Secondary Glioblastoma Multiforme Research Articles

The PTPRZ1-MET/STAT3/ISG20 axis in glioma stem-like cells modulates tumor-associated macrophage polarization

Recent studies have revealed that PTPRZ1-MET (ZM) fusion plays a pivotal role in the progression of glioma to glioblastoma multiforme (GBM), thus serving as a biomarker to distinguish between primary GBM and secondary GBM (sGBM). However, the mechanisms through which ZM fusion influences this progression remain to be elucidated. GBMs with ZM showed poorer prognoses and greater infiltration of tumor-associated macrophages (TAMs) than those without ZM. Glioma stem-like cells (GSCs) and TAMs play complex roles in glioma recurrence, glioma progression and therapy resistance. In this study, we analyzed RNA-seq data from sGBM patients' glioma tissues with or without ZM fusion, and found that stemness and macrophage markers were more highly expressed in sGBM patients harboring ZM than in those without ZM fusion. ZM enhanced the self-renewal and proliferation of GSCs, thereby accelerating glioma progression. In addition, ZM-positive GSCs facilitated the infiltration of TAMs and drove their polarization toward an immunosuppressive phenotype, which was primarily accomplished through the extracellular secretion of ISG20. Our research identified the MET–STAT3–ISG20 axis within GSCs, thus demonstrating the critical role of ZM in GBM initiation and progression. Our study demonstrated that, in contrast to ZM-positive differentiated glioma cells, ZM-positive GSCs upregulated ISG20 expression through the MET–STAT3–ISG20 axis. The extracellular secretion of ISG20 recruited and induced M2-like polarization in macrophages, thereby promoting tumor progression. Our results reveal a novel mechanism involved in ZM-positive GBM pathogenesis and identify potential therapeutic targets.

Locoregional Treatment of Glioblastoma With Targeted α Therapy: [ 213 Bi]Bi-DOTA-Substance P Versus [ 225 Ac]Ac-DOTA-Substance P-Analysis of Influence Parameters.

Glioblastoma (GB) is the most malignant primary brain tumor. Therefore, introduction of new treatment options is critically important. The aim of this study was to assess local treatment with α emitters [ 213 Bi]Bi-DOTA-substance P (SP) and [ 225 Ac]Ac-DOTA-SP. Treatment was performed as salvage therapy in patients with recurrent primary and secondary GB. [ 213 Bi]Bi-DOTA-SP with injected activity 1.85 GBq per cycle was used in 20 primary (48.2 ± 11.8 years old) and in 9 secondary (38.8 ± 10.8 years old) GB patients and [ 225 Ac]Ac-DOTA-SP in 15 primary (45.1 ± 9.9 years old) and in 6 secondary (37.8 ± 6.4 years old) GB patients with a dose escalation scheme (10, 20, and 30 MBq). Local treatment with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP was well tolerated with only few adverse effects. There was no statistically significant difference between [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP groups in survival parameters. For primary GB, survival parameters of patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows(in months): progression-free survival time, 2.7 versus 2.4; OS-d (overall survival from time of diagnosis to death from any cause), 23.6 versus 21.0; OS-t (overall survival from the start of treatment to death from any cause), 7.5 versus 5.0; and OS-r (overall survival from recurrence in primary tumors to death from any cause), 10.9 versus 12.0. Survival parameters of secondary GB patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows (in months): progression-free survival time, 5.8 versus 2.4; OS-d, 52.3 versus 65.0; OS-t, 16.4 versus 16.0; and OS-c (overall survival from conversion into secondary GB multiforme to death from any cause), 18.4 versus 36.0. The similarity results of 213 Bi or 225 Ac may suggest that the local treatment of brain tumors can be greatly simplified. The experience to date shows that local radioisotope treatment of brain tumors requires further dosimetry studies, taking into account the complexity of biological processes.

Clinicopathological Correlation of Glioma Patients with respect to Immunohistochemistry Markers: A Prospective Study of 115 Patients in a Tertiary Care Hospital in North India.

Background:With the incorporation of molecular subtyping in glioma patients in 2016 WHO classification, there is a need to understand the immunohistochemistry (IHC) marker expression in various glioma patients and to clinically correlate with various subgroups.Objective:Aim of the study was to assess IHC marker expression profile in glioma patients and to clinically correlate them in various subgroups.Materials and Methods:The prospective study included 115 glioma patients. IHC markers (isocitrate dehydrogenase [IDH] 1, ATRX, P53, Ki-67 antibody) were done in all patients. Patients received treatment as per the grade of tumor. The patients were followed in 3 monthly intervals, for a period of 12 months. SPSS software version 20.0 was used for statistical analysis. Tables were prepared in Microsoft Excel sheet. Kaplan–Meier method was used for survival analysis.Results:There were 11 Grade 1, 33 Grade 2, 26 Grade 3, and 45 glioblastoma multiforme (GBM) patients out of which 10 patients were secondary GBM cases. IDH1 mutation is frequent in Grade 2 and Grade 3 tumors of both astrocytic and oligodendroglia tumors. Its mutation is also common in secondary GBM patients. ATRX mutation is specific to astrocytic lineage, Grade 2, Grade 3, and secondary GBM patients.Conclusion:Molecular nature of DA and AA cases can be accurately confirmed by combined IDH1 and ATRX IHC thereby avoiding costly investigations such as fluorescence in situ hybridization. In astrocytic tumors, p53 can act as a surrogate marker. IDH-mutant glioma patients have better prognoses than IDH wild gliomas.

Evaluation of effect of epidermal growth factor receptor and vascular endothelial growth factor overexpression in survival of patients with glioblastoma multiforme

Background. In the central nervous system, glioblastoma multiforme (GBM) is one of the most important neoplasms in adults. Amplification of EGFR and VEGF genes is common in GBM. However, the role of overexpression of EGFR and VEGF in survival of patients with GBM has been a contentious issue. Therefore, we performed the present study to assess the survival rate of patients with EGFR and VEGF overexpression. Materials and methods. Resected samples of GBM patients were evaluated by immunohistochemistry for overexpression of VEGF and EGFR. The patients were followed up for a year. Results. The mean±sd of age of patients was 56.2±13.1 years. The majority of the patients were male (65.9%). Most of the patients had primary GBM (67%), notwithstanding 33% of the patients with secondary GBM. Moreover, 19.2% and 49.5% of the samples were VEGF-positive and EGFR-positive, respectively. Overall 6, 12-, and 18-month survival rates were shown to be 61.5±5.1%, 17.6±4%, and 4.4±2.1%, respectively. There was a significant difference between the mean±se survival rate in VEGF-negative patients (12±1.9 months) VEGF-positive patients (7.8±0.5 months) (P=0.045). Conclusions. We found an association between VEGF and EGFR over-expression and the survival rate of GBM patients. The VEGF overexpression was significantly associated with the overall survival rate of the GBM patients, but failed to have a prognostic value for their mortality rate. However, EGFR was a predictor of overall survival rate and mortality of GBM patients. Moreover, VEGF overexertion has a stronger association with survival rate in GBM, compared to EGFR overexpression.

Proceeding of Glioblastoma Multiforme (GBM): An Advanced Overview

Glioblastoma multiforme (GBM) is a central nervous system tumor of grade IV histological malignancy according to the WHO classification. GBM is an extraordinary tumor and the worldwide incidence is less than 10 per 100,000 individuals. The prognosis of this tumor is meagre and survival rate is 15 months subsequent to diagnosis. Such an atrocious image of this tumor is responsible for a major issue of public health. This tumor develops from normal glial cells through multistep oncogenesis. Genetic alterations and deregulations of molecular pathways are responsible for development of both primary and secondary GBM. Diagnosis of GBM is performed by imaging techniques. These non-invasive imaging techniques are magnetic resonance imaging (MRI), computed tomography (CT) and Positron emission tomography (PET). Definitive diagnosis of GBM is based on histopathological examination of the intra operatively removed tumor or its parts, using traditional histological, cytologic and histochemical methods. NMR (Nuclear Magnetic Resonance) spectroscopy based possible diagnostic significance of GBM is also reported. Treatment of glioblastoma multiforme includes tumor resection, as well as radiotherapy and chemotherapy. Nanomedicine and bacterial protein based therapeutic approaches are in the developmental stage. There is always need of the development of new therapeutic approaches for GBM to improve the survival and quality of life.

Detection of IDH mutations in cerebrospinal fluid: A discussion of liquid biopsy in neuropathology

Isocitrate dehydrogenase (IDH) mutations are a common event in secondary glioblastoma multiforme and lower-grade adult infiltrative astrocytomas and independently confer a better prognosis [1,2]. These are highly conserved mutations during glioma progression and thus also a useful diagnostic marker amenable to modern molecular sequencing methods. These mutations can even be detected in sites distant from the primary tumour. We use an illustrative case of a patient with radiologically suspected recurrent astrocytoma and negative histology, but positive IDH-mutated tumour DNA detected within CSF. Our results demonstrated the usefulness of liquid biopsy for recurrent glioma within the context of equivocal or negative histopathological results, whilst also showing the ability to detect a de-novo IDH-2 mutation not present in the previous resection. Building on this ‘proof-of-concept’ result, we also take the opportunity to briefly review the current literature describing the various liquid biopsy substrates available to diagnose infiltrative gliomas, namely the study of circulating tumour DNA, circulating tumour cells, and extracellular vesicles. We outline the current challenges and prospects of liquid biopsies in these tumours and suggest that more studies are required to overcome these challenges and harness the potential benefits of liquid biopsies in guiding our management of gliomas.

Whole-transcriptome sequencing profiling identifies functional and prognostic signatures in patients with PTPRZ1-MET fusion-negative secondary glioblastoma multiforme.

Gliomas are the most common type of primary brain tumor in adults with a high mortality rate. Low-grade gliomas progress to glioblastoma multiforme (GBM) in the majority of cases, forming secondary GBM (sGBM), followed by rapid fatal clinical outcomes. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1)-MET proto-oncogene receptor tyrosine kinase (MET) (ZM) fusion has been identified as a biomarker for sGBM that is involved in glioma progression, but the mechanism of gliomagenesis and pathology of ZM-negative sGBM has remained to be fully elucidated. A whole-transcriptome signature is thus required to improve the outcome prediction for patients with sGBM without ZM fusion. In the present study, whole-transcriptome sequencing on 42 sGBM samples with or without ZM fusion from the Chinese Glioma Genome Atlas database identified mRNAs with differential expression between patients with and without ZM fusion and the most significant survival-associated genes were identified. A 6-gene signature was identified as a novel prognostic model reflecting survival probability in patients with ZM-negative sGBM. Clinical characteristics in patients with a high or low risk score value were analyzed with the Kaplan-Meier method and a two-sided log-rank test. In addition, ZM-negative sGBM patients with a high risk score exhibited an increase in immune cells, NF-κB-induced pathway activation and a decrease in endothelial cells compared with those with a low risk score. The present study demonstrated the potential use of a next-generation sequencing-based cancer gene signature in patients with ZM-negative sGBM, indicating possible clinical therapeutic strategies for further treatment of such patients.

Quantitative analysis of 2-hydroxyglutarate as a controversial oncometabolite in malignant gliomas.

There is a great effort to connect the accumulation of 2-hydroxyglutarate (2-HG) oncometabolite with cellular onco-epigenetic status and subsequently predict the prognoses of glioma patients. In this observational study, the concentrations of D- and L- 2-HG were determined in 57 tumor tissue samples of glioma patients (n=57) WHO grade I through IV (astrocytoma, oligodendroglioma, secondary glioblastoma, and glioblastoma multiforme) in vitro. Also, genetic mutation status on isocitrate dehydrogenase 1 and 2 (IDH 1/2) was determined from these samples. The objective of this study was to confirm or to reject the hypothesis of the direct correlation of 2-HG concentration in tumor tissue and the results from IDH 1/IDH 2 point mutation analyses. The concentrations of 2-HG were quantified using high sensitive HPLC and Q-TOF HRMS spectrometer setup. Concurrently, the genetic mutation analyses of both IDH 1 (cytosolic) and IDH 2 (mitochondrial) were performed by the isolation of tumor tissue DNA, PCR amplification, and subsequent Sanger forward sequencing. Our results indicate that there is no definite correlation between the two as we identified cases of glioma tumors with significantly increased concentration of one or both L- and D- 2-HG but no IDH 1/2 mutations (44% 2-HG positive cases).

Copy number variations in critical cell-signalling genes with potential targeted therapeutic application

Abstract Background Brain tumours are among “hard-to treat” world malignancy with the median survival time of 15 months for the most aggressive form - Glioblastoma multiforme (GBM). It is extremely complex and heterogeneous brain cancer, characterized by rapid progression, infiltration and therapeutic resistance. Currently, many trials for target therapy are focused on understanding the molecular heterogeneity of GBM and designing molecules that inhibit most common genetic alterations. Methods In the present study, somatic copy number variations (CNVs) in critical signalling genes suitable for future target therapy are examined among Bulgarian patients. Fresh brain biopsies were collected from patients with primary and secondary GBM. Genomic DNA was isolated and CNVs were analysed by Multiplex ligation – dependent probe amplification (MLPA). Results CDKN2A deletion is the most frequent genetic alteration (78%) among Bulgarian patients with GBM. The loss of this gene is a progression-associated genetic marker. Nearly 60% of GBM patients showed EGFR amplification. It is a prognostic and predictive marker and some patients with this aberration are suggested to respond better to EGFR inhibitors in combination therapy. PTEN deletion is another common event with the incidence rate of 33% and its loss corelates with the choice of mTOR and MEK inhibitors, as well as, the resistance to some EGFR inhibitors. TP53 deletion was found in only 11% of the analysed patients which is a positive marker and the presence of wild-type TP53 is targeted by a MDM2 inhibitors. In addition, MDM2 amplification was observed in one patient and this event also serve as a potential target by MDM2 inhibitors.Amplification in PDGFRA is observed in one patient. Depending on the status of other receptor tyrosine kinases, it could be targeted by PDGFR inhibitor and is also suggested to be a poor prognostic marker. Conclusions Personalized treatment, customized for an individual patient genetics, has the potential to improve the therapy response. CNVs data could be useful for designing more effective personalized therapy. This is a small study on CNVs with potentially targeted therapeutic application in GBM for Bulgaria and recruitment of more patients is in progress. Legal entity responsible for the study The authors. Funding Medical University Sofia, Grant number D-127/2019. Disclosure All authors have declared no conflicts of interest.

Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature.

Glioblastoma multiforme (GBM) is still a deadly disease with a poor prognosis and high mortality, despite the discovery of new biomarkers and new innovative targeted therapies. The role of genetic mutations in GBM is still not at all clear; however, molecular markers are an integral part of tumor assessment in modern neuro-oncology. We performed a Medline search for the key words "glioblastoma," "glioblastoma multiforme," and "genetic" or "genetics" from 1990 to the present, finding an exponential increase in the number of published articles, especially in the past 7 years. The understanding of molecular subtypes of gliomas recently led to a revision of the World Health Organization classification criteria for these tumors, introducing the concept of primary and secondary GBMs based on genetic alterations and gene or protein expression profiles. Some of these genetic alterations are currently believed to have clinical significance and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65%), isocitrate dehydrogenase 1/2 mutations (50% of secondary GBMs), and also O6-methylguanine-DNA methyltransferase promoter methylation (75% of secondary GBMs). From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM.

Is High Altitude an Emergent Occupational Hazard for Primary Malignant Brain Tumors in Young Adults? A Hypothesis

Abstract Introduction: Brain cancer accounts for approximately 1.4% of all cancers and 2.3% of all cancer-related deaths. Although relatively rare, the associated morbidity and mortality affecting young- and middle-aged individuals has a major bearing on the death-adjusted life years compared to other malignancies. Over the years, we have observed an increase in the incidence of primary malignant brain tumors (PMBTs) in young adults. This observational analysis is to study the prevalence and pattern of brain tumors in young population and find out any occupational correlation. Materials and Methods: The data were obtained from our tertiary care cancer institute's malignant diseases treatment center registry from January 2008 to January 2018. A total of 416 cases of PMBT were included in this study. Results: Our analysis suggested an overall male predominance with most PMBTs occurring at ages of 20–49 years. The glial tumors constituted 94.3% while other histology identified were gliosarcoma (1) gliomatosis cerebri (1), hemangiopericytoma (3), and pineal tumors (3). In our institute, PMBT constituted 1% of all cancers while 2/416 patients had secondary glioblastoma multiforme with 40% showing positivity for O-6-methylguanine-DNA-methyltransferase promoter methylation. Conclusions: Most patients belonged to a very young age group without any significant family history. A probable hypothesis could be excessive cosmic radiation exposure to persons staying at high altitude areas due to occupational exigencies for which in-depth case–control epidemiological studies are required to reach any conclusion.

Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor-transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma.

A deletion variant of epidermal growth factor receptor (EGFRvIII) is a known driver mutation in a subset of primary and secondary glioblastoma multiforme. Adoptive transfer of genetically modified chimeric antigen receptor (CAR) lymphocytes has demonstrated efficacy in hematologic malignancies but is still early in development for solid cancers. The surface expression of the truncated extracellular ligand domain created by EGFRvIII makes it an attractive target for a CAR-based cancer treatment. Patients with recurrent glioblastoma expressing EGFRvIII were enrolled in a dose escalation phase I trial, using a third-generation CAR construct derived from a human antibody. Transduced cells were administered after lymphodepleting chemotherapy and supported posttransfer with intravenous interleukin-2. The dose escalation proceeded at half-log increments from 10 to >10 cells. Primary endpoints were safety and progression-free survival. Eighteen patients were treated with final infusion products ranging from 6.3×10 to 2.6×10 anti-EGFRvIII CAR T cells. Median progression-free survival was 1.3 months (interquartile range: 1.1-1.9), with a single outlier of 12.5 months. Two patients experienced severe hypoxia, including one treatment-related mortality after cell administration at the highest dose level. All patients developed expected transient hematologic toxicities from preparative chemotherapy. Median overall survival was 6.9 months (interquartile range: 2.8-10). Two patients survived over 1 year, and a third patient was alive at 59 months. Persistence of CAR cells correlated with cell dose, but there were no objective responses. Administration of anti-EGFRvIII CAR-transduced T cells did not demonstrate clinically meaningful effect in patients with glioblastoma multiforme in this phase I pilot trial.

On the Concepts and History of Glioblastoma Multiforme - Morphology, Genetics and Epigenetics.

Glioblastoma multiforme (GBM) is a grade IV WHO malignant tumor with astrocytic differentiation. As one of the most common clinically diagnosed central nervous system (CNS) oncological entries, there have been a wide variety of historical reports of the description and evolution of ideas regarding these tumors. The first recorded reports of gliomas were given in British scientific reports, by Berns in 1800 and in 1804 by Abernety, with the first comprehensive histomorphological description being given in 1865 by Rudolf Virchow. In 1926 Percival Bailey and Harvey Cushing gave the base for the modern classification of gliomas. Between 1934 and 1941 the most prolific researcher in glioma research was Hans-Joachim Scherer, who postulated some of the clinico-morphological aspects of GBM. With the introduction of molecular and genetic tests the true multifomity of GBM has been established, with different genotypes bearing the same histomorphological and IHC picture, as well as some of the aspects of gliomagenesis. For a GBM to develop, a specific trigger mutation needs to occur in a GBM stem cell - primary GBM, or a slow aggregation of individual mutations, without a distinct trigger mutation - secondary GBM. Knowledge of GBM has been closely related to general medical knowledge of the CNS since these malignancies were first described more than 200 years ago. Several great leaps have been made in that time, in the footsteps of both CNS and advancements in general medical knowledge.

The Multifaceted Metabolism of Glioblastoma.

Glioblastoma multiforme (GBM) develops on glial cells and is the most common, as well as the deadliest, form of brain cancer [1]. As in pancreatic cancers, distinct combinations of genetic alterations in GBM subtypes induce a multiplicity of metabolic phenotypes, which explains the variability of GBM sensitivity to current therapies targeting its reprogrammed metabolism. Therefore, it is becoming imperative for cancer researchers to account for the metabolic heterogeneity within this cancer type before making generalized conclusions about a particular drug’s efficacy against all cancers of that type. GBMs can be classified initially into two subsets consisting of primary and secondary GBMs, and this categorization stems from cancer development. GBM is the highest grade of gliomas, which includes glioma I, glioma II, glioma III, and glioma IV (GBM). Secondary GBM develops from a low-grade glioma to advanced stage cancer, while primary GBM provides no signs of progression and is identified as an advanced stage glioma from the onset. The differences in prognosis and histology correlated with each classification are normally negligible, but the demographics of individuals affected and the accompanying genetic/metabolic properties show distinct differentiations [2].

<i>IDH1</i> Mutation in Gliomas in Baghdad by Immunohistochemical Study

IDH1 (isocitrate dehydrogenase 1) mutation might be encounter in the low-grade glioma occurs in early stages of development and directs the progression of the tumor to a higher grade. Aim of the study was to assess the frequency of IDH1 mutation in Iraqi patients with gliomas by immunohistochemical study, to correlate its immunoreactivity with some clinicopathological parameters. The study did on formalin fixed, paraffin embedded tumor tissue from 66 patients with different grades of intracranial gliomas of both gender and all age groups in the Baghdad city were collected in this retrospective and prospective randomized study. Ten normal brain tissue samples in form of paraffin blocks took from forensic medicine unit. New technique used, which is manual tissue microarray Immunohistochemical detection of IDH1 antibodies did by Dako autostainer link 48. Positive cytoplasmic IDH1 staining was found in 38 (57.6%) of cases of glioma. In adult gliomas, secondary glioblastoma multiforme, low grade astrocytoma and oligodendroglial tumors had the greatest values of IDH1 positivity (87%, 80% and 72.72% respectively) followed by anaplastic astrocytoma (42%), then primary glioblastoma multiforme (26%). Males and females expressed the IDH1 equally. The conclusions from the work were IDH1 mutation commonly existed in adult gliomas, low-grade gliomas and secondary glioblastoma, it had no role in pediatric gliomas, and it could be a diagnostic and prognostic marker.

The Na, K-ATPase β-Subunit Isoforms Expression in Glioblastoma Multiforme: Moonlighting Roles.

Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Recent studies point out that gliomas exploit ion channels and transporters, including Na, K-ATPase, to sustain their singular growth and invasion as they invade the brain parenchyma. Moreover, the different isoforms of the β-subunit of Na, K-ATPase have been implicated in regulating cellular dynamics, particularly during cancer progression. The aim of this study was to determine the Na, K-ATPase β subunit isoform subcellular expression patterns in all cell types responsible for microenvironment heterogeneity of GBM using immunohistochemical analysis. All three isoforms, β1, β2/AMOG (Adhesion Molecule On Glia) and β3, were found to be expressed in GBM samples. Generally, β1 isoform was not expressed by astrocytes, in both primary and secondary GBM, although other cell types (endothelial cells, pericytes, telocytes, macrophages) did express this isoform. β2/AMOG and β3 positive expression was observed in the cytoplasm, membrane and nuclear envelope of astrocytes and GFAP (Glial Fibrillary Acidic Protein) negative cells. Interestingly, differences in isoforms expression have been observed between primary and secondary GBM: in secondary GBM, β2 isoform expression in astrocytes was lower than that observed in primary GBM, while the expression of the β3 subunit was more intense. These changes in β subunit isoforms expression in GBM could be related to a different ionic handling, to a different relationship between astrocyte and neuron (β2/AMOG) and to changes in the moonlighting roles of Na, K-ATPase β subunits as adaptor proteins and transcription factors.

Immunohistochemical expression of IDH1R132H in Astrocytictumours and its association with histopathological grade, TP53 and EGFR protein expression

Background: Molecular studies have uncovered that histopathologically diagnosed Astrocytomas are genetically heterogeneous. Majority of Diffuse Astrocytomas (DA), Anaplastic Astrocytomas (AA) and secondary Glioblastoma multiforme (GBM) have concurrent mutations of IDH, TP53 and ATRX. Astrocytomas without IDH mutation have distinct genotype and poor prognosis. Primary GBM show EGFR amplification and lack IDH mutation. Methods: We studied 95 Astrocytic tumors including 15 Pilocytic Astrocytoma (PA), 21 Diffuse astrocytomas, 7 Anaplastic astrocytomas and 52 GBM using tissue-microarray (TMA) to assess immunohistochemical expression of IDH1R132H, TP53 and EGFR protein in all four grades and the association between these three immunohistochemical markers. TMA blocks with core size 3.0 mm were constructed using manual tissue-microarrayer. IHC for IDH1R132H, TP53 and EGFR was performed. Results: 13%(2/15) of PA showed IDH1R132H expression. TP53 and EGFR expression was not seen in any case. 52%(11/21), 71%(15/21) and 9%(2/21) of DA showed expression of IDH1, TP53 and EGFR respectively. Frequency of mutant IDH1, TP53 and EGFR in Anaplastic astrocytoma was 85%(6/7), 85%(6/7) and 0%(0/7). Among GBMs there was significant difference in IHC expression of IDH1 and EGFR. Primary GBMs show high EGFR expression of 70%(26/37) and low IDH1 expression of 21%(8/37). Secondary GBM in contrast show higher IDH1 expression 80%(12/15) and low EGFR expression of 13%(2/15). Conclusion: IDH and TP53 mutations are seen in majority of DA, AA and secondary GBM and are hallmarks of these tumors. Primary GBMs have distinct molecular pathway. They lack IDH, TP53 mutation and overexpress EGFR. DOI:10.21276/APALM.1458

Correlation between grading and IDH1 mutation in Indonesian glioma

Background: Glioma is the most common primary brain tumor, originally arise from glial cells. In Indonesia, other than surgery, other therapy has not yet been developed. Thus, glioma patients showed high therapy resistancy and recurrency. Isositrat dehidrogenase (IDH) catalyzes decarboxylation of isositrat to alfa-ketoglutarat. IDH1 mutations were found in 70-80% glioma grade II, III and secondary glioblastoma multiforme (GBM). It is related to better prognosis and eligibility of IDH1 inhibitor administration.

Nanomedicine associated with photodynamic therapy for glioblastoma treatment.

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most recurrent and malignant astrocytic glioma found in adults. Biologically, GBMs are highly aggressive tumors that often show diffuse infiltration of the brain parenchyma, making complete surgical resection difficult. GBM is not curable with surgery alone because tumor cells typically invade the surrounding brain, rendering complete resection unsafe. Consequently, present-day therapy for malignant glioma remains a great challenge. The location of the invasive tumor cells presents several barriers to therapeutic delivery. The blood-brain barrier regulates the trafficking of molecules to and from the brain. While high-grade brain tumors contain some "leakiness" in their neovasculature, the mechanisms of GBM onset and progression remain largely unknown. Recent advances in the understanding of the signaling pathways that underlie GBM pathogenesis have led to the development of new therapeutic approaches targeting multiple oncogenic signaling aberrations associated with the GBM. Among these, drug delivery nanosystems have been produced to target therapeutic agents and improve their biodistribution and therapeutic index in the tumor. These systems mainly include polymer or lipid-based carriers such as liposomes, metal nanoparticles, polymeric nanospheres and nanocapsules, micelles, dendrimers, nanocrystals, and nanogold. Photodynamic therapy (PDT) is a promising treatment for a variety of oncological diseases. PDT is an efficient, simple, and versatile method that is based on a combination of a photosensitive drug and light (generally laser-diode or laser); these factors are separately relatively harmless but when used together in the presence of oxygen molecules, free radicals are produced that initiate a sequence of biological events, including phototoxicity, vascular damage, and immune responses. Photodynamic pathways activate a cascade of activities, including apoptotic and necrotic cell death in both the tumor and the neovasculature, leading to a permanent lesion and destruction of GBM cells that remain in the healthy tissue. Glioblastoma tumors differ at the molecular level. For example, gene amplification epidermal growth factor receptor and its receptor are more highly expressed in primary GBM than in secondary GBM. Despite these distinguishing features, both types of tumors (primary and secondary) arise as a result dysregulation of numerous intracellular signaling pathways and have standard features, such as increased cell proliferation, survival and resistance to apoptosis, and loss of adhesion and migration, and may show a high degree of invasiveness. PDT may promote significant tumor regression and extend the lifetime of patients who experience glioma progression.

Glioblastoma in natalizumab-treated multiple sclerosis patients.

We present two natalizumab‐treated multiple sclerosis patients who developed glioblastoma multiforme (GBM) with variable outcomes. One patient had an isocitrate dehydrogenase (IDH)‐wildtype GBM with aggressive behavior, who declined treatment and died 13 weeks after symptoms onset. The other patient underwent resection of an IDH‐mutant secondary GBM that arose from a previously diagnosed grade II astrocytoma. He is still alive 5 years after the diagnosis of GBM. JC virus was not detected in either case. Whether natalizumab played a role in the development of GBM in those patients deserves further investigation.