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Diffuse gliomas with MYB or MYBL1 alterations are rare tumours mostly affecting children or young adults with long-term epilepsy. This category of glioma includes two morphological subtypes. The angiocentric subtype is characterized by an angiocentric pattern of growth and a frequent MYB:QKI fusion. The isomorphic subtype corresponds to a highly differentiated astrocytic glioma with low cellularity, low proliferation and no specific microscopic features. The diagnosis is based on the imaging, demonstrating a supratentorial tumor, associated with the confirmation of a MYB or MYBL1 rearrangement. Here, we report the case of a 7-year-old child who presented a right frontal brain lesion corresponding to an isomorphic diffuse glioma with MYBL1 alteration.

BACKGROUND Diffuse astrocytic gliomas, IDH wildtype, with molecular features of glioblastoma (molecular glioblastomas) are associated with a poor prognosis. We previously found that these tumors frequently display gyriform infiltration, defined as areas of elective cortical hypersignal on MRI FLAIR sequence. The objective of the present study was to assess the diagnostic value of gyriform infiltration as an imaging marker for these tumors. MATERIAL AND METHODS MRI scans from 430 patients with newly diagnosed glioma (molecular glioblastoma n = 31, IDH wildtype glioblastoma n = 298, IDH-mutant astrocytoma n = 50, IDH-mutant and 1p19q codeleted oligodendroglioma n= 51) were evaluated for the presence of a gyriform infiltration by 2 independent reviewers. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the performance of the presence of a gyriform infiltration for identifying molecular glioblastoma. RESULTS A gyriform infiltration was observed in 16/31 (52%) patients with a molecular glioblastoma, 40/298 (13%) patients with an IDH-wildtype glioblastoma but in none of the patients with an IDH-mutant astrocytomas or an IDH-mutant and 1p19q codeleted oligodendroglioma. Among the 56 patients with a gyriform infiltration, 54 patients had an IDH wildtype pTERT mutant glioma and 2 an IDH wildtype pTERT wildtype glioma. Interrater agreement was good (κ= 0.68, P < 0.001). Specificity, sensitivity, PPV and NPV of the presence of a gyriform infiltration for the diagnosis of molecular glioblastoma were 90%, 29%, 52% and 96% and for the diagnosis of an IDHwt pTERT mutant glioma were 97%, 15%, 96% and 20%. The presence of a gyriform infiltration was associated with a worse prognosis in the entire cohort (13.6 months vs 29.3 months, P = .001). CONCLUSION Gyriform infiltration is a specific imaging marker of molecular glioblastomas and IDH wildtype pTERT mutant diffuse gliomas.

Purpose: This study aimed whether the uptake of amino tracer positron emission tomography (PET) can be used as an additional imaging biomarker to estimate the prognosis of glioma.Methods: Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) gradeⅡ-Ⅳ astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution.Results: Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (PFS) (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10-0.41, pp=0.025; glioblastoma: HR 11.52, 95%CI 2.27-58.47, p=0.0032), preoperative KPS≥80 (HR 0.23, 95%CI 0.09-0.62, p=0.004), maximum lesion-to-contralateral normal brain tissue (LN max)≥4.03 (HR 0.24, 95%CI 0.08-0.71, p=0.01), and isocitrate dehydrogenase (IDH) status (HR 14.06, 95%CI 1.81-109.2, p=0.011) were factors influencing overall survival (OS) in multivariate Cox regression. OS was shorter in patients with LN max≥ 4.03 (29.3 months) than in patients with LN maxp=0.03). OS differed significantly between patients with IDH mutant/LN maxIDH mutant/LN max ≥4.03.Conclusions: LN max using 11C-methionine PET may be used in prognostic markers for newly identified and untreated WHO gradeⅡ-Ⅳ astrocytic glioma.

Background& Objective: Micro-vascular proliferation is an important histological feature of brain glioma with more vascular proliferation is present in higher grades of glioma. CD 105 is expressed in new actively proliferating and immature endothelial cells in tumor environment and appears to be capable to distinguish between malignant neo-vasculature and normal vessels. Methods: This study was designed to evaluate the Micro-Vessel Density(MVD) in different grades of brain glioma based on CD 105 expression by Immunohistochemistry method to determine whether it can be a helpful marker for rumor grading or not. Paraffin blocks of formalin fixed samples of brain astrocytic glioma were retrieved and IHC was performed using anti-CD105 monoclonal mouse antibody. Results: Total number of 48cases of low and high grade astrocytic gliomas were evaluated.We noted that there was a positive correlation between MVD evaluated by CD105 and tumor grade, meaning that expression was significantly greater in tumors with higher grade (P=0.019). Conclusion: We concluded that MVD quantified by CD 105 has positive correlation with tumor grade. Also we think that expression of CD 105 specially in low-grade glioma can serve as a basis for selective treatment option in combination with current standard care .

Astrocytic gliomas are highly aggressive and lethal brain tumours that depend on angiogenesis for growth. The endothelial progenitor cell (EPCs) and von Willebrand factor (vWF) involved in the formation of new blood vessels in astrocytic glioma. Objectives: This study aimed to investigate the association between circulating and tissue resident EPCs with vWF in astrocytic glioma patients. Methods: Blood specimen and brain tissue biopsy were collected from a total of 22 astrocytic glioma patients admitted to Hospital Universiti Sains Malaysia. Circulating EPCs (blood) and tissue resident EPCs (tissue biopsy) were characterized using EPC-specific markers, CD133 and VEGFR2 and quantified using fluorescenceactivated cell sorting analysis and immunofluorescence microscopy, respectively. The plasma vWF was measured by using commercialized Elisa kit (Cusabio Biotech Co.,Ltd). Results: The mean percentage of circulating EPCs was (0.01 ± 0.01%), brain tumor tissue EPCs (0.48 ± 0.38%) and adjacent normal brain tissue EPCs (0.18 ± 0.23%). The mean plasma vWF was 9.23 ± 7.57%. Positive correlation was found between brain tumor EPCs and plasma vWF (Spearman’s rho r = 0.45, p = 0.035). However no correlation was found between adjacent normal brain EPCs and plasma vWF. About 14 patients had (mild vWF level of> 5%), 8 patients had (moderate vWF level of 1-5%) and no patients had (severe vWF level of < 1%). The mean percentage of patients with mild vWF level was 12.48 ± 7.77% and moderate vWF level was 3.53 ±1.32%. There was a significant correlation between circulating EPCs and patients with mild vWF level(Spearman’s rho r = 0.63, p = 0.015). Conclusion: This study demonstrated that EPCs have significant positive association with vWF suggesting the homing of plasma vWF at the tumor site. Article DOI: https://dx.doi.org/10.20319/lijhls.2015.11.4859 This work is licensed under the Creative Commons Attribution-Non-commercial 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/ or send a letter to Creative Commons, PO Box 1866, Mountain View, CA 94042, USA.

cIMPACT‐NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. From 2016 to 2019 (Round 1), cIMPACT published four updates. Update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed use of the additional term NEC (Not Elsewhere Classified). Update 2 issued clarifications regarding two diagnoses: Diffuse Midline Glioma, H3 K27M‐mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH‐mutant. Update 3 proposed molecular criteria that could be used in the setting of an IDH‐wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma to infer that the tumor would behave similarly to a grade IV glioblastoma. Update 4 suggested that, in children and young adults, subtypes of IDH‐wildtype/H3‐wildtype diffuse gliomas may have distinct clinical features in the setting of a BRAF (V600E) mutation, FGFR1 alteration, other MAPK pathway alteration, or a MYB or MYBL1 rearrangement. The practical diagnostic relevance of these cIMPACT proposals is highlighted in this summary.

2557 Background: In 2018, The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommended that IDH-wildtype diffuse astrocytic glioma Grade II/III with either EGFR amplification, combined whole chromosome 7 gain and whole chromosome 10 loss (+7/−10), or TERT promoter mutation should receive an integrated histological and molecular grade classification: Diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma, WHO grade IV. The natural history, radiologic characteristics and standard management for these patients has not been well described. They are typically excluded from clinical trials for WHO Grade IV gliomas. Methods: Adults diagnosed at Massachusetts General Hospital with IDH wildtype diffuse astrocytoma and EGFR amplification or TERT promoter mutation from 2011-2019 were identified. Demographics, functional status, radiologic features, MGMT promoter methylation status, time to progression, and overall survival were collected retrospectively. Qualitative MRI data was analyzed using the VASARI feature set. Response assessment was performed using the RANO criteria. Results: 50 patients were identified (table). 37/50 patients received standard Stupp protocol, 2/50 received hypofractionated radiotherapy with temozolomide, 6/50 received radiotherapy alone, and 1 patient received a MEK inhibitor. None were enrolled in clinical trials at diagnosis. mPFS was 10 months in the 47/50 with confirmed progression and mOS in the patients with confirmed deaths (40/50) was 17.5 months (4-47). 9/50 patients are alive with survival ranging 6-52 months. Conclusions: Outcomes for patients with molecularly defined GBM were variable. Analysis of the cohort to characterize factors that led to the observed variability is in progress. More studies on molecularly defined glioblastomas are required to better understand their behavior and to provide guidance for their inclusion or exclusion in clinical trials. [Table: see text]

Working Committee 1 concluded that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that contain high-level EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (+7/−10), or TERT promoter mutations, correspond to WHO grade IV and should be referred to as diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV. Assessment of classification by DNA methylation profiling and additional +7/−10 signatures appear to be promising as well and could be considered in the future following additional experience and validation. We also concluded that specific molecular signatures in subsets of IDH-wildtype diffuse astrocytic gliomas are associated with better clinical outcomes and should not lead to a high-grade designation, including, but not limited to, those gliomas with MYB/MYBL or BRAF alterations as individual drivers.

BACKGROUND The treatment strategies of astrocytoma have not changed considerably due to the restricted appreciation of its biology. OBJECTIVES This study aimed to evaluate the expression of the stem cell-related proteins (CD133 and Sox2) and their prognostic value in astrocytic glioma. METHODS The immunohistochemical expression of CD133 and Sox2 in 40 patients with an astrocytic glioma of different grades was studied. The recorded data on the overall survival (OS), progression-free survival (PFS) and the response to the therapeutic protocol were collected and lastly analyzed. RESULTS CD133 expression was observed in 87.5% of the cases, while positive Sox2 expression was found in all the studied cases. There was a significant association of CD133 expression with the histological grade and the tumor size (p< 0.001). A significant association of Sox2 with the histological grade and the tumor size was noted (p= 0.004, p= 0.006 respectively). Up-regulation of both CD133 and Sox2 had a significant association with poor clinical response to the therapy (p< 0.001 for each). Shorter OS and PFS were related to CD133 and Sox2 overexpression. CONCLUSIONS Astrocytoma with CD133 and Sox2 overexpression had an unfavorable prognosis and poor clinical response to the current therapeutic protocol.

To date the management of glioma remains a great challenge in cancer therapy worldwide. The identification of novel diagnostic and therapeutic methods is required. Although there is data indicating that matrix metalloproteinase (MMP)-26 serves an important role in many human cancer types, its clinical significance in glioma remains uncertain. The present study aimed to evaluate MMP-26 expression in human astrocytic glioma specimens, and investigate its role and significance in the progression of astrocytic glioma. Immunohistochemistry was performed to assess MMP-26 expression in astrocytic glioma tissues. The levels of MMP-26 expression and its relevance to the clinicopathological features and prognostic factors in patients with astrocytic glioma patients were then investigated. The results demonstrated that MMP-26 expression was significantly assocaited with the World Health Organization grade (P

Astrocytic gliomas are the most common and lethal form of intracranial tumors. These tumors are characterized by a significant heterogeneity in terms of cytopathological, transcriptional, and (epi)genomic features. This heterogeneity has made these cancers one of the most challenging types of cancers to study and treat. To uncover these complexities and to have better understanding of the disease initiation and progression, identification, and characterization of underlying cellular and molecular pathways related to (epi)genetics of astrocytic gliomas is crucial. Here, we discuss and summarize molecular and (epi)genetic mechanisms that provide clues as to the pathogenesis of astrocytic gliomas. (Figure presented.). © 2018 International Society for Neurochemistry

Objectives The significance of conventional neuroimaging features for predicting molecular diagnosis and patient survival based on the updated World Health Organization (WHO) classification remains uncertain. We assessed the relevance of neuroimaging features (ring enhancement [RE], non-ring enhancement [non-RE], overall gadolinium enhancement [GdE], and intratumoral calcification [IC]) for molecular diagnosis and survival in glioma patients. Patients and methods We evaluated 234 glioma patients according to the updated WHO classification. Isocitrate dehydrogenase (IDH), H3F3A, BRAF hotspot mutations, TERT promotor mutation, and chromosome 1p/19q co-deletion were examined. RE, non-RE, GdE, and IC were evaluated as significant neuroimaging findings. Kaplan-Meier analyses were performed to evaluate overall survival (OS) and the correlations of prognostic factors were evaluated by log-rank tests. Univariate and multivariate analyses were performed to detect prognostic factors for OS. Results A total of 207 patients were eligible. In 110 patients presenting RE, 102 (93%) were glioblastoma (GBM), IDH-wild type. In 97 patients without RE, presence of GdE or IC were not significantly different between IDH-mutant and -wild type tumors, whereas presence of GdE was a significant indicator of higher WHO grades. IC was the only significant finding for 1p/19q co-deleted tumors. TERT promoter mutation was observed in 7/17 patients with diffuse astrocytic glioma, IDH-wild type; recently-defined as “molecular GBM.” IC, RE, and GdE were observed with lower prevalence in molecular GBMs. While presence of RE, GdE, and absence of IC were significant factors of OS in overall cohort, presence of GdE was not significant in OS in cases without RE, and IDH-mutant tumors. IC was a significant predictor of favorable OS in cases without RE and IDH-wild type tumors. Multivariate analysis also validated these findings. Conclusion GdE alone is not a significant predictor of IDH mutation status, but the pattern of enhancement is a significant predictor with RE demonstrating high sensitivity and specificity for GBM, IDH-wild type. Predicting “molecular GBM” by conventional neuroimaging is difficult. Moreover, GdE is not a significant factor of survival analyzed with pattern of enhancement or molecular stratifications. IC is an important radiographic finding for predicting molecular diagnosis and survival in glioma patients.

BACKGROUND Although the word “glioblastoma” still denotes a grade-IV pathology, basic molecular studies have clearly indicated that a significant proportion of lower-grade gliomas harbor genetic alterations typical of glioblastomas. Based on these findings cIMPACT-NOW update 3 has defined an entity called the “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. A TERT-promoter mutation is one of these typical molecular markers of glioblastomas. In this study we analyzed IDH-wild type, TERT-mutant diffuse gliomas of different pathological grades to look for differences in demographic, clinical and survival characteristics. MATERIAL AND METHODS 147 adult hemispheric diffuse-gliomas with wild-type IDH1/2 and mutant TERT-promoter (C228T or C250T) were retrospectively analyzed. Primary thalamic, cerebellar brainstem or spinal cases were excluded. 126 (86%), 16(11%) and 5(3%) patients were WHO grade IV, III and II respectively. After surgical treatment or stereotactic biopsy all patients underwent chemoradiation. Median follow-up was 16mo (1–110). Tumors of different grades were compared for age, gender, multifocality, gliomatosis pattern, Ki-67 index, progression-free survival and overall-survival. RESULTS Mean age at presentation for grade II, III and IV were comparable (58.1, 58 and 58.1; ANOVA, p=0.72). There was a slight male predominance in both lower-grades and WHO-grade IV (M:F ratios 1.625 and 1.74). Mean Ki-67 index was significantly higher in higher grades (0.06, 0.14 and 0.25 for grades II, III and IV; ANOVA, p=0.001). Multifocality was comparable (chi-sq, p=1) in lower-grades (3/21; 14.3%) vs. WHO-grade IV (18/126; 14.3%). Gliomatosis pattern was comparable (chi-sq, p=0.095) in lower-grades (2/21; 9.5%) vs. (3/126; 2.3%). Median recurrence free survival (RFS) was 16 months (0–63) in lower-grades and 8months (1–50) in WHO-grade IV. PFS was significantly different between 3 WHO-grades (Log rank, p=0.007) and also between lower-grades and WHO-grade IV (Log rank, p=0.002). Median overall survival was 26 months(2–110) in lower-grades and 15mo(1–91) in WHO-grade IV. OS was significantly different between 3 WHO-grades (Log rank, p=0.014) and also between lower-grades and WHO-grade IV (Log rank, p=0.007). CONCLUSION Increasing pathological grades of hemispheric “IDH-wild type, TERT-mutant diffuse gliomas” have similar demographic and clinical characteristics but incrasing proliferation indices, decrasing progression free survival and shorter overall survival. The findings may be suggesitve of different grades of one common tumor entity.

Fifty patients of both sexes of Astrocytic Glioma from Sheikh Zayed Hospital and Lahore General Hospital Lahore were included in this study. Ten normal brain tissues (control) were taken from accident cases. Out of 50 study cases there were 16 (32%) were low grade (I-II) Astrocytic Glioma and 34 (68%) were high grade Astrocytic Glioma. The male to female percentage was found out to be 26 (52%) and 24 (48%) respectively. Among the males, 11 (22%) were in grade I-II while 15 (30 %) were in grade III-IV Astrocytic Glioma, while 5 (10 %) females were in grade I-II and 19 (38 %) were in grade No statistical sex difference was seen in the ratio of male and female who developed Astrocytic Glioma (P>0.05). The ages of the patients ranged from 10 to 76 years with maximum number of cases in the age group 30-49 years. In this age group, 11 (22%) patients had grade I-II while 20 (40%) were in grade type of Astrocytic Glioma. The statistical difference of age in different groups was found to be highly significant, (P

Astrocytic gliomas are the most common glioma subtype and constitute the majority of all primary brain tumor types. The malignancy of an astrocytic glioma is classified into one of four grades (I-IV) based on its infiltrative and proliferative characteristics, wherein the extent of this diffuse tissue and depth of embedment into normal brain tissue correlates to the degree of difficulty in accurately identifying and directly visualizing the requisite tumor tissue for achieving its complete resection. To date, no single- or multimodal imaging agent can noninvasively identify intracranial gliomas or accurately distinguish its grade as well as facilitate the direct visualization of its diffuse and deeply-embedded tissue in real-time. The standard imaging modalities for lesion detection (MRI and CT) provide anatomical information which have limited application in the pre- and post-surgical setting for identifying and grading tumor types as well as in monitoring for early-stage and recurrent growth, thereby creating a critical gap in evaluating invasive brain tumors that these techniques cannot successfully fill. Positron emission tomography (PET) is the ideal imaging modality that could fill this gap due to its ability to report on biological processes with superior sensitivity. However, conventional PET probes for gliomas operate on ubiquitously-expressed targets which provide insufficient or unreliable contrast levels between tumor and normal brain tissue or amongst low-grade gliomas. The standard of care for treating brain tumors entails unguided surgical resection followed by a tailored radio- and/or chemotherapy regimen that depends on tumor type and grade. As such, the extent of surgical resection largely governs patient survival time. Fluorescence-guided surgery (FGS) improves maximal resection of tumor tissue while preserving eloquent brain tissue. Primarily 5-aminolevulinic acid (5-ALA) is used in the FGS of brain tumors. However, its fluorescent product emits at short wavelengths and operates via nonselective signal accumulation, which affords limited tissue penetration and false-positive demarcations. The advent of near-infrared fluorescence (NIRF)-guided surgery leverages conventional (nontargeted and/or unactivatable) NIR fluorophores for tumor tissue visualization at 10-fold greater penetration depths, but poorly delineate tumor margins due to generating minimal signal accumulation and high background. To these ends, we have worked to develop a PET/NIRF smart probe for noninvasively identifying and grading intracranial astrocytic gliomas as well as affording direct visualization of its diffuse and deeply-embedded tumor tissue upon its application to NIRF-guided surgery. The multimodal smart probe uses a molecular logic gate design strategy to target a select active enzyme that serves as a validated prognostic factor for astrocytic gliomas. Citation Format: Kenneth S. Hettie, Eben L. Rosenthal, Frederick T. Chin. A multimodal (PET/NIRF) smart probe for selectively identifying, grading, and visualizing astrocytic gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4113.

The current WHO classification of brain tumors defines gliomatosis cerebri (GC) as an extensively infiltrating astrocytic glioma involving at least three cerebral lobes. The relation of GC to diffuse astrocytomas and glioblastoma is uncertain. Due to malignant biological behavior, GC is allotted to WHO grade III. Recent reports showed IDH1 mutations in astrocytic and oligodendroglial tumors WHO grades II and III and in secondary glioblastomas with a frequency of up to 90%, whereas IDH1 mutations occurred in only 5% of primary glioblastomas. Here, we examined the frequency of IDH1 mutations in 35 GC samples by direct sequencing, derived cleaved amplified polymorphic sequence analysis and immunohistochemistry. We identified IDH1 mutations in 10/24 (42%) cases, which also included a solid tumor portion (type 2 GC), but not in 11 “classical” cases without solid tumor mass (type 1 GC). TP53 mutations were revealed in two type 2 GC, but not in any type 1 GC, while combined chromosomal losses of 1p and 19q were not found at all. Our data suggest that GC consists of two histological/molecular subtypes, type 1 being clearly distinct from diffuse astrocytoma, and type 2 sharing features with diffuse astrocytoma.

Background: Identification of the cellular origin of astrocytic gliomas is a step for improving the treatment strategies. Tumor stem cells have been detected in different neoplasms and have a major role in tumor initiation, progression and therapy resistance. Objective: The study aimed to investigate the expression of nestin and survivin in different grades of astrocytic glioma as well as evaluation of their prognostic role in relation to other prognostic parameters. Methods: Immunohistochemical expressions of nestin and survivin were evaluated in 40 paraffin blocks of different grades of astrocytic glioma and correlated with other prognostic parameters. The obtained data were statistically analyzed. Results: The cases included 10 low grade, 12 anaplastic and 18 glioblastoma multiforme. There was a significant correlation between each of nestin and survivin with the histological grade of astrocytoma and tumor size (p < 0.001). Nestin was strongly correlated to survivin index (p < 0.001). The univariate analysis showed that high histological grade, high nestin score and high survivin index were significantly correlated with overall survival. Multivariate analysis for all investigated cases proved the independent prognostic significance of the nestin expression (p = 0.011). Conclusion: Nestin and survivin are adverse prognostic markers for astrocytic glioma that increase significantly with tumor progression and associated with poor overall survival. Therefore, nestin and survivin could be used to predict high risk group of astrocytoma with unfavorable outcome.

Diffuusisti infiltroivat astrosytoomat ovat primaareista aivokasvaimista yleisimpiä ja pahanlaatuisimpia. Nykyisillä hoitomuodoilla, kasvaimen kirurgisella poistolla sekä mahdollisella sädehoidolla ja kemoterapialla, ei saavuteta sairautta parantavaa hoitotulosta. Gliooman aggressiivisinta tautimuotoa eli glioblastoomaa sairastavien kuolleisuus on kolmannen vuoden jälkeen 95 prosenttia. Tutkimuksen kohteena olevat hiilihappoanhydraasit (carbonic anhydrase, CA) ovat keskeisiä syövän synnyssä monissa kasvaimissa. Niiden ilmentyminen liittyy usein potilaiden huonoon ennusteeseen, ja niitä on pidetty mahdollisina kohdemolekyyleinä syöpähoidoille. Syöpäsolujen lisääntynyt jakautuminen eli proliferaatio on tyypillinen piirre aggressiivisille glioomille. Väitöskirjassa kuvattiin uusi proliferaatiovärjäysmenetelmä (Ultrarapid-Ki67®). Tämän avulla voidaan neurokirurgisen leikkauksen aikana tehdä nopeasti diagnostiikkaa helpottava Ki-67 värjäys jääleikenäytteestä. Sen tulokset olivat morfologisesti ja kvantitatiivisesti identtiset verrattuna tavalliseen Ki-67 / MIB-1 -värjäykseen. Lisäksi väitöskirjassa kuvattiin ensimmäistä kertaa hiilihappoanhydraasien II, IX ja XII ilmentyminen laajassa astrosytooma-materiaalissa. Immunohistokemia osoitti CA II:n ilmentyvän glioblastoomien uudisverisuonien endoteelissä. CA IX sekä CA XII esiintyivät pääasiassa syöpäsoluissa. RT-PCR -menetelmän avulla havaittiin, että CA XII on pääasiallisesti vaihtoehtoisen silmukoinnin avulla tuotettu lyhyempi variantti. CA -entsyymit eivät assosioituneet syöpäsolujen proliferaatioon. Endoteeliin paikantuvan CA II:n sekä syöpäsolujensisäisten CA IX:n ja CA XII:n esiintyminen ennusti potilaiden lyhyempää eloonjäämisaikaa. Lisäksi CA IX ja CA XII toimivat itsenäisinä ennustetekijöinä monimuuttuja-analyyseissä. Tutkimuksen johtopäätöksinä Ki-67 pikavärjäysmenetelmä (Ultrarapid-Ki67®) on nopeutensa ja luotettavuutensa perusteella käyttökelpoinen kasvaimien leikkauksenaikaisessa diagnostiikassa. Hiilihappoanhydraasit ilmentyvät laajasti astrosyyttisissä glioomissa. Niillä vaikuttaisi olevan tärkeä biologinen merkitys kasvainten pahanlaatuistumisessa, ja ne toimivat ennustetekijöinä. Background: Diffusely infiltrating astrocytomas are the most common primary brain tumours and most malignant of all brain tumours. These malignant gliomas are classified to WHO grades II to IV. Grade IV glioblastoma represents a devastating tumour type with a 5-year survival rate below 10%. The best treatment option available today, that is surgery possibly combined with radiation- and/or chemotherapy, is insufficient. Therefore, brain tumour research has focused on understanding of the pathogenesis, and accordingly, has aimed to develop better methods for cancer diagnostics and treatment. Carbonic anhydrases (CAs), investigated in this study, have previously been linked to carcinogenic processes of several malignancies, and are proposed to represent an attaractive target for cancer therapy. Aims: The purpose of this study is to describe the expression of CAs in astrocytic gliomas and study their relationship to clinicopathological features, especially the proliferation of cancer cells measured by Ki-67 / MIB-1. Another aim is to develop methods for improved diagnostics and to predict more accurately survival of patients with astrocytic gliomas. The additional objective of this study is to characterize possible targets for future therapeutic interventions of gliomas. Results: In the first study, a new method is introduced for intraoperative immunohistochemical staining of a proliferation marker, Ki-67 (Ultrarapid-Ki67®). This method was practical to perform and morphologically and quantitatively indistinguishable from the conventional Ki-67 / MIB-1 staining. In the following three studies, the expression of CAs II, IX, and XII is described in a large series of diffusely infiltrating astrocytomas for the first time. By immunohistochemistry, CA II was detected in the neovessels of high-grade gliomas, whereas CA IX and CA XII were mainly located in cancer cells. A short isoform of CA XII by alternative splicing was also introduced into gliomas. None of the CAs correlated to tumour cell proliferation by Ki-67 / MIB-1, whereas CA IX was associated with necrotic tumour regions. The expression of all CAs was significantly associated with higher WHO grade. Most importantly, the expression of all CAs predicted poor survival of patients in univariate analysis, and CA IX and CA XII were significant predictors of survival even in multivariate analysis. Conclusions: CA II, IX, and XII are expressed in astrocytic gliomas and the expression increases within increasing WHO grade. Being involved in carcinogenesis, CAs could be used in predicting poor survival of patients. CAs seem to be potential target molecules for therapy in gliomas, which should be evaluated in clinical trials. CAs were not associated with tumour cell proliferation as evaluated by Ki-67 / MIB-1 staining. In addition, Ultrarapid-Ki67® immunostaining, as a fast and reliable method for proliferation estimation, could be used in routine intraoperative diagnosis of gliomas.

Contains fulltext : 50070.pdf (Publisher’s version ) (Closed access) Time trends in the incidence of glioma may reflect changes in the prevalence of environmental risk factors for glioma. We therefore investigated trends in the incidence of childhood and adult glioma in The Netherlands from 1989 to 2003. We used population-based incidence data from the Netherlands Cancer Registry. We calculated European standardised incidence rates for glioma, and stratified for age, gender and glioma subgroups. Changes in the incidence were estimated by calculating the Estimated Annual Percentage Change. Similar to other countries, the overall incidence of glioma was fairly stable in The Netherlands during the period 1989 to 2003, for both children and adults. In adult astrocytic glioma, a significantly increasing incidence of high-grade astrocytoma was balanced by simultaneous decreases of low-grade astrocytoma, astrocytoma with unknown malignancy grade and glioma of uncertain histology. Most of these time trends can be explained by improving detection and diagnostic precision. Stable incidence rates of adult and childhood glioma suggest that no major changes in environmental risk factors have occurred, which influenced the incidence of glioma in the studied period.

Introduction: Astrocytic gliomas are the most common and lethal intracranial brain tumours and rely on angiogenesis for the tumour development. Endothelial progenitor cells (EPCs) contribute to the angiogenesis of glioma tumour. Objectives: The study aimed to investigate the matured circulating endothelial cells population in the peripheral blood mononuclear cells (PBMCs) and its associations with tissue resident angiogenic cells in astrocytic glioma patients. Methods: A total of 22 astrocytic glioma patients were recruited from Hospital Universiti Sains Malaysia. Tumour were sliced and stained with CD133+ and VEGFA+ for angiogenic cells (n=22). The circulating (CD133-/VEGFR2+) matured endothelial cells in PBMCs (n=22) were quantified using FACS. The paired t-test and Pearson correlation test were used for the data analysis. Results: The angiogenic cells in brain tumour tissue were significantly higher compared to adjacent normal brain tissue (median 1.07±0.96% vs. median 0.69±0.68%; Wilcoxon signed rank test Z=-3.100; p=0.002). Positive correlation was found between the angiogenic cells of brain tumour tissue and adjacent normal brain tissue (Spearman’s rho correlation test, r=0.56; p=0.007). Significant positive correlation was found between matured endothelial cells in peripheral circulating systems and angiogenic cells in tumour of astrocytic glioma patients (Pearson correlation test, r=0.60, p=0.003).Conclusion:The findings of the study give support to the possible roles of EPCs in astrocytic glioma patients. Thus targeting tissue resident angiogenic cells and matured circulating endothelial cells by antiangiogenic treatment might be useful to prevent the tumour growth.