DENDRITIC CELLS IN GLIOBLASTOMA TREATMENT: A MODERN VIEW OF THE PROBLEM AND OWN EXPERIENCE.

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults. The improvement of the efficacy of GBM treatment is an urgent problem encouraging the development of novel therapeutic strategies, in particular, immunotherapeutic modalities. With more understanding of the intimate interrelationships between the immune system and the mechanisms involved in cancer origin and progression, the skepticism related to the relevance of the immunotherapeutic approaches in the treatment of brain tumors is gradually decreasing. The review discloses the modern concepts on the association between CNS and the immune system. For a long time, CNS was considered as the immunoprivileged site that prevents the effects of immunotherapy in the treatment of brain tumors. Nowadays, these views are reconsidered, which opens the way to the use of immunotherapeutic approaches in GBM treatment. The results of the recent clinical trials on immunotherapy as a supplement to the conventional GBM treatment are considered. Vaccines based on the dendritic cell (DC) technology are regarded as the most promising for this purpose. The preliminary results of the Ukrainian clinical study are also presented and discussed. The results of the international clinical trials as well as our own experience give evidence of the relevance for using DC vaccines in the complex treatment of GBM, which is supported by the increased survival of patients and the safety of vaccine application. It is of high importance that GBM patients with the most unfavorable prognosis can benefit from DC vaccines as a component of the complex treatment. The prospects for immunotherapy in neurooncology are discussed.

RADIOSURGICAL TREATMENT OF RECURRENT GLIOBLASTOMA AND PROGNOSTIC FACTORS AFFECTING TREATMENT OUTCOMES.

BACKGROUND: Glioblastoma (GBM) is the most prevalent malignant tumor of the brain in adults with the inherent aggressive behavior and high recurrence rate. The stereotactic radiosurgery (SRS) is currently considered as one of the effective modalities for GBM treatment allowing for the improvement of survival with the acceptable toxicity level. AIM: To assess the effects of various factors on the survival of GBM patients following SRS. PATIENTS AND METHODS: We retrospectively reviewed treatment outcomes of 68 patients who received SRS for recurrent GBM treatment in 2014-2020. SRS was delivered with Trilogy linear accelerator (6 MeV). The area of recurrent tumor/continued tumor growth was irradiated. For the treatment of the primary GBM, the adjuvant radiotherapy was provided at the standard fractionated regimen with the total boost dose of 60 Gy divided to 30 fractions (Stupp's protocol) in the setting of the concomitant chemotherapy with temozolomide. 36 patients then received temozolomide as the maintenance chemotherapy. SRS for the treatment of recurrent GBM was provided at a boost dose of 20.2 Gy on average being delivered into 1-5 fractions with average single dose of 12.4 Gy. The survival was analyzed by the Kaplan-Meier method with a log-rank test used for assessing the impact of the independent predictors on the survival risks. RESULTS: The median overall survival (OS) was 21.7 months (95% confidence interval (CІ) 16.4-43.1), median survival after SRS was 9.3 months (95% CІ 5.6-22.7). The majority of patients (72%) were alive for at least 6 months following SRS and about half of patients (48%) survived for at least 24 months following the resection of the primary tumor. OS and survival after SRS depend significantly on the extent of the surgical resection of the primary tumor. The addition of temozolomide to radiotherapy prolongs survival in GBM patients. The relapse time affected significantly OS (p = 0.00008), but not survival after SRS. Neither OS, nor survival after SRS were affected significantly by such factors as the age of patients, the number of SRS fractions (one fraction vs several fractions), and target volume. CONCLUSION: Radiosurgery improves the survival in patients with recurrent GBM. The extent of the surgical resection and adjuvant alkylating chemotherapy of the primary tumor, overall biologically effective dose and time between the primary diagnosis and SRS affect significantly the survival. The search for the more effective schedules for treating such patients requires further studies with more numerous cohorts of patients and extended follow-up.

Temozolomide in glioblastoma treatment: 15-year clinical experience and analysis of its efficacy.

AIM: To analyze retrospectively the efficacy of temozolomide (TMZ) in various treatment regimens in glioblastoma patients accounting for varying parameters of their treatment. MATERIALS AND METHODS: 302 glioblastoma patients were treated at the State Institution "Romodanov Institute of Neurosurgery of the National Academy of Medical Sciences of Ukraine" from 2003 through 2017. All the patients were surgically treated. In 205 patients, the surgery was followed by adjuvant radiotherapy (RT) with concomitant TMZ (RT + TMZ group). In 97 patients, the surgery was followed by adjuvant RT only (RT group). Kaplan - Meier survival analysis with log-rank test and Cox proportional hazards regression analysis were used for comparing overall survival (OS) and recurrence-free survival (RFS) depending on the age and gender of the patients, the extent of tumor resection, the chemotherapy intensity and the type of RT. RESULTS: In RT + TMZ group as a whole, OS median was 20.7 months vs 10.8 months in RT group (р < 0.0001). The RFS was 14.8 months vs 7.9 months, correspondingly (р < 0.0001).The survival did not depend on the age, gender or localization of the tumor. On the contrary, the intensity of CTX (the number of TMZ cycles in adjuvant mode), the extent of tumor resection, and the type of RT were among the factors affecting significantly OS and RFS. The improvement in OS and RFS with increasing number of the maintenance TMZ courses was more significant in the patients aged below 60. The use of stereotactic conformal mode for RT provides an advantage in the survival over the conventional RT in RT + TMZ group. CONCLUSIONS: The combination of concomitant and adjuvant maintenance CTX with TMZ was the most effective CTX regimen affecting positively OS and RFS.

Incorporation of labelled N-acylethanolamine (NAE) into rat brain regions in vivo and adaptive properties of saturated NAE under x-ray irradiation.

Regional distribution of exogenous N-palmitoylethanolamine in the rat brain was investigated in the study. Possible protective and adaptive effect of N-stearoylethanolamine under 2 Gy whole-body X-irradiation and changes of brain lipid composition were also studied. It was found that after per os administration to rats N-([9,10-3H]-palmitoyl)-ethanolamine was primarily accumulated in hypothalamus, pituitary and adrenal glands and the label amount in brain was 0.95% of the oral dose. Quantities of palmitic acid in total brain phospholipids and plasmalogen form of phosphatidylcholine were increased; free cholesterol and diacyl form of phosphatidylcholine were decreased in 2 weeks after irradiation. 11-OH-corticosteroid level in the blood of exposed rats was decreased in comparison with control animals. N-stearoylethanolamine pre-treatment prevented from increasing the plasmalogen form of phosphatidylcholine and decreasing its diacyl form and restored 11-OH-corticosteroid level in the blood of irradiated rats. Recovering of brain free cholesterol level was observed when N-stearoylethanolamine was post-treated. So, the accumulation of N-([9,10-3H]-palmitoyl)ethanolamine in brain indicates its penetration through blood-brain barrier and suggests the possible role of saturated N-acylethanolamines in brain functioning, particularly, in stress response regulation of the organism by hypothalamus-pituitary-adrenal system. N-stearoylethanolamine treatment of irradiated rats causes protective effect concerning the of irradiation induced changes in the brain lipid composition and in 11-OH-corticosteroid level and modifies phospholipid fatty acid composition.