[Pregnancy in paroxysmal nocturnal hemoglobinuria: from survival to life].

BACKGROUND: Pregnancy in paroxysmal nocturnal hemoglobinuria (PNH) patients has historically been a high-risk situation. The combination of chronic complement-mediated hemolysis caused by the disease and physiological activation of the complement system during pregnancy, significantly worsened the prognosis for the life. For a long time, there were no effective methods for the PNH treatment, and pregnancy in patients seemed to be extremely risky, as it significantly increased the risk of life-threatening complications. The advent of targeted therapy with eculizumab turned the prognosis of this disease upside down: patients began not only to survive, but also to live comparable to healthy people. A comparative analysis of the course and outcomes of pregnancy in patients with PNH treated with eculizumab and in patients without targeted therapy was carried out. AIM: The study was to evaluate the course and outcomes of pregnancy in patients with PNH, depending on the therapeutic approach. MATERIALS AND METHODS: We analyzed data from 57 pregnancies in 49 women (31 used eculizumab, 26 with supportive care only) observed at the Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology or with remote consultation (23 clinics from 19 cities of Russia). RESULTS: The high probability of pregnancy complications and its adverse outcomes outside of targeted therapy indicates the vital need for its use: all observations were accompanied by complications of varying severity. The course of pregnancy with the eculizumab is generally more favorable: an apparently higher rate of live births and a lower likelihood of complications are registered. Without increasing the incidence of complications, eculizumab significantly improves pregnancy outcomes for both mother and fetus, and does not adversely affect the health of newborns. CONCLUSION: Thus, eculizumab allows not only to increase the survival rate of patients with PNH, but also to comprehensively improve their quality of life, including the possibility of safe childbirth.

[The efficacy and safety of eculizumab biosimilar in patients with paroxysmal nocturnal hemoglobinuria. Results of a phase III randomized open-label comparative clinical trial].

AIM: To establish the equivalent efficacy and comparable safety profile of biosimilar Acveris and referent eculizumab product Soliris used for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). MATERIALS AND METHODS: Were included in the phase III multicenter 28 PNH patients, open-label clinical trial. Participants were randomized (1:1) into 2 treatment groups: investigational product (Acveris, n=14) and referent product (Soliris, n=14). Patients received eculizumab as the intravenous infusion 600 mg once a week during the first 4 weeks, 900 mg at week 5 and then 900 mg every 14 days (2 days) up to week 27 of the study. The efficacy, pharmacokinetics, pharmacodynamics, safety and immunogenicity of the compared products were analyzed after the end of 27 weeks of the study. The primary efficacy endpoint was the area under the curve LDH concentrationtime (AUCLDH) throughout the study period weeks 527. RESULTS: The difference between the mean AUCLDH values between the Acveris and Soliris groups was 5380.0 [-38 773.87; 49 533.87] U/ldays. The 95% CI limits for the difference in mean AUCLDH values between the groups fit the preset 95% CI [-146 500.9146 500.9] U/ldays and establish the equivalent efficacy of the biosimilar and referent product according to the primary efficacy endpoint. The safety profile of both Acveris and Soliris was expected and comparable according to the proportion of patients with adverse events. The formation of binding antibodies to eculizumab was not detected in both the groups. CONCLUSION: The study established the equivalent efficacy of biosimilar product Acveris and referent eculizumab product with the evidence of effective suppression of intravascular hemolysis in PNH patients along with a comparable favorable safety profile.

[Fecal microbiota transplantation for graft-versus-host disease in children and adults: methods, clinical effects, safety].

AIM: Was to evaluate clinical efficacy, adverse events and changes in the gut microbiome after fecal microbiota transplantation (FMT) in patients with gastrointestinal (GI) form of graft-versus-host disease (GVHD). MATERIALS AND METHODS: The prospective single-center study in R.M. Gorbacheva institute included 27 patients with GI GVHD after allogeneic stem cell transplantation. 19 patients received FMT, 8 patients received placebo. Clinical scales for GI autoimmune diseases were used to evaluate response. Microbiome alterations were assessed with multiplex PCR. RESULTS: After FMT higher overall bacterial mass (р=0.00088), higher bacterial numbers ofBifidobacteriumspp. (р=0.021),Escherichia coli(р=0.049) andBacteroides fragilisgr. (р=0.000043) compared to placebo group. Also higher bacterial mass was observed in patients with clinical response (р=0.0057). The bacterial mass after procedure in non-responders was compared to the placebo group (р=0.31). Partial response of GVHD was achieved faster in the FMT group compared to placebo (median 4 days vs 48 days,p=0.014). Complete response was observed in 8 (42%), 14 (74%) and 16 (84%) at 30, 60 and 90 days respectively, while in the placebo group only 0%, 1 (13%) and 4 (50%) achieved complete response at the same time points. The incidence and severity of adverse events was comparable between FMT and the placebo group. CONCLUSION: FMT in patients with refractory GI GVHD was associated with favorable clinical outcomes and recovery in certain marker bacterial populations. Multiplex PCR can be used to assess an engraftment of a donor microbiota. FMT in GI GVHD was not associated with life-threatening adverse events, but further studies are required to validate clinical efficacy.

[Results of phase Ib open multicenter clinical trial of the safety, pharmacokinetics and pharmacodynamics of first biosimilar of eculizumab in untreated patients with paroxysmal nocturnal hemoglobinuria during induction of therapy].

Currently, the main pathogenetic method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is the treatment with recombinant monoclonal antibodies that block the C5 component of the complement system. Eculizumab is the first biotechnological drug, which is a monoclonal antibody, with proven clinical efficacy and safety for the treatment of patients with PNH, which is used in world clinical practice. In Russia, in the framework of the state program Development of the pharmaceutical and medical industry for 20132020 was developed Elizaria (JSC GENERIUM) the first biosimilar of the original drug eculizumab. AIM: To evaluate the pharmacokinetic and pharmacodynamic parameters, as well as safety and immunogenicity parameters of the drug Elizara in the induction phase of therapy in previously untreated patients with PNH. MATERIALS AND METHODS: The study included 11 patients with PNH aged 26 to 75 years who had not previously received eculizumab. Each of the study participants was injected with the studied drug Elizaria at a dose of 600 mg intravenously once a week for 4 weeks. RESULTS: During the clinical study, it was noted that the concentration of the studied drug significantly increased by the time the infusion was completed and then gradually decreased to a minimum at the end of the dosing interval. The average concentration of eculizumab 5 minutes before the administration of the study drug at all visits exceeded 35 g/ml, the minimum concentration sufficient to completely inhibit intravascular hemolysis in patients with PNH. The pharmacodynamic efficacy of the drug Elizaria was confirmed by a decrease in the concentration of the membrane-attack complex (MAC) after the first infusion of the drug was maintained at stable levels until visit 5. A persistent decrease in the level of MAC and a four-fold decrease in the average values of lactate dehydrogenase to visit 5 from 1286.4 to 280.9 U/l demonstrated a marked decrease in activity and stabilization of the hemolytic process against the background of the induction of therapy with Elizaria at a dose of 600 mg once a week and confirmed the effecacy of the study drug. Among the 9 adverse events, only 5 had a relationship with the studied drug, including one serious adverse event in the form of an allergic reaction, which, according to the researcher, had a possible cause-effect relationship with the infusion of the studied drug. In 2 patients, low-titer binding anti-drug antibodies were detected without neutralizing activity during treatment with the studied drug, which may indicate its low immunogenicity. CONCLUSION: The study evaluated the pharmacokinetic and pharmacodynamic properties of the drug Elizaria in the regimen of induction therapy in previously untreated patients with PNH, confirming its efficacy. The study demonstrated the safety and low immunogenicity of the study drug.

Profiles of pro-inflammatory cytokines in allogenic stem cell transplantation with post-transplant cyclophosphamide.

Large number of studies was published about predictive value of cytokines for graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Recently, there has been a growing interest in GVHD prophylaxis with post-transplant cyclophosphamide (PTCy). Clinical data on the dynamics of proinflammatory cytokines with this prophylaxis is lacking. In this study, we have measured the levels of IL-17, IL-6, IL-8, IFN-γ and TNF-α in plasma on days -7, 0, +7, +14 and after engraftment in 20 patients with acute GVHD and 40 matched control patients with PTCy-based prophylaxis. Low levels of IL-8 (p=0.04) on day +7 and IFN-γ (p=0.03) after engraftment were associated with grade II-IV acute GVHD. The same pattern was observed for severe acute GVHD. Low IFN-γ after engraftment was also associated with increased non-relapse mortality (p=0.014). No impact of cytokine levels on overall survival and relapse incidence was observed (p>0.05). In conclusion, the dynamics of IL-8 and IFN-γ in GVHD patients after PTCy was different from previously reported after conventional prophylaxis.

[Hygienic assessment of the impact of diesel fuel on the ordinary black soil microbiocenosis].

The main sources of soil contamination by oil products in the Dnepropetrovsk region are oil depots, gas stations and all types of transport that use and transport oil. The diesel fuel was found to be the one of the priority multicomponent components of the petroleum products, so it there was occurred the necessity for the hygienic regulation of the oil component in order to monitor a multicomponent composition ofpetroleum products in the study of complex influence of environmental factors on health population. In the study of the effect of various concentrations of diesel fuel on the number of total bacterial count (TBC) as the threshold for general sanitary indicator of hazard, there was recommended the concentration of4000 mg/kg, which oppressed the vital activity of soil microorganisms by 50-27.3% for the first 2 weeks of the laboratory experiment.

[Evaluation of the content and migration of heavy metals in components of river ecosystems' of mining territories of the Republic of Bashkortostan].

Exploration and development of mineral deposits in the Transurals of the Republic of Bashkortostan are accompanied by a comprehensive environmental impact. Ones of the most vulnerable elements of the landscape are the surface water bodies used for fishery purposes, recreation and household needs of the population. Extraction and processing of ores lead to the contamination of aquatic ecosystems by heavy metals (HM), which by passing into a pond, can actively be involved in the cycling of matter and migrate via food chains to the human under the consumption of fish products. Possessing by cumulative properties, HM can express mutagenic, teratogenic and carcinogenic properties. The aim of research was the study of the impact of mining facilities on the content of the priority HM in the components of river ecosystems in the Transurals of the Republic of Bashkortostan and the development of a complex of preventive measures on the improvement of the human environment. There was studied the content of Zn, Cu and Cd in the water, bottom sediments and phytomass of Elodea canadensis Michx. The measurements of mass concentrations of metals were performed by stripping voltammetry with the use of the STA device. The results showed that for the cross-sections there is typical the following descending series of elements in the river components: Zn > Cu > Cd. In water samples there is observed the exceedance of standards for water bodies of potable, cultural and community water use and fishery basins. The concentration of zinc varies in the range of 0.016-5.24 mg/dm; copper - 0.0024-0.095 mg/dm; cadmium - 0.0001-0.019 mg/dm. In bottom sediments, in general, the content of metals in comparison with control plots is increased to the tenfold value. The meaning of mobile forms of zinc in the ground varies in the range of 0.81-9.62 mg/kg; copper - 0.12-18.69 mg/kg; cadmium - 0.00013-0.092 mg/kg. The zinc concentration in above-ground phytomass of Elodea canadensis compared to control increases by 2-3.5 times, copper - 4-8 times, cadmium - 2-7 times. Univariate analysis of variance confirmed the accuracy of the impact of the degree of contamination on the accumulation of metals by Elodea canadensis. The results testify to the potential danger to health of water bodies of the region's population.

Artificial intelligence methods to estimate overall mortality and non-relapse mortality following allogeneic HCT in the modern era: an EBMT-TCWP study.

Allogeneic haematopoietic cell transplantation (alloHCT) has curative potential counterbalanced by its toxicity. Prognostic scores fail to include current era patients and alternative donors. We examined adult patients from the EBMT registry who underwent alloHCT between 2010 and 2019 for oncohaematological disease. Our primary objective was to develop a new prognostic score for overall mortality (OM), with a secondary objective of predicting non-relapse mortality (NRM) using the OM score. AI techniques were employed. The model for OM was trained, optimized, and validated using 70%, 15%, and 15% of the data set, respectively. The top models, "gradient boosting" for OM (AUC = 0.64) and "elasticnet" for NRM (AUC = 0.62), were selected. The analysis included 33,927 patients. In the final prognostic model, patients with the lowest score had a 2-year OM and NRM of 18 and 13%, respectively, while those with the highest score had a 2-year OM and NRM of 82 and 93%, respectively. The results were consistent in the subset of the haploidentical cohort (n = 4386). Our score effectively stratifies the risk of OM and NRM in the current era but do not significantly improve mortality prediction. Future prognostic scores can benefit from identifying biological or dynamic markers post alloHCT.

Tandem autologous hematopoietic stem cell transplantation for embryonal brain tumors in infants and very young children.

Withdrawal of radiotherapy in patients with brain tumors under four years decreases chance for cure. AutoHSCT in a series of pilot studies demonstrated a potential to improve outcomes in these patients. The study included 50 patients with median age of 39 months (7-53). Medulloblastoma (n = 28, 56%), ETMR (n = 9, 18%) and other histological types (n = 13, 26%) were most commonly diagnosed. Forty two patients (84%) received tandem autoHSCT by HIT-MED protocol, and single autoHSCT was performed in eight children (16%). Adjuvant radiotherapy was administered in 25 (50%) children and treatment of relapse included radiotherapy in 6 (12%). Median follow-up was 39.6 months (6-121). Long-term CIR was 37%, and TRM - 6%. Five-year OS was 71% in medulloblastoma, 37% in ETMR and in other tumors - 51% (p = 0.07). Irradiation-free OS at 5 years for children with medulloblastoma was 24%. For the whole cohort of CNS tumors, independently of histology, OS and PFS at five years were 60% and 46%, respectively Young children with medulloblastoma, following tandem autoHSCT, demonstrate OS comparable to older children. Patients with other histological types demonstrate suboptimal long-term survival rates after autoHSCT and one should assess whether these patients benefit from autoHSCT.

[Retropharyngeal abscess in an adult patient complicated by purulent meningoencephalitis].

The authors report a case of successful treatment of an adult woman presenting with retropharyngeal abscess complicated by purulent meningoencephalitis. Peculiarities of diagnostics and treatment of retropharyngeal abscess in adult patients are discussed.

[Polyclonal rabbit antithymocyte globulin (thymoglobulin): immunomodulatory effects and new aspects of its clinical application].

Antithymocyte immunoglobulins remain to be one of the most effective immunosuppressants used in transplantology and in the treatment of autoimmune diseases. The unique features of the mechanisms of individual antithymocyte globulin preparations should be borne in mind. Due to its polyclonal nature, thymoglobulin provides a wide spectrum of diverse immunomodulatory effects, which is the basis for its wide use in order to reduce the risk for graft rejection and a graft-versus-host reaction and to treat aplastic anemia.

[Diagnosis and treatment of aquired aplastic anemia].

AIM: To analyse the results of diagnosis and treatment of patients with aquired aplastic anemia (AA) in one center. MATERIAL AND METHODS: All AA patients, diagnosed and treated in one clinic in 1998-2005, were included in the trial. In severe and very severe AA (SAA/VSAA) the patients (n = 19) received combined immunosuppressive therapy (IST) with antithymocytic globulin (ATG) and cyclosporin A (CsA), in non-severe AA (NSAA) the patients (n = 9) were given monotherapy with CsA. Allogenic transplantation of bone marrow (alloTBM) was made in 4 young patients with SAA/VSAA. RESULTS: The diagnosis of AA was established in 33 patients (19 males and 14 females): NSAA in 9, SAA in 19, VSAA in 5, idiopathic--in 26, posthepatic--in 5, associated with pregnancy--in 2 patients. Age median was 20 years (13-53). The clone of paroxysmal nocturnal hemoglobinuria (PNH) was identified in 7 of 33 patients (21%), antigen HLA-DRB1 *15 in 6 of 11 patients (55%). In median of 26-month follow-up 31 patients (94%) were alive. In IST, complete or partial remissions were obtained in 88% patients. Median of the interval to achievement of transfusion independence made up 2.5 months. All the patients after alloTBM are in complete remission, chronic extensive transplant against host reaction was observed in one case. CONCLUSION: Introduction of updated protocols provides long-term survival of more than 80% AA patients. To optimize treatment outcomes, it is necessary to include newly diagnosed AA patients into ongoing multicenter studies.

[The tolerance to exogenous energy substrates in the post aggression period in children]. / Tolerantnost' k ékzogennym énergeticheskim substratam v postagressivnom periode u detei.

Pharmacokinetic parameters of glucose and fatty emulsion elimination from the vascular bed have been studied using prolonged glucose-fat tolerance test. Forty-four children have been examined upon various aggressive interventions. Surgical intervention or mechanical trauma have been regarded as an aggressive factor. It has been established that children in the post aggression period are characterized by a pronounced increase of exogenous fatty emulsion tolerance and a reduction of glucose tolerance. The most marked changes in the elimination of basic energy substrates are observed in the first three days after the aggression.

[Experience in tube feeding of children in intensive care]. / Opyt primeneniia zondovogo pitaniia u detei v usloviiakh intensivnoi terapii.

Tube feeding was used in 97 children aged 0 to 8 years hospitalized in intensive care wards. Daily rations were calculated on the basis of daily requirements. The feeding was carried out continuously or intermittently. Algorithms of the methods are presented. If requirements to tube feeding are strictly adhered to, the incidence and severity of complications are minimal.

[High epidural anesthesia in the correction of congenital heart defects with artificial circulation in children]. / Vysokaia épidural'naia anesteziia pri korrektsii vrozhdennykh porokov serdtsa s iskusstvennym krovoobrashcheniem u detei.

Effects of high thoracic epidural anesthesia (TEA) on hemodynamics were studied in patients undergoing cardiopulmonary bypass (CPB) surgery. In 7 patients aged 3-7 years, TEA was used as an adjunct to standard oxygen-air-isoflurane anesthesia. We prefer using a combination of lidocaine with fentanyl for epidural anesthesia. Usually we take a loading dose of 4.5 mg/kg of lidocaine and 1 microgram/kg of fentanyl, which is followed after 40-50 min by 3.5 mg/kg lidocaine and 1 microgram/kg fentanyl. TEA ensures good pain relief and hemodynamic stability and can be accepted as a safe and effective anesthetic technique in combination with inhalation anesthesia in children subjected to CPB.

[The effect of pulp extirpation on the function of the hard dental tissues]. / Vliianie depul'pirovaniia na sostoianie tverdykh tkanei zuba.

The authors analyze the results of clinical and experimental studies of the status of hard dental tissues before and after pulp removal. The findings evidence that Ca and P levels reduce and O2 and oxide levels increase in the hard tissues of pulpless teeth, this probably resulting in changed color and friability of pulpless teeth. These data may be useful in dental surgery when forming carious cavities in pulpless teeth and in orthodontics to make pulp insertions with due consideration for the friability of pulpless teeth.