Artem Yu. Belyaev

Background. Glioblastoma is the most common primary malignant brain tumor with an extremely unfavorable prognosis. The frequency of the “longevity” phenomenon (>3 years of overall survival – OS) in this disease is 5–10 %. The reasons for the more favorable prognosis in these patients are still unclear.Aim. To compare the clinical and MRI data as well as features of complex treatment of patients with supratentorial glioblastomas among the control group (OS 3 years).Material and methods. This study included 41 patients with hemispheric glioblastomas: 17 with the “longevity” phenomenon (study group – long-term survival (LTS), prospective set); 24 patients in the control group (retrospective set). Taking into account the average age of patients, the following MRI features were examined: tumor localization relative to the frontal lobe; invasion of deep brain structures; the ratio of contrastenhancing and non-contrast-enhancing parts of the glioma; tumor contrast intensity; localization of recurrent tumor (local / distant) in case of disease progression. Comparative analysis of complex treatment took into account the following parameters: the number of chemotherapy (ChT) courses and radiation regimens after the 1^st operation and after disease recurrence; the fact and number of repeated tumor resections after recurrence; the presence of IDH1 mutation.Results. The localization of the lesion relative to the frontal lobe, the number of affected lobes of the brain and the invasion of deep structures did not differ significantly in the examined groups. Patients of study group (LTS, prospective set) were significantly younger than the patients of the control group (p 0.05). The tumor contrast intensity was 1.5 in average compared to the intact cerebral hemisphere. Among patients of LTS group, 8 patients (47 %) were re-operated due to disease recurrence, while in the control group there were no repeated operations (p 0.05); the number of temozolomide courses in the LTS group were 9 (6–22), while in the control group it was 6 (3–10), p p p IDH1 mutation was studied only in 15 patients: positive – in 1 (LTS group); negative – in 14 patients (7 from the control group).Conclusion. The following significant differences were revealed: patients with supratentorial glioblastomas were younger in the LTS group. The important features of the complex treatment of patients in LTS group included statistically higher frequency of repeated resections in case of recurrence (47 %) and repeated sessions of radiotherapy (RT) in various modes (52 %); significantly more aggressive and prolonged ChT (with the predominance of temozolomide in the 1^st line of treatment and bevacizumab in case of recurrence). There were no significant differences between two examined groups in tumor localization, intensity of its contrasting, the ratio of contrasted and non-contrast parts of the tumor, invasion of deep structures of the brain, involvement of functionally significant areas (FSA).

OBJECTIVE To study 11C-methionine (MET) metabolism in gliomas using CNS tumor biobank imaging data. MATERIAL AND METHODS MRI and 11C-MET PET/CT were performed in 225 patients (49±14 years, M/F=84/101) according to standard protocols with analysis of 11C-MET accumulation index and volumetric parameters (V_FLAIR, V_PET and V_PET/FLAIR). These results were compared with molecular genetic testing and 2-year overall survival. RESULTS We examined 225 patients with gliomas (97 glioblastomas, 70 astrocytomas, 58 oligodendrogliomas). Accumulation index and volume of 11C-MET in glioblastomas were significantly higher in the general group (AI=2.90, Se 69%, Sp 76%, AUC 0.76; V_PET=24.3 cm³, Se 67%, Sp 60%, AUC 0.65; V_PET/FLAIR 0.46, Se 60%, Sp 69%, AUC 0.67) and within the group of astrocytomas (AI=2.93, Se 68%, Sp 89%, AUC 0.84; V_PET=8.06 cm³, Se 91%, Sp 35%, AUC 0.66; V_PET/FLAIR 0.27, Se 77%, Sp 60%, AUC 0.71). The median 2-year overall survival in patients with glioblastomas was 13 months that was significantly lower compared to IDH «+» gliomas (p3.59 (Se 89%, Sp 67%, AUC 0.79) was additionally obtained in subgroup of patients with glioblastomas >50 years (n=34) for EGFR «+» tumors. CONCLUSION We found variable 11C-MET metabolism in WHO 2021 gliomas and confirmed significant difference in metabolic activity and volume of 11C-MET accumulation in glioblastomas compared to IDH «+» gliomas. Moreover, we revealed the relationship between high accumulation index and shorter survival. Analysis of 11C-MET metabolism in patients over 50 years old revealed higher accumulation index in the EGFR «+» group. Further comparison of these imaging methods and assessment of other significant mutations are necessary to identify the anatomical and metabolic patterns of IDH «+» gliomas.

Introduction. Malignant brain tumors, such as anaplastic astrocytomas and anaplastic oligodendrogliomas grade 3, are characterized by high aggressiveness and pose a serious clinical problem. This study focuses on assessing intratumoral heterogeneity in anaplastic astrocytomas and anaplastic oligodendrogliomas and its impact on disease prognosis.Aim. To study characteristics of intratumoral heterogeneity, in particular such morphological criteria as necrosis, vascular proliferation, mitoses, and mutations in the most significant for glioma progression genes in the groups of grade III astrocytomas and oligodendrogliomas, as well as analysis of prognostic significance of these parameters.Materials and methods. The study included 389 patients with IDH-mutant astrocytomas and 200 patients with oligodendrogliomas. The mean Ki-67 labeling index of astrocytomas was 12.78 %, while that of oligodendrogliomas was 8.54 %.Results. The presence of vascular proliferation, necrosis, of more than 20 % of the area of the specimen occupied by sarcomatous-like areas and the number of mitoses significantly affected not only disease-free survival but also overall survival of patients. In the clinical setting, mutations in the TERT promoter gene, amplification and mutation of the EGFR gene, deletion of the CDKN2A gene, and TP53 gene had a significant negative impact on recurrence-free and overall survival.Conclusion. The results of single-cell RNA sequencing showed additional factors, including sarcomatous-like areas, as well as TERT, EGFR, CDKN2A and TP53 mutations, in the progression of the tumors under consideration and in ensuring an increase in their malignant potential.

Анапластическая астроцитома (АА) — редкая внутримозговая опухоль, поэтому количество исследований, посвященных изучению факторов, определяющих прогноз общей и безрецидивной выживаемости пациентов с АА, невелико. Настоящая работа посвящена изучению различных факторов, влияющих на прогноз лечения в этой группе больных, и основана на клиническом материале одного центра. МАТЕРИАЛ И МЕТОДЫ Исследование носило ретроспективный характер и базировалось на клиническом материале 389 пациентов с диагнозом «астроцитома grade 3 головного мозга». Целью работы стало изучение зависимости общей и безрецидивной выживаемости от следующих факторов: пол, возраст дебюта заболевания, распространенность опухоли, вид операции, динамика неврологического дефицита до и после операции, оцененного по шкале NANO, значение индекса Ki-67, проведение лучевой и химиотерапии после операции (количество курсов, схемы лечения). РЕЗУЛЬТАТЫ Факторами, достоверно определяющими прогноз общей и безрецидивной выживаемости, стали распространенность и объем опухоли, нарастание неврологического дефицита после операции, величина индекса пролиферативной активности, наличие мутации IDH, факт проведения лучевой и химиотерапии. Такие факторы, как возраст, локализация опухоли в лобной доле и вариант манифестации заболевания оказались значимыми только для общей, но не для безрецидивной выживаемости. ЗАКЛЮЧЕНИЕ Настоящее исследование проведено на материале одной из крупнейших клинических серий пациентов с АА, оперированных в одном центре в «молекулярную» эру. Его результаты в целом согласуются с проведенными ранее аналогичными работами. Перспективными исследованиями в этом направлении могут стать работы, посвященные изучению биологии опухолей и факторов риска для IDH-негативных АА без молекулярных признаков глиобластомы.

ЦЕЛЬ ИССЛЕДОВАНИЯ Изучение связи активности экспрессии NMDA-рецепторов глутамата с пролиферативной активностью и генетическими свойствами анапластических астроцитом, а также выживаемостью пациентов с данным заболеванием. МАТЕРИАЛ И МЕТОДЫ Для решения поставленной задачи мы сопоставили активность экспрессии наименее изученных в данном контексте NMDA-рецепторов глутамата, выявляемую с помощью иммунофлюоресцентного исследования и полимеразной цепной реакции, с данными гистологического и молекулярного исследований, пролиферативной активностью новообразований, а также выживаемостью пациентов. РЕЗУЛЬТАТЫ Было показано, что активность экспрессии NMDA-рецепторов глутамата выше в астроцитомах, grade 3, которые не несут мутацию в генах IDH1 и IDH2. Кроме того, было выявлено, что активность экспрессии NMDA-рецепторов прямо коррелирует с пролиферативной активностью в опухолях. Также установлено, что активность экспрессии NMDA-рецепторов оказывает значимое влияние на прогноз безрецидивной выживаемости пациентов. ЗАКЛЮЧЕНИЕ Впервые показана существенная роль NMDA-рецепторов глутамата в прогрессировании диффузных астроцитом, что может стать основой для создания новых лечебных и диагностических подходов.

Introduction. Metabolic navigation with 5‑ALA is one of methods for intraoperative imaging in neuro‑oncology.Aim. To perform a comparative analysis of sensitivity of metabolic navigation with 5‑ALA during surgery of primary and secondary brain tumors of various histological nature and degree of malignancy.Materials and methods. During the period from 2013 to 2020, our group have performed surgery to 403 patients using metabolic navigation: microsurgical resections were performed in 384 people with brain tumors, 220 of them were with glial tumors, 101 were with intracranial meningiomas, 63 were with metastatic brain damage. Among patients with metastases, 39 patients had a solitary injury, 16 had a multi‑focal injury, so 72 cases of metastatic nodes were considered in this group. Stereotactic biopsies with 5‑ALA‑assistance were performed in 19 people. Metabolic navigation was performed with the drug 5‑ALA, which was taken orally at a dose of 20 mg/kg 2 hours before surgery. Intraoperative fluorescence was evaluated using microscope with a fluorescent module.Results. Metabolic navigation using microscope has a high sensitivity when employed during microsurgery (including repeated implementation of surgery) in cases of anaplastic gliomas (65 % in total, 58 % with bright glow), glioblastomas (94 % in total, 53 % with bright glow), intracranial meningiomas (94 % in total, 64 % – with bright glow). The use of 5‑ALA has significant limitations in sensitivity in cases of diffuse gliomas (46 % – in total, 27 % – with bright glow) and brain metastases (in total 87 % – for the solid part, 52 % – for the bed, with bright glow – 51 %). In diffuse gliomas, the glow areas had significantly higher proliferative index and cell nuclei density than the fluoronegative zones. Among the most important factors affecting the glow of gliomas it can be noted: the status of the IDH1 mutation, the volume of the contrasting part of the glioma according to MRI data, the methionine accumulation index according to positron emission tomography, the tumor blood flow indicators according to the arterial spin marking method – ASL perfusion.Conclusions. Implementation of 5‑ALA navigation with the use of microscope provides high sensitivity in cases of glioblastomas, anaplastic gliomas (especially for detecting of non‑contrasting part of tumor that is not visually altered in the white light of operating microscope) and brain meningiomas. The method is less effective in low‑grade gliomas and intracranial metastases.

Diffuse gliomas continue to be an important problem in neuro-oncology. To solve it, studies have considered the issues of molecular pathogenesis from the intratumoral heterogeneity point. Here, we carried out a comparative dynamic analysis of the different cell populations’ content in diffuse gliomas of different molecular profiles and grades, considering the cell populations’ functional properties and the relationship with patient survival, using flow cytometry, immunofluorescence, multiparametric fluorescent in situ hybridization, polymerase chain reaction, and cultural methods. It was shown that an increase in the IDH-mutant astrocytomas and oligodendrogliomas malignancy is accompanied by an increase in stem cells’ proportion and mesenchymal cell populations’ appearance arising from oligodendrocyte-progenitor-like cells with cell plasticity and cells’ hypoxia response programs’ activation. In glioblastomas, malignancy increase is accompanied by an increase in both stem and definitive cells with mesenchymal differentiation, while proneuronal glioma stem cells are the most likely the source of mesenchymal glioma stem cells, which, in hypoxic conditions, further give rise to mesenchymal-like cells. Clinical confirmation was a mesenchymal-like cell and mesenchymal glioma stem cell number, and the hypoxic and plastic molecular programs’ activation degree had a significant effect on relapse-free and overall survival. In general, we built a multi-vector model of diffuse gliomas’ pathogenetic tracing up to the practical plane.

The aim of this study was to evaluate average ¹¹ C-methionine uptake for grade II (anaplastic) gliomas in a large cohort, as well as relations between MRI and PET characteristics and their unfluence on overall and progression-free survival. Materials and methods . The study was based upon 78 patients with supratentorial tumors, among them 48 with anaplastic astrocytoma (AA) and 30 with anaplastic oligodendroglioma (AO). ALL patients underwent PET-CT with ¹¹ C-methionine and MRI study (Т1, Т2, Т2-FLAIR, DWI и 3D Т1+Gd regimes). Tumor removal was performed in 71 cases, stereotactic biopsy in 8 patients. Tumor specimen were assessed by neuropatomorphologists and IDH1-status and 1p/19q co-deletion were evaluated. Study results . AA IDH ⁻ tumors demonstrated statistically significant bigger metabolic volume and radiotracer uptake comparing with AA IDH ⁺ . Moreover, AA IDH − characterized by higher fractional MET uptake. The smallest tumors (by MRI) were AOs, meanwhile their fractional contrast enhancement was higher than for AAs. AOs were also known as tumors with minimal difference between MRI and PET-CT volume. MET uptake decreased in a row АА IDH ⁻ – АОД – AA IDH ⁺ , but the difference has not reached statistical significance. For wild-type AAs metabolic volume correlated with OS and PFS, meanwhile for IDH-mutant AAs tumor volume (measured by MRI) correlated only with PFS. Conclusion . Present study based on the largest cohort of patients with anaplastic gliomas who underwent both MRI and PET with ¹¹ C-methionine. It turned out, that unlike grade II oligodendogliomas, AOs do not always demonstrate higher than their astrocytic counterparts MET uptake levels.

The aim of the study was to evaluate the relationship between tumor blood flow (TBF) measured by the pseudo-continuous arterial spin labeling (PCASL) method and IDH1 mutation status of gliomas as well as Ki-67 proliferative index. Methods. The study included 116 patients with newly diagnosed gliomas of various grades. They received no chemotherapy or radiotherapy before MRI. IDH1 status assessment was performed after tumor removal in 106 cases—48 patients were diagnosed with wildtype gliomas (Grade 1–2—6 patients, Grade 3–4—42 patients) and 58 patients were diagnosed with mutant forms of gliomas (Grade 1–2—28 patients, Grade 3–4—30 patients). In 64 cases out of 116 Ki-67 index was measured. Absolute and normalized tumor blood flow values were measured on 3D PCASL maps. Results. TBF and normalized TBF (nTBF) in wildtype gliomas were significantly higher than in IDH1-mutant gliomas (p < 0.001). ASL perfusion showed high values of sensitivity and specificity in the differential diagnosis of gliomas with distinct IDH1 status (for TBF: specificity 75%, sensitivity 77.6%, AUC 0.783, cutoff 80.57 mL/100 g/min, for nTBF: specificity 77.1%, sensitivity 79.3%, AUC 0.791, cutoff 4.7). TBF and nTBF in wildtype high-grade gliomas (HGG) were significantly higher than in mutant forms (p < 0.001). ASL perfusion showed the following values of sensitivity and specificity in the diagnosis of mutant HGG and wildtype HGG (for TBF: specificity 83.3%, sensitivity 60%, AUC 0.719, cutoff 84.18 mL/100 g/min, for nTBF: specificity 88.1%, sensitivity 60%, AUC 0.729, cutoff 4.7). There was a significant positive correlation between tumor blood flow and Ki-67 (for TBF Rs = 0.63, for nTBF Rs = 0.61). Conclusion. ASL perfusion may be an informative factor in determining the IDH1 status in brain gliomas preoperative and tumor proliferative activity.

ЦЕЛЬ ИССЛЕДОВАНИЯ Изучить влияние TERT-мутации у пациентов с IDH-негативными диффузными астроцитомами grade III (анапластическими глиомами) на прогноз лечения (показатели общей и безрецидивной выживаемости). МАТЕРИАЛ И МЕТОДЫ В исследуемую группу включены 45 пациентов, их средний возраст составил 45,5 года. Всем больным, за исключением троих, произведено удаление опухоли, в 3 случаях выполнена ее стереотаксическая биопсия. Мутация TERT выявлена у 21 из 45 пациентов. Дистанционная лучевая терапия (60 Гр) проведена 35 больным, химиотерапия — 34 пациентам (преимущественно темозоломид). Катамнез прослежен у 44 из 45 пациентов. РЕЗУЛЬТАТЫ Медиана показателя общей выживаемости для больных с TERT-мутацией составила 15,3 мес, для пациентов с TERT-негативными опухолями — 65,1 мес. Медиана безрецидивной выживаемости у пациентов с TERT-положительными анапластическими астроцитомами (АА) составила 13,3 мес, у больных с TERT-негативными глиомами — 57,7 мес. Названные различия не достигли статистической значимости. Безрецидивная выживаемость оказалась выше у больных группы с АА без TERT-мутации во всех интервалах, но особенно на ранних стадиях — 12 мес и 24 мес. ВЫВОДЫ Включение TERT-мутации в обязательную панель исследования глиом вообще и глиом grade II и III без IDH-мутации в частности с накоплением статистически значимых величин может привести в ближайшем будущем к субклассификации этих групп опухолей, а рутинное исследование TERT-мутации послужит вспомогательным инструментом для корректного медицинского консультирования пациентов в вопросах прогноза и формулирования адекватной тактики адъювантного лечения.