Efficacy of dual-task training on stability and function in children with ataxia after medulloblastoma resection: A randomized controlled trial.

BACKGROUND/OBJECTIVE: In children, medulloblastoma (MB) is the most prevalent posterior fossa tumor. The first line of treatment is maximal safe resection. Therefore, symptoms of ataxia are commonly seen. Training the brain on balance and cognitive tasks makes balance more automatic than without cognitive tasks. The goal was to assess the effectiveness of dual-task practice on balance after MB excision in children with ataxia. METHODS: Thirty children with ataxia after MB resection at Children Cancer Hospital Egypt were randomized into two equal groups. Exercises for mobility, balance, and gait training were given to both groups. The research group underwent a specific dual-task program (balance and cognitive). The program ran 3 days per week for 8 weeks. Children were evaluated before and after the treatment regimen using the Scale of Assessment and Rating of Ataxia (SARA), the HUMAC Balance System, Pediatric Balance Scale, and Functional Independent Measurement. All children's legal guardians signed an ethical agreement. RESULTS: A notable improvement in balance was found in the dual group in Pediatric Balance Scale (PBS) (p = .028) and stability test (p = .0001) in favor of the study group. No discernible difference was observed in the Functional Independent Measurement score among the two groups (p = .158), although there was a statistically significant increase in both groups after treatment. CONCLUSION: Dual-task program is more effective than traditional physical therapy alone in improving balance in children with ataxia after MB resection.

Prognostic factors affecting infantile medulloblastoma outcomes in the molecular era: a 12-year single-center experience from Egypt.

Aims: To assess the clinical, pathological and molecular characteristics (Sonic hedgehog and group 3/4 molecular subtypes expression) and treatment modalities for infantile medulloblastoma in correlation with outcomes. Materials & methods: A retrospective study of 86 medulloblastoma patients (≤3 years) was conducted. M0 patients <2.5 years received four cycles of chemotherapy followed by focal radiotherapy (FRT) and chemotherapy. Between 2007 and 2015, Metastatic patients <2.5 years received craniospinal irradiation (CSI) after the end of chemotherapy. After 2015, metastatic patients <2.5 years received CSI postinduction. Results: The hazard ratio for death was significantly higher in the FRT (HR = 2.8) group compared with the CSI group (hazard ratio = 1). Metastatic disease significantly affected the overall survival of the Sonic hedgehog group and the overall survival and event-free survival of group 3/4. Conclusion: Metastatic disease had a significant impact on outcomes. FRT is not effective in treating infantile medulloblastoma.

This study aimed to analyze the management of and prognostic factors affecting the outcomes of 86 young children (<3 years of age at presentation) diagnosed with medulloblastoma, an aggressive brain tumor that is commonly seen in this age group. All children had surgical operations aiming at resecting their tumors, followed by chemotherapy and irradiation. Study results showed that disease disseminated into the nervous system was associated with poorer outcomes compared with localized disease. Administration of local irradiation to the primary tumor site in the brain only, without exposing the spinal cord to radiotherapy, was associated with a higher risk of death.

F18-FET PET in pediatric brain tumors: integrative analysis of image derived parameters and clinico-pathological data.

BACKGROUND: F18-FET PET has an established diagnostic role in adult brain gliomas. In this study we analyzed image derived static and dynamic parameters with available conventional MRI, histological, clinical and follow-up data in assessment of pediatric brain tumor patients at different stages of the disease. METHODS: Forty-four pediatric patients with median age 7 years, diagnosed with brain tumors and underwent forty-seven 18F-FET PET scans either initially (20 scans) or post-therapy (27 scans) were enrolled. Standardized analysis of summed FET PET images early from 10-20 min and late from 30-40 min post-injection were used for static (mean and maximum tumor to brain ratio [TBR] and biological tumor volume [BTV]) parameters evaluation as well as the time activity curve [TAC]. RESULTS: Nineteen out of 20 initially assessed patients had pathologically and/or clinico-radiologically proven neoplastic lesions and one patient had pathologically proven abscess. Receiver operator curve (ROC) marked early TBR max 2.95, early TBR mean 1.76, late TBR max 2.5 and late TBR mean 1.74 as discriminator points with diagnostic accuracy reaching 90% when TBR max was combined with dynamic parameters. Significant association was found between initial FET scans, early and late BTV and event free survival (EFS) (P value=0.042 and 0.005 respectively). In post-therapy assessment, the diagnostic accuracy of conventional MRI was 81.48% when used alone and 96.30% when combined with F18-FET PET scan findings. A cutoff point of 3.2 cm3 for late BTV, in post-therapy scans, was successfully marked as a predictor for therapy response (P value 0.042) and was significantly associated with EFS (P value 0.002). In FET-avid / MRI non-enhancing lesions, early TBR max was able to detect highly malignant processes (high-grade tumors in initial scans and residue/recurrence in post-therapy scans) with 80% sensitivity and 100% specificity when cutoff value of 2.25 was used (P value=0.024). In patients with FET-avid brainstem lesions, whether enhancing or non-enhancing in MRI scans, 81.8% were associated with high risk diagnoses and 68.2% of them were associated with poor therapy outcome. The degree of FET uptake matched tumor-grading, but did not show significant association with OS or EFS (P value>0.05). CONCLUSIONS: F18-FET PET seems to be an evolving pediatric neuro-imaging technique with valuable diagnostic and prognostic information at initial and post-therapy evaluation.

Multiplex ligation-dependent probe amplification versus fluorescent in situ hybridization for screening RB1 copy number variations in Egyptian patients with retinoblastoma.

BACKGROUND: Retinoblastoma (RB) is the most common primary intraocular malignant tumor in children. RB is mostly caused by biallelic mutations in RB1 and occurs in hereditary and non-hereditary forms according to the "two-hit" theory. RB1 mutations comprise point mutations, indels, large deletions, and duplications. Genetic testing is essential for the comprehensive treatment and management of patients with RB. AIM: The aim was to evaluate RB1 copy number variations (CNVs) using MLPA versus FISH assays in group of Egyptian patients with RB. RESULTS: 16.67% showed an RB1 deletion, abnormal methylation status, or both. CONCLUSION: Our results suggested MLPA is a fast, reliable, and powerful method and should be used as a first-line screening tool for detecting RB1 CNVs in patients with RB. Moreover, MLPA is advantageous as it evaluates the methylation status/inactivation of RB1, not possible by FISH.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Ketogenic diet treatment in diffuse intrinsic pontine glioma in children: Retrospective analysis of feasibility, safety, and survival data.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating diseases among children with cancer, thus novel strategies are urgently needed. AIMS: We retrospectively evaluated DIPG patients exposed to the carbohydrate restricted ketogenic diet (KD) with regard of feasibility, safety, and overall survival (OS). METHODS AND RESULTS: Searches of MEDLINE and Embase identified five hits meeting the search criteria (diagnosis of DIPG and exposure to KD). One additional case was identified by contact with experts. Individual patient data were extracted from publications or obtained from investigators. The inclusion criteria for analysis of the data were defined as DIPG patients who were exposed to the KD for ≥3 months. Feasibility, as described in the literature, was the number of patients able to follow the KD for 3 months out of all DIPG patients identified. OS was estimated by the Kaplan-Meier method. Five DIPG patients (males, n = 3; median age 4.4 years; range, 2.5-15 years) meeting the inclusion criteria were identified. Analysis of the available data suggested that the KD is generally relatively well tolerated. Only mild gastro-intestinal complaints, one borderline hypoglycemia (2.4 mmol/L) and one hyperketosis (max 7.2 mmol/L) were observed. Five out of six DIPG patients identified adhered for ≥3 months (median KD duration, 6.5 months; range, 0.25-2 years) to the diet. The median OS was 18.7 months. CONCLUSION: Our study provides evidence that it may be feasible for pediatric DIPG patients to adhere for at least 3 months to KD. In particular cases, diet modifications were done. The clinical outcome and OS appear not to be impacted in a negative way. KD might be proposed as adjuvant therapy when large prospective studies have shown feasibility and safety. Future studies might ideally assess the impact of KD on clinical outcome, quality of life, and efficacy.

Histone H3K27M Mutation Overrides Histological Grading in Pediatric Gliomas.

Pediatric high-grade gliomas (HGG) are rare aggressive tumors that present a prognostic and therapeutic challenge. Diffuse midline glioma, H3K27M-mutant is a new entity introduced to HGG in the latest WHO classification. In this study we evaluated the presence of H3K27M mutation in 105 tumor samples histologically classified into low-grade gliomas (LGG) (n = 45), and HGG (n = 60). Samples were screened for the mutation in histone H3.3 and H3.1 variants to examine its prevalence, prognostic impact, and assess its potential clinical value in limited resource settings. H3K27M mutation was detected in 28 of 105 (26.7%) samples, and its distribution was significantly associated with midline locations (p-value < 0.0001) and HGG (p-value = 0.003). Overall and event- free survival (OS and EFS, respectively) of patients with mutant tumors did not differ significantly, neither according to histologic grade (OS p-value = 0.736, EFS p-value = 0.75) nor across anatomical sites (OS p-value = 0.068, EFS p-value = 0.153). Detection of H3K27M mutation in pediatric gliomas provides more precise risk stratification compared to traditional histopathological techniques. Hence, mutation detection should be pursued in all pediatric gliomas. Meanwhile, focusing on midline LGG can be an alternative in lower-middle-income countries to maximally optimize patients' treatment options.

Investigating fine motor deficits during maintenance therapy in children with acute lymphoblastic leukemia.

OBJECTIVES: Children diagnosed with acute lymphoblastic leukemia (ALL) in their early childhood are more susceptible to neuromuscular and musculoskeletal impairments. This cross-sectional study was designed to address different types of fine motor impairments in Egyptian children diagnosed with ALL. METHODS: Fifty-four children treated for ALL in maintenance phase aged from four to seven years were compared with an age- and sex-matched control group. Fine motor performance was assessed using the total fine motor form of the Bruininks-Oseretsky Test of Motor Proficiency-second edition (BOT-2). Sex- and age-specific norms of BOT-2 were used to calculate scale and standard scores in both groups. RESULTS: Children with ALL had significantly impaired fine motor skills in all subtests and composites of BOT-2 compared with the typically developing group (P < 0.00001). Cumulative doses of vincristine, methotrexate, and dexamethasone revealed no significant correlation with any BOT-2 measure. Males performed significantly better than females in all BOT-2 scores except for the fine motor integration subtest and the total fine motor control composite as no significant differences were observed. The protocol risk stratum, duration of maintenance treatment, and the age at assessment did not significantly affect the BOT-2 measures. CONCLUSION: About 67% of children with ALL on maintenance treatment experienced fine motor difficulties. Periodic evaluation along the course of chemotherapy could identify specific impaired fine motor domains providing the base for a successful rehabilitation program.

Occurrence of high-grade glioma in Noonan syndrome: Report of two cases.

Noonan syndrome (NS) is an autosomal dominant disorder commonly caused by PTPN11 germline mutations. Patients are characterized by short stature, congenital heart defects, facial dysmorphism, and increased risk of malignancies including brain tumors. Commonly associated brain tumors are dysembryoplastic neuroepithelial tumor and low-grade glioma. We report two cases of anaplastic astrocytoma with PTPN11-related NS. We conducted a systematic search of medical databases looking for other reported cases of high-grade glioma associated with NS and identified 24 cases of brain tumors, all of which were low-grade glial or glioneuronal tumors except for one case of medulloblastoma.

Concurrent IDH1 and SMARCB1 Mutations in Pediatric Medulloblastoma: A Case Report.

Isocitrate Dehydrogenase-1 (IDH1) is a driver gene in several cancers including brain tumors such as low-grade and high-grade gliomas. Mutations of SMARCB1 were described in atypical teratoid rhabdoid tumors and to date have not been associated with the pathogenesis of medulloblastoma. We report concurrent IDH1 and SMARCB1 mutations in a medulloblastoma patient. We searched the catalog of somatic mutations in cancer (COSMIC) database and other mutation databases and -to our knowledge- this is the first reported case of medulloblastoma harboring both mutations together. Our patient is a 13-year-old male presenting with headache and vomiting at diagnosis. MRI revealed left cerebellar expansive lesion with no evidence of metastasis. A histopathological diagnosis of desmoplastic/nodular medulloblastoma was made after complete resection of the tumor. Immunophenotypic characterization and methylation profiling suggested a medulloblastoma with SHH activation. Next generation sequencing of a panel of 400 genes revealed heterozygous somatic IDH1(p.R132C), SMARCB1(p.R201Q), and CDH11(p.L625T) mutations. The patient was treated according to the HIT-SIOP PNET 4 protocol. He is in complete remission more than 2 years after diagnosis. In conclusion, increasing use of high throughput sequencing will certainly increase the frequency with which rare mutations or mutation combinations are identified. The exact frequency of this mutation combination and whether it has any particular therapeutic implications or prognostic relevance requires further investigation.

High-grade glioma in very young children: a rare and particular patient population.

In the past years, pediatric high-grade gliomas (HGG) have been the focus of several research articles and reviews, given the recent discoveries on the genetic and molecular levels pointing out a clinico-biological uniqueness of the pediatric population compared to their adult counterparts with HGG. On the other hand, there are only scarce data about HGG in very young children (below 3 years of age at diagnosis) due to their relatively low incidence. However, the few available data suggest further distinction of this very rare subgroup from older children and adults at several levels including their molecular and biological characteristics, their treatment management, as well as their outcome. This review summarizes and discusses the current available knowledge on the epidemiological, neuropathological, genetic and molecular data of this subpopulation. We discuss these findings and differences compared to older patients suffering from the same histologic disease. In addition, we highlight the particular clinical and neuro-radiological findings in this specific subgroup of patients as well as their current management approaches and treatment outcomes.