BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

BACKGROUND AND OBJECTIVE

Awake craniotomy is often used in the surgery of glioma, the most common primary brain tumor. It has been proven to maximize the extent of tumor resection while minimizing post-operative neurologic deficits. Extensive research has been conducted on this topic, and we would like to perform a bibliometric analysis to identify the top 100 most cited articles in awake glioma surgery. Knowing the relevant and most impactful studies in the field would help clinicians streamline the evidence and determine its application in their practice.

In October 2023, we performed a title-specific search on the Scopus and PubMed databases using (“glioma*” OR “astrocytoma*” OR “glioblastoma” OR “low grade glioma” OR “high grade glioma”) and (“awake craniotomy” OR “awake surgery” OR “awake brain surgery” OR “awake neurosurgery”) as our query term without any restriction criteria. The top 100 most cited articles were identified, reviewed, and analyzed.

Our search yielded a total of 5557 articles published. The top article had a citation count of 834 and reported on functional outcome after language mapping in glioma resection. Journal of Neurosurgery had the most number of publications. Neurosurgeons (n=81) were the primary author in most publications, followed by anesthesiologists (n=22) and neurologists (n=6). Three countries (USA, France, Italy) contributed to 74% of the articles. Most of the articles were reviews and case reports/series.

This study identified the top 100 most cited articles on awake glioma surgery. The content dealt with several aspects of awake craniotomy such as brain mapping, intraoperative techniques and adjuncts, and practice recommendations. This analysis can help identify knowledge gaps and potential areas of research in glioma surgery.

Objective To investigate the expression and correlation of LY86-AS1 and KHDRBS2 in glioblastoma (GBM), and their impacts on the prognosis of patients and immune cell infiltration. Methods Based on the GSE50161 dataset from the Gene Expression Omnibus (GEO) database, LY86-AS1 and KHDRBS2, which are closely related to the development of GBM, were identified by WGCNA and differential expression analysis. The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases were used to analyze the relationship between the expression of LY86-AS1 and KHDRBS2 and the prognosis of GBM patients. Multiple datasets were employed to analyze the correlation between the expression levels of LY86-AS1 and KHDRBS2 and its relationship with immune cell infiltration. Real-time quantitative PCR was used to verify the expression of LY86-AS1 and KHDRBS2 in GBM and normal brain tissues. The Human Protein Atlas (HPA) database was accessed to obtain the protein expression of KHDRBS2, and immunohistochemical staining was conducted to verify the protein expression of KHDRBS2. Results LY86-AS1 and KHDRBS2 were lowly expressed in GBM tissues and were closely related to the development of GBM, showing a significant positive correlation. Patients with low expression levels of LY86-AS1 and KHDRBS2 had a lower overall survival rate than those with high expression levels. LY86-AS1 was positively correlated with naive B cells, plasma cells, activated NK cells, M1 macrophages, activated mast cells and monocytes. KHDRBS2 was positively correlated with naive B cells, plasma cells, helper T cells, activated NK cells and monocytes. Conclusion The low expression levels of LY86-AS1 and KHDRBS2 in GBM, which is associated with poor prognosis, affect the tumor immune microenvironment and may serve as potential new biomarkers for the diagnosis of GBM and the prognosis assessment of patients.
Humans ; Glioblastoma/metabolism* ; Prognosis ; Brain Neoplasms/pathology* ; Gene Expression Regulation, Neoplastic ; RNA-Binding Proteins/metabolism*

Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
Ferroptosis/drug effects* ; Humans ; Iron/metabolism* ; Glioblastoma/metabolism* ; Tumor Suppressor Protein p53/metabolism* ; Homeostasis/physiology* ; Ferritins/metabolism* ; Brain Neoplasms/genetics* ; Mutation ; Astrocytes/drug effects* ; Cell Line, Tumor ; Piperazines/pharmacology* ; Quaternary Ammonium Compounds/pharmacology* ; Ferric Compounds

OBJECTIVE

To present a long-term follow-up report of a 10-year-old male with optic nerve glioma who underwent surgical removal and postoperative chemotherapy.

Case report.

A 10-year-old Filipino boy was referred to a tertiary institution for a five-year history of progressive right eye proptosis with vision loss. Pertinent findings included right eye proptosis, lagophthalmos, and limited elevation and adduction. He also had several hyperpigmented lesions on the abdomen and upper torso. Vision on the right was no light perception, with a relative afferent pupillary defect, exposure keratopathy, and optic nerve pallor. Vision on the left eye was 20/20 with a temporal visual field defect. Cranial and orbital computed tomography (CT) scan showed a circumscribed enhancing mass within the right intraconal space with widened right optic nerve canal. Additional magnetic resonance imaging (MRI) revealed a heterogeneously enhancing mass diffusely involving the intraorbital and intracanalicular segments of the right optic nerve suspicious for optic nerve glioma. He underwent excision of the orbital portion of the mass via lateral orbitotomy. Histopathology showed pilocytic astrocytoma. Eight cycles of chemotherapy with carboplatin and vincristine was completed. Significant improvement of globe position and resolution of ocular exposure was achieved postoperatively with residual right ptosis. These findings remained stable at six years after treatment.

Optic nerve gliomas with intracanalicular and chiasmal extension can be managed with surgical removal of the orbital component and postoperative chemotherapy. This can result in improvement of proptosis and long-term remission.

Although melanoma only accounts for 1% of skin cancers, it is responsible for most skin cancer deaths. Glioblastoma multiforme, a high-grade astrocytoma, is the most aggressive and devastating primary brain tumor. These two diseases remain to be the biggest therapeutic challenge in both specialties of dermatology and neuro-oncology. A 53-year-old Filipino male who presented with a 2-year history of generalized dark brown and black patches on the body developed weakness and numbness of the left extremities. Biopsy and immunohistochemical staining of the skin revealed nodular melanoma with adjacent regressing melanoma. Biopsy of the intracranial mass showed glioblastoma multiforme. One month after the partial excision of the intracranial mass, the patient expired due to brain herniation. Nodular melanoma and glioblastoma multiforme may occur concomitantly in a patient. A review of the literature suggests a shared genetic predisposition. Its existence carries a poor prognosis and requires early detection to start aggressive treatment.
Melanoma ; Glioma ; Glioblastoma ; Association

Glioblastoma multiforme (GBM) represents the most malignant form of brain tumor and is relatively common, comprising nearly almost 20% of all primary malignancies of the central nervous system1. GBM is a WHO grade IV tumor with several variants, depending primarily on their genetic signature and on the predominant histological architecture. Among the variants of GBM, epithelioid glioblastoma (E-GBM) has been one of the more recently described. This tumor, documented to be highly malignant and clinically aggressive, has been separated from close variants and thus differentials, pleomorphic anaplastic xanthoastrocytoma, rhabdoid GBM, small cell and giant cell GBM, GBM with neuroectodermal differentiation, and gliosarcoma2. Autoimmune diseases have been linked within creased risk of CNS complications, from the constant effects of chronic inflammatory milieu. Systemic lupus erythematosus (SLE) has been associated with several CNS abnormalities, hence the terms CNS lupus or neuropsychiatric lupus. Likewise, SLE has been repeatedly associated with CNS malignancies in several cases and case reports. To date, there is paucity in the reported cases of malignant brain tumors, especially rare variants, in patients with SLE. While it is hypothesized that the inflammatory milieu that bathes the brain in a dynamic microenvironment that influences the incidence of rare variants of GBM, clinicians should be mindful, as treatment is challenging: it may either induce exacerbation of autoimmunity or cause undertreatment of the malignancy. This complex interplay births curiosity into the enigma of autoimmunity and oncology. In this particular report, we highlight the case of a patient with SLE who developed E-GBM. We identify the clinicopathologic features of the tumor present in the patient and explore the known aspects of the crosstalk between SLE and E-GBM.
Lupus Erythematosus, Systemic ; Glioblastoma

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with a poor prognosis and limited survival. Patients with GBM have a high demand for palliative care. In our present case, a 21-year-old female GBM patient received inpatient palliative care services including symptom management, mental and psychological support for the patient, psychosocial and clinical decision support for her family members, and pre- and post-death bereavement management for the family. Furthermore, we provided the family members with comprehensive psychological preparation for the patient's demise and assisted the patient's family throughout the mourning period.The aim of this study is to provide a reference and insights for the clinical implementation of palliative care for patients with malignant brain tumors.
Female ; Humans ; Young Adult ; Brain Neoplasms/therapy* ; Glioblastoma/therapy* ; Inpatients ; Palliative Care ; Terminal Care

Humans ; Glioblastoma ; Cell Line, Tumor ; Neoplasm Invasiveness ; Cell Movement ; Brain Neoplasms

Leucine-rich repeats containing 4 ( LRRC4 , also named netrin-G ligand 2 [NGL-2]) is a member of the NetrinGs ligands (NGLs) family. As a gene with relatively high and specific expression in brain, it is a member of the leucine-rich repeat superfamily and has been proven to be a suppressor gene for gliomas, thus being involved in gliomagenesis. LRRC4 is the core of microRNA-dependent multi-phase regulatory loops that inhibit the proliferation and invasion of glioblastoma (GB) cells, including LRRC4/NGL2-activator protein 2 (AP2)-microRNA (miR) 182-LRRC4 and LRRC4-miR185-DNA methyltransferase 1 (DNMT1)-LRRC4/specific protein 1 (SP1)-DNMT1-LRRC4. In this review, we demonstrated LRRC4 as a new member of the partitioning-defective protein (PAR) polarity complex that promotes axon differentiation, mediates the formation and plasticity of synapses, and assists information input to the hippocampus and storage of memory. As an important synapse regulator, aberrant expression of LRRC4 has been detected in autism, spinal injury and GBs. LRRC4 is a candidate susceptibility gene for autism and a neuro-protective factor in spinal nerve damage. In GBs, LRRC4 is a novel inhibitor of autophagy, and an inhibitor of protein-protein interactions involving in temozolomide resistance, tumor immune microenvironment, and formation of circular RNA.
Humans ; Cell Line, Tumor ; Glioblastoma/metabolism* ; Leucine ; Leucine-Rich Repeat Proteins/genetics* ; MicroRNAs ; Nerve Tissue Proteins/genetics* ; Tumor Microenvironment