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Molecular Brain Jul 2024Glioblastoma (GBM) is an aggressive nervous system tumor with a poor prognosis. Although, surgery, radiation therapy, and chemotherapy are the current standard protocol... (Review)
Review
Glioblastoma (GBM) is an aggressive nervous system tumor with a poor prognosis. Although, surgery, radiation therapy, and chemotherapy are the current standard protocol for GBM patients, there is still a poor prognosis in these patients. Temozolomide (TMZ) as a first-line therapeutic agent in GBM can easily cross from the blood-brain barrier to inhibit tumor cell proliferation. However, there is a high rate of TMZ resistance in GBM patients. Since, there are limited therapeutic choices for GBM patients who develop TMZ resistance; it is required to clarify the molecular mechanisms of chemo resistance to introduce the novel therapeutic targets. MicroRNAs (miRNAs) regulate chemo resistance through regulation of drug metabolism, absorption, DNA repair, apoptosis, and cell cycle. In the present review we discussed the role of miRNAs in TMZ response of GBM cells. It has been reported that miRNAs mainly induced TMZ sensitivity by regulation of signaling pathways and autophagy in GBM cells. Therefore, miRNAs can be used as the reliable diagnostic/prognostic markers in GBM patients. They can also be used as the therapeutic targets to improve the TMZ response in GBM cells.
Topics: Humans; Temozolomide; Glioblastoma; MicroRNAs; Drug Resistance, Neoplasm; Brain Neoplasms; Animals; Dacarbazine; Autophagy; Gene Expression Regulation, Neoplastic
PubMed: 38956588
DOI: 10.1186/s13041-024-01113-6 -
Scientific Reports Jul 2024This study aimed to apply pathomics to predict Matrix metalloproteinase 9 (MMP9) expression in glioblastoma (GBM) and investigate the underlying molecular mechanisms...
This study aimed to apply pathomics to predict Matrix metalloproteinase 9 (MMP9) expression in glioblastoma (GBM) and investigate the underlying molecular mechanisms associated with pathomics. Here, we included 127 GBM patients, 78 of whom were randomly allocated to the training and test cohorts for pathomics modeling. The prognostic significance of MMP9 was assessed using Kaplan-Meier and Cox regression analyses. PyRadiomics was used to extract the features of H&E-stained whole slide images. Feature selection was performed using the maximum relevance and minimum redundancy (mRMR) and recursive feature elimination (RFE) algorithms. Prediction models were created using support vector machines (SVM) and logistic regression (LR). The performance was assessed using ROC analysis, calibration curve assessment, and decision curve analysis. MMP9 expression was elevated in patients with GBM. This was an independent prognostic factor for GBM. Six features were selected for the pathomics model. The area under the curves (AUCs) of the training and test subsets were 0.828 and 0.808, respectively, for the SVM model and 0.778 and 0.754, respectively, for the LR model. The C-index and calibration plots exhibited effective estimation abilities. The pathomics score calculated using the SVM model was highly correlated with overall survival time. These findings indicate that MMP9 plays a crucial role in GBM development and prognosis. Our pathomics model demonstrated high efficacy for predicting MMP9 expression levels and prognosis of patients with GBM.
Topics: Humans; Glioblastoma; Matrix Metalloproteinase 9; Male; Female; Middle Aged; Prognosis; Machine Learning; Aged; Brain Neoplasms; Support Vector Machine; Adult; Kaplan-Meier Estimate; ROC Curve; Biomarkers, Tumor
PubMed: 38956384
DOI: 10.1038/s41598-024-66105-x -
Neurospine Jun 2024Epidemiological studies on spinal cord tumors are rare, and studies on primary intramedullary tumors are even rarer. The incidence and survival of patients with primary...
OBJECTIVE
Epidemiological studies on spinal cord tumors are rare, and studies on primary intramedullary tumors are even rarer. The incidence and survival of patients with primary intramedullary spinal cord tumors have not been well documented. We aimed to study the incidence and survival of patients with primary spinal cord malignant and borderline malignant tumors based on data from the Surveillance, Epidemiology, and End Results (SEER) database and provide information for revealing the epidemiology and exploring the prognosis of patients with primary intramedullary tumors.
METHODS
Patients in the SEER database with microscopically diagnosed malignant and borderline malignant primary spinal cord tumors from 2000 and 2019 were included in this study. We analyzed the distribution of patients according to the demographic and clinical characteristics. Then, we extracted the incidence rate and 5-year relative survival for the whole cohort and different subgroups of the cohort. Finally, multivariate Cox proportional hazards models were used to analyze the independent prognostic factors associated with overall survival.
RESULTS
A total of 5,211 patients with malignant and borderline malignant primary spinal cord tumors were included in this cohort study. Ependymoma, astrocytoma (including oligodendrogliomas and glioblastoma), lymphoma and hemangioblastoma were the most common pathological types. The age-adjusted incidence rates of primary spinal cord ependymoma was 0.18 per 100,000. The incidence rate for females was significantly lower than that for males. The incidence rate was highest in Caucasian. The incidence rate of ependymoma was significantly higher than that of other pathological types. The incidence of astrocytoma was highest among people aged 0-19 years, the incidence of ependymoma was highest among people aged 40-59 years, and the incidence of lymphoma was highest among people aged 60 years or older. The 5-year observed survival and relative survival rates for the whole cohort were 82.80% and 86.00%, respectively. Patients diagnosed with ependymoma had significantly better survival than their counterparts. We also found the impact of surgery and chemotherapy on the prognosis of patients with different tumors varies a lot.
CONCLUSION
We conducted a population-based analysis of malignant and borderline malignant primary spinal cord tumors with the aim of revealing the epidemiology and survival of patients with primary intramedullary spinal cord tumors. Despite some shortcomings, this study provides valuable information to help us better understand the epidemiological characteristics of primary intramedullary spinal cord tumors.
PubMed: 38955530
DOI: 10.14245/ns.2347300.650 -
American Journal of Veterinary Research Jul 2024To develop an innovative process for stereotactic brain biopsies in dogs and cats that would provide a definitive diagnosis and optimize the management of patients with...
Using a three-dimensional-printed device with the patient's maxillary dental impression allows to perform minimally invasive brain biopsies in dogs and cats: a preliminary study.
OBJECTIVE
To develop an innovative process for stereotactic brain biopsies in dogs and cats that would provide a definitive diagnosis and optimize the management of patients with brain lesions.
ANIMALS
4 dogs and 1 cat diagnosed with 1 or more brain lesion(s) underwent brain biopsies between March 24, 2023, and October 25, 2023.
METHODS
Based on trajectories selected on images of MRI and CT scan performed on each patient, a computerized software program was used to design a 3-D-printed patient-specific device with maxillary dental impression located on a baseplate to secure the patient's head and with insertion ports for the biopsy instrumentations located on a C-arm. As proof of concept, the device was successfully used in 2 cadavers before being used on clinical patients. All biopsy samples were submitted for histopathological examination.
RESULTS
Histological diagnosis was obtained in 80% (4/5) of the cases (choroid plexus tumor, astrocytoma, meningioma, and chronic meningoencephalitis of unknown origin). In 1 patient, the results of biopsy were nondiagnostic; postmortem diagnosis was consistent with a low-grade oligodendroglioma. All the patients were discharged within 24 hours after the procedure without complications. This novel stereotactic system allows the surgeon to perform safe, easy-to-use, inexpensive, and minimally invasive precise brain biopsies in dogs and cats, without complications.
CLINICAL RELEVANCE
This unique technique could be applied to any size and type of skull and for any type of brain lesions and would provide diagnostic information that would be valuable for future treatment planning and prognosis.
PubMed: 38955214
DOI: 10.2460/ajvr.24.04.0122 -
Cell Reports. Medicine Jun 2024Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of...
Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).
PubMed: 38955178
DOI: 10.1016/j.xcrm.2024.101630 -
PloS One 2024Developing T1-weighted magnetic resonance imaging (MRI) contrast agents with enhanced biocompatibility and targeting capabilities is crucial owing to concerns over...
Developing T1-weighted magnetic resonance imaging (MRI) contrast agents with enhanced biocompatibility and targeting capabilities is crucial owing to concerns over current agents' potential toxicity and suboptimal performance. Drawing inspiration from "biomimetic camouflage," we isolated cell membranes (CMs) from human glioblastoma (T98G) cell lines via the extrusion method to facilitate homotypic glioma targeting. At an 8:1 mass ratio of ferric chloride hexahydrate to gallic acid (GA), the resulting iron (Fe)-GA nanoparticles (NPs) proved effective as a T1-weighted MRI contrast agent. T98G CM-coated Fe-GA NPs demonstrated improved homotypic glioma targeting, validated through Prussian blue staining and in vitro MRI. This biomimetic camouflage strategy holds promise for the development of targeted theranostic agents in a safe and effective manner.
Topics: Gallic Acid; Humans; Magnetic Resonance Imaging; Cell Line, Tumor; Contrast Media; Iron; Biomimetic Materials; Glioblastoma; Nanoparticles; Ferric Compounds; Cell Membrane
PubMed: 38954698
DOI: 10.1371/journal.pone.0306142 -
Cancer Immunology, Immunotherapy : CII Jul 2024Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these...
Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial tumors due to relatively low toxicity and tumor specificity. Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice. Furthermore, vaccine-induced T cells were able to recognize and kill B16 cells after a short in vitro culture. Having found that glioblastoma multiforme (GBM) expresses significant levels of PD-L1 and IDO1, with PD-L1 correlating with poorer survival in patients with the mesenchymal subtype of GBM, we decided to combine SCIB1 ImmunoBody® with PD-1 immune checkpoint blockade to treat mice harboring intracranial tumors expressing TRP-2 and gp100. Time-to-death was significantly prolonged, and this correlated with increased CD4 and CD8 T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled.
Topics: Animals; Mice; Vaccines, DNA; Brain Neoplasms; Immune Checkpoint Inhibitors; Humans; Programmed Cell Death 1 Receptor; Cancer Vaccines; Mice, Inbred C57BL; Female; B7-H1 Antigen; Immunotherapy; Glioblastoma; Cell Line, Tumor; Intramolecular Oxidoreductases
PubMed: 38954031
DOI: 10.1007/s00262-024-03770-x -
Cancer Immunology, Immunotherapy : CII Jul 2024Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach....
Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach. Nonetheless, the localized delivery method of intratumoral injection poses challenges for treating metastatic tumors or distal tumors that are difficult to reach. To address this obstacle, we employed HSV-1-infected CAR-T cells, which systemically delivery HSV into solid tumors. The biological function of CAR-T cells remained intact after loading them with HSV for a period of three days. In both immunocompromised and immunocompetent GBM orthotopic mouse models, B7-H3 CAR-T cells effectively delivered HSV to tumor lesions, resulting in enhanced T-cell infiltration and significantly prolonged survival in mice. We also employed a bilateral subcutaneous tumor model and observed that the group receiving intratumoral virus injection exhibited a significant reduction in tumor volume on the injected side, while the group receiving intravenous infusion of CAR-T cells carrying HSV displayed suppressed tumor growth on both sides. Hence, CAR-T cells offer notable advantages in the systemic delivery of HSV to distant tumors. In conclusion, our findings emphasize the potential of CAR-T cells as carriers for HSV, presenting significant advantages for oncolytic virotherapy targeting distant tumors.
Topics: Animals; Mice; Oncolytic Virotherapy; Humans; Oncolytic Viruses; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Herpesvirus 1, Human; Xenograft Model Antitumor Assays; Cell Line, Tumor; T-Lymphocytes; Female; Glioblastoma
PubMed: 38953982
DOI: 10.1007/s00262-024-03757-8 -
Operative Neurosurgery (Hagerstown, Md.) Jul 2024Augmented reality (AR) is expected to serve as an assistive intraoperative technology in neurosurgery.1 Awake craniotomy (AC) for gliomas benefits the extent of...
Augmented reality (AR) is expected to serve as an assistive intraoperative technology in neurosurgery.1 Awake craniotomy (AC) for gliomas benefits the extent of resection, survival, and postoperative neurofunctional outcomes.2 In AC, it is critical to understand the cortical and subcortical anatomy.3 We describe the use of AR superimposing tumor and deep white matter tracts in AC. A 29-year-old right-handed woman presented to a local hospital after an episode of generalized convulsions. MRI of the head revealed a widely spreading tumor in the left middle frontal gyrus. After a left frontal craniotomy while the patient was asleep, AR was used to indicate the tumor boundary with subcortical fibers including the corticospinal tract, inferior fronto-occipital fasciculus, and cingulate fasciculus. We performed AR-assisted removal of the tumor on the surface of the middle frontal gyrus. On subcortical stimulation (SCS) of the frontal aslant tract and inferior fronto-occipital fasciculus, the patient stopped naming objects in the picture-naming test, while SCS of the left cingulate gyrus caused the patient to mistake colors in the Stroop test. The subcortical fibers identified by AR coincided with the sites of symptom elicitation by SCS. We eventually removed a large part of the tumor. Postoperative MRI confirmed 96.2% resection. The patient was discharged without any new neurological deficits. AC with AR is useful for resection of gliomas in the dominant hemisphere. The patient consented to the procedure and to the publication of her image. The ethics committee of our hospital does not require approval for case reports.
PubMed: 38953629
DOI: 10.1227/ons.0000000000001255 -
Scientific Reports Jun 2024Glioblastoma (GBM) continues to exhibit a discouraging survival rate despite extensive research into new treatments. One factor contributing to its poor prognosis is the...
Glioblastoma (GBM) continues to exhibit a discouraging survival rate despite extensive research into new treatments. One factor contributing to its poor prognosis is the tumor's immunosuppressive microenvironment, in which the kynurenine pathway (KP) plays a significant role. This study aimed to explore how KP impacts the survival of newly diagnosed GBM patients. We examined tissue samples from 108 GBM patients to assess the expression levels of key KP markers-tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenase (IDO1/2), and the aryl hydrocarbon receptor (AhR). Using immunohistochemistry and QuPath software, three tumor cores were analyzed per patient to evaluate KP marker expression. Kaplan-Meier survival analysis and stepwise multivariate Cox regression were used to determine the effect of these markers on patient survival. Results showed that patients with high expression of TDO2, IDO1/2, and AhR had significantly shorter survival times. This finding held true even when controlling for other known prognostic variables, with a hazard ratio of 3.393 for IDO1, 2.775 for IDO2, 1.891 for TDO2, and 1.902 for AhR. We suggest that KP markers could serve as useful tools for patient stratification, potentially guiding future immunomodulating trials and personalized treatment approaches for GBM patients.
Topics: Humans; Kynurenine; Glioblastoma; Female; Male; Prognosis; Middle Aged; Indoleamine-Pyrrole 2,3,-Dioxygenase; Receptors, Aryl Hydrocarbon; Biomarkers, Tumor; Tryptophan Oxygenase; Aged; Adult; Brain Neoplasms; Kaplan-Meier Estimate; Tumor Microenvironment; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors
PubMed: 38951170
DOI: 10.1038/s41598-024-65907-3