Международный неврологический журнал Том 18, №8, 2022
Вернуться к номеру
Гліобластома: огляд літератури
Авторы: Dipak Chaulagain, V. Smolanka, A. Smolanka, T. Havryliv
Uzhhorod Regional Clinical Center of Neurosurgery and Neurology, Uzhhorod National University, Uzhhorod, Ukraine
Рубрики: Неврология
Разделы: Справочник специалиста
Версия для печати
Резюме
Гліобластома є найбільш агресивним типом пухлини головного мозку, визначена як астроцитома 4-го типу відповідно до 5-го видання класифікації пухлин центральної нервової системи Всесвітньої організації охорони здоров’я. Це рак, що починається в гліальних клітинах, які є підтримуючими клітинами мозку. Гліобластома є рідкісним типом пухлини головного мозку і становить близько 15 % усіх цих пухлин. Найчастіше вона зустрічається в дорослих віком понад 50 років, причому в чоловіків розвивається частіше, ніж у жінок. Симптоми гліобластоми можуть відрізнятися залежно від локалізації пухлини в головному мозку. Загальні симптоми включають головний біль, нудоту, блювання та зміни зору. Іншими симптомами можуть бути судоми, зміни в поведінці або особистості, а також труднощі з мовою або рухами. Стандартом лікування гліобластоми є поєднання хірургічного втручання, променевої та хіміотерапії. Хірургічне втручання є першим кроком у лікуванні, метою якого є видалення якомога більшої частини пухлини. Променева та хіміотерапія зазвичай використовуються для знищення будь-яких залишкових ракових клітин. Однак, незважаючи на ці методи лікування, прогноз при гліобластомі, як правило, поганий, більшість пацієнтів живуть менше двох років після встановлення діагнозу. Загалом гліобластома є дуже агресивною пухлиною головного мозку з поганим прогнозом. Стандартне лікування передбачає поєднання хірургічного втручання, променевої та хіміотерапії. Останні дослідження були зосереджені на розробці нових методів лікування, таких як цільова терапія та імунотерапія, що показали обнадійливі результати в клінічних випробуваннях.
Glioblastoma is the most aggressive type of brain tumor classified as type 4 astrocytoma according to 5th edition of the World Health Organization сlassification of tumors of the central nervous system. It is a cancer that begins in the glial cells, which are the supporting cells of the brain. Glioblastoma is a rare type of brain tumor and accounts for about 15 % of all brain tumors. It is most commonly found in adults over the age of 50, and men are more likely to develop it than women. The symptoms of glioblastoma can vary depending on the location of the tumor in the brain. Common symptoms include headaches, nausea, vomiting, and changes in vision. Other symptoms can include seizures, changes in behavior or personality, and difficulty with speech or movement. The standard treatment for glioblastoma is a combination of surgery, radiation therapy, and chemotherapy. Surgery is usually the first step in treatment, with the goal of removing as much of the tumor as possible. Radiation therapy and chemotherapy are typically used to kill any remaining cancer cells. However, despite these treatments, the prognosis for glioblastoma is generally poor, with most patients surviving for less than two years after diagnosis. Overall, glioblastoma is a highly aggressive brain tumor with poor prognosis. The standard treatment is a combination of surgery, radiation therapy and chemotherapy. Recent research has focused on developing new treatments, such as targeted therapies and immunotherapies, which have shown promising results in clinical trials.
Ключевые слова
гліобластома; гліома; астроцитома
glioblastoma; glioma; astrocytoma
Introduction
Glioblastoma (GBM) is an aggressive and fast-growing brain tumor that is classified as a grade 4 astrocytoma. Affected brain tissue usually does not spread to distant organs, although nearby brain tissue can be invaded. A GBM can develop from a lower-grade astrocytoma or develop de novo. Among adults, GBM usually affects the cerebral hemispheres, primarily the temporal and frontal lobes. In the event of untreated GBM, the patient can expect to die within 6 months or less, so expert neuro-oncological and neurosurgical care is essential to ensure overall survival (OS). There is no known specific age at which glioblastomas occur; however, older adults tend to be more prone to developing them. Headaches, nausea, vomiting, and seizures may become more severe when the condition worsens. Glioblastoma is a most difficult form of cancer to treat and often cannot be cured. Symptoms and signs of the disease may be reduced with treatments.
Incidence/epidemiology/distribution of glioblastoma
In general, glioblastoma constitutes 47.7 % of the cases of brain and central nervous system tumors. The incidence of glioblastoma is 3.21 per 100,000 people. It is more common in men than in women, and the median age of diagnosis is 64 years. In the first year after diagnosis, the survival is low at 40 %, and then drops to 17 % in the second year. Prior cancer therapy, reduced susceptibility to allergies, and weakened immunity are all associated with glioblastoma risk. Glioblastoma is greatly influenced by a number of hereditary cancer syndromes, including Li-Fraumeni syndrome and Lynch syndrome. Glioblastoma has an incidence of 5 per 100,000 per year. GBM has an incidence of less than 10 people per 100,000 worldwide, but with a poor prognosis and a survival rate of only 14–15 months after diagnosis, it is a medical problem (Iacob and Dinca, 2009; Thakkar et al., 2014). While it can show up at any age, but is most common in people aged 55 to 60 (Ohgaki and Kleihues, 2005). A total of 50 % of all gliomas are found in this age group (Rock et al., 2014). According to Saltman (1990), malignant gliomas cause 2.5 % of deaths due to cancers in persons 15 to 34 years of age (Salcman, 1990). According to Ohgaki and Kleihues (2005) and Thakkar et al. (2014), the incidence of GBM is significantly higher in men than in women. There is a higher incidence of gliomas in the Western world than in less developed countries (Thakkar et al., 2014). This may be due to underreporting of gliomas cases, a lack of access to health care and diffe-rences in diagnostic practices (Fisher et al., 2007; Ohgaki, 2009) [1, 2]. According to Mansouri, Karamchandani and Das (2017), it is estimated that 5 % of secondary GBMs are related to clinical or imaging criteria (vs. 6–13 % based on isocitrate dehydrogenase (IDH) status) [3].
Symptoms/characteristics of GBM
A person’s ideas, emotions, and behaviors are all controlled by the brain. It interprets information from their senses as well. Different parts of the brain govern various functions. Some of GBM symptoms are related to the location of the tumor. If it develops in a region that regulates arm motions, for example, the arm may become weak. If it develops in a part of the brain that governs speech, the person may have difficulty producing words. As the tumor grows, it takes up more and more space. This raises the pressure inside the skull. The increased pressure in the brain causes some of the symptoms of GBM. Depending on tumor location, patients may complaint of recurring headaches, double vision, vomiting, loss of appetite, changes in mood and attitude, in thinking and learning capabilities, and the onset of new seizures.
Histopathology and molecular features of glioblastoma
Among malignant gliomas, GBM makes up 60–70 %. Based on its histopathological characteristics, it has been classified as a grade IV tumor, and it is the most prevalent and malignant tumor of the central nervous system, mostly affecting males.
Several investigations have revealed that GBMs can be histologically undergraded due to sampling errors of small tissue samples. Researchers wanted to see how much histological features in GBMs are affected by the quantity of live tissue on routine slides from biopsied and resected tumors. They looked at the presence or degree of 24 histopathological and two immune-histochemical characteristics, as well as the volume of tissue on hematoxylin-eosin slides, in 106 newly diagnosed GBM patients. For each example, the amount of live tissue was classified as “sparse”, “medium”, or “significant”. Tissue quantity was also examined for correlations with magnetic resonance imaging (MRI) volumetrics and surgery type. There was a significant association between tissue amount and about half of the assessed histological and immune-histochemical features (46 %) throughout the study. A smaller amount of tissue resulted in fewer or lesser significant features. Significant features of the study included small necrosis, palisades, microvascular proliferation, atypia, mitotic count, and Ki-67/MIB-1 proliferative index. Since the amount of viable tissue on hematoxylin-eosin slides was limited, a substantial proportion of the assessed histological features might be underrepresented. It is important to consider sampling errors in diffuse astrocytic tumor grading because most of the grading features are dependent on tissue amount. Aspects of tissue collection also illuminate the importance of high-quality diagnostics and histology research, according to the findings of the authors.
Classification of glioblastoma according to molecular profiles
GBMs are considered to be de novo gliomas, characterized by a high propensity to invade brain tissue. GBMs have also been classified based on their molecular profiles. Specific clinical strategies should be developed based on the gene expression profiles that identify different clinically relevant GBM subtypes (pro-neural, neural, classical, and mesenchymal). As a result of recent findings, GBMs are now categorized based on their inability to identify the IDH gene mutational status. IDH wild type corresponds most frequently with primary or de novo GBM, IDH mutant corresponds with secondary GBM, and neither of the above are classified as not otherwise specified. The use of genetic markers in predicting outcomes or guiding disease management decisions has proven to be marginal in GBM, despite numerous genetic alterations being described. The molecular characterization of GBM could provide a more comprehensive understanding of the genomic landscape of GBM and provide more efficient techniques to analyze tumor cells and tissues rapidly and at high throughput. GBM is characterized by both an anaplastic and a highly heterogeneous morphology, despite its common clinical presentation and histology. GBM diagnosis requires the existence of microvascular proliferation and/or necrosis. An extensive clinicopathological assessment has been used to diagnose GBM, which has been an extremely valuable approach. GBM is characterized by areas of necrosis with surrounding pseudopalisades, along with microvascular hyperplasia. These features are thought to be involved in its rapid growth (Zhang et al., 2012) [4].
Radiological features of glioblastoma
The anatomic anomaly associated with GBM has been visualized using computed tomography and MRI. On computed tomography scans, the lesions are often hypointense in comparison to the adjacent brain matter, and the presence of moderate to severe edema causes mass effect and frequently leads to midline displacement. Because of their greater soft tissue contrast, MR images clearly reveal the intricacy and variety of GBMs. On T1-weighted imaging, the lesions are often hypointense, hyperintense on proton density weighted images, and hyperintense on T2-weighted images. The relatively recent heavily T2-weighted fast fluid-attenuated inversion recovery (FLAIR) sequence, which removes signal from cerebrospinal fluid and reveals the lesion with a relatively high intensity compared to normal white matter, may allow for improved characterization of tumor heterogeneity (Nelson et al., 2003) [5].
The usual approach for evaluating glioblastoma is gadolinium-enhanced MRI, which often shows a large, heterogeneous mass in the cerebral hemisphere with necrosis, blee-ding, and enhancement. In adults, metastasis and abscess are also possibilities for a single, heterogeneously enhancing intraaxial tumor with necrosis. Although metastatic illness can take many forms, the vast size of the lesion and absence of multiplicity in this case imply that it is a primary tumor. A brain abscess may also show distinct imaging findings. An abscess, for example, will not normally have an increased choline-creatine ratio on MR spectroscopy (Altman et al., 2007) [6].
Surgical treatment of glioblastoma
This is frequently the first-line therapy for glioblastoma. If the tumor can be removed without endangering the nervous system, the doctor may remove a portion of the skull and as much of the tumor as possible. If the tumor is in a location where key brain functions are performed, the doctor may only remove a tiny portion of the tumor (biopsy). The surgery purpose is to remove as many tumor cells as possible while also providing tissue for pathologists to examine. The findings of such investigation will decide future therapies as well as the overall prognosis. Your symptoms may improve if the tumor is removed.
The study of Brown et al. (2016) found that gross total resection (GTR) had lower mortality at one year (risk ratio (RR) 0.62; 95% confidence interval (CI) 0.56–0.69; P < 0.001; number required to treat (NNT) 9) and two years (RR 0.84; 95% CI 0.79–0.89; P < 0.001; NNT 17). The one-year risk of death for subtotal resection was considerably lower than for biopsy (RR 0.85; 95% CI 0.80–0.91; P < 0.001). At one year (RR 0.77; 95% CI 0.71–0.84; P = 0.001; NNT 21) and two years (RR 0.94; 95% CI 0.89–1.00; P = 0.04; NNT 593), any resection was associated with a lower risk of death. At six months (RR 0.72; 95% CI 0.48–1.09; P = 0.12; NNT 14) and one year (RR 0.66; 95% CI 0.43–0.99; P = 0.001; NNT 26), GTR reduced the chance of disease progression compared to subtotal resection [7].
Role of intraoperative neuromonitoring in the surgical resection of glioblastoma
When tumors are in prominent places, the risk of persistent neurological damage limits the possibility of GTR, worsening patients’ quality of life. Clinicians may now pinpoint eloquent cortical and subcortical fibers using mapping techniques, and intraoperative neurophysiological monitoring (IONM) allows them to monitor the function of at-risk neurological structures during surgery. The authors have developed a number of factors that may provide us with a reliable and efficient method of monitoring those structures. The sensitivity, specificity, and safety of such approaches have all increased. Tumor excision using fluorescence is more effective, although there is a danger of chronic neurological impairments. IONM reduces this risk without jeopardizing the likelihood of a successful resection. If the language parts of the brain are not implicated, careful monitoring may allow physicians to avoid doing surgery while the patient is awake. In case of high-grade gliomas, GTR is the most important prognostic indicator for patient survival. IONM and monitoring approaches improve the efficacy of GTR and are linked to lower incidence of surgery-related impairments.
The use of intraoperative neuromonitoring reduces the chance of paralysis and other complications during these life-saving surgical operations. Traditional methods of monitoring blood pressure, pulse, respiration, and blood gas content to assess patient health during surgery have a large margin for error, which can be reduced with intraoperative neuromonitoring with real-time feedback involving the brain, spinal cord, and peripheral nervous system. This protects against paralysis, muscular weakness, sensory impairments, and other complications.
For intraoperative neuromonitoring to be effective, a well-trained neuromonitorist must gather baseline patient metrics prior to the surgical operations utilizing a range of electrophysiological tests. The neuromonitor must assess any changes to these measures during the procedure, which might indicate when difficulties occur. Somatosensory evoked potentials, motor evoked potentials, brainstem auditory evoked potentials, electroencephalograms, and electromyography are among the tests conducted. Monitoring clinicians, as members of the operating room team, give crucial information and assistance to the surgical team du-ring critical points of the surgery.
Role of intraoperative MRI in the surgical resection of glioblastoma
Khan et al. (2017) studied the role of intraoperative MRI in improving resection and survival of patients with glioblastoma multiforme. The authors say that multiple surgical tools have been devised to increase the extent of resection (EOR) in patients with GBM while preventing additional neurological deficits. For over two decades, neurosurgical literature has questioned the efficacy and expense of intraoperative MRI (iMRI). According to the previous literatures, improved EOR in GBM patients who received iMRI-assisted surgical resections resulted in greater OS and progression-free survival (PFS). iMRI gives decent quality real-time intraoperative imaging. No research employing iMRI found a higher incidence of new postoperative deficits with increasing EOR. The degree of evidence for iMRI prognostic advantages is currently of poor quality.
Senft et al. (2010) published a prospective study of 103 GBM patients who had iMRI-assisted resection from 2004 to 2009. iMRI detected remaining tumor tissue in 49.5 % of patients, leading to additional resection in 30.1 % of cases. Those with full resection had better results than patients with residual tumor (50% OS at 57.8 weeks vs. 33.8 weeks, p = 0.003). No correlation was found between the degree of resection and the rate of neurological deficits [8].
Li F.Y. et al. (2013) published a prospective cohort analysis of 76 GBM patients who had iMRI- and multimodal na-vigation-assisted resection. iMRI confirmed 31.6 % of GTR misestimated by neurosurgeons and increased rates of GTR from 52.6 to 78.9 % (χ2 = 11.692, P < 0.001), with entire resection obtained in 26.3 % of cases. Total resection resulted in a longer PFS and OS compared to partial resection (PFS: 12 vs 9 months; χ2 = 4.756, P = 0.029; OS: 16 vs 12 months; χ2 = 7.885, P = 0.005). The total survival rate after two years was 19.7 % [9].
Role of 5-ALA fluorescence in the surgical resection of glioblastoma
In the study of Gandhi et al. (2019), a comprehensive analysis of all relevant studies evaluating the GTR rate and survival outcomes (OS and PFS) in high-grade glioma was done. A meta-analysis of relevant trials was conducted to determine the impact of 5-ALA-guided resection on GTR, OS, and PFS. GTR was defined as more than > 95% resection. The meta-analysis comprised 19 papers reporting GTR rates out of 23 eligible trials. The pooled cohort included 998 high-grade glioma patients, 796 of whom were newly diagnosed. The pooled GTR rate among patients undergoing 5-ALA-guided resection was 76.8 % (95% CI 69.1–82.9 %). A comparative subgroup analysis of 5-ALA-guided vs. conventional surgery (controlling for within-study variables) revealed that the 5-ALA subgroup had a 26 % higher GTR rate (odds ratio 3.8; P < 0.001). There were 11 trials suitable for survival outcome analysis, with four of them reporting PFS. The pooled mean difference in OS and PFS favoring 5-ALA vs. control was 3 and 1 months, respectively (P < 0.001) [10].
5-ALA is a naturally occurring metabolite in the human body that is formed by the haemoglobin metabolic pathway. In brain tumors [8–10], 5-ALA functions as a pro-agent and has extraordinary penetration of the blood-brain barrier and tumor interface. So far, no other recognized oral agent for FSG accumulation within malignant brain tumors and surrounding infiltrating cancer cells outside of the tumor mass is available. 5-ALA is converted by malignant glioma cells producing the fluorescent metabolite protoporphyrin IX (Stummer et al., 1998) [11]. Following stimulation with 405 nm blue light, increased protoporphyrin IX synthesis inside malignant brain tumor cells allows for violet-red fluorescence imaging of malignant tumor tissue.
Reduced levels of ferrochelatase (a heme synthesis enzyme that creates heme with the addition of iron) and selective absorption by an ATP-binding cassette transporter are thought to cause preferential accumulation of 5-ALA within malignant glioma cells (ABCB6). Cellular density, tumor cell proliferative activity, tumor neovascularity, and blood-brain barrier permeability are other characteristics that correlate with fluorescence generated by 5-ALA (Ennis et al., 2003) [12].
Radiotherapy
In the present era, radiation alone results in a one-year median survival, and the addition of the oral alkylating drug temozolomide (TMZ) extends survival to more than 14 to 16 months.
Radiation therapy (RT) approaches have progressed significantly over the decades since it was first used to treat GBM. The entire brain was initially treated, but radiation volumes have reduced, and inverse planning and dose regulation using intensity-modulated radiation treatment have allowed for more accurate targeting and sparing of key, normal brain structures. Image guiding during radiation admi-nistration has improved therapy, and further advancements are being investigated with particle treatments like as protons or carbon ion.
Aside from the mode of radiation administration, chan-ges in dosage have been investigated. The initial research tried to determine the best dose that could be safely provided with the greatest effect. These concerns, which were investigated decades ago, have lately been revisited in the light of contemporary radiation delivery systems. Hypofractionation has been widely employed, particularly in older or low-performance groups.
Mann et al. (2018) made a study on the advances in RT for glioblastoma multiforme [13]. The authors say that external beam radiation has long been an integral part of the treatment for glioblastomas. Through improved image-guidance technology and advancements in RT treatment over the past several decades, definitive treatments and salvage treatments were optimized greatly. The review presented several of the latest developments and controversies related to radiothe-rapy, including: treatment of elderly patients who remain at risk of high mortality; potential salvage options for recurrent cancer, including chemotherapy; with the latest imaging techniques, it is possible to delineate treatment areas more accurately and precisely to maximize the therapeutic ratio of conformal RT; immunotherapy in conjunction with RT is being studied preclinically and clinically; and there are signs that cancer stem cells occupy a subventricular niche that may be an interesting target for local therapies. Lastly, continuing development has brought modest improvements while at the same time limiting the impact of toxicity on outcomes.
Chemotherapy
According to Minniti et al. (2009), chemoradiotherapy with temozolomide is the current standard treatment for GBM after surgical resection [14]. Various targeted medicines are now being tested in GBM after the identification of many molecular genetic and signal transduction pathways implicated in oncogenesis. Several medicines are studied, including EGFR-TKIs (gefitinib and erlotinib), antiangiogenic medications (bevacizumab, enzastaurin), mTOR inhibitors (temsirolimus, everolimus), and integrin inhibitors (cilengitide). Although bevacizumab was recently licensed as a single drug for individuals with GBM who had progres-sing illness, the majority of the molecular targeted treatment phase II clinical studies in GBM did not show substantial survival benefits. Better molecular characterization of GBM might help to prevent bad findings in big clinical trials including diverse patient cohorts, as well as possibly allowing the design of “individualized” medicines based on the genetic and molecular features of each tumor. To overcome tumor resistance, new chemotherapeutic techniques include the combination of multitargeted medicines with cytotoxic chemotherapy and radiation. Randomized clinical trials continue to be the gold standard for evaluating novel targeted agents. The majority of multicenter randomized European (EORTC) and American (RTOG, NABTG) clinical trials are comparing these novel drugs to conventional chemoradiotherapy alone (RT + concurrent and adjuvant temozolomide). This is significant because all patients will receive proper care.
From June 2011 through August 2018, Huang, Yu, and Liang (2021) conducted a single-center retrospective analysis of GBM patients who underwent complete resection, concomitant chemoradiotherapy, and at least 6 rounds of adjuvant TMZ treatment [15]. Patients were separated into two groups depending on their adjuvant TMZ treatment plan: group A (n = 27) received conventional 6-cycle adjuvant TMZ therapy, and group B (n = 26) — adjuvant TMZ the-rapy for more than 6 cycles. PFS and OS were the primary goals. The authors conclude that long-term adjuvant TMZ treatment increased PFS and 2-year survival rates in GBM patients while also improving their quality of life. However, OS did not improve considerably.
Radiotherapy and chemotherapy combination
Wang et al. (2017) say that GBM, a main subtype of grade IV glioma, has a poor prognosis nowadays [16]. The effectiveness of chemotherapy as an adjuvant to RT in the treatment of GBM remains debatable. The goal of this research is to look at OS and PFS in patients with newly diagnosed GBM who had RT + chemotherapy or RT alone. The authors conclude that a combination of oral chemotherapy with radiotherapy contributes to a better survival in patients who were newly diagnosed with glioblastoma.
Zhang et al. (2013) discovered that adjuvant chemothe-rapy was effective in the treatment of anaplastic glioma [17]. Despite this, treatment with procarbazine, lomustine, and vincristine plus RT did not improve survival in patients with anaplastic oligodendroglioma and anaplastic oligoastrocytoma when compared to RT alone. As a result, we decided to assess the efficacy of adjuvant chemotherapy plus RT against RT in the treatment of GBM.
Overall survival
Baid et al. (2020) conducted a study on the overall survi-val prediction in GBM with radiomic features using machine learning [18]. In this study, the problem of predicting survival was separated into two parts. One of them aimed at categorizing patients into three survival groups using unsupervised two-step clustering. These groups are similar to the known survival groups in GBM. There were long (e.g., > 900 days), short (e.g., 300 days), and mid-survivors (e.g., between 300 and 900 days). It is useful to classify a patient into one of these survival categories for more accurate therapy planning. This will allow clinicians to determine how aggressively a patient should be treated.
In the study of Witthayanuwat et al. (2018), the median survival time for all GBM patients was 12 months (n = 77; 95% CI 9.9–14 months) [19]. The overall survival rates after two and five years was 21.3 and 13.8 %, respectively. Those who received surgery and postoperative radiotherapy alone had a median survival time of 11 months (95% CI 8.8–13.2 months), whereas patients treated with concurrent radiotherapy with or without adjuvant TMZ had a median survival time of 23 months (95% CI 13.7–32 months, p = 0.03). Patients who received surgery and postoperative radiotherapy alone had 2- and 5-year survival rates of 17.2 and 11.8 %, respectively, whereas patients treated with concurrent radiotherapy with or without adjuvant TMZ had rates of 38.2 and 19.1 %, respectively.
In the study of Yersal (2017), the overall survival in the entire research population was 13.7 months, 12.3 months in women and 15.1 months in males (p: 0.4) [20]. Patients with secondary tumors (progression from low-grade diffuse astrocytoma or anaplastic astrocytoma) lived longer than those with primary glioblastomas, although the difference was not statistically significant (13.3 vs 23.9 months; p: 0.25). Overall survival varied depending on tumor location. Patients with the longest mean overall survival had tumors in the frontotemporal area (20.3 months), followed by frontal location (17.4 months). Overall survival rates for malignancies on both sides were comparable (p: 0.19). Patients who had cyberknife following recurrence had a longer OS, according to univariate and multivariate analyses.
Received 02.12.2022
Revised 15.12.2022
Accepted 20.12.2022
Список литературы
1. Ohgaki H., Kleihues P. Genetic pathways to primary and se-condary glioblastoma. American Journal of Pathology. 2007. 170(5). 1445-1453. doi: 10.2353/ajpath.2007.070011.
2. Kleihues P., Ohgaki H. Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-Oncology. 1999. 1(1). 44-51. doi: 10.1093/neuonc/1.1.44.
3. Mansouri A., Karamchandani J., Das S. Molecular Genetics of Secondary Glioblastoma. 2017. doi: 10.15586/codon.glioblastoma.2017.ch2.
4. Zhang X., Zhang W., Cao W.D., Cheng G., Zhang Y.Q. Glioblastoma multiforme: molecular characterization and current treatment strategy (review). Experimental and Therapeutic Medicine. 2012. 3(1). 9-14. doi: 10.3892/etm.2011.367.
5. Nelson Sarah J., Cha Soonmee. Imaging Glioblastoma Multiforme. Cancer Journal. 2003. 9(2). 134-145. doi: 10.1097/00130404-200303000-00009.
6. Altman David A., Atkinson Denis S., Brat Daniel J. Glioblastoma Multiforme. Radiographics. 2007. 27(3). 883-888. doi: 10.1148/rg.273065138.
7. Brown T.J., Brennan M.C., Li M., Church E.W., Brandmeir N.J. et al. Association of the Extent of Resection With Survival in Glioblastoma: A Systematic Review and Meta-analysis. JAMA Oncology. 2016. 2(11). 1460-1469. doi: 10.1001/jamaoncol.2016.1373.
8. Senft C., Franz K., Ulrich C.T., Bink A., Szelényi A., Gasser T. et al. Low field intraoperative MRI-guided surgery of gliomas: a single center experience. Clinical Neurology and Neurosurgery. 2010. 112. 237-43.
9. Li F.Y., Chen X.L., Sai X.Y., Zhang J.S., Hu S., Li J.J. et al. Application of intraoperative magnetic resonance imaging and multimodal navigation in surgical resection of glioblastoma. Chinese Journal of Surgery. 2013. 51. 542-6 (in Chinese).
10. Gandhi S., Tayebi Meybodi A., Belykh E., Cavallo C., Zhao X. et al. Survival Outcomes Among Patients With High-Grade Glioma Treated With 5-Aminolevulinic Acid-Guided Surgery: A Systematic Review and Meta-Analysis. Front. Oncol. 2019. 9. 620. doi: 10.3389/fonc.2019.00620.
11. Stummer W., Stocker S., Novotny A. et al. In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. Journal of Photochemistry and Photobiology B: Biology. 1998 Sep. 45(2–3). 160-169.
12. Ennis S.R., Novotny A., Xiang J. et al. Transport of 5-aminolevulinic acid between blood and brain. Brain Research. 2003 Jan 10. 959(2). 226-234.
13. Mann J., Ramakrishna R., Magge R., Wernicke A.G. Advan-ces in Radiotherapy for Glioblastoma. Frontiers in Neurology. 2018. 8. 748. doi: 10.3389/fneur.2017.00748.
14. Minniti G., Muni R., Lanzetta G., Marchetti P., Maurizi Enrici R. Chemotherapy for Glioblastoma: Current Treatment and Future Perspectives for Cytotoxic and Targeted Agents. Anticancer Research. 2009. 29. 5171-5184.
15. Huang B., Yu Z., Liang R. Effect of long-term adjuvant temozolomide chemotherapy on primary glioblastoma patient survival. BMC Neurol. 2021. 21. 424. doi: 10.1186/s12883-021-02461-9.
16. Wang Zhuo, Yang Guozi, Zhang Yu-Yu, Yao Yan, Dong Li-Hua. A comparison between oral chemotherapy combined with radiotherapy and radiotherapy for newly diagnosed glioblastoma. Medicine. 2017 Nov. 96(44). e8444. doi: 10.1097/MD.0000000000008444.
17. Zhang L., Wu X., Xu T. et al. Chemotherapy plus radiotherapy versus radiotherapy alone in patients with anaplastic glioma: a systematic review and meta-analysis. J. Cancer Res. Clin. Oncol. 2013. 139. 719-26.
18. Baid Ujjwal, Rane Swapnil U., Talbar Sanjay, Gupta Sudeep, Thakur Meenakshi H. et al. Overall Survival Prediction in Glioblastoma With Radiomic Features Using Machine Learning. Frontiers in Computational Neuroscience. 2020. 14. 61. doi: 10.3389/fncom.2020.00061.
19. Witthayanuwat S., Pesee M., Supaadirek C., Supakalin N., Thamronganantasakul K., Krusun S. Survival Analysis of Glioblastoma Multiforme. APJCP. 2018. 19(9). 2613-2617. doi: 10.22034/APJCP.2018.19.9.2613.
20. Yersal Özlem. Clinical outcome of patients with glioblastoma multiforme: single center experience. Journal of Oncological Sciences. 2017. 3(3). 123-126. doi: 10.1016/j.jons.2017.10.005.