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MGMT promoter methylation is related to the increased sensitivity of tumour tissue to chemotherapy with temozolomide (TMZ) and thus to improved patient survival. However, it is unclear how the extent of MGMT promoter methylation affects outcomes. In our study, a single-centre retrospective study, we explore the impact of MGMT promoter methylation in patients with glioblastoma who were operated upon with 5-ALA. Demographic, clinical and histology data, and survival rates were assessed. A total of 69 patients formed the study group (mean age 53.75 ± 15.51 years old). Positive 5-ALA fluorescence was noted in 79.41%. A higher percentage of MGMT promoter methylation was related to lower preoperative tumour volume (p = 0.003), a lower likelihood of 5-ALA positive fluorescence (p = 0.041) and a larger extent of resection EoR (p = 0.041). A higher MGMT promoter methylation rate was also related to improved progression-free survival (PFS) and overall survival (OS) (p = 0.008 and p = 0.006, respectively), even when adjusted for the extent of resection (p = 0.034 and p = 0.042, respectively). A higher number of adjuvant chemotherapy cycles was also related to longer PFS and OS (p = 0.049 and p = 0.030, respectively). Therefore, this study suggests MGMT promoter methylation should be considered as a continuous variable. It is a prognostic factor that goes beyond sensitivity to chemotherapy treatment, as a higher percentage of methylation is related not only to increased EoR and increased PFS and OS, but also to lower tumour volume at presentation and a lower likelihood of 5-ALA fluorescence intraoperatively.

Background In the management of meningiomas, single-fraction stereotactic radiosurgery (SRS) is an established alternative treatment to surgical resection. However, its effects on tumorigenesis and malignant transformation are still uncertain. Case Description We have described a grade II parafalcine meningioma that was initially surgically resected (Simpson 2 clearance) and then managed with a single dose of SRS on recurrence. The tumor recurred again 7 years later, with histological features of a grade III rhabdoid–papillary lesion, with local brain invasion. Conclusion To the best of our knowledge, this is the first report to describe malignant transformation of a grade II to grade III meningioma after SRS to date.

Purpose: The 2016 WHO tumour classification highlights the role of IDH1/2 gene mutation and 1p/19q co-deletion in classifying grade II/III gliomas. A recent cIMPACT-NOW update proposes the use of t...

Traumatic (crush) asphyxia is a rare condition caused by severe compression of the chest and trunk leading to often extreme so-called asphyxial signs, including cyanosis in head and neck regions, multiple petechiae, and subconjunctival haemorrhage as well as neurological manifestations. Aims To investigate the neuropathology and brain weight in traumatic asphyxia caused by different accidents such as industrial accidents and road traffic collision. Material and Methods Post mortem records of 20 cases of traumatic asphyxia (TA) resulting from different causes of which four brains are available for comprehensive neuropathological examination. The expected brain weights for given body height and associated 95% confidence range were calculated according to the following formula: baseline brain weight (BBW) + body height x rate (g/cm). The 95% confidence range was calculated by adding and subtracting the standard error (SE) x 1.96 (7–8). Results There was a trend for higher brain weight in the TA cohort but it was not significant (1494 g vs 1404 g, p = 0.1). The upper limits of the brain weight of 95% confidence was 1680 g vs 1660 g, p = 0.9. The neuropathological examination of four available brains from the TA cohort showed severe congestion of blood vessels, perivascular haemorrhages and occasional βAPP deposits consistent with early axonal disruption. Conclusion Brain examination is informative as part of investigation of TA. Developing ischaemic changes and an increase in brain weight are the most likely indicators of a prolonged period of patient's survival.

Pseudoprogression (PsP) is a treatment-related phenomenon which hinders response interpretation. Its prevalence and clinical impact have not been evaluated in children/adolescents. We assessed the characteristics, risk factors and prognosis of PsP in children/adolescents and young-adults diagnosed with non-brainstem high grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). Patients aged 1-21 years diagnosed with HGG or DIPG between 1995 and 2012 who had completed radiotherapy were eligible. PsP was assessed according to study-specific criteria and correlated with first-line treatment, molecular biomarkers and survival. Ninety-one patients (47 HGG, 44 DIPG) were evaluable. Median age: 10 years (range, 2-20). Eleven episodes of PsP were observed in 10 patients (4 HGG, 6 DIPG). Rates of PsP: 8.5 % (HGG); 13.6 % (DIPG). Two episodes of PsP were based on clinical findings alone; nine episodes had concurrent radiological changes: increased size of lesions (n = 5), new focal enhancement (n = 4). Temozolomide, MGMT methylation or H3F3A mutations were not found to be associated with increased occurrence of PsP. For HGG, 1-year progression-free survival (PFS) was 41.9 % no-PsP versus 100 % PsP (p = 0.041); differences in 1-year overall survival (OS) were not significant. For DIPG, differences in 1-year PFS and OS were not statistically significant. Hazard ratio (95 %CI) of PsP for OS was 0.551 (0.168-1.803; p = 0.325) in HGG; and 0.308 (0.107-0.882; p = 0.028) in DIPG. PsP occurred in both pediatric HGG and DIPG patients at a comparable rate to adult HGG. PsP was associated with improved 1-yr PFS in HGG patients. PsP had a protective effect upon OS in DIPG patients.

Background: Primary CNS malignant rhabdoid tumors are very rare in adults and much less is known about their biological behavior than in children. Recently, two adult cases of SMARCB1 (also known as INI1)-deficient tumor with rhabdoid cells have been described, suggesting an emerging group of primary meningeal SMARCB1-deficient tumors. We have recently encountered a case of INI1-deficient tumor with similar histology and immunophenotype to the above cases, but with a superficial cerebral, yet apparent intra-axial origin. Case Description: A 22-year-old woman presented with approximately one year history of focal sensorimotor right upper limb seizures and recently developed a slowly progressive weakness in her right hand. An MRI of the brain demonstrated an avidly enhancing lesion centered on the left perirolandic region with no definite dural involvement. The patient underwent a complete surgical excision. Histology revealed a tumor with monotonous epithelioid and spindle-shaped cells in a mucoid/myxoid background. There was focal mitotic activity and a few necrotic areas, in addition to many rhabdoid cells. The immunohistochemistry was negative for INI1 and there was strong positivity with CD34, while focal smooth muscle actin (SMA) and epithelial membrane antigen (EMA) immunoreactivity were also noted. Conclusions: As an addition to the two cases of adult SMARCB1-deficient tumors recently described, we present a further adult case with a similar immunohistochemical profile but with an apparent intra-axial origin, questioning the necessary meningeal origin of this type of tumor. The prognosis of this adult INI1/SMARCB1-deficient tumor is to be determined, but may be better than the pediatric atypical/teratoid tumor (AT/RT).

An unusual multinodular and vacuolating neuronal tumour (MVNT) has been described in the cerebral hemispheres of ten patients with adult-onset seizures. We report the findings in two cases with similar features, a surgical resection and the other an autopsy specimen. Case 1, a 34-year-old female, underwent surgical resection for a multinodular non-enhancing frontal white matter lesion causing intractable epilepsy. Case 2, presented with motor neurone disease (MND) at the age of 71 and MRI scanning revealed extensive multinodular non-enhancing white matter lesions in the temporal lobe. There was no history of epilepsy and post mortem histology confirmed MND. Macroscopically multiple small grey well-formed, discrete and coalescent nodules were seen in the deep cortex and subcortical white matter. On histology, mature-looking neurons with large cytoplasmic vacuoles were distributed in a fibrillary background, where vacuoles were also noted. In the resected tumour scattered oligodendroglia-like cells were present. No ganglion cells were seen. The vacuolated cells exhibited immunopositivity for synaptophysin, HuC/HuD and p62 but were negative for NeuN, neurofilament, GFAP, IDH1, nestin and CD34. Electron microscopy showed non-membrane bound cytoplasmic vacuoles in the neurons and in some neuronal processes. The seizures recurred in Case 1. Some clinicopathological features of this lesion suggest a possible relationship with dysembryoplastic neuroepithelial tumour (DNT) although the morphological features are not typical of DNT. Case 2 demonstrates that MVNT may remain asymptomatic.

Background: MGMT methylation, along with 1p/19q co-deletion and IDH1 mutation, is an important biomarker in high grade gliomas. MGMT methylation indicates an improved response to temozolomide chemotherapy; patients with 1p/19q co-deleted anaplastic oligodendrogliomas benefit preferentially from adjuvant chemotherapy. Pyrosequencing is a method that allows the level of MGMT methylation to be measured in a quantitative manner. Aim: To compare the mean MGMT promoter methylation level of high grade gliomas and correlate it with other clinical parameters and markers including 1p/19q co-deletion and mutation to IDH1or IDH2. Methods: Pyrosequencing was used to quantitatively detect the level of MGMT promoter methylation for 171 high grade gliomas mutations to IDH1 and IDH2 genes were also detected by pyrosequencing, or immunohistochemistry (n=166). Screening for 1p/19q deletion was by fluorescence in situ hybridisation (n=46). Statistical analysis was performed using R-Stats v2.15.2. Results: Higher methylation was correlated with lower grade and mutation to either IDH1 or IDH2 (27.0% vs. 16.6% p = 0.008; and 27.5 vs. 16.1 p = 0.002 respectively). 1p/19q co-deletion versus non co-deletion was associated with a particularly high level of methylation (42.2% vs. 17.7% p = 0.001). No significant differences were seen for age or gender. Conclusions: The results offer a potential explanation for the improved prognosis seen in glioma patients with 1p/19q co-deletion.

Glioblastoma multiforme with an oligodendroglial component (GBMO) has been recognized in the World Health Organization classification-however, the diagnostic criteria, molecular biology, and clinical outcome of primary GBMO remain unclear. Our aim was to investigate whether primary GBMO is a distinct clinicopathological subgroup of GBM and to determine the relative frequency of prognostic markers such as loss of heterozygosity (LOH) on 1p and/or 19q, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation.We examined 288 cases of primary GBM and assessed the molecular markers in 57 GBMO and 50 cases of other primary GBM, correlating the data with clinical parameters and outcome.GBMO comprised 21.5% of our GBM specimens and showed significantly longer survival compared with our other GBM (12 mo vs 5.8 mo, P = .006); there was also a strong correlation with younger age at diagnosis (56.4 y vs 60.6 y, P = .005). Singular LOH of 19q (P = .04) conferred a 1.9-fold increased hazard of shorter survival. There was no difference in the frequencies of 1p or 19q deletion, MGMT promoter methylation, or IDH1 mutation (P = .8, P = 1.0, P = 1.0, respectively).Primary GBMO is a subgroup of GBM associated with longer survival and a younger age group but shows no difference in the frequency of LOH of 1p/19q, MGMT, and IDH1 mutation compared with other primary GBM.

Glioblastoma is a highly aggressive tumour with marked heterogeneity at the morphological level in both the tumour cells and the associated highly prominent vasculature. As we begin to develop an increased biological insight into the underlying processes driving the disease, fewer attempts have thus far been made to understand these phenotypic differences. We sought to address this by carefully assessing the morphological characteristics of both the tumour cells and the associated vasculature, relating these observations to the IDH1/MGMT status, with a particular focus on the early onset population of young adults who develop primary glioblastoma. 276 primary glioblastoma specimens were classified into their predominant cell morphological type (fibrillary, gemistocytic, giant cell, small cell, oligodendroglial, sarcomatous), and assessed for specific tumour (cellularity, necrosis, palisades) and vascular features (glomeruloid structures, arcades, pericyte proliferation). IDH1 positive glioblastomas were associated with a younger age at diagnosis, better clinical outcome, prominent oligodendroglial and small cell tumour cell morphology, pallisading necrosis and glomeruloid vascular proliferation in the absence of arcade-like structures. These features widen the phenotype of IDH1 mutation-positive primary glioblastoma in young adults and provide correlative evidence for a functional role of mutant IDH1 in the differential nature of neo-angiogenesis in different subtypes of glioblastoma.

INTRODUCTION: Previously we have shown that glioblastomas with an oligodendroglial component (GBMO) did not differ from other glioblastomas in the frequency of 1p/19q deletion or isocitrate dehydrogenase mutation. Here we seek to determine whether anaplastic oligodendrogliomas with necrosis and very prominent endothelial cell hyperplasia (AO + N), often diagnosed as GBMO, differ in prognosis from the classic grade III counterpart (AOIII) and GBMO. METHOD: Anaplastic oligodendrogliomas with 1p/19q co-deletion and mutation to IDH1 or IDH2 were classed as either grade III or IV dependent upon the presence of the above mentioned high grade features. GBMO with neither 1p/19q co-deletion nor mutation to IDH1 or IDH2 were also selected for comparison. Statistical analyses were performed using R-Stats v2.15.2. RESULTS: AO + N (n = 16) with a median survival of 66.5 months had a worse prognosis than AOIII (n = 30) (median not reached, p = 0.04) and a better prognosis than GBMO (n = 46) (median survival 9 months, p = 1.04X10-5). The difference in survival between AO + N and GBMO remained significant when adjusted for age and gender (HR 0.17 95% CI 0.07-0.4, 6.3X10-5). CONCLUSION: The results suggest that anaplastic oligodendroglioma with necrosis and prominent endothelial cell hyperplasia behave worse than classic anaplastic oligodendroglioma and better than GBMO. Proper consideration should be given to including these neoplasms as a novel WHO grade IV classification if these results can be replicated in a larger cohort.

Many molecular genetic studies of human diseases involve determining the genotypes for single nucleotide polymorphisms. This chapter summarises a number of different techniques for the single nucleotide polymorphism genotyping which can be applied to MMP genes. The chapter also provides a protocol and technical notes for the 5'-nuclease assay, one of the most commonly used genotyping techniques.

Many molecular genetic studies of human diseases involve determining the genotypes for single nucleotide polymorphisms. This chapter summarises a number of different techniques for the single nucleotide polymorphism genotyping which can be applied to MMP genes. The chapter also provides a protocol and technical notes for the 5'-nuclease assay, one of the most commonly used genotyping techniques.

DNA sequence variations contribute to inter-individual variability in susceptibility to and/or severity of common diseases such as cancer, diabetes, and asthma. About 90% of all sequence variations in the human genome are single nucleotide polymorphisms. Each single nucleotide polymorphism arises from a single nucleotide substitution, resulting in the presence of two alleles which differ by one base pair of DNA. The second most common form of DNA sequence variation is microsatellite polymorphism, which is also known as short tandem repeat polymorphism. A microsatellite is a run of tandem repeats of a short DNA sequence, usually 1–4 base pairs. A microsatellite polymorphism can be di-allelic or multi-allelic, with the different alleles differing in the number of repeat units, and hence in length. It is likely that only a very small percentage of DNA sequence variations in the human genome are functionally important, exerting effects on gene expression or function. A DNA sequence variant that is functionally neutral can still be found to be associated with disease susceptibility, arising from linkage disequilibrium with a functional variant located on the same chromosome. Identification of genetic variants that contribute to disease susceptibility and/or severity can provide understanding of the molecular basis of the disease, could have diagnostic and prognostic value, and may provide useful molecular targets for developing novel therapeutics. There is evidence suggesting that polymorphisms in certain matrix metalloproteinase (MMP) genes could influence cancer susceptibility and/or prognosis. This chapter will highlight some of these findings, focusing on MMP1, MMP2, MMP3, MMP9, and MMP12.

Gene amplification at chromosome 4q12 is a common alteration in human high grade gliomas including glioblastoma, a CNS tumour with consistently poor prognosis. This locus harbours the known oncogenes encoding the receptor tyrosine kinases PDGFRA, KIT, and VEGFR2. These receptors are potential targets for novel therapeutic intervention in these diseases, with expression noted in tumour cells and/or associated vasculature. Despite this, a detailed assessment of their relative contributions to different high grade glioma histologies and the underlying heterogeneity within glioblastoma has been lacking. We studied 342 primary high grade gliomas for individual gene amplification using specific FISH probes, as well as receptor expression in the tumour and endothelial cells by immunohistochemistry, and correlated our findings with specific tumour cell morphological types and patterns of vasculature. We identified amplicons which encompassed PDGFRA only, PDGFRA/KIT, and PDGFRA/KIT/VEGFR2, with distinct phenotypic correlates. Within glioblastoma specimens, PDGFRA amplification alone was linked to oligodendroglial, small cell and sarcomatous tumour cell morphologies, and rare MGMT promoter methylation. A younger age at diagnosis and better clinical outcome in glioblastoma patients is only seen when PDGFRA and KIT are co-amplified. IDH1 mutation was only found when all three genes are amplified; this is a subgroup which also harbours extensive MGMT promoter methylation. Whilst PDGFRA amplification was tightly linked to tumour expression of the receptor, this was not the case for KIT or VEGFR2. Thus we have identified differential patterns of gene amplification and expression of RTKs at the 4q12 locus to be associated with specific phenotypes which may reflect their distinct underlying mechanisms.