The diagnosis and treatment of gliomas have traditionally been both a research hotspot and a challenge in clinical medicine. Intracranial multiple gliomas are rare, and their diagnosis and treatment are often more difficult than those of solitary gliomas. In this article, we report our experience with the diagnosis and treatment of a case of intracranial multiple glioblastomas that closely resembled metastatic tumors in terms of neuroimaging and anatomy. This case may provide a useful reference and insight into the clinical management of this type of disease.
Background and Aim: Glioma is one of the most prevalent and refractory brain cancers with a high recurrence rate. Current limitations of experimental in vitro models include their inability to remodel the heterogeneity of the parental tumors and their incapacity to effectively reflect antitumor effects and mechanisms observable in vivo. Organoid models, as a new technology developed in recent years, can preserve the histological characteristics, cellular diversity, and gene expression of parental tumors to the fullest extent, thereby delivering more reliable data. This study intends to construct a simple organoid model developed from glioma patient material. Materials and Methods: Glioma samples were taken intraoperatively and cultured in the organoid medium using a continuous horizontal shaker. Sample collection and scientific research were authorized and approved by the Ethics Committee of Kowloon Hospital, China (Approval No. KY-2021-007). Immunofluorescence was applied to identify CD31 and Sox2 protein expression in the organoid model. The differences between primary glioblastomas and transplanted organoid tumors were analyzed by hematoxylin and eosin (H and E) staining. Immunohistochemistry (IHC) and Western blot assay were used to analyze the Sox2, Ki67, and CD31 protein expression levels. Results: The success rate of establishing organoid models was 90.9% in the primary glioblastomas, 75.0% in the WHO Grade III gliomas, and 42.9% in the Grade I–II gliomas. Immunofluorescence demonstrated that in vitro cultured organoids expressed CD31 and Sox2. Similarly, IHC and Western blot assay showed that orthotopically transplanted organoid tumors could exhibit high expressions of Sox2, Ki67, and CD31. There were no significant differences regarding the pathological features of primary glioblastomas and glioma organoid model as judged by H and E staining. Conclusions: This study presents a simple in vitro organoid model established from glioma patient samples. The success rate of constructing an organoid model is correlated with the degree of glioma malignancy. The established organoid model displays original model properties and simplifies the development of new experimental platforms that can support preclinical glioma treatment studies.
Glioblastoma (GBM) is characterized by a high recurrence rate, significant heterogeneity, and poor prognosis. While there has been a shift in recent years to focus on molecular phenotyping, there are limited data regarding the relationship between the immune milieu and heterogeneous molecular signatures in GBM. Given the success of immunotherapies in other cancers such as non-small-cell lung cancer and melanoma, there has been a concerted effort to correlate the immune compartment of the GBM tumor microenvironment to clinical outcomes. The aim of this narrative review is to establish the role of immunophenotyping in GBM classification. Major immune cell groups in GBM involve myeloid cells (e.g. myeloid-derived suppressor cells, tumor-associated macrophages and microglia, neutrophils, and dendritic cells), lymphocytes (e.g., T, natural killer, and B-cells), and stromal cells (e.g., fibroblasts, pericytes, and endothelial cells). Understanding the relationships between these different immune cell populations and correlating their roles with the current molecular classification scheme as described in the 2021 World Health Organization criteria may further elucidate patterns of clinical response, especially in light of recent advances in new immunotherapies.
Glioblastoma multiforme (GBM) is one of the most aggressive tumors known to occur in the brain. Metabolism is one of the driving factors enabling the successful proliferation of tumor cells, thus increasing the tumor mass. Tumor metabolism is now recognized as a major hallmark of oncogenesis. Since the brain largely relies on its glucose supply for growth, glucose metabolism significantly contributes to oncogenesis in brain cancers. Here, we review the major metabolic pathways seen in normal brain physiology in addition to the Warburg effect, aberrant tricarboxylic acid cycle, and oxidative phosphorylation observed in GBM. We highlight the important differences in glucose metabolism between the normal and cancerous environments. In addition, we provide insights into lactate shuttling, the pentose phosphate pathway, and immune interactions with glucose metabolism, which drive the nutritional pathways in both the normal and cancerous environment.
The placebo-controlled INDIGO trial recently demonstrated a major gain in progression-free survival in patients with central nervous system (CNS) WHO Grade 2 isocitrate dehydrogenase (IDH)-mutant gliomas, with a progression-free survival of 27.7 months in the experimental arm versus 11.1 months in the control arm (hazard ratio, for disease progression or death, 0.39; 95% confidence interval [CI], 0.27–0.56; P < 0.001).[1] The positive outcome of this study will profoundly stimulate experimental and clinical research in this area and represent new hope for many patients with brain tumors. First, the previously controversial question of whether the function of the mutant IDH protein is still relevant once a tumor has formed appears to have been clarified: if the mutated function was superfluous, then the therapy would not have been effective. That the metabolite 2-hydroxyglutarate is responsible for tumor progression and that inhibitors of the mutated protein act by preventing the synthesis of this metabolite is plausible, but by no means causally proven. The convincing results in the INDIGO study with rather moderate effects, if any, on progression after radiotherapy or chemotherapy in the early studies[2,3] suggest that the importance of mutated IDH function may diminish throughout the disease. This leads to speculation that inhibiting the mutated IDH function in later phases of the disease could be ineffective or even counterproductive, but there is currently no clinical evidence for a detrimental effect in the clinic. However, since the mutant IDH function is most likely a "moving target" in the truest sense of the word, expansions of indications for such drugs should be carried out in controlled studies, from which a lot can be learned. Time to next intervention, a key secondary endpoint, was also prolonged in the vorasidenib arm (19 months vs. 6 months, hazard ratio, 0.26; 95% CI, 0.15–0.43; P < 0.001). However, after progression per central review, only 19 of 47 patients (40%) with progression in the vorasidenib arm received treatment, versus 58 of 88 patients (66%) in the control arm, raising the questions of the concordance between local and central magnetic resonance imaging review and why some patients were not treated at progression. Time to the second intervention would thus also be an exploratory endpoint of interest. The inclusion criteria for the study were very narrow: a year had to have passed since the last surgery, measurable disease had to be present, and contrast enhancement was not allowed. According to the current EANO guidelines,[4] the enrolled patients with residual tumors – 139 patients (82.7%) in the vorasidenib arm and 137 patients (84%) in the placebo arm had the longest diameter of residual tumor of 2 cm or more – would have been candidates for alkylator-based chemoradiotherapy; therefore, one might argue that the benefit in these patients should have been compared to chemoradiotherapy and not to placebo. However, the fact that 331 patients were enrolled in 26 months demonstrates that the current definition of low risk versus high risk, based on inclusion criteria of previous randomized trials, is no longer convincing for participating centers. Of note, 76 of 466 patients (16%) and 59 of 390 patients (15%) were declared screen failure at prescreening or screening, respectively. The narrow inclusion criteria, therefore, naturally led to the question of whether there could be other patients with IDH-mutant gliomas who might also benefit from therapy with IDH inhibitors. This seems plausible for patients who have not had the operation at least 1 year ago, but the question remains whether newly diagnosed tumors with contrast enhancement would also benefit from IDH inhibition. The fact that this was not the case in the recurrent situation[2,3] per se is not sufficient as an argument against this since we do not know with certainty whether contrast enhancement in the recurrent situation means the same as in the newly diagnosed setting. The question of the differentiation between WHO Grade 2 and 3 gliomas has remained controversial over the last few years and the definition in the WHO classification is not too clear in this regard. Regardless, we have recently reported that assignment to CNS WHO grade by central neuropathology review revealed a clear difference in overall survival between Grade 2 and 3 tumors.[5] Thus, if therapy with IDH inhibitors was expanded to patients with newly diagnosed WHO Grade 3 tumors, this must be done within the framework of controlled studies with close magnetic resonance monitoring. A "neoadjuvant" approach of using inhibitors of mutant IDH to induce tumor shrinkage and consequently lower volumes for radiotherapy appears unrealistic, given the very low objective response rate.[1] Furthermore, whether IDH inhibitors can be usefully combined with radiotherapy and chemotherapy also requires controlled studies because we do not know how mutant IDH inhibition might affect the activity of radiotherapy and chemotherapy. Of note, such studies are challenging to carry out because, at least for WHO Grade 2 and Grade 3 tumors, very long follow-up times must be expected until it can be assessed whether IDH inhibitors provide benefit in this setting. In conclusion, INDIGO[1] thus opens up a new perspective for the therapy of patients with IDH-mutated tumors, the first perspective in decades, but numerous important questions remain unanswered regarding the integration of this new therapeutic option into the current treatment algorithms, the answers to which will be complex, expensive, and lengthy. However, it remains to be hoped that the pharmaceutical industry will continue to engage in this important area of neuro-oncology. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
