В данном разделе указаны критерии оценки клинической значимости применения дорогостоящей противоопухолевой лекарственной терапии в соответствии со шкалой, разработанной экспертной группой (см. стр. 7). В тексте они обозначены, как магнитуда клинической значимости (МКЗ).

Relevance. Despite all the treatment glioblastoma recurs as an aggressive and therapy-resistant tumor, and patients quickly die from these neoplasms. The study of glioblastoma recurrence processes and search for prognostic factors of the disease should lead to the improvement of survival rates of patients with this pathology. Purpose of the study. To study the influence of clinical and molecular-genetic factors on the median second recurrence-free period. Materials and methods. Progression-free survival after first recurrence in 34 patients aged 28 to 81 years with recurrent glioblastoma was analyzed. The diagnosis was established according to the WHO 2021 classification of CNS tumors. In each observation we studied such clinical parameters as patient’s age, functional status according to the Karnovsky scale pre- and postoperatively, peculiarities of neuroimaging picture (prevalence of tumor process, localization of recurrence, tumor volume), conducted treatment and molecular-genetic characteristics of the tumor (determination of mRNA expression level of genes: MGMT, VEGF, PDGFRA, β-tubulin III, ERCC-1, TOP2A). Results. Among the clinical and demographic characteristics, the median of the survival was influenced by the patients’ age and functional status after surgery. The median of the survival was more than 2 times higher in the group of patients under 50 years old, compared to patients over 50 years old (18.5 vs 8 weeks). The dependence of the median of the survival on the post- operative functional status (according to the Karnovsky scale) was determined (p = 0.001). The median of the survival in case of a single brain lobe lesion was more than 5 times higher than in case of widespread tumor process, though without statistical reliability (p = 0.09, 21.5 vs 4 weeks). Survival rates were higher when recurrence was localized within 2 cm of the area of removal of the primary neoplasm. After disease progression, the MGMT gene lost its predictive value. Patients with low expression of the TOR2A gene had a higher survival rate than those with medium and high expression (47.5 vs 3 weeks, p = 0.001; 47.5 vs 22.5 weeks, p = 0.06). The median of survival was higher than at high levels at low and medium PDGFRA gene expression levels (29 vs 0 weeks, p = 0.04; 21 vs 0 weeks; p = 0.05, respectively). Maximum survival rates were recorded in the group of patients after total and subtotal removal of tumor recurrence (22 and 18.5 weeks, p = 0.05). Administration of second-line chemotherapy with temozolomide statistically significantly increased the median of the second BRS (p = 0.01). Conclusion. Recurrent glioblastomas are characterized by an extremely aggressive course. Therefore, such prognostic factors as patient age, degree of tumor resection, tumor process prevalence, degree of tumor resection and 2nd line chemotherapy come to the forefront. It should be noted that the MGMT gene loses its predictive value during disease progression, while the TOR2A gene and PDGFRA gene become prognostic markers.

Introduction. Due to the active research of the molecular and genetic features of glioblastoma, the performance of the biological processes occurring in tumor cells has become more distinct. In the modern scientific literature, the number of scientific studies is growing, which emphasizes the priority importance of the genetic status of the tumor in the prognosis of the disease.Purpose statement. To study the influence of clinical and molecular genetic factors on the median of the first relapse-free period.Materials and methods. The first progression-free survival (PFS) was analyzed in 30 patients aged 28 to 81 years with glioblastoma. The diagnosis was established in accordance with the WHO classification of CNS tumors in 2021. After the first operation, all patients underwent a course of radiation therapy (LT) (60Gr) and chemotherapy with temozolomide (2–18 cycles). In each case, clinical parameters such as the patient’s age, functional status on the Karnovsky scale both before and after surgery, features of the neuroimaging picture (prevalence of the tumor process, localization, tumor volume), treatment (degree of tumor resection, radiation therapy with or without temozolomide and the number of cycles of chemotherapy) and molecular genetic parameters of tumor (determination of the mRNA expression level of genes: MGMT, VEGF, PDGFRA, β-tubulin III, ERCC-1, TOP2A) were studied.Results. Of all the studied clinical parameters, only the postoperative functional status on the Karnovsky scale (p = 0.001) influenced the median of PFS. The median of the first PFS was not affected by such radiological characteristics as involvement of basal structures of the brain in the tumor process (p = 0.9), the side of the lesion (p = 0.67), the prevalence of the tumor process (p = 0.6) and the volume of the tumor (p = 0.52). The duration of the first PFS with statistical reliability was higher in the group of patients after subtotal resection of the tumor (14.9 months; p ³ 0.05). The median of the first PFS was influenced by the presence of a mutation in the IDH1 gene (22.5 vs 11.5 months) and the expression level of the MGMT gene (p = 0.036). Total tumor resection increases the first BRP only at a high level of MGMT gene expression, although without statistically significant differences (7.6 vs 2.7 months; p = 0.6). The addition of temozolomide to radiation therapy (75 mg/m2, orally, daily) led to an increase in the first relapse-free period by more than 6.9 months, but only in patients with low expression of the MGMT gene in the tumor.Conclusion. In the conditions of standard patient therapy (surgical removal of the tumor, chemoradiotherapy followed by adjuvant therapy with temozolomide), the first PFS primarily depends on the molecular genetic characteristics of the tumor, namely, the presence of a mutation in the IDH1 gene and the level of MGMT in the tumor. For patients with an expected lack of response to therapy (i.e., a high level of MGMT gene activity), the role of other factors increases, and first of all, the volume of cytoreduction.

Introduction. Intratumor heterogeneity is one of the key reasons for unfavourable prognosis in malignant tumors. Astrocytic tumors are known to develop therapy resistance inevitably during the course of disease. One of possible reason is tumor heterogeneity. Purpose. The aim of this work was to assess the intratumor morphologic and molecular heterogeneity in diffuse astrocytoma, anaplastic astrocytomas and primary glioblastomas. Material and methods. We conducted morphologic (n=22) and molecular-genetic (n=8) analysis of surgical specimens obtained from primarily operated glioblastoma giv (gb), anaplastic astrocytomas giii (aa) and diffuse astrocytoma gii (da) patients aged 18 years and older in whom total or subtotal tumor resection was performed. Tissue sampling for the analysis was performed from 5 equidistant areas of each tumor. Morphologic diagnosis was established according to who classification of central nervous system tumors (2007/2016). Mgmt, c-kit, top2a, pdgfr-α, ercc1, vegf genes mrnaexpression was assessed by rt-pcr. Idh1 and idh2 mutational status was evaluated by allele-specific pcr. Results. Morphologic heterogeneity was evident in 72,7 % tumors (16/22) overall. Heterogeneity was observed in 68,8 % (11/16) of gb, 80 % (4/5) of aa and in the only case of da. In 50 % of cases at least 3 different morphologic variants were seen in different areas of the tumor. This morphologic heterogeneity presented as the combination of different grades of anaplasia (gii – giv) in one tumor. Molecular profile was assessed in 48 expression analysis of genes: mgmt, c-kit, top2a, pdgfr-α, ercc1, vegf from 8 patients. Intratumoral molecular heterogeneity was revealed in 41,7 % of cases (20/48). Conclusion. The presence of intratumoral heterogeneity should be taken into account during surgery for adequate tumor sampling for histologic and molecular analysis which is critical for proper assessment of prognosis and following treatment planning.

Background. Over the past 10–15 years, there has been a clearer understanding of the processes occurring in cells of the primary glioblastoma. However, the change in MGMT gene expression and its role after disease relapse remain understudied. Purpose: to study changes in MGMT gene expression in case of recurrent primary glioblastoma after the standard therapy; to determine influence of clinical factors and MGMt gene expression on relapse-free survival of patients. Materials and Methods. We carried out a prospective analysis of clinical and molecular genetic characteristics of 21 patients aged from 28 to 63 with primary glioblastoma before and after recurrence. Relative mRna expression of MGMT gene and mutations in IDH1/IDH2 genes were determined in surgical biopsies using PCR techniques. after the first surgery, all patients received radiation therapy (60 Gy) and chemotherapy with adjuvant temozolomide (2–18 cycles). the second-line chemotherapy was performed in 17 (80.9 %) patients, and 8 patients received (47 %, 8/17) temozolomide.Results. the relationship between the progression-free survival (PFs) and mRna expression of MGMT gene (73.5 vs 33 weeks, p=0.013) and objective response to therapy (88 vs 36 weeks, p=0.046) was found. The number of cycles of first-line chemotherapy with temozolomide influenced the duration of the first PFs (65 weeks vs 21.5 weeks, p=0,07). the first PFs was not affected by patients’ age (p=0.64), sex (p=0.17), Karnofsky performance scale index (p=0.43), extent of brain damage (p=0.41) and extent of the resection (p=0.27). after onset of relapse, mRna expression of MGMT gene remained the same, being 66.7 % (14/21). The increased expression was observed in 23.8 % (5/21) of cases, and decreased gene expression was observed in 9.5 % (2/21) of cases. the second PFs was affected by the extent of tumor resection, although there were no statistically significant differences (p=0.52). the effect of mRna expression of MGMT gene on the median second PFs was not revealed (p=0.39). no objective response to therapy was found in patients with a low mRna expression of MGMT gene. Conclusion. Recurrent glioblastoma becomes more resistant to further therapy. With the development of tumor recurrence, the predictive value of MGMT gene is lost and the role of the extent of cytoreductive surgery increases.

Background. Еmbryonal tumors of the central nervous system are malignant neoplasms that mainly occur in pediatric patients with a peak incidence at the age of 4 years. These tumors usually have small round blue cell histology and low differentiation.Method and case description. A report of three cases with embryonal CNS tumors of supratentorial localization has been presented. Immunohistochemical analysis classified these tumors as neuroblastoma (2 cases: Syn (+), NSE (+), CD (+) and Ki67 10/40 %; ages were 33 and 52 years) or ganglioneuroblastoma (1 case: Syn (+), NSE (+), CD 99 (+) and Ki67 40 %; age was 37 year). All patients underwent RT in a total dose of 60 Gy delivered to the area of the removed tumor and 6 cycles of adjuvant chemotherapy: patients with neuroblastoma received chemotherapy using EP regimen (cisplatin + etoposide), and patient with ganglioneuroblastoma received temozolomide.Results. An objective response to therapy was achieved in all 3 patients. The relapse-free survival (RFS) in the first case of neuroblastoma was 51 months, the overall survival (OS ) was more than 105 months (8 years 9 months); in the second case of neuroblastoma, RFS was 25 months 2 weeks and OS was more than 26 months. Both neuroblastomas contained ID H1(R132H) mutation. In the patient with ganglioneuroblastoma, the RFS was 87 months, and the OS was over 93 months (7 years, 9 months, 3 weeks).Conclusion. Supratentorial embryonal tumors of the central nervous system in adults are exceptionally rare and have a relatively favorable response to the standard treatment.

Primary glioblastoma (GB) is a rapidly progressing central nervous system tumor with aggressive biological behavior. Long-term glioblastoma survival, defined as survival beyond 3 years, is a rare phenomenon. Various factors contributing to such prolonged lifespan have been proposed.Aim. This study aimed to compare demographic, clinical, morphologic, immunohistochemical and molecular features of primary GB in patients with different survival.Material andMethods. This prospective study included 69 patients, who were treated at A.L. Polenov Neurosurgery institute. The analysis considered clinical, morphologic, immunohistochemical (Ki67, P53, INA , EGFR) and genetic (MGMT, VEGF and PDGFRA gene expression; ID H1/2 mutational status, 1p/19q co-deletion) characteristics of the disease.Results. 11 (15.9 %) patients survived beyond 3 years. Prolonged survival was associated with younger patient age (p=0.002), use of more than 6 cycles of temozolomide in the 1st line therapy (p=0.016), use of the 2nd line therapy (p=0.017) and low level of MGMT expression in the tumor tissue (p=0.038). Other factors including patients’ gender, VEGF and PDGFRA mRNA expression levels, ID H1 mutation, 1p/19q deletion, and the immunohistochemical markers Ki67, p53, INA , EGFR, were not associated with prolonged survival (p>0.05).Conclusion. Prolonged survival in GB patients is a non-random event and can be explained by several clinical and biological factors. A high percentage of 3-year survival of GB patients in our study may be explained by an individual approach to treatment and intensive chemotherapeutic tactics (from 6 to 15 cycles of temozolomide in the 1st line therapy and use of the 2nd line therapy), as opposed to standard short treatment protocols.

Background. Gemistocytic astrocytomas (GA) are a variant of diffuse astrocytomas GII (WHO, 2016), which is characterized by a shorter overall survival of patients than diffuse astrocytoma. The role of vascular endothelial growth factor (VEGF) gene expression and its association with the index of proliferative activity (Ki-67) in GA has not been studied Objective. To estimate the correlation of VEGF gene expression on Ki-67 in GA. Design and methods . A retrospective and prospective analysis of morphological and molecular-genetic features of tumors was performed on 9 patients with the diagnosis of GA. Patients over 18 years of age with supratentorial tumor localization were included in the study. The patients were aged from 27 to 37 years, the median age was 32 years. There were 4 men. Fragments of tumor tissue obtained during surgery were subjected to histological, immunohistochemical (Ki-67 and GFAP) and molecular genetic studies. By real-time PCR method was used to determine the level of the VEGF gene expression and the presence of a mutation in IDH1/IDH2 genes. Histological diagnosis was made in accordance with the classification of tumors of the CNS WHO (2016) and the AFIP atlas (2007). Results. The tumor most often affected several lobes of the brain (44,4%). The first clinical manifestations of the disease in the vast majority of cases were epileptic and hypertensive syndromes (55,6%). For the proliferative activity index Ki-67 >5% (71,4% of cases) the moderate proliferation of vascular endothelium was noted in 85,7% of cases and the middle/high level of VEGF gene expression (except one case). In patients with low Ki-67 (≤5%), the low level of the VEGF gene expression was determined in 100% cases, the proliferation of the vascular endothelium was absent. Conclusion. High Ki-67 (>5%), the proliferation of the vascular endothelium, middle/high level of VEGF gene expression are typical attributes of anaplastic astrocytomas. That’s why some GA have features of astrocytomas GIII.

Gemistocytic astrocytomas (GA) are a variant of diffuse astrocytomas GII (WHO, 2016). Like all diffuse astrocytomas, GA recur with time, which is often accompanied by malignant degeneretion into the anaplastic astrocytoma GIII or to the secondary glioblastoma GIV. However, the progression-free survival and overall survival in patients with GA is less than in patients with diffuse astrocytomas. Given that this group of patients, according to the WHO classification (2016), is classified as GII, patients with GA usually do not receive comprehensive treatment. We have conducted a thorough analysis of research on this problem for the period from 1956 to 2017. Differences in the histological pattern, immunohistochemical and molecular-genetic profiles, survival of patients with GA and diffuse astrocytomas GII are shown there. A clinical case of a patient with transformation of a diffuse astrocytoma in GA (GIII) and then into a secondary glioblastoma is presented.

В онкологической практике достаточно прочно устоялось правило – лечение назначается пациентам только после морфологической верификации диагноза. Подразумевается, что речь идет о правильном диагнозе, но, как показывает практика, невзирая на внедрение метода иммуногистохимической диагностики, по-прежнему имеет место большое число диагностических, порой принципиальных, ошибок, что связано, прежде всего, с недостаточной квалификацией специалистов в области нейроонкологии вообще и нейроморфологии - в частности. Адекватный морфологический диагноз дает возможность рекомендовать лечение в соответствии с установленной нозологической единицей: больным со злокачественными глиальными опухолями в первой линии терапии назначать препараты алкильной группы; больным с примитивными нейроэктодермальными опухолями, нейрональными и нейрональноглиальными опухолями – препараты платины; больным с атипическими и анапластическими менингиомами – как препараты алкильной группы, так и антрациклиновые антибиотики и т.д.

Radiochemotherapy is leading the universal research effort in fighting lethality: it is improving relapse-free survival of patients with inoperable glioblastoma, the most pernicious brain tumor in adults. Its effectiveness was found to depend on expression of Mgmt gene of tumor DNA reparation following radiochemotherapy and adequate medication based on the molecular phenotype of tumor. Our study involved a 40-year old male with a low level of Mgmt gene expression as established by stereotactic biopsy. The patient received hypofractionated three-dimensional conformational proton therapy with the benefit of temozolomide (140 mg/24 hr). Subsequently, the dose was raised to 360 mg/24 hr, on days 1-5 of the cycle. Contrast-enhanced MRI examination established significant diminishing of the size of tumors on completion of cycles 7 and 8; patients felt better, memory and blood indices improved. As of the time this paper was written, relapse-free survival was 17.5 months, as compared with the literature data on inoperable glioblastoma--5.5 months.