Several studies have shown that the increased expression of delta–like noncanonical Notch ligand 1 (DLK-1) is associated with more aggressive tumor characteristics in patients with glioblastoma. The aim of the study was to estimate the diagnostic and prognostic values of DLK-1 serum levels in glioblastoma patients. Material and Methods. The study included 39 patients with newly diagnosed glioblastoma. The DLK-1 level was evaluated in paired serum and cerebrospinal fluid samples in glioblastoma patients before starting chemoradiotherapy (CRT). All patients with glioblastoma received combined modality treatment. The DLK-1 level in blood serum was additionally assessed during follow-up visits. Results. The median levels of DLK-1 in paired CSF and serum samples before CRT were 1.17 ng/ml (95 % CI 0.78; 2.89) and 0.27 ng/ml (95 % CI 0.26; 0.29), respectively (p=0.006). The assessment of the DLK-1 serum level in glioblastoma patients didn’t show any significant differences related to the response to therapy. In patients with tumor progression after CRT, the median serum DLK-1 level before CRT was 0.43 ng/ml, and in patients with stable disease, the median serum level was 1.7 ng/ml (p=0.012). The DLK-1 serum levels were 1.60 ng/ml and 0.32 ng/ml in patients with favorable prognosis for progression–free survival and in patients with unfavorable prognosis, respectively (p=0.005). The median concentrations of DLK-1 in serum before starting CRT were 1.01 ng/ml and 0.32 ng/ml in patients with favorable prognosis of overall survival and in patients with unfavorable prognosis, respectively (p=0.04). The DLK-1 levels in 4 weeks after CRT were 1.53 ng/ml and 0.23 ng/ml in patients with favorable prognosis of overall survival and in patients with the unfavorable prognosis, respectively (p=0.04). Conclusion. The DLK-1 serum level in patients with glioblastoma cannot be used to diagnose disease progression. However, this marker is a prognostic factor for overall and progression-free survival, and allows identification of patients with favorable and unfavorable prognosis.

The purpose of the study was to evaluate the efficacy of neutron therapy (NT) for salivary gland cancer and recurrent breast cancer. Material and Methods. The study included 130 patients with salivary gland cancer and 125 patients with recurrent breast cancer. Fast neutron therapy using U-120 cyclotron was given to the patients of the study group. Patients of the control group received standard radiotherapy (external beam radiotherapy). Results. Among patients with salivary gland cancer, a recurrence rate was significantly lower in patients who received a postoperative course of NT compared to patients of the control group (21.1 vs 45 %, p<0.05). The five-year overall survival rates were 73.8 ± 9.5 % and 43.2 ± 9.4 % in the study group and the control group, respectively (p<0.05). The five-year disease-free survival rates were 65.6 ± 7.5 % and 34.8 ± 9.1 % in the study and control groups, respectively (p<0.05). In patients with recurrent breast cancer, a significant increase in the frequency of complete regression in the study group compared to the control group was observed (91.8 vs 51.3 %, p<0.05). Ten-year survival rates in patients with no evidence of re-recurrence were 77.4 ± 8.7 % and 44.7 ± 8.8 % in the study group and the control group, respectively (p<0.05). Conclusion. The study demonstrated efficacy of fast neutron therapy in patients with salivary gland cancer and recurrent breast cancer. Neutron therapy did not result in serious complications, improved survival of the patients and decreased the recurrence rate compared with standard radiotherapy.

The purpose: To evaluate the efficiency of combined treatment of patients with salivary gland cancer using neutron therapy. Material and methods: The study included 130 patients with salivary gland cancer who underwent combined treatment with adjuvant neutron or standard photon radiotherapy. Neutron therapy was performed on a cyclotron U-120. The average energy of fast neutrons was 6.3 MeV. Results: There was observed a significant decrease in the frequency of relapses in the group of patients who received a postoperative course of NT compared with the control group (21.1 % vs. 45 %, p<0.05). The five-year overall survival in the study group was 73.8±9.5 %, in the control group ‒ 43.2±9.4% (p<0.05). The value of five-year relapse-free survival in the study group was 65.6±7.5 %, in the control group ‒ 34.8±9.1 % (p<0.05). Erythema of the skin in the irradiation area (grade I) was the most frequent type of local acute radiation reaction and was observed in 60 % of patients in the study group and in 25 % of patients in the control group. The most frequent late complication in both groups of patients was skin atrophy and subcutaneous fibrosis (grade I on the RTOG/EORTC scale). In the study group, this indicator was 34.4 %, in the control group ‒ 20 % (p>0.05). Conclusion: Thus, the study confirmed the high effectiveness of fast neutron therapy against malignant tumors of the salivary glands. Neutron therapy does not cause serious complications, encourages to increase of patients life expectancy and to decrease the number of relapses after combined treatment in comparison with standard methods of treatment.

Purpose: to summarize available data on the diagnostic value of various circulating biomarkers for the detection of glioblastoma recurrence. Material and Methods. A literature search was conducted using PubMED ExoCarta and SILVA databases. Results. Glioblastoma multiforme (GBM) is the most common glioma in adults with an unfavorable prognosis. Treatment of tumor recurrence can improve the survival of patients. Neuroimaging is the standard method of diagnosing brain tumor recurrence. However, a neuroimaging method to clearly distinguish between pseudo progression and tumor progression has not been found to date. Current molecular tumor profling relies heavily on tissue resection or biopsy. Tissue profling has several disadvantages in the central nervous system’s tumors, including the challenge associated with invasive biopsy, the heterogeneous nature of many malignancies where a small biopsy can under represent the mutational profle. Liquid biopsy is a promising method in diagnosing malignant tumors. Blood collection is a simple, minimally invasive procedure, but cerebrospinal fuid allows tumor markers to be detected more confdently. However, collection of cerebrospinal fuid is a complex and invasive procedure that can be accompanied by serious complications. Conclusion. Biological fuid markers such as circulating tumor cells, extracellular vesicles, cell-free DNA and cell-free RNA allow for the detection of GMB, determination of molecular genetic features of cancer during response to therapy, and early detection of GBM recurrence.

The level of spontaneous and radiation-induced DNA damage varies depending on genetic and environmental factors in human somatic cells. This variation may be associated with transcriptional changes in cells, allowing the use of gene expression levels as markers of individual sensitivity to mutagenic effects. This study aimed to identify and characterize differentially expressed genes (DEGs) in lymphocytes of individuals with various frequencies of endogenous γH2AX foci and radiation-induced micronuclei (n = 37). The low-focus group was characterized by 0.18 ± 0.02 endogenous γH2AX foci per cell and a 155.78 ± 47.19‰ radiation-induced micronucleus frequency. The high-focus group was characterized by 0.49 ± 0.07 foci/cell and a 78.44 ± 33.21‰ micronucleus frequency. Seven DEGs (ENST00000424415, CRNDE, ADAMTS1, ENST00000424084, EIF2A, PNPLA5, and FRG2C) (FDR < 0.2) were identified by gene expression analysis with microarrays. As the extracellular matrix metalloproteinase, ADAMTS1 is able to activate the latent form of TGFβ, and TGFβ is involved in radiation-induced cellular response; the effects of ADAMTS1 knockout and overexpression on the gene expression profile were further validated in adherent HeLa cells. Twenty-nine of 160 identified DEGs are involved in apoptosis, DNA DSB repair, G2/M cell cycle transition, and the TGFβ signaling pathway. Thus, ADAMTS1 may be useful as a potential target for antitumor therapy.

The article reviews studies highlighting the role of extracellular molecules in non-invasive diagnosis of glioblastoma recurrence. Glioblastoma is the most common malignant tumor of the brain characterized by fatal outcome prognosis. Current treatment of tumor recurrence allows to increase patient survival, improve functional outcome and decrease caregivers» load. The standard method of recurrence diagnosis is neuroimaging which at early stages cannot distinguish between tumor recurrence and post-radiation changes. Currently in oncology, liquid biopsy and marker detection in circulating extracellular vesicles are considered promising approaches allowing to obtain early and differential tumor diagnosis, determine dynamic molecular and genetic status of the tumor, diagnose tumor recurrence at early stages. In this context, the most promising approach to glioblastoma diagnosis is associated with studying of expression of glial fibrillary acidic protein (GFAP), epidermal growth factor receptor (EGFR), its mutant variant EGFRvIII, podoplanin (PDPN) and isocitrate dehydrogenase 1 (IDH1) in extracellular vesicles; for primary glioblastoma diagnosis and early recurrence: studying of microRNA-210, -301a, -222, -123-3p, -21; for control of immunotherapy effectiveness in patients with recurrent forms of glioblastoma after standard treatment: evaluation of СD9+ / GFAP+ / survivin+ exosomes in plasma.

Проведен анализ выживаемости клеток, оценка уровня фокусов белков репарации ДНК и частоты радиационно-индуцированных микроядер в условиях дифференциальной экспрессии генов ADAMTS1, RBFOX2, THBS1 и WHSC1 в модельных системах in vitro и в лимфоцитах периферической крови человека. Полученные результаты указывают на потенциальную возможность использования уровня экспрессии данных генов для выявления индивидов с повышенной радиочувствительностью. In this study, we investigated the cell survival, the DNA repair foci level and the radiation-induced micronuclei frequency in the model systems in vitro and in the human peripheral blood lymphocytes with differential expression of ADAMTS1, RBFOX2, THBS1 and WHSC1 genes. The results indicate the potential opportunity of using these genes expression level to identify the individuals with increased radiosensitivity.

In this study, we investigated the cell survival, the DNA repair foci level and the radiation-induced micronuclei frequency in the model systems in vitro and in the human peripheral blood lymphocytes with differential expression of ADAMTS1, RBFOX2, THBS1 and WHSC1 genes. The results indicate the potential opportunity of using these genes expression level to identify the individuals with increased radiosensitivity.

The goal of radiotherapy is to maximize the radiation dose to abnormal cancer cells while preventing damage to healthy tissue. in neutron therapy, the optimum regime of treatment is uncertain to date.The purpose of the study to develop a set of methodological approaches that ensure the permissible frequency and severity of radiation-induced reactions in cancer patients subjected to neutron and neutron-photon therapy (NFt) using u-120 cyclotron.Material and methods. We used the dependence of the relative biological effectiveness (RBE) of neutrons on the dose and time-dose-fractionation model (tdF). the interaction of neutrons with various types of tissues was analyzed, and the algorithm for summing neutron and photon doses in neutronphoton therapy was developed.Results. Clinical studies of neutron-photon therapy showed that the developed approaches can predict and prevent serious damage to normal tissue with a satisfactory accuracy. the role of all factors influencing the nature of radiation reactions was taken into account in the computer program, which allowed the main characteristics of the planned courses of neutron-photon therapy to be obtained.

Unsatisfactory results of complex treatment for malignant brain tumors stimulate search of new effective methods of treatment. Radiation therapy is an integral part of the combined treatment but often does not influence lethally on resistant tumor cells. Thereby in recent decades there has been an active search for different modifiers, which can increase the sensitivity of tumors to chemotherapy and radiotherapy. One of the universal sensitizers is the local hyperthermia. Experimental data showed that the effect of high temperatures had both a direct damaging effect on tumor cells and a sensitizing effect. The literature review given in the article provides an overview of the existing methods of the local hyperthermia for brain tumors treatment.

This paper presents the results of temperature shift measurements in a brain phantom based on agar gel and including elements simulating a tumor (glioblastoma) and cerebrospinal fluid for assessment of the safety of real courses of high-frequency hyperthermia using a Celsius TCS system. No “hot spots” formed at the boundary between normal brain tissue and fluid and the temperature did not excess physiological values. Higher tempera-tures were produced in the model viable tumor (glioblastoma), reaching the values required for hyperthermic radiosensitization.

The treatment of patients with glioblastoma continues to be one of the greatest challenges. Glioblastoma is the most aggressive malignant primary brain tumor and is the most lethal among all cancers. Despite advances in the standard treatment, the prognosis for patients with glioblastoma remains poor, therefore, the development of novel treatment strategies is required.Material and methods.Our study included 30 patients with newly diagnosed glioblastoma, who underwent concurrent chemoradiotherapy and local hyperthermia.Results.The median disease-free and overall survival rates were 9.6 months and 23 months, respectively. The analysis of clinical, molecular-genetic and prognostic factors related to treatment modality showed statistically significant differences in survival between patient groups representing different times for starting adjuvant therapy after surgery. The median disease-free survival was significantly higher in patients who received chemoradiotherapy with local hyperthermia within 6 weeks after surgery than in patients who started adjuvant treatment earlier. The overall survival rate was statistically higher in patients receiving a special treatment for tumor recurrence compared to that in patients receiving symptomatic therapy. The evaluation of molecular-genetic prognostic factors showed no statistically significant differences in survival among patients with methylated and nonmethylated MGMT promoter. The presence of IDH1 mutations was identified in only one case. Evaluation of prognostic factors does not allow identification of clinical and molecular biological factors that group patients with hypersensitivity to the proposed treatment regimen. However, high rates of overall and disease-free survival, even in patients with non-methylated MGMT, allow us to recommend this treatment modality for patients with newly diagnosed glioblastoma.

A new technique of concurrent chemoradiotherapy and local electromagnetic hyperthermia for treatment of patients with newly diagnosed glioblastoma was developed at the Cancer Research Institute of Tomsk National Research Medical Center. A total of 20 patients with glioblastoma received concurrent chemoradiotherapy with temozolamide and local hyperthermia. Local hyperthermia was performed using the Celsius TCS device, 2 times a week (8–10 sessions). All patients tolerated the treatment well. The most common toxicity profile of concurrent thermochemoradiotherapy with temozolamide was hematological and neurological. It should be noted that no neurological toxicity was found in randomized trials of chemoradiotherapy with temodal. If the predominant hematologic toxicity might be associated with a small sample of patients in the study, the neurologic toxicity was likely to be related with greater toxic effects of chemotherapy on the brain during local hyperthermia, however, the causes of neurological toxicity during adjuvant chemotherapy courses at the moment we can not explain. Short-term results of concurrent thermochemoradiotherapy demonstrated the objective response rate of 70 %, however, adjuvant chemotherapy produced an increase in the incidence of disease progression during adjuvant chemotherapy. One-year recurrence-free survival rate was 53.3 ± 13.3 %, with a median time to progression of 10.5 months. One-year overall survival rate was 91.7 ± 8 % at a median follow-up time of 9 months. The median overall survival was not reached. A short follow-up time did not allow us to make conclusions about the impact of local hyperthermia on the treatment outcomes. However, there was a tendency towards increase in recurrence-free and overall survivals in patients with newly diagnosed glioblastoma.

The preliminary treatment outcomes for 8 patients with sinonasal carcinoma have been presented. All the patients received a multimodality treatment including thermoradiotherapy followed by the operation and intraoperative radiotherapy. Clinical testing of the method of the combined treatment of sinonasal carcinomas with local hyperthermia has showed that the positive effect was achieved in all patients without causing pronounced complications during the treatment. Further studies with careful quality control are required to solve the existing problems of local hyperthermia in the head and neck region before this method of treatment can be recommended for a wide clinical application.

Резюме: Комбинированное лечение с использованием ИОЛТ (интраоперационная лучевая терапия) предполагает максимально радикальное удаление основного опухолевого процесса, а возможные микрофокусы рака в прилежащих тканях, оставшиеся микрометастазы девитализировать с помощью интраоперационного облучения, основной точкой приложения которого является область большего онкологического риска. Помимо этого, использование ИОЛТ позволяет сократить время лечения и значительно снизить лучевую нагрузку на кожу и критические органы при сочетании с наружным облучением. Ключевым моментом при планировании ИОЛТ является правильный выбор однократной дозы, кроме того, при сочетании с ДГТ (дистанционная гамма-терапия) необходимо решить вопрос об изоэффективности их воздействия на нормальные ткани. Величина суммарной курсовой дозы смешанного облучения ИОЛТ и ДГТ не должна превышать 60–65 иГр, или в показателях фактора ВДФ 100–125 усл. ед. в очаге-мишени. В Томском НИИ онкологии разработана методика комбинированного лечения злокачественных опухолей полости носа и придаточных пазух с предоперационным курсом фотонной терапии в режиме среднего фракционирования дозы, последующим хирургическим вмешательством и ИОЛТ на ложе удаленной опухоли. Однократную дозу ИОЛТ определяли по формуле. Интраоперационная лучевая терапия проводилась на малогабаритном бетатроне МИБ-6Э с энергией 6 МэВ, разовая очаговая доза равнялась 10–12 Гр. Доказательства эффективности применения ИОЛТ получены при клинической апробации метода. Проведено лечение 115 больных раком полости носа Т3–4. Лечение удовлетворительно перенесли все больные. Анализ локализации рецидивов после комбинированного лечения с ИОЛТ и ДГТ показал, что дополнительное облучение зон «риска» в операционной полости позволяет снизить частоту рецидивов в этих зонах и существенно повлиять на показатели выживаемости больных. Показатели 5-летней безрецидивной выживаемости в основной и контрольной группах составили 66,2 ± 8,8 % и 40 ± 9,2 % соответственно. Накоплен собственный клинический опыт, осуществлена методологическая и методическая разработка проведения интраоперационного облучения. Проведенные исследования продемонстрировали безопасность доставки ИОЛТ при лечении пациентов с локально развитым раком головы и шеи в контексте агрессивной комбинированной терапии.

The article presents the results of combined modality treatment for stage III-IV (T3N0-2M0) laryngeal and hypopharyngeal cancers. All patients (55) were divided into 2 groups. Group I patients (n = 25) received pre-operative thermoradiation therapy and Group II patients (n = 30) received pre-operative radiation therapy alone. The follow-up period was 6-24 months. In Group I patients, partial tumor regression was achieved in 21 (84%) patients and stable disease was observed in 4 (16%) patients. In group II patients, partial tumor regression and stable disease were diagnosed in 18 (60%) and 12 (49%) patients, respectively. Local and regional recurrences occurred in 1 patient (4%) of Group I within the first year of follow-up and in 11 patients of Group II (7 within the first year and 4 within two years of followup). The 2-year overall survival rate was 100% in Group I patients and 76.7% +/- 10.1% in Group II patients. Disease-free survival rates were 96.6 +/- 3.5% and 63.3 +/- 13.9%, respectively.