BackgroundRhabdomyosarcoma (RMS) is the most commonly diagnosed malignant soft tissue tumour in children and adolescents. Aberrant expression of Anaplastic Lymphoma Kinase (ALK) and MET gene has been implicated in the malignant progression of RMS, especially in the alveolar subtype. This observation suggests that crizotinib (PF-02341066), a kinase inhibitor against ALK and MET, may have a therapeutic role in RMS, although its antitumour activity in this malignancy has not yet been studied.MethodsRH4 and RH30 alveolar RMS (ARMS) cell lines were treated with crizotinib and then assessed by using proliferation, viability, migration and colony formation assays. Multiple approaches, including flow cytometry, immunofluorescence, western blotting and siRNA-based knock-down, were used in order to investigate possible molecular mechanisms linked to crizotinib activity.ResultsIn vitro treatment with crizotinib inhibited ALK and MET proteins, as well as Insulin-like Growth Factor 1 Receptor (IGF1R), with a concomitant robust dephosphorylation of AKT and ERK, two downstream kinases involved in RMS cell proliferation and survival. Exposure to crizotinib impaired cell growth, and accumulation at G2/M phase was attributed to an altered expression and activation of checkpoint regulators, such as Cyclin B1 and Cdc2. Crizotinib was able to induce apoptosis and autophagy in a dose-dependent manner, as shown by caspase-3 activation/PARP proteolytic cleavage down-regulation and by LC3 activation/p62 down-regulation, respectively. The accumulation of reactive oxygen species (ROS) seemed to contribute to crizotinib effects in RH4 and RH30 cells. Moreover, crizotinib-treated RH4 and RH30 cells exhibited a decreased migratory/invasive capacity and clonogenic potential.ConclusionsThese results provide a further insight into the molecular mechanisms affected by crizotinib in ARMS cells inferring that it could be a useful therapeutic tool in ARMS cancer treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0228-4) contains supplementary material, which is available to authorized users.

Post-operative pediatric cerebellar mutism syndrome (PPCMS) is a clinical syndrome arising from cerebellar injury and characterized by absence of speech and other possible symptoms and signs. Rare reports described some benefit after administration of dopamine agonist therapy, but no treatment has proven efficacy. In this paper, we report on the dramatic, sudden resolution of PPCMS induced by midazolam administration in a boy who underwent posterior fossa surgery for choroid plexus papilloma of the fourth ventricle. In addition to clinical improvement, post-midazolam single-photon emission computed tomography also demonstrated amelioration of brain perfusion.

A 26-year-old pregnant woman with a fast-growing malignant deep-seated brain glioma was offered a therapeutic abortion to allow subsequent surgical resection. This option was refused by the mother, but the fast tumor growth placed the life of both mother and child at risk. A staged CyberKnife radiosurgery treatment was then planned, aiming to provide at least temporary tumor growth control and allow a safe delivery while keeping the doses received by the fetus well below the allowed doses. Growth control and the safe delivery of a healthy child were achieved after this first treatment. An intensive chemotherapy program based on the combination of Avastin, irinotecan, and Temodal was then started. Recurring tumor growth was treated with a second CyberKnife procedure while continuing the above chemotherapy protocol. At 43 months after the second CyberKnife procedure, the tumor had disappeared on magnetic resonance imaging. Neither mother nor child showed the neurological sequelae.Staged radiosurgery and deferred chemotherapy proved to be a safe and effective treatment to allow the delivery of a healthy child and the long-term control of an aggressive brain glioma.

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