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Journal of Clinical Medicine Jun 2024Glioma surgery has been remarkably enhanced in the past 2 decades, with improved safety and limited but improved life expectations. The fluorescence-guided resection of...
Glioma surgery has been remarkably enhanced in the past 2 decades, with improved safety and limited but improved life expectations. The fluorescence-guided resection of high-grade gliomas (HGGs) plays a central role in this sense, allowing a greater extent of resection (EOR). The introduction of exoscopic-guided surgery may be considered in implementing fluorescence techniques over traditional microscopes. We present the application and the advantages of exoscopic-guided surgery compared to microscopic surgery in tumor resection guided by 5-ALA fluorescence in patients with HGGs. Ten consecutive patients underwent surgery for HGG resection. The surgery was performed via an exoscopic-guided procedure (Olympus ORBEYE) and after the oral administration of Gliolan 5 h before the procedure. During surgery, the procedure shifted to using a microscopic (Kinevo 900, Zeiss) view. The intensity of the fluorescence under the two different procedures was subjectively measured in different picture samples during the surgery on a 1 to 5 (from minimum to maximum) scale. The brightness of the surgical field and the detailing of the anatomy were also analyzed comparatively. Among the ten patients, the histopathological diagnosis was an high-grade glioma in all cases. In nine cases, it was possible to achieve gross total resection. There was no perioperative mortality. The median fluorescence intensity, on a scale of 1-5, was 4.5 in the exoscope group and 3.5 in the microscope group ( < 0.01). The exoscopic-guided surgery adds advantages to traditional fluorescence-guided surgery with 5-aminolevulinic acid. Beyond the important advantage of low cost and the possibility to perform collaborative surgeries, it adds a plain and continuous visualization of the tumor and offers advantages in the surgical field of fluorescence-guided glioma surgery compared to the microscopic-guided one.
PubMed: 38930021
DOI: 10.3390/jcm13123493 -
International Journal of Molecular... Jun 2024Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence...
Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence frequently occurs after removal. Tumoral angiogenesis, the formation of neovessels, has a positive impact on tumor progression and invasion, although there are controversial results in the specialized literature regarding its impact on survival. This study aims to correlate the immunoexpression of angiogenesis markers (CD34, CD105) with the proliferation index Ki67 and in primary and secondary glioblastomas. This retrospective study included 54 patients diagnosed with glioblastoma at the Pathology Department of County Emergency Clinical Hospital Târgu Mureș. Microvascular density was determined using CD34 and CD105 antibodies, and the results were correlated with the immunoexpression of , , and Ki67. The number of neoformed blood vessels varied among cases, characterized by different shapes and calibers, with endothelial cells showing modified morphology and moderate to marked pleomorphism. Neovessels with a glomeruloid aspect, associated with intense positivity for CD34 or CD105 in endothelial cells, were observed, characteristic of glioblastomas. Mean microvascular density values were higher for the CD34 marker in all cases, though there were no statistically significant differences compared to CD105. Mutant and glioblastomas, wild-type glioblastomas, and those with a Ki67 index above 20% showed a more abundant microvascular density, with statistical correlations not reaching significance. This study highlighted a variety of percentage intervals of microvascular density in primary and secondary glioblastomas using immunohistochemical markers CD34 and CD105, respectively, with no statistically significant correlation between evaluated microvascular density and p53 or Ki67.
Topics: Humans; Glioblastoma; Tumor Suppressor Protein p53; Ki-67 Antigen; Female; Middle Aged; Male; Aged; Adult; Isocitrate Dehydrogenase; Brain Neoplasms; X-linked Nuclear Protein; Neovascularization, Pathologic; Microvascular Density; Retrospective Studies; Endoglin; Antigens, CD34; Biomarkers, Tumor; Immunohistochemistry
PubMed: 38928515
DOI: 10.3390/ijms25126810 -
International Journal of Molecular... Jun 2024Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms... (Review)
Review
Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.
Topics: Glioblastoma; Humans; Neoplasm Recurrence, Local; Brain Neoplasms; Tumor Microenvironment; Oncolytic Virotherapy; Animals
PubMed: 38928445
DOI: 10.3390/ijms25126733 -
International Journal of Molecular... Jun 2024SARS-CoV-2 is the causative agent of the COVID-19 pandemic, the acute respiratory disease which, so far, has led to over 7 million deaths. There are several symptoms...
SARS-CoV-2 is the causative agent of the COVID-19 pandemic, the acute respiratory disease which, so far, has led to over 7 million deaths. There are several symptoms associated with SARS-CoV-2 infections which include neurological and psychiatric disorders, at least in the case of pre-Omicron variants. SARS-CoV-2 infection can also promote the onset of glioblastoma in patients without prior malignancies. In this study, we focused on the Envelope protein codified by the virus genome, which acts as viroporin and that is reported to be central for virus propagation. In particular, we characterized the electrophysiological profile of E-protein transfected U251 and HEK293 cells through the patch-clamp technique and FURA-2 measurements. Specifically, we observed an increase in the voltage-dependent (Kv) and calcium-dependent (KCa) potassium currents in HEK293 and U251 cell lines, respectively. Interestingly, in both cellular models, we observed a depolarization of the mitochondrial membrane potential in accordance with an alteration of U251 cell growth. We, therefore, investigated the transcriptional effect of E protein on the signaling pathways and found several gene alterations associated with apoptosis, cytokines and WNT pathways. The electrophysiological and transcriptional changes observed after E protein expression could explain the impact of SARS-CoV-2 infection on gliomagenesis.
Topics: Humans; Glioblastoma; HEK293 Cells; SARS-CoV-2; COVID-19; Cell Line, Tumor; Membrane Potential, Mitochondrial; Coronavirus Envelope Proteins; Apoptosis; Brain Neoplasms
PubMed: 38928376
DOI: 10.3390/ijms25126669 -
International Journal of Molecular... Jun 2024Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the...
Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In , T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn) or MIOS (mios). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the mios cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified.
Topics: Glioblastoma; Abietanes; Humans; Mechanistic Target of Rapamycin Complex 1; Autophagy; Cell Line, Tumor; Dictyostelium; Cell Proliferation; Nuclear Proteins; Sestrins
PubMed: 38928292
DOI: 10.3390/ijms25126586 -
Genes Jun 2024Glioblastoma multiforme (GBM)is the most common and aggressive primary brain tumor. Although temozolomide (TMZ)-based radiochemotherapy improves overall GBM patients'...
Glioblastoma multiforme (GBM)is the most common and aggressive primary brain tumor. Although temozolomide (TMZ)-based radiochemotherapy improves overall GBM patients' survival, it also increases the frequency of false positive post-treatment magnetic resonance imaging (MRI) assessments for tumor progression. Pseudo-progression (PsP) is a treatment-related reaction with an increased contrast-enhancing lesion size at the tumor site or resection margins miming tumor recurrence on MRI. The accurate and reliable prognostication of GBM progression is urgently needed in the clinical management of GBM patients. Clinical data analysis indicates that the patients with PsP had superior overall and progression-free survival rates. In this study, we aimed to develop a prognostic model to evaluate the tumor progression potential of GBM patients following standard therapies. We applied a dictionary learning scheme to obtain imaging features of GBM patients with PsP or true tumor progression (TTP) from the Wake dataset. Based on these radiographic features, we conducted a radiogenomics analysis to identify the significantly associated genes. These significantly associated genes were used as features to construct a 2YS (2-year survival rate) logistic regression model. GBM patients were classified into low- and high-survival risk groups based on the individual 2YS scores derived from this model. We tested our model using an independent The Cancer Genome Atlas Program (TCGA) dataset and found that 2YS scores were significantly associated with the patient's overall survival. We used two cohorts of the TCGA data to train and test our model. Our results show that the 2YS scores-based classification results from the training and testing TCGA datasets were significantly associated with the overall survival of patients. We also analyzed the survival prediction ability of other clinical factors (gender, age, KPS (Karnofsky performance status), normal cell ratio) and found that these factors were unrelated or weakly correlated with patients' survival. Overall, our studies have demonstrated the effectiveness and robustness of the 2YS model in predicting the clinical outcomes of GBM patients after standard therapies.
Topics: Humans; Glioblastoma; Brain Neoplasms; Male; Female; Magnetic Resonance Imaging; Middle Aged; Prognosis; Adult; Aged; Disease Progression; Temozolomide; Genomics; Survival Rate; Clinical Relevance
PubMed: 38927654
DOI: 10.3390/genes15060718 -
Genes May 2024Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of...
Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of azoospermia, where no germ cells are found in the tubules. Recently, FANCM gene variants were reported as novel genetic causes of spermatogenic failure. At the same time, FANCM variants are known to be associated with cancer predisposition. We performed whole-exome sequencing on a male patient diagnosed with SCOS and a healthy father. Two compound heterozygous missense mutations in the FANCM gene were found in the patient, both being inherited from his parents. After the infertility assessment, the patient was diagnosed with diffuse astrocytoma. Immunohistochemical analyses in the testicular and tumor tissues of the patient and adequate controls showed, for the first time, not only the existence of a cytoplasmic and not nuclear pattern of FANCM in astrocytoma but also in non-mitotic neurons. In the testicular tissue of the SCOS patient, cytoplasmic anti-FANCM staining intensity appeared lower than in the control. Our case report raises a novel possibility that the infertile carriers of FANCM gene missense variants could also be prone to cancer development.
Topics: Humans; Male; Astrocytoma; Sertoli Cell-Only Syndrome; Mutation, Missense; Adult; Exome Sequencing; DNA Helicases; Azoospermia
PubMed: 38927643
DOI: 10.3390/genes15060707 -
Biomedicines Jun 2024The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.... (Review)
Review
The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types. These updates, encompassing changes in diagnostic techniques, genomic integration, terminology, and grading, are crucial for radiologists, who play a critical role in interpreting brain tumor imaging. Such changes impact the diagnosis and management of nearly all central nervous system tumor categories, including the reclassification, addition, and removal of specific tumor entities. Given their pivotal role in patient care, radiologists must remain conversant with these revisions to effectively contribute to multidisciplinary tumor boards and collaborate with peers in neuro-oncology, neurosurgery, radiation oncology, and neuropathology. This knowledge is essential not only for accurate diagnosis and staging, but also for understanding the molecular and genetic underpinnings of tumors, which can influence treatment decisions and prognostication. This review, therefore, focuses on the most pertinent updates concerning the classification of adult diffuse gliomas, highlighting the aspects most relevant to radiological practice. Emphasis is placed on the implications of new genetic information on tumor behavior and imaging findings, providing necessary tools to stay abreast of advancements in the field. This comprehensive overview aims to enhance the radiologist's ability to integrate new WHO classification criteria into everyday practice, ultimately improving patient outcomes through informed and precise imaging assessments.
PubMed: 38927556
DOI: 10.3390/biomedicines12061349 -
Biomedicines May 2024Glioblastoma (GBM) is a fatal astrocytic glioma with poor prognosis and treatment resistance. Repurposing potential FDA-approved drugs like anti-psychotics can address...
Glioblastoma (GBM) is a fatal astrocytic glioma with poor prognosis and treatment resistance. Repurposing potential FDA-approved drugs like anti-psychotics can address the concerns in a timely and cost-effective manner. Epidemiological studies have shown that patients with schizophrenic using anti-psychotics have a low incidence of GBM. Therefore, we aimed to investigate the therapeutic potential of atypical anti-psychotic Iloperidone (ILO) alone and in combination with Temozolomide (TMZ) against GBM. The study assessed the growth inhibitory effect of ILO, TMZ, and their combination (ILO + TMZ) on U-87MG and T-98G cell lines using an MTT assay. The drug interaction coefficient (CDI) was determined, and doses with synergistic effects were used for subsequent experiments, including migratory, invasion, and TUNEL assays. The expressions of DRD2, β-catenin, Dvl2, Twist, and Slug were assessed by RTq-PCR, whereas the β-catenin protein expression was also determined by immunocytochemistry. ILO ( < 0.05) and TMZ ( < 0.01) significantly inhibited the growth of U-87MG cells at all tested doses. The combination of 60 µM of both drugs showed synergistic activity with CDI < 1. The inhibition of migration and apoptosis was more pronounced in the case of combination treatment ( < 0.001). Inhibition of the invading cells was also found to be significant in ILO- and combination-treated groups ( < 0.001). ILO and combination treatment also significantly downregulated the expression of DRD2, while TMZ upregulated the expression ( < 0.001). The expressions of β-catenin ( < 0.001), Dvl2 ( < 0.001), Twist ( < 0.001), and Slug ( < 0.001) were also significantly downregulated in all treatment groups as compared to the vehicle control. The data suggest that ILO possesses strong growth inhibitory activity, possibly due to its effect on DRD2 and β-catenin expression and has the potential to be repurposed against GBM.
PubMed: 38927341
DOI: 10.3390/biomedicines12061134 -
Acta Neuropathologica Communications Jun 2024A novel histomolecular tumor of the central nervous system (CNS), the "diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)," has...
Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC), new name and new problems: an illustration of one case with atypical morphology and biology.
A novel histomolecular tumor of the central nervous system (CNS), the "diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)," has recently been identified, based on a distinct DNA methylation profile and has been added to the 2021 World Health Organization Classification of CNS Tumors. This glioneuronal tumor mainly affects the supratentorial area in children and recurrently presents with a monosomy of chromosome 14. Herein, we report the case of a DNA-methylation based diagnosis of DGONC having atypical features, such as pseudo-rosettes and the absence of a chromosome 14 monosomy, thus rendering its diagnosis very challenging. Because of the wide variety of morphologies harbored by DGONC, a large range of differential diagnoses may be hypothesized from benign to malignant. Interestingly, the current case, like one previously reported, exhibited a co-expression of OLIG2, synaptophysin and SOX10, without GFAP immunopositivity. This particular immunophenotype seems to be a good indicator for a DGONC diagnosis. The classification of DGONC amongst glioneuronal or embryonal tumors is still debated. The clinical (a pediatric supratentorial tumor), morphological (from a benign oligodendroglioma-like tumor with microcalcifications and possible neuropil-like islands to a malignant embryonal tumor with a possible spongioblastic pattern), and immunohistochemical (co-expression of OLIG2 and synaptophsyin) profiles resemble CNS, neuroblastoma, FOXR2-activated and may potentially bring them together in a future classification. Further comprehensive studies are needed to conclude the cellular origin of DGONC and its prognosis.
Topics: Child; Humans; Brain Neoplasms; DNA Methylation; Oligodendroglioma
PubMed: 38926880
DOI: 10.1186/s40478-024-01822-y