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Objective: To investigate the effect of two fractionation regimens on survival in patients with Grade IV gliomas depending on rapid early progression (REP)., Material and Methods: Fractionation with prescribed doses of 2 and 3 Gy was alternately used in 140 patients with morphologically confirmed Grade IV glioma using a pairwise modeling strategy., Results: REP was diagnosed in 60 (42.9%) out of 140 patients with Grade IV gliomas and 55 (45.5%) out of 121 patients with glioblastomas. Fatal outcome was observed in 111 (79.3%) patients, 99 (70.7%) ones died from progression of glioma. In case of no REP, the median overall survival as of December 2023 was 32.20 (95% CI 25.7-38.7) months, with REP - only 16.03 (95% CI 13.5-18.6) months ( p <0.0001). Median survival was slightly lower in patients with glioblastoma - 28.2 and 16.5 months, respectively ( p <0.0001)., In patients with Grade IV gliomas and no REP, 3 Gy ( n =40) fractionation regimen was followed by median overall survival 44.98 (95% Cl 15.3-74.6) months, 2 Gy ( n =40) - 20.99 (95% CI 9.2-32.7) months ( p =0.027). In case of glioblastoma, differences between fractionation regimes lose significance - medians 33.7 and 19.7 months, respectively ( p =0.081). According to multivariate analysis, 3 Gy fractionation regimen is more effective than standard radiotherapy ( p =0.009) in patients without REP, while significance of isoeffective doses <59.5Gy≥ is slightly lower ( p =0.020). Radiotherapy on the background of temozolomide is equally important ( p =0.007)., In patients with grade 4 gliomas and REP, 3 Gy ( n =30) fractionation regimen was followed by median overall survival 17.18 (95% CI 14.2-20.2) months, 2 Gy ( n =30) - 12.88 (95% CI 5.4-20.3) months ( p =0.849). In case of glioblastoma, Cox model classification matrix looks as follows: fractionation variant ( p =0.423), isoeffective dose <59.5Gy≥ ( p <0.0001), temozolomide during radiotherapy ( p =0.701), functional status ( p =0.485)., Conclusion: In patients with Grade IV gliomas and no REP, 3 Gy fractionation regimen has significant advantages over standard radiotherapy regarding overall survival. In case of more aggressive course of tumor (REP), higher single dose does not improve treatment outcomes. Isoeffective dose ≥59.5Gy is of great importance.

Objective: To analyze the influence of continued growth of glioblastoma between surgery and radiotherapy on subsequent survival., Material and Methods: Fractionation with a prescribed dose of 2 and 3 Gy was alternately applied using a pairwise modeling strategy in 140 patients with morphologically confirmed glioblastoma (grade 4). Early progression of disease between microsurgery and radiotherapy was diagnosed in 60 patients, and no tumor growth was noted in 80 patients., Results: The minimum period of early progression was 0.33 months, maximum - 4.27 months (median 1.1 (95.0% CI: 0.9-1.3)). The most significant predictors of early progression were resection quality ( p <0.0001), large residual tumor ( p =0.003) and no MGMT promoter methylation ( p =0.001). IDH1 status did not affect early progression. In residual tumor ≥1.2 cm 3 , the median period of early progression was 1.9 months ( n =70; 95% Cl: 1.3-2.5), <1.2 cm 3 - 3.5 months ( n =70; p =0.019). After resection of less than 76% of tumor, this value was 1.1 months ( n =28), ≥76% - 3.1 months ( n =112; p =0.006). Without tumor growth, the median overall survival was 33.41 months ( n =80; 95% Cl: 27.1-39.7), with early progression - 16.03 months ( n =60; 95% Cl: 13.5-18.6; p <0.0001). This predictor was significant for fractionation with a prescribed dose of 3 Gy ( p <0.0001) and standard radiotherapy (2 Gy; p =0.028). By December 2022, 26 out of 40 patients without early progression survived two years after treatment (3 Gy) (65%, median not reached). In case of fractionation with a prescribed dose of 2 Gy, 20 patients survived this period (50%, median reached)., Conclusion: Almost half of patients with newly diagnosed glioblastoma develop early progression between microsurgery and radiotherapy. Therefore, patients with and without early progression should be probably assigned to different prognostic groups regarding overall survival.

Objective: To develop a prognostic scale suitable for distinguishing a group of poor prognosis with low survival prior to deciding on the appropriateness of radiotherapy., Material and Methods: We analyzed only those patients with reliably known date of death after previous WBRT to determine objective criteria allowing WBRT abandonment. WBRT was carried out in 100 patients with non-small cell lung cancer ( n =49) and breast cancer ( n =51) and confirmed metastatic brain disease. All procedures have been conducted at the radiotherapy department of the Herzen Moscow Oncology Research Institute since January 2014. The prescribed dose of 3 Gy was ensured in all patients. Total focal dose of 30 Gy delivered in 10 fractions was achieved in 77 cases, 36 Gy delivered in 12 fractions - in 23 cases., Results: Death date was recorded in all patients ( n =100) by January 2020. In the electronic SPSS database, death information was digitized for each patient up to 2-24 months, respectively. We identified eight the most significant factors by using of correlation analysis: primary tumor (controlled (0), uncontrolled (1)), number of brain metastases (<17 (0), ≥17 (1)), volume of brain metastases (<48 cm 3 (0) ≥48 cm 3 (1)), extracranial control (no metastases (0), metastases with positive dynamics after chemotherapy (1), continued growth after chemotherapy (2)), metastatic lesion of liver and lungs, respectively (no (0), yes (1)), functional status (≥ 70% (0), ≤ 60% (1)), carcinomatosis of the meninges (no (0), yes (1)). A simple summation of digital variables for factors 1-8 in each patient resulted a prognostic scale. Low risk of early mortality after WBRT was determined by 0-3 scores, intermediate risk - 4-5 scores, high risk - 6-9 scores. According to univariate analysis (log-rank 0.000), median survival rate varied in these groups: low risk - 15.5 months (11.4-19.7), intermediate risk - 5.26 months (4.6-6.0), high risk - only 1.35 months (0.9-1.8). Only 1 out of 15 high-risk patients (6-9 scores) survived 3 months (3.25 months). Inclusion of all eight factors into multivariate analysis revealed significant impact of only risk group on short-term survival. A 3-month survival in the high-risk group was 20.6 times lower ( p =0.002) compared to the low and intermediate risk groups., Conclusion: High significance of prognostic model and low informative value of each of the included factors emphasize the advisability of determining risk groups for short-term survival according to the suggested scale for each patient scheduled for WBRT. A simple assessment of separate predictors is pointless to decide whether WBRT is necessary.

Hypofractionation has the dual advantage of increased cell death with a higher dose per fraction and a reduced effect of accelerated tumor cell repopulation due to a shorter overall treatment time. However, the potential advantage may be offset by increased toxicity in the late-responding neural tissues. Recently, investigators have attempted delivering radical doses of HFRT by escalating the dose in the immediate vicinity of the enhancing tumor and postoperative surgical cavity and reported reasonable outcomes with acceptable toxicity levels. Three different studies of high-dose HFRT have reported on the paradoxical phenomenon of improved survival in patients developing radiation necrosis at the primary tumor site. The toxicity criteria of RTOG and EORTC have defined clinically or radiographically suspected radionecrosis as Grade 4 toxicity. However, most patients diagnosed with radiation necrosis in the above studies remained asymptomatic. Furthermore, the probable association with improved survival would strongly argue against adopting a blind approach for classifying radiation necrosis as Grade 4 toxicity. The data emerging from the above studies is encouraging and strongly argues for further research. However, the majority of these studies are predominantly retrospective or relatively small single-arm prospective series that add little to the overall quality of evidence. Notwithstanding the above limitations, HFRT appears to be a safe and feasible strategy for glioblastoma patients.

A novel, previously unknown cip gene of Pseudomonas aeruginosa phage D3112 was discovered. The cip gene is responsible for inhibiting the intracellular growth of the related heteroimmune phage B39 of P. aeruginosa. It was shown that the cip gene product inhibits replication of the B39 genome, interacting, apparently, with the definite s+ site in the phage B39 genome. Mutants cip- of phage D3112, incapable of inhibiting the growth of phage B39, and B39 mutants, insensitive to the action of the cip gene product of phage D3112, were isolated.

Human placenta RNase inhibitor has been shown to suppress the interfering ribonucleases, virtually not affecting the RNase H activity. This allows the usage of the inhibitor in the course of site-specific cleavage of high molecular weight RNAs by ribonuclease H.

Mutants and recombinants of transposable Pseudomonas aeruginosa bacteriophage B39 with a specific phenotype Pde- (pleiotropic developmental effect) were studied. Pde- phages produce clear minute plaques on lawns of P. aeruginosa PAO1 and fail to grow in cells of PAO1 harbouring Rms 163 (Inc P5) plasmid. Pde+ character is under control of the two loci in phage genome which were designated pdeX and pdeY. In hybrid phages the pdeX and pdeY loci originating from different transposable phages (pdeX from B39 and pdeY from PH132) do not accomplish their function and, as a result, the hybrid phages have the Pde- phenotype. The frequency of integration (f.o.i.) of Pde- phages into bacterial chromosome is lower than f.o.i. for Pde+ phages, as well as the frequency of stable lysogenization of infected bacteria; lytic development of the Pde- phages is also limited. The great difference among the transposable phages in their reaction to the presence of Rms163 plasmid is caused by some differences in the specific rms site in the phage genome. The site is located inside the interval 1.1-3.9 kb of the physical genome map, being closely linked to cI gene of phage B39. The growth of Pde- phages in cells with Rms163 can be restored, due to additional mutations in phage genes affecting lysogenization.

Bacterial cells lysogenic for D3112, a transposable Pseudomonas aeruginosa phage restrict the growth of a related heteroimmune B39 phage. The lysogens are divided into two different types PAO(D3112). In the lysogens of the type I the efficiency of B39 growth only decreases slightly, the lysogens of the type II restricting completely the growth of this phage (e.o.p. is less than 10(-7). As shown by the results of Southern hybridization experiments, lysogens of the type I are monolysogens, while those of the type II are double or polylysogens. Restriction of B39 in PAO(D3112) is caused by expression of a locus in the D3112 genome. The locus has been termed as cip (control of interaction of phages). The cip locus was mapped at the interval 1.3-2.45 kb of the D3112 physical map using different deletion derivatives of D3112. Expression of cip only takes place in the prophage state and not during the phage lytic development. When expressed, cip affects the early steps in the growth of B39 lowering the level of integration and transposition processes; the effect is not dependent on the way of initiation of the lytic cycle (through prophage induction or infection).

Using a large group of newly isolated deletion mutants of prophage D3112 the location of all known mutations of D3112 phage was more precisely defined. The mutations affecting establishment of lysogenic state were mapped in two regions of the genome- 0-1.3 and 29-30 kb. The replicative A gene is mapped between 1.3 and 4.9 kb, the second replicative B gene being situated on the right of the A gene, between 4.9 and 9.4 kb. The C gene which is responsible for positive regulation of phage late genes' expression is mapped within the 9-12 kb region. It is suggested that promoter of the gene C is situated within the same interval. Mutations were isolated in the Lys gene which is responsible for host cell lysis. The gene is located within the interval 14-22 kb of the physical map. The order of morphogenetic genes in the late genome region was also established.

The influence of Rms163 plasmid on lysogenization of Pseudomonas aeruginosa cells by B39 phage was studied. Plasmid Rms163 was shown to increase the frequency of lysogenization of PAO1 cells 7-8 times. C-mutants of B39 phage were isolated. According to complementation test, c-mutants were distributed into two groups--cI and cII/III. The product of cI is essential for establishment and maintenance of lysogenic state, cII/cIII product being only necessary for establishment of lysogenization. The mutants with special characteristics were isolated: B39cx1 phage carries a mutation which seems to be located on a regulatory site essential for establishment of lysogenic state. The region of the B39 genome responsible for interaction with Rms163 plasmid was mapped. Possible mechanisms of Rms163 plasmid interference with transposable B39 phage are discussed.