Magnetic resonance imaging spectrum of medulloblastoma.

INTRODUCTION: Two medulloblastoma variants were recently added to the WHO classification of CNS tumours. We retrospectively analysed the imaging findings of 37 classic and 27 cases of variant medulloblastomas to identify imaging characteristics that might suggest a particular MB subtype. METHODS: Sixty-four patients from three institutions were included. Location, tumour margins, signal intensities on conventional MRI, enhancement pattern, the presence of haemorrhage, calcifications and hydrocephalus were recorded and analysed. Signal characteristics on diffusion-weighted MR images and MR spectra were evaluated when available. RESULTS: Thirty-seven classic type of MB (CMB), twelve cases of desmoplastic/nodular medulloblastoma (DMB), nine medulloblastomas with extensive nodularity (MB-EN), five cases of anaplastic and one of large-cell medulloblastoma were included. Fifty of 64 tumours were located in the 4th ventricle region. On T2WI, CMB were all hyperintense, whereas DMB and MB-EN showed isointensity in up to 66%. One third of the classic MB showed only subtle marginal or linear enhancement. All medulloblastoma variants showed marked enhancement. CONCLUSION: The results of our study suggest: (a) an age-dependent distribution of MB variants, with DMB and MB-EN more common in younger children; (b) a female predominance in DMB; (c) a more common off-midline location in DMB (50%) and MB-EN (33%) variants.

Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study.

BACKGROUND: Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication. OBJECTIVE: We describe the design of the PanCareLIFE consortium's work packages that address the genetic susceptibility of platinum-induced ototoxicity. METHODS: As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening. RESULTS: This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020. CONCLUSIONS: Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11868.

Cerebellar medullomyoblastoma with melanotic tubular structures.

This report describes a midline cerebellar primitive neuroectodermal tumor with muscular differentiation, that is, medullomyoblastoma with melanotic tubular structures, which developed in the cerebellar vermis in a 23-month-old male. Rhabdomyoblastic differentiation consisted both of striated muscle fibers and undifferentiated cells showing immunoreactivity for desmin and myogenic transcription factors. The presence of melanotic epithelial structures raised the issue of a teratomatous tumor. This case demonstrates the occurrence of this very rare tumor in early childhood as well as the utility of a careful search for the presence of myogenic and/or melanotic features in medulloblastomas.

Stereotactically guided conformal radiotherapy for progressive low-grade gliomas of childhood.

PURPOSE: To describe the rationale, technique, and early results of stereotactically guided conformal radiotherapy (SCRT) in the treatment of progressive or inoperable low-grade gliomas (LGGs) of childhood. METHODS AND MATERIALS: Between September 1994 and May 1999, 14 children (median age 6 years, range 5-16) with LGG were treated with SCRT at the Royal Marsden NHS Trust. Tumors were located at the optic chiasm (n = 9), third ventricle (n = 2), hypothalamus, craniocervical junction, and pineal region (each n = 1). Four patients received chemotherapy before SCRT. Immobilization was in a Gill-Thomas-Cosman frame (n = 12) and subsequently in a specially designed pediatric version of the frame (n = 2). Stereotactic coordinates and the tumor were defined by CT scanning with a fiducial system and MRI fusion. The median tumor volume was 19.5 cm(3) (range 7.5-180). The planning target volume was defined as the area of enhancing tumor plus a 5-10-mm margin. The treatment technique consisted of 4 isocentric, noncoplanar, conformal, fixed fields. Treatment was delivered in 30-33 daily fractions to a total dose of 50-55 Gy. RESULTS: SCRT was well tolerated, with transient hair loss the only acute toxicity. The median follow-up was 33 months (range 2-53). At 6 months after SCRT, 4 of 12 children with neurologic deficits improved and 5 remained stable. Twelve children were available for MRI evaluation. Two had a complete response, 6 a partial response, and 4 stable disease. One child with optic chiasm glioma had local progression at 25 months, and 1 developed diffuse leptomeningeal disease without local progression at 27 months. The 3-year local progression-free survival and overall survival rate after SCRT was 87% and 100%, respectively, compared with 89% and 98% for an historic control treated with conventional RT. New endocrine deficiencies were noted in 2 children after a follow-up of 20 and 23 months. CONCLUSION: SCRT is a feasible, high-precision technique of RT for children with LGGs for whom RT is considered appropriate. The local control and acute toxicity of SCRT are comparable to a historic control of patients with conventionally delivered RT. The frequency of delayed hypothalamic-pituitary axis dysfunction reflects tumor location adjacent to the hypothalamus and pituitary. Additional follow-up is required to demonstrate that SCRT contributes to a reduction in treatment-related late toxicity, while maintaining the local control achieved with conventionally delivered RT in children with progressive LGGs.

Congenital multifocal rhabdoid tumor: a case with peculiar biological behavior and different response to treatment according to location (central nervous system and kidney).

Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system and malignant rhabdoid tumor of the kidney (MRTK) may present with different responses to chemotherapy and outcomes. We describe the case of an infant with multifocal rhabdoid tumor with different behavior and response to treatment, depending on the anatomic site.

Claudin-6 is of limited sensitivity and specificity for the diagnosis of atypical teratoid/rhabdoid tumors.

Recent gene expression microarray analyses have indicated that claudin-6 is specifically expressed in atypical teratoid rhabdoid tumors (AT/RTs), suggesting a role as a positive diagnostic marker in addition to SMARCB1 (INI1) loss, which is encountered in the majority of AT/RTs. In order to investigate the potential of claudin-6 as a diagnostic marker, expression was investigated in 59 AT/RTs and 60 other primary central nervous system (CNS) tumors, including primitive neuroectodermal tumors, medulloblastomas, choroid plexus tumors, and both pediatric and adult low- and high-grade gliomas using immunohistochemistry. Claudin-6 was expressed in 17/59 AT/RTs (29%), but also in a variety of other primary CNS tumors, including 60% of medulloblastomas and 21% of malignant gliomas. Even though high staining scores (2+ or 3+) were more often encountered in AT/RTs (Chi-square 4.177; P=0.041), the overall frequency of claudin-6 staining was not significantly higher in AT/RTs as compared with the other tumors (17/59 vs. 16/60; Chi-square=0.328; P=0.567). In a subgroup of 43 AT/RT patients, of which follow-up data were available, claudin-6 expression did not show any correlation with survival. In conclusion, claudin-6 immunohistochemistry is of limited sensitivity and specificity for the diagnosis of AT/RT and does not correlate with clinical behavior.

Subtype-specific expression and genetic alterations of the chemokinereceptor gene CXCR4 in medulloblastomas.

Recent findings indicate that the chemokine receptor Cxcr4 is essential for normal development of the cerebellar cortex. As medulloblastomas (MBs), the most common malignant brain tumors of childhood, are believed to arise from neuronal cerebellar precursors, we asked whether there is a potential role for Cxcr4 in the pathogenesis of MB. RT-PCR and immunohistochemistry revealed expression of Cxcr4 in different variants of MBs. Whereas 18/20 classic MBs showed very low levels of CXCR4 mRNA, high amounts were expressed in 17/18 desmoplastic and 6/7 extensively nodular MBs. In addition, a significant correlation of high CXCR4 mRNA levels and presence of the neurotrophin receptor p75NTR or expression of ATOH1 and GLI1 suggests that CXCR4 is a reliable marker for tumors derived from the cerebellar external granular layer. Because Cxcr4 is important for migration and cell cycle control of granular precursors, we screened for mutations in the coding region by SSCP and gene sequencing. In a series of 90 MBs and 8 MB cell lines, we found one germline and one somatic mutation resulting in amino acid substitutions in the first (Ile53Leu) and second (Asp97Asn) transmembrane regions, respectively. These data suggest that Cxcr4 may be involved in the pathogenesis of MBs.