Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model.

BACKGROUND: The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood-brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). MATERIALS AND METHODS: The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls. RESULTS: Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P<0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination. CONCLUSION: CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic.

Sudden unexpected death from an undiagnosed histiocytic sarcoma in an adolescent female.

A previously well 15-year-old female who was awaiting medical investigations for a proptosed right eye collapsed and died suddenly while walking. Postmortem examination revealed diffuse distortion and infiltration of multiple organs by a suspected neoplastic process. Histology confirmed the invasion of multiple organs by atypical cells and myocardial infiltration was the likely cause of death. An extensive panel of immunohistochemistry established the diagnosis of a histiocytic sarcoma. Sudden unexpected death due to a clinically undiagnosed neoplasia in childhood and adolescence is uncommon. This is the first report of a histiocytic sarcoma causing sudden unexpected death and highlights the importance of considering undiagnosed hematological malignancies when examining a case of sudden death at postmortem.

Diagnostic challenges of primary thalamic gliomas-identification of a minimally enhancing neuroradiological subtype with aggressive neuropathology and poor clinical outcome.

AIM: To evaluate neuropathology and neuroradiology in the diagnosis and clinical outcome of a retrospective cohort of thalamic gliomas. METHODS: Neuropathological and neuroradiological review was undertaken in 25 cases of radiologically suspected thalamic glioma (excluding childhood pilocytic astrocytoma) over an 8 year period (2004-2012) at Frenchay Hospital and compared to the clinical outcome. RESULTS: In 12/25 (48%) there was a difference in neuropathological and suspected neuroradiological grading of the lesion of one or more grades. In 5/12 (42%) cases, the neuroradiology was lower grade than the pathology. In 4/5 (80%) of these cases, we identified a minimally enhancing subtype where the neuroradiology was predicted to be of lower grade than neuropathology. In 4/12, (33%) the suspected neuroradiology grade was higher than the final pathology. In 3/4, (75%) of these cases the suspected neuroradiology grade was higher than the neuropathology possibly because of unusual differentiation within the thalamic glioma (central neurocytoma, anaplastic oligoastrocytoma, and diffuse astrocytoma with pilocytic features). In 3/12 (25%) the biopsy was non-diagnostic. Neuropathology was a better predictor of clinical outcome than neuroradiology. 9/10 (90%) WHO Grade 4 gliomas and 8/9 (88%) Grade 3 gliomas on neuropathology were dead between 3-7 years after diagnosis. 3/3 (100%) Grade 2 gliomas on neuropathology were alive 3-7 years after diagnosis. 2/3 (67%) of the non-diagnostic cases were alive 3-7 years after biopsy. In 1/3 (33%) of the non-diagnostic cases the outcome was unknown. CONCLUSIONS: Diagnosis of primary thalamic glioma is challenging. We have identified that in the thalamus, a pattern of diffuse infiltration with minimal enhancement on imaging may often represent high-grade glioma. Neuropathology is overall the best predictor of clinical outcome.

A 29-year-old female with progressive myoclonus and cognitive decline.

Myoclonic epilepsy with red ragged fibres (MERRF) is a rare mitochondrial disorder presenting with progressive myoclonus, epilepsy, and cognitive decline. Here, the authors present a case of a 29-year-old lady presenting with myoclonus and describe the subsequent investigations that led to a diagnosis of MERRF. In addition, we examine her cognitive decline over a 9-year period, demonstrating a feature commonly seen in mitochondrial cytopathies.

IDH mutation analysis in gliomas as a diagnostic and prognostic biomarker.

INTRODUCTION: There is a high rate of IDH1/2 mutations in low grade gliomas and in high grade gliomas deriving from them. IDH analysis of gliomas is a novel method of classification and an independent prognostic marker. We compared antibody and sequencing methods for the detection of IDH mutations. METHOD: 88 samples from 74 patients were identified. For immunohistochemistry: sections were stained with anti-IDH1R132H antibody. For sequencing: DNA was extracted from fresh, frozen tissue. RESULTS: 28% (20/71) of cases were positive for the R132H IDH1 mutation by antibody. An IDH1 mutation was detected by molecular genetics in 37% (21/57) of cases and no IDH2 mutations were detected. 24% (5/21) had rare IDH1 mutations not detected by immunohistochemistry. Where sufficient tissue was available, immunohistochemistry and DNA analysis were fully concordant for the p.Arg132His mutation. Both Grade II gliomas and anaplastic astrocytomas showed a statistically different distribution of IDH1 mutation load compared to GBMs (p < 0.0001; p = 0.0021 respectively). CONCLUSION: A rationalised combined approach involving R132H antibody testing and sequencing of negative cases would be ideal for the detection of IDH1 mutations--antibody testing is cheaper than sequencing but sequencing demonstrates rare IDH1 mutations not detected by immunohistochemistry.

Thrombus formation in a dilated torcula following aneurysmal subarachnoid haemorrhage.

A case of thrombus formation occurring within a dilation of the dural venous sinuses following aneurysmal sub-arachnoid haemorrhage is presented. Acute neurological deterioration accompanied propagation of the thrombus. The patient was anticoagulated on day 5 post-SAH with no haemorrhagic complications and made a full recovery. The optimum time to commence anticoagulation is not clear and is discussed.