Assessment of iron metabolism disorders and adequate treatment of anemic syndrome in patients with breast cancer on the background of adjuvant chemotherapy.

Early and adequate correction of the anemic syndrome (AS) of cancer patients can prevent deterioration in the quality of life and be considered as a reserve for increasing the effectiveness of treatment for breast cancer (BC). The aim of the study was to assess the status of iron using modern methods of ferrokinetics in breast cancer patients on the background of adjuvant chemotherapy for early diagnosis and adequate treatment of AS. The object of the study included 21 breast cancer patients with a relatively favorable prognosis, with luminal types A and B (Her 2 / neu positive or negative), three times negative type. The examination was carried out in the postoperative period, against the background of adjuvant chemotherapy. The main metabolites of ferrokinetics were studied: hepcidin 25 (GP25); ferritin (FR); soluble transferrin receptors (rRTP); transferin (TRF); iron (Fe); erythropoietin (EPO); CRP and IL-6 indicators. AC correction was performed (ferinject, epotin-alpha, B12). 10 (47.6%) patients with breast cancer had AS. Most of them were diagnosed with IDA with microcytic, hypochromic characteristics of erythrocytes, low concentration of FR, Fe, GP25, IL-6, CRP, and high levels of TRP and rRTP. Functional iron deficiency (FDF) was established in some patients. In contrast to patients with IDA, they had a high concentration of FR, CRP and significant production of GP25, IL-6. The EPO level was not optimal for the majority of patients with AS. In isolated cases, during treatment with recombinant erythropoietins, a deficiency of vitamin B12 (cyanocobalamin) was revealed. The rational use of iron preparations, vitamins, and recombinant forms of EPO made it possible to restore Fe metabolism, stabilize the hemoglobin level, and also improve the condition of most breast cancer patients. The obtained data on IL-6, GP25, CRP indicate a certain relationship between them in the development of anemia with VDF in breast cancer patients and the need for further study of the characteristics of iron metabolism in cancer patients.

Оxidative stress and endogenous intoxication in cancer patients.

In the blood serum of 93 patients with various localities of the malignant process, the content of nitric oxide (NO), indicators of lipid peroxidation (POL): superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione in red blood cells were determined. 9 patients with ovarian cancer were examined during chemotherapy (6 courses), 40 patients with colon cancer, previously operated, were with malignant liver damage. In 39 patients with anemia, NO indicators were compared with the level of interleukin 6 (IL-6) and hepcidin-25 (GP-25). As a control, 60 practically healthy individuals were examined. It was shown that the NO content was significantly reduced in 69.7% of patients, regardless of the location of the primary tumor. There was a gradual increase in the NO content before each course of chemotherapy. A high concentration of NO (more than 22 µM) was detected in 22 patients with functional iron deficiency (FJ) against the background of anemia of chronic diseases (AHZ), which was accompanied by hyperexpression of IL-6 (27.0±10.5 pg/ml) and GP-25 (25.2±7.1 ng/ml). In contrast, the lowest NO values (less than 22 µM) were observed in 17 patients with IDA. There is no doubt that there is a certain relationship between the development of oxidative stress with the accumulation of highly toxic lipoperoxidation products that affect the overall homeostasis of the body, and the development of anemic syndrome.

The role of interleukin-6 and hepcidin 25 in the pathogenesis of anemic syndrome associated with malignant neoplasms with breast cancer patients before neoadjuvant chemotherapy.

A study of interleukin-6 (IL-6), hepcidin-25 (GP-25) was conducted in 22 patients with breast cancer before neoadjuvant chemotherapy and in 27 healthy women in the control group. Significant expression of the GP-25 protein was revealed in breast cancer patients, compared to control. The rates were high both in patients with anemic sindrome (AS) and without it (p <0.01). Latent iron deficiency, AS, IDA and functional iron deficiency (FJ) were more often detected in patients with stage III disease. A significant difference in the parameters of GP-25 and IL-6 was noted, the indicators were higher in patients with stage III (p <0.01). No close correlation was found between IL-6, GP-25 and other acute-phase proteins (FR, CRP) at the initial stages of AS formation. On the contrary, a positive correlation was observed in patients with IDA and FJ between IL-6 and all acute-phase proteins (GP-25, FR, CRP). However, a small number of observations do not allow an unambiguous conclusion about the role of IL-6 and GP-25 expression in the development of AS in cancer patients with breast cancer and requires further study.

Morphological and functional features of peripheral blood neutrophils in cancer patients with sepsis in the early postoperative period (review of literature and results of our own studies).

The study was performed in 9 cancer patients with sepsis. A clinical blood test of patients with sepsis was accompanied by a neutrophilic leukemoid reaction, with the appearance in the differential count of white blood cells of young cells (myelocytes, metamyelocytes). According to the literature, it is shown that in severe sepsis, a local infection is accompanied by systemic of neutrophil activation (NF). Moreover, excessive activation and location of NF in the microvasculature, especially its young forms and the formation of extracellular trap networks (NETs), can contribute to pathological manifestations of multiple organ failure and thrombosis.

[Characterization of anemic syndrome in cancer patients with sepsis in the early postoperative period.]

A study of the main indicators of red blood (RBC, HGB, HCT, MCV, MCH) and the concentration of EPO, sTfR in 9 cancer patients with anemic syndrome (AS) against sepsis was carried out. Among them, patients with chronic disease anemia (ACh), with normocytic, normochromic characteristics of red blood cells and low hematocrit predominated. In 2 patients, microcytosis and erythrocyte hypochromia were noted, the concentration of sTfR was significantly higher than normal (0.9 ± 0.07 µg / ml), amounted to 2.7 µg / ml in one of them and 1.9 µg / ml in the other, which testified to t iron deficiency erythropoiesis (IDE) on the background of the ACh,. In 7 patients with ACh without IDE, sTfR values were within the normal range (0.1-1.2) µg / ml, the median was 0.5 µg/ml. In all patients with sepsis, the production of EPO was inadequate for the severity of the AS, to a lesser extent in patients with IDE. The average EPO production in the group was 19.4 ± 5.1 (7.7-52.8) mU / ml, median = 12.1 mE / ml. Further studies of EPO, sTfR are planned in order to determine their role in therapeutic tactics in the correction of AS in cancer patients with sepsis.

[Modern ferrokinetics metabolites in the diagnostics of anemic in patients with disseminated stages of Hodgkin's lymphoma when conducting intensive chemotherapy.]

Evaluation of anemic syndrome (AS) was performed in 79 patients with advanced stages of Hodgkin's lymphoma (LH) at various stages of chemotherapy (CT) according to the EACOPP-14 scheme. Against the background of the treatment, the number of erythrocytes and, accordingly, the HCT indices decreased with each subsequent cycle of chemotherapy (CTC) and reached the maximum reduction to 5, 6 th CCT. Absolute iron deficiency (IDA), which was combined with a low level of EPO and an inadequate degree of anemia, was found in a few LH patients (5 people, 6.3%). Functional iron deficiency (FDZH) was diagnosed in 9 patients (11.4%), had the same morphological signs as IDA. Namely, microcytosis, erythrocyte hypochromia and low hemoglobin content in reticulocytes (RET-HE). In contrast to IDA, patients with FDZh concentration of FR, GP-25 and IL-6 were high. Despite the fairly large reserves of iron, the level of rRTF testified to the "iron hunger" of the erythrocariocytes of the bone marrow, its index exceeded the upper limit of the norm, while RET-HE was low. In 34 (43%) patients, LH revealed a deficiency of endogenous erythropoietin (EPO), which was observed not only in patients with AHZ, but also in patients with IDA. Lower levels of EPO were detected in patients with leukopenia and very low erythropoietic activity of the bone marrow.

[Development of strategic approaches to modern diagnosis of anemic syndrome in patients with breast cancer.]

A study of the clinical analysis of blood and major metabolites of ferrokinetics in 107 breast cancer patients before treatment was conducted. In 31 (28.9%) patients revealed anemic syndrome (AS). A feature of the AS is pronounced microcytosis, erythrocyte hypochromia and low hemoglobin content in reticulocytes. Most often (n = 22; 71%) there was iron deficiency (IDA), which was characterized by a low concentration of iron (F), ferritin (FR), hepcidin 25 (GP25), interleukin-6 (IL-6) and high - soluble transferrin receptors (rTFR), transferrin (TRF). In 9 (29%) patients with AS, on the basis of a high concentration of FR, GP25, IL-6, the anemia of chronic disease (AHZ) with functional iron deficiency (FDI) was established. In 23 (74.2%) patients with AS, the was a deficiency of erythropoietin (EPO), the lowest rates were found in the group of patients with a common tumor process and FDI, with less in patients with IDA.

[The main metabolites ferrokinetics in differential diagnostic of anemic syndrome with microcytic, hypochromic characteristics of erythrocytes in patients with colorectal cancer.]

The clinical analysis of blood and main metabolites of ferrokinetics was implemented before treatment in 46 patients with colorectal cancer mainly in stage III-IV. The analysis of obtained results demonstrated that the technique of detection of hepcidin 25 can be used as an additional diagnostic criterion of anemic syndrome in complex with ferritin, soluble receptors of transferrin and expanded clinical analysis of blood. This is especially important in differential diagnostic of anemia of chronic diseas combined with iron-deficiency anemia and anemia of chronic disease with functional iron deficiency because treatment differs in the main. The perspective consists in pathogenic approach to treatment of anemia of chronic disease in oncologic patients using anti-hepcidin medications on the basis of antibodies to hormone, inhibitors and blockers of its expression under control of concentration of hepcidin.

[THE DIFFERENTIAL DIAGNOSTIC POSSIBILITIES IN EVALUATION OF IRON-DEFICIENT CONDITION UNDER ANEMIAS].

The article presents data concerning differential diagnostic possibilities of evaluation of genuine iron-deficient anemia and anemia of chronic diseases. The variety of mechanisms of development of anemia of chronic diseases is demonstrated, including effect of humoral inhibitors of erythropoiesis, disorder of iron metabolism at the expense of its redistribution into cells of macrophage system, suppression of erythropoiesis resulted in redistributed or functional iron deficiency. The data is presented concerning significance in diagnostic of anemia of chronic diseases of such factors as content of ferritin, dissolving receptors of transferrin and role of hepcidin protein in pathogenesis of anemia of chronic diseases. The analysis of scientific publications demonstrated that hepcidin is a negative regulator of iron metabolism. Under iron-deficient anemia its level in blood decreases that contribute to extensive absorption of iron in gastrointestinal tract. On the contrary, under anemia of chronic diseases its content drastically increases and results in blocking of iron transport everywhere, including internal epithelium, macrophages, placenta and other types of cells. The hyper-production of hepcidin during infection and inflammation is responsible for anemia of chronic diseases. The perspectives of development of pharmaceuticals decreasing level of hepcidin for treatment of anemia of chronic diseases is demonstrated.

[Differential diagnosis of anemia in true and functional iron deficiency in patients with chronic diseases (malignant tumors)]. / Differentsial'naya diagnostika anemicheskogo sindroma pri istinnom zhelezodefitsitnom sostoyanii i funktsional'nom defitsite zheleza u bol'nykh s khronicheskimi zabolevaniyami (zlokachestvennymi novoobrazovaniyami).

AIM: To make a differential diagnosis of true and functional iron deficiency (ID) in anemia of chronic diseases (ACD). MATERIALS AND METHODS: A total of 540 patients (785 investigations) and 311 healthy individuals (a control group) were examined. Among them, there were 118 cancer patients admitted for surgical treatment and 226 for chemotherapy (CT), 56 blood cancer patients, 86 with breast diseases without anemia, and 54 workers of the institute with the signs of ID. An enzyme immunoassay was used to determine the plasma levels of ferritin (FR), soluble transferrin receptor (sTFR), and endogenous erythropoietin (EPO). RESULTS: 183 cancer patients did not receive specific treatment, 161 had different cycles of CT. In true ID, anemia was microcytic (average red blood cell size, <80.0 fl) and hypochromic (mean corpuscular hemoglobin concentration, <27.0 pg) with low FR levels (less than 20 ng/ml) and high sTFR concentrations (more than 4.0 µg/ml). The EPO level corresponded to the degree of anemia and was 4-5-fold the normal values. In ACDs, 292 (55%) patients had normocytic normochromic anemia with high FR levels (more than 100 ng/ml), the level of sTFR was low and that of EPO did not correspond to the degree of anemia in 74% of the patients. Functional ID was detected in 108 (37%) cancer patients in the presence of ACD. Despite high FR levels and low sTFR, anemia in Hodgkin's and non-Hodgkin's lymphomas was hypochromic microcytic, which may be considered as severe functional ID in ACD. CONCLUSION: In addition to a clinical blood test, the pharmacokinetic parameters (FR, sRFR, and EPO) should be determined for the differential diagnosis of true and functional ID.

[The main metabolites of ferrokinetics in differentiated diagnostic of anemic syndrome].

The article presents data concerning clinical significance of interleukin 6, hepcidin-25 and its predecessor prohepcidin in differentiated diagnostic of anemic syndrome. The sampling of 192 workers of the oncologic center undergoing annual dispensarization was examined. The genuine reference values for immune enzyme (interleukin 6, hepcidin-25, prohepcidin, soluble receptors of transferrin, ferritin, erythropoietin) techniques are presented. The analysis of results demonstrated that values of interleukin 6, hepcidin-25, prohepcidin can be applied as additional diagnostic criteria of anemic syndrome and especially in differentiated diagnostic of anemia of chronic disease with functional iron deficiency. The carried out study is a new perspective direction of modern concept of iron metabolism in patients with anemic syndrome.

[The anemic syndrome in patients with prevalent stages of Hodgkin's lymphoma under application of intensive chemotherapy according the scheme EACOPP-14.]

The sampling of 61 patients with prevalent stages of Hodgkin's lymphoma at various stages of chemotherapy became subject of clinical blood analysis and evaluation of anemic syndrome. The anemia of I-IV degrees was diagnosed in all patients with Hodgkin's lymphoma. Among them patients with anemia of chronic disease prevailed. The single cases of iron-deficient and auto-immune hemolytic anemia were marked. In 24 patients with Hodgkin's lymphoma (39.3%) the deficiency of endogenous erythropoietin which was marked in both patients with anemia of chronic disease and patients with iron-deficient anemia. The lower level of endogenous erythropoietin was fixed in patients with leukopenia and very low erythropoietic activity of marrow. In 8 patients (13.1%) functional deficiency of iron against the background of anemia of chronic disease was established. Therefore, anemic syndrome in patients with prevalent stages of Hodgkin's lymphoma both inactive phase of disease and during application of chemotherapy represents complicated complex of symptoms. It requires accurate laboratory analysis and individual approach in treatment that in turn will favor optimal efficiency of therapy.

[Oxidative stress in platelets at an oncopathology].

To determine the biochemical disorders in the blood coagulation mechanism associated with oxidative stress parameters of the antioxidant status were examined in platelets of 57 colorectal cancer patients, (including 21 patients before and after surgery), and 40 healthy individuals. We determined the total content of nitric oxide (NOx), levels of superoxide dismutase (Cu/ZnSOD), glutathione and malondialdehyde (MDA). Before treatment, we observed the changes in the antioxidant defense system of platelets, which did not depend on the prevalence of malignancy: elevated levels of SOD by 16% (p<0.05), reduced glutathione and MDA in 5.2 and 1.7 times, respectively. NOx levels did not differ from the norm. Significant shifts were found in the postoperative period: they consisted of the increase in the generation of NOx both on the third, and on the 10-th day after surgery. These changes reflect apparently platelet response to the inflammatory process associated with the surgical trauma and confirm the role of NOx as a mediator of inflammation. The content of SOD after surgery was significantly reduced, but return to a baseline on the 10-th day. Despite the significant increase in the number of platelets, no correlations of the studied parameters and their aggregation ability were found.The findings suggest that metabolic disorders in vascular-platelet hemostasis are associated with oxidative stress, which provides a basis for further study of the relationship of cancer to thrombosis.

[The characteristics of anemic syndrome in patients with prevalent phases of Hodgkin lymphoma before treatment].

The study was carried out to analyze peripheral blood covering 23 patients with prevalent phases of Hodgkin lymphoma received no treatment previously. The clinical analysis of blood was implemented using hematologic analyzer Sysmex XE-2100. The content of ferritin, soluble receptors of transferrin and erythropoietin was estimated using enzyme-linked immunosorbent assay. The free hemoglobin was estimated using hemoglobin cyanide method. The direct Coombs test, counting of leukogram and analysis of morphology of erythrocytes were applied to all patients. The anemia is diagnosed in 19 patients (83%). In 18 out of them the anemic syndrome corresponded to anemia of chronic disease and in one patient asiderotic anemia was established. The rest of patients had no anemia. The anemia of chronic diseases characterized by microcytosis and hypochromia of erythrocytes, inadequate degree of anemia by production of erythropoietin and functional deficiency of iron in most of the patients. It should be emphasized that anemia of chronic diseases commonly is normocyte normochrome anemia whereas in patients with prevalent phases of Hodgkin Iymphoma the microcyte hypochrome anemia was detected before the treatment and it was followed by functional deficiency of iron. In patients without anemic syndrome microcytosis and hypochromia of erythrocytes were marked too. The techniques of laboratory diagnostic objectively reflecting iron metabolism (evaluation of level of soluble receptors of transferrin andferritin) and appropriate hormonal response to degree of anemia (production of erythropoietin) are to be included into algorithm of treatment of patients. The purpose is to timely detect type of anemia with the purpose of its appropriate correction prior to treatment onset.

[The possibilities of modern automated clinical blood analysis in differentiated diagnostic of true and redistributing (functional) iron deficiency under anemic syndrome in oncologic patients].

The clinical blood analysis implemented at modern hematological analyzers can be used as a foundation for primary differentiated diagnostic of anemic syndrome related to true and functional iron deficiency in oncologic patients. The normocyte normochromic anemia with normal and higher level of hemoglobin of reticulocytes (RET-HE) testifies presence in higher degree of anemia of chronic diseases which is more often combined with higher content of serum ferritin (Ferr), lower level of soluble receptors of ferritin (sTfR) and production of erythropoietin (EPO) inadequate to anemia degree. The microcyte hypochromic anemia can be present both under iron-deficient anemia and under functional iron deficiency as a result of its blocking in macrophages under anemia of chronic diseases in oncologic patients. Hence the differentiated diagnostic of these states demands additional analysis of content of serum ferritin, soluble receptors of ferritin and production of erythropoietin.

[The algorithm of modern laboratory diagnostics of anemic syndrome in oncologic patients].

The algorithm of analysis of blood of oncologic patients with anemic syndrome was elaborated using large clinical sampling (n = 284). It is established that 72% of oncologic patients developed anemia by kind of chronic diseases anemia. However in some patients the anemic syndrome was caused by the iron deficiency The cases of B12 deficient, autoimmune hemolytic anemia were registered and inefficient erythropoiesis under metastatic lesion of bone marrow and myelodysplasia syndromes as well. The high importance of methods of objective evaluation of iron resources (level of ferritin and soluble receptors of transferrin), erythropoietic activity of bone marrow (reticulocytes and reticulocyte indices) and adequate response to anemia degree (level of endogenic erythropoietin). The possibility to detect the concentration of hemoglobin in reticulocytes makes it possible to monitor the restoration of hemoglobin content on early stages of treatment of patient with iron deficiency anemia.

[Determination of anti-Xa activity in cancer patients].

Low molecular-weight heparins (clexan, fraxiparin, fragmin) were used in cancer patients to prevent hemostatic system disorders and related complications. The adequacy and safety of therapy were assessed measuring plasma anti-Xa activity in 239 patients. When the prophylactic doses of the low molecular-weight heparins clexan, fraxiparin, and fragmin were given, their anticoagulative effect was similar as judged from anti-Xa activity. Clexan exhibited the maximum anti-Xa activity when the therapeutic doses of the low molecular-weight heparins were used.

[Low molecular-weight heparin (clexane) in the prevention of thrombotic events in patients with malignancies].

The basic links of the hemostatic system and the markers of intravascular thrombogenesis were studied, by using an automatic STA Compact analyzer in 80 patients with locomotor tumors. The patients were divided into 2 groups: 1) 50 patients received clexane, 40 mg, 12 hours before and within 7-18 days after surgery (a study group); 2) 30 patients underwent only nonspecific prevention of thrombotic events (a control group). Postoperatively, hypercoagulation was shown to persist long (up to 18 days) in patients with locomotor tumors. Clexane used in the pre- and postoperative periods within 18-20 days was effective in reducing the rate of intravascular blood coagulation, preventing thrombotic events, and failing to cause hemorrhages.