Diffuse Midline H3K27-Altered Gliomas in the Spinal Cord: A Systematic Review.

PURPOSE: To systematically review the clinical features, management, and outcomes of diffuse midline H3K27-altered gliomas of the spinal cord (DMG-SCs). METHODS: PubMed, Ovid EMBASE, Scopus, and Web of Science were searched from database inception to 23 September 2023 for histologically confirmed cases of DMG-SC. Patient demographics, tumor characteristics, management information, and survival outcomes were extracted and analyzed. RESULTS: A total of 279 patients from 39 studies were collected. Patients were mostly male (61%), with an average age of 32 years. Patients were treated with surgery, radiotherapy, and chemotherapy combined (31%) or surgery only (24%), and extent of resection was most often subtotal (38%). Temozolomide was the most common chemotherapeutic agent (81%). Radiation therapy was delivered with mean dose of 47 Gy in 23 fractions. At mean follow-up time of 21 months, 13% of patients were alive. Average median overall survival was 24 months (range of 13 to 40 months) with a median progression-free survival of 14 months. Historical WHO grades of 2 or 3 appeared to exhibit a longer average median overall survival time than that of grade 4 DMG-SCs (32 vs. 23 months, p = 0.009). CONCLUSIONS: Outcomes for DMG-SCs are poor overall but appear to be favorable compared to intracranial DMGs. Despite the recent WHO 2021 grade 4 classification for all DMGs, given the differences in overall survival reported based on historical grading systems, future studies on DMG-SCs are needed to further define if DMG-SCs may represent a heterogeneous group of tumors with different prognoses.

A Feasibility Study on a Portable Vision Device for Patients with Stroke and Brain Tumours.

This prospective, single-centre cohort study aimed to evaluate the impact of a portable vision reading device, OrCam Read, on vision-related quality-of-life and independent functional status in patients with low vision due to stroke or brain tumours. Six patients with poor visual acuity or visual field defects due to a stroke or a brain tumour were enrolled at a U.S. Ophthalmology Department. Participants were trained to use OrCam Read and given a loaner device for the 1 month duration of the study. Various assessments, including daily function tests, the National Eye Institute Visual Function Questionnaire-25, and the 10-item neuro-ophthalmic supplement, were administered at the first and last visits. Patients' experience with the device was evaluated with weekly telephone and end-of-study satisfaction surveys. The main outcome measures were the patient satisfaction with OrCam and the mean assessment scores between enrolment and final visits. The intervention with OrCam significantly improved patients' ability to complete daily tasks and participants reported good satisfaction with the device. The results also show non-significant improvement with distant activities, dependency, and role difficulties. Our findings demonstrate the feasibility of studying vision-related quality-of-life using a portable vision device in this patient population and pave the way for a larger study to validate the results of this study.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Diffuse astrocytic glioma, IDH-Wildtype, with molecular features of glioblastoma, WHO grade IV: A single-institution case series and review.

OBJECTIVE: In 2018, cIMPACT-NOW update 3 concluded that WHO grade II/III IDH-wildtype diffuse astrocytomas that contain TERT promoter mutations, chromosome 7 gain/10 loss, and/or EGFR amplification, correspond to a WHO grade IV diagnosis and should be classified as Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV (DAG-G). We present a single-institution series of patients with DAG-G and IDH-mutant astrocytomas and compare their clinical, molecular, and radiographic characteristics. METHODS: Patient data was retrospectively extracted from the EMR for all patients undergoing surgical biopsy/resection of a diffuse astrocytoma at our institution from 2018 to 2020. Clinical presentation, molecular alterations, radiographic appearance, surgery, and survival were reviewed for each patient. RESULTS: Six DAG-G patients were identified in our cohort. All patients had diffuse disease, and presented with expansile, T2 hyperintense lesions with minimal enhancement. Compared to patients with classic IDH-mutant astrocytomas, mean age for DAG-G patients was older (68 vs 33 years, p < 0.0001), tumors were more diffuse (p = 0.02), with patients more likely to present with focal deficits and receive a biopsy only (p = 0.005). Overall survival was significantly shorter for DAG-G patients (p = 0.03). CONCLUSION: Patients with DAG-G are more likely to be older than typical IDH-mutant diffuse astrocytoma patients. They are more likely to present with tumors in a diffuse pattern with focal deficits. When such patients are encountered, prompt biopsy/resection to confirm the diagnosis and immediate initiation of adjuvant therapy is recommended, as the disease progression and overall prognosis is similar to glioblastoma.

Systemic and local immunosuppression in patients with high-grade meningiomas.

AIM: Despite current treatments, high-grade meningiomas continue to have a poor prognosis. Immunotherapy targeting immune checkpoints, such as PD-L1, has demonstrated significant success in controlling numerous malignancies. In this study, we investigate the extent of systemic and local immunosuppression in meningiomas to assess the potential benefit of immune checkpoint inhibitors for the treatment of high-grade meningiomas. METHODS: Peripheral blood was collected from patients undergoing resection of meningiomas (WHO grade I, n = 18; grade II, n = 25; grade III, n = 10). Immunosuppressive myeloid cells (CD45+CD11b+PD-L1+), myeloid-derived suppressor cells (MDSCs) (CD11b+CD33+HLA-DRlow), and regulatory T cells (Tregs) (CD3+CD4+CD25+FoxP3+) were quantified through flow cytometry. Tissue sections from the same patients were assessed for PD-L1 expression and T cell infiltration via immunohistochemistry. RESULTS: Patients with grade III meningiomas demonstrated increased peripheral monocyte PD-L1 compared to patients with grade I/II meningiomas and healthy controls. Peripheral MDSC abundance was increased in grades II and III meningioma patients. PD-L1 staining of meningioma tissue demonstrated increased positivity in grade III meningiomas. Intratumoral PD-L1 was not associated with progression-free survival. High-grade meningiomas had increased T-cell infiltration. However, a significant proportion of these T cells were exhausted PD1+ T cells and immunosuppressive Tregs. CONCLUSIONS: Patients with meningiomas exhibit signs of peripheral immunosuppression, including increased PD-L1 on myeloid cells and elevated MDSC abundance proportional to tumor grade. Additionally, the tumors express substantial PD-L1 proportional to tumor grade. These results suggest a role for immune checkpoint inhibitors targeting the PD-L1/PD-1 pathway in combination with standard therapies for the treatment of high-grade meningiomas.

Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer.

INTRODUCTION: Brain metastases are a significant source of morbidity and mortality for patients with lung cancer. Lung cancer can induce local and systemic immunosuppression, promoting tumor growth and dissemination. One mechanism of immunosuppression is tumor-induced expansion of programmed death-ligand 1 (PD-L1) expressing myeloid cells. Here, we investigate peripheral blood immune phenotype in NSCLC patients with or without brain metastasis. METHODS: Peripheral blood was collected from patients with lung metastatic brain tumors and pre-metastatic lung cancer. Immunosuppressive monocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were quantified through flow cytometry. T cell reactivity was analyzed via ELISpot. Brain metastasis conditioned media was collected from tumor-derived cell cultures and analyzed for cytokines by ELISA. Naïve monocytes were stimulated with brain metastasis conditioned media to evaluate PD-L1 stimulation. RESULTS: Patients with brain metastatic lung carcinoma demonstrated increased peripheral monocyte PD-L1, MDSC abundance, and Treg percentage compared to early stage pre-metastatic patients and healthy controls. Patients with elevated peripheral monocyte PD-L1 had less reactive T cells and worse survival. Brain metastasis conditioned media stimulation increased monocyte PD-L1, and conditioned media IL-6 levels correlated with PD-L1 induction. Treatment with anti-IL-6 or anti-IL-6 receptor antibodies reduced PD-L1 expression. In summary, patients with lung cancer and brain metastases exhibit multiple markers of peripheral immunosuppression. CONCLUSIONS: The frequency of PD-L1+ myeloid cells correlated with the presence of brain metastases. Tumor-derived IL-6 was capable of inducing PD-L1+ myeloid cells in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients.

Lymphopenia predicts response to stereotactic radiosurgery in lung cancer patients with brain metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) can enhance immune activation and improve disease control through stimulation of anti-tumor immunity. However, patients with cancer receiving chemotherapy are often immunosuppressed, which may impact the efficacy of SRS. Here we investigate the relationship between systemic lymphopenia and response to SRS in patients with brain-metastatic lung cancer. METHODS: We reviewed 125 patients with lung cancer brain metastases treated with SRS between January 2014 and May 2017. Complete blood counts from the time of SRS were reviewed, and lymphopenia was defined as absolute lymphocyte count < 1×109 cells/L. Kaplan-Meier survival analysis and cox proportional-hazards models were used to evaluate risks of progression and death. RESULTS: The median age was 65 years (range 43-86), with 54% female patients. Lymphopenia was present in 60 patients. In univariate analysis, lymphopenic patients had significantly shorter PFS (HR = 2.995, p < 0.0001) and OS (HR = 3.928, p < 0.0001). When accounting for age, gender, smoking history, ECOG score, surgery, and tumor histology in a multivariate model, lymphopenia remained significantly predictive of worse PFS (HR = 1.912, p = 0.002) and OS (HR = 2.257, p < 0.001). Patients who received immunotherapy within 3 months of SRS demonstrated significantly shorter PFS (HR = 3.578, p = 0.006) and OS (HR = 6.409, p = 0.001) if lymphopenic. CONCLUSIONS: Brain-metastatic lung cancer patients with lymphopenia treated with SRS had significantly worse PFS and OS. The effect of lymphopenia was even more pronounced in patients receiving immunotherapy. These data demonstrate the significant impact of deficient immunity on disease control and survival. Lymphopenic patients may benefit from interventions to improve immune function prior to SRS for brain metastases.

Gross total resection and adjuvant radiotherapy most significant predictors of improved survival in patients with atypical meningioma.

BACKGROUND: Atypical and malignant meningiomas are far less common than benign meningiomas. As aggressive lesions, they are prone to local recurrence and may lead to decreased survival. Although malignant meningiomas typically are treated with maximal surgical resection and adjuvant radiotherapy (RT), to the authors' knowledge the optimal treatment for atypical lesions remains to be defined. There are limited prospective data in this setting. METHODS: The National Cancer Data Base was queried to investigate cases of histologically confirmed meningiomas diagnosed from 2004 to 2014. This included 7811 patients with atypical meningiomas (World Health Organization grade 2) and 1936 patients with malignant meningiomas (World Health Organization grade 3); during the same period, a total of 60,345 patients were diagnosed with benign meningiomas (World Health Organization grade 1). Data collected included patient and tumor characteristics, extent of surgical resection, and use of RT. Survival analysis was performed using Kaplan-Meier estimates with the log-rank test of significance and Cox univariate and multivariate regression. Logistic regression was used to determine factors associated with use of RT. RESULTS: The 5-year overall survival rate was 85.5% in patients with benign meningiomas, 75.9% in patients with atypical meningiomas, and 55.4% in patients with malignant meningiomas (P<.0001). In patients with atypical meningiomas, gross (macroscopic) total resection (GTR) and adjuvant RT were found to be associated with significantly improved survival, independently and especially in unison (GTR plus RT: hazard ratio, 0.47; P = .002). On multivariate analysis, the combination of GTR plus RT was found to be the most important factor for improved survival. However, GTR was associated with significantly lower rates of RT use. CONCLUSIONS: GTR and adjuvant RT appear to be highly associated with improved survival, independent of other factors, in patients with atypical meningiomas. Cancer 2018;124:734-42. © 2017 American Cancer Society.

Postoperative stereotactic radiosurgery for patients with resected brain metastases: a volumetric analysis.

PURPOSE: Postoperative stereotactic radiosurgery (SRS) is increasingly utilized following resection of brain metastases (BM); however, there are no volumetric data guiding dose selection. We performed a volumetric analysis to guide cavity SRS dosing for resected BM. METHODS: 83 consecutive patients with gross total resection who underwent postoperative SRS to 90 cavities were identified. The 12 Gy isodose lines (V12total) along with the volume of brain parenchyma receiving 12 Gy excluding cavity fluid, ventricular fluid, and calvarium (V12parenchyma) were contoured. Local recurrence (LR) and radionecrosis (RN) were calculated using cumulative incidence rates. Multivariate analysis (MVA) and cutpoint analysis were conducted. RESULTS: Median follow-up was 12.3 months; median dose was 16 Gy. 1- and 2-year cumulative incidence rates of LR were 7.9% and 11.0%. Radiation dose [hazard ratio (HR) 2.04, p = 0.002] was significantly associated with time to LR on MVA. 1- and 2-year cumulative incidence rates of RN were 2.6% and 5.5% respectively. MVA demonstrated increased risk of RN with a larger V12parenchyma (HR 1.46, p = 0.0496). Cavities ≤ 10 cc showed a low 2-year RN risk (4.3%), but had a modest LR risk (13.9%). A radiation dose ≥ 18 Gy significantly improved LC (HR 4.79, p = 0.01). CONCLUSIONS: V12parenchyma should be examined in postoperative SRS to assess RN risk. Cavities > 10 cc treated with 16 Gy achieved excellent LC and minimal RN at 2 years. Cavities ≤ 10 cc may be better treated with a dose ≥ 18 Gy to significantly improve LC given the low RN rate observed with 16 Gy.

Predictors of recurrence in the management of chordoid meningioma.

Management of chordoid meningiomas (CMs) is complicated by high rates of recurrence, particularly following subtotal resection. Optimal management is not established given the paucity of published experience. To identify prognostic factors for recurrence following resection, the authors conducted the largest systematic review of CMs to date. A comprehensive search on MEDLINE (OVID and Pubmed), Scopus, Embase, and Web of Science utilizing the search terms "chordoid" AND "meningioma" was performed to identify all reports of pathologically confirmed intracranial CMs. A total of 221 patients were included, comprising 120 females and 101 males. Mean age, MIB-1/Ki67, and tumor size was 45.5 years, 4.3% (range 0.1-26.6%), and 4.1 cm (range 0.8-10 cm), respectively. 5-, and 10- year progression free survival was 67.5 and 54.4%, respectively. Gross total resection (GTR) and subtotal resection was achieved in 172 and 48 patients, respectively. Adjuvant radiotherapy (RT) was given to 30 patients. Multivariate analysis found GTR was strongly correlated with decreased recurrence rates (HR 0.04, p = <0.0001), while higher MIB-1 labeling index (≥5 vs <5%) was associated with increased recurrence (HR 7.08; p = 0.016). Adjuvant RT, age, gender, and tumor location were not associated with recurrence. GTR resection is the strongest predictor of tumor control, and should be the goal to minimize local progression. Additionally, higher MIB-1 labeling was associated with increased rates of tumor recurrence. Tumors that are subtotally resected or demonstrate higher MIB-1 are at greater recurrence and warrant consideration for RT and close long term follow up.

Immunomonitoring in glioma immunotherapy: current status and future perspectives.

Given the continued poor clinical outcomes and refractory nature of glioblastoma multiforme to traditional interventions, immunotherapy is gaining traction due to its potential for specific tumor-targeting and long-term antitumor protective surveillance. Currently, development of glioma immunotherapy relies on overall survival as an endpoint in clinical trials. However, the identification of surrogate immunologic biomarkers can accelerate the development of successful immunotherapeutic strategies. Immunomonitoring techniques possess the potential to elucidate immunological mechanisms of antitumor responses, monitor disease progression, evaluate therapeutic effect, identify candidates for immunotherapy, and serve as prognostic markers of clinical outcome. Current immunomonitoring assays assess delayed-type hypersensitivity, T cell proliferation, cytotoxic T-lymphocyte function, cytokine secretion profiles, antibody titers, and lymphocyte phenotypes. Yet, no single immunomonitoring technique can reliably predict outcomes, relegating immunological markers to exploratory endpoints. In response, the most recent immunomonitoring assays are incorporating emerging technologies and novel analysis techniques to approach the goal of identifying a competent immunological biomarker which predicts therapy responsiveness and clinical outcome. This review addresses the current status of immunomonitoring in glioma vaccine clinical trials with emphasis on correlations with clinical response.

Heat shock protein vaccines against glioblastoma: from bench to bedside.

Current adjuvant treatment regimens available for the treatment of glioblastoma are widely ineffective and offer a dismal prognosis. Advancements in conventional treatment strategies have only yielded modest improvements in overall survival. Immunotherapy remains a promising adjuvant in the treatment of GBM through eliciting tumor specific immune responses capable of producing sustained antitumor response while minimizing systemic toxicity. Heat shock proteins (HSP) function as intracellular chaperones and have been implicated in the activation of both innate and adaptive immune systems. Vaccines formulated from HSP-peptide complexes, derived from autologous tumor, have been applied to the field of immunotherapy for glioblastoma. The results from the phase I and II clinical trials have been promising. Here we review the role of HSP in cellular function and immunity, and its application in the treatment of glioblastoma.

Epidermal growth factor-like module containing mucin-like hormone receptor 2 expression in gliomas.

Epidermal growth factor (EGF) module-containing mucin-like receptor 2 (EMR2) is a member of the seven span transmembrane adhesion G-protein coupled receptor subclass. This protein is expressed in a subset of glioblastoma (GBM) cells and associated with an invasive phenotype. The expression pattern and functional significance of EMR2 in low grade or anaplastic astrocytomas is unknown and our goal was to expand and further define EMR2's role in gliomas with an aggressive invasive phenotype. Using the TCGA survival data we describe EMR2 expression patterns across histologic grades of gliomas and demonstrate an association between increased EMR2 expression and poor survival (p < 0.05). This data supports prior functional data depicting that EMR2-positive neoplasms possess a greater capacity for infiltrative and metastatic spread. Genomic analysis suggests that EMR2 overexpression is associated with the mesenchymal GBM subtype (p < 0.0001). We also demonstrate that immunohistorchemistry is a feasible method for screening GBM patients for EMR2 expression. Protein and mRNA analysis demonstrated variable expression of all isoforms of EMR2 in all glioma grades, however GBM displayed the most diverse isoforms expression pattern as well as the highest expression of the EGF1-5 isoform of EMR2. Finally, a correlation of an increased EMR2 expression after bevacizumab treatment in glioma cells lines is identified. This observation should serve as the impetus for future studies to determine if this up-regulation of EMR2 plays a role in the observation of the diffuse and increasingly invasive recurrence patterns witnessed in a subset of GBM patients after bevacizumab treatment.

Immunotherapy for malignant gliomas.

Cancer immunotherapy aims to harness the innate ability of the immune system to recognize and destroy malignant cells. Immunotherapy for malignant gliomas is an emerging field that promises the possibility of highly specific and less toxic treatment compared to conventional chemotherapy. In addition, immunotherapy has the added benefit of sustained efficacy once immunologic memory is induced. Although there are numerous therapeutic agents that boost general immune function and facilitate improved antitumor immunity, to date, immunotherapy for gliomas has focused primarily on active vaccination against tumor-specific antigens. The results of numerous early phase clinical trials demonstrate promising results for vaccine therapy, but no therapy has yet proven to improve survival in a randomized, controlled trial. The major barrier to immunotherapy in malignant gliomas is tumor-induced immunosuppression. The mechanisms of immunosuppression are only now being elucidated, but clearly involve a combination of factors including regulatory T cells, tumor-associated PD-L1 expression, and CTLA-4 signaling. Immunomodulatory agents have been developed to combat these immunosuppressive factors and have demonstrated efficacy in other cancers. The future of glioma immunotherapy likely lies in a combination of active vaccination and immune checkpoint inhibition.

Vaccine therapies in malignant glioma.

Glioblastoma is a grade IV astrocytoma that is widely accepted in clinical neurosurgery as being an extremely lethal diagnosis. Long-term survival rates remain dismal, and even when tumors undergo gross resection with confirmation of total removal on neuroimaging, they invariably recur with even greater virulence. Standard therapeutic modalities as well as more contemporary treatments have largely resulted in disappointing improvements. However, the therapeutic potential of vaccine immunotherapy for malignant glioma should not be underestimated. In contrast to many of the available treatments, vaccine immunotherapy is unique because it offers the means of delivering treatment that is highly specific to both the patient and the tumor. Peptide, heat-shock proteins, and dendritic cell vaccines collectively encapsulate the majority of research efforts involving vaccine-based treatment modalities. In this review, important recent findings for these vaccine types are discussed in the context of ongoing clinical trials. Broad challenges to immunotherapy are also considered.

Stable luciferase expression does not alter immunologic or in vivo growth properties of GL261 murine glioma cells.

BACKGROUND: GL261 cells are murine glioma cells that demonstrate proliferation, invasion, and angiogenesis when implanted in syngeneic C57BL/6 mice, providing a highly useful immunocompetent animal model of glioblastoma. Modification of tumor cells for luciferase expression enables non-invasive monitoring of orthotopic tumor growth, and has proven useful for studying glioblastoma response to novel therapeutics. However, tumor modification for luciferase has the potential for evoking host immune response against otherwise syngeneic tumor cells, thereby mitigating the tumor cells' value for tumor immunology and immunotherapy studies. METHODS: GL261 cells were infected with lentivirus containing a gene encoding firefly luciferase (GL261.luc). In vitro proliferation of parental (unmodified) GL261 and GL261.luc was measured on days 0, 1, 2, 4, and 7 following plating, and the expression of 82 mouse cytokines and chemokines were analyzed by RT-PCR array. Cell lines were also evaluated for differences in invasion and migration in modified Boyden chambers. GL261 and GL261.luc cells were then implanted intracranially in C57BL/6 mice, with GL261.luc tumor growth monitored by quantitative bioluminescence imaging, and all mice were followed for survival to compare relative malignancy of tumor cells. RESULTS: No difference in proliferation was indicated for GL261 vs. GL261.luc cells (p>0.05). Of the 82 genes examined by RT-PCR array, seven (9%) exhibited statistically significant change after luciferase modification. Of these, only three changed by greater than 2-fold: BMP-2, IL-13, and TGF-ß2. No difference in invasion (p=0.67) or migration (p=0.26) was evident between modified vs. unmodified cells. GL261.luc cell luminescence was detectable in the brains of C57BL/6 mice at day 5 post-implantation, and tumor bioluminescence increased exponentially to day 19. Median overall survival was 20.2 days versus 19.7 days for mice receiving implantation with GL261 and GL261.luc, respectively (p=0.62). Histopathologic analysis revealed no morphological difference between tumors, and immunohistochemical analysis showed no significant difference for staining of CD3, Ki67, or CD31 (p>0.05 for all). CONCLUSIONS: Luciferase expression in GL261 murine glioma cells does not affect GL261 proliferation, invasion, cytokine expression, or in vivo growth. Luciferase modification increases their utility for studying tumor immunology and immunotherapeutic approaches for treating glioblastoma.

Immunocompetent murine models for the study of glioblastoma immunotherapy.

Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches.

Vaccine therapies for patients with glioblastoma.

Glioblastoma (GBM) is a high-grade glial tumor with an extremely aggressive clinical course and a median overall survival of only 14.6 months following maximum surgical resection and adjuvant chemoradiotherapy. A central feature of this disease is local and systemic immunosuppression, and defects in patient immune systems are closely associated with tumor progression. Immunotherapy has emerged as an important adjuvant in the therapeutic armamentarium of clinicians caring for patients with GBM. The fundamental aim of immunotherapy is to augment the host antitumor immune response. Active immunotherapy utilizes vaccines to stimulate adaptive immunity against tumor-associated antigens. A vast array of vaccine strategies have advanced from preclinical study to active clinical trials in patients with recurrent or newly diagnosed GBM, including those that employ peptides, heat shock proteins, autologous tumor cells, and dendritic cells. In this review, the rationale for glioma immunotherapy is outlined, and the prevailing forms of vaccine therapy are described.

Gross total resection improves overall survival in children with choroid plexus carcinoma.

Choroid plexus carcinoma (CPC) is a rare, malignant, primary brain tumor with a poor prognosis. While previous reports have shown benefits of aggressive surgery, very few large-scale studies have focused exclusively on the pediatric population, for whom the risks of aggressive surgery must be weighed carefully against the benefits. We performed a comprehensive systematic review of pediatric CPCs to test the effects of gross total resection (GTR) on overall survival (OS) and progression-free survival (PFS). A Pubmed search was performed to identify children with CPC who underwent surgical resection. Only disaggregated clinical cases in which extent of resection was confirmed by CT or MRI were included for analysis. Kaplan-Meier and multivariate Cox regression survival analyses were performed to determine the effects of extent of resection on OS and PFS. Disaggregated clinical data from a total of 102 pediatric CPC patients (age ≤18 years) with known extent of resection and overall survival were analyzed. GTR was significantly associated with better OS by Kaplan-Meier analysis (logrank p < 0.001). Multivariate Cox regression analysis adjusting for age, gender, tumor location (supratentorial vs. infratentorial), and type of adjuvant therapy (chemotherapy, radiation, and combined therapy), showed that GTR independently increased OS (p = 0.006). While GTR also improved PFS on Kaplan-Meier analysis (p = 0.027), the effect did not meet our criteria for significance in our multivariate Cox model (p = 0.120). GTR improved OS of pediatric CPC and is recommended if it can be safely performed.

Metabolomic characterization of human glioblastomas and patient plasma: a pilot study.

Background: Glioblastoma (GBM) is a clinically challenging primary brain tumor with poor survival outcome despite surgical resection and intensive chemoradiation. The metabolic heterogeneity of GBM can become biomarkers for treatment response, resistance, and outcome prediction. The aim of the study is to investigate metabolic distinctions between primary and recurrent GBM tissue and patient plasma to establish feasibility for metabolic profiling. Methods: A single-center cohort study analyzed tissue and blood samples from 15 patients with GBM using untargeted metabolomic/lipidomic assays. Metabolomic, lipidomic, and biogenic amine analyses were conducted on GBM tissue and patient plasma at diagnosis and recurrence using untargeted mass spectrometry. The study utilized a small but longitudinally collected cohort to evaluate alteration in metabolites, lipids, and biogenic amines between specimens at diagnosis and recurrence. Results: Exploratory analysis revealed significant alteration in metabolites, lipids, and biogenic amines between diagnostic and recurrent states in both tumor and plasma specimens. Notable metabolites differed at recurrence, including N-alpha-methylhistamine, glycerol-3-phosphate, phosphocholine, and succinic acid in tissue, and indole-3-acetate, and urea in plasma. Principal component analysis revealed distinct metabolomic profiles between tumor tissue and patient plasma. Distinct metabolic profiles were observed in GBM tissue and patient plasma at recurrence, demonstrating the feasibility of using metabolomic methodologies for longitudinal studies. One patient exhibited a unique tumor resistance signature at diagnosis, possibly indicating a high-risk metabolomic phenotype. Conclusions: In this small cohort, the findings suggest the potential of metabolomic signatures of GBM tissue and patient plasma for risk stratification, outcome prediction, and the development of novel adjuvant metabolic-targeting therapies. The findings suggest metabolic discrepancies at diagnosis and recurrence in tissue and plasma, highlighting potential implications for evaluation of clinical response. The identification of significant changes in metabolite abundance emphasizes the need for larger studies using targeted metabolomics to validate and further explore these profiles.