Dynamic interplay between corticosteroid treatment and the role of SRC-1 gene dysregulation in the progression of WHO-Grade 4 Astrocytoma.

BACKGROUND: Corticosteroid is commonly used before surgery to control cerebral oedema in brain tumours and is frequently continued throughout treatment. Its long-term effect of on the recurrence of WHO-Grade 4 astrocytoma remains controversial. The interaction between corticosteroid, SRC-1 gene and cytotoxic T-cells has never been investigated. METHODS: A retrospective cohort of 36 patients with WHO-Grade 4 astrocytoma were examined for CD8 + T-cell and SRC-1 gene expressions through IHC and qRT-PCR. The impact of corticosteroid on CD8+T-cells infiltration, SRC-1 expression, and tumour recurrence was analyzed. RESULTS: The mean patients age was 47-years, with a male to female ratio 1.2. About 78% [n = 28] of the cases showed reduced or no CD8+T-cell expression while 22% [n = 8] of cases have showed medium to high CD8+T-cell expression. SRC-1 gene was upregulated in 5 cases [14%] and 31 cases [86%] showed SRC-1 downregulation. The average of total days and doses of administered corticosteroid from the preoperative period to the postoperative period was at range of 14-106 days and 41-5028 mg, respectively. There was no significant statistical difference in RFI among tumours expressing high or low CD8+T-cells when corticosteroid was administered in recommended or exceeded doses [p-value = 0.640]. There was a significant statistical difference in RFI between CD8+T-Cell expression and SRC-1 gene dysregulation [p-value = 002]. Tumours with high CD8+T T-cell expression and SRC-1 gene downregulation had late recurrence. CONCLUSIONS: Corticosteroid treatment can directly affect the SRC-1 gene regulation but does not directly influence cytotoxic T-cells infiltration or tumor progression. However, SRC-1 gene downregulation can facilitate late tumor recurrence.

The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory.

Background: The dysregulation of Isocitrate dehydrogenase (IDH) and the subsequent production of 2-Hydroxyglutrate (2HG) may alter the expression of epigenetic proteins in Grade 4 astrocytoma. The interplay mechanism between IDH, O-6-methylguanine-DNA methyltransferase (MGMT)-promoter methylation, and protein methyltransferase proteins-5 (PRMT5) activity, with tumor progression has never been described. Methods: A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors. Both groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR analysis. Inter-cohort statistical significance was evaluated. Results: Both IDH-mutant WHO grade 4 astrocytomas (n = 22, 64.7%) and IDH-wildtype glioblastomas (n = 12, 35.3%) had upregulated PRMT5 gene expression except in one case. Out of the 22 IDH-mutant tumors, 10 (45.5%) tumors showed MGMT-promoter methylation and 12 (54.5%) tumors had unmethylated MGMT. All IDH-wildtype tumors had unmethylated MGMT. There was a statistically significant relationship between MGMT-promoter methylation and IDH in G4 astrocytoma (p-value = 0.006). Statistically significant differences in progression-free survival (PFS) were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide (TMZ) or TMZ plus other chemotherapies, regardless of their IDH or MGMT-methylation status (p-value=0.0014). Specifically, IDH-mutant tumors that had upregulated PRMT5 activity and MGMT-promoter methylation, who received only TMZ, have exhibited longer PFS. Conclusions: The relationship between PRMT5, MGMT-promoter, and IDH is not tri-directional. However, accumulation of D2-hydroxyglutarate (2-HG), which partially activates 2-OG-dependent deoxygenase, may not affect their activities. In IDH-wildtype glioblastomas, the 2HG-2OG pathway is typically inactive, leading to PRMT5 upregulation. TMZ alone, compared to TMZ-plus, can increase PFS in upregulated PRMT5 tumors. Thus, using a PRMT5 inhibitor in G4 astrocytomas may help in tumor regression.

The Efficacy of Trigger Site Surgery in the Elimination of Chronic Migraine Headache: An Update in the Rate of Success and Failure.

Migraine headache (MH) is a prevalent neurovascular disorder that affects approximately 15% of the global population. They are more common in women and typically affect young and middle-aged individuals. Chronic MH is characterized by headaches occurring on ≥15 days per month for over three months. While only 5% of MHs are refractory, about 20%-50% do not respond to pharmacologic treatments. As a result, surgical interventions have emerged as an alternative method to eliminate MH since 2000 AD. These surgical treatments primarily target the peripheral mechanisms of MH, focusing on common trigger sites. Migraine surgery involves neurolysis of sensory branches of trigeminal and occipital nerves that supply the face and back of the head. Numerous clinical studies conducted between 2000 and 2021 have extensively described surgical interventions and their prognostic outcomes. After surgery, up to 80% of patients reported complete elimination of headaches, while 20%-35% experienced no relief. The failure to achieve complete elimination of MH can be attributed to various factors. The most common reason for a partial clinical response is the failure to identify all trigger sites or inadequate surgery on the trigger sites. In this review, we aim to provide an overview of current surgical interventions for MH at different trigger sites, including recent updates, success and failure rates, and potential causes of failure.

The effect of p53 on the activity of NRF2 and NDRG2 genes through apoptotic pathway in IDH-wildtype glioblastoma.

BACKGROUND: Tumor suppressor (p53) acts to integrate multiple stress signals into diverse antiproliferative responses. Its potential to transactivate or downregulate genes through apoptotic pathway in IDH-wildtype glioblastoma has never been explored. METHODS: A group of twenty patients diagnosed with IDH-wildtype glioblastoma, were tested for p53 expression and NDRG2/NRF2 genes activity through protein and gene profiling assays. The connotation between these elements has been explored. RESULTS: The mean patients' age was 64-years. All tumors were IDH-wildtype. p53 was expressed in 12 tumors and absent in 8 tumors. The activity of NDRG2 gene was downregulated in all cases. The activity of NRF2 gene was upregulated in 17 tumors and downregulated in 3 tumors. There was a significant statistical difference in PFS among tumors exhibiting different levels of p53 expression and NDRG2 gene activity [p-value= 0.025], in which 12 tumors with downregulated NDRG2 expression and positive p53 expression had earlier tumor recurrence. This statistical difference in PFS was insignificant when we compared p53 expression with NRF2 gene activity [p-value= 0.079]. CONCLUSIONS: During cell cycle arrest at G2 phase, p53 expression in IDH-wildtype glioblastoma in elderly individuals, coupled with the downregulation of NDRG2 gene activity, led to an aberrant increase in tumor cell proliferation and accelerated tumor recurrence. However, the influence of p53 on NRF2 gene activity was found to be insignificant.

Immune microenvironment of medulloblastoma: The association between its molecular subgroups and potential targeted immunotherapeutic receptors.

Medulloblastoma (MB) is considered the commonest malignant brain tumor in children. Multimodal treatments consisting of surgery, radiation, and chemotherapy have improved patients' survival. Nevertheless, the recurrence occurs in 30% of cases. The persistent mortality rates, the failure of current therapies to extend life expectancy, and the serious complications of non-targeted cytotoxic treatment indicate the need for more refined therapeutic approaches. Most MBs originating from the neurons of external granular layer line the outer surface of neocerebellum and responsible for the afferent and efferent connections. Recently, MBs have been segregated into four molecular subgroups: Wingless-activated (WNT-MB) (Group 1); Sonic-hedgehog-activated (SHH-MB) (Group 2); Group 3 and 4 MBs. These molecular alterations follow specific gene mutations and disease-risk stratifications. The current treatment protocols and ongoing clinical trials against these molecular subgroups are still using common chemotherapeutic agents by which their efficacy have improved the progression-free survival but did not change the overall survival. However, the need to explore new therapies targeting specific receptors in MB microenvironment became essential. The immune microenvironment of MBs consists of distinctive cellular heterogeneities including immune cells and none-immune cells. Tumour associate macrophage and tumour infiltrating lymphocyte are considered the main principal cells in tumour microenvironment, and their role are still under investigation. In this review, we discuss the mechanism of interaction between MB cells and immune cells in the microenvironment, with an overview of the recent investigations and clinical trials.

Extracranial metastasis of brain glioblastoma outside CNS: Pathogenesis revisited.

BACKGROUND: The most prevalent malignant tumor of the CNS in adults is glioblastoma. Despite undergoing surgery and chemoradiotherapy, the prognosis remains unfavorable, with a median survival period ranging between 15 and 20 months. The incidence of glioblastoma metastasis outside CNS is uncommon with only 0.4%-2% reported rate, compared to other tumors that exhibit a 10% incidence rate of metastasis to the brain. On average, it takes about 11 months from the time of initial diagnosis for the tumor to spread beyond CNS. Consequently, the prognosis for metastatic glioblastoma is grim, with a 6-month survival rate following diagnosis. FINDINGS: The rarity of extracranial metastasis is attributed to the blood-brain barrier and lack of a lymphatic drainage system, although rare cases of hematogenous spread and direct implantation have been reported. The possible mechanisms remain unclear and require further investigation. Risk factors have been widely described, including previous craniotomy or biopsies, ventricular shunting, young age, radiation therapy, prolonged survival time, and tumor recurrence. Due to the lack of understanding about extracranial metastasis of glioblastoma pathogenesis, no effective treatment exists to date. Aggressive chemotherapies are not recommended for metastatic glioblastoma as their side effects may worsen the patient prognosis. CONCLUSION: The optimal treatment for extracranial metastasis of glioblastoma requires further investigation with a wide inclusion of patients. This review discusses the possible causes, factors, and underlying mechanisms of glioblastoma metastasis to different organs.

The Cancer Driver Genes IDH1 and IDH2 and CD204 in WHO-Grade 4 Astrocytoma: Crosstalk Between Cancer Metabolism and Tumour Associated Macrophage Recruitment in Tumour Microenvironment.

Purpose: IDH1 and IDH2 are hotspot mutations commonly identified in WHO-grade 4 astrocytomas. Their association with TAMs has never been investigated. We aim to explore the crosstalk between the IDH1/2 mutation metabolic effect and TAMs in tumour microenvironment and how this relationship affects the tumour recurrence. Patients and Methods: The study included 20 samples of patients with WHO-grade 4 astrocytoma. The alteration hotspot in codon IDH1R132 and IDH2R172 was examined using direct sequencing. The protein expression of CD204 on TAM was detected through immunohistochemistry. Results: IDH1R132 and IDH2R172 were symmetrically identified as wildtype in 18/20 tumours (90%) and the remaining 2 tumours (10%) showed synonymous mutations on both codons. Tumours with IDH1/2-wildtype showed high expression of CD204+TAMs in 10 cases and low expression in 8 cases. Typical expression was seen equally in IDH1/2 mutant tumours. There was no significant association between IDH1/2 and CD204+TAM expression (p= 0.999). The association between the two groups was significantly observed among IDH-wildtype tumours (p=0.027). Highly expressed CD204 in IDH-wildtype tumours showed a median recurrence at 10 months compared to low CD204 expression, showed a median recurrence interval at 24 months. Conclusion: IDH1R132 or IDHR172 has the same impact on the classification and prognosis of WHO-grade 4 astrocytoma. There was no crosstalk between IDH1/2 metabolic effect and CD204+TAM. However, IDH-wildtype glioblastomas with dense CD204+TAM are associated with early recurrence. Because the sample size is small, a larger study is recommended to determine the impact of IDH1/2 on TAMs.

The synergistic effect of IDH mutation and NDRG-2 dysregulation in the progression of WHO-grade 4 astrocytomas.

BACKGROUND: NDRG2 is a tumour suppressor gene involved in tumor growth inhibition. Its effect on tumour recurrence remains controversial. The aim of this study is to explore the dual effect of IDH mutation and NDRG2 dysregulation in WHO-Grade 4 astrocytoma recurrence. METHODS: A group of 36 patients with WHO-Grade 4 astrocytoma were examined for NDRG2 expression using protein and gene expression assays. The relationship between IDH, NDRG2 protein and gene expressions, and recurrence-free interval [RFI] was explored. RESULTS: The mean patients age in this study was 45-years with 21 males and 15 females. IDH was mutant in 22 tumors. NDRG2 protein expression was low in 23 tumors, and high in 13 tumors. NDRG2 gene expression was upregulated in 4 tumors and 32 tumors showed NDRG2 gene downregulation. The consistency between two tasting methods of NDRG2 expression was 52.8%. There was a significant statistical difference in RFI among tumors with varying NDRG2 gene expression and IDH mutation [p-value= 0.021]. IDH-mutant tumours with downregulated NDRG2 expression showed late recurrence compared to IDH-wildtype glioblastoma. CONCLUSIONS: IDH-mutant WHO Grade-4 astrocytoma with downregulated NDRG2 gene are associated with late tumor recurrence. IDH mutations cause excessive accumulation of D-2-hydroxyglutarate, that may inhibit the activity of TET proteins, potentially leading to DNA hypermethylation and gene silencing.

The effect of chemotherapies on the crosstalk interaction between CD8 cytotoxic T-cells and MHC-I peptides in the microenvironment of WHO grade 4 astrocytoma.

INTRODUCTION: CD8 + T-cells and MHC-I have been detected in brain gliomas with a significant outcome. The effect of chemotherapies on the crosstalk interaction between CD8 + T-cells and MHC-I has never been explored. MATERIAL AND METHODS: The protein expression profiling of CD8 cytotoxic T-cells and the gene expression assay of MHC-I in 35 patients diagnosed with WHO grade 4 astrocytoma were performed. The impact of these two factors on tumor recurrence was analyzed. RESULTS: IDH was wildtype in 13 tumors. MHC-I protein expression was absent or low in 34 tumors and dense in a single case. MHC-I gene expression was upregulated in 10 tumors and 25 tumors showed MHC-I gene downregulation. Temozolomide (TMZ) was given to 24 patients and 11 patients received TMZ plus other chemotherapies. No statistically significant association was observed between IDH mutation and CD8 + T-cells ( p = 0.383). However, this association was significant in recurrence-free interval (RFI) ( p = 0.012). IDH-wildtype tumors with highly infiltrated CD8 + T-cells or IDH-mutant tumors with low CD8 + T-cells showed late tumor recurrence. There was a statistically significant difference in RFI between tumors with different MHC-I expression and CD8 + T-cell counts after treatment with TMZ or TMZ plus ( p = 0.026). CONCLUSIONS: No association between IDH mutation and CD8+ cytotoxic T-cell was found. IDH is directly linked to tumor recurrence regardless of CD8 + T-cells infiltration. TMZ plus other adjuvants is proved to be more effective in improving patient survival and delaying tumor recurrence, as compared to using TMZ alone. Nonetheless, none-TMZ adjuvants may increase tumor sensitization to cytotoxic T-cells more than TMZ.

Major Histocompatibility Class-I (MHC-I) downregulation in glioblastoma is a poor prognostic factor but not a predictive indicator for treatment failure.

BACKGROUND: MHC-I expression is a crucial factor in cancer immunity, and its regulations can impact tumor progression and recurrence. The mechanism through which glioblastoma use MHC-I to avoid immunosurveillance has been rarely investigated. METHODS: A retrospective cohort of 35 patients with IDH-mutant WHO-Grade 4 astrocytoma and IDH-wildtype glioblastoma were examined for MHC-I using protein and gene expression assays. The association between IDH mutation, TP53 mutation, and MHC-I expression with recurrence-free interval were investigated. RESULTS: The average patients' age was 49.6 year. IDH was wildtype in 13 tumors. MHC-I protein expression was absent in 30 tumors, faint in 4 tumors, and membrane bound dense expression in single tumor. MHC-I expression was upregulated in 10 tumors and 25 tumors showed MHC-I downregulation. P53 was positively expressed in 19 cases and lost in 13 cases. A significant statistical difference was observed in the RFI between tumors with distinct MHC-I expression and IDH-mutation [p-value = 0.008]. IDH-wildtype tumors with upregulated MHC-I expression showed late tumor recurrence compared to IDH-wildtype tumors with downregulated MHC-I expression. There was insignificant statistical difference in RFI among patients with varying degree of MHC-I expression, who received TMZ or TMZ and other chemotherapies [P-value = 0.44] CONCLUSIONS: Glioblastoma with upregulated MHC-I showed a delayed tumor recurrence in comparison to those with downregulated MHC-I expression. However, downregulated MHC-I may not necessarily be an indicator of poor problems.

Simple approach for the histomolecular diagnosis of central nervous system gliomas based on 2021 World Health Organization Classification.

The classification of central nervous system (CNS) glioma went through a sequence of developments, between 2006 and 2021, started with only histological approach then has been aided with a major emphasis on molecular signatures in the 4th and 5th editions of the World Health Organization (WHO). The recent reformation in the 5th edition of the WHO classification has focused more on the molecularly defined entities with better characterized natural histories as well as new tumor types and subtypes in the adult and pediatric populations. These new subclassified entities have been incorporated in the 5th edition after the continuous exploration of new genomic, epigenomic and transcriptomic discovery. Indeed, the current guidelines of 2021 WHO classification of CNS tumors and European Association of Neuro-Oncology (EANO) exploited the molecular signatures in the diagnostic approach of CNS gliomas. Our current review presents a practical diagnostic approach for diffuse CNS gliomas and circumscribed astrocytomas using histomolecular criteria adopted by the recent WHO classification. We also describe the treatment strategies for these tumors based on EANO guidelines.

Association Between CD204-Expressed Tumor-Associated Macrophages and MGMT-Promoter Methylation in the Microenvironment of Grade 4 Astrocytomas.

Background: Tumor-associated macrophages (TAMs) are principal immune cells in glioma microenvironment which support tumor growth and proliferation. Our aim in this study was to assess the relationship between CD204-expressed TAMs and O6-methylguanine-DNA methyltransferase (MGMT)-promoter methylation in World Health Organization (WHO) grade 4 astrocytomas, and its impact on patient's clinical outcome. Methods: The expression of CD204 + TAMs was quantitively assessed on 45 samples of WHO grade 4 astrocytomas using immunohistochemistry. MGMT-promoter methylation was tested by methylation techniques. The relationship between TAMs, MGMT-promoter methylation, and recurrence-free interval (RFI) was statistically analyzed. Results: There were 10 cases (22.2%) with isocitrate dehydrogenase (IDH)-mutant grade 4 astrocytoma and 35 cases (77.8%) with IDH-wildtype glioblastoma. MGMT-promotor was methylated in 18 cases (40%), unmethylated in 15 cases (33%), and the remaining 12 cases showed no MGMT status because of nucleic acid degradations. The expression of CD204+ TAMs was high in 32 cases (71.7%) and low in 13 cases (28.8%). The relationship between IDH1 mutation and CD204+ TAM expression was insignificant (P = 0.93). However, the significant difference was found between MGMT methylation and CD204+ TAMs expression (P = 0.01), in which CD204+ TAMs were diffusely expressed in MGMT-methylated cases. There was no significant difference in RFI between CD204+ TAMs expression, MGMT-promoter methylation and treatment modalities. Conclusions: Grade 4 astrocytomas with diffusely expressed CD204+ TAMs are usually associated with MGMT-promoter methylation. Although this association is unclear, CD204+ TAMs may neutralize the effect of MGMT-DNA protein to loss its function, which contributes to tumor progression. This relationship had no significant impact on the patient's clinical outcome after different treatment modalities.

Immunolocalization of neurokinin 1 receptor in WHO grade 4 astrocytomas, oral squamous cell and urothelial carcinoma.

INTRODUCTION: Neurokinin-1 receptor (NK-1R) induces inflammatory reactions in peripheral tissues but its regulatory effects in target tissues is dependent on receptor signalling. Substance P (SP) has a high affinity for the NK-1R, to which it binds preferentially. We aimed to investigate the expression of NK-1R in World Health Organization (WHO) grade 4 astrocytomas as well as in oral squamous cell carcinoma (OSCC) and urothelial carcinoma, and its association with disease progression. MATERIAL AND METHODS: The study included tissue samples from 19 brain astrocytomas, 40 OSCCs and 10 urothelial carcinomas. NK-1R expression was quantitatively assessed in the tumour cells using immunohistochemistry. The relationship between NK-1R expression in astrocytomas and recurrence-free interval has been explored. RESULTS: The results showed that the NK-1R was intensely expressed in patients with WHO grade 4 astrocytoma, OSCC and urothelial carcinoma. However, cases clinically diagnosed as a low-grade cancer showed reduced NK-1R expression. CONCLUSIONS: NK-1R is overexpressed in all cases of WHO grade 4 astrocytoma, OSCC and urothelial carcinoma. The ubi-quitous presence of SP/NK-1R complex during tumour development and progression suggests a possible therapeutic key strategy to use NK-1R antagonist as an adjuvant therapy in the future.

Can oligodendrocyte transcriptional factor-2 (Olig2) be used as an alternative for 1p/19q co-deletions to distinguish oligodendrogliomas from other glial neoplasms?

AIM OF THE STUDY: Oligodendrocyte transcriptional factor-2 (Olig2) is an essential marker for oligodendrocytes expression. We aimed to explore the expression of Olig2 in different glial neoplasms and to investigate if diffuse Olig2 expression can replace 1p19q co-deletion for the diagnosis of oligodendroglioma. MATERIAL AND METHODS: Olig2 was performed on 53 samples of different glial neoplasms using immunohistochemistry (IHC). 1p/19q deletions were investigated using fluorescence in situ hybridization (FISH). RESULTS: Olig2 labelling of different glial neoplasms revealed various expressions, in which 26 tumours showed diffuse expression (≥ 60%) and 23 tumours showed partial focal expression (< 50%). Four tumours showed no expression. Of the 26 tumours, 6 oligodendrogliomas had 1p19q co-deletion and the remaining 3 oligodendrogliomas showed no co-deletion. Three non-oligodendroglial tumours were found to have 19q deletion. The FISH of the remaining tumours (14/26) showed no aberrations. There was no significant difference in the final diagnosis by using 1p19q co-deletion test among glial neoplasms with diffuse Olig2 expression (p = 0.248). CONCLUSIONS: Olig2 marker cannot be used as an alternative diagnostic method for 1p19q co-deletion to distinguish oligodendrogliomas from other glial neoplasms. Although some glial tumours showed diffuse Olig2 expression, 1p19q co-deletion testing is the best diagnostic method.