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Maher Kurdi,1,2 Nasser Mulla,3 Yousef Katib,4 Taghreed Alsinani,5 Sahar Hakamy,2 Bassam MJ Addas,6 Husam Malibary,7 Taher F Halawa,8 Marwa S Farhan,9 Eyad Faizo,10 Saleh Baeesa6 1Department of Pathology, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia; 2Brain Tumour Unit, KFMRC, King Abdulaziz University, Jeddah, Saudi Arabia; 3Department of Internal Medicine, Faculty of Medicine, Taibah University, Medina, Saudi Arabia; 4Department of Radiology, Faculty of Medicine, Taibah University, Madinah, Saudi Arabia; 5Department of Surgery, King Fahad General Hospital, Jeddah, Saudi Arabia; 6Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 7Department of Internal Medicine, Faculty of Medicine, King Abdul Aziz University, Jeddah, Saudi Arabia; 8Pediatric Hematology and Oncology Consultant, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia; 9Clinical Pathology Department, Cairo University, Cairo, Egypt; 10Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Tabuk University, Tabuk, Saudi ArabiaCorrespondence: Maher Kurdi, Department of Pathology, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia, Tel +966 556655467, Email Ahkurdi@kau.edu.saPurpose: 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.Keywords: WHO-grade 4 astrocytoma, IDH1/2 mutation, TAM, CD204, recurrence

Background: Isocitrate dehydrogenase [IDH]-wildtype glioblastoma is an aggressive brain cancer associated with high recurrence and poor overall survival., Aim: Our study aims to explore the prognostic effects of radiotherapy [RT] alone versus concomitant RT with temozolomide [TMZ]., Methods: A multicentre retrospective study included a cohort of 244 patients diagnosed with IDH-wildtype glioblastoma, and it was analysed from 2013 to 2020. All patients underwent complete surgical resection of the tumour followed by standard postsurgical therapies, including RT alone [group A] or concomitant RT with TMZ chemotherapy [group B]. Intra-statistical cohort data analysis was performed., Results: The mean age of the patients was 53.9 years [SD 16.3 years], with 87 [35.7%] females and 157 [64.3%] males. Group "A" patient [n = 67, 27.5%] received RT alone, and group "B" patient [n = 177, 72.5%] received concomitant RT with TMZ chemotherapy. All patients' mean progression-free survival [PFS] was 391.8 days (13.1 months). There was a statistically significant difference in PFS between the two treatment groups [P value<0.0001]. The hazard ratio [HR] for PFS in group "b" compared with group "a" was 0.48 [95% CI: 0.36-0.64, P < 0.001] in the univariable analysis, indicating a significant benefit of the combined treatment. This benefit was maintained in the multivariable analysis with an HR of 0.50 [95% CI: 0.37-0.67, P < 0.001]. Age was found to be a significant factor in PFS, with each additional year of age increasing HR by 2% in the univariable analysis [HR: 1.02, 95% CI: 1.01-1.03, P < 0.001] and the multivariable analysis (HR of 1.01 [95% CI: 1.01-1.02, P < 0.001)]., Conclusions: Concomitant RT with TMZ chemotherapy significantly increased PFS beyond that observed from isolated RT in patients with IDH-wildtype glioblastoma., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Metabolic reprogramming within tumor cells involves a shift towards either glycolysis or mitochondrial respiration, depending on the stage of tumor progression. Consequently, irreversible dysfunction of the mitochondria is considered a crucial mechanism driving the progression mechanism. While numerous mutations in mitochondrial DNA (mtDNA) have been identified across various tumor types, including glioblastoma, many studies have been limited in the scope, focusing on small segments of mtDNA or utilizing sequencing methods with restricted sensitivity. As a result, several potentially significant mtDNA mutations may have been underestimated, along with their heteroplasmic states, which play a crucial role in determining the phenotypic impact of mtDNA mutation. Although both somatic and germline mtDNA mutations have been observed in different tumor types, research on the mtDNA mutations linked to glioblastoma remains scarce. The mitochondrial genome encodes thirteen protein-coding genes that are essential for the proper functioning of respiratory complex chains. Alterations in mitochondrial function manifest at various levels, including structural and functional changes, impacting mitogenic, hemodynamic, bioenergetic, and apoptotic signaling pathways. These alterations often signify a reduced efficiency of the oxidative phosphorylation system and energy production in tumor cells. As the crucial role of mitochondrial dysfunction in glioma development grows, mitochondria have emerged as promising targets for therapy aimed at overcoming chemoresistance and eliminating cancer cells. This brief review outlines the association between mtDNA alteration and glioblastoma, as well as the current advancements in therapeutic strategies targeting mtDNA alterations., (© 2024 The Author(s). Published by IMR Press.)

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 G 2 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., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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., (© 2023. The Author(s).)

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.

Novel Severe Acute Respiratory Syndrome-Corona Virus-2 infection (SARS-CoV-2) is an acute respiratory and infectious disease. This perspective aims to provide a basic understanding of the inflammation caused by SARS-CoV-2 and its relation to the trigeminal ganglion (TG). The virus enters through the mucous membranes of the orofacial region and reaches the TG, where it resides and takes control of its peptides including Substance P (SP). SP is the main neuropeptide, neuromodulator, and neuro-hormone of TG, associated with nociception and inflammation under noxious stimulus. SP release is triggered and, consequently, affects the immune cells and blood vessels to release the mediators for inflammation. Hence, cytokine storm is initiated and causes respiratory distress, bronchoconstriction, and death in complicated cases. Neurokinin-1 Receptor (NK-1R) is the receptor for SP and its antagonists, along with glucocorticoids, may be used to alleviate the symptoms and treat this infection by blocking this nociceptive pathway. SP seems to be the main culprit involved in the triggering of inflammatory pathways in SARS-CoV-2 infection. It may have a direct association with cardio-respiratory rhythm, sleep-wake cycle, nociception, and ventilatory responses and regulates many important physiological and pathological functions. Its over-secretion should be blocked by NK-1R antagonist. However, experimental work leading to clinical trials are mandatory for further confirmation. Here, it is further proposed that there is a possibility of latency in SARS-CoV-2 virus infection if it is acting through TG, which is the main site for other viruses that become latent., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mehboob, Kurdi, Bamaga, Aldardeir, Nasief, Moshref, Alsinani, Rayes and Jabbad.)

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.