Search

Purpose - to study the features of COVID-19 in hospitalized children. Materials and methods. Retrospective multicenter clinical and epidemiological study which includes 328 hospitalized children with laboratory-confirmed COVID-19 for the period from January to August 2021. Results. the highest specific weight among all hospitalized children falls on children of the first year (75/328; 22.8%), in general, early childhood (up to 3 years) accounted for 43% (141/328) of all hospitalizations of children with COVID-19. Common symptoms of the disease included fever, upper respiratory symptoms, intoxication, diarrhea. In 99/328 (30.1%) hospitalized children pneumonia has developed, 50/99 (50.5%) of which needed oxygen support, 10/99 (10.1%) - mechanical ventilation. Pneumonia was most common in children under 1 year, children of the first 5 years of life accounted for more than a half of all pneumonia cases (53/99; 53,5%). 13/328 (3.9%) children were hospitalized to the intensive care unit. Comorbidities including endocrine, oncological, neurological diseases, congenital malformations and others, were noted in 24.6% of hospitalized children. In children with comorbid conditions, pneumonia occurred 2 times more often (relative risk factor RR=1.98, CI 95%), the relative risk of getting into resuscitation RR in the presence of comorbidity is 10.86 (CI 95%). In addition to children with pneumonia, oxygen support or mechanical ventilation required children with obstructive syndrome, pancytopenia, convulsions. The largest proportion of comorbidities in patients hospitalized to the intensive care unit were diseases of the nervous system (congenital malformations of the CNS, cerebral palsy, epilepsy, astrocytoma). Lymphopenia and thrombocytopenia were most commonly associated with severe COVID-19. Conclusions. Children of all ages are susceptible to COVID-19. The main risk factors for severe disease are early age and the presence of comorbid conditions, among which the most relevant are diabetes, obesity, neurological diseases and cancer. The presence of comorbidities in children determines the priority groups for the prevention of coronavirus infection through vaccination. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the Shupyk National Healthcare University of Ukraine. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

Purpose - to study the state of protection against vaccine-controlled infections in children with primary immunodeficiency (PID) and in children on immunosuppressive therapy. Materials and methods. The object of the study was the level of intensity of humoral immunity against viral (measles, rubella) and bacterial (diphtheria, tetanus) vaccine-controlled infections in immunosuppressed patients. Protective levels of specific IgG antibodies against vaccine antigens were determined in 58 children with primary immunodeficiency and 20 children receiving immunosuppressive therapy. Among the 58 children with primary immunodeficiency, there were 26 children with preserved antibody function and 32 children with antibody deficiencies and combined immunodeficiencies on immunoglobulin replacement therapy. The state of immunity of immunocompromised patients was compared with that of healthy children in the control group. Results. In the group of children with PID with preserved antibody function, vaccinated against measles, rubella and 94.4% of children had a protective level of antibodies against measles, 100% of children against rubella. 78.6% of vaccinated children in this group were protected against tetanus and only 57.1% were protected against diphtheria. All children with PID with impaired antibody production receiving intravenous immunoglobulin replacement therapy (IVIG) were protected against measles, rubella, diphtheria, and tetanus. Among 10 patients on immunosuppressive therapy vaccinated against measles and rubella, antibodies to the measles virus in the protective titer were detected in 80% of children, to rubella - in 90% of patients in this group. Almost all children with rheumatic diseases on immunosuppressive therapy vaccinated against tetanus and diphtheria were protected against these pathogens, except for 2 out of 14 (14,2%) children who did not have antibodies to diphtheria. Children with glomerulonephritis with nephrotic syndrome had insufficient protection against diphtheria and tetanus, only 3 out of 6 (50%) children had antibodies in the protective titer against tetanus, no patient with this pathology had antibodies against diphtheria. Conclusions. The findings of the studies suggest that most patients with PID with preserved antibody function may develop a sufficient immune response to vaccination against viral (measles, rubella) and bacterial (tetanus) infections. IVIG replacement therapy protects children with PID against vaccine-controlled infections that impair antibody production. Most children with rheumatic diseases vaccinated according to the Calendar before starting immunosuppressive therapy retain postvaccination protection of antibodies against vaccine-controlled infections. Immune protection against vaccine-controlled infections is reduced in patients with glomerulonephritis with nephrotic syndrome, they need close monitoring and, if necessary, replacement therapy with immunoglobulins. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors. Key words: primary immunodeficiency, replacement therapy, children, vaccination, immunosuppressive therapy, specific antibodies to measles, rubella, diphtheria and tetanus.

When satellites are placed in orbit, often times a specific orientation is required to achieve mission purposes. Different factors (such as atmospheric drag, magnetic fields, solar winds) or tumbling upon deployment from the launch vehicle, may result in an undesirable satellite orientation. To address these challenges, the ability to control the orientation, termed as attitude determination, becomes critical to any mission. This thesis will focus on developing an earth-pointing and sun-pointing mode in order to meet the objectives of the ESSENCE CubeSat. The earth-pointing mode orients the vehicle to point towards a desired target on the earth surface, and the sun-pointing mode orients the vehicle such that the maximum solar array surface area is exposed to the sun when the vehicle is out of eclipse.

The J Project is a Central-Eastern European collaborative program in the field of physician education and clinical research aimed at improving the clinical care and diagnosis of primary immunodeficiency disorders (PIDs). Ukraine was one of the first to participate in the project, which allowed us to join the whole European PID community. Since 2004, the country has been holding annual J Project meetings with the involvement of new regions. The spread of the J Project impact has contributed to significantly improved early PID diagnosis in Ukraine. Progress has been made not only in identifying patients but also in arranging the treatment. The assistance in genetic diagnosis made it possible to detect PIDs, study their features, and improve approaches to the management. This also gave an impetus to the development of regional PID centers and participation in scientific research. Of utmost importance is the cooperation with colleagues from Poland, Hungary, and Belarus, who are active members of the J Project.

The emergence of acute, severe non hepA–E hepatitis of unknown etiology (ASHUE) has attracted global concern owing to the very young age of the patients and its unknown etiology. Although this condition has been linked to several possible causes, including viral infection, drugs and/or toxin exposure, the exact cause remains unknown; this makes treatment recommendation very difficult. In this review, we summarize recent updates on the clinical manifestations, complemented with laboratory results, case numbers with the global distribution and other epidemiological characteristics, and the possible etiologies. We also provide the proposed actions that could be undertaken to control and prevent further spread of this hepatitis. Since many etiological and pathological aspects of the acute non hepA–E hepatitis remain unclear, further research is needed to minimize the severe impact of this disease.

Background Fatigue is one of the most common adverse events of systemic therapy in patients with metastatic renal cell carcinoma (RCC). The aim of multicenter randomized phase 2 study was to determine the efficacy and safety of testosterone in patients with fatigue developed during targeted therapy. Patients and methods Male patients with metastatic clear-cell RCC, normal prostate-specific antigen level, low testosterone level, and no evidence of hypothyroidism receiving first-line sunitinib or pazopanib with fatigue were randomly assigned (1:1) to either testosterone undecanoate (1000 mg) and targeted therapy or targeted therapy alone. The primary endpoint was the mean change of fatigue from baseline to 28 days according to the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary endpoints were safety, Functional Assessment of Cancer Therapy-Kidney Symptom Index 19, testosterone serum concentrations, red blood cell count, and hemoglobin level. Results Sixty patients were assigned to receive testosterone and targeted therapy (N=30) or targeted therapy alone (N=30). As of the data cutoff on December 30, 2019, median follow-up was 18.2 months. The study achieved its primary endpoint based on the significant differences at day 28 favoring testosterone over targeted therapy alone regarding the decreased level of fatigue (difference between groups, 22.5 points; 95% confidence interval, 18.4-26.6; P=0.012). Significant changes in scores demonstrating the enhanced quality of life with testosterone compared with targeted therapy were also observed for Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 disease-related symptoms (P=0.01). There were nonsignificant differences in red blood cell count and hemoglobin level between the 2 groups (all P>0.05). Conclusion Male patients with metastatic RCC and hypogonadism receiving testosterone had less fatigue and better symptom control during targeted therapy.

Introduction. Ataxia-telangiectasia (A-T) is a neurodegenerative disorder characterised by progressive ataxia, telangiectasia, immunodeficiency, increased susceptibility to malignancies and radiation sensitivity. The objective of the study was to determine the clinical and immunological features, as well as the consequences of A-T in the Ukrainian population. Material and methods. Sixty-four patients with A-T, registered at the Ukrainian National Registry of primary immunodeficiencies, were first included in the study. The evaluation of clinical signs and investigations were possible in 53/64 patients with A-T. Results. Neurological signs and telangiectasies were evidenced in all patients, and were followed by recurrent infections (81.1%), lymphoid hypoplasia (66.0%), and malignancies (15.1%). Poor weight gain was observed in 73.6% of patients, orthopaedic disorders in 52.8%, and bronchiectasis in 30.8%. High alpha-fetoprotein levels were seen in 93.5% of patients, mean level- 150.3 IU/mL. Among immunoglobulin changes, the most significant was a decreased IgA level (83.0%), followed by a high IgM level (50.9%), low IgG (18.9%) and IgE levels (49.1%). Reduced CD3, CD4 and CD8 T-lymphocytes were observed in 85.7% of patients. Infections and cancer were the most often causes of mortality. The mean age at death was 14.1 years, ranging from 6 to 21 years. Conclusions. Ataxia in combination with recurrent infections is the key to A-T diagnosis. In addition to syno-pulmonary infections, pyoderma and stomatitis are also frequent presentations. Children with ataxia should be referred to an immunologist, as well as genetic testing should be recommended for all patients with ataxia for timely diagnosis.

The object of research is the process of management and treatment of crushed stone production waste. Modern approaches to the disposal of crushed stone production waste are analyzed. It is revealed that crushed stone production wastes are mainly used in the construction industry, and their volumes of use are insufficient to neutralize the impact of dumps on the environment. The chemical composition of crushed stone production wastes was analyzed and an experiment was carried out to determine the possibility of their use as fertilizers for the cultivation of industrial energy crops. For the experiment, an energy crop was chosen – sorghum. Sorghum seeds were placed in two types of soil: regular peat substrate and peat substrate with the addition of rock in a ratio of 60:40. Waste from crushed stone production – rock, which includes: quartzite – 90–98%, pyrophyllite – 1–9%, ore mineral – 0.3–1%. The results of the experiment showed an increase in the biomass of sorghum grown on a peat substrate with the addition of rock, 1.5 times, compared with that grown on a conventional peat substrate. Accordingly, the energy yield of sorghum per hectare of field will also grow by 50%. In addition to increasing the biomass of sorghum, as a result of the experiment, an increase in the number of secondary and tertiary roots was found when it was grown on a peat substrate with the addition of rock. A more developed root system allows the plant to receive more moisture and nutrients, thereby increasing its endurance and drought resistance. The results obtained can be explained by the positive effect of silica, of which more than 90% of the rock is composed, on the growth and development of plants. It is proposed to increase the level of environmental safety of mining regions through the use of crushed stone waste as fertilizers for industrial energy crops and the transition to alternative energy sources, in particular biofuels made on the basis of these crops.

Novel coronavirus disease (COVID-19), named a pandemic by the WHO, is the current global health crisis. National and international collaboration are indispensable for combating COVID-19 and other similar potential outbreaks. International efforts to tackle this complex problem have led to remarkable scientific advances. Yet, as a global society, we can and must take additional measures to fight this pandemic. Undoubtedly, our approach toward COVID-19 was not perfect, and testing has not been deployed fast enough to arrest the epidemic early on. It is critical that we revise our approaches to be more prepared for pandemics as a united body by promoting global cooperation and commitment.

Background: Very little is known about receptor tyrosine kinase (RTK) expression on peripheral blood mononuclear cells (PBMC) in humans including renal cell carcinoma (RCC) patients. Objectives: The primary objective of this study was to evaluate expression levels of major RTKs on PBMC and tumor-infiltrating lymphocytes (TIL) isolated from RCC patients. The secondary aim was to compare levels of RTK expression in RCC patients before surgery and on the 180th day after surgery (lymphocyte lifetime) and to compare them with the expression in healthy donors. In addition, we compared RTK and PD-L1 expression in TIL. Methods: Tumor and blood samples were obtained from 20 patients with primary RCC immediately after surgical resection. Blood samples were collected from 20 healthy donors. Tumors were harvested into RPMI 1640 medium (Gibco) and processed within 4 h. TIL isolation was performed using a modified protocol [Baldan et al. Br J Cancer. 2015;112:1510–18]. Expression of RTKs was evaluated with NovoExpress Software. Twenty tumors from the same patients were stained with PD-L1 IHC assay (clone SP142; Ventana). Results: PBMC and TIL express RTKs in humans. The RTK expression level was significantly lower on peripheral blood cells in patients with RCC (mean 41%, range 27.1–62.6%) as compared with healthy donor PBMC (mean 77.1%, range 72.1–80.1%, all p < 0.05). Furthermore, RTK expression was significantly downregulated on intratumoral cells (mean 40%, range 23.2–52.3%) in comparison with healthy donor PBMC. There was no significant recovery of RTK expression on the 180th day except for VEGFR2. Five of 20 (25%) patients were PD-L1 positive. PD-L1 expression on TIL was strongly associated with downregulated expression of PDGFRα (p = 0.017) and PDGFRβ (p = 0.024). Conclusions: PBMC and TIL had similar low RTK expression levels in RCC patients. PBMC of healthy humans had a significantly higher expression of RTK. PD-L1 and PDGFRα-β expression could correlate. Comprehensive basic and clinical studies will be needed to define a biological role of RTKs on different lymphocyte subsets and correlations between clinical outcomes and expression levels.

The facial nerve is most often, as compared with other cranial nerves, damaged due to surgical interventions. In the first place, as the cause of iatrogenic damage, is neurosurgical treatment for neoplasms of the ponto-cerebellar angle and temporal bone, brain injuries. The neuropathy of the facial nerve is the cause of neurological and cosmetic defects that have a serious traumatic effect on the patient. The psychological consequences of facial neuropathy are more important for the patient than physical damage. Paresis of mimic muscles cannot be hidden and often leads to social maladjustment, isolation and a marked reduction in the quality of life. Facial neuropathy, in most cases, is not a life-threatening condition, but it definitely changes the patient’s life. This article proposes an effective rehabilitation system, tested on 172 patients with facial nerve damage after neurosurgical treatment. The combined use of physiotherapy, massage, therapeutic gymnastics, including posture treatment with taping, during the early period of the disease, allows restoring nerve function and maintaining mimic muscles, as well as avoiding undesirable complications such as pathological synkinesis and corneal atrophy.

PURPOSE: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs. METHODS: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variation by IL12RB1-targeted next-generation sequencing (NGS). RESULTS: We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on PHA-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, in either the homozygous state (n=1) or in trans (n=4) with a single nucleotide variation (n=3) or a small indel (n=1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). CONCLUSION: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.

SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. Studies of outliers—individuals remaining uninfected despite viral exposure and healthy young patients with life-threatening disease—present a unique opportunity to reveal human genetic determinants of infection and disease.

Hepatitis C virus (HCV) interferes with activation of innate and adaptive immune responses. Theoretically, the efficacy and toxicity of immune checkpoint inhibitors in cancer patients infected with HCV may differ. Nevertheless, HCV was an exclusion criterion in most checkpoint inhibitor trials. We evaluated the efficacy and safety of nivolumab in metastatic renal cell carcinoma (mRCC) patients with or without chronic HCV infection. In a matched cohort study, data were collected from 174 patients, retrospectively. All patients had clear-cell mRCC, chronic HCV infection (case study group), no evidence of other malignancy or cirrhosis, and had received nivolumab (3 mg/kg every 2 weeks) until disease progression or unacceptable toxicity. Quantitation of HCV RNA in plasma samples was performed before and during treatment with nivolumab with the automated HCV test (Hoffmann-La Roche, Switzerland). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and rate of grade 3–4 adverse events in study and control cohorts. A total of 44 matched patients were included. Groups were well balanced. HCV-infected patients had significantly longer OS and PFS. Median OS was 27.5 (95% CI 25.3–29.7) and 21.7 (20.3–23.1) in study and control groups, respectively (P = 0.005). Median PFS was 7.5 (5.7–9.3) and 4.9 (4–5.8) (P = 0.013). Despite no differences in ORR between groups (27% vs. 23%, P = 0.7), patients with HCV had significantly more durable responses (P = 0.01). Nivolumab was well tolerated in all HCV-positive patients. No unexpected toxicity was observed. Assessment of viral load during nivolumab therapy was available in 14 of 22 (64%) patients with HCV. Nivolumab did not significantly impact HCV concentration (mean change 210 IU/ml, P = 0.82) in the absence of antiviral therapy. The efficacy and safety profiles observed in this study support the administration of nivolumab in mRCC patients infected with HCV and warrant further investigation.

Introduction: Metastatic renal cell carcinoma (mRCC) can cause hypogonadism as an adverse effect in male patients. Hypogonadism can also result from adverse effects of targeted therapy of mRCC, such as fatigue, pain, anorexia, asthenia or hypothyroidism. The objective of this multicenter randomized phase 2 study was to determine efficacy and safety of testosterone undecanoate (T) in mRCC patients with hypogonadism. Methods: Eighty-two male patients with clear cell mRCC were screened. Patients with low testosterone level and normal PSA level receiving first-line sunitinib or pazopanib were randomly assigned (1:1) to either T (Nebido®, 1,000 mg) and targeted therapy or targeted therapy alone (control group). T was injected intramuscular deeply on Day 1 of a new treatment cycle. Symptom index (FKSI-19), fatigue score (FACIT-Fatigue), erectile function (IIEF-5), testosterone serum concentrations, red blood cells (RBC) count and hemoglobin level were evaluated. The assessments were performed at baseline and Day 28 of a treatment cycle. Results: Sixty (75.6%) patients had hypogonadism. Mean age was 52 years (range 33-71) in the T group (N=30) and 55 years (42-69) in the control group (N=30). 45 (75%) patients reported a negative change in their sexual life, and 16 (27%) patients had no sexual activity since the start of the targeted therapy. T was well tolerated in mRCC patients. No unexpected toxicity was observed. The health-related quality-of-life scores in the T group were better than those in the control group, respectively (mean (SD) - FKSI-19: baseline, 46.5 (12.2) vs. 44.2 (9.4), Day 28, 27.5 (12.5) vs. 39.9 (9.8); FACIT-Fatigue: baseline, 37 (4.7) vs. 35.3 (3.1), Day 28, 20.3 (8.1) vs. 42.5 (8.4), all P≤0.01). Therapy with T improved significantly sexual function (IIEF-5: baseline, 16 (3.3) vs. 19 (2.6), Day 28, 21 (1.5) vs. 8 (1.9), P=0.003). There was non-significant positive trend in hemoglobin level between 2 groups (baseline, 124.5 (11.7) g/l vs. 119 (10.4), Day 28, 133 (13.5) vs. 108 (17). Testosterone level increased significantly in T group (baseline, 6.21 (1.78) nmol/l, Day 28, 33.2 (14.3). Conclusions: Male patients with mRCC receiving targeted therapy had significantly less fatigue, better symptom control, and better erectile function with T. T therapy was safe. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections. The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86. Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels. Whole exome sequencing (WES) identified a novel heterozygous mutation in RAC2(c.275A > C, p.N92 T). Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP. Cell lines transfected with RAC2 [N92 T] displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA. Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease.

Clinical trials of immune checkpoint inhibitors have historically excluded patients with chronic hepatitis C (HCV) infection. The safety and efficacy profile of nivolumab is unknown in this under-represented population. Data were collected in a retrospective fashion on 36 patients with metastatic clear-cell mRCC. Patients were required to have a chronic HCV infection, no evidence of other malignancy or cirrhosis, and to have received nivolumab (3 mg/kg every 2 weeks) as second- or third-line therapy. Clinical outcomes included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety was evaluated. Median follow-up was 17.5 months. Nivolumab was well tolerated in all HCV-infected patients (grade 3-4 toxicity was found in 6 of 36 cases [17%]). No unexpected toxicity was observed. Exposure to nivolumab was not associated with increased risk for hepatocellular carcinoma and cirrhosis (N=0). Medians OS and PFS were 23.9 (95% CI 20.7-26.5) and 6.8 (95% CI 4.9-8.7) months, respectively. 23% of patients had partial responses. The efficacy and safety profile observed in this study supports the administration of nivolumab in mRCC patients infected with HCV and warrants further investigation. Citation Format: Ilya Tsimafeyeu, Rustem Gafanov, Anna Semenova, Ani Oganesyan, Anastasia Bondarenko, Sufia Safina, Kristina Zakurdaeva, Svetlana Protsenko. Clinical outcomes in patients with chronic hepatitis C and metastatic renal cell carcinoma (mRCC) after treatment with nivolumab [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A1.

Background A paraneoplastic syndrome is observed in 5% to 10% of cancer patients. Paraneoplastic vasculitis (PV) in metastatic renal cell carcinoma (mRCC) patients has been poorly investigated. Aims In our case series study, we evaluated the incidence and development of PV in patients with mRCC. Methods and results Patients were required to have previously untreated clear-cell or papillary mRCC and no evidence of autoimmune diseases or venous thrombosis in history. Patients had a careful examination including Doppler ultrasonography of the blood vessels and skin punch biopsy in the presence of suspicious skin rash. Sixteen (8.2%) of 196 patients were diagnosed with PV, which was manifested clinically by leukocytoclastic vasculitis on the lower extremities. Skin biopsy confirmed vasculitis. Progression-free survival and overall survival were significantly better in patients without PV. Conclusions PV is not rare paraneoplastic syndrome in mRCC. Leukocytoclastic vasculitis was the most common type of PV in this study.

Background Metastatic renal cell carcinoma (mRCC) can cause sexual dysfunction as an adverse effect in male patients. Erectile dysfunction (ED) can also result from adverse effects of targeted therapy of mRCC, such as fatigue, pain, anorexia, asthenia or hypothyroidism. The objective of the study was to evaluate the rate of ED in a male population with mRCC. Methods One hundred thirty-two male patients with clear cell mRCC were enrolled. All patients were evaluated for erectile function with the 5-item version of the International Index of Erectile Function (IIEF-5) before and after the first cycle/month of the first-line targeted therapy with sunitinib, pazopanib, bevacizumab+IFN, sorafenib, or temsirolimus. Results Median age was 59 years (range 43–67 years). 89 (67%) patients had at least one cardiovascular risk factor. At baseline, IIEF-5 mean score was 19 (SD, 2.6). Patients with 2 and more IMDC risk factors (39%) had a lower IIEF-5 mean score (14; SD, 3.3). 99 (75%) patients reported a negative change in their sexual life since the start of the targeted therapy. 35 (27%) patients had no sexual activity. After the first treatment cycle/month IIEF-5 mean score reduced to 8 (SD, 1.9), which was statistically significant (P 0.05). Conclusions Prospective evaluation in a large cohort of patients with mRCC revealed mild ED (19/25) in the treatment-naive male population and severe ED (8/25) after the first cycle/month of the first-line targeted therapy. Significant decrease in erectile function should be considered as a potential adverse event in male patients undergoing treatment of mRCC with targeted agents. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

574 Background: In multicenter randomized phase 2 study (FARETES) we showed that male patients with mRCC receiving targeted therapy had significantly less fatigue and better symptom control with testosterone undecanoate (T) (MASCC 2018, LBA004). Here we described exploratory endpoints in FARETES study. Methods: Sixty male patients with clear cell mRCC, normal PSA level, low testosterone level and no evidence of hypothyroidism receiving first-line sunitinib or pazopanib with fatigue were randomly assigned (1:1) to either T (Nebido, 1,000 mg) and targeted therapy or targeted therapy alone (control group). T was injected intramuscular deeply on Day 1 of a new treatment cycle. Exploratory endpoints included rate of adverse events (AE) of targeted therapy, duration of targeted therapy, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: As of the data cutoff on October 17, 2018, median (range) follow-up was 15.2 (9.9 -16.5) months. No unexpected toxicity of T was observed. Grade 3-4 targeted therapy-related AE occurred in 11 (37%) and 3 (10%) patients in the control group and T group, respectively. Discontinuation due to AE was observed in 3% (1/30) of patients in the T group and in 17% (5/30) of patients in the control group. ORR and PFS were significantly better in the T group (all P < 0.05, Table). Median OS was not reached in either group. Clinical trial information: NCT03379012. Conclusions: T therapy could decrease rate of serious AE of targeted therapy. Male mRCC patients receiving T had longer duration of targeted therapy, better PFS and ORR. Larger trials are needed to evaluate efficacy of T in this group of patients.[Table: see text]

Haemophilus influenzae type b (Hib) conjugate vaccine was included into the national vaccination schedule of Ukraine in 2006. The objective of this study was to demonstrate the effectiveness of Hib conjugate vaccine against radiologically-confirmed hospitalized pneumonia in children.Children2 years old with radiologically confirmed pneumonia admitted to 11 participating hospitals in Kiev and Dnepropetrovsk between April 2007 and June 2009 were included in a case-control evaluation. Four controls were matched to each case by date of birth (within 14 days) and outpatient clinic. We estimated ORs for vaccination and vaccine effectiveness ((1 - OR)*100%) using conditional logistic regression, adjusting for comorbid conditions and contraindications for vaccination.We enrolled 188 case-children and 735 controls. Median age was 16 months (range 4-24 months). Fifty-one percent of cases and 67% of controls received ≥1 doses of Hib conjugate vaccine; 26% of cases and 37% of controls received ≥3 doses. The effectiveness of ≥1 dose Hib conjugate vaccine was estimated at 45% (95% CI 18%-63%).Our study showed that Hib infections are important causes of hospitalized radiologically confirmed pneumonia in young children in Ukraine.

International audience; Background : Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients.Objective : Our objective was to assess the effect of mycobacterial disease in patients with CGD.Methods : We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria.Results : Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients.Conclusion : Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

Whole-exome sequencing reveals activating STAT1 mutations in some patients with autosomal dominant chronic mucocutaneous candidiasis disease., Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

4569Background: Fatigue is a frequent symptom of metastatic renal cell carcinoma (mRCC), and most common adverse event of treatment with tyrosine kinase inhibitors. The aim of this multicenter rand...

Background Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1 . Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. Objective To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida -exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. Results The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida -induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. Conclusions The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.

e12540Background: RANK is a transmembrane protein which expression has been initially found only in dendritic cells and mature osteoclasts. Soon the notice saying that a RANK-marker expression was ...

e12541Background: Osteoprotegerin – OPG plays a key role in the regeneration of bone and in the development of metastases in them. Overall survival and time of occurrence of bone metastases depends...