N A Romanenko’s research while affiliated with Russian Research Institute of Hematology and Transfusiology and other places

INTRODUCTION . In the Russian Federation, among all malignant diseases in the male population, gastric cancer ranks the 4 th , in women – 5 th place, and in terms of mortality in both sexes from malignant diseases – 2 nd place. During surgical treatment of patients with gastric cancer, anemia is detected in more than ¹ /4 of patients, who significantly worsens the prognosis due to postoperative complications. Timely correction of anemia can reduce the risk of complications during surgical treatment and improve the course of the postoperative period. OBJECTIVE is to evaluate the effectiveness of correction of anemia in the preoperative period and the results of radical surgical treatment in patients with gastric cancer METHODS AND MATERIALS . The article presents the analysis of medical records of 30 patients aged 56–75 years with a diagnosis of gastric cancer complicated by anemia (hemoglobin level < 80 g/l). All patients in the preoperative period for the correction of anemia were prescribed iron (III) hydroxide oligoisomaltose intravenously at the dose of 20 mg/kg 21 days before surgery, due to the detection of iron deficiency in them. RESULTS . The target blood hemoglobin level was more than 95 g/l. In the absence of the desired effect, erythrocyte transfusion was performed. The use of iron preparations made it possible to correct anemia in 14 (46.7 %) patients without resorting to transfusions, in 16 (53.3 %) patients, it was required to additionally transfuse 1 dose of erythrocytes, while earlier in the preoperative anemia was corrected using transfusions of 2–3 doses of erythrocytes. All patients underwent radical surgery with D2 lymph node dissection. Operations were accompanied by blood loss of 201.0±94.4 ml (120–475 ml). It was revealed that radical surgeries for gastric cancer in patients who received anemia correction in the preoperative period are accompanied by a low number of purulent-inflammatory (in 27.3 % of patients) and cardiovascular complications (in 20 % of patients). CONCLUSION . Correction of anemia is a mandatory part of therapy in the preoperative period and allows to perform a full range of radical surgical intervention, improve the safety of surgical treatment and improve the course of the postoperative period.

Aplastic anemia (AA) is a non-neoplastic hematological disease closely associated with bone marrow failure which is typical of paroxysmal nocturnal hemoglobinuria (PNH) and myelodysplastic syndrome (MDS). The PNH clones can be detected in more than a half of AA patients at onset of the disease, and there is a probability for AA/PNH co-variants to progress to classic hemolytic PNH. At the same time, the AA patients treated by immunosuppressive therapy undergo the risk of disease transformation to MDS and acute myeloid leukemia. Currently known risk factors and possible precursors of such transformation are considered in the brief literature review. In addition to that, the paper provides a case report of AA/PNH transformation to MDS during complete AA remission after immunosuppressive therapy combined with a successful haploidentical transplantation of hematopoietic stem cells.

Aim. To study the features of the pathogenesis of anemia in patients with colorectal cancer and metastatic liver damage, as well as to evaluate the effectiveness of etiological correction of anemia in the preoperative period. Methods. 90 patients with colorectal liver metastases and anemia (hemoglobin content 7595 g/L), who were observed at the City Clinical Oncological Center of St. Petersburg between 2014 and 2020, were included. The patients were divided into two groups. The first group consisted of prospectively assessed patients with the preoperative correction of anemia by iron supplements (intravenously 7 mg/kg once a week) and recombinant erythropoietin (subcutaneously 150 IU/kg 3 times a week). The second group included retrospectively assessed patients with the correction of anemia only by red blood cell (RBC) transfusion (13 doses). The groups were comparable for gender [sex ratio (male/female) was 17:31 and 16:26 for the first and the second groups, respectively; p 0.5], age (63.31.4 and 60.21.2 years, respectively; p 0.1) and hemoglobin content (87.41.0 and 86.70.9 g/l, respectively; p 0.2). Results. In studying the causes of anemia, a decrease in the mean serum endogenous erythropoietin level was revealed in most patients (36.71.9 mIU/ml with the required 70 mIU/ml). A decrease in the concentration of serum iron (6.60.3 versus 15.10.8 mol/l) and ferritin (15.51.9 versus 102.48.4 g/ml) levels were revealed. At the same time, there was no difference in the concentration of pro-inflammatory cytokines in patients with anemia and healthy controls (tumor necrosis factor , interleukin-1, interleukin-6; p 0.2), which indicates a low activity of the immune system in response to a tumor, due to conducted chemotherapy. In the preoperative correction of anemia, a positive effect was achieved with both iron supplementation with erythropoietin preparation (the hemoglobin level increased from 87.61.0 to 108.10.9 g/l; p 0.01) and RBC transfusion (from 86.70.9 to 114.60.6 g/l; p 0.01). Conclusion. In patients with colorectal liver metastases, the most common causes of anemia were low levels of erythropoietin and iron deficiency; also for this group of patients, the prescription of erythropoietin and intravenous iron preparations are effective for the preoperative correction of anemia.

Anemia in patients with malignant neoplasms affects the quality of life of the patient and sometimes limits the timely implementation of antitumor treatment. In the pathogenesis of anemia of the malignant neoplasms the largest role play infiltration of the bone marrow by tumor cells, suppression of hematopoiesis by inflammation cytokines, development of functional iron deficiency, reduction of sensitivity of receptors to erythropoietin or its synthesis. The doctor can prescribe effective pathogenetic therapy after evaluating the mechanisms of anemia development in this category of patients. In the article are described in detail the methods of pathogenetic correction of anemic syndrome using parenteral iron preparations, recombinant erythropoietin, indications for their appointment, effectiveness in patients with cancer, as well as possible side effects and complications of therapy. The mechanisms of action, pharmacokinetics, and features of the use of different erythropoietin adents are described. It is shown the effectiveness of erythropoietin preparations in patients with lymphoproliferative disorders based on the results of our own study. A positive response was observed in 77.3 % of patients with non-Hodgkin’s lymphomas, in 61.8 % – with multiple myeloma and 60.9 % with chronic lymphocytic leukemia. It is presented the prognostic factors for the response to erythropoietin therapy and showed own datum in patients with myelodysplastic syndrome (in case of the serum erythropoietin <500 mMU / ml a positive response was found in 35.6 %, with higher level – no response) and with lymphoproliferative disorders (in case of erythropoietin was <130 mMU / ml, the positive response was 80 %, at 130–499 mMU / ml – 63.6 %, and at ≥500 mMU / ml – 25 %). In the article are described the principles of anemia correction using red blood cells transfusions and features of their use in patients with cancer. Special attention is paid to the study of blood saturation as one of the indicators that allow us to assess the adequacy of the gas transport function of blood during red blood cells transfusions. The algorithm for correcting anemia in malignant neoplasms using red blood cells transfusions and erythropoietin agents are presented. It is shown low blood saturation (<60 %) in 32 % hematological malignancie’s patients with a hemoglobin 8.0 g / dL. This datum suggests presence of tissue hypoxia and gives approval to expand the threshold for red blood cells transfusions

Anemia is considered one of the manifistations of many neoplasms affecting the overall survival and reducing the quality of life of patients. The prevalence of anemia varies from 20 to 90% depending on the nosology, the stage of the disease, antitumor treatment. The pathogenesis of anemia in cancer patients is complex. Among pathogenetic factors, such factors are distinguished as tumor infiltration of the bone marrow by malignant cells, inhibition of erythroid growth by cytokines of inflammation, decreased sensitivity of receptors to erythropoietin and its production, increased levels of hepcidin, defects of nutrition, increased deposition and sequestration of blood cells in the spleen, excessive bone fibrosis, hemorrhagic syndrome, antitumor therapy. The article presents the pathogenesis of anemia in oncological disease with a detailed description of the suppressive effect on hematopoiesis of a number of proinflammatory cytokines (interleukin-1, interleukin-6, tumor necrosis factor-, interferon-) produced by cells of the immune system. The mechanism of influence of cytokines on erythropoiesis, synthesis of erythropoietin as well as on the enhancement of hepcidin production in the body is presented in detail. The article also describes the mechanism of impairment of iron kinetics in the body in patients with cancer and subsequent development of functional deficiency. This review of the literature contains up-to-date information about the factors involved in the pathogenesis of anemia in cancer patients, understanding of which will allow the clinical physician to choose a rational way of pathogenetic or substitution correction of anemic syndrome, taking into account the personalized approach to treatment and prevention, especially in patients receiving surgical, chemotherapy, radiation treatment.

Background & Aims. Paroxysmal nocturnal hemoglobinuria (PNH) is a disease caused by an acquired clonal disorder of hematopoietic stem cells with clone cell membrane hypersensitivity to the complement. PNH can exist as an independent disease and can also be associated with other pathological conditions characterized by bone marrow deficiency, first of all with aplastic anemia (AA). In PNH-associated AA (AA/PNH) pathological clones may be initially of different size. In some patients a gradual growth of PNH clone is observed together with occurring signs of intravascular hemolysis and transformation into classical hemolytic PNH. In this case it is important to assess the clinical situation and determine eligibility for complement inhibitor therapy. During targeted therapy it is necessary to assess the efficacy of treatment based on monitoring of complement-mediated hemolysis and to identify probable reasons for insufficient effect. Materials & Methods. The paper deals with 1 clinical case. A female patient born in 1964, with initial diagnosis of AA was followed-up from 1989 till present at the Russian Research Institute of Hematology and Transfusiology. Her treatment included blood-component therapy, the use of antilymphocyte immunoglobulin, cyclosporine, plasmapheresis, eculizumab, and symptom-relieving drugs. Results. The study deals with the case of transformation of non-severe AA with remission after immune-suppressive therapy into classical hemolytic PNH. The case report describes the characteristic features, AA/PNH diagnosis and treatment issues at different stages of the disease, and the reasons for incomplete effect of targeted therapy. Conclusion. The case under discussion confirms the relevance of current methods of detecting PNH clone at early stages of AA diagnosis and dynamic follow-up with respect to a probable growth of clone with PNH phenotype, especially at the stage of hematopoietic recovery. Determination of PNH clone size and lactate dehydrogenase serum level is required for timely amendment of treatment strategy with a switch to long-term targeted monitoring of hemolysis which allows to prevent irreversible visceral changes and severe complications. In case of insufficient effect of targeted therapy with ongoing anemia Coombs test is recommended because of probability of C3-mediated extravascular hemolysis.

Background The insertion of the central venous catheter (CVC) is a vascular access method used in resuscitation and oncohematology and it is required during intensive infusion and chemotherapy. However, due to the invasiveness of the procedure, complications are possible due to the procedure and course of the underlying disease. Aims Assess the frequency of complications related to central vein catheterization in patients with hematology malignancies (HM). Methods We have analyzed 2506 cases of CVC performed to patients with HM for the period from 2003 to 2018. All patients underwent catheterization of the right (82%), left (17.6%) subclavian vein or v. Jugularis externa (0.4%). Bacteriology tests were performed if a catheter‐related infection was suspected (n = 353). Results Out of 2506 catheterizations bloodstream infections in the form of sepsis or bacteremia were documented in 2.5% of patients (n = 63), phlebitis, thrombophlebitis and infiltrate at CVC area were revealed in 2.6% (n = 66), lymphorrhea – in 1.3% (n = 33), catheter bleeding – in 3.9% (n = 73), haematoma – in 4.3% (n = 109), artery puncture (a. Subclavia dextra or sinistra) – in 3.0% (n = 76), pain, numbness, paresthesia of the upper limb – in 1.6% (n = 41), weakness, collapse – in 1.1% (n = 27), pneumothorax – in 0.2% of patients(n = 4). Positive bacterial cultures from venous blood were detected in 63 patients, with mixed infection in 8 cases (2 or 3 microorganisms). Detailed analysis of the infectious pathogens have demonstrated the prevalence of coagulase‐negative staphylococcus (Staph. epidermidis) – 56.3% (n = 40), At the same time, a relatively large percentage was represented by Staphylococcus aureus – 5.7% (n = 4), Micrococcus spp. – 1.4% (n = 1), Enterococcus spp. – 1.4% (n = 1). Gram‐negative microorganisms were detected in 26.7% (n = 19) of cases: Escherichia coli – 14.1% (n = 10) patients, Enterobacter spp. – 5.6% (n = 4), Enterobacter aerogenes – 1.4% (n = 1), Acinetobacter spp. – 1.4% (n = 1), Pseudomonas aeruginosa – 1.4% (n = 1), Neisseria spp. – 2.8% (n = 2). Causative agents of fungal infections were found for 8.5% of patients (n = 6), including fungi of the genus Candida – 7.1% (C. albicans (n = 4), C. crusei (n = 1), Rhodotorula spp. – 1.4% (n = 1). Summary/Conclusion In patients with HM among catheter‐associated infections, coagulase‐negative staphylococcal infection (Staph. epidermidis) is most prevalent, which is most likely due to contact route of infection.

Background It is well known that the effectiveness of stem cell collection and the possibility to harvest suboptimal CD34+ cells number during the single apheresis session is dependent on the number of CD34+ cells circulating in the peripheral blood (PB), i.e. on the effectiveness of mobilization regimen. Aims To determine the rate of unseccessful collections in patients with multiple myeloma (MM) when the number of CD34+ cells circulating in the PB is in accordance with the optimal level 20/1 mkl or more. Methods Retrospective analyses of autotransplant collection in 55 MM patients have been done. Median age of patients was 56 (31‐67) years. Complete response, very good partial response and partial response were diagnosed in 12 (21.8%), 13 (23.6%) and 30 (54,5%) patients accordingly. 25 (45.5%) patients were treated with lenalidomide previously. Cyclophosphamide 3 g/m2 with granulocyte colony‐stimulating factor (G‐CSF) were used for stem cell mobilization in 28 (50.9%) patients. 26 (47.3%) patients were mobilized with vinorelbine 35 mg/m2 with G‐SCF and G‐SCF monotherapy was used in 1 (1.8%) patient. Results The number of CD34+ cells circulating in PB at the day of the first apheresis procedure was 5‐694/1 mkl (Me 118). Median number of collected CD34+ cells was 5.53 × 10/6/kg (0.27‐29.23). The correlation between number of circulating CD34+ cells and the quantity of harvested CD34+ cells was confirmed: r = 0.503; p < 0.05. At the same time there were 7 (12.7%) cases in which the number of collected CD34+ cells were lower than suboptimal level (0.25‐1.9 × 10/6/kg, Me 1.33 × 10/6/kg) despite the successful mobilization rate: 26‐118/1 mkl (Me 44). The second procedure of apheresis was done on the next day and in all cases except for the one there was the possibility to harvest CD34+ cell number enough to perform a single stem cell transplantation: 2.58‐3.48 × 10/6/kg. The place of central veun catheterization has been changed in all these cases except for the one. Summary/Conclusion We suppose that a reason of unseccessful stem cell collection in MM patients with adequate rate of mobilization may be disturbance of the bloodstream speed in the apheresis system due to the anatomical characteristics of subclavia vein localization. A method to correct the problem is relief the central catheter puncture place.

Background Aplastic anemia (AA) is severe blood system disease, in which more than half of patients may have PNH clone, and there may occur associated variants AA with PNH (AA/PNH). The most frequently observed is the development of classical hemolytic PNH at AA remission, but possibly a combination of the two diseases. For such cases, there is a positive experience of AA combined treatment with immunosupressive therapy (IST) and targeted therapy using complement activation inhibitors. With resistant AA a therapeutic optionis possible using thrombopoietin receptor agonists. Aims To treat of patient with SAA/PNH in absence of possibility of full use of IST Methods A clinical observation of a 53‐year‐old female with AA/PNH in the course of the disease is presented. Since 1994 patient, aged 53 yrs, has been under our supervision. The diagnosis was established according to a comprehensive examination, with severity determination in accordance to international criteria. The examination used morphological, histological, immunological (including highly sensitive flow cytometry), biochemical methods. No compatible donor for bone marrow transplantation was found. Anti‐lymphocyte globulin (ALG), cyclosporin‐A (CyA), Eculizumab and thrombopoietin receptor agonists were used in treatment. Results ALG and cyclosporine treatment gave only a temporary effect – an improvement in hemogram parameters and a reduction in transfusion dependence. CyA doses were reduced (about 3 mg per day) due to adverse effects. The possibilities of active IST were also limited by comorbidities, including chronic hepatitis B. Since 1999, signs of chronic intravascular hemolysis and hemolytic crises have been observed. Flow cytometry have detected PNH clone. Subsequently, according to ICNN protocol testing data, from 2011 to the present, the clone size was determined 96‐99% with a predominance of type III erythrocytes. According to repeated bone marrow assessments, severe aplasia with pancytopenia in the peripheral blood was maintained. Anemia persisted up to 65 g/dL with transfusion dependence (up to 12‐16 doses of red blood cells per year), leukopenia within 0.9‐1.5 x10 ⁹ /l and thrombocytopenia 5‐15 x10 ⁹ /l with cutaneous hemorrhagic syndrome. On 2013, after vaccination with meningococcal vaccine, Eculizumab treatment was started according to the standard scheme with achievement of an adequate control of hemolysis. Clinical manifestations of hemolysis are absent; the level of LDH does not exceed 1.5 ULN. Therapy continues to the present. Until 2015, CyA therapy was periodically resumed due to the persistence of SAA criteria. In 2013‐2015 the patient additionally received thrombopoetin agonist therapy: Romiplostimum (4‐6 ug/kg once a week) with breaks every 3‐4 months. Two months after the start of therapy, a clinical effect was obtained – a decrease in hemorrhagic syndrome. After 3 months, there was a trend towards an increase in platelet levels. At present, severe leukopenia (1.0 – 2.2 x10 ⁹ /l) and neutropenia (0.5‐0.7x10 ⁹ /l) persist. At the same time, the platelet level is 30‐70 x10 ⁹ /l without spontaneous hemorrhages, since January 2018 the patient does not receive blood transfusions and hemoglobin stays at 10.2‐11.0 g/dL. Also there has been a significant improvement in the quality of life. Summary/Conclusion This case demonstrates the possibility of a significant improvement in the course of sAA/PNH (including quality of life) in the absence of a sufficient effect of IST, but adequate target control of hemolysis and the use of thrombopoietin receptor agonists.

The article is dedicated to administration of human intravenous immunoglobulin for patients with different pathology accompanied by immunity disorders. Pharmacokinetics of human intravenous immunoglobulin and mechanisms of its action are presented in detail. Capabilities for its use as replacement (in immunodeficiencies, agammaglobulinemia) and immunomodulatory therapy (in autoimmune disorders) are discussed. We present algorithms for correction treatment with intravenous immunoglobulin of lymphoproliferative diseases (such as chronic lymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma), patients after hematopoietic stem cell transplantation with recurrent infections, patients with different autoimmune diseases including systemic collagenosis (systemic lupus erythematosus, systemic vasculitis, systemic sclerosis), autoimmune agranulocytosis, immune thrombocytopenia. Capability for the use of intravenous immunoglobulin is considered for treatment of different septic, septicotoxemic complications, herpetic infections (cytomegalovirus infection, infection caused by Epstein-Barr virus) occuring in oncology, surgical and obstetric practice as well as for complex treatment of sepsis including in neonates. The article presents in detail the used doses of intravenous immunoglobulin and methods of its infusion for different groups of diseases. Timely administration of intravenous immunoglobulin in optimal doses allows reducing the duration of treatment of active infection in patients with immunosuppresion of different causes, bleeding in immune thrombocytopenia, intensity of autoimmune disease manifestation as well as reducing the risk of severe infection in innate and acquired agammaglobulinemia without serious adverse effects.