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 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.

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.

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.

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.

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.

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.

The Diagnostic Value of Pan-Trk Expression to Detect Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusion in CNS Tumours: A Study Using Next-Generation Sequencing Platform.

Background: Neurotrophic tyrosine receptor kinase (NTRK) fusion has been detected in rare types of CNS tumours, which can promote tumorigenesis. The efficacy of Trk inhibitor became a significant therapeutic interest. Our aim was to investigate whether Pan-Trk immunohistochemistry (IHC) is a reliable and efficient marker for detecting NTRK-fusion in different brain tumours. Methods: This study included 23 patients diagnosed with different types of CNS tumours. Testing for Pan-Trk IHC with monoclonal Ab (EPR17341) has been performed on all FFPE tissues. Parallelly, NTRK-rearrangements were tested using both DNA and RNA-based next-generation sequencing (NGS) assay using TruSight Onco500 platform. Results: The cohort included eight pilocytic astrocytomas, one oligodendroglioma, six IDHwildtype glioblastomas, four IDHmutant grade four astrocytomas, and one sample of each (astroblastoma, central neurocytoma, medulloblastoma, and liponeurocytoma). The mean age was 35 years; seven cases were in the paediatric age group, and 16 were adult. Pan-Trk expression was detected in 11 (47.8%) tumours, and 12 (52.1%) tumours showed no Pan-Trk expression. Nine Cases (82%) with different Pan-Trk expressions did not reveal NTRK-rearrangement. The other two positively expressed cases (liponeurocytoma and glioblastoma) were found to have NTRK2-fusions (SLC O 5A1-NTRK2, AGBL4-NTRK2, BEND5-NTRK2). All the 12 cases (100%) with no Pan-Trk expression have shown no NTRK-fusions. There was no statistically significant association between Pan-Trk expression and NTRK-fusion (p = 0.217). The detection of NTRK- fusions using NGS had high specificity over NTRK-fusion detection by using Pan-Trk IHC. Conclusion: Pan-Trk IHC is not a suitable tissue-efficient biomarker to screen for NTRK-fusions in CNS tumours, however RNA-based NGS sequencing should be used as an alternative method.

Intracranial Meningiomas Developed after Traditional Scalp Thermal Cautery Treatment in Childhood: Clinical Reports and Gene Expression Analysis.

BACKGROUND: Human skin cautery, a traditional thermal therapy, is traced back to Hippocrates beyond the 5th century. Those ancient healers used this method to control bleeding and infection and remove cancerous tumors. Such traditional procedure is still in practice in several regions of Asia and Africa to treat certain conditions. There is a lack of reports in the literature regarding the long-term complication and the possible tumorigenesis following traditional treatment with thermal cauterization. Here, we report two patients with intracranial meningiomas and investigate the gene expression profile for a patient. Cases presentations: We report two adult patients who presented with a headache and hemiparesis over six months. Brain magnetic resonance imaging (MRI) scans of both patients revealed intracranial meningiomas. During preoperative preparation of the patients, cautery marks were noticed over the scalp region above the intracranial tumors site, which was performed during childhood. The patients underwent uneventful resection of meningiomas with no local recurrence over a 5-year follow up. In addition, we performed a biofunctional genetic microarray expression analysis on the affected meningioma. CONCLUSION: There is a lack of evidence-based scientific reports in the literature regarding the long-term complications and tumorigenesis following aggressive treatment with thermal cauterization. Herein, we report the first possible association between previous scalp traditional cautery and the development meningioma in two patients and discuss a proposed causal relationship. However, further advanced studies and research should be done to support, or reject, our hypothesis.

Diagnostic Discrepancies Between Intraoperative Frozen Section and Permanent Histopathological Diagnosis of Brain Tumors.

OBJECTIVE: Intraoperative frozen section (IOFS) diagnosis of brain tumors plays an important role in assessing the adequacy of the sample and determining the treatment plan. The aim of this study was to investigate the diagnostic accuracy between IOFS and permanent sections. MATERIAL AND METHOD: The authors reviewed the histopathological results of 383 brain tumors, including IOFS and permanent histological diagnosis. The cases were classified into three diagnostic compatibilities (i) Perfect fit; the diagnosis of IOFS was identical to the permanent diagnosis, (ii) Partial compatibility; IOFS diagnosis was not incorrect but was too broad to be considered full compatibility, (iii) Conflict; IOFS diagnosis is completely different from the permanent diagnosis. The permanent diagnosis was used as a primary criterion and was compared to IOFS diagnosis and recurrence rate using different statistical methods. RESULTS: 84% of the patients underwent craniotomy and tumor resection, while 15% only underwent tumor biopsy. Approximately, 53.8 % of the cases revealed perfect matching in the diagnosis between IOFSs and permanent sections, while 16.2% of the cases revealed complete mismatching in the diagnosis between the sections. The remaining 30% of the cases showed partial compatibility in the diagnosis between the two diagnostic methods. There was no significant difference in recurrence rate among all cases of different diagnostic compatibility (p=0.54). CONCLUSION: There is a diagnostic discrepancy between IOFSs and permanent sections. However, cases that revealed no consensus in the diagnoses showed no negative effect on the patient outcome. Further studies should be conducted to explore the reasons of this conflict in the two diagnostic methods.

Substance P/ Neurokinin-1 Receptor, Trigeminal Ganglion, Latency, and Coronavirus Infection-Is There Any Link?

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.

Comprehensive Analysis of Genes Associated With Sudden Infant Death Syndrome.

Background: Sudden infant death syndrome (SIDS) is a tragic incident which remains a mystery even after post-mortem investigation and thorough researches. Methods: This comprehensive review is based on the genes reported in the molecular autopsy studies conducted on SIDS so far. A total of 20 original studies and 7 case reports were identified and included in this analysis. The genes identified in children or adults were not included. Most of the genes reported in these studies belonged to cardiac channel and cardiomyopathy. Cardiac channel genes in SIDS were scrutinized for further analysis. Results: After screening and removing the duplicates, 42 unique genes were extracted. When the location of these genes was assessed, it was observed that most of these belonged to Chromosomes 11, 1 and 3 in sequential manner. The pathway analysis shows that these genes are involved in the regulation of heart rate, action potential, cardiac muscle cell contraction and heart contraction. The protein-protein interaction network was also very big and highly interactive. SCN5A, CAV3, ALG10B, AKAP9 and many more were mainly found in these cases and were regulated by many transcription factors such as MYOG C2C1 and CBX3 HCT11. Micro RNA, "hsa-miR-133a-3p" was found to be prevalent in the targeted genes. Conclusions: Molecular and computational approaches are a step forward toward exploration of these sad demises. It is so far a new arena but seems promising to dig out the genetic cause of SIDS in the years to come.

Immunohistochemical expression of Olig2, CD99, and EMA to differentiate oligodendroglial-like neoplasms.

INTRODUCTION: This study has assessed the diagnostic ability of oligodendrocyte-2 (Olig2), CD99, and epithelial membrane antigen (EMA) immunohistochemical stains to diagnose oligodendroglial-like neoplasms as central neurocytoma, ependymoma, or oligodendroglioma. MATERIAL AND METHODS: An immunohistochemistry (IHC) panel of Olig2, EMA, and CD99 was performed on 18 central neurocytomas, 46 ependymomas, and 28 oligodendrogliomas. A quantitative labelling index of stained tumor cells was assessed using a scoring system, and its diagnostic predictability was evaluated with multinomial logistic regression. RESULTS: Significant differences in IHC expression patterns were observed between all tumor groups (p < 0.001). The labeling indices of the histochemical expression of Olig2, EMA, and CD99 were related to diagnostic predictability. Olig2 was unlikely to differentiate ependymoma from central neurocytoma (p = 0.154), while EMA and CD99 were significant in diagnosing these two tumors (p < 0.05). Olig2 was a specific marker of oligodendroglioma, differentiating it from ependymoma and central neurocytoma (p 0.05), but CD99 significantly differentiated ependymoma from oligodendroglioma (p = 0.022). These labelling indices were used to re-assess the diagnostic accuracy, regardless of tumor location and histology, and yielded significantly different tumor diagnoses. CONCLUSIONS: The IHC panel of Olig2, EMA, and CD99 should be used to differentiate oligodendroglial-like neoplasms. Olig2 is a specific IHC marker to diagnose oligodendroglioma and differentiate it from ependymoma and central neurocytoma. Lack of Olig2 expression rules out oligodendroglioma and suggests the diagnosis of ependymoma rather than central neurocytoma if the EMA labelling index shows diffuse/partial expression. CD99 is considered a sensitive marker for ependymoma but not central neurocytoma.

Adult-type dermatomyositis with secondary lymphoid follicles harbouring reactive B-cells component.

Dermatomyositis (DM) is an immune-mediated inflammatory disease characterized by pathognomic lesions in skin and skeletal muscle including lymphocytic infiltrates. It rarely presents with ectopic lymphoid structures, as other autoimmune and chronic inflammatory diseases. We describe a case of a 47-year-old male, who presented clinically with proximal muscle weakness, skin rash and elevated creatin kinase (CK) levels. The muscle biopsy revealed inflammatory myopathy, with perifascicular pathology, and scattered ectopic lymphoid follicles-like structures harboring reactive B-cells. Clonality analysis of B-cells using polymerase chain reaction ruled out malignant lymphoma. The patient responded favorably to steroid therapy, and his muscle weakness improved. In conclusion, the clinical and histopathologic features of DM can be atypical, and the presence of lymphoid follicles, although rare, is not inevitably linked to an unfavorable prognosis.