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First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 (NCT03409614), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5–not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9–16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53–0.93; P = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies.

Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC.To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC.This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021.Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks.The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P .012). There were 13 secondary outcomes, including progression-free survival and adverse events.Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group.Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population.ClinicalTrials.gov Identifier: NCT04063163.

PURPOSE Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte–associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882 ) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy. PATIENTS AND METHODS Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival. RESULTS In total, 155 women (median age, 50 years [range, 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab; 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1–positive and programmed death ligand-1–negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events. CONCLUSION Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte–associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing.

After the Human Genome Project was declared complete, the strategic focus area of contemporary genetics shifted towards functional genomics whose research sphere comprises, among others, the study of noncoding DNA regions. The noncoding regions are located in heterochromatin. The functions of heterochromatin remain so far, to a considerable degree, unclear. The telomeres of the short arm of each human acrocentric chromosome (13, 14, 15, 21, 22) have satellite strands consisting of heterochromatin and are called nucleolar organizer regions (NORs). Human NORs contain from 250 to 670 copies of ribosomal RNA (rRNA) genes and only 50% of these copies are transcribed. Satellite strands in the chromatids of some acrocentric chromosomes are bound, forming “satellite associations” (SAs), which are always transcriptionally active. The phenomenon of SAs is a highly specific indicator for the structure and function of the nucleolus within the preceding interphase. In cancer, rDNA in the human genome may change. In this study, the epigenetic variability of ribosomal cistrons in lung cancer (LC) has been determined. It has been found that the frequency of chromatid SAs per cell was significantly higher (p 13 = 14 > 21 > 22. A similar phenomenon was observed for the associations of chromatids of homologous chromosomes (15:15) in patients with LC, which significantly exceeded the indicator for this type of SA in healthy middle-aged individuals (p < 0.001). The results have shown that the differential activity of satellite strands in the chromatids of chromosome 15 in patients with LC is characterized by epigenetic variability, which underlines the importance of studying SAs in terms of diagnosis and treatment strategy. The study of epigenetic variability in the activity of ribosomal cistrons in acrocentric chromatids in pathologies is a new medical area aiming at the diagnosis of diseases and determining new treatment strategies in the future.

A new technique is proposed, verified, and described for measuring photosensitivity spectra of semiconductor materials and devices in the wavelength range of 200–4100 nm utilizing an innovative setup termed “Polychromator” with a system of cut-off optical filters that provide a sharp edge of the spectrum of radiation impinging on the sample. The measured value, referred to as selective integral photosensitivity (SIPhS), is calculated for the particular subbands of the spectrum taking into account the radiation power. Certain IR spectral characteristics, measured with a monochromator, are provided for comparison. It is shown that the presented “Polychromator” measurement data do not contradict these results, and in fact, complement them. The reliability of the method is demonstrated by three types of test photodiodes fabricated using three base materials: 1) B+ ion-implanted n-Si; 2) InGaAs/InP; and 3) undoped AlGaN/GaN heterostructures. The selected materials and the devices made therefrom differ in the nature of photoresponse revealed in the various wavelength ranges. This allows for comprehensively describing the methodology. The information gained using this method as well as its advantages and ways of improving the setup are discussed.

Background Camizestrant (C), a next-generation oral selective estrogen receptor (ER) antagonist and degrader (ngSERD) has shown promising clinical activity in ER+ breast cancer (BC) in the Phase 1 SERENA-1 study1,2 with a dose-dependent safety profile. The Phase 2 randomized SERENA-2 study (NCT04214288) initially assessed three doses of C vs fulvestrant (F) in post-menopausal women with ER+ HER2˗ BC with disease recurrence or progression after ≤1 endocrine therapy (ET) in the advanced setting. Methods SERENA-2 evaluated efficacy and safety of C 75, 150 or 300 mg monotherapy QD vs F (per label). Eligible patients were randomized 1:1:1:1. The Primary objective was to determine clinical efficacy of C vs F by investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate, response duration, clinical benefit rate at 24 weeks, overall survival and safety. Patients had no prior F or oral SERD and ≤1 ET and ≤1 chemotherapy (CTX) in the advanced setting. To assess the impact of prior CDK4/6 inhibitor (CDK4/6i) treatment, randomization was stratified so that 50% of patients had prior CDK4/6i. Planned enrolment of 288 patients began in April 2020. The C 300 arm was closed after 20 patients were enrolled, changing target enrolment to 236. By August 2021, 240 patients had been randomized. Primary analysis was triggered when 108 progression events (75% maturity) had occurred in the best performing pair (C vs F) in August 2022. Efficacy analyses compared C 75 and 150 mg doses with F, with no formal analyses of C 300 vs F. 108 events for pairwise comparison vs F gave 86% power at the 2-sided 10% significance level. Primary analyses used a Cox proportional hazards model to compare PFS, adjusting for prior CDK4/6i and lung/liver metastases. ESR1 mutations (ESR1m) were detected in plasma samples using next-generation sequencing. Results 119/240 (49.6%) patients had had prior CDK4/6i therapy. At baseline, 88 (36.7%) patients had detectable ESR1m and 140 (58.3%) had lung/liver metastases. Prior CTX or ET rates in the advanced setting were 19.2 and 65.4%. Treatment-emergent adverse events (AEs) (grade ≥3) occurred in 77.0 (12.2), 90.4 (21.9) and 68.5 (13.7) % of patients in the C 75, C 150 and F arms. AEs leading to treatment discontinuation occurred in 2.7, 0 and 0% of patients in the C 75, C 150 and F arms. The most common AEs considered by the investigator to be causally related to study drug were photopsia (18.4%) and (sinus) bradycardia (13.6%) – all were grade 1 or 2. Hot flush (2.7%) and myalgia (2.7%) were the most common AEs related to F. Conclusions SERENA-2 is the first Phase 2 trial investigating multiple dose levels of an ngSERD vs F in post-menopausal women with advanced ER+ HER2˗ BC with disease recurrence or progression after ≤1 ET in the advanced setting. C at both 75 and 150 mg dose levels showed a statistically significant and clinically meaningful benefit in PFS vs F in the overall study population, and was well tolerated. The results of SERENA-2 support the further development of C in ER+ HER2- BC. Acknowledgements AstraZeneca sponsored this trial and funded medical writing support from Helen Heffron (InterComm International). References 1. Baird R, Oliveira M, Ciruelos Gil EM, et al. SABCS 2020 Virtual Meeting. Abstract PS11-05; 2. Oliveira M, Hamilton EP, Incorvati J et al. ASCO 2022 Annual Meeting, Chicago, IL, USA. Abstract 1032. Citation Format: Mafalda Oliveira, Denys Pominchuck, Zbigniew Nowecki, Erika Hamilton, Yaroslav Kulyaba, Timur Andabekov, Yevhen Hotko, Tamar Melkadze, Gia Nemsadze, Patrick Neven, Yuriy Semegen, Vladmir Vladmirov, Claudio Zamagni, Hannelore Denys, Frederic Forget, Zsolt Horvath, Alfiya Nesterova, Maxine Bennett, Bistra Kirova, Teresa Klinowska, Justin Lindemann, Delphine Lissa, Alastair Mathewson, Christopher Morrow, Zuzana Traugottova, Ruaan Van Zyl, Ekaterine Arkania. GS3-02 Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-02.

Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma.COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791.Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5-17·2) in the progression-free survival ITT population and 13·3 months (10·5-16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6-8·3) in the combination treatment group versus 4·2 months (2·8-7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44-0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7-17·7) in the combination treatment group versus 15·5 months (12·1-not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69-1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (1%) patient in the sorafenib group (general physical health deterioration), and one (1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage).Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed.Exelixis and Ipsen.

The inclusion of 7-10-year-old children in the school system occurs in the context of the interaction of two processes: activation of ontogenesis at this stage of age development and stimulation of biological and psychological adaptation of younger schoolchildren to the learning activity. The main factors negatively affecting the health of elementary school students are the following: hypokinesia, mental and psycho-emotional stress related to computer and digital learning technologies, prolonged stay in closed rooms of the educational institution rather than in the natural environment. In this regard, it is relevant to find ways to improve the adaptive capacity of children, their physical development (PD), musculoskeletal system (MS), and muscular core as a biological basis for learning activities.To determine the trends of the state of regulatory systems (RS), adaptation, and PD in primary school children in Moscow shaped by preventive physical fitness (PF) classes developed within the framework of the federal state educational standard (FSES) to improve adaptation, PD, MS, and muscular core state.A pedagogical experiment was conducted; 120 schoolchildren of both sexes in the 1st-4th forms at two Moscow schools were examined during the initial stage of the experiment. All students were engaged in preventive physical fitness classes, including game-based activities and exercises embedded in the FSES for primary schools. More than 50% of students attended extracurricular sports sections in football (17.5%), ballroom dancing (10.0%), karate (6.6%), swimming (5.8%), gymnastics (including acrobatics) (5.0%), basketball (5.0%) and figure skating (3.3%). Diagnostic methods included: anthropometric methods to measure height, bodyweight using a stadiometer and automatic medical scales; dynamometer method, in standing position, arm with dynamometer extended horizontally at shoulder level; a motor test to determine coordination abilities; diagnostics of heart rhythm variability (HRV) using Varicard-Express hardware-software complex. The calculated HRV parameters were determined: a regulatory systems activity index (RSAI) to determine the adaptive capacity of the body, and stress index (SI) to assess the subject's exposure to stress.It was demonstrated that schoolchildren in the Moscow metropolitan area are characterized by slower growth processes with activation at 8-9 years instead of 6-7 years. The baseline RSAI values in all children were at level 5, which corresponds to the state of RS stress of the body. Preventive PF classes led to improved adaptation in 7-8-year-old children. The condition of 50% of schoolchildren based on SI was optimal;Monitoring of the RS adaptation and health state allows teaching, preventive, health-improving, and recreational activities in educational institutions with respect to individual and typological features of students, as well as minimizing the negative effects of the education digitalization on the physical and mental development of schoolchildren.Включение детей 7—10 лет в систему школьного обучения происходит в условиях взаимодействия двух процессов на уровне организма: активизации онтогенеза на этом этапе возрастного развития и интенсификации биологической и психологической адаптации младших школьников к условиям учебной деятельности. Основными негативно воздействующими на здоровье младших школьников факторами являются: гипокинезия, ментальные и психоэмоциональные нагрузки при компьютерно-цифровых технологиях обучения, длительное нахождение в закрытых помещениях образовательного учреждения, а не в естественной среде. В этой связи актуален поиск путей для улучшения приспособительных возможностей организма детей, их физического развития (ФР), состояния опорно-двигательного аппарата (ОДА) и мышечного корсета как биологической основы учебной деятельности.Определить динамику состояния регуляторных систем (РС), адаптации и ФР у школьников начальных классов школ Москвы под влиянием разработанной в рамках федерального государственного образовательного стандарта (ФГСО) методики уроков физической культуры (ФК) профилактической направленности для улучшения адаптации, ФР, состояния ОДА и мышечного корсета.Проведен педагогический эксперимент, на его констатирующем (начальном) этапе обследованы 120 школьников обоего пола 1—4-х классов двух московских школ. Все школьники занимались на уроках ФК по профилактической методике, включающей игровые занятия и упражнения, встроенные во ФГОС по ФК для начальной школы. Более 50% обучающихся посещали внешкольные спортивные секции по футболу (17,5%), спортивным бальным танцам (10,0%), каратэ (6,6%), плаванию (5,8%), гимнастике (в том числе акробатике) (5,0%), баскетболу (5,0%) и фигурному катанию (3,3%). Методы диагностики включали: антропометрические методы измерения роста, массы тела с помощью ростомера и автоматических медицинских весов; метод динамометрии (в положении стоя, рука с динамометром вытянута горизонтально на уровне плеча); двигательный тест определения координационных способностей; диагностику вариабельности ритма сердца (ВСР) аппаратно-программным комплексом «Варикард-экспресс». Определяли расчетные параметры ВСР: показатель активности РС для определения адаптационных возможностей организма (ПАРС) и стресс-индекс (СИ) для оценки подверженности обследуемых стрессу.Выявлено, что для школьников младших классов в Московском мегаполисе характерно замедление ростовых процессов, активация которых наступает в 8—9 лет вместо 6—7 лет. Исходные значения ПАРС у всех детей находились на 5-м уровне, что соответствует состоянию напряжения РС организма. Профилактические занятия ФК привели к улучшению адаптации у детей 7—8 лет. Состояние 50% школьников по СИ являлось оптимальным, уМониторинг состояния РС адаптации и здоровья позволяет проводить обучающие, профилактические, оздоровительные и рекреационные мероприятия в образовательных учреждениях с учетом индивидуально-типологических особенностей учеников, а также минимизировать негативные последствия цифровизации образования для физического и ментального развития школьников.