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Simple Summary: Meningiomas are the most common primary intracranial tumor in adults. Meningiomas are usually benign and slow growing. Treatment is surgical resection in the case of symptomatic growth. Dramatic growth can occur during pregnancy, complicating clinical management and entailing a risk to the well-being of the mother and fetus. Authors of a previous review paper raised the hypothesis that prolactin may be a key contributor to the sudden growth seen in pregnancy-related meningiomas. We set out to investigate the presence of prolactin receptors/prolactin, as well as other female hormones and histopathological characteristics of pregnancy-related meningiomas in Denmark, compared to meningiomas from female controls within the same age group. No differences in hormone receptor distribution were found between the groups and very few meningiomas expressed prolactin receptors, which contradicts the above-mentioned hypothesis. Interestingly, we observed above cut-point proliferative indices of the meningiomas for the entire study population of females in the reproductive age. Meningiomas are the most common intracranial tumor. During pregnancy, explosive growth of a known meningioma occasionally occurs, but the underlying reasons remain unknown. Prolactin has been suggested as a possible key contributor to pregnancy-related meningioma growth. This study sets out to investigate prolactin and prolactin receptor status in 29 patients with pregnancy-related meningiomas in Denmark, from January 1972 to December 2016, as compared to 68 controls aged 20–45 years, also undergoing resection of a meningioma. Furthermore, we investigated potential differences in the progesterone and estrogen receptor statuses, WHO grade, Ki-67 labeling indices, and locations of the resected meningiomas between the cases and controls. Immunohistochemical analyses were performed, and histopathology and intracranial location were assessed with the investigator blinded for the case–control status. None of the samples stained positive for prolactin and very few samples stained positive for prolactin receptors, equally distributed among cases and controls. Estrogen and progesterone receptors generally followed the same distributional pattern between groups, whereas above cut-point Ki-67 labeling indices for both groups were observed. In conclusion, our results did not support the notion of prolactin as a key contributor to pregnancy-related meningioma growth. Rather, the similarities between the cases and controls suggest that meningiomas early in life may comprise a distinct biological entity. [ABSTRACT FROM AUTHOR]

Neuroinflammation is an essential part of neurodegeneration. Yet, the current understanding of neuroinflammation-associated molecular events in distinct brain regions of prion disease patients is insufficient to lay the ground for effective treatment strategies targeting this complex neuropathological process. To address this problem, we analyzed the expression of 800 neuroinflammation-associated genes to create a profile of biological processes taking place in the frontal cortex and cerebellum of patients who suffered from sporadic Creutzfeldt–Jakob disease. The analysis was performed using NanoString nCounter technology with human neuroinflammation panel+. The observed gene expression patterns were regionally and sub-regionally distinct, suggesting a variable neuroinflammatory response. Interestingly, the observed differences could not be explained by the molecular subtypes of sporadic Creutzfeldt–Jakob disease. Furthermore, analyses of canonical pathways and upstream regulators based on differentially expressed genes indicated an overlap between biological processes taking place in different brain regions. This suggests that even smaller-scale spatial data reflecting subtle changes in brain cells' functional heterogeneity and their immediate pathologic microenvironments are needed to explain the observed differential gene expression in a greater detail. [ABSTRACT FROM AUTHOR]

Simple Summary: Malignant meningiomas are rare primary intracranial tumors associated with considerable morbidity and mortality. The diagnosis is based on the number of mitotic figures (mitotic index, MI). Consequently, the quantification of mitotic figures is prone to inter- and intraobserver variability. The mitotic marker, phosphohistone-H3 (PHH3), has been shown to be a more robust mitotic marker. Despite the prognostic value of MI across all meningioma grades, little is known of the prognostic value of the MI within malignant meningioma. Therefore, this study investigates the MI in a series of malignant meningiomas to analyze the association to progression-free survival and mitotic and proliferative indices. Furthermore, we investigated the precision (repeatability) of mitotic counts and the agreement between MI and PHH3 MI. Meningiomas with inherently high mitotic indices and poor prognosis, such as WHO grade III meningiomas, have not been investigated separately to establish interchangeability between conventional mitotic index counted on H&E stained slides (MI) and mitotic index counted on phosphohistone-H3 stained slides (PHH3 MI). This study investigates the agreement of MI and PHH3 MI and to analyze the association of progression-free survival (PFS) and MI, PHH3 MI, and the proliferative index (PI, Ki-67) in WHO grade III meningioma. Tumor specimens from 24 consecutive patients were analyzed for expression of Ki-67, PHH3 MI, and MI. Quantification was performed independently by two observers who made replicate counts in hot spots and overall tumor staining. Repeatability in replicate counts from MI and PHH3 MI was low in both observers. Consequently, we could not report the agreement. MI, PHH3 MI and hot spot counts of Ki-67 were associated with PFS (MI hot spot HR = 1.61, 95% CI 1.12–2.31, p = 0.010; PHH3 MI hot spot HR = 1.59, 95% CI 1.15–2.21, p = 0.006; Ki-67 hot spot HR = 1.06, 95% CI 1.02–1.11. p = 0.004). We found markedly low repeatability of manually counted MI and PHH3 MI in WHO grade III meningioma, and we could not conclude that the two methods agreed. Subsequently, quantification with better repeatability should be sought. All three biomarkers were associated with PFS. [ABSTRACT FROM AUTHOR]

Until recently, diagnostics of brain tumors were almost solely based on morphology and immunohistochemical stainings for relatively unspecific lineage markers. Although certain molecular markers have been known for longer than a decade (combined loss of chromosome 1p and 19q in oligodendrogliomas), molecular biomarkers were not included in the WHO scheme until 2016. Now, the classification of diffuse gliomas rests on an integration of morphology and molecular results. Also, for many other central nervous system tumor entities, specific diagnostic, prognostic and predictive biomarkers have been detected and continue to emerge. Previously, we considered brain tumors with similar histology to represent a single disease entity. We now realize that histologically identical tumors might show alterations in different molecular pathways, and often represent separate diseases with different natural history and response to treatment. Hence, knowledge about specific biomarkers is of great importance for individualized treatment and follow‐up. In this paper we review the biomarkers that we currently use in the diagnostic work‐up of brain tumors. [ABSTRACT FROM AUTHOR]

Key Clinical Message: The clinician should always consider extracranial metastases in glioblastoma. Increased risk factors are young age at diagnosis, histology of gliosarcoma, and prior intracranial tumor surgery. Clinical guidelines are needed for this rare event, including consideration for prophylactic intervention. The clinician should always consider extracranial metastases in glioblastoma. Increased risk factors are young age at diagnosis, histology of gliosarcoma, and prior intracranial tumor surgery. Clinical guidelines are needed for this rare event, including consideration for prophylactic intervention. [ABSTRACT FROM AUTHOR]

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups. [ABSTRACT FROM AUTHOR]

I TERT i promoter mutations have been associated with increased risk of recurrence in meningioma cohorts, thus a potential biomarker for aggressive phenotypes. I TERT i p-mut affected 45 out of the 410 patients (12.3%), comprising 12 C250T and 33 C228T (73.3%) I TERT i promoter mutations, whereas the remaining 365 patients had the I TERT i promoter wild-type counterpart ( I TERT i p-wt). We recently described an association between patients with a I Telomerase reverse transcriptase i ( I TERT i ) gene alterations and a poor prognosis irrespective of the WHO grade in a meta-analysis of individual patient data encompassing all hitherto published meningioma patients with such alterations [3]. [Extracted from the article]

The article presents a cancer research report on exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output. Topics include Eukaryotic initiation factor 4A-III (eIF4A3), a core helicase component of the exon junction complex nonsense-mediated decay processes emerging as targets in cancer therapy; and unravel eIF4A3's tumor-promoting function by demonstrating its role in ribosome biogenesis (RiBi) and p53 (de)regulation.

Pediatric ependymomas frequently develop in the cerebellum and are currently treated using non‐specific therapies, in part, because few somatically mutated driver genes are present, and the underlying pathobiology is poorly described. Circular RNAs (circRNAs) constitute as a large class of primarily non‐coding RNAs with important roles in tumorigenesis, but they have not been described in pediatric ependymomas. To advance our molecular understanding of ependymomas, we performed Next Generation Sequencing of rRNA‐depleted total RNA of 10 primary ependymoma and three control samples. CircRNA expression patterns were correlated to disease stage, outcome, age, and gender. We found a profound global downregulation of circRNAs in ependymoma relative to control samples. Many differentially expressed circRNAs were discovered and circSMARCA5 and circ‐FBXW7, which are described as tumor suppressors in glioma and glioblastomas in adults, were among the most downregulated. Moreover, patients with a dismal outcome clustered separately from patients with a good prognosis in unsupervised hierarchical cluster analyses. Next, NanoString nCounter experiments were performed, using a custom‐designed panel targeting 66 selected circRNAs, on a larger cohort that also included medulloblastomas and pilocytic astrocytomas. These experiments indicated that circRNA expression profiles are different among distinct pediatric brain tumor subtypes. In particular, circRNAs derived from RMST, LRBA, WDR78, DRC1 and BBS9 genes were specifically upregulated in ependymomas. In conclusion, circRNAs have different expression profiles in ependymomas relative to controls and between survivors and patients with a dismal outcome, suggesting that circRNAs could be exerted as diagnostic and prognostic biomarkers in the future if further validated in larger cohorts. [ABSTRACT FROM AUTHOR]

Purpose: Positron emission tomography (PET) with 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) provides a noninvasive assessment of tumour proliferation in vivo and could be a valuable imaging modality for assessing malignancy in meningiomas. We investigated a range of static and dynamic [18F]FLT metrics by correlating the findings with cellular biomarkers of proliferation and angiogenesis. Methods: Seventeen prospectively recruited adult patients with intracranial meningiomas underwent a 60-min dynamic [18F]FLT PET following surgery. Maximum and mean standardized uptake values (SUVmax, SUVmean) with and without normalization to healthy brain tissue and blood radioactivity obtained from 40 to 60 min summed dynamic images (PET40–60) and ~ 60-min blood samples were calculated. Kinetic modelling using a two-tissue reversible compartmental model with a fractioned blood volume (VB) was performed to determine the total distribution volume (VT). Expressions of proliferation and angiogenesis with key parameters including Ki-67 index, phosphohistone-H3 (phh3), MKI67, thymidine kinase 1 (TK1), proliferating cell nuclear antigen (PCNA), Kirsten RAt Sarcoma viral oncogene homolog (KRAS), TIMP metallopeptidase inhibitor 3 (TIMP3), and vascular endothelial growth factor A (VEGFA) were determined by immunohistochemistry and/or quantitative polymerase chain reaction. Results: Immunohistochemistry revealed 13 World Health Organization (WHO) grade I and four WHO grade II meningiomas. SUVmax and SUVmean normalized to blood radioactivity from PET40–60 and blood sampling, and VT were able to significantly differentiate between WHO grades with the best results for maximum and mean tumour-to-whole-blood ratios (sensitivity 100%, specificity 94–95%, accuracy 99%; P = 0.003). Static [18F]FLT metrics were significantly correlated with proliferative biomarkers, especially Ki-67 index, phh3, and TK1, while no correlations were found with VEGFA or VB. Using Ki-67 index with a threshold > 4%, the majority of [18F]FLT metrics showed a high ability to identify aggressive meningiomas with SUVmean demonstrating the best performance (sensitivity 80%, specificity 81%, accuracy 80%; P = 0.024). Conclusion: [18F]FLT PET could be a useful imaging modality for assessing cellular proliferation in meningiomas. [ABSTRACT FROM AUTHOR]

We investigated possible clinical and histopathological prognostic factors in a malignant meningioma cohort with comprehensive long-term population-based follow-up data. Twenty-four consecutive patients treated surgically for malignant meningioma at the Department of Neurosurgery and the Department of Pathology, Rigshospitalet, Copenhagen, Denmark, from December 2000 to March 2014 were retrospectively evaluated regarding progression-free survival (PFS) and overall survival (OS). Clinical parameters were recorded. All specimens underwent immunohistochemical analysis for Ki-67 and phosphohistone-H3 (PHH3). Prognostication was assessed with Cox proportional hazard regression analysis. The median follow-up was 46.1 months (range 0.7–150.7). The median progression-free survival was 16.5 months (95% CI 11.4–43.0) and the median overall survival was 46.6 months (95% CI 20.4–NA). Six patients were alive at the end of follow-up; two of these had not experienced a recurrence. No clinical parameter showed significant association with PFS or OS. Mitotic index (MI) was significantly associated with PFS and OS, and PHH3 MI with PFS. Immunohistochemical reactivity of Ki-67 > 10% was a negative predictor of PFS (HR 3.92, 95% CI 1.47–10.4, p = 0.0063) and OS (HR 3.35, 95% CI 1.12–10.1, p = 0.0313). The histological subgrouping of grade III meningioma into anaplastic and non-anaplastic revealed increased PFS for the latter (HR 4.57, CI 95% 1.32–15.7, p = 0.0164). We could not verify previous clinical parameters as prognostic factors in malignant meningioma. MI and the PHH3 MI were prognostic within WHO grade III meningiomas for PFS. An overall tumor staining of Ki-67 > 10% correlated with PFS and OS within grade III tumors. [ABSTRACT FROM AUTHOR]

Purpose: Medulloblastoma is the most common malignant brain tumor in childhood. Radical surgery in the non-metastatic stage is an important factor with respect to overall survival. In this case, 5-aminolevulinic acid (5-ALA) was used at second-look surgery in order to improve surgical results. Methods: The child was pretreated with 3 × 4 mg dexamethasone for 4 days prior to the second surgery. At 5 a.m. on the day of surgery, a freshly prepared solution of 5-ALA (20 mg/kg body weight; Medac, Germany) was given orally. Results: At surgery, through the original opening, the vague red fluorescence of the tumor was clearly distinctive from the cerebellum with no tumor infiltration. All fluorescent tissue was removed. Postoperative MRI gave suspicion of yet at small tumor residue, but this structure is less than 1.5 ml in calculated volume, and consequently the recommended adjuvant therapy of the child changed from the high-risk medulloblastoma regimen to the standard-risk regimen. Conclusions: In this particular difficult case of non-contrast-enhancing tumor, 5-ALA was of vital importance to improve rate of resection and change the aggressiveness needed in postsurgery radiation therapy. [ABSTRACT FROM AUTHOR]

Objective Mesial temporal lobe epilepsy ( MTLE) is one of the most common types of the intractable epilepsies and is most often associated with hippocampal sclerosis ( HS), which is characterized by pronounced loss of hippocampal pyramidal neurons. micro RNAs (mi RNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that mi RNAs could be involved in the pathogenesis of MTLE and HS. Methods mi RNA expression was quantified in hippocampal specimens from human patients using mi RNA microarray and quantitative real-time polymerase chain reaction RT- PCR, and by RNA-seq on fetal brain specimens from domestic pigs. In situ hybridization was used to show the spatial distribution of mi RNAs in the human hippocampus. The potential effect of mi RNAs on targets genes was investigated using the dual luciferase reporter gene assay. Results mi RNA expression profiling showed that 25 mi RNAs were up-regulated and 5 were down-regulated in hippocampus biopsies of MTLE/ HS patients compared to controls. We showed that miR-204 and miR-218 were significantly down-regulated in MTLE and HS, and both were expressed in neurons in all subfields of normal hippocampus. Moreover, miR-204 and miR-218 showed strong changes in expression during fetal development of the hippocampus in pigs, and we identified four target genes, involved in axonal guidance and synaptic plasticity, ROBO1, GRM1, SLC1A2, and GNAI2, as bona fide targets of miR-218. GRM1 was also shown to be a direct target of miR-204. Significance miR-204 and miR-218 are developmentally regulated in the hippocampus and may contribute to the molecular mechanisms underlying the pathogenesis of MTLE and HS. [ABSTRACT FROM AUTHOR]

Viral infections enhance cancer risk and threaten host genome integrity. Although human cytomegalovirus (HCMV) proteins have been detected in a wide spectrum of human malignancies and HCMV infections have been implicated in tumorigenesis, the underlying mechanisms remain poorly understood. Here, we employed a range of experimental approaches, including single-molecule DNA fiber analysis, and showed that infection by any of the four commonly used HCMV strains: AD169, Towne, TB40E or VR1814 induced replication stress (RS), as documented by host-cell replication fork asymmetry and formation of 53BP1 foci. The HCMV-evoked RS triggered an ensuing host DNA damage response (DDR) and chromosomal instability in both permissive and non-permissive human cells, the latter being particularly relevant in the context of tumorigenesis, as such cells can survive and proliferate after HCMV infection. The viral major immediate early enhancer and promoter (MIEP) that controls expression of the viral genes IE72 (IE-1) and IE86 (IE-2), contains transcription-factor binding sites shared by promoters of cellular stress-response genes. We found that DNA damaging insults, including those relevant for cancer therapy, enhanced IE72/86 expression. Thus, MIEP has been evolutionary shaped to exploit host DDR. Ectopically expressed IE72 and IE86 also induced RS and increased genomic instability. Of clinical relevance, we show that undergoing standard-of-care genotoxic radio-chemotherapy in patients with HCMV-positive glioblastomas correlated with elevated HCMV protein markers after tumor recurrence. Collectively, these results are consistent with our proposed concept of HCMV hijacking transcription-factor binding sites shared with host stress-response genes. We present a model to explain the potential oncomodulatory effects of HCMV infections through enhanced replication stress, subverted DNA damage response and induced genomic instability., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Background: Central nervous system (CNS) tumors cause the highest death rates among childhood cancers, and survivors frequently have severe late effects. Magnetic resonance imaging (MRI) is the imaging modality of choice, but its specificity can be challenged by treatment-induced signal changes. In adults, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET can assist in interpreting MRI findings. We assessed the clinical impact and diagnostic accuracy of adding [18F]FET PET to MRI in children with CNS tumors., Methods: A total of 169 [18F]FET PET scans were performed in 97 prospectively and consecutively included patients with known or suspected childhood CNS tumors. Scans were performed at primary diagnosis, before or after treatment, or at relapse., Results: Adding [18F]FET PET to MRI impacted clinical management in 8% [95% confidence interval (CI): 4%-13%] of all scans (n = 151) and in 33% [CI: 17%-53%] of scans deemed clinically indicated due to difficult decision making on MRI alone (n = 30). Using pathology or follow-up as reference standard, the addition of [18F]FET PET increased specificity (1.00 [0.82-1.00] vs 0.48 [0.30-0.70], P = .0001) and accuracy (0.91 [CI: 0.87-0.96] vs 0.81 [CI: 0.75-0.89], P = .04) in 83 treated lesions and accuracy in 58 untreated lesions (0.96 [CI: 0.91-1.00] vs 0.90 [CI: 0.82-0.92], P < .001). Further, in a subset of patients (n = 15) [18F]FET uptake correlated positively with genomic proliferation index., Conclusions: The addition of [18F]FET PET to MRI helped discriminate tumor from non-tumor lesions in the largest consecutive cohort of pediatric CNS tumor patients presented to date., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The stem cell marker CD133 has been sporadically investigated in meningioma, but because of the rarity of malignant meningioma (WHO grade III), only 7 malignant meningioma specimens have been included in previous studies. We investigated CD133 expression using the AC133 antibody clone in a consecutive cohort of 38 malignant meningiomas. Our results showed few, small CD133-positive hot spots with a pattern dominated by membranous staining and capping of the proteins without any nuclear CD133 staining in 30 of the 38 tumors. We could not corroborate spatial co-expression of hot spots with the proliferative marker, Ki-67, and CD133 hot spots in adjacent slides, nor did we find differences between Ki-67 expression in CD133-negative and -positive tumor specimens (Fisher's exact test: p = 0.69). CD13-positive niches represented only 0 - 1% of meningioma cells in most of the malignant meningioma, while CD133-positive cells were undetectable in 21% of the whole-section tumor samples. We found stem cell niches in 79% of malignant meningioma specimens in our cohort.

Somatostatin receptor (SSTR)-targeted peptide receptor radionuclide therapy (PRRT) represents a promising approach for treatment-refractory meningiomas. Methods: We performed an individual patient data meta-analysis, including all published data on meningioma patients treated with SSTR-targeted PRRT. The main outcomes were toxicity, response to treatment, progression-free survival (PFS), and overall survival (OS). We applied the Kaplan-Meier method to estimate survival probabilities and report incidence rates per 100 person-years. We applied Cox proportional hazards models to determine the effect of covariates. Results: We screened 537 papers and identified 6 eligible cohort studies. We included a total of 111 patients who had treatment-refractory meningioma and received SSTR-targeted PRRT. Disease control was achieved in 63% of patients. The 6-mo PFS rates were 94%, 48%, and 0% for World Health Organization grades I, II, and III, respectively. The risk of disease progression decreased by 13% per 1,000-MBq increase in the total applied activity. The 1-y OS rates were 88%, 71%, and 52% for World Health Organization grades I, II, and III, respectively. The risk of death decreased by 17% per 1,000-MBq increase in the total applied activity. The main side effects comprised transient hematotoxicity, such as anemia in 22% of patients, leukopenia in 13%, lymphocytopenia in 24%, and thrombocytopenia in 17%. Conclusion: To our knowledge, this individual patient data meta-analysis represents the most comprehensive analysis of the benefits of and adverse events associated with SSTR-targeted PRRT for treatment-refractory meningioma. The treatment was well tolerated, achieved disease control in most cases, and showed promising results regarding PFS and OS., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Neuroinflammation is an essential part of neurodegeneration. Yet, the current understanding of neuroinflammation-associated molecular events in distinct brain regions of prion disease patients is insufficient to lay the ground for effective treatment strategies targeting this complex neuropathological process. To address this problem, we analyzed the expression of 800 neuroinflammation-associated genes to create a profile of biological processes taking place in the frontal cortex and cerebellum of patients who suffered from sporadic Creutzfeldt-Jakob disease. The analysis was performed using NanoString nCounter technology with human neuroinflammation panel+. The observed gene expression patterns were regionally and sub-regionally distinct, suggesting a variable neuroinflammatory response. Interestingly, the observed differences could not be explained by the molecular subtypes of sporadic Creutzfeldt-Jakob disease. Furthermore, analyses of canonical pathways and upstream regulators based on differentially expressed genes indicated an overlap between biological processes taking place in different brain regions. This suggests that even smaller-scale spatial data reflecting subtle changes in brain cells' functional heterogeneity and their immediate pathologic microenvironments are needed to explain the observed differential gene expression in a greater detail.

Purpose: DOTA-D-Phe 1 -Tyr 3 -octreotide with gallium-68 ([ 68 Ga]Ga-DOTA-TOC) is one of the PET tracers that forms the basis for peptide receptor radionuclide therapy based on somatostatin receptor subtype 2 (SSTR2) expression in meningiomas. Yet, the quantitative relationship between [ 68 Ga]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [ 68 Ga]Ga-DOTA-TOC PET metric(s) as imaging surrogate(s) of the receptor binding in meningiomas by correlating the PET results with SSTR2 expression from surgical specimens. We additionally investigated possible influences of secondary biological factors such as vascularization, inflammation and proliferation., Methods: Fifteen patients with MRI-presumed or recurrent meningiomas underwent a 60-min dynamic [ 68 Ga]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUV max , SUV mean ) with and without normalization to reference regions, and quantitative measurements derived from kinetic modelling using a reversible two-tissue compartment model with the fractional blood volume (V B ). Expressions of SSTR2 and proliferation (Ki-67, phosphohistone-H3, proliferating cell nuclear antigen) were determined by immunohistochemistry and/or quantitative polymerase chain reaction (qPCR), while biomarkers of vascularization (vascular endothelial growth factor A (VEGFA), endothelial marker CD34) and inflammation (cytokine interleukin-18, microglia/macrophage-specific marker CD68) by qPCR., Results: Histopathology revealed 12 World Health Organization (WHO) grade I and three WHO grade II meningiomas showing no link to SSTR2. The majority of [ 68 Ga]Ga-DOTA-TOC PET metrics showed significant associations with SSTR2 protein, while all PET metrics were positively correlated with SSTR2 mRNA with the best results for mean tumour-to-blood ratio (TBR mean ) (r = 0.757, P = 0.001) and SUV mean (r = 0.714, P = 0.003). Significant positive correlations were also found between [ 68 Ga]Ga-DOTA-TOC PET metrics, and VEGFA and V B . SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539, P = 0.038). Neither [ 68 Ga]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation., Conclusion: [ 68 Ga]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBR mean being the best PET metric for assessing SSTR2.

DOTA-D-Phe-Tyr-octreotide labeled with Ga (Ga-DOTATOC) is the commonly used PET tracer for imaging meningioma because of its high affinity to somatostatin receptor subtype 2 (SSTR2) and an established imaging modality for planning radiation and radionuclide therapy. However, SSTR2 is not an exclusive marker for meningioma, and not all meningiomas express high levels of SSTR2. The SSTR2 expression has been reported in other intracranial tumors, for example, glioma, pituitary adenoma, medullablastoma, primitive neuroectodermal tumors, and hemangioblastoma leading to a significant risk of misinterpretation of PET/CT findings. We present 2 cases with similar Ga-DOTATOC uptakes in 2 distinct etiologies, for example, cerebral lymphoma and meningioma.

Patients with recurrent glioblastoma achieving response to bevacizumab combined with chemotherapy have clinical improvement and prolonged survival. High gene expression of angiotensinogen (AGT) is associated with a poor bevacizumab response. Because AGT expression is epigenetically regulated, we aimed to investigate whether AGT promoter methylation in tumor tissue predicts response to bevacizumab combination therapy in patients with recurrent glioblastoma. The study included 159 patients with recurrent glioblastoma, treated with bevacizumab combination treatment (training cohort, n = 77; validation cohort, n = 82). All patients could be evaluated for treatment response and biomarkers. DNA methylation of 4 CpG sites in the AGT promoter was measured using pyrosequencing. A model for nonresponse was established using logistic regression analysis. In the training cohort, lower methylation of each of the four CpG sites in the AGT promoter was significantly associated with nonresponse (all P < 0.05). Moreover, the mean methylation level of all four CpG sites was associated with an increased likelihood of not achieving response to bevacizumab combination therapy (twofold decrease: odds ratio = 3.01; 95% confidence interval: 1.41-6.44; P = 0.004). We developed a model for nonresponse in the training cohort, where a threshold of mean AGT promoter methylation levels was set to below 12%. The model could predict bevacizumab nonresponse with 96% specificity. Importantly, this predictor was also significantly associated with nonresponse in the validation cohort (P = 0.037). Taken together, our findings suggest that low AGT promoter methylation in tumor tissue predicts nonresponse to bevacizumab combination treatment in patients with recurrent glioblastoma. We have, thus, established and successfully validated a predictor for nonresponse that can be used to identify patients who will not benefit from bevacizumab combination therapy., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: TERT gene alterations ( TERT -alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought., Methods: We applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to TERT -alt (n=59) or TERT promoter wild-type ( TERT p-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs., Results: TERT -alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all TERT- alt patients versus 101 months for all TERT p-wt patients. The HR for TERT -alt was 3.74 in reference to TERT p-wt. For all TERT -alt patients versus all TERT p-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for TERT -alt was 2.77 compared with TERT p-wt. TERT -alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II TERT -alt patients compared with WHO-III TERT p-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II TERT -alt patients compared with WHO-III TERT p-wt patients., Conclusions: TERT -alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. TERT -alt should be managed and surveilled aggressively. We propose that TERT -alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification., Trial Registration Number: PROSPERO: CRD42018110566., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Standard treatment for glioblastoma (GBM) patients is surgery and radiochemotherapy (RCT) with temozolomide (TMZ). TMZ is a substrate for ABCB1, a transmembrane drug transporter. It has been suggested that survival for GBM patients receiving TMZ is influenced by different single-nucleotide variants (SNV) of ABCB1. We therefore examined SNV:s of ABCB1, namely 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T and correlated to survival for GBM patients receiving RCT. In a pilot cohort (97 patients) a significant correlation to survival was found for SNV 1199G>A, with median OS for variant G/G patients being 18.2 months versus 11.5 months for A/G (p = 0.012). We found no correlation to survival for the other SNV:s. We then expanded the cohort to 179 patients (expanded cohort) and also included a confirmatory cohort (49 patients) focusing on SNV 1199G>A. Median OS for G/G versus A/G plus A/A was 15.7 and 11.5 months, respectively (p = 0.085) for the expanded cohort and 13.8 versus 16.8 months (p = 0.19) for the confirmatory. In conclusion, in patients with GBM receiving RCT with TMZ, no correlation with survival was found for the SNV:s 1236C>T, 2677G>T/A, and 3435C>T of ABCB1. Although the SNV 1199G>A might have some impact, a clinically significant role could not be confirmed.

Coccidioides immitis is a dimorphic fungus endemic to the southwestern North America and Central America. Infection is acquired through inhalation of soil containing spores. This case report describes a case of C. immitis lung abscess and meningoencephalitis in an otherwise healthy 65-year-old woman, who had been on vacation in California. She passed away after three months of medical investigations and treatments, and not until after her death was the diagnosis C. immitis made through a polymerase chain reaction testing of her cerebrospinal fluid. Knowledge of the disease, including proper diagnosis and treatment, is important, also for physicians in non-endemic areas.

Background: Gliosarcoma (GS) is a rare histopathologic variant of glioblastoma (GBM) characterized by a biphasic growth pattern consisting of both glial and sarcomatous components. Reports regarding its relative prognosis compared to conventional GBM are conflicting and although GS is treated as conventional GBM, supporting evidence is lacking. The aim of this study was to characterize demographic trends, clinical outcomes and prognostic variables of GS patients receiving standardized therapy and compare these to conventional GBM. Methods: Six hundred and eighty GBM patients, treated with maximal safe resection followed by radiotherapy with concomitant and adjuvant temozolomide at a single institution, were retrospectively reevaluated by reviewing histopathological records and tumor tissue for identification of GS patients. Clinico-pathological- and tumor growth characteristics were obtained via assessment of medical records and imaging analysis. Kaplan-Meier survival estimates were compared with log-rank testing, while Cox-regression modeling was tested for prognostic factors in GS patients. Results: The cohort included 26 primary gliosarcoma (PGS) patients (3.8%) and 7 secondary gliosarcoma (SGS) patients (1.0%). Compared to conventional GBM tumors, PGS tumors were significantly more often MGMT-unmethylated (73.9%) and located in the temporal lobe (57.7%). GS tumors often presented dural contact, while extracranial metastasis was only found in 1 patient. No significant differences were found between PGS and conventional GBM in progression-free-survival (6.8 and 7.6 months, respectively, p = 0.105) and in overall survival (13.4 and 15.7 months, respectively, p = 0.201). Survival following recurrence was not significantly different between PGS, SGS, and GBM. Temporal tumor location and MGMT status were found associated with PGS survival ( p = 0.036 and p = 0.022, respectively). Conclusion: Despite histopathological and location difference between GS and GBM tumors, the patients present similar survival outcome from standardized treatment. These findings support continued practice of radiation and temozolomide for GS patients., (Copyright © 2019 Frandsen, Broholm, Larsen, Grunnet, Møller, Poulsen and Michaelsen.)

Background: Diagnostic accuracy in previous studies of O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) PET in patients with suspected recurrent glioma may be influenced by prolonged dynamic PET acquisitions, heterogeneous populations, different non-standard-of-care therapies, and PET scans performed at different time points post radiotherapy. We investigated the diagnostic accuracy of a 20-minute 18F-FET PET scan in MRI-suspected recurrent glioblastoma 6 months after standard radiotherapy and its ability to prognosticate overall survival (OS)., Methods: In total, 146 glioblastoma patients with 168 18F-FET PET scans were reviewed retrospectively. Patients with MRI responses to bevacizumab or undergoing re-irradiation or immunotherapy after 18F-FET PET were excluded. Maximum and mean tumor-to-background ratios (TBRmax, TBRmean) and biological tumor volume (BTV) were recorded and verified by histopathology or clinical/radiological follow-up. Thresholds of 18F-FET parameters were determined by receiver operating characteristic (ROC) analysis. Prognostic factors were investigated in Cox proportional hazards models., Results: Surgery was performed after 104 18F-FET PET scans, while clinical/radiological surveillance was used following 64, identifying 152 glioblastoma recurrences and 16 posttreatment changes. ROC analysis yielded thresholds of 2.0 for TBRmax, 1.8 for TBRmean, and 0.55 cm3 for BTV in differentiating recurrent glioblastoma from posttreatment changes with the best performance of TBRmax (sensitivity 99%, specificity 94%; P < 0.0001) followed by BTV (sensitivity 98%, specificity 94%; P < 0.0001). Using these thresholds, 166 18F-FET PET scans were correctly classified. Increasing BTV was associated with shorter OS (P < 0.0001)., Conclusion: A 20-minute 18F-FET PET scan is a powerful tool to distinguish posttreatment changes from recurrent glioblastoma 6-month postradiotherapy, and predicts OS., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The purpose of this study was to perform an updated reclassification of all definite prion disease cases with available fresh-frozen samples referred to the Danish Reference Center over the past 40 years, putting a special emphasis on the molecular characterization of novel disease subtypes. Investigation of the Danish prion diseases cohort revealed rare sporadic Creutzfeldt-Jakob disease cases with mixed subtypes and subtypes with previously uncharacterized white matter plaques, a new case of sporadic fatal insomnia, and 3 novel mutations, including 2 large octapeptide repeat insertions, and a point mutation in the prion protein gene. The evaluation of methionine and valine distribution at codon 129 among the prion disease patients in the cohort revealed the increased prevalence of methionine homozygotes compared to the general population. This observation was in line with the prevalence reported in other Caucasian prion disease cohort studies. Reclassification of the old prion diseases cohort revealed unique cases, the molecular characterization of which improves prion diseases classification, diagnostic accuracy, genetic counseling of affected families, and the understanding of disease biology., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Complete resection is the treatment of choice for most pediatric brain tumors, but early postoperative MRI for detection of residual tumor may be misleading because of MRI signal changes caused by the operation. PET imaging with amino acid tracers in adults increases the diagnostic accuracy for brain tumors, but the literature in pediatric neurooncology is limited. A hybrid PET/MRI system is highly beneficial in children, reducing the number of scanning procedures, and this is to our knowledge the first larger study using PET/MRI in pediatric neurooncology. We evaluated if additional postoperative 18 F-fluoro-ethyl-tyrosine ( 18 F-FET) PET in children and adolescents would improve diagnostic accuracy for the detection of residual tumor as compared with MRI alone and would assist clinical management. Methods: Twenty-two patients (7 male; mean age, 9.5 y; range, 0-19 y) were included prospectively and consecutively in the study and had 27 early postoperative 18 F-FET PET exams performed preferentially in a hybrid PET/MRI system (NCT03402425). Results: Using follow-up (93%) or reoperation (7%) as the reference standard, PET combined with MRI discriminated tumor from treatment effects with a lesion-based sensitivity/specificity/accuracy (95% confidence intervals) of 0.73 (0.50-1.00)/1.00 (0.74-1.00)/0.87 (0.73-1.00) compared with MRI alone: 0.80 (0.57-1.00)/0.75 (0.53-0.94)/0.77 (0.65-0.90); that is, the specificity for PET/MRI was 1.00 as compared with 0.75 for MRI alone ( P = 0.13). In 11 of 27 cases (41%), results from the 18 F-FET PET scans added relevant clinical information, including one scan that directly influenced clinical management because an additional residual tumor site was identified. 18 F-FET uptake in reactive changes was frequent (52%), but correct interpretation was possible in all cases. Conclusion: The high specificity for detecting residual tumor suggests that supplementary 18 F-FET PET is relevant in cases where reoperation for residual tumor is considered., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Octapeptide repeat insertions (OPRI) found in the prion protein gene (PRNP) constitute a subgroup of pathogenic mutations linked to inherited prion diseases, a hallmark of which is a misfolded prion protein. The number of repeats in OPRI has been associated with different disease phenotypes. However, due to the rarity of the cases and heterogenous disease manifestations, the recognition and classification of these variants has been difficult. Here, we report the first Danish family, the fifth worldwide, carrying a novel 8-OPRI with a unique sequence of the additional 8 inserts: R1-R2-R2-R3-R2-R2-R2a-R2-R3g-R2-R2-R3-R4. The mutation was found on the allele coding for methionine at codon 129 in the PRNP gene. The clinical exome sequencing revealed that no other dementia-associated genes harbored pathogenic alterations. Mutation carriers had onset of symptoms in their early thirties, but disease duration varied from 5 to 11 years. Progressive dementia with psychiatric and motor symptoms were the most prominent clinical features. Clinical, pathological, and genetic characteristics of other 4 reported families with 8-OPRI were reviewed and compared with the findings in the Danish family., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Despite extensive treatment, overall survival (OS) for glioblastoma (GBM) remains poor. A small proportion of patients present long survival over 3 years, but the underlying molecular background separating these long-term survivors (LTS) from short-term survivors (STS) are insufficiently understood. Accordingly, study aim was to identify independent prognostic biomarkers for survival. Study cohort consisted of 93 primary GBM patients treated with radiation-, chemo- and bevacizumab therapy, among which 14 STS (OS ≤ 12 months) and 6 LTS (OS ≥ 36 months) were identified, all confirmed being IDH wild-type. RNA expression levels in diagnostic tumor specimen for 792 genes were analyzed by NanoString technology. While no differences were found with regard to GBM subtype between LTS versus STS, comparative analysis of individual genes identified 14 significantly differently expressed candidate genes. Univariate analysis in the whole patient cohort found that 12 of these were significantly associated with OS, of which increased IFNG, CXCL9, LGALS4, CD34 and decreased MGMT levels remained significant associated with prolonged OS in multivariate analysis correcting for known prognostic variables. Validation analyses in an independent dataset from the AVAglio study confirmed CD34 as significant in comparative analysis between STS and LTS patients and as an independent prognostic factor. Analysis of this dataset further supported CD34 expression to be associated with improved bevacizumab efficacy, while CD34 immunohistochemistry indicated variation in CD34 expression to result primarily from varying tumor vascularization. Collectively, CD34 expression candidates as a prognostic biomarker in GBM able to identify survival outliers and could also be predictive for efficacy of bevacizumab.

Objective: The diagnostic accuracy of O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET scanning in detecting the malignant transformation of low-grade gliomas (LGGs) is controversial. In this study, the authors retrospectively assessed the diagnostic potential of FET PET in patients with MRI-suspected malignant progression of LGGs that had previously been treated and the relationship between FET uptake and MRI and molecular biomarkers., Methods: Forty-two patients who had previously undergone surgical or multimodal treatment for a histologically verified LGG were referred for FET PET assessment because of clinical signs and/or MRI findings suggestive of tumor progression. Maximal and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively) on FET PET as well as kinetic FET PET parameters (time to peak [TTP] and time-activity curve [TAC]) were determined. Final diagnoses were confirmed histologically. The diagnostic accuracy of FET parameters, separately and combined, for the detection of malignant progression was evaluated using receiver operating characteristic (ROC) curve analysis. Possible predictors that might influence the diagnostic accuracy of FET PET were assessed using multiple linear regression analysis. Spearman’s rank correlation r method was applied to determine the correlation between TBRmax and TAC, and molecular biomarkers from tumor tissues., Results: A total of 47 FET PET scans were obtained and showed no significant association between FET parameters and contrast enhancement on MRI. ROC curve analyses overall were unable to demonstrate any significant differentiation between nontransformed LGGs and LGGs that had transformed to high-grade gliomas when evaluating FET parameters separately or combined. After excluding the oligodendroglial subgroup, a significant difference was observed between nontransformed and transformed LGGs when combining FET parameters (i.e., TBRmax > 1.6, TAC describing a plateau or decreasing pattern, and TTP < 25 minutes), with the best result yielded by a combined analysis of TBRmax > 1.6 and TAC with a plateau or decreasing pattern (sensitivity 75% and specificity 83%, p = 0.003). The difference was even greater when patients who had previously undergone oncological treatment were also excluded (sensitivity 93% and specificity 100%, p = 0.001). Multiple linear regression analysis revealed that the presence of an oligodendroglial component (p = 0.029), previous oncological treatment (p = 0.039), and the combined FET parameters (p = 0.027) were significant confounding factors in the detection of malignant progression. TBRmax was positively correlated with increasing cell density (p = 0.040) and inversely correlated with IDH1 mutation (p = 0.006)., Conclusions: A single FET PET scan obtained at the time of radiological and/or clinical progression seems to be of limited value in distinguishing transformed from nontransformed LGGs, especially if knowledge of the primary tumor histopathology is not known. Therefore, FET PET imaging alone is not adequate to replace histological confirmation, but it may provide valuable information on the location and delineation of active tumor tissue, as well as an assessment of tumor biology in a subgroup of LGGs.

Surgery is the only treatment option with the potential to cure epilepsy. This review is a description of the multidisciplinary and multimodal presurgical evaluation process and the outcome of the Danish epilepsy surgery programme. The outcome aligns with international results and serious complications to surgery are very rare. The annual number of operations per capita compares to neighbouring countries and is equally distributed across Denmark. In accordance with international recommendations, Danish drug-resistant patients should be referred to epilepsy surgery evaluation at an early stage of the disease.

Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Perfusion CT (PCT) measurements of regional cerebral blood flow (rCBF) have been proposed as a fast and easy method for identifying angiogenically active tumours. In this study, quantitative PCT rCBF measurements in patients with brain tumours were compared to the gold standard PET rCBF with (15)O-labelled water ((15)O-H(2)O)., Methods: On the same day within a few hours, rCBF was measured in ten adult patients with treatment-naïve primary brain tumours, twice using (15)O-H(2)O PET and once with PCT performed over the central part of the tumour. Matching rCBF values in tumour and contralateral healthy regions of interest were compared., Results: PCT overestimated intratumoural blood flow in all patients with volume-weighted mean rCBF values of 28.2 ± 18.8 ml min(-1) 100 ml(-1) for PET and 78.9 ± 41.8 ml min(-1) 100 ml(-1) for PCT. There was a significant method by tumour grade interaction with a significant tumour grade rCBF difference for PCT of 32.9 ± 15.8 ml min(-1) 100 ml(-1) for low-grade (WHO I + II) and 81.5 ± 15.4 ml min(-1) 100 ml(-1) for high-grade (WHO III + IV) tumours, but not for PET. The rCBF PCT and PET correlation was only significant within tumours in two patients., Conclusion: Although intratumoural blood flow measured by PCT may add valuable information on tumour grade, the method cannot substitute quantitative measurements of blood flow by PET and (15)O-H(2)O PET in brain tumours.

Since variant Creutzfeldt-Jakob disease (vCJD) was described for the first time in 1995 and fears of an epidemic ensued, the assumed culprit the prion protein (PrP) and its precursor the prion-gene (PRNP) have been subjects to intense studies. Several polymorphisms in PRNP modify disease probability and phenotype. Importantly, two common variants of codon 129 in PRNP code for methionine (Met) or valine (Val), respectively. All hitherto known cases of vCJD have been Met/Met homozygotes. The aim of this study was to investigate the susceptibility to vCJD in the Danish population by determining the distribution of the codon 129 polymorphism. The occurrence of three other relevant polymorphisms were investigated: An alanine (Ala) silent mutation on codon 117, an aspargine-serine (Asn-Ser) mutation on codon 171 and deletions or insertions in the moeity known as the octapeptide region of PRNP. DNA was isolated from 352 samples and alleles were detected by allele specific real-time PCR and/or restriction endonuclease treatment followed by agarose gelelectrophoresis. The distribution of the genotypes at codon 129 was found to be Met/Met 35%, Met/Val 48% and Val/Val 17%. The other polymorphisms were found to be very rare. These data are similar to British data; but differ from the Finnish, Slovakian, Turkish and Japanese distributions, where the Met allele is more abundant. The genetic results indicate that the Danish population is vulnerable to vCJD to the same degree as the British. In Finland, Slovakia, Turkey and Japan the higher frequency of the Met allele may increase the vulnerability to vCJD.

Introduction: Histological classification of brain tumours, including gliomas, can be difficult, and genetic investigations are increasingly significant in their classification and the development of treatment strategies. Oligodendrogliomas often show a loss of heterozygocity for the short arm of chromosome 1 and the long arm of chromosome 19 (LOH 1p/19q), changes that influence both treatment and prognosis. Our aim was to evaluate the incidence of combined loss of heterozygocity 1p and 19q in various glioma groups., Materials and Methods: A total of 10 oligodendrogliomas (5 WHO grade II and 5 grade III), 10 mixed gliomas (5 WHO grade II and 5 grade III), 10 astrocytomas (5 WHO grade II and 5 grade III) and 11 glioblastomas (WHO grade IV) were investigated. Normal hippocampal tissue was used as a control. Formalin-fixed paraffin-embedded tissue was scrutinized with fluorescent in situ hybridization (FISH) with fluorochrome-conjugated double-strand DNA probes for 1p and 19q, respectively., Results: A significiant loss of 1p/19q was found in the oligodendrogliomas; the astrocytomas showed a selective loss of 19q; the glioblastomas showed a selective loss of 1p but also polyploidy., Conclusion: This investigation confirms other reports on increased LOH 1p/19q in oligodendrogliomas. Various studies have demonstrated a large variation in the incidence of LOH 1p/19q. This might be due to inter- and intraobserver variability in the histological classification. Another factor might be variations in techniques. Most studies have been made on imprints. A standard for the method, including the number of cells counted, the cutoff limit and the statistical variation, is necessary for future studies and clinical use.