Expressed in Medulloblastomas of Adults and Children.

Medulloblastoma is a highly aggressive brain tumor that typically affects children, while in adults it represents ~1% of all brain tumors. Little is known about microRNA expression profile of the rare adult medulloblastoma. The main aim of this study was to identify peculiar differences in microRNA expression between childhood and adult medulloblastoma. Medulloblastomas were profiled for microRNA expression using the Exiqon Human miRNome panel (I + II) analyzing 752 microRNAs in a training set of six adult and six childhood cases. Then, the most differentially expressed microRNAs were validated in a total of 21 adult and 19 childhood cases. Eight microRNAs (miR-196b-5p, miR-183-5p, miR-200b-3p, miR-196a-5p, miR-193a-3p, miR-29c-3p, miR-33b-5p, and miR-200a-3p) were differentially expressed in medulloblastoma of adults and children. Analysis of the validation set confirmed that miR-196b-5p and miR-200b-3p were significantly overexpressed in medulloblastoma of adults as compared with those of children. We followed an in silico approach to investigate direct targets and the pathways involved for the two microRNAs (miR-196b and miR-200b) differently expressed between adult and childhood medulloblastoma. Adult and childhood medulloblastoma have different miRNA expression profiles. In particular, the differential dysregulation of miR-196b-5p and miR-200b-3p characterizes the miRNA profile of adult medulloblastoma and suggests potential targets for novel diagnostic, prognostic, or therapeutic strategies.

Survival and prognostic factors in childhood medulloblastoma: A Brazilian single center experience from 1995 to 2016.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in the pediatric population. Despite prognosis improvement in the past two decades, one-third of the patients still remain incurable. New evidence suggests that medulloblastoma comprises four distinct entities; therefore, treatment de-escalation is required. The aim of this article is to evaluate epidemiological data from patients treated at our institution. The primary objective is to analyze overall survival (OS) and event-free survival (EFS) and the secondary objective is to identify prognostic factor from this cohort. METHODS: We retrospectively analyzed 69 patients who underwent surgical resection for medulloblastoma among 423 children from the tumor registry data bank of Santo Antônio Children's Hospital from 1995 to 2016. Kaplan-Meier method and Cox regression analysis were used to identify OS, EFS, and prognostic factors. RESULTS: The 5-year OS and EFS rates found were 44.5% and 36.4%, respectively. The extent of resection and radiotherapy as adjuvant treatments was positively correlated to outcome while metastatic disease at diagnosis was negatively related to OS. Age younger than 3 years old did not have a worse outcome in our cohort. CONCLUSION: Similar results to population-based studies were found, but we still face difficulties due to living in a developing country. In the near future, we look forward to new diagnostic techniques that will enable us to classify medulloblastomas according to molecular subgroups.

Childhood Medulloblastoma: Current Therapies, Emerging Molecular Landscape and Newer Therapeutic Insights.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children, currently treated uniformly based on histopathology and clinico-radiological risk stratification leading to unpredictable relapses and therapeutic failures. Identification of molecular subgroups have thrown light on the reasons for these and now reveals clues to profile molecularly based personalized therapy against these tumors. METHODS: Research and online contents were evaluated for pediatric medulloblastoma which included latest information on the molecular subgroups and their clinical relevance and update on efforts to translate them into clinics. RESULTS: Scientific endeavors over the last decade have clearly identified four molecular variants (WNT, SHH, Group 3, and Group 4) and their demographic, genomic, and epigenetic profile. Latest revelations include significant heterogeneity within these subgroups and 12 different subtypes of MB are now identified with disparate outcomes and biology. These findings have important implications for stratification and profiling future clinical trials against these formidable tumors. CONCLUSION: With the continued outpouring of genomic/epigenomic data of these molecular subgroups and evolution of further subtypes in each subgroup, the challenge lies in comprehensive evaluation of these informations. Current and future endeavors are now needed to profile personalized therapy for each child based on the molecular risk stratification of medulloblastoma, with a hope to improve survival outcome and reduce relapses.

Evaluación de la talla final y sobrevida libre de eventos en pacientes sobrevivientes de meduloblastoma con deficiencia de hormona de crecimiento, tratados o no con hormona de crecimiento biosintética recombinante humana en la niñez. Comparación con pacientes con craneofaringioma tratados con rhGH / Evaluation of final height and event-free survival in medulloblastoma patients with growth hormone deficiency with and without biosynthetic recombinant human growth hormone treatment in childhood

Introduccion: La deficiencia de GH (DGH) y la radioterapia espinal (RE) han sido implicadas en la etiología de la talla adulta (TA) baja en los sobrevivientes de meduloblastoma en la niñez. Sin embargo la dinámica del crecimiento luego del diagnóstico tumoral y la efectividad de la Hormona de crecimiento biosintética recombinante humana (rhGH) sobre la TA en comparación con sobrevivientes no tratados con rhGH no han sido reportadas. Objetivo. Evaluación de la talla (T) SDS (SDST) desde el diagnóstico del meduloblastoma y el efecto de la rhGH en pacientes con DGH comparando con pacientes no tratados con rhGH y con pacientes con craniofaringioma y DGH, tratados con rhGH. Analizar si había alguna diferencia en la sobrevida libre de eventos en los pacientes con meduloblastoma al ser tratados con rhGH. Material Clínico y Métodos. Catorce pacientes con meduloblastoma recibieron rhGH hasta la TA, grupo meduloblastoma tratado con GH (GrMGH). Diecinueve pacientes rechazaron la terapia con rhGH, grupo meduloblastoma control (GrMC). Se midieron la talla parada (T) y la talla sentada (Tsent). Ocho pacientes con craneofaringioma recibieron rhGH hasta la TA (GrCra). Se realizó seguimiento de 72 pacientes con meduloblastoma, 20 con tratamiento con rhGH. Resultados. En GrMGH, la media±DS SDST disminuyó de 0.09±0.63 al diagnóstico del tumor a -1.38±0.91 al diagnóstico del DGH, y a -1.90±0.72 al comienzo de rhGH, p<0.01, pero se mantuvo sin cambios durante el tratamiento con rhGH (TA -2.12±0.55). En GrMC la SDST (-0.25±0.88) no fue diferente de GrMGH al diagnóstico del tumor, pero fue -3.40±0.88 a la TA, significativamente menor que en GrMGH, p=0.001. La Tsent SDS a la TA (-4.56±0.82) fue significativamente menor que al comienzo de rhGH (-2.86±0.75), p=0.003, y no fue diferente de GrMC (-4.85±1.77). El GrCra mostró la mayor ganancia de talla (GT = TA-SDSTinicial), p< 0.007, y la menor pérdida de talla (PT= Tblanco - TA), p < 0.0001. Conclusión. El tratamiento con rhGH mejora la TA en sobrevivientes de meduloblastoma en la niñez con DGH, pero no el crecimiento espinal. Las características del crecimiento y la respuesta a rhGH son diferentes en GrMGH y en GrCra, mientras que el primer grupo sólo pudo mantener la talla relativa, el segundo mostró una franca recuperación del crecimiento. Además no hubo diferencias en la sobrevida libre de eventos en los pacientes con meduloblastoma con y sin tratamiento con rhGH (AU)

Background. GH deficiency (GHD) and spine irradiation (SI) have been implicated in the mechanism of reduced adult height (AH) in childhood survivors of medulloblastoma. However, growth dynamics after tumor diagnosis and the effectiveness of (rhGH) Recombinant human Growth Hormone on AH in comparison with rhGH-untreated survivors has not been reported. Aim. Follow up of height (H) SDS (HSDS) after diagnosis of meduloblastoma, and the effect of rhGH in GHD meduloblastoma patients. Comparison with GH-untreated GHD meduloblastoma patients and with GHD craniopharyngioma patients treated with rhGH. To evaluate event free survival in medulloblastoma patiens treated with rhGH. Clinical Material and Methods. Fourteen survivors of medulloblastoma received rhGH treatment until AH, Medulloblastoma GH-treated group (MGHGr). Nineteen patients refused rhGH therapy, GH-untreated Control Medulloblastoma Group, (MCGr). Standing H and sitting H (SitH) were measured. Eight patients with craniopharyngioma received rhGH treatment until AH (CraGr). 72 patients with medulloblastoma were followed up, 20 with rhGH. Results. In MGHGr, mean±SD HSDS decreased from 0.09±0.63 at tumor diagnosis to -1.38±0.91 at diagnosis of GHD, and to -1.90±0.72 at the onset of rhGH, p<0.01, but it remained unchanged during rhGH (AH -2.12±0.55). MCGr HSDS (- 0.25±0.88) was not different from MGHGr at tumor diagnosis, but it was -3.40 ± 0.88 at AH, significantly lower than in MGHGr, p=0.001. SitH SDS at AH (-4.56±0.82) was significantly lower than at the onset of rhGH (-2.86±0.75), p=0.003, and it was not different from MCGr (-4.85 ± 1.77). CraGr showed the highest height SDS gain (HG = FH ­ startHSDS), p<0.007, and the lowest height lost (HL = targetH - AH), p< 0.0001. Conclusions. rhGH treatment improves AH in GH-deficient childhood medulloblastoma survivors but not spinal growth. Growth pattern and response to rhGH differed in MGHGr and CraGR, while the former just could maintain height SDS under treatment, the latter showed a clear catch up growth. There wasn't any difference in the event free survival in medulloblastoma patients with or without rhGH (AU)