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.
Glioblastoma is the most common malignant tumor in the adult primary central nervous system. It has a strong proliferative ability, high recurrence rate, and high malignant degree. Despite standard radiotherapy combined with temozolomide chemotherapy, the prognosis was poor, with a 5-year survival of <10%. Therefore, more effective treatments need to be explored. Oncolytic viruses (OVs) have attracted the attention of researchers because of their unique targeting, safety, and antitumor effects. OV therapy has achieved remarkable efficacy in the treatment of many kinds of malignant tumors, and it has also made great progress in the treatment of glioblastoma. This article reviews the recent clinical research progress of OVs in the treatment of glioblastoma.
Glioma is a common type of brain tumor. Current treatment for glioma includes surgical resection, radiotherapy, chemotherapy, and tumor-treating fields. The application of immunotherapy to treat glioma is still far from satisfactory in the clinic. Here, we review the mechanisms of immunotherapy for glioma (including immune checkpoint inhibitor, chimeric antigen receptor-T-cell, tumor vaccine, and oncolytic virus) and the results of completed clinical trials, and will discuss the current status of immunotherapy and possible future directions.
Neuro-oncology, notably the field of gliomas, has undergone major changes over the last decades, notably with regard to how we classify and diagnose gliomas. This has resulted in updates of the WHO classification in 2007, 2016, and 2021. A recent publication by Girardi et al.[1] published in a Neuro-oncology reported global survival trends for the major groups of gliomas in adulthood, astrocytomas, oligodendrogliomas, and glioblastomas, based on the analysis of 556,237 adult patients diagnosed in 59 countries from 2000 to 2014. The authors conclude that survival improvements have been "extensive" and that some countries still lag behind. This publication has resulted in discussions, notably on the country-specific data, in several countries. For China, it had been noteworthy in a preceding publication of Girardi et al.[2] that less than 10% of tumors were diagnosed with glioblastoma but that 52% of tumors were "unspecified tumors." For the 5-year survival rates reported in 2022,[1] China was average for astrocytomas and oligodendroglioma, whereas survival was among the highest for glioblastoma. Does that truly inform the quality of diagnosis and care in China? Is this merely reflecting the fact that pathologists and oncologists in China diagnose glioblastoma less frequently and that most tumors considered glioblastoma elsewhere ended up in the category of "unspecified tumors" in China? Are we sure that the small group of glioblastomas diagnosed in China are the same tumors as more than 50% of glioblastomas diagnosed in the US and in most European countries?[2] Or do we believe that treatment and care are better in China than in most other parts of the world? Our caveat is that such data are very different to interpret because gliomas are not a simple uniform disease category and because diagnostic and therapeutic approaches have evolved significantly over time, but still vary widely worldwide. For instance, in the first population-based Zurich cantonal registry study, nonbiopsied patients were still included, whereas today, such patients would not enter into the cancer registry or would be excluded from reporting.[3] It also seems premature and an overinterpretation of the data to conclude that the introduction of temozolomide alone accounted for the major improvement in survival noted in some countries. A more balanced view would be to also take into consideration that radiotherapy, while potentially not being more active than 20 years ago, today is much more focused and likely to cause much less long-term toxicity, in turn, will no longer render patients less eligible for salvage treatments and thereby contribute to inferior survival. We also do think that the quality of neurosurgery is essential and that it varies significantly across the countries included in this study. To what degree the extent of resection contributes to the outcome remains controversial, yet, our personal view is that the role of surgery in shaping survival curves is likely more prominent for astrocytoma and oligodendroglioma than for glioblastoma. The improved access to neuroimaging and to supportive and palliative care interventions may also have contributed to improved survival in some countries. The standardized approach to evaluating the data included in the study[1] cannot overcome the inherent limitations of the source data that are likely to be incomplete and of heterogeneous quality. Why the increase in survival should not be visible in glioblastoma patients aged 40 or less remains unclear and enforces the view that the data should not be overinterpreted. Conversely, as indicated above, it is also noteworthy that the rate of brain tumors coded as nonspecific histology varied significantly: it was 64% of all brain tumor diagnoses in China which appears high. In conclusion, the exchange of high-quality data across countries in a global registry would certainly contribute to our understanding of gliomas as a disease category in general. Molecular analyses have so far not provided evidence that gliomas differ very much genetically worldwide; in contrast, the tumors appear strikingly similar regarding the major molecular genetic pathways involved. Treatment algorithms will continue to differ and are largely driven by the financial resources available for the treatment and care of patients. We should remain modest with regard to recognizing that, at least for glioblastoma, our interventions do not have a major impact, the cure does not exist, and long-term survival remains the exception. Meanwhile, our patient populations worldwide would undoubtedly benefit from more structured pathways along the disease trajectory, including adherence to the WHO classification as feasible, access to specialized neurosurgery and adequate radiation oncology facilities, access to alkylating agents, and systematic recognition and management of complications during standardized follow-up.[4] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Editor note: MW is an Editorial Board member of Glioma. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups. Acknowledgments Nil.
Gliosarcoma is a rare subtype of glioblastoma with the histological features of both glioblastoma and soft-tissue sarcoma. Triple-negative breast cancer (TNBC) is a special type of breast cancer that is different from other breast cancers. It is characterized by strong invasiveness, high recurrence rate, and poor prognosis. The concurrent occurrence of gliosarcoma and TNBC was rarely seen and reported. A 63-year-old woman with a history of TNBC was found to have an intracranial mass due to headache. Intracranial tumor resection surgery was undergone, and histopathological examination postoperation revealed gliosarcoma. After craniotomy, the patient underwent standard radiotherapy and chemotherapy. Postoperative follow-up observation showed no obvious recurrence of either tumor. In conclusion, gliosarcoma and TNBC are tumors with poor prognosis. It is rare to encounter two types of malignant tumors in the same patient. When we encounter intracranial space-occupying patients with a history of malignant tumors, we should first consider tumor metastasis. When excluding the possibility of cancer metastasis, the possibility of two primary tumors should be considered.
Dear Editor, Mellinghoff et al.[1] conducted a double-blinded randomized study INDIGO investigating the effect of brain-penetrant vorasidenib against low-grade gliomas with mutated isocitrate dehydrogenase (IDH-1) and IDH-2. This is based on the rationale that these two enzymes with gain-of-function mutations led to the production and accumulation of oncometabolite 2-hydroxyglutarate within the local tumor microenvironment, setting off a cascade of epigenetic changes that favor glioma development and progression.[2] Typically, low-grade glioma patients are categorized as high risk for progression if they are older than 40 years of age or undergo incomplete resection of tumor. Other than resection, radiation or chemotherapy may be postponed at the time of diagnosis because the speed of progression is slow, and patients then undergo serial head magnetic resonance imaging (MRI) monitoring. The investigators took advantage of this observation period and introduced vorasidenib to delay tumor progression and prolong survival. Under blinded imaging-based independent assessment, they found that vorasidenib significantly improved progression-free survival (PFS) compared to the control population. This small molecule targeted agent also delayed time to next intervention (TTNI). Response, PFS, and overall survival (OS) are three classic pillars of efficacy assessment in cancer clinical trials. Positive outcomes from 2 of these 3 endpoints are typically required for regulatory approval or acceptance as standard of care. Unfortunately in the glioma population, radiologic response to treatment is rarely seen on head MRI. Indeed, there were only 2 responders in the INDIGO study, and the results may be more appropriately viewed and compared to our prior experience in glioma trials. For example, the EORTC/NCIC (radiotherapy plus concomitant and adjuvant temozolomide)[3] and the EF-14 (adjuvant temozolomide with or without tumor treating fields)[4] trials for glioblastoma showed prolongation of PFS and OS, and both treatment modalities won regulatory approval in the United States accordingly. However, this was not the case for RTOG 0625 and AVAglio trials (radiotherapy and temozolomide with or without bevacizumab)[5] because they only showed prolongation of PFS but not OS, despite an apparent decrease in contrast enhancement due to pseudoresponse. The designers of the INDIGO trial introduced the concept of TTNI as a key secondary efficacy endpoint. This is probably because, for the low-grade glioma population, lack of response and long duration of follow-up required for OS determination are major impediments to timely efficacy assessment. However, we should be cautious in asking whether TTNI is a relevant benchmark for this trial. First, prolonged PFS would lead to a delay in TTNI anyway, and therefore, these two benchmarks are not necessarily independent. Second, patients in the control group can cross over to receive vorasidenib, and their threshold for crossing over to another pill is probably lower compared to those in the experimental cohort considering additional brain surgery, radiation, or cytotoxic chemotherapy. Inertia for next intervention may, therefore, be greater among patients taking the placebo. Third, the criteria for the next intervention were not prespecified in the original protocol, and it was only introduced as a key secondary endpoint for analysis on July 20, 2021, in Amendment 3, probably after the first interim analysis and the steering committee noticed a signal. Finally, whether or not there is a difference in the number of neurologic versus radiologic progression in the two cohorts is unclear. Obviously, neurologic deficits are more serious conditions and carry a greater propensity for intervention than just observed tumor enlargement on head MRI without clinical sequela. For these reasons, TTNI is probably an inadequate secondary endpoint and the regulatory agency may need to consider mandating the sponsor to maintain careful and detailed OS follow-up, which may take decades, as the basis for approval. For example, in RTOG 9802, a randomized trial of radiotherapy plus procarbazine, vincristine for supratentorial low-grade gliomas, it took at least a decade of follow up in order to detect an OS difference.[6,7] In INDIGO however, the control group’s postprogression crossover to vorasidenib may attenuate or even negate any detectable difference in OS. Proponents of vorasidenib assert that delaying glioma progression in this younger and productive population is clinically meaningful. No one can dispute this point. However, the magnitude of delay in tumor progression is an issue. At a median follow-up of only 14 months, the investigators found a difference of 17 months in PFS between the two cohorts (28 months for vorasidenib vs. 11 months for the control). This period is only a fraction, or ≤15%, of the overall longevity of this population, which is in the order of >10 years, and the short duration may not allow them to finish college or acquire additional employable skills. Therefore, whatever measurable gain attained during this 17-month period must be discounted against the cost of this drug, which may be substantial due to the limited time for patent exclusivity before generics compete with the manufacturer. Furthermore, INDIGO was not designed to address the neurocognitive benefit of vorasidenib treatment, and the health-related quality of life data presented in public thus far did not compared with those subjects who received standard of care radiation, chemotherapy or both. Despite the imperfections, vorasidenib still represents a significant step forward in the management of low-grade glioma patients. The optimal use of this IDH-1/2 inhibitor alone or in combination with other treatment modalities, as well as nuances on the nonmedical impact on the patient, remains to be determined. Financial support and sponsorship Nil. Conflicts of interest Dr. Eric T Wong received consulting honoraria from Novocure, Ltd., and Zai Laboratory, Ltd., and participates in clinical research sponsored by Imvax, Inc., Novocure, Ltd., Oblato, Inc., and Orbus Biotherapeutics, Inc. He also serves on data safety monitoring committees for Turning Point Therapeutics, Inc., (now Bristol Myers Squibb) and Optimal TTF-2.
Glioblastoma (GBM) is the most common type of primary brain tumor in adults. Due to the lack of clinical data, there is no standard treatment for GBM in old patients, and the prognosis is poor. We report a case of a 69-year-old female patient diagnosed with GBM who received tumor resection, radiotherapy, and temozolomide combined with tumor-treating fields (TTFields), and the overall survival (OS) of this patient was 13 months. The addition of TTFields to standard chemoradiotherapy may prolong the OS and not exacerbate toxicities in the treatment of old GBM patients. This provides more treatment options for old GBM patients. The study was approved by the Ethics Committee of The First Affiliated Hospital of Soochow University, China (No. 499/2023) on November 28, 2023.
Background and Aim: World Health Organization (WHO) grade 4 glioma is a malignancy of the central nervous system characterized by refractoriness to treatment and a high mortality rate. Isocitrate dehydrogenase (IDH) mutation is a crucial molecular event for the classification of glioma and associated with prognosis and exploring genetic and molecular differences between IDH mutant and wildtype glioma is crucial. The aim of this study was to investigate the prognostic gene between IDH mutant and wildtype WHO grade 4 glioma and its functional significance. Materials and Methods: The mRNA expression profile data of WHO grade 4 glioma were downloaded from the Gene Expression Omnibus and Chinese Glioma Genome Atlas databases. Bioinformatic analysis was performed to identify the differentially expressed genes between IDH1-mutant and wildtype WHO grade 4 glioma. Survival analysis, functional enrichment analysis, immune cell infiltration evaluation, and in vitro experimental validation were conducted to evaluate the prognostic and functional significance of Fras1-related extracellular matrix 3 (FREM3). This study was approved by the Institutional Ethics Committee of Xinqiao Hospital, Third Military Medical University (approval No. 2021-Y068-01). Results: Elevated expression of FREM3 in IDH1-mutant WHO grade 4 astrocytoma predicted favorable prognosis in glioma. FREM3 was negatively associated with epithelial–mesenchymal transition (EMT), angiogenesis, and hypoxia; notably, low expression of FREM3 was associated with a higher degree of immune cell infiltration. In vitro experiments demonstrated that high FREM3 expression might attenuate the process of EMT and cellular proliferation in glioma. Conclusions: The gene FREM3 plays a major role in IDH1-mutant WHO grade 4 glioma and elevated FREM3 predicts a favorable prognosis of glioma. Further investigation on FREM3 is warranted to elucidate the mechanisms underlying the malignant evolution of glioma.
The recent papers published on neuro-oncology by Girardi et al. showed glioblastomas (GBM) data from China are quite different compared to Western Countries, especially the incidence and 5-year survival.[1,2] Are those data represented real-world GBM patients in China: lower incidence and higher 5-year survival? What we can learn from those data? Considering the results showed a promising 5-year survival of patients with GBM in China (almost 18%), does it might indicate that patients received a more comprehensive multidisciplinary treatment care including surgery, radiotherapy, and chemotherapy, or there are different treatment modalities, which might provide patients with more chances for prolonged survivals? Although the 5-year survival of Chinese patients with GBM from these data might seem quite promising at first glance, close scrutiny of the data and result may indicate insufficient evidence and explanation. As a result, further information needs to be obtained to substantiate their accuracy. First of all, concerning China as the second-population Nation around the world, only 21 Chinese registries (areas) were selected in the CONCORD-3. The collected data from those Chinese registries deserve a deeper consideration into the accuracy and effectiveness of the results. To be more specific, most of the selected Chinese registries might not be representative since the sample might be too limited from small regions, and China is so big country with many disparate populations. We could not rule out the possibility that a smaller number of Chinese registries contributed to comparatively higher 5-year survival rates. Likewise, many other developed Chinese regions were not enrolled in the study, and those regions could provide exhaustive information about the survival data, and we could not unhesitatingly admit that the 5-year survival rates reminded unchanged with additional information. Therefore, we are inclined to reserve our approval of the 5-year survival of Chinese patients from more completed data. Based on what mentioned above, the selected Chinese cancer registries were limited. The 2021 WHO Classification of Tumors of the Central Nervous System was published, and it demonstrated a systematic and detailed diagnosis of GBM.[3] Previously, the diagnosis of center nervous system tumor was confirmed by the histological features; however, the confirmation of central nervous system tumor was not limited to the histological features and should be based on the combination of histological presentation and a series of molecular biomarkers with the gradually advanced diagnostic technology and cumulative clinical experience. Therefore, the previous diagnoses of GBM in China were suspicious in that article because of the present complex and delicate classification of gliomas. Simultaneously, the article itself mentioned that 52% of tumors were unspecific in the enrolled Chinese cancer registries, which may weaken the confidence of results in the article. Conversely, if more evidence about the previous and well-documented pathohistological diagnoses could be provided, the incidence as well as survival result were shored up. In addition, we could not turn a blind on the effects of ethnicity and race on the incidence and survivals of tumors. The data indicated that the GBM incidence was the highest in non-Hispanic and the lowest in American Indians or Alaska Natives.[4] More importantly, the data showed that Asians or Pacific Islanders had relative highest 5-year survival among all groups, which was consistent with the aforementioned discussion. At the same time, our single institutional real-world clinical data (but not regional registration) also showed a GBM incidence of 19.5%, and the 5-year survival was 18.6%.[5] Asia patients diagnosed with GBM accounted for a very small amount of the whole groups in those researches. Thus, only after collecting and weighing an increasing number of data about 5-year GBM survival among Asian patients, could we better evaluate the impacts of ethnicity and race on the results. In view of the palliative care in China, palliative care always faces many challenges such as insufficient educational, financial, and legal resources, and most Chinese people rarely realize the importance of palliative care for patients with cancer.[6] At the same time, Chinese patients with cancer often lack the autonomy to make a decision, and Chinese families of patients with cancer also confront an ethical and traditional cultural dilemma; therefore, those families opt to choose to continue anti-tumor treatment for those late-stage patients. On the one hand, patients who receive more aggressive anti-tumor treatment or supportive care even undergo more pain. On the other hand, those active treatments might be conducive to the prolonged overall survival of those patients. Consequently, based on the different choices of subsequent treatment at the end stage of cancer, we need to investigate whether Chinese patients may benefit or in spite of suffering from those treatments. To summarize, the Chinese GBM results in CONCORD-3 attributed a silver lining to patients with glioblastoma. However, the current data in the articles quoted might not provide conclusive information about 5-year survival for Chinese patients with GBM and we cannot logically draw a concrete conclusion about GBM prognosis in China based solely on this information. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Editor note: The author Zhong-ping Chen is the Editor-in-Chief of Glioma. He did not participate in the peer review of decision-making of the manuscript.
Background and Aim: High-grade glioma is the most common malignant primary brain tumor in the central nervous system. Multiple strategies such as surgery, radiotherapy, and chemotherapy have been used, but the prognosis of patients with high-grade glioma remains poor. No standard treatment exists for recurrent gliomas; however, combination therapies of programmed cell death protein 1 blockades with antiangiogenic agents have demonstrated promising effects in different solid tumors. Therefore, since the end of 2020, a clinical trial designed to evaluate the safety and efficiency of neoadjuvant therapy using camrelizumab and apatinib in patients with recurrent high-grade gliomas has been carried out in our institution. Methods/Design: In this prospective, Phase II, single-arm study, patients with recurrent high-grade gliomas will receive single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before reoperation for tumor resection. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. Treatment of camrelizumab and apatinib will be continued until disease progression or unacceptable toxicity or death. The primary outcome measure will be the median overall survival rate. Secondary outcome measures will include progression-free survival rate at 6 months and at 12 months and other measures. The trial is planned to enroll 30 patients. This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (Guangzhou, China; approval No. SL-B2020-149-01) on July 27, 2020. Results and Conclusions: Although an evaluation is still impossible to be conducted yet, 11 patients had been enrolled by the end of January 2022. Some patients have shown a promising outcome. These preliminary data suggest that this study would be worthwhile. We hope that this study will provide scientific evidence to better care of patients with recurrent high-grade glioma. Trial registration: This study was registered with ClinicalTrials.gov under identifier NCT04588987 on October 19, 2020.
Significant new progress was made 10 years ago in the hypothesis that neuroglial cells, neural stem cells, and glioma stem cells (GSCs) depend on the tumor microenvironment (TME) transformation: (1) Because GSCs also have heterogeneity, they are a state, not an entity. (2) The importance of the border niche among many tumor niches is emphasized because it is a shelter for tumor resistance to radiotherapy and chemotherapy. (3) The plasticity of GSCs and TME cells allows TME cells to become GSC-initiating cells. (4) Future development will entail a close interaction between high-throughput molecular biology and artificial intelligence. In this review, we summarize recent advances in GSCs and their microenvironment from the following three aspects: the constantly updated of concept of stem cells, the concept of TME and niche, and the plasticity of GSCs and TME cells.
The clinical hallmarks of tumor growth, angiogenesis, and invasion were identified in a patient with isocitrate dehydrogenase-1 wild-type glioblastoma at initial diagnosis and management issues were examined. The head magnetic resonance imaging (MRI) showed multiple solid and cystic contrast enhancements in the rostral portion of the tumor located within the left motor gyrus and the adjacent brain. Extensive tumor invasion was noted along the left corticospinal tract extending into the cerebral peduncle and pons. After an open craniotomy for tissue biopsy, the patient underwent external beam radiotherapy and concomitant temozolomide, and his motor deficit was stabilized with concurrent bevacizumab infusion while dexamethasone was weaned off. After two cycles of adjuvant temozolomide, the patient experienced worsening motor deficit in the right hand. A repeat gadolinium-enhanced head MRI revealed increased fluid-attenuated inversion recovery hyperintensity in the left cerebral peduncle indicating tumor progression. This case illustrates the extensive invasion from a glioblastoma that cannot be adequately quantified or effectively treated. A wider margin of radiation may be needed to cover microscopic and infiltrative tumor cells. The early use of bevacizumab can also reverse neurological deficits and obviate the long-term use of dexamethasone and insulin in this patient. This study was approved by the Institutional Review Board at Dana Farber Cancer Institute #12-519 onMay 5, 2020.
Surgical resection is the core of the comprehensive treatment of glioma. However, with infiltrative growth features, glioma often invades the surrounding area, making surgical resection more difficult. This review introduces relevant topics presented at the World Federation of Neurosurgical Societie Foundation Asian Congress of Neurological Surgeons (ACNS) Minimally Invasive Neurosurgery Web Seminar in 2022. First, we review assistive surgical techniques' characteristics, advantages, and disadvantages. Second, we summarize some state-of-the-art surgical views in glioma resection. Advanced modalities and surgical theories in glioma resection make better “maximum safe resection” achievable.
Glioblastoma multiforme (GBM) is the most common malignant tumor in the adult central nervous system, and surgery combined with radiotherapy and chemotherapy represents the main treatment regimens. Temozolomide (TMZ) is currently the first-line chemotherapeutic agent used in GBM therapy and is widely used subsequent with surgical resection of GBM. TMZ can significantly prolong the survival time of patients with glioma. However, the high incidence of resistance to TMZ, which seriously affects the overall outcome of GBM treatment, is a serious concern facing clinicians. The mechanisms of resistance to TMZ in patients with GBM include biological processes involving DNA damage repair, cellular autophagy, glioma stem cells, and the tumor microenvironment. Therefore, exploring the mechanisms inducing GBM resistance to TMZ treatment and how to effectively reduce TMZ resistance and improve its efficacy has become an urgent question. This review summarizes the effects and mechanisms of TMZ resistance in the treatment of glioma. It is hoped that intensive investigation of the mechanisms of resistance of TMZ to GBM can lay the foundation for successful outcomes in patients with GBM.
Gliomas are tumors that originate from glial cells and the most common neoplasms in the central nervous system. The World Health Organization (WHO) has classified glioma into four grades, I to IV, with multidisciplinary therapies required for the management of high-grade gliomas (grades III and IV). Molecular pathology has become increasingly critical in guiding the treatment and predicting the prognosis of patients with gliomas. A 35-year-old man diagnosed with WHO grade III diffuse astrocytic glioma initially underwent surgical resection, followed by immunohistochemical and molecular diagnosis. The patient was administered adjuvant radiotherapy and chemotherapy based on the molecular characteristics of the tumor. Long term follow-up showed a relatively satisfactory therapeutic response. Molecular classification may help guide decisions on the comprehensive treatment of patients with WHO grade III diffuse astrocytic glioma. This study was approved by the Ethics Committee of Zhongda Hospital of Southeast University, China (approval No. 20211015001, approval date: October 15, 2021).
This study aimed to compare the safety and efficacy of CyberKnife (CK) versus TomoTherapy for the treatment of brain metastases (BMs). Three cases of BM treated at our hospital – two with CK and one with TomoTherapy – were compared and analyzed. Both treatments showed good therapeutic effects, but CK was more effective. No radiation-related adverse reactions were observed in the three patients. It is concluded that both CK and TomoTherapy can effectively control target lesions by allowing a higher dose in a single treatment while minimizing damage to surrounding normal brain tissue. This can reduce the total number of treatments needed, improve the prognosis of patients, and save medical resources.
