Treatment of early recurrent medulloblastoma in children with cisplatin and etoposide: a preliminary report

The prognosis of recurrent medulloblastoma remains extremely poor. Combination chemotherapy with cisplatin (CDDP) and etoposide (VP-16) was given to five children with early recurrent medulloblastoma. As a rule, CDDP 20 mg/m² per day and VP-16 60 mg/m² per day were administered intravenously for 5 days. This cycle was repeated three times at 4-week intervals. After this therapy, cerebellar signs improved in one case and were unchanged in four cases. Weakness and sensory disturbance, however, improved in three of four patients. Moreover, neck and/or back pain resolved in all these four. Radiological findings improved in three cases. Myelosuppression appeared in all patients, but receded rapidly. No other significant complications were noticed. Two patients died 5 and 6 months after this therapy. There results seem to suggest that this therapy has a use in improving neurological symptoms, particularly neck and/or back pain, although its efficacy is limited.     

Congenital medulloblastoma: an inquiry into origins

An infant aged 8 h died from cardiorespiratory causes. At autopsy, a microscopic midline cerebellar medulloblastoma was found. Neoplastic cells occurred within the fetal external granular cell layers, with invasion of perivascular spaces as well as the molecular and internal granular cell layers. This extremely rare occurrence lends support to the hypothesis that cerebellar medulloblastoma occurring in older patients originates within retained rests of primitive cells in the fetal external granular cell layer.     

儿童髓母细胞瘤的MRI诊断

目的探讨儿童髓母细胞瘤的MR I表现特点。方法收集经手术证实的髓母细胞瘤22例,其中男13例,女9例,年龄3~13岁。所有病例均行MR I平扫与增强扫描,并对其临床MR I表现进行回顾性分析。结果肿块位于小脑蚓部17例,位于小脑半球2例,位于第四脑室内3例,肿瘤内发生囊变10例。MR I扫描T1W I呈等或稍低信号,T2W I呈等或稍高信号,增强扫描呈中等或明显强化,2例沿脑脊液播散。MR I对儿童髓母细胞瘤的定位准确率为95.5%,定性准确率达90.9%。结论MR I能提供肿瘤浸润的范围、继发改变及其与周围组织的关系,还能够做出明确的定位与定性诊断,此外,MR I还对髓母细胞瘤沿脑脊液种植转移的诊断具有重要诊断价值。     

免疫组织化学标记在儿童髓母细胞瘤分子分型中的应用及其临床意义

目的:探讨免疫组织化学标记在儿童髓母细胞瘤分子分型中应用的可行性,分析分子分型相关蛋白的表达与肿瘤临床病理特点及预后的关系.方法:应用组织芯片技术及免疫组织化学Elivision法检测β-catenin,Gli-1,NPR3及KCNA1在40例儿童髓母细胞瘤中的表达,分析根据表达结果行分子分型的可行性及蛋白表达与年龄、性别、肿瘤部位、病理分型及预后的关系.结果:40例肿瘤组织中β-catenin,Gli-1,NPR3及KCNA1的阳性率分别为10％,55％,50％及30％,Gli-1阳性表达与患儿年龄及病理类型相关(P＞0.05).Kaplan-Meier生存分析提示＜3岁年龄组及Gli-1阳性组患儿预后较差(P＜0.05).Cox比例风险回归分析显示患儿年龄、病理分型、Gli-1蛋白及NPR3蛋白表达是儿童髓母细胞瘤的独立预后因子(P＜0.05).22例髓母细胞瘤(medulloblastoma,MB)行分子分型,其中WNT型4例,SHH型10例,3型6例,4型2例,Kaplan-Meier生存分析提示分子分型与预后无关(P＜0.05).结论:p-catenin核阳或核浆阳可作为WNT型髓母细胞瘤的蛋白标志物,Gli-1表达与患儿年龄及病理学类型密切相关,阳性表达提示患儿预后较差,是独立的预后因子之一,但其表达与NPR3及KCNA1的表达有部分重叠,因此尚需结合SHH型、3型及4型髓母细胞瘤的其它分子检测方法进行准确的分子分型.     

Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis

Background

Medulloblastoma is the most common malignant brain tumor in children. Current standard treatments cure 40%–60% of patients, while the majority of survivors suffer long-term neurological sequelae. The identification of 4 molecular groups of medulloblastoma improved the clinical management with the development of targeted therapies; however, the tumor acquires resistance quickly. Mebendazole (MBZ) has a long safety record as antiparasitic in children and has been recently implicated in inhibition of various tyrosine kinases in vitro. Here, we investigated the efficacy of MBZ in various medulloblastoma subtypes and MBZ''s impact on vascular endothelial growth factor receptor 2 (VEGFR2) and tumor angiogenesis.

Methods

The inhibition of MBZ on VEGFR2 kinase was investigated in an autophosphorylation assay and a cell-free kinase assay. Mice bearing orthotopic PTCH1-mutant medulloblastoma allografts, a group 3 medulloblastoma xenograft, and a PTCH1-mutant medulloblastoma with acquired resistance to the smoothened inhibitor vismodegib were treated with MBZ. The survival benefit and the impact on tumor angiogenesis and VEGFR2 kinase function were analyzed.

Results

We determined that MBZ interferes with VEGFR2 kinase by competing with ATP. MBZ selectively inhibited tumor angiogenesis but not the normal brain vasculatures in orthotopic medulloblastoma models and suppressed VEGFR2 kinase in vivo. MBZ significantly extended the survival of medulloblastoma models derived from different molecular backgrounds.

Conclusion

Our findings support testing of MBZ as a possible low-toxicity therapy for medulloblastomas of various molecular subtypes, including tumors with acquired vismodegib resistance. Its antitumor mechanism may be partially explained by inhibition of tumor angiogenesis.     

Papilledema and Infiltrative Optic Neuropathy as Presenting Signs of Medulloblastoma

This report demonstrates that bilateral papilledema and infiltrative optic neuropathy can be the only initial presenting signs of a medulloblastoma. A 23-year-old man had no cerebellar signs and no lesions on MRI to suggest such a tumor. His cerebrospinal fluid cytology was inconclusive. Progression of his disease was so rapid that postmortem biopsy of the affected optic nerves and cerebellum with immunohistochemical staining for neuronal marker proteins established the diagnosis of disseminated medulloblastoma. Disseminated medulloblastoma has a poor prognosis especially when tumor cells spread to the optic nerves.