Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials.

BACKGROUND: The phase III MONALEESA trials tested the efficacy and safety of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date, we identified potential biomarkers of response to ribociclib. PATIENTS AND METHODS: Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival (PFS) was carried out to identify potential biomarkers of response to ribociclib. RESULTS: Multiple frequently altered genes were identified. Alterations in ERBB2, FAT3, FRS2, MDM2, SFRP1, and ZNF217 were associated with a greater PFS benefit with ribociclib versus placebo. Patients with high tumour mutational burden (TMB) and with ANO1, CDKN2A/2B/2C, and RB1 alterations exhibited decreased sensitivity to ribociclib versus placebo. CONCLUSIONS: Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted. GOV IDENTIFIERS: NCT01958021, NCT02422615, NCT02278120.

Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival.

BACKGROUND: Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months). PATIENTS AND METHODS: This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2- ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling). RESULTS: Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) [hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90]. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug-drug interaction between ribociclib and fulvestrant or new safety signals were observed. CONCLUSIONS: This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2- ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy.

[Catering for client groups during the XXII Olympic winter games and XI Paralympic winter games of 2014 in Sochi].

The problems of catering control various client groups during the XXII Olympic Winter Games and XI Paralympic Winter Games of 2014 in Sochi is one of the priorities of the sanitary and epidemiological welfare of the population during mass events. The data on the order of nutrition of guests and participants of the games, control of food items, sanitary and microbiological monitoring of drinking water, food raw materials and products are presented. It is noted that the ongoing supervisory activities contributed to the sanitary and epidemiological well-being during the Games. The purpose of this study was to lighting modern achievements in the field of nutrition and food microbiology in the period of the Olympic Games and the determination of their value to the further improvement and use at when conducting mass gatherings.

[ORGANIZATION OF THE QUALITY CONTROL OF PLACEMENT AND ACCOMMODATION OF PARTICIPANTS ATTENDANTS AND GUESTS OF THE XXII OLYMPIC WINTER GAMES AND XI PARALYMPIC WINTER GAMES OF 2014 IN THE RESORT CITY OF SOCHI].

There is presented the analysis of activities of the Federal Service for Supervision of Consumer Rights protection and Human Welfare to ensure adequate conditions of accommodation of the participants, attendants and guests of the XXII Olympic Winter Games and XI Paralympic Winter Games of 2014 in the Resort city of Sochi according to regulated requirements. There were detected ways of the strengthening the supervision for the quality of the accommodation during mass sports activities for the assurance of the rights for consumers.

[Analysis of foreign experience of maintenance of biological safety of the Olympic Games].

The analysis of the international experience in providing measures of health and disease safety at the Olympic Games was done. The stages of the formation of bio-security system at public events were considered, including measures to prevent infection outbreaks, the use of computer and information technologies.

[The epidemiological situation in the Republic of Abkhazia in 2013-2014 and Rospotrebnadzor participation in activities for its stabilization].

Official statistics of Republican SES on infectious diseases are used. The characteristics of the current epidemiological situation in the Republic of Abkhazia is given. The analysis of infectious dis- eases from 2012 to 2014 is presented. It was found that the most widespread infectious diseases are acute respiratory viral and acute intestinal infection. During the analyzed period in the country outbreaks of dysentery, whooping cough and measles were reported. Epidemic threat is the presence of active natu- ral foci of infectious diseases and permanently disadvantaged anthrax points on the territory ofAbkhazia. Activities carried out by the Ministry of Health of the Republic of Abkhazia with the help and active participation of Rospotrebnadzor contributed stabilization the epidemiological situation.

[Epidemiological risk of introduction of dangerous and exotic infectious diseases on the territory of the XXII Olympic Winter Games and XI Paralympic Winter Games 2014 in Sochi].

To assess the epidemiological risk of introduction of serious infectious diseases in the pre-Olympic period defined list of dangerous and exotic infections and held assessment of potential danger threatening. Initial external information to assess the potential risk of skidding were reports, forecasts, posted on the official websites. The risk of skidding and epidemiological complications conditionally designated as high, moderate and minimal risk importation of measles virus-Rate was considered as high. In confirmation of the forecast for the period of the Olympic Games in Sochi have been registered about 100 cases of measles. Moderate risk of importation was determined for poliomyelitis due to wild poliovirus, Lassa fever, cholera, plague, and the minimal--for Dengue fever, yellow fever, the Middle East and respiratory syndrome, diseases caused by viruses Marburg and Ebola. Based on of analysis of previous Olympic Games and subsequent co-events related to the activity of the infectious diseases in the world, mate-cluded that even a slight risk of importation of infectious diseases requires maximum alertness and readiness to conduct adequate epidemiological issues incorporated.

Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†.

BACKGROUND: The BOLERO-2 study previously demonstrated that adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) by more than twofold in patients with hormone-receptor-positive (HR(+)), HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors (NSAIs). The overall survival (OS) analysis is presented here. PATIENTS AND METHODS: BOLERO-2 is a phase III, double-blind, randomized international trial comparing EVE 10 mg/day plus EXE 25 mg/day versus placebo (PBO) + EXE 25 mg/day in postmenopausal women with HR(+) advanced breast cancer with prior exposure to NSAIs. The primary end point was PFS by local investigator assessment; OS was a key secondary end point. RESULTS: At the time of data cutoff (3 October 2013), 410 deaths had occurred and 13 patients remained on treatment. Median OS in patients receiving EVE + EXE was 31.0 months [95% confidence interval (CI) 28.0-34.6 months] compared with 26.6 months (95% CI 22.6-33.1 months) in patients receiving PBO + EXE (hazard ratio = 0.89; 95% CI 0.73-1.10; log-rank P = 0.14). Poststudy treatments were received by 84% of patients in the EVE + EXE arm versus 90% of patients in the PBO + EXE arm. Types of poststudy therapies were balanced across arms, except for chemotherapy (53% EVE + EXE versus 63% PBO + EXE). No new safety concerns were identified. CONCLUSIONS: In BOLERO-2, adding EVE to EXE did not confer a statistically significant improvement in the secondary end point OS despite producing a clinically meaningful and statistically significant improvement in the primary end point, PFS (4.6-months prolongation in median PFS; P < 0.0001). Ongoing translational research should further refine the benefit of mTOR inhibition and related pathways in this treatment setting. TRIAL REGISTRATION NUMBER: NCT00863655.

Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2.

BACKGROUND: In the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study. PATIENTS AND METHODS: Patients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations. RESULTS: The safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%). CONCLUSIONS: Most EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education. TRIAL REGISTRATION NUMBER: NCT00863655.

[Epidemiologic situation on dangerous infectious diseases on the territory of Republic of Abkhazia].

Data from literature and results of epizootological examination of the territory of Republic of Abkhazia in 2011 and 2012 that confirm the presence in the republic of natural foci of hemorrhagic fever with renal syndrome, West Nile fever, Crimean hemorrhagic fever, tick-borne encephalitis, Q fever, tahyna, inkoo, bhanja, sindbis fever, anaplasmosis, tick-borne borreliosis, tularemia and leptospirosis are presented. Rabies and anthrax are actual for Abkhazia. Spread of Aedes aegypti mosquitos in the republic may become a threat to the epidemiological welfare of the region in case of introduction of dangerous arbovirus infections.

[Increase in efficacy of antibiotic therapy of anthrax under experimental conditions]. / Povyshenie éffektivnosti antibiotikoterapii sibirskoi iazvy v éksperimente.

The results of experimental therapy of antraxis infected mice with cefazoline (kefzol) and ampicillin incapsulated into liposomes are presented. Protective activity of the same free antibiotics combinated with amixine and leukinferone was evaluated also. Treatment with liposomal cefazoline enhanced mice survival upto 60 per cent, and life period upto 1.3 +/- 0.3 days. After liposomal ampicillin administration for 3 times the same indices were 60 per cent and 6.5 +/- 0.9 days, after 2 times administration--80 per cent and 14 +/- 1.8 days when compared to the groups of the animals treated with free antibiotics. It was shown that administration of ampicillin with amixine or with leukinferone provided enhanced mice survival upto 20 per cent, administration of cefazoline with leukinferone--upto 30 per cent.

[Effect of inhibitors of energy-dependent Ca2+-transporting systems on ATP-hydrolase activity of smooth muscle actomyosin]. / Vliianie ingibitorov énergozavisimykh Ca2+-transportiruiushikh sistem na ATP-gidrolaznuiu aktivnost' aktomiozina gladkoi myshtsy.

Comparative investigation of of smooth muscle actomyosine ATP-ase sensitivity to some inhibitors of energy-dependent Ca(2+)-transporting systems has been carried out. It is proved that the ATP-ase of actomyosine is nonselectively inhibited by thapsigargin (imaginary inhibition constant Ki is equal 29.4 +/- 5.2 nM), cyclopiazonic acid (Ki = 626 +/- 118 nM), eosin Y (Ki = 70 +/- 14 nM) and p-chlormercurybenzoate (Ki = 380 +/- 151 nM). The data obtained could be used for the further development of the ideas about regularities of Ca(2+)-dependent control of the smooth muscles contraction-relaxation.

[Effect of incubation medium dielectric permeability on enzymatic activity of functionally different ATPases of smooth muscles]. / Vliianie diélectricheskoi pronitsaemosti sredy inkubatsii na fermentativnuiu aktivnost' funktsional'no razlichnykh ATP-az gladkoi myshtsy.

Some organic solvents (2-10%) have been comparatively studied for their effect on purified transporting Ca2+, Mg(2+)-ATPase, solubilized from the plasma membrane of smooth muscle cells and on actomyosine ATPase of the smooth muscle. The inhibiting effect of solvents on the initial maximum specific activity of Ca2+, Mg(2+)-ATPase corresponds to the sequence dioxane > acetone > ethanol > dimethyl sulfoxide (DMSO). Like the case with Ca2+, Mg(2+)-ATPase, dioxane inhibits actomyosine ATPase; acetone, ethanol and DMSO stimulate ATP-hydrolase reaction which is catalyzed by the complex of contractile proteins. It is proved that the effect of the decrease of ATPase activity with decrease of incubation medium polarity is exceptionally determined by the value of incubation medium the dielectric permeability. This effect is independent of chemical nature of organic solvents which were used with the aim to obtain the corresponding values of D. It is supposed that the cause of activity inhibition of solubilized transporting Ca2+, Mg(2+)-ATPase under the effect of dioxane, acetone, ethanol and inhibition of activity of actomyosine ATPase as affected by dioxane is mainly connected with the increase of electrostatical interaction between opposity charged active centre of ATPase and the product (products) of ATP-hydrolase reaction (Mg ADP-, HPO4(2-)), which is induced by the decrease of incubation medium polarity (the decrease of D value). Stimulating effect of acetone and ethanol on actomyosine ATPase is probably determined by superposition of two components: that connected with direct effect of these solvents on the protein catalyst (interaction with enzyme with the future break of hydrogen and hydrophobic bonds in the protein and its "fluffing") and "electrostatic component" determined by the change of D value of the incubation medium. Possible role of electrostatic interactions between ATPases and reagents as the factor of non-specific control of catalytic activity of these enzymes is discussed.

[Effect of temperature on superprecipitation of actomyosin of myometrial smooth muscle and reactions of ATP hydrolysis catalyzed by this protein]. / Vliianie temperatury na superpretsipitatsiiu aktomiozina gladkoi myshtsy miometriia i reaktsiiu gidroliza ATP, kataliziruemuiu étim belkom.

The experiments carried out on the preparation of myometrium actomyosin were carried out. The reaction of superprecipitation of this protein and ATP hydrolysis were studied as affected by temperature. For the both processes the value of temperature optimum is 45 degrees C. The value of activation energy Ea is equal to 20 +/- 3 and 23 +/- 3 kJ/mol for the reaction of superprecipitation and ATP hydrolysis, respectively. Preincubation of actomyosin (45-60 degrees C, 1-5 min) in the medium not including ions of Ca, Mg and ATP with following introduction of the components to this medium and ten-minute incubation of protein in it causes the inhibition of the both reactions at the incubation temperature 45 degrees C and their stimulation at the incubation temperature 55 and 60 degrees C. Data obtained are discussed with regard for the structure organization of actomyosin of the smooth muscle.

[The calcium pump in the sarcolemma controls smooth muscle relaxation]. / Kal'tsievyi nasos sarkolemmy kontroliruet rasslablenie gladkoi myshtsy.

In order to identify the functional role of the sarcolemma calcium pump in the control over smooth muscle relaxation there was studied the effect of temperature on relaxation kinetics of myometrium carbachol contracture, actomyosin superprecipitation isolated from this object and Mg2+, ATP-dependent transport of Ca2+ in the fraction of uterus sarcolemma vesicles. The activation energies of the processes under study were determined in comparison. It was concluded from the evidence obtained that relaxation of the smooth muscle contracture is controlled by the stimulated temperature increase and by Na(+)-independent trans-sarcolemma release of Ca2+ from the myocytes sensitive to La3+ effect. The release is provided by the calcium pump of the plasmic membrane.

[Reaction of glycine with acetoacetate and various properties of the catalyzing enzyme from the rat liver]. / Reaktsiia glitsina s atsetoatsetatom i nekotorye svoistva kataliziruiushchego ee fermenta iz pecheni krys.

The enzymic interaction between acetoacetate and glycine which are added outside is established to occur in the tissue homogenates of the liver, kidneys and spleen of rats. The interaction leads to a decrease of the both components in the equivalent quantities. Homogeneous crystalline preparations of the enzyme catalyzing the above mentioned reaction are isolated from the liver tissues and purified. Certain properties of the enzyme are studied.