A case series of osseous metastases in patients with glioblastoma.

BACKGROUND: Extracranial metastases occur in <2% of cases of glioblastoma (GBM). When metastases do occur, bone is the most common destination. Herein, we review clinical characteristics of GBM patients with osseous metastases and evaluate both potential risk factors and prognostic significance. METHODS: Using an institutional database, we identified and retrospectively analyzed 6 patients with both GBM and osseous metastases. We collected data on patient demographics, tumor genetics, clinical courses, and outcomes. Given the rarity of metastatic GBM, we conducted historical comparisons using previously published literature. RESULTS: Five patients with osseous metastases (83%) were male, with a median age of 46 years at GBM diagnosis (range: 20-84). All patients had IDH-wildtype, MGMT promoter unmethylated GBM and 5 (83%) had alterations in TP53. All patients underwent surgical resection for GBM followed by radiation with concurrent and adjuvant temozolomide. Four patients (67%) received bevacizumab prior to bone metastasis diagnosis. Bone metastases were discovered at a median of 12.2 months (range: 5.3-35.2) after GBM diagnosis and 4.8 months after starting bevacizumab (range: 3.5-13.2). Three patients (50%) received immunotherapy. After osseous metastasis diagnosis, the median survival was 25 days (range: 13-225). CONCLUSION: In our cohort, most patients were male and young at the time of GBM diagnosis. All patients had IDH-wildtype, MGMT promoter unmethylated GBM, and most had alterations in TP53, which may be important for osseous metastasis. Most patients received bevacizumab, which has been associated with earlier metastasis. Osseous metastases of GBM occur and portend a dismal prognosis in an already aggressive malignancy.

Carbon-ion radiotherapy alone vs. standard dose photon radiation with carbon-ion radiotherapy boost for high-grade gliomas: a retrospective study.

BACKGROUND: This study aimed to compare the survival outcome and side effects in patients with primary high-grade glioma (HGG) who received carbon ion radiotherapy (CIRT) alone or as a boost strategy after photon radiation (photon + CIRTboost). PATIENTS AND METHODS: Thirty-four (34) patients with histologically confirmed HGG and received CIRT alone or Photon + CIRTboost, with concurrent temozolomide between 2020.03-2023.08 in Wuwei Cancer Hospital & Institute, China were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and acute and late toxicities were analyzed and compared. RESULTS: Eight WHO grade 3 and 26 grade 4 patients were included in the analysis. The median PFS in the CIRT alone and Photon + CIRTboost groups were 15 and 19 months respectively for all HGG cases, and 15 and 17.5 months respectively for grade 4 cases. The median OS in the CIRT alone and Photon + CIRTboost groups were 28 and 31 months respectively for all HGG cases, and 21 and 19 months respectively for grade 4 cases. No significant difference in these survival outcomes was observed between the CIRT alone and Photon + CIRTboost groups. Only grade 1 acute toxicities were observed in CIRT alone and Photon + CIRTboost groups. CIRT alone group had a significantly lower ratio of acute toxicities compared to Photon + CIRTboost (3/18 vs. 9/16, p = 0.03). No significant difference in late toxicities was observed. CONCLUSION: Both CIRT alone and Photon + CIRTboost with concurrent temozolomide are safe, without significant differences in PFS and OS in HGG patients. It is meaningful to explore whether dose escalation of CIRTboost might improve survival outcomes of HGG patients in future randomized trials.

Photophysical Characterization and In Vitro Evaluation of α-Mangostin-Loaded HDL Mimetic Nano-Complex in LN-229 Glioblastoma Spheroid Model.

Cytotoxic activity has been reported for the xanthone α-mangostin (AMN) against Glioblastoma multiforme (GBM), an aggressive malignant brain cancer with a poor prognosis. Recognizing that AMN's high degree of hydrophobicity is likely to limit its systemic administration, we formulated AMN using reconstituted high-density lipoprotein (rHDL) nanoparticles. The photophysical characteristics of the formulation, including fluorescence lifetime and steady-state anisotropy, indicated that AMN was successfully incorporated into the rHDL nanoparticles. To our knowledge, this is the first report on the fluorescent characteristics of AMN with an HDL-based drug carrier. Cytotoxicity studies in a 2D culture and 3D spheroid model of LN-229 GBM cells and normal human astrocytes showed an enhanced therapeutic index with the rHDL-AMN formulation compared to the unincorporated AMN and Temozolomide, a standard GBM chemotherapy agent. Furthermore, treatment with the rHDL-AMN facilitated a dose-dependent upregulation of autophagy and reactive oxygen species generation to a greater extent in LN-229 cells compared to astrocytes, indicating the reduced off-target toxicity of this novel formulation. These studies indicate the potential therapeutic benefits to GBM patients via selective targeting using the rHDL-AMN formulation.

Brain tumor classification in VIT-B/16 based on relative position encoding and residual MLP.

Brain tumors pose a significant threat to health, and their early detection and classification are crucial. Currently, the diagnosis heavily relies on pathologists conducting time-consuming morphological examinations of brain images, leading to subjective outcomes and potential misdiagnoses. In response to these challenges, this study proposes an improved Vision Transformer-based algorithm for human brain tumor classification. To overcome the limitations of small existing datasets, Homomorphic Filtering, Channels Contrast Limited Adaptive Histogram Equalization, and Unsharp Masking techniques are applied to enrich dataset images, enhancing information and improving model generalization. Addressing the limitation of the Vision Transformer's self-attention structure in capturing input token sequences, a novel relative position encoding method is employed to enhance the overall predictive capabilities of the model. Furthermore, the introduction of residual structures in the Multi-Layer Perceptron tackles convergence degradation during training, leading to faster convergence and enhanced algorithm accuracy. Finally, this study comprehensively analyzes the network model's performance on validation sets in terms of accuracy, precision, and recall. Experimental results demonstrate that the proposed model achieves a classification accuracy of 91.36% on an augmented open-source brain tumor dataset, surpassing the original VIT-B/16 accuracy by 5.54%. This validates the effectiveness of the proposed approach in brain tumor classification, offering potential reference for clinical diagnoses by medical practitioners.

The CEBPB+ glioblastoma subcluster specifically drives the formation of M2 tumor-associated macrophages to promote malignancy growth.

Rationale: The heterogeneity of tumor cells within the glioblastoma (GBM) microenvironment presents a complex challenge in curbing GBM progression. Understanding the specific mechanisms of interaction between different GBM cell subclusters and non-tumor cells is crucial. Methods: In this study, we utilized a comprehensive approach integrating glioma single-cell and spatial transcriptomics. This allowed us to examine the molecular interactions and spatial localization within GBM, focusing on a specific tumor cell subcluster, GBM subcluster 6, and M2-type tumor-associated macrophages (M2 TAMs). Results: Our analysis revealed a significant correlation between a specific tumor cell subcluster, GBM cluster 6, and M2-type TAMs. Further in vitro and in vivo experiments demonstrated the specific regulatory role of the CEBPB transcriptional network in GBM subcluster 6, which governs its tumorigenicity, recruitment of M2 TAMs, and polarization. This regulation involves molecules such as MCP1 for macrophage recruitment and the SPP1-Integrin αvß1-Akt signaling pathway for M2 polarization. Conclusion: Our findings not only deepen our understanding of the formation of M2 TAMs, particularly highlighting the differential roles played by heterogeneous cells within GBM in this process, but also provided new insights for effectively controlling the malignant progression of GBM.

Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments.

Glioblastoma (GBM) tumors are the most aggressive primary brain tumors in adults that, despite maximum treatment, carry a dismal prognosis. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness and maintenance of glioma stem cells and creates an overall immunosuppressive landscape. This article reviews how hypoxic conditions overlap with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, represent promising avenues for GBM treatment. However, challenges such as tumor heterogeneity, immunosuppressive TME, and BBB restrictiveness hinder their effectiveness. Strategies to address these challenges, including combination therapies and targeting hypoxia, are actively being explored to improve outcomes for GBM patients. Targeting hypoxia in combination with immunotherapy represents a potential strategy to enhance treatment efficacy.

From bench to bedside: the application of cannabidiol in glioma.

Glioma is the most common malignant tumor in central nervous system, with significant health burdens to patients. Due to the intrinsic characteristics of glioma and the lack of breakthroughs in treatment modalities, the prognosis for most patients remains poor. This results in a heavy psychological and financial load worldwide. In recent years, cannabidiol (CBD) has garnered widespread attention and research due to its anti-tumoral, anti-inflammatory, and neuroprotective properties. This review comprehensively summarizes the preclinical and clinical research on the use of CBD in glioma therapy, as well as the current status of nanomedicine formulations of CBD, and discusses the potential and challenges of CBD in glioma therapy in the future.

Stigma and related influencing factors in brain cancer patients: a cross-sectional study and parallel mediation analysis.

PURPOSE: Patients with brain cancer and painful symptoms of the disease experience heavy pressure and negative inner experiences, leading to a sense of stigma. Therefore, this study assessed the level of stigma in patients with brain cancer and analyzed the risk factors for stigma to analyze the underlying relationships among depression, social support, low self-esteem, and stigma. METHODS: Patients completed the Social Impact Scale, Self-rating Depression Scale, Rosenberg Self-Esteem Scale, Herth Hope Index, Social Support Rating Scale, and Self-Perceived Burden Scale. Multiple linear regression analysis was used to identify factors independently associated with stigma. Parallel mediation analysis was used to evaluate the mediating role of the relationship between psychoemotional factors and stigma. RESULTS: A multivariate linear regression analysis demonstrated significant associations between age (ß = - 0.189, P = 0.002), treatment (ß = 0.184, P = 0.003), self-esteem (ß = - 0.128, P = 0.046), depression (ß = 0.273, P < 0.001), hope (ß = - 0.217, P = 0.003), and self-perceived burden (ß = 0.260, P < 0.001) with brain cancer. It was observed that the social support received by brain cancer patients directly impacted their stigma (total effect, - 0.851, P = 0.001). Additionally, this relationship was influenced by depression and self-esteem through two distinct pathways. CONCLUSION: Increased stigma among brain cancer patients was found to be associated with severe depression, feelings of inferiority, diminished hope, and a heavy perceived burden. The structural equation modeling (SEM) revealed that social support negatively influenced stigma through depression and self-esteem. It is imperative to grasp patients' inner needs, implement psychological interventions, and cultivate a cancer-friendly social environment to prevent stigmatization and discrimination based on their patient status.

Fully Endoscopic Nontubular Retractor Approach for Intraaxial Tumors.

BACKGROUND: Fully endoscopic or endoscope-controlled approaches are essentially keyhole approaches in which rigid endoscopes are the sole visualization tools used during the whole procedure. At the early attempts of endoscope-assisted cranial surgery, it was noted that rigid endoscopes enabled overcoming the problem of suboptimal visualization when small exposures are used. The technical specifications and design of the currently available rigid endoscopes are associated with a group of unique features that define the endoscopic view and lay the basis for its superiority over the microscopic view during brain surgery. Fully endoscopic resection of intraparenchymal brain tumors is a minimally invasive approach that is not routinely practiced by neurosurgeons, with a few major series published so far. Unfamiliarity with the technique, steep learning curve, and concerns about inadequate exposure and decreased visibility may explain this fact. The majority of the purely endoscopic resections for intraparenchymal brain lesions are performed nowadays through tubular retractor systems. In very limited instances, however, the fully endoscopic technique is performed without tubular retractors. In this chapter, we elaborate on the surgical technique and nuances of the fully endoscopic nontubular retractor approach for intraaxial tumors. METHODS: From a prospective database of endoscopic procedures maintained by the senior author, clinical data, imaging studies, and operative charts and videos of cases undergoing fully endoscopic excision for intraaxial brain tumors were retrieved and analyzed. The pertinent literature was also reviewed. RESULTS: The surgical technique of the fully endoscopic nontubular retractor approach for intraaxial tumors was formulated. CONCLUSION: The endoscopic technique has many advantages over the conventional procedures. In our hands, the technique has proven to be feasible, efficient, and minimally invasive with excellent results.

Endoport-Guided Endoscopic Excision of Intraaxial Brain Tumors.

OBJECTIVE: Transcortical approaches using a spatula-based retraction system have traditionally been used for the microsurgical resection of deep-seated intraventricular and parenchymal brain tumors. Recently, transparent cylindrical or tubular retractors have been developed to provide a stable corridor to access deeper brain lesions and perform bimanual microsurgical resection. The flexible endoports minimize brain retraction injury during surgery and, along with the superior vision of endoscopes, offer several advantages over standard microsurgery. In this chapter, we describe the surgical technique of the endoport-guided endoscopic excision of deep-seated intraaxial brain tumors. METHODS: The endoscopic endoport technique that we use at our institution for the surgical management of intraventricular and intraparenchymal brain tumors has been described in detail with illustrative cases. RESULTS: Results from the literature review of intraventricular and intraparenchymal port surgery were analyzed, and the feasibility and safety of this technique were discussed. Surgical complication avoidance and management were highlighted. The port technique offers numerous potential advantages, including (1) reducing focal brain injury by distributing retraction forces homogenously, (2) minimizing white matter disruption and the risk of fascicle injury during cannulation, (3) ensuring the stability of the surgical corridor during the procedure, (4) preventing inadvertent expansion of the corticectomy and white fiber tract dissection throughout surgery, and (5) protecting the surrounding tissues against iatrogenic injuries caused by instrument entry and reentry. CONCLUSION: The endoport-assisted endoscopic technique is safe and offers an effective alternative option for the resection of intraventricular and intraparenchymal lesions.

Purely Endoscopic Supracerebellar Infratentorial Approach to the Pineal Region in Pediatric Population.

Pineal lesions represent less than 1% of all brain tumors (Villani et al., Clin Neurol Neurosurg 109:1-6, 2007). The abysmal location and critical neurovascular structures remain a surgical challenge, despite the advent of microneurosurgery. The classical wide surgical suboccipital craniotomy with the supracerebellar infratentorial approach, described by Sir Victor Horsley (Victor, Proc R Soc Med 3:77-78, 1910), is infamous for its considerable surgical morbidity and mortality. This was later upgraded microneurosurgically by Stein to improve surgical outcomes (Stein, J Neurosurg 35:197-202, 1971).Ruge et al. reported the first purely endoscopic fenestration of quadrigeminal arachnoid cysts via this corridor (Ruge et al., Neurosurgery 38:830-7, 1996). A cadaver-based anatomical study by Cardia et al. demonstrated the viability for endoscope-assisted techniques (Cardia et al., J Neurosurg 2006;104(6 Suppl):409-14). However, the first purely endoscopic supracerebellar infratentorial (eSCIT) approach to a pineal cyst was performed in 2008 by Gore et al. (Gore PA et al., Neurosurgery 62:108-9, 2008).Unlike transventricular endoscopy, eSCIT approach poses no mechanical risk to the fornices and can be utilized irrespective of ventricular size. More vascular control and resultant reduction in uncontrolled hemorrhage improve the feasibility of attaining complete resection, especially around corners (Zaidi et al,, World Neurosurg 84, 2015). Gravity-dependent positioning and cerebrospinal fluid (CSF) diversion aid cerebellar relaxation, creating the ideal anatomical pathway. Also, angle of the straight sinus, tentorium, and tectal adherence can often influence the choice of approach; thus direct endoscopic visualization not only counteracts access to the engorged Galenic complex but also encourages sharp dissection of the arachnoid (Cardia et al., J Neurosurg 104:409-14, 2006). These tactics help provide excellent illumination with magnification, making it less fatiguing for the surgeon (Broggi et al., Neurosurgery 67:159-65, 2010).The purely endoscopic approach thwarts the dreaded risk of air embolisms, via simple copious irrigation from a small burr hole (Shahinian and Ra, J Neurol Surg B Skull Base 74:114-7, 2013). The tiny opening and closure are rapid to create, and the smaller wound decreases postoperative pain and morbidity. Recent literature supports its numerous advantages and favorable outcomes, making it a tough contender to traditional open methods.

Porphyrin-Based Organic Nanoparticles with NIR-IIa Fluorescence for Orthotopic Glioblastoma Theranostics.

The development of efficient theranostic nanoagents for the precise diagnosis and targeted therapy of glioblastoma (GBM) remains a big challenge. Herein, we designed and developed porphyrin-based organic nanoparticles (PNP NPs) with strong emission in the near-infrared IIa window (NIR-IIa) for orthotopic GBM theranostics. PNP NPs possess favorable photoacoustic and photothermal properties, high photostability, and low toxicity. After modification with the RGD peptide, the obtained PNPD NPs exhibited enhanced blood-brain barrier (BBB) penetration capability and GBM targeting ability. NIR-IIa imaging was employed to monitor the in vivo biodistribution and accumulation of the nanoparticles, revealing a significant enhancement in penetration depth and signal-to-noise ratio. Both in vitro and in vivo results demonstrated that PNPD NPs effectively inhibited the proliferation of tumor cells and induced negligible side effects in normal brain tissues. In general, the work presented a kind of brain-targeted porphyrin-based NPs with NIR-IIa fluorescence for orthotopic glioblastoma theranostics, showing promising prospects for clinical translation.

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR).

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).

Origin recognition complex 6 overexpression promotes growth of glioma cells.

The discovery of novel oncotargets for glioma is of immense significance. We here explored the expression patterns, biological functions, and underlying mechanisms associated with ORC6 (origin recognition complex 6) in glioma. Through the bioinformatics analyses, we found a significant increase in ORC6 expression within human glioma tissues, correlating with poorer overall survival, higher tumor grade, and wild-type isocitrate dehydrogenase status. Additionally, ORC6 overexpression is detected in glioma tissues obtained from locally-treated patients and across various primary/established glioma cells. Further bioinformatics scrutiny revealed that genes co-expressed with ORC6 are enriched in multiple signaling cascades linked to cancer. In primary and immortalized (A172) glioma cells, depleting ORC6 using specific shRNA or Cas9-sgRNA knockout (KO) significantly decreased cell viability and proliferation, disrupted cell cycle progression and mobility, and triggered apoptosis. Conversely, enhancing ORC6 expression via a lentiviral construct augmented malignant behaviors in human glioma cells. ORC6 emerged as a crucial regulator for the expression of key oncogenic genes, including Cyclin A2, Cyclin B2, and DNA topoisomerase II (TOP2A), within glioma cells. Silencing or KO of ORC6 reduced the mRNA and protein levels of these genes, while overexpression of ORC6 increased their expression in primary glioma cells. Bioinformatics analyses further identified RBPJ as a potential transcription factor of ORC6. RBPJ shRNA decreased ORC6 expression in primary glioma cells, while its overexpression increased it. Additionally, significantly enhanced binding between the RBPJ protein and the proposed ORC6 promoter region was detected in glioma tissues and cells. In vivo experiments demonstrated a significant reduction in the growth of patient-derived glioma xenografts in the mouse brain subsequent to ORC6 KO. ORC6 depletion, inhibited proliferation, decreased expression of Cyclin A2/B2/TOP2A, and increased apoptosis were detected within these ORC6 KO intracranial glioma xenografts. Altogether, RBPJ-driven ORC6 overexpression promotes glioma cell growth, underscoring its significance as a promising therapeutic target.

Pan-cancer analysis identifies olfactory receptor family 7 subfamily A member 5 as a potential biomarker for glioma.

Background: Human olfactory receptors (ORs) account for approximately 60% of all human G protein-coupled receptors. The functions of ORs extend beyond olfactory perception and have garnered significant attention in tumor biology. However, a comprehensive pan-cancer analysis of ORs in human cancers is lacking. Methods: Using data from public databases, such as HPA, TCGA, GEO, GTEx, TIMER2, TISDB, UALCAN, GEPIA2, and GSCA, this study investigated the role of olfactory receptor family 7 subfamily A member 5 (OR7A5) in various cancers. Functional analysis of OR7A5 in LGG and GBM was performed using the CGGA database. Molecular and cellular experiments were performed to validate the expression and biological function of OR7A5 in gliomas. Results: The results revealed heightened OR7A5 expression in certain tumors, correlating with the expression levels of immune checkpoints and immune infiltration. In patients with gliomas, the expression levels of OR7A5 were closely associated with adverse prognosis, 1p/19p co-deletion status, and wild-type IDH status. Finally, in vitro experiments confirmed the inhibitory effect of OR7A5 knockdown on the proliferative capacity of glioma cells and on the expression levels of proteins related to lipid metabolism. Conclusion: This study establishes OR7A5 as a novel biomarker, potentially offering a novel therapeutic target for gliomas.

AGBL4 promotes malignant progression of glioblastoma via modulation of MMP-1 and inflammatory pathways.

Introduction: Glioblastoma multiforme (GBM), the most common primary malignant brain tumor, is notorious for its aggressive growth and dismal prognosis. This study aimed to elucidate the molecular underpinnings of GBM, particularly focusing on the role of AGBL4 and its connection to inflammatory pathways, to discover viable therapeutic targets. Methods: Single-cell sequencing was utilized to examine the expression levels of AGBL4 and functional assays were performed to assess the effects of AGBL4 modulation. Results: Our findings identified the significant upregulation of AGBL4 in GBM, which correlated with adverse clinical outcomes. Functional assays demonstrated that AGBL4 knockdown inhibited GBM cell proliferation, migration, and invasion and influenced inflammatory response pathways, while AGBL4 overexpression promoted these activities. Further investigation revealed that AGBL4 exerted its oncogenic effects through modulation of MMP-1, establishing a novel regulatory axis critical for GBM progression and inflammation. Discussion: Both AGBL4 and MMP-1 may be pivotal molecular targets, offering new avenues for targeted therapy in GBM management.

Low-Grade Gliomas: A New Mutation, New Targeted Therapy, and Many Questions.

The discovery in 2008 that many adult gliomas harbor a hitherto unknown mutation in the metabolic gene isocitrate dehydrogenase (IDH) initiated revolutionary advances in our understanding of the biology, and correspondingly our classification, of gliomas. IDH mutations are found in most nonglioblastoma adult gliomas and portend a better prognosis. Massive efforts have unraveled many of the pleiotropic cellular effects of these mutations and spawned several lines of investigation to target the effect to therapeutic benefit. In this article are reviewed the implications of the IDH mutation in gliomas, in particular focusing on recent studies that have culminated in a rare positive phase 3 trial in these generally refractory tumors.