Management Of Medulloblastoma Research Articles

Abstract 5115: Designing targeted approaches for recurrent medulloblastoma

Abstract Designing targeted therapies for recurrent medulloblastomaPediatric brain tumors are the leading cause of cancer-related death in children, with medulloblastoma (MB) being the most common type. Despite significant progress in the field, approximately 30% of children with MB will relapse. Recurrent MB is commonly metastatic and virtually none of these patients will live beyond the one-year hallmark. These sobering statistics highlight the significant unmet need for effective therapies for recurrent MB. The likely underlying cause of the constant failure of our current clinical approaches, which are based on data obtained from disease models recapitulating primary tumors, is the disparity in genomic and transcriptomic data between primary and relapsed disease. Because of these disparities, we hypothesize that by conducting mechanistic studies and drug screens in relapse disease models, we can improve the outcomes for children with recurrent MB. Our data, obtained through a bioinformatics mining approach to predict tumor response, enabled us to identify a clinically relevant candidate drug for the treatment of recurrent MB: Minnelide. This compound acted on MYC to reduce tumor growth and the metastatic dissemination of tumors with the genetic background often found in relapsed MB patients. Additionally, to further support the translational relevance of our data, Minnelide increased the efficacy of adjuvant therapeutics used in the clinical management of MB. Our findings not only highlight the potential for repurposing Minnelide to treat children with recurrent MB, but also the potential of our research approaches aimed at identifying novel therapeutics for relapsed cancers. Citation Format: Jezabel Rodriguez Blanco. Designing targeted approaches for recurrent medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5115.

Evolution of Systemic Therapy in Medulloblastoma Including Irradiation-Sparing Approaches.

The management of medulloblastoma in children has dramatically changed over the past four decades, with the development of chemotherapy protocols aiming at improving survival and reducing long-term toxicities of high-dose craniospinal radiotherapy. While the staging and treatment of medulloblastoma were until recently based on the modified Chang's system, recent advances in the molecular biology of medulloblastoma have revolutionized approaches in the management of this increasingly complex disease. The evolution of systemic therapies is described in this review.

Research progress in molecular pathology markers in medulloblastoma.

Medulloblastoma (MB) is the commonest primary malignant brain cancer. The current treatment of MB is usually surgical resection combined with radiotherapy or chemotherapy. Although great progress has been made in the clinical management of MB, tumor metastasis and recurrence are still the main cause of death. Therefore, definitive and timely diagnosis is of great importance for improving therapeutic effects on MB. In 2016, the World Health Organization (WHO) divided MB into four subtypes: wingless-type mouse mammary tumor virus integration site (WNT), sonic hedgehog (SHH), non-WNT/non-SHH group 3, and group 4. Each subtype of MB has a unique profile in copy number variation, DNA alteration, gene transcription, or post-transcriptional/translational modification, all of which are associated with different biological manifestations, clinical features, and prognosis. This article reviewed the research progress of different molecular pathology markers in MB and summarized some targeted drugs against these molecular markers, hoping to stimulate the clinical application of these molecular markers in the classification, diagnosis, and treatment of MB.

Role of Radiotherapy in Patients With Relapsed Medulloblastoma

During the last three decades, the management of medulloblastoma (MBL) has made enormous progress with a multidisciplinary approach, incorporating surgery, radiotherapy (RT), and chemotherapy. Despite this improvement, 20%-30% of patients with MBL remain at risk of disease recurrence, with its relapse being possibly fatal. To date, the salvage treatment for relapse remains challenging, and various approaches have been suggested for the retreatment. In this review, I have described the characteristics of patients with relapsed MBL, patterns of relapse and the most commonly prescribed treatment. Further, I have reviewed the studies on re-irradiation and its associated issues to conclusively suggest the RT recommendations for patients with relapsed MBL.

Management of Medulloblastoma Metastases: Algerian Experience

This work is based on the study of patients treated for medulloblastoma metastasis at diagnosis between January 2006 and December 2015 in the neurosurgery department of the Ait IDDIR Health Hospital Establishment. Our series consisted of 16 patients, 11 men and 5 women; the median age was 16.9 years. The baseline, presentation of symptoms and signs, imaging results (MRI), surgical results and clinical results were recorded. The clinical manifestation was revealed by intracranial hypertension syndrome (100%), associated with cerebellar syndrome (80%). The localization was in Intra-nevraxics: (81.25%) and in Extra-nevraxics (18.75%). 68.75% of patients underwent total surgical excision and 31.25% underwent subtotal surgical excision. The presence of malignant cells in the CSF is marked in 56.25%. The pathological study revealed that 62.5% of cases had a classic variant and 37.5% a desmoplastic variant. 30% of the cases were classified as “standard risk” and 70% as “high risk”. The surgery was supplemented by radiotherapy of the entire neuraxis using the “movable junctions” technique in all cases. The average delay was 70 days. Adjuvant chemotherapy was performed in 9 cases. The long-term survival rate after metastasis varies between 06 months to 24 months, only 04 cases (25%) are still alive. The management of medulloblastoma must be multidisciplinary involving neurosurgeons and radiotherapist oncologists. This collaboration is the only guarantee of an improvement in his prognosis

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

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

Sequential improvement in paediatric medulloblastoma outcomes in a low-and-middle-income country setting over three decades

Background: Medulloblastoma (MB) is the commonest malignant brain tumour of childhood. Accurate clinical data on paediatric MB in the low-and-middle-income countries (LMIC) setting are lacking. Sequential improvements in outcomes seen in high-income countries are yet to be reflected in LMICs.Aim: The aim of this study was quantification of paediatric MB outcomes in the LMIC setting over three decades of advances in multidisciplinary intervention.Setting: Cape Town, South Africa.Methods: This was a retrospective study of 136 children with MB diagnosed between 1985 and 2015. The modified Chang criteria were used for risk stratification. The primary objective of this study was overall survival (OS), quantified by analysis of epidemiological, clinical and pathological data.Results: OS improved significantly during the most recent decade (2005–2015) when compared with the preceding two decades (1985–1995 and 1995–2005). Despite reduced-dose craniospinal irradiation (CSI) for standard risk cases, OS was significantly greater than during the preceding two decades. High-risk disease was identified in 71.4% of cases and was associated with significantly inferior OS compared with standard-risk cases. Improved OS was positively correlated with the therapeutic era, three-dimensional (3D) conformal radiotherapy technique, older age at diagnosis, classic and desmoplastic histology, extent of resection and absence of leptomeningeal spread on imaging.Conclusion: Advances in multidisciplinary management of MB in our combined service are associated with improved survival. Access to improved imaging modalities, advances in surgical techniques, increased number of patients receiving risk-adapted combination chemotherapy or radiotherapy, as well as CSI using a linear accelerator with 3D planning, are considered as contributing factors.

Cerebellar swelling after surgery for medulloblastoma with leptomeningeal dissemination in children. A case based-update

ObjectDespite the improvement in the overall management of medulloblastomas in recent years, certain phenomena and in particular postoperative cerebellar swelling remain an enigma. This rare complication, little described in the literature, is nonetheless life threatening for the patients. Case reportsWe report our experience about two children who developed severe cerebellar swelling with hydrocephalus and upward herniation soon after a gross total resection of a fourth ventricle medulloblastoma by a telo-velar approach. Despite rapid management of ventricular dilation and optimal medical intensive treatment of intracranial hypertension, both children died quickly after the surgery. Pathological examination analyses were in favour of anaplastic/large cell medulloblastoma. DiscussionDiffuse cerebellar swelling with upward herniation may occur postoperatively in young children with anaplastic/large cell medulloblastoma with leptomeningeal spread. In the literature, only 4 cases have been so far described with delayed onset of symptoms. Two children survived with an aggressive management (decompressive surgery and early radio-chemotherapy). ConclusionCerebellar swelling is an unrecognised and sudden complication of posterior fossa surgery for metastatic anaplastic medulloblastoma with leptomeningeal dissemination in young children. An initial less invasive surgical approach could be considered in such cases, in order to prevent this complication with potentially tragic issue, and which cannot be managed with a CSF shunt alone.

Data mining of pediatric medulloblastoma microarray expression reveals a novel potential subdivision of the Group 4 molecular subgroup.

Medulloblastoma is the most common type of solid brain tumor in children. This type of embryonic tumor is highly heterogeneous and has been classified into 4 molecular subgroups based on their gene expression profiles: WNT, SHH, Group 3 (G3) and Group 4 (G4). WNT and SHH tumors exhibit the specific dysregulation of genes and pathways, whereas G3 and G4 tumors, two of the more frequent subtypes, are the least characterized. Thus, novel markers to aid in the diagnosis, prognosis and management of medulloblastoma are required. In the present study, microarray gene expression data was downloaded from the Gene Expression Omnibus database, including data from the 4 subgroups of medulloblastoma and healthy cerebellum tissue (CT). The data was utilized in an in silico analysis to characterize each subgroup at a transcriptomic level. Using Partek Genomics Suite software, the data were visualized via hierarchical clustering and principal component analysis. The differentially expressed genes were uploaded to the MetaCore portal to perform enrichment analysis using CT gene expression as baseline, with fold change thresholds of <-5 and >5 for differential expression. The data mining analysis of microarray gene expression data enabled the identification of a range of dysregulated molecules associated with each subgroup of medulloblastoma. G4 is the most heterogeneous subgroup, as no definitive pathway defines its pathogenesis; analysis of the gene expression profiles were associated with the G4α and G4β subcategories. TOX high mobility group box family member 3, synuclein α interacting protein and, potassium voltage-gated channel interacting protein 4 were identified as three novel potential markers for distinguishing the α and β subcategories of G4. These genes may be associated with medulloblastoma pathogenesis, and thus may provide a basis for researching novel targeted treatment strategies for G4 medulloblastoma.

Management of Medulloblastoma in the Pediatric Population

Dr. Brown is a Resident, and Dr. Boop is Professor and Chairman, Department of Neurosurgery, University of Tennessee, 6325 Humphreys Blvd, Memphis, TN 38120; E-mail: [email protected]. All authors and staff in a position to control the content of this CME activity, and their spouses/life partners (if any), have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations related to this CME activity.Category: TumorLippincott Continuing Medical Education Institute, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.Lippincott Continuing Medical Education Institute, Inc. designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the CME article and complete the quiz and evaluation on the enclosed form, answering at least 70% of the quiz questions correctly. This activity expires on July 31, 2017.

Management of Medulloblastoma in the Pediatric Population

Contemporary Neurosurgery: May 30, 2016 - Volume 38 - Issue 8 - p 8 doi: 10.1097/01.CNE.0000489897.03988.5f

From small to big: microRNAs as new players in medulloblastomas

Medulloblastomas (MB) are the most common malignant neoplasms of the central nervous system in children. Although the molecular basis of medulloblastoma has received considerable attention over the past decade, the underlying cellular and molecular mechanisms of medulloblastoma initiation, maintenance, and progression remain unclear. MicroRNAs (miRNAs) are short non-coding RNAs that function as key regulators of diverse biological processes by exerting negative gene regulation at the post-transcriptional level. Emerging evidence indicates that miRNAs play an important role in the development of human cancers; miRNA deregulation results in altered activities of downstream tumor suppressors, oncogenes, and other signaling molecules. In this review, we comprehensively discuss the versatile roles of miRNAs in medulloblastoma and their potential applications in the diagnosis, prognosis, and treatment of this malignancy. As a rapidly evolving field of basic and biomedical sciences, miRNA research will certainly have a revolutionary impact on the management of medulloblastoma.

Anaplastic medulloblastoma in a child with Duchenne muscular dystrophy

A 9-year-old boy with known Duchenne type muscular dystrophy (DMD) presented with signs of increased intracranial pressure. Radiological investigations revealed a lesion in the midline of the posterior fossa. Subtotal resection was performed. Pathology findings were consistent with the diagnosis of anaplastic medulloblastoma. The postoperative lumbar CSF was positive for malignant cells. Postoperatively, the patient showed severe neurological deterioration and lost his capacity to walk. He was treated with craniospinal radiation followed by nonintensive chemotherapy. At 30 months postsurgery, he was still in complete remission but had not recovered his walking ability. This is the second report of a malignant brain tumor in a boy with DMD. The possible link between the 2 conditions is discussed, as are ethical considerations regarding the management of medulloblastoma in children with DMD.

Non‐pineal supratentorial primitive neuro‐ectodermal tumors (sPNET) in teenagers and young adults: Time to reconsider cisplatin based chemotherapy after cranio‐spinal irradiation?

Supratentorial PNET (sPNET) are rare CNS tumors of embryonal origin arising in children and adults. The treatment of sPNET for all age groups at our cancer center has been based on the management of medulloblastoma (MB), involving neurosurgical debulking followed by cranio-spinal irradiation (CSI) and systemic chemotherapy. Medical records were reviewed to gather demographic and clinical data about all embryonal CNS tumors in children and adults from 2001 to 2007. Tumor pathology, clinical management and survival data were also assessed, particularly as regards those patients who received the Packer chemotherapy regimen for either sPNET or MB. Eleven patients (five children and six adults) were identified with non-pineal sPNET, three children with pineal sPNET, and 19 patients (18 children and 1 adult) with MB. There was no difference in overall survival (OS) rates between pediatric and adult sPNET. When all sPNET were compared to all MB, 5-year OS was 14% versus 73%, respectively, but was only 9% for non-pineal sPNET. When only considering those patients treated with the Packer chemotherapy regimen, the 5-year OS was 12% for sPNET versus 79% for MB. This retrospective study demonstrates that non-pineal sPNET are clinically distinct from MB and are resistant to the Packer chemotherapy regimen. We suggest that it is time to reconsider the use of this regimen in teenage and young adult non-pineal sPNET and to investigate the utility of alternative approaches.

Treatment of Early Childhood Medulloblastoma by Postoperative Chemotherapy Alone—A Critical Review

Despite comprehensive treatment with surgery, radiation, and chemotherapy, medulloblastoma remains the most common malignant brain tumor in children with a five-year disease free survival rate of only 40% in those less than 10 years of age. Although adjuvant regimens are an integral component in patient management, radiotherapy in very young children is limited by the susceptibility of the immature brain to radiation-induced cognitive deficits. Thus, the development of an effective adjuvant protocol employing chemotherapy alone is of substantial interest. Rutkowski and colleagues published the results of their trial investigating the treatment of medulloblastoma solely with postoperative chemotherapy (Rutkowski et al. Treatment of Early Childhood Medulloblastoma by Postoperative Chemotherapy Alone. N Engl J Med. 2005;352(10): 978–986). In this multi-institutional clinical trial, 43 patients with histologically confirmed medulloblastoma were treated after surgery with an intensive chemotherapy protocol, consisting of three cycles of intravenous cyclophosphamide, vincristine, methotrexate, carboplatin, and etoposide, as well as intraventricular methotrexate. Results were as follows: in children with complete resection, partial resection, and macroscopic metastases, the five-year progression-free and overall survival rates were 82% and 93%, 50% and 56%, and 33% and 38%, respectively. Furthermore, desmoplastic histology, metastatic disease, and age less than two years were found to be independent prognostic factors for tumor relapse and poor survival. Of note, there were no instances of unexpected toxicity, with only asymptomatic leukoencephalopathy occurring in the majority of patients. Although the mean IQ of patients in this cohort was significantly lower than that of healthy, matched controls, it was higher than that of patients receiving cerebral radiation. Based on these findings, the authors concluded that in young children without metastases, chemotherapy may be used alone as adjuvant treatment for medulloblastoma, especially after gross total resection or those with desmoplastic variants, which portends a more favorable prognosis. This article highlights the growing importance of chemotherapy in the treatment of pediatric brain tumors, and represents a substantial step forward in the management of medulloblastoma. In the past, postoperative radiotherapy was frequently used in this patient population. Although highly effective, the risk of permanent cognitive side effects severely limits its use in children younger than five years of age. In such cases, chemotherapy may be employed to delay neuraxis irradiation. This study, which is the largest conducted to date in children <3 years old, demonstrates that patients receiving intensive chemotherapy may not only achieve excellent outcomes, but may also avoid the need for radiotherapy all together. As expected, cognitive testing in this cohort demonstrated milder side effects from chemotherapy than radiotherapy. It is important to note, however, factors other than radiation therapy may impact on quality of life and neuropsychiatric development. Regardless, the authors’ findings have implications for the current management guidelines of pediatric CNS malignancies by supporting the notion that radiotherapy may be avoided in young children without compromising prognosis.

A Case of Cerebello-Thalamo-Cortical Diaschisis

Abstract: Diaschisis is classically defined as an inhibition of func-tion produced by a focal disturbance in an anatomically intactportion of the brain, remote from the original seat of injury, butanatomically connected with it through fiber tracts. As describedduring thalamo-cortical diaschisis, this functional impairment couldlead to neurobehavioral and neuropsychological deficits. In contrast,cases of cortico-cerebellar diaschisis, which are the most reported,do not lead to significant motor features. We present a rare case ofcerebello-thalamo-cortical diaschisis demonstrated with F-18FDG PET, involving precentral cortex without clinical pyramidalsyndrome. Key Words: diaschisis, brain imaging, F-18 FDG-PET( Clin Nucl Med 2008;33: 000–000) REFERENCES 1. Eisenstat DD. Clinical management of medulloblastoma in adults. ExpertRev Anticancer Ther . 2004;4:795–802.2. Chen W. Clinical applications of PET in brain tumors. J Nucl Med .2007;48:1468–1481.3. Vermeere V, Burg S, Wager M, et al. Inte´reˆt de la TEP au 18F -FDGdouble phase avec acquisition tardive dans la de´tection des tumeursce´re´brales.

Outcome of children with posterior fossa medulloblastoma: a single institution experience over the decade 1994–2003

While the impact of radiotherapy in the management of medulloblastoma was recognised, the introduction of chemotherapy was investigated in clinical trials and shown to confer an additional advantage. We reviewed the outcome of a series of consecutive patients to assess the impact in a population-based clinical establishment. A series of 38 children treated for medulloblastoma at Birmingham Children's Hospital between 1994 and 2003 was analysed. The effect of surgery, radiotherapy, chemotherapy and metastasis on survival was analysed. The overall 5-year survival rate was 61.4% for the 36 patients who had resective surgery, while 2 patients had biopsy only and died within a few months. There was no operative mortality. The incidence of hydrocephalus needing permanent shunting was higher in the first 3 years of life (p = 0.007, chi-square). The 5-year survival rate of patients with total and sub-total excision of medulloblastoma was 61.1% and 61.8%, respectively. The 5-year survival rate of patients older than 3 years was 73.4% and for patients under 3 years was 36.3% (p = 0.007, log rank). Metastases at presentation did not influence survival. All deaths occurred in the first 32 months. The contribution of chemotherapy in the improvement of the overall survival appears more evident in children younger than 3 years or presenting with metastases. The absence of significant difference in survival between patients with total or sub-total excision of medulloblastoma supports the view that total excision of medulloblastoma can be avoided when the risk for potential intra-operative damage and consequent neurological deficits is high.

3. 髄芽腫の治療(L1-D 悪性脳腫瘍への多角的戦略)

3. 髄芽腫の治療(L1-D 悪性脳腫瘍への多角的戦略)

Current Management of Medulloblastoma

Current Management of Medulloblastoma

Radiotherapy for medulloblastoma in children: a perspective on current international clinical research efforts.

The North America and four European pediatric cooperative groups have undertaken prospective studies for medulloblastoma continuously since the 1970s. In this article, we will review the results of these studies with respect specifically to the use of radiotherapy, and trace the developments that have led up to the present trials for patients with this tumor. Published and unpublished data from the North American CCG and POG and now COG studies, from the UKCCG and SIOP groups, as well as from the French and German groups were reviewed. Issues of especial interest included radiotherapy dose and dose fractionation schedules, scheduling of chemotherapy and radiotherapy, and technical aspects of treatment with radiotherapy that might impact on outcome. Much progress has been made in the management of medulloblastoma in childhood as a consequence of the studies undertaken sequentially by these groups over the past two decades. It now seems clear that chemotherapy plays an important role for all patients. In patients with average risk disease, the use of chemotherapy has allowed a reduction in the dose of radiotherapy to the craniospinal axis and the combination of chemotherapy with radiotherapy appears to have brought about a significant improvement in disease-free and overall survival in this patient population. Patients with high-risk disease fare better now than in the past as a consequence of the routine use of aggressive chemotherapy and preliminary data suggest that the use of higher doses of radiation as in the POG studies is associated with a particularly favorable outcome. Accurate delivery of radiotherapy is essential for optimal results. The avail-ability of better tools at the treating centres and quality control as an integral part of cooperative studies are likely to bring about further improvements in outcome in the future.