Kieren Allinson

18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.

The extent to which the tau tracer [18F]AV-1451 can differentiate between tauopathies is unknown. By comparing patients with Alzheimer’s disease and progressive supranuclear palsy (PSP), Passamonti et al. show that [18F]AV-1451 displays greater specificity for Alzheimer-related tau pathology than PSP-related pathology. A machine learning algorithm correctly diagnosed 94% of cases.

[18F]AV-1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation

The validation of tau radioligands could improve the diagnosis of frontotemporal lobar degeneration and the assessment of disease‐modifying therapies. Here, we demonstrate that binding of the tau radioligand [18F]AV‐1451 was significantly abnormal in both magnitude and distribution in a patient with familial frontotemporal dementia due to a MAPT 10 + 16C>T gene mutation, recapitulating the pattern of neuropathology seen in her father. Given the genetic diagnosis and the non‐Alzheimers pathology, these findings suggest that [18F]AV‐1451 might be a useful biomarker in primary tauopathies. Largerscale in vivo and post‐mortem studies will be needed to assess the techniques specificity.

The genome of the sparganosis tapeworm Spirometra erinaceieuropaei isolated from the biopsy of a migrating brain lesion.

BackgroundSparganosis is an infection with a larval Diphyllobothriidea tapeworm. From a rare cerebral case presented at a clinic in the UK, DNA was recovered from a biopsy sample and used to determine the causative species as Spirometra erinaceieuropaei through sequencing of the cox1 gene. From the same DNA, we have produced a draft genome, the first of its kind for this species, and used it to perform a comparative genomics analysis and to investigate known and potential tapeworm drug targets in this tapeworm.ResultsThe 1.26 Gb draft genome of S. erinaceieuropaei is currently the largest reported for any flatworm. Through investigation of β-tubulin genes, we predict that S. erinaceieuropaei larvae are insensitive to the tapeworm drug albendazole. We find that many putative tapeworm drug targets are also present in S. erinaceieuropaei, allowing possible cross application of new drugs. In comparison to other sequenced tapeworm species we observe expansion of protease classes, and of Kuntiz-type protease inhibitors. Expanded gene families in this tapeworm also include those that are involved in processes that add post-translational diversity to the protein landscape, intracellular transport, transcriptional regulation and detoxification.ConclusionsThe S. erinaceieuropaei genome begins to give us insight into an order of tapeworms previously uncharacterized at the genome-wide level. From a single clinical case we have begun to sketch a picture of the characteristics of these organisms. Finally, our work represents a significant technological achievement as we present a draft genome sequence of a rare tapeworm, and from a small amount of starting material.

Less Invasive Phenotype Found in Isocitrate Dehydrogenase-mutated Glioblastomas than in Isocitrate Dehydrogenase Wild-Type Glioblastomas: A Diffusion-Tensor Imaging Study

Purpose To explore the diffusion-tensor (DT) imaging-defined invasive phenotypes of both isocitrate dehydrogenase (IDH-1)-mutated and IDH-1 wild-type glioblastomas. Materials and Methods Seventy patients with glioblastoma were prospectively recruited and imaged preoperatively. All patients provided signed consent, and the local research ethics committee approved the study. Patients underwent surgical resection, and tumor samples underwent immunohistochemistry for IDH-1 R132H mutations. DT imaging data were coregistered to the anatomic magnetic resonance study and reconstructed to provide the anisotropic and isotropic components of the DT. The invasive phenotype was determined by using previously published criteria and correlated with IDH-1 mutation status by using the Freeman-Halton extension of the Fisher exact probability test. Results Nine patients had an IDH-1 mutation and 61 had IDH-1 wild type. All of the patients with IDH-1 mutation had a minimally invasive DT imaging phenotype. Among the IDH-1 wild-type tumors, 42 of 61 (69%) were diffusively invasive glioblastomas, 14 of 61 (23%) were locally invasive, and five of 61 (8%) were minimally invasive (P < .001). Conclusion IDH-mutated glioblastomas have a less invasive phenotype compared with IDH wild type. This finding may have implications for individualizing the extent of surgical resection and radiation therapy volumes.

Local alkylating chemotherapy applied immediately after 5-ALA guided resection of glioblastoma does not provide additional benefit

Grade IV glioma is the most common and aggressive primary brain tumour. Gross total resection with 5-aminolevulinic acid (5-ALA) guided surgery combined with local chemotherapy (carmustine wafers) is an attractive treatment strategy in these patients. No previous studies have examined the benefit carmustine wafers in a treatment programme of 5-ALA guided resection followed by a temozolomide-based chemoradiotherapy protocol. The objective of this study was to examine the benefit of carmustine wafers on survival in patients undergoing 5-ALA guided resection. A retrospective cohort study of 260 patients who underwent 5-ALA resection of confirmed WHO 2007 Grade IV glioma between July 2009 and December 2014. Survival curves were calculated using the Kaplan–Meier method from surgery. The log-rank test was used to compare survival curves between groups. Cox regression was performed to identify variables predicting survival. A propensity score matched analysis was used to compare survival between patients who did and did not receive carmustine wafers while controlling for baseline characteristics. Propensity matched analysis showed no significant survival benefit of insertion of carmustine wafers over 5-ALA resection alone (HR 0.97 [0.68–1.26], p = 0.836). There was a trend to higher incidence of wound infection in those who received carmustine wafers (15.4 vs. 7.1%, p = 0.064). The Cox regression analysis showed that intraoperative residual fluorescent tumour and residual enhancing tumour on post-operative MRI were significantly predictive of reduced survival. Carmustine wafers have no added benefit following 5-ALA guided resection. Residual fluorescence and residual enhancing disease following resection have a negative impact on survival.

Cerebral Metastasis of a Malignant Pleural Mesothelioma: A Case Report and Review of the Literature.

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignant neoplasm that was thought to be a localised disease with limited metastatic capability. However, recent post-mortem studies have identified metastases to the central nervous system (CNS) in about 3% of cases. Case Description: We present the case of a 65-year-old with a solitary supratentorial metastatic deposit of MPM treated with surgical resection and adjuvant whole brain radiotherapy. Despite a good surgical outcome with symptomatic recovery, the patient died of cardiopulmonary compromise five months postoperatively. Conclusions: Although rare, CNS metastasis of MPM is a condition that neurosurgeons should be aware of. CNS metastases may occur via three distinct mechanisms, namely perineural spread, leptomeningeal carcinomatosis and, most commonly, haematogenous spread leading to parenchymal deposits. Surgical resection of these deposits can lead to symptomatic improvement, and together with radiotherapy, to local disease control. However, the overall survival remains poor.

Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma

Aberrant genetic and epigenetic variations drive malignant transformation and are hallmarks of cancer. Using PCR-free sample preparation we achieved the first in-depth whole genome (hydroxyl)-methylcytosine, single-base-resolution maps from a glioblastoma tumour/margin sample of a patient. Our data provide new insights into how genetic and epigenetic variations are interrelated. In the tumour, global hypermethylation with a depletion of 5-hydroxymethylcytosine was observed. The majority of single nucleotide variations were identified as cytosine-to-thymine deamination products within CpG context, where cytosine was preferentially methylated in the margin. Notably, we observe that cells neighbouring tumour cells display epigenetic alterations characteristic of the tumour itself although genetically they appear “normal”. This shows the potential transfer of epigenetic information between cells that contributes to the intratumour heterogeneity of glioblastoma. Together, our reference (epi)-genome provides a human model system for future studies that aim to explore the link between genetic and epigenetic variations in cancer progression.

Slowly progressive behavioural presentation in two UK cases with the R406W MAPT mutation.

Mutations in the gene encoding microtubule-associated protein tau (MAPT) are associated with neurodegeneration characterized by the accumulation of taupositive intracellular inclusion bodies and manifest clinically as frontotemporal dementia (FTD), with variations in clinical phenotype arising due to differences in the location of the mutation (eg intronic versus exonic) and the topographical distribution of the associated neuronal loss. The R406W MAPT mutation is typically associated with a slowly progressive memory decline clinically similar to that associated with typical Alzheimer’s disease [1-8] with symmetrical frontotemporal atrophy observed on MRI [9]. Here we report the first UK cases of the R406W mutation in two unrelated patients with familial FTD, who present with a hitherto-undescribed clinico-radiological phenotype in the form of a slowly progressive behavioural disorder associated with predominantly rightsided temporal lobe atrophy.

Concomitant Primary CNS Lymphoma and FSH-Pituitary Adenoma Arising Within the Sella. Entirely Coincidental?

Abstract BACKGROUND AND IMPORTANCE: Collision tumors are the simultaneous occurrence of more than one type of neoplasm within an anatomic space. In the pituitary sella, collision tumors are exceedingly rare, and not much is known about their etiology and prognosis. CLINICAL PRESENTATION: A 74-year-old man presented with a concomitant primary pituitary lymphoma (diffuse large B-cell non-Hodgkins lymphoma; DLBCL) and follicle-stimulating hormone (FSH)-adenoma diagnosed histologically after clinical features of apoplexy prompted urgent surgical decompression and resection. Strong immunoreactivity for FSH by the lymphoma was evident. Full-body workup demonstrated no other source for the lymphoma. He subsequently underwent 4 cycles of chemotherapy and has been in remission for over 32 months. His ophthalmoplegia at presentation persisted with no further deficits. CONCLUSIONS: Four cases of collision tumors of primary pituitary lymphoma and adenoma have previously been reported. This case represents the first combination of an FSH-adenoma and a DLBCL in the literature. Prompt involvement of the hematology-oncology team contributed to the good outcome seen in this case. The putative role played by pituitary hormones in tumorigenesis is reviewed in this case report. The association is either a chance occurrence or due to the induction of lymphoma cell proliferation by the binding of FSH produced by the adenoma to the FSH receptors on the lymphoma cells.

An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures.

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.