Unfavorable Disease Outcome Research Articles

Years of potential life lost due to hepatitis B with or without Delta agent in the Kyrgyz Republic

Recent studies indicate that a marked percentage of chronic viral hepatitis B patients is coinfected with hepatitis D virus known to accelerate the progression of liver disease and contribute to unfavourable disease outcome. Data on premature mortality assessed by the Lost Years of Potential Life (LYPL) indicator, provide the most accurate social burden estimate for such coinfection able to contribute to strengthening viral hepatitis control measures. The aim of the study was to conducting comparative LYPL analyses due to acute and chronic hepatitis B infection without and with delta agent in the Kyrgyz Republic in the years 2014–2018. Materials and methods. LYPL magnitude was calculated using the number of recorded deaths in the reporting form of the 2014–2018 National Statistics Committee «C51-Distribution of deaths by sex, age groups and causes of death». Results. In 2014–2018, 145 cases of death of patients with viral hepatitis B without (HB) and with a delta agent (D) were registered in the Kyrgyz Republic. Of these, 66% (96/145) of patients died from hepatitis B, of which a third (32/96) had an acute disease course. And among those who died from hepatitis D (19/49), acute course was registered in 39%. LYPL for the 145 deceased patients totaled 3766 years, of which 63% (2365 years) were due to HB. Despite that only 35% of patients (51/145) died from acute forms of such hepatitides, their LYPL accounted for 52% (1968) of total years lost that decreased by 4.5-fold for 2014–2018 due to AHB (6.3‰ and 1.41‰, 2014 and 2018, respectively) but increased by 1.1-fold due to AHD (2.7‰ and 3.1‰, 2014 and 2018, respectively). Chronic hepatitis B vs CHD resulted in 1.6 times higher LYPL magnitude (1108 and 691, respectively). At the same time, LYPL due to CHB dynamically increased by 2.6 times, whereas due to CHD — by 6.3 times. Сonclusion. The high LYPL level due to hepatitis B and D infection related to pediatric cases evidence about a heavy burden of such diseases in the Kyrgyz Republic. The data obtained prove that it is necessary to increase adherence of adult population to hepatitis B vaccination and examine children at the site of infection, regardless of vaccination history. Abruptly increased LYPL due to chronic hepatitis cases requires strengthening secondary prevention measures and ensuring timely access to specialized care at infection sites. It is also necessary to evaluate epidemiological surveillance after fatal viral hepatitis.

Breast Cancer With HER2 Immunohistochemical Score 2 and Average HER2 Signals/Cell 6 or More and HER2/CEP17 Ratio Less Than 2 ('ISH Group 3'): A Multi-Institutional Cohort Analysis Emphasizing Outcome and Molecular Subtype

Breast cancer (BC) with average human epidermal growth factor receptor 2 (HER2) signals/cell ≥6 and HER2/chromosome enumeration probe 17 (CEP17) ratio <2 (in situ hybridization [ISH] group 3) is very rare, accounting for 0.4% to 3.0% of cases sent for the dual-probe ISH assay. Although such patients are currently eligible for treatment with HER2-targeted therapy, their characteristics and outcomes remain poorly understood. Sixty-two BCs with equivocal HER2 immunohistochemical score (2+) and reflex ISH group 3 results were identified across 4 institutions. Available clinicopathologic characteristics, MammaPrint and BluePrint molecular results, and follow-up information were retrospectively analyzed. Most BCs with HER2 equivocal immunohistochemical and ISH group 3 results were histologic grade 2 or 3 (100%), estrogen receptor (ER) positive (90.3%), with an average HER2 signals/cell of 7.3. Molecular profiles revealed that 80% (16/20) of tumors were luminal subtypes, and HER2 molecular subtype was identified in 10% of tumors (2/20). Twelve (19.4%) out of 62 patients developed local recurrence and/or distant metastasis with a median follow-up of 50 months. One (10%) of 10 patients achieved pathologic complete response after neoadjuvant chemotherapy. Forty-nine (79%) out of 62 patients completed anti-HER2 agents, and exploratory analysis showed no statistically significant difference in disease outcomes between patients who completed anti-HER2 treatment and those who did not. Univariate analysis revealed advanced clinical stage, and ER/progesterone receptor negativity was associated with unfavorable disease outcomes, and exploratory multivariate analysis demonstrated that clinical stage was the most significant factor associated with disease outcomes in the studied population. These findings increase our understanding of this rare, but clinically important HER2 category. Large-scale prospective randomized studies are needed to further evaluate the role of perioperative HER2-targeted therapy in this patient population.

TSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer.

Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer (BC). TSPAN8+ myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)-related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 (SIRT6) reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8+ myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6) at Ser772 by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated GLS1 and PYCR1, which caused TSPAN8+ myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8+SIRT6low myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8+ myCAFs is a promising approach to circumvent chemoresistance.

Deficiency in DNA Damage Repair Proteins Promotes Prostate Cancer Cell Migration through Oxidative Stress

Introduction: DNA damage repair gene deficiency defines a subgroup of prostate cancer patients with early metastatic progression and unfavorable disease outcome. Whether deficiency in DNA damage repair genes directly promotes metastatic dissemination is not completely understood. Methods: The migratory behavior of prostate cancer cells was analyzed after siRNA-mediated knockdown of DNA damage repair and checkpoint proteins, including BRCA2, ATM, and others, using transwell migration assays, scratch assays and staining for F-actin to ascertain cell circularity. Cells deficient in BRCA2 or ATM were tested for oxidative stress by measuring reactive oxygen species (ROS). The effects of ROS inhibition on cell migration were analyzed using the antioxidant N-acetylcysteine (NAC). The correlation between BRCA2 deficiency and oxidative stress was ascertained via immunohistochemistry for methylglyoxal (MG)-modified proteins in 15 genetically defined primary prostate cancers. Results: Prostate cancer cells showed a significantly increased migratory activity after the knockdown of BRCA2 or ATM. There was a significant increase in ROS production in LNCaP cells after BRCA2 knockdown and in PC-3 cells after BRCA2 or ATM knockdown. Remarkably, the ROS scavenger NAC abolished the enhanced motility of prostate cancer cells after the knockdown of BRCA2 or ATM. Primary prostate cancers harboring genetic alterations in BRCA2 showed a significant increase in MG-modified proteins, indicating enhanced oxidative stress in vivo. Conclusions: Our results indicate that DNA damage repair gene deficiency may contribute to the metastatic dissemination of prostate cancer through enhanced tumor cell migration involving oxidative stress.

Abstract 4565: Reckless mitotic entry as a chemosensitization approach for alkylating agents

Abstract The cell cycle is tightly regulated by checkpoints, playing a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anti-cancer treatments, allowing for DNA repair prior to cell division. Therefore, manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies such as alkylating agents and radiation. In this study, we conducted a forward genome scale CRISPR/Cas9 chemogenomic screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress. Our findings revealed that canonical DNA repair pathways, including ATM/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of the membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, known as Myt1 (encoded by PKMYT1), in ensuring cell survival. Analysis on patient cohort demonstrated that PKMYT1 is not only highly presented in malignancy, but also predisposes an unfavorable disease outcome. Genetic depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between TMZ and other clinically used alkylating agents, such as carmustine, busulfan, and dacarbazine, when combined with a novel Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage, as indicated by a substantial increase in γH2AX-positive cells in mitosis. Moreover, RP-6306 dramatically altered cell cycle timing, reducing the threshold time for mitotic entry. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities, including unaligned and partially condensed chromosomes, lagging chromosomes, chromosome bridges, and multipolar spindles. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Importantly, preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice. Collectively, our findings highlight the potential of targeting cell cycle timing through Myt1 inhibition as an effective strategy to enhance the efficacy of current standard cancer therapies, potentially leading to improved disease outcomes. Citation Format: Fengchao Lang, James A. Cornwell, Karambir Kaur, Mirit I. Aladjem, Michael Aregger, Steven D. Cappell, Chunzhang Yang. Reckless mitotic entry as a chemosensitization approach for alkylating agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4565.

Relationship between the Expression of CHK2 and p53 in Tumor Tissue and the Course of Papillary Thyroid Cancer in Patients with CHEK2 Germline Mutations.

The aim of this study was to determine whether the expression of CHK2 and p53 in tumor tissue in carriers of germline CHEK2 mutations can serve as a prognostic marker for PTC, and whether CHEK2 and TP53 copy numbers correlates with the course of PTC disease. This study included 156 PTC patients previously tested for the presence of CHEK2. Clinicopathological features, treatment response, disease outcome, and germline mutation status of the CHEK2 gene were assessed with respect to CHK2 and p53 expression, and CHEK2 and TP53 gene copy statuses. In patients with and without a germline mutation in CHEK2 and with higher CHK2 expression, the chances of an excellent treatment response and no evidence of disease were lower than in patients without or with lower CHK2 expression. TP53 deletion was associated with angioinvasion. In patients with a truncating mutation, the chance of a CHEK2 deletion was higher than in patients with WT CHEK2 alone or those with WT CHEK2 and with the missense I157T mutation. Higher CHK2 expression was associated with poorer treatment responses and disease outcomes. Higher CHK2 expression and positive p53 together with a TP53 deletion could be a prognostic marker of unfavorable disease outcomes in patients with germline truncating mutations in CHEK2.

Эндотелиальная дисфункция у пациентов с коронавирусной инфекцией COVID-19

Endothelial dysfunction is the main cause of thrombotic complications and unfavorable disease outcome in COVID-19. The study of markers of endothelial dysfunction in patients with COVID-19 will help to determine additional directions for the treatment of hemostatic disorders. The purpose — to evaluate the diagnostic significance of endothelial dysfunction markers in moderate and severe forms of COVID-19. Material and methods. The study was carried out in 28 patients with COVID-19 hospitalized at the Republic Clinical Infectious Diseases Hospital (Kazan) from 02.16.2023 to 03.07.2023. The median age of patients was 66.5 years. The control group consisted of 20 healthy people of the same age. Results. It was found that moderate and severe forms of COVID-19 are accompanied by increased values of D-dimer and VWF in the blood, the medians of which were 2.6 and 1.9 times higher than control values, respectively. No significant differences in the values of P-selectin and thrombomodulin were detected in the compared groups. A moderate correlation was established between the level of P-selectin and the absolute number of neutrophils in the blood. It was found that the values of D-dimer and thrombomodulin were significantly higher in patients with COVID-19 who had two or more comorbid diseases. The high likelihood ratios of FFB and D-dimer positivity (LR+ = 8.4) allow considering them as reliable parameters for assessing endothelial dysfunction in patients with COVID-19. Conclusion. Endothelial dysfunction in COVID-19 disease is manifested by increased levels of D-dimer and VWF in the blood. The identified changes indicate the possibility of using medications that neutralize VWF in addition to anticoagulant drugs.

Comparison Between the Advanced Cardiac Life Support and Adult Advanced Life Support Protocols: A Simulation-Based Pilot Study.

Introduction: Cardiac arrest is a public health concern associated with unfavorable disease outcomes. Cardiopulmonary resuscitation (CPR) of optimal quality is widely acknowledged as an indispensable technique in restoring spontaneous circulation. In order to perform advanced cardiac life support (ACLS), chest compression must be paused twice: once to assess the rhythm and again to administer the shock. Australian advanced life support (ALS) recommends that the defibrillator needs to be precharged in order to administer the shock during a solitary interval in chest compressions. While performing chest compressions, precharging defibrillators can decrease hands-off time without posing a risk of injury. Aim: To compare chest compression fraction (CCF)-which is the cumulative time spent providing chest compressions divided by the total time taken for the entire resuscitation-by calculating the hands-off time duration in cardiac arrest between the Australian Resuscitation Council (ARC) and American Heart Association (AHA) protocols for CPR. Methods: A simulation-based pilot study was designed using a Laerdal Resusci Anne mannequin and a LIFEPACK 20 defibrillator. The study included six participants recruited from King Khalid University Hospital in Riyadh, Saudi Arabia, where three participants were certified ACLS providers and there were certified ALS providers. Participants were divided into two groups, ALS and ACLS, each following one protocol. For each scenario, a random job was assigned to each participant, regardless of their role as assistant, team leader, or performer of CPR. Each case's shockable and nonshockable rhythms were hidden from the team leader and the chest compressor. Ten trials of CPR were performed, each for four cycles with a total time of 8 min. The simulation was video recorded for hands-off time counting. Comparison between CCF (seconds) per cycle between the two protocols was performed using an independent sample t-test. A p value of 0.05 was used to measure statistical significance. Results: Comparing CCF in shockable rhythms between ARC and AHA protocols, it was observed that the CCF of ALS-ARC was significantly higher than ACLS-AHA in all cycles; the first cycle: t = 3.782, p=0.004; the second cycle: t = 3.380, p=0.007; the third cycle: t = 3.803, p=0.003; and the fourth cycle: t = 4.341, p=0.001. Conclusion: Precharging a defibrillator before a rhythm check during chest compression, in anticipation of a potentially shockable rhythm, reduces the time required for defibrillation and limits interruptions in chest compression during CPR. This practice effectively enhances the CCF. Enhancing the continuity of chest compressions can potentially improve survival rates in ARC.

The predicting value of circular DNA particles of T- and B-cell receptors for the dismal acute period outcomes and the disease severity of COVID-19 infection

The pandemic of the new coronavirus infection COVID-19, caused by the SARS-CoV-2 virus, continues to be a serious problem for the entire global community. Currently, most patients experience mild COVID-19, with only about 20% of those infected requiring hospitalization. The severe course of COVID-19 is most often associated with damage to the patient’s bronchopulmonary system by the virus and serious abnormalities, including damage to the air-hematological barrier, systemic inflammation, dysfunction of the immune system and the addition of secondary infections. Severe disease and poor outcome in hospitalized patients with COVID-19 may be associated with lymphopenia in combination with neutrophilia. Restoring the number of lymphocytes is important to improve the prognosis of the patient’s outcome. Patients with COVID-19 experience an immune imbalance where systemic inflammation and dysfunction of circulating T and B cells lead to more severe disease. TREC/KREC analysis can characterize the function of the central organs of the immune system and its relationship with clinical and laboratory data. Decreased TREC/KREC levels were observed in patients with unfavorable disease outcomes compared to patients with favorable disease outcomes. Additionally, a higher neutrophil to lymphocyte ratio was found. Levels of TREC and KREC in the blood negatively correlate with the neutrophil-lymphocyte ratio. Thus, the TREC/KREC assay is a potential prognostic marker for assessing the severity and outcome of COVID-19.

Morphological changes in hematopoietic parameters in COVID-19 and their prognostic significance

The types of morphological changes in the complete blood count, along with other laboratory parameters, can help establish the severity of the condition and provide the prognostic value in determining the survival of a patient with COVID-19. Peripheral blood smear (PBS) examination is a routine and simple procedure that can be performed at any medical institution. However, data on morphological changes in PBS during COVID-19 are still insufficient. Therefore, it is relevant to identify the features and patterns of these changes, taking into account the severity of the clinical presentation of COVID-19, and establish their prognostic significance. The aim. To review the literature on the presence of morphological changes in hematopoietic parameters in the case of SARS-CoV-2 infection with respect to the disease course.Results and Conclusions. Morphological changes in at least one blood cell lineage were observed in all cases of SARS-CoV-2 infection. The most common are nuclear and cytoplasmic disorders of neutrophils, such as hypogranulation and hypo/hypersegmentation of neutrophil nuclei, often with toxogenic stippling. Typical changes in lymphocyte morphology include monocytoid, lymphoplasmacytoid, granular, and atypical cells with nucleoli. Prognostically unfavorable morphological signs in the PBS include giant neutrophils and their toxic granulation, plasmacytization of lymphocytes, and a dynamic decrease in granular and abnormal lymphocytes and monocytes. A low count of lymphocytes and their subpopulations is associated with a severe clinical presentation and an unfavorable outcome of COVID-19 disease, which suggests the feasibility of their immunophenotypic evaluation and monitoring. The detection and serial monitoring of inflammatory monocytes using flow cytometry may be valuable in predicting the course and choosing adequate therapy for SARS-CoV-2 infection. Additionally, an increase in the red cell distribution width was also shown to have prognostic importance.

Clinical significance of MET alterations in non-small cell lung cancer and currently available therapies

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality both in Russia and worldwide. At diagnosis, most patients have advanced disease when the use of local treatment modalities is limited and systemic chemotherapy fails to provide a pronounced and sustained benefit. The advent of targeted therapies has significantly changed the treatment paradigm of NSCLC. Genetic alterations representing potential molecular targets have been identified in up to 60 % of non-squamous NSCLC cases, and agents directed against 50 % oncogenic targets have been approved. Various activat ing mutations of the MET signaling pathway (gene amplifications and alterations) associated with unfavorable disease outcomes occur in 2–4 % of NSCLC patients. Recently, significant advances in the development of therapies targeting this signaling pathway have been made. The article provides an overview of the key studies evaluating novel therapeutic options for NSCLC with MET alterations.

Immune analysis of natural neurotropic autoantibodies in blood serum of patients with COVID-19 associated ischemic stroke

The aim of the present study was to perform a comparative quantitative analysis of natural neurotropic autoantibodies (Nabs) in blood serum of patients with COVID-19 associated ischemic strokes (IS) in dynamics of disease. A total of 150 consecutive patients with acute primary IS were included, being divided in two groups: 100 patients with IS on the background of COVID-19 pneumonia (main group No. 1) and 50 patients with IS without COVID-19 symptoms and positive viral test (comparison group No. 2). The stroke severity and consciousness were measured by NIHSS and Glasgow coma scale. In blood serum of patients (n = 110), we have studied the levels of IgG Nabs to NF-200, GFAP, S100β, MBP, receptors to dopamine, serotonin, choline, glutamate, GABA by means of ELISA technique. The blood samples for analyses were taken at the 5th, 14th and 28th days of disease. In group 1 (n = 80), the Nabs levels have been increased as follows: antibodies to NF-200 (132.9±4.1 CU), by 1.09 and 1.8 times; for GFAP (118.9±3.9 CU), by 1.4 and 2 times; S100β antibodies (129.5±10.2 CU), by 1.05 and 1.6 times; MBP antibodies (97.3±4.5 CU) were 1.14 and 1.6 times higher; antibodies to dopamine receptors (77.9±4.4 CU) in 1.2 and 1.6 times; to serotonin receptors (81.96±3.25 CU) in 1.2 and 1.4 times; choline receptor antibodies (61.42±3.6 CU) were increased 1.4- and 1.8-fold; to glutamate (85.28±4.25 CU) by 1.19 and 1.4 times; to GABA (82.4±5.2 CU) the increase was 1.5- and 1.8-fold, respectively, when compared with group 2 and controls. The time-dependent monitoring of Nabs level in patients with COVID-19 associated ischemic stroke showed the highest increase in Nabs to the S-100, NF-200 and MBP proteins at the day +28 following the brain stroke. In patients with COVID-19 associated IS, more enhanced production of serum autoantibodies to neuroproteins and neurotransmitter receptors was detected, which accompanied a worse course of IS and can be considered as a predictor of unfavorable outcome of disease.

Immunoglobulin genes and stereotyped antigenic receptors in chronic lymphocytic leukemia and other lymphoproliferative diseases

Introduction. The mutational status of immunoglobulin heavy chain variable region genes (IGHV) is the most important prognostic factor in chronic lymphocytic leukemia (CLL). Furthermore, a significant narrowing of the IGHV gene repertoire is found in CLL and other lymphoproliferative diseases. Aim — to review the publication data on the IGHV genes repertoire and mutational status in CLL and other lymphoproliferative diseases regarding their clinical significance. General information. Nucleotide sequence of rearranged IGHV genes is a unique marker of a tumor clone. CLL patients with unmutated IGHV genes have an extremely unfavorable disease outcome in contrast to the patients with mutated IGHV genes. Patients with mutated IGHV genes benefit from conventional immunochemotherapy, while non-mutated IGHV patients require therapy escalation with new targeted drugs. The study of IGHV genes and stereotyped antigen receptors repertoire makes possible to identify additional groups of CLL patients with specific genetic and clinical features. Stereotype receptors are also detected in other lymphoproliferative diseases, but their clinical significance has not yet been defined. However, stereotyped receptors are found to be disease-specific.

Transforming growth factor beta 1 (TGF-β1) in COVID-19 patients: relation to platelets and association with the disease outcome.

Transforming growth factor beta (TGF-β) is a ubiquitously distributed cytokine known to contribute to the pathogenesis of numerous pathological processes. The aim of this study was to measure serum concentrations of TGF-β1 in severely ill COVID-19 patients and to analyze its relationship with selected hematological and biochemical parameters and with the disease outcome. The study population included 53 COVID-19 patients with severe clinical expression of the disease and 15 control subjects. TGF-β1 was determined in serum samples and supernatants from PHA-stimulated whole blood cultures using ELISA assay. Biochemical and hematological parameters were analyzed using standard accepted methods. Our results showed that serum levels of TGF-β1 in COVID-19 patients and controls correlate with the platelet counts. Also, positive correlations of TGF-β1 with white blood cell and lymphocyte counts, platelet-to-lymphocyte (PLR) ratio, and fibrinogen level were shown, while negative correlations of this cytokine with platelet distribution width (PDW), D-dimer and activated partial thromboplastin time (a-PTT) values in COVID-19 patients were observed. The lower serum values of TGF-β1 were associated with the unfavorable outcome of COVID-19. In conclusion, TGF-β1 levels were strongly associated with platelet counts and unfavorable disease outcome of severely ill COVID-19 patients.

The use of 8-diff clinical blood testing of patients to assess the severity of the new coronavirus infection

Introduction. A new coronavirus infection causes a variety of changes in the body of an infected person, which can be monitored using clinical blood analysis. The capabilities of flow cytometry allow to expanding the range of analyzed cell populations, which gives a more complete picture of the patient’s condition and the course of infection process.Aim. To study the extended 8-diff clinical blood analysis in patients with COVID-19 and to identify the parameters characterizing a severe course and an unfavorable outcome.Material and Methods. The study group comprised 282 patients with a confirmed diagnosis of a new coronavirus infection. The following parameters of the extended 8-diff clinical blood test were evaluated: the total content of leukocytes and their populations, the number of reactive and antibody-synthesizing lymphocytes (RE-LYMPH, AS-LYMPH), indicators characterizing the reactivity and granularity of neutrophils (NEUT-RI, NEUT-GI), erythrocyte count, hemoglobin level, normoblast count, and platelet count. Statistical data were processed using the Statistica 10.0 software.Results. The blood picture of patients with a severe course of COVID-19 as well as of those with an unfavorable outcome of disease was characterized by neutrophilia, normoblastemia, and an increase in the number of immature granulocytes. At the same time, there was a significant decrease in the number of lymphocytes and monocytes below the reference interval and a decrease in the number of eosinophils to the extent of complete absence. The performed logistic regression analysis allowed to determine the most significant hematological parameters in predicting the outcome of COVID-19 as follows: the total number of leukocytes (OR 1.3), neutrophils (OR 2.1), reactive neutrophils (OR 1.3), eosinophils (OR 0.05), monocytes (OR 0.2), lymphocytes (OR 0.4), and neutrophil-to-lymphocyte ratio (NLR) (OR 1.4). Also, the threshold values were established for these parameters as follows: the total number of leukocytes &gt; 7.2 × 109/L, neutrophils &gt; 5 × 109/L, reactive neutrophils &gt; 48.6 Fi, eosinophils &lt; 0.05 × 109/L, lymphocytes &lt; 1.3 × 109/L, monocytes &lt; 0.5 × 109/L, and NLR &gt; 2.9 were associated with an unfavorable outcome of the disease.Conclusion. The obtained data may be used for a comprehensive evaluation of COVID-19 patient condition along with other laboratory markers of the severe course of the infection.

Психоневрологические проявления, ассоциированные с вирусом SARS-CoV-2

Objective: To evaluate the psychoneurological status of post-COVID-19 patients using diagnostic tests for psychoemotional state, cognitive functions, sleep disorders. Design: a retrospective study. Materials and methods. We conducted psychoneurological tests on 68 post-COVID-19 patients (38 women and 30 men) (mean age: women — 44.6 ± 6.4 years old, men — 46.8 ± 7.8 years old). The control group included 30 persons without a history of coronavirus infection. Neuropsychological tests were performed using the asthenia scale developed by L. D. Malkova and adapted by T. G. Chertova, Hospital Anxiety and Depression Scale, Spiegel Sleep Questionnaire, Epworth Sleepiness Scale, cognitive function testing (memorising 10 words, Munsterberg test, mechanical memory test). Results. The main psychoneurological manifestations in post-COVID-19 patients are asthenoneurotic or anxiodepressive symptoms (57.4 %), insomnia (39.7 %) and cognitive-mnestic disorders (32.4 %) associated with somatic-vegetative disorders (hyperhydrosis, palpitations, blood pressure fluctuations, dispeptric disorders, episodes of dizziness). A lot of patients had persistent smell and taste disorders (26.5 %), impaired visual acuity (25 %), impaired hearing (23.5 %), limb numbness and paresthesia (20.6 %). Conclusion. Management of patients with coronavirus infection requires a comprehensive diagnostic approach involving assessment of their mental health. Psychoneurological features of post-COVID-19 patients demonstrate the need in improved efficiency of rehabilitation and therapeutic measures due to restoration of mental, cognitive, somatic-vegetative functions. SARS-CoV-2-associated symptoms of neural system involvement are a sign of unfavourable disease progression and outcome. Keywords: psychoneurological disorders, coronavirus infection, neuropsychological testing, psychological assessment, post-COVID syndrome.

Disseminated purulent peritonitis outcome affects NKT cell phenotype

The aim of our study was to investigate the main characteristics of peripheral blood NKT cell phenotype in patients with disseminated purulent peritonitis (DPP) in dynamics of postoperative period, depending on the disease outcome. Fifty-two patients with acute surgical diseases and injuries of the abdominal organs complicated by DPP, and 68 healthy individuals in control group, were examined. Blood sampling was performed before surgery (preoperative period), as well as on the day 7, 14 and 21 of postoperative period. All patients with DPP were divided into two groups depending on disease outcome in postoperative period: patients with favorable disease outcome (n = 34); and patients with unfavorable outcome (n = 18). Study of the phenotype of blood NKT lymphocytes was performed by flow cytometry using direct immunofluorescence of whole peripheral blood samples with monoclonal antibodies. The low relative and absolute level of NKT cells was observed in DPP patients regardless of outcome disease in preoperative period. At the same time, the absolute level of NKT cells returned to normal only in patients with favorable DPP outcome and only by day 21 after surgery. Patients with favorable DPP outcome by the end of examination period had normalized quantity of mature NKT-lymphocytes and significantly decreased level of cytotoxic cells which was apparently associated with migration of such cell subsets to site of inflammation. A reduced level of non-classical (expressing CD8 marker) mature and cytokine-producing NKT cells was detected only in patients with favorable DPP outcome in preoperative period which returned to normal by the end of postoperative period. At the same time, patients with unfavorable disease outcome had reduced quantity of NKT cells of these subsets by day 21 of postoperative treatment. Patients with favorable outcome had high level of mature and cytotoxic CD11b+ NKT cells already in the preoperative period, while patients with unfavorable DPP outcome had increased level of cytotoxic CD11b+ NKT cells only by day 21 after surgery. The proportion of NKT cells expressing activation markers (CD28 and CD57) was reduced in patients in preoperative period that returned to normal immediately after surgery with favorable outcome, while it recovered with unfavorable outcome closer to the end of postoperative examination. The defined features of NKT cell phenotype in patients with unfavorable DPP outcome characterize disturbances in subset ratio and mechanisms of functioning of this cell fraction. This determines a need to develop immunotherapeutic methods aimed at stimulating immunoregulatory activity of NKT cells.

A case of abscessed pneumonia due to COVID-19 infection in a young patient

Viral infections are the first ranked conditions among infectious diseases causing 515% of all community-acquired pneumonia. The aim of the study was to describe a case of COVID-19 infection, proceeding with acquired bacterial infection and developing abscess pneumonia in a young patient.&#x0D; Material and methods. The accompanying medical documentation was examined, clinical and morphological analysis was carried out for assessing macro- and micropreparations.&#x0D; Results. Patient A.E., 31 years old, within 5 hours 10 minutes was at in-hospital treatment with a diagnosis of Coronavirus infection, severe course. Community-acquired bilateral polysegmental pneumonia. The patient admitted with complaints of respiratory difficulty, shortness of breath, weakness, fever up to febrile level, severe pain in the right groin area, both lower extremities, swelling in hands and feet. However, despite initiated treatment, the patients condition worsened and biological death was verified. The postmortem examination revealed signs of total bilateral hemorrhagic pneumonia. Histological examination showed areas of necrosis in the alveolar epithelium and signs of marked edema with a hemorrhagic component; hemolyzed erythrocytes were found in alveolar lumen. Focal hemorrhages were visualized in the pulmonary parenchyma, sometimes merging along with lung tissue with forming microabscesses. a well-defined shaft consisting of granular leukocytes and congested vessels with erythrocyte sludge was noted on the periphery of necrosis area. In the alveoli located closer to the abscesses, fibrinous and serous exudate was detected. Signs of edema were observed in the brain; histological examination revealed perivascular, pericellular optical voids with vascular congestion, erythrocyte sludge and minor hemorrhages. SARS-CoV-2-caused pneumonia and acquired bacterial infection, in this case due to staphylococcus, led to abscess pneumonia and severe respiratory failure with developing acute distress syndrome. Obviously, the high frequency of destructive processes in staphylococcal pneumonia is due to the pathogenic staphylococci characterized by production of high-level proteolytic enzymes destroying body tissues. Thus, the current case of COVID-19 infection in a young patient is of particular importance and relevance, because it demonstrates an unfavorable disease outcome despite patient young age and lack of concomitant pathology.

Costimulatory molecule-related lncRNA model as a potential prognostic biomarker in non-small cell lung cancer.

Costimulatory molecules have been demonstrated to exert essential roles in multiple cancers. However, their role in lung cancer remains elusive. Here, we sought to identify costimulatory molecule-related lncRNAs in non-small cell lung cancer (NSCLC) and establish a prognostic signature to predict the prognosis of patients with NSCLC. A total of 535 lung adenocarcinoma (LUAD) and 502 lung squamous cell carcinoma (LUSC) patients from the cancer genome atlas (TCGA) database were recruited. A novel costimulatory molecule-based lncRNA prognostic model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm to predict the overall survival. The Homo_sapiens.GRCh38 data set was set as a reference file for probe annotation. A total of 593 costimulatory molecule-related lncRNAs were extracted. After analysis, six costimulatory molecule-related lncRNAs (AC084859.1, AC079949.2, HSPC324, LINC01150, LINC01150, and AC090617.5) were screened. A prognostic model based on the six lncRNAs was established using systematic bioinformatics analyses. The prognostic model had a prognostic value in NSCLC patients. Furthermore, a prognostic nomogram was established based on clinical parameters and a risk-score model. Patients with different risk scores had considerably different tumor-infiltrating immune cells, somatic mutational loading, clinical outcomes, signaling pathways, and immunotherapy efficacy. In addition, LINC01137 was associated with unfavorable disease outcomes and fueled tumor progression in NSCLC. Taken together, our study demonstrated that a costimulatory molecule-related lncRNA model could be a potential prognostic biomarker in NSCLC. Moreover, LINC01137 could facilitate the proliferation and invasion of lung cancer.

598P Can circulating PD-L1 levels, age at diagnosis and peritoneal carcinomatosis act as survival predictors in patients with advanced high-grade serous ovarian cancer?

High-grade serous ovarian cancer (HGSOC) is the most frequent subtype of epithelial ovarian cancer (OC) with the greater immunogenic potential due to the abundance of tumor-infiltrating immune cells which modulate the anticancer immune response. Cancer cells may evade immune surveillance, by activating immunomodulatory proteins such as programmed death protein (PD-1) and its ligand PD-L1, butyrophilin sub-family 3A/CD277 receptors (BTN3A), butyrophilin sub-family 2 member A1 (BTN2A1), and the B and T lymphocyte attenuator (BTLA). Our study aimed to assess whether circulating levels of different immunoregulatory proteins could be helpful for predicting survival of advanced HGSOC patients. The plasma PD-L1, PD-1, BTN3A1, pan-BTN3As, BTN2A1 and BTLA concentrations were analyzed in 100 advanced HGSOC women prior surgery and starting therapy, using specific ELISA tests not yet commercially available. This investigation allowed, for each tested circulating biomarker, to discriminate advanced HGSOC patients based on long (≥30 months) versus short Progression-free Survival (PFS <30 months). Through specific cut-offs obtained by ROC analysis, we showed that high baseline concentrations of PD-L1 (>0.42 ng/mL), PD-1 (>2.48 ng/mL), BTN3A1 (>4.75 ng/mL), pan-BTN3As (>13.06 ng/mL), BTN2A1 (>5.59 ng/mL) and BTLA (>2.78 ng/mL) were associated with unfavorable prognosis and median PFS from 6 to 16 months shorter. Additionally, age at diagnosis >60 years, BMI>25 or peritoneal carcinomatosis were correlated with a lower PFS (<30 months). Finally, a multivariate analysis highlighted that plasma levels of PD-L1≤0.42 ng/mL (HR: 2.23; 95% CI: 1.34 to 3.73; p=0.002), age at diagnosis ≤60 years (HR: 1.70; 95% CI: 1.07 to 2.70; p=0.024) and absence of peritoneal carcinomatosis (HR: 1.87; 95% CI: 1.23 to 2.85; p=0.003) were significant prognostic factors for a longer PFS in advanced HGSOC women. Assessing circulating PD-L1, PD-1, BTN3A1, pan-sBTN3As, BTN2A1 and BTLA levels could facilitate the identification of high-risk patients with unfavorable disease outcomes, suggesting their potential use as prognostic biomarkers.