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.

A case report of an unusual cerebral hydatid cyst.

Background: Intracranial hydatid cyst is an exceedingly uncommon condition. Typically, it manifests as hydatid cysts in the liver, lungs, kidney, and spleen. In this report, we present a rare case of a hydatid cyst located in the brain, exhibiting atypical radiological characteristics, and successfully treated with complete microsurgical excision. Case Description: A 45-year-old male, a former smoker, presented with a new-onset seizure. Brain imaging revealed a solitary, intra-axial, and cystic lesion with wall enhancement in the right temporal region. The cyst extended into the temporal horn of the right lateral ventricle, surrounded by mild edema. Differential diagnoses included brain metastasis, abscess, and tuberculoma. However, following computed tomography (CT) scans of the chest, abdomen, and pelvis (CAP) and serological tests, the provisional diagnosis included a hydatid cyst. The CT CAP showed diffuse non-specific cystic lesions of variable sizes in the liver and spleen, along with numerous bilateral pulmonary cysts. A right temporal craniotomy was performed, and the cyst was microsurgically excised without rupture. Microscopic and histopathological examination confirmed the presence of a hydatid cyst. Conclusion: Intracranial hydatid cyst is an extremely rare condition and should always be considered a possible differential diagnosis in cases of cerebral cystic lesions. Hydrodissection is the preferred surgical method for resection; however, in atypical cases such as the one described here, meticulous dissection of the cyst capsule from the brain parenchyma may be successful with minimal risk of intraoperative rupture.

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.

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.

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.

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.

The Role of Liquid Biopsy in the Diagnosis and Prognosis of WHO Grade 4 Astrocytoma.

Liquid biopsy, as a non-invasive diagnostic tool, has recently gained significant attention in the field of oncology. It involves the analysis of various biomarkers present in bodily fluids, such as blood or cerebrospinal fluid, to provide information about the underlying cancer. In the case of WHO grade 4 astrocytomas, liquid biopsy has the potential to significantly impact the diagnosis and prognosis of this aggressive malignant brain tumor. By detecting specific genetic mutations, such as IDH1 or EGFR, and monitoring levels of circulating tumor DNA, liquid biopsy can aid in the early detection and monitoring of disease progression. This innovative approach is gradually being acknowledged as a less invasive and cost-effective procedure for cancer diagnosis and management to improve patient outcomes and quality of life. Various kinds of biomarkers circulating in cerebrospinal fluid (CSF), such as circulating tumor cells (CTC) and different types of nucleic acids like cell-free DNA (cfDNA), cell-free RNA (ctRNA), and microRNAs (miRNA), have been identified. These biomarkers, which require dependable detection methods, are comparatively simple to obtain and allow for repeated measurements, making them significantly superior for disease monitoring. This review aims to compare the latest liquid biopsy analysis tools for both CSF and plasma in the central nervous system.

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.

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.

Dermoid Cyst in the Posterior Fossa Associated With Dermal Sinus and Abscess Formation: A Case Report.

Posterior fossa dermoid cysts are rare intracranial tumors. Most are congenital and develop during early pregnancy but manifest later in life. We report a case of a congenital posterior fossa dermoid cyst in a 22-year-old patient presenting with fever and multiple neurological complaints. Imaging studies revealed a bony defect in the occipital bone suggestive of sinus formation, heterogeneous hypointensity on T1-weighted image (T1WI), and post-contrast peripheral enhancement suggestive of an infectious process and abscess formation. The histopathological examination was typical for a dermoid cyst containing adnexal structures. This report reviews the case with its unique location and unusual radiological features. Further, the clinical presentation, diagnosis modalities, and treatment outcomes are discussed.

Antibiotics Usage and Resistance among Patients with Severe Acute Respiratory Syndrome Coronavirus 2 in the Intensive Care Unit in Makkah, Saudi Arabia.

Antibiotic resistance is a global health and development threat, especially during the Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19) pandemic. Therefore, the current study was conducted to describe antibiotic usage and resistance among patients with COVID-19 in the intensive care unit (ICU) in Makkah, Saudi Arabia. In this cross-sectional study, only patients with positive COVID-19 status (42 patients) admitted to the ICU at the King Faisal Hospital were selected using a census sampling method. The susceptibility test of bacteria was carried out according to the standard protocol. The identified strains were tested in-vitro against several antibiotics drugs. Statistical analysis was performed using SPSS version 24. A total of 42 patients were included, with a mean age of 59.35 ± 18 years. Of them, 38.1% were males, and 61.9% were females. 35.7% have blood group O +. For age and blood groups, statistically significant associations were found between males and females, with p-values = 0.037 and 0.031, respectively. A large percentage (42.7%) of the obtained samples contained Klebsiella Pneumoniae; all bacteria were multidrug-resistance bacteria. Furthermore, 76.2% of bacteria were resistant to Ampicillin, 66.7% were resistant to Ciprofloxacin, 64.3% were resistant to Levofloxacin, 57.1% were resistant to Imipenem, and 57.1% were resistant to Moxifloxacin. On the contrary, among the 40 examined antibiotics, the effective antibiotics were Daptomycin, Linezolid, Mupirocin, Synercid, Teicoplanin, Vancomycin, and Nitrofurantoin. Our study demonstrates that antibiotic resistance is highly prevalent among ICU patients with COVID-19 at the King Faisal Hospital. Additionally, all bacteria were multidrug-resistance bacteria. Therefore, this high prevalence should be seriously discussed and urgently considered.

Factors associated with delayed hospital presentation for patients with acute stroke in Makkah: A cross-sectional study.

Despite the recent advancements in the treatment of acute ischemic stroke, the delayed patient arrival to emergency department or hospital serve as crucial factor for the selection of appropriate intervention program. This study was aimed to identify factors associated with late hospital arrival for patients with acute ischemic stroke in Makkah, Saudi Arabia. A prospective cross-sectional study was carried out at Al-Noor Specialist Hospital among 98 enrolled patients with the mean age of 60.4 ± 10.3 years over the period of March 2019 and June 2019. The data were collected through review of patient records and interview of patients and attendants. Fifty-four of these (55%) presented early (within 4.5 hours) and 44 (45%) presented late (after 4.5 hours). Factor associated with late arrival included low educational level (P = .01) and unemployment status (P = .033). The relationship between time of presentation and computed tomography findings showed statis,tically significant relationship between the former and early computed tomography findings (P = .017). A statistically significant relationship between time of presentation and knowledge of stroke was also observed (P = .013). Increased public awareness is important in order to minimize the time between stroke onset and emergency room presentation.

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.

Epilepsy Stigma Among University Students in Makkah: A Cross-Sectional Study.

Background: Epilepsy is a neurological disorder characterized by a persistent propensity to generate recurring epileptic seizures. Young adults such as university students can bridge the gap and improve attitudes toward patients with epilepsy and reduce stigma. This study aims to assess the knowledge and attitude of university students in the city of Makkah about epilepsy. Methods: This cross-sectional descriptive study was carried out at main universities in the Makkah region of Saudi Arabia. The study was conducted after getting approval from Umm Al-Qura University's ethics and research committee. A total of 394 participants were enrolled in the study, and a stratified random sampling (probability sampling) technique was used to select respondents. Results: The study included students with a mean age of 20.9 ± 4.6 (18-28 years), 271 (68.8%) students were females, 374 (94.9%) of the students agreed that epilepsy is not contagious, and 215 (54.6%) refused the impact of epilepsy on patients' marital status, relationships and fertility, respectively, 213 (54.1%) of the students reported that they feel scared to witness a seizure. About 334 (84.8%) respondents believed that epilepsy is an affliction, and 123 (31.2%) reported that they thought epilepsy was a supernatural phenomenon or black magic. Conclusion: The study concluded a satisfactory level of awareness among university students in Makkah related to dealing with patients with epilepsy. Further scientific studies will help build student's positive attitudes through simulation programs and interventional studies.

Effect of health education on female primary school teachers' knowledge of seizure first aid: An interventional study.

INTRODUCTION: Epilepsy is a common neurological disease. Patients with epilepsy are at risk of developing seizure at any time. The aim of this study was to assess the effects of health education on schoolteachers' first aid management of epileptic seizure. METHODS: A self-administered questionnaire was distributed to participating primary school teachers in the city of Makkah. It included baseline demographic data, a teacher's awareness about epilepsy, as well as first aid measures. An educational lecture was later delivered to teachers and was followed by a discussion. Awareness and attitude were re-assessed using the same questionnaire. RESULTS: A total of 259 female primary school teachers completed the study. Before intervention, 134 (51.7%) of the teachers had good awareness regarding epilepsy, which was significantly increased to 86.9% after the intervention. For seizure first aid, 45.9% of teachers correctly reported that would make sure the person is safe and ask for help in the case of witnessing a seizure attack, which was improved to 84.2% after intervention, with a percent change of 38.2% (p = 0.001). In addition, rolling a person onto their side and asking for help after the end of a seizure was known by 53.3% of the teachers before the intervention and increased to 84.6% after the intervention, showing a percent change of 31.2% (p = 0.001). CONCLUSION: The health education program resulted in significant improvements to teachers' responses to seizure and improvements in all aspects of epilepsy awareness.

Electron Microscopic Evidence of Photoreceptor Outer-segments in the Trabecular Meshwork in a Case of Schwartz-Matsuo Syndrome.

PURPOSE: To describe a case of photoreceptor outer segment glaucoma (Schwartz-Matsuo syndrome) with electron microscopic evidence of photoreceptor outer segments in the trabecular meshwork (TM). DESIGN: This is a clinicopathologic case report. PARTICIPANT: A 48-year-old Filipino man. METHODS: Specimens of aqueous humor and TM in a clinical case of Schwartz-Matsuo syndrome were examined by electron microscopy. MAIN OUTCOME MEASURES: Electron photomicroscopy. RESULTS: Electron microscopy showed evidence of retinal photoreceptor outer-segments in both an aqueous humor and a TM specimen. CONCLUSION: Schwartz-Matsuo syndrome is associated with the presence of photoreceptor outer segments in the TM.

Colletotrichum truncatum species complex: Treatment considerations and review of the literature for an unusual pathogen causing fungal keratitis and endophthalmitis.

We present a case of Colletotrichum truncatum species complex fungal keratitis and endophthalmitis in an 87-year-old immunocompetent male in whom oral triazole antifungals were contraindicated. The patient had recently returned from 4 months in Jamaica with a one month history of progressively increasing pain and inflammation in his left eye. Corneal samples grew a filamentous fungus and internal transcribed spacer sequencing polymerase chain reaction confirmed the presence of C. truncatum species complex. Samples showed no microbial growth.