Differential Expression of SRY-Related HMG-Box Transcription Factor 2, Oligodendrocyte Lineage Transcription Factor 2, and Zinc Finger E-Box Binding Homeobox 1 in Serum-Derived Extracellular Vesicles: Implications for Mithramycin Sensitivity and Targeted Therapy in High-Grade Glioma.

Glioblastoma multiforme (GBM) is the most aggressive type of glioma and is often resistant to traditional therapies. Evidence suggests that glioma stem cells (GSCs) contribute to this resistance. Mithramycin (Mit-A) targets GSCs and exhibits antitumor activity in GBM by affecting transcriptional targets such as SRY-related HMG-box transcription factor 2 (SOX2), oligodendrocyte lineage transcription factor 2 (OLIG2), and zinc finger E-box binding homeobox 1 (ZEB1). However, its clinical use has been limited by toxicity. This study explored the diagnostic potential of serum extracellular vesicles (EVs) to identify Mit-A responders. Serum EVs were isolated from 70 glioma patients, and targeted gene expression was analyzed using qRT-PCR. Using chemosensitivity assay, we identified 8 Mit-A responders and 17 nonresponders among 25 glioma patients. The M-score showed a significant correlation (p = 0.045) with isocitrate dehydrogenase 1 mutation but not other clinical variables. The genes SOX2 (p = 0.005), OLIG2 (p = 0.003), and ZEB1 (p = 0.0281) were found to be upregulated in the responder EVs. SOX2 had the highest diagnostic potential (AUC = 0.875), followed by OLIG2 (AUC = 0.772) and ZEB1 (AUC = 0.632).The combined gene panel showed significant diagnostic efficacy (AUC = 0.956) through logistic regression analysis. The gene panel was further validated in the serum EVs of 45 glioma patients. These findings highlight the potential of Mit-A as a targeted therapy for high-grade glioma based on differential gene expression in serum EVs. The gene panel could serve as a diagnostic tool to predict Mit-A sensitivity, offering a promising approach for personalized treatment strategies and emphasizing the role of GSCs in therapeutic resistance.

Liquid biopsy-from bench to bedside.

Over the last decade, molecular markers have become an integral part in the management of Central Nervous System (CNS) tumors. Somatic mutations that identify and prognosticate tumors are also detected in the bio-fluids especially the serum and CSF; the sampling of which is known as liquid biopsy (LB). These tumor-derived biomarkers include plasma circulating tumor cells (CTCs), cell-free DNA (cf/ctDNAs), circulating cell-free microRNAs (cfmiRNAs), circulating extracellular vesicles, or exosomes (EVs), proteins, and tumor educated platelets. Established in the management of other malignancies, liquid biopsy is becoming an important tool in the management of CNS tumors as well. This review presents a snapshot of the current state of LB research its potential and the possible pitfalls.

Primary intracranial synovial sarcoma: A case report and review of literature.

Background: Primary intracranial synovial sarcomas (PrISS) are unusual dural based mesenchymal tumors seen most commonly in the supratentorial compartment. They can mimic a spontaneous intracranial hemorrhage or a high-grade glioma on imaging. Case Description: A 31-year-old male presented with headache and right hemiparesis for 2 weeks. CT brain revealed a left frontal spontaneous intracerebral hemorrhage. PrISS revealed a heterogeneously ring enhancing solid cystic lesion with attachment to convexity dura. Intraoperatively, it mimicked a high-grade glioma. Histopathology report showed features of a synovial sarcoma, which was later confirmed with IHC. Classical SYT-SSX2 translocation was confirmed only on RTPCR after fluorescent in situ hybridization (FISH) was negative for same. Whole body positron emission tomography (PET-CT) did not show any extracranial tumor. Despite radiotherapy, there were recurrence and tumor progression at 6 months and the patient succumbed 11 months later. Conclusion: PrISS is an unusual aggressive intracranial neoplasm that carries a worse prognosis when compared nonintracranial synovial sarcomas. Molecular cytogenetics (FISH and RTPCR) are essential for confirming the diagnosis, though FISH seems to have a lower sensitivity and can yield false negative results as was noted in this case.

Exosomal PTEN as a Predictive Marker of Aggressive Gliomas.

Background: Liquid biopsies have emerged as convenient alternative diagnostic methods to invasive biopsies, by evaluating disease-specific biomarkers and monitoring the disease risk noninvasively. Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) is a potent tumor suppressor, and its deletion/mutations are common in gliomas. Objective: Evaluate the feasibility of non-invasive detection of PTEN and its downstream genes in serum exosomes of glioma patients. Materials and methods: PTEN, Yes-associated-protein 1 (YAP1), and lysyl oxidase (LOX) transcript expression were monitored through polymerase chain reaction (PCR) in serum exosomes and their paired tumor tissues. The impact of PTEN and its axis genes expression on the overall survival (OS) was monitored. Results: Out of the 106 glioma serum samples evaluated, PTEN was retained/lost in 65.4%/34.6% of the tumor samples while it was retained/lost in 67.1%/32.9% of their paired exosomal fractions. PTEN expression in both tissue and paired exosomal fractions was observed in 48.11% of the samples. Sanger sequencing detected three mutations (Chr10: 89720791(A>G), Chr10:89720749(C>T), and Chr10:89720850(A>G). Both PTEN-responsive downstream genes (YAP1) and LOX axis were upregulated in the PTEN-deficient samples. PTEN loss was associated with poor survival in the glioma patients (hazard ratio (HR) 0.68, confidence interval (CI): 0.35-1.31, P = 0.28). The OS of the exosomal PTEN cohort coincided with the tumor-tissue PTEN devoid group (HR 1.08, CI: 0.49-2.36, P = 0.85). While, old age yielded the worst prognosis; gender, location, and grade were not prognostic of OS in the multivariate analysis. Conclusions: PTEN and its responsive genes YAP1 and LOX can be detected in serum exosomes and can serve as essential tools for the non-invasive evaluation/identification of aggressive gliomas.

Decompressive surgery for severe cerebral venous sinus thrombosis.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is one of the common causes of stroke in young people. Mortality in CVST, in addition to progressive thrombosis, is related to elevated intracranial pressure causing transtentorial herniation. The role of decompressive surgery in CVST is not well established. AIMS: We report our experience with decompressive surgery in CVST and review the literature. SETTINGS AND DESIGN: This is a retrospective study carried out in the Stroke Unit of a multispeciality tertiary care hospital in south India. MATERIALS AND METHODS: The medical records of patients admitted with the diagnosis of CVST between December 2003 and July 2009 were reviewed. The clinical presentation, etiology, medical management, indications for surgery and outcomes were assessed for patients undergoing decompressive surgery. The sensorium was assessed using the Glasgow Coma Scale (GCS), while the outcome was assessed using the modified Rankin scale (mRS). Descriptive statistics were used as appropriate. RESULTS: One hundred and six patients were admitted with the diagnosis of CVST during the study period. Eleven patients (10%) underwent decompressive surgical procedure. Indications for surgery included a low GCS at admission with large infarct on the computed tomography scan, mass effect and midline shift, clinical and radiological signs of transtentorial herniation, deterioration in the sensorium in spite of anti-edema measures and postthrombolysis hematoma. Eight patients (73%) had a good outcome while three patients (27%) died. Of the patients who died, two had a low GCS and bilaterally nonreactive pupils before the surgery while one had thrombosis of the deep venous system. CONCLUSION: Decompressive surgery for patients with large cerebral venous infarcts is a life-saving procedure. Patients with CVST who develop clinical and radiological features of transtentorial herniation either at presentation or during the course of medical management may benefit from decompressive surgery.

Liquid Biopsy in Gliomas- A Review.

BACKGROUND: Are we witnessing the end of the biopsy as we know it? Is this the start of a revolution in cancer diagnostics and treatment where analysis of somatic mutations present in the blood, CSF, or urine followed by targeted therapy replaces the traditional surgery followed by chemo-radiation? Since 2016, molecular markers are an integral part of the 'glioma' treatment decision-making process- diagnostic, prognostic, and therapeutic. A lot of these somatic mutations that identify and prognosticate tumors are also detected in the adjoining bio-fluids in serum or CSF- the sampling of which is known as liquid biopsy. OBJECTIVE: The objective of this study is to review the advancement of scientific techniques that now allows the investigation of these bio-fluids, to diagnose, prognosticate and treat gliomas. MATERIAL AND METHODS: This review article is an exhaustive review of the literature that summarises the role of the three main liquid biopsy modalities- Circulating Tumor Cells, Cell-free Tumor DNA and Exosomes in the detection of known diagnostic and prognostic markers in gliomas. RESULTS: The current review highlights the strengths and weaknesses of the diffrerent modalities in use, and their potential use in the clinical setting. CONCLUSION: Liquid biopsies hold tremendous potential in the diagnosis and management of gliomas in the future.

Exosomes as a biomarker platform for detecting epidermal growth factor receptor-positive high-grade gliomas.

OBJECTIVE High-grade glial brain tumors are often characterized by an elevated expression of the tumorigenic epidermal growth factor receptor variant III ( EGFRvIII). The authors sought to establish a clinically adaptive protocol as a noninvasive diagnostic tool for EGFRvIII detection through serum exosomes. METHODS Purity of serum exosome/RNA was confirmed by electron microscopy and flow cytometry and through an RNA bioanalyzer profile. EGFRvIII amplification was initially established by semiquantitative polymerase chain reaction in tumor tissues and exosomes. Diagnostic performance of EGFRvIII transcript in tissue versus exosome was determined using a 2 × 2 clinical table approach. Overall survival was determined using Kaplan-Meier analysis. RESULTS The EGFRvIII transcript was detected in 39.5% of tumor tissue samples and in 44.7% of their paired serum exosome samples; 28.1% of biopsy tumors coexpressed wild-type EGFR and EGFRvIII. Tissue EGFRvIII amplification served as the reference-positive control for its paired serum expression. The overall clinical sensitivity and specificity of semiquantitative exosome EGFRvIII polymerase chain reaction detection assay in serum were 81.58% (95% CI 65.67%-92.26%) and 79.31% (95% CI 66.65%-88.83%), respectively. Age, sex, tumor location, and side of the body on which the tumor was located had no effect on the detection rate of exosomal EGFRvIII transcript. EGFRvIII expression either in exosomes or tissue correlated with poor survival. CONCLUSIONS The authors established a serum-based method for detection of EGFRvIII in high-grade brain tumors that might serve as an optimal noninvasive method for diagnosing EGFRvIII-positive high-grade gliomas.

Treatment of cervical carcinoma with high-dose rate intracavitary brachytherapy: two years follow-up study.

AIMS: This study focused on pelvic recurrence rate and late complications following treatment with high dose rate brachytherapy with a three fractionation scheme. SETTING AND DESIGN: This retrospective observational study was conducted from 1st November 2003 to 31st March 2005 at a tertiary care centre. METHODS AND MATERIALS: Women were treated with external beam radiotherapy and three fractions of high dose rate brachytherapy, divided into two broad groups IIB+ IIIA and IIIB+IVA. Duration of follow-up was 2 years and main outcome measures were recurrence and rectal and urinary bladder complications. Results were assessed with the Chi square test and P-values using an alpha level of 0.05 for Type I error. RESULTS: Of the total of 286 women, 72 (25.4%) developed central-regional recurrence. Overall two year pelvic control rate was 74.6%, with values of 78.1% and 72.8% for stages IIB+ IIIA, IIIB+IVA, respectively. Five women developed distant metastasis and 21.5% suffered low grade rectal complications. After two years the prevalence of bladder complications was only 5.4%. CONCLUSION: Using a three fraction scheme, high dose rate brachytherapy is safe and effective in the management of cervix cancer.