Anemia of Chronic Disease: Key Mechanisms of Pathogenesis in Patients with Malignancies and Feasible Classification Approaches

VT Sakhin1, ER Madzhanova1, EV Kryukov3, AV Sotnikov2, AV Gordienko2, OA Rukavitsyn3

1 1586 Military Clinical Hospital, 4 Mashtakova str., Moscow Region, Podolsk, Russian Federation, 142110

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3 NN Burdenko Central Military Clinical Hospital, 3 Gospital’naya sq., Moscow, Russian Federation, 105229

For correspondence: Valerii Timofeevich Sakhin, MD, PhD, 4 Mashtakova str., Moscow Region, Podolsk, Russian Federation, 142110; Tel.: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

For citation: Sakhin VT, Madzhanova ER, Kryukov EV, et al. Anemia of Chronic Disease: Key Mechanisms of Pathogenesis in Patients with Malignancies and Feasible Classification Approaches. Clinical oncohematology. 2019;12(3):344–9 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-344-349


ABSTRACT

Aim. To study the effect of hepcidin, soluble transferrin receptor (sTfR), and cytokines on iron metabolism and occurrence of anemia in patients with malignancies and to propose, on this basis, a draft classification of anemia of chronic disease (ACD) based on the major pathogenic factor.

Materials & Methods. The trial included 63 patients with malignancies of stage II/IV: 41 patients with anemia (34 men, 7 women, mean age 67.1 ± 9.9 years), 22 patients without anemia (17 men, 5 women, mean age 60.2 ± 14.9 years). Comparative analysis was based on the values of iron metabolism, C-reactive protein (CRP), hepcidin, sTfR, as well as pro-inflammatory (interleukin-6 [IL-6], tumour necrosis factor α [TNF-α]) and anti-inflammatory (IL-10) cytokines in solid malignancy patients with and without anemia. The correlation analysis between IL-6, IL-10, TNF-α, hepcidin, sTfR, and blood count was performed.

Results. Compared with the control group patients with anemia show lower levels of iron concentration, total iron-binding capacity (TIBC), and percent transferrin saturation (TSAT), as well as higher level of CRP, hepcidin, sTfR, IL-6, IL-10, and TNF-α (< 0.05). IL-6 (r = –0.58), TNF-α (r = –0.32), and hepcidin (r = –0.57) proved to negatively affect erythrocyte level. A negative correlation was established between hemoglobin concentration and IL-6 (r = –0.57), IL-10 (r = –0.64), TNF-α (r = –0.65), hepcidin (r = –0.3), and sTfR (r = –0.57). A correlation was identified between concentrations of hepcidin and IL-6 (r = 0.58), IL-10 (r = 0.33), TNF-α (r = –0.4), as well as between concentrations of sTfR and IL-10 (r = 0.58), TNF-α (r = –0.53). A relationship was identified between IL-6 concentration and iron status (r = –0.38), TIBC (r = –0.56), TSAT (r = –0.31), ferritin (r = 0.56), transferrin (r = –0.72), CRP (r = 0.86) as well as between concentrations of IL-10 and iron (r = –0.63), TSAT (r = –0.67), transferrin (r = –0.7), ferritin (r = 0.55), CRP (r = 0.65), TIBC (r = –0.71). A correlation between the levels of TNF-α and TIBC (r = –0.36), transferrin (r = –0.5) was confirmed.

Conclusion. The paper deals with multi-factorial pathogenesis of anemia in patients with malignancies. Most important factors are iron deficiency and erythropoietic disorder. A draft ACD classification based on the major pathogenic factor of anemia (ACD with dominating iron deficiency, ACD with impaired regulatory mechanism of erythropoiesis, and ACD with insufficient erythropoietin production) is proposed.

Keywords: cancer, anemia, iron metabolism, interleukin-6, interleukin-10, tumor necrosis factor alpha, hepcidin, soluble transferrin receptor.

Received: January 21, 2019

Accepted: June 18, 2019

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Pathogenetic Characteristics of Anemia in Patients with Solid Tumors

VT Sakhin1, ER Madzhanova1, EV Kryukov3, AV Sotnikov2, AV Gordienko2, OA Rukavitsyn3

11586 Military Clinical Hospital, 4 Mashtakova str., Podolsk, Russian Federation, 142110

2SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3NN Burdenko Main Military Clinical Hospital, 3 Gospitalnaya sq., Moscow, Russian Federation, 105229

For correspondence: Valery Timofeevich Sakhin, PhD, 4 Mashtakova str., Podolsk, Russia, 142110; Tel.: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

For citation: Sakhin VT, Madzhanova ER, Kryukov EV, et al. Pathogenetic Characteristics of Anemia in Patients with Solid Tumors. Clinical oncohematology. 2017;10(4):514–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-514-518


ABSTRACT

Aim. To study the impact iron metabolism disturbances and cytokine levels on the development of anemia in patients with solid tumors.

Materials & Methods. The research included 42 patients with malignant neoplasms, including 24 patients with anemia (19 men and 5 women, median age 67.7 ± 10 years) and 18 patients without anemia (15 men, 3 women, median age 65.7 ± 14 years). Anemia was diagnosed according to the WHO criteria (in men: erythrocytes < 4.0 × 1012/L, hemoglobin < 130 g/L, hematocrit < 39 %; in women: erythrocytes < 3.8 × 1012/L, hemoglobin < 120 g/L, hematocrit < 36 %).

Results. A comparative analysis of iron metabolism in patients with and without anemia was performed. The lower values of serum iron and transferrin saturation in patients with anemia were shown (< 0.05). The total iron-binding capacity, the levels of ferritin, transferrin, C-reactive protein, indirect bilirubin were similar between groups (> 0,05). Higher levels of interleukins 6 and 10 (IL-6 and IL-10) were observed in patients with anemia (< 0.05). For IL-6, correlations were observed with levels of erythrocytes (r = –0,58), hemoglobin (r = –0,57), hematocrit (r = –0,52), and leukocytes (r = 0,42). The levels of IL-10 slightly correlated with the levels of erythrocytes, leukocytes, platelets, MCV, and MCH (r < 0.3). For IL-10, correlations were established with levels of MCHC (r = –0,71), hemoglobin (r = –0,64) and hematocrit (r = –0,32). Correlations between the levels IL-6, IL-6 and hemoglobin, erythrocytes and several color indices may indicate their influence on the development of anemia in patients with malignant neoplasms.

Conclusion. A functional iron deficiency in patients with anemia was found. Several causes of anemia development and significant role of interleukins in anemia pathogenesis were also discovered.

Keywords: cancer, anemia, iron metabolism, interleukin-6, interleukin-10.

Received: March 21, 2017

Accepted: June 22, 2017

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  4. Waters JS, O’Brien MER, Ashley S. Management of anemia in patients receiving chemotherapy. J Clin Oncol. 2002;20(2):601–3. doi: 10.1200/JCO.2002.20.2.601.
  5. Grotto HZ. Anaemia of cancer: an overview of mechanisms involved in its pathogenesis. Med Oncol. 2008;25(1):12–21. doi: 10.1007/s12032-007-9000-8.
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  11. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011–23. doi: 10.1056/nejmra041809.
  12. Maccio A, Madeddu C, Massa D, et al. Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia. Blood. 2005;106(1):362–7. doi: 10.1182/blood-2005-01-0160.
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Pathological Metabolism of Methionine in Malignant Cells Is a Potential Target for the Antitumor Therapy

VS Pokrovskii1, DZh Davydov1, NV Anufrieva2, DD Zhdanov3, EM Treshchalina1, TV Demidkina2, EA Morozova2

1 NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 VA Engelhardt Institute of Molecular Biology, 32 Vavilova str., Moscow, Russian Federation, 119991

3 VN Orekhovich Institute of Biomedical Chemistry, 10 bld. 8 Pogodinskaya str., Moscow, Russian Federation, 119121

For correspondence: Vadim Sergeevich Pokrovskii, DSci, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: 8(499)324-14-09; e-mail: vadimpokrovsky@yandex.ru

For citation: Pokrovskii VS, Davydov DZh, Anufrieva NV, et al. Pathological Metabolism of Methionine in Malignant Cells Is a Potential Target for the Antitumor Therapy. Clinical oncohematology. 2017;10(3):324–32 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-324-332


ABSTRACT

This review presents the characteristics of the cellular metabolism of methionine, as well as known data on the mechanisms of the development of methionine dependence in malignant cells. The possibilities of using a non-methionine diet for the control of the tumor growth in patients with various forms of cancer are considered. The newest information about methionine-γ-lyase, an enzyme providing elimination of methionine from plasma, is grouped and summarised. Its role as a potential antitumor enzyme is disclosed. Data on methionine-γ-lyase producers, activity of this enzyme, obtained from various sources, and information on tumor models and cell cultures, showing methionine dependence are summarised.

Keywords: methionine-γ-liase, methionine, methionine dependency, cancer cells, cancer, anticancer enzymes, antitumor therapy.

Received: December 16, 2016

Accepted: March 6, 2017

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Chromothripsis in Oncology: Literature Review and Case Report

NN Mamaev1, TL Gindina1, EG Boichenko2

1 RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

2 Municipal Children’s Hospital No. 1, 14 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

For correspondence: Tat’yana Leonidovna Gindina, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel: +7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

For citation: Mamaev NN, Gindina TL, Boichenko EG. Chromothripsis in Oncology: Literature Review and Case Report. Clinical oncohematology. 2017;10(2):191–205 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-191-205


ABSTRACT

The article presents a clinical case and literature review dwelling on the recently discovered chromothripsis phenomenon in oncology. Chromothripsis is a type of complex genome changes when a chromosome is first torn into dozens and even thousands of fragments, and then these fragments are bound in a random manner. Sometimes, several chromosomes are involved in the restructuring. As a result, genome mutant zones are formed which trigger malignancies and congenital diseases. In other words, the use of certain methodological approaches (multicolor fluorescence in situ hybridization, SKY technique, and some others) permits to observe under a microscope the splitting of two or more chromosomes and further reunification of these fragments into new unusual two- or multicolor structures, chromosomal markers. Chromothripsis is a rare phenomenon with a peculiar pattern observed in clones of cells of various tumors including hematopoietic and lymphoid tissue malignancies. There are published data on a higher incidence of this phenomenon in patients with myelodysplastic syndromes and bone tumors. TP53 gene mutations play an important role in the development of chromothripsis. The use of paired-sequencing DNA or SNP approaches in oncology is promising both in theoretical and clinical application. The first subject cohort should include patients with TP53 and MLL gene mutations, complex chromosomal aberrations, EVI-1 gene overexpression, and some others. The article presents the chromothripsis phenomenon in an 8-month-old girl with M7 acute myeloid leukemia.

Keywords: chromothripsis, oncohematology, cancer, TP53 gene mutations.

Received: October 2, 2016

Accepted: January 6, 2017

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Anemias in Oncology: Potential of Maintenance Therapy

AV Snegovoi, VB Larionova, LV Manzyuk, IB Kononenko

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Anton Vladimirovich Snegovoi, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-41-09; e-mail: anvs2012@gmail.com

For citation: Snegovoi AV, Larionova VB, Manzyuk LV, Kononenko IB. Anemias in Oncology: Potential of Maintenance Therapy. Clinical oncohematology. 2016;9(3):326-35 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-326-35


ABSTRACT

Development of anemia during chemotherapy or chemoradiotherapy of malignancies is a serious adverse event negatively affecting the quality of life and effectiveness of the treatment. In this regard, the leading consensus committees of NCCN, ESMO, ASCO, and RUSSCO have prepared and are regularly updating recommendations for diagnosing and treatment of anemia in cancer patients. The article presents recent data on the pathogenesis and methods of treatment of anemia in cancer patients, including administration of erythropoiesis stimulating agents: recombinant erythropoietins, intravenous iron products, vitamins, and red blood cell transfusions.


Keywords: cancer, anemia, erythropoietins, intravenous iron products, red blood cell transfusions.

Received: February 29, 2016

Accepted: March 31, 2016

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Taxonomic Structure and Antibiotic Resistance of Bloodstream Infection Pathogens in Oncohematological Patients

NS Bagirova

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Natal’ya Sergeevna Bagirova, DSci, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-18-60; e-mail: nbagirova@mail.ru

For citation: Bagirova NS. Taxonomic Structure and Antibiotic Resistance of Bloodstream Infection Pathogens in Oncohematological Patients. Clinical oncohematology. 2015;8(2):191–200 (In Russ).


ABSTRACT

Background & Aims. In oncohematology, infections are one of main causes of morbidity and mortality in patients with hematological malignancies. Changing epidemiological patterns of infections in patients with hematological malignancies are characterized not only by the appearance of new pathogens of bloodstream infections, but also by the growth of pathogens resistant to antimicrobial drugs. It is important to conduct constant monitoring of taxonomic structure of bloodstream infections pathogens and their antimicrobial resistance in order to ensure adequate and timely treatment of severe infections. The aim of the study is the following: analysis of the taxonomic structure of pathogens isolated while diagnosing bacteremia in adult cancer patients using modern devices taking into account efficacy of the therapy of severe infections.

Methods. A microbiological study of blood samples of adult patients with hematological malignancies was carried out over the period from 2005 till 2013, if sepsis and other severe infections were suspected. Bacteremia was diagnosed using hematological analyzer/incubator Bactec FX400 (Becton Dickinson, USA) and Bact/Alert (BioMerieux, France), identification of strains was done using mass-spectrometer MALDI-TOF Microflex LT (Biotyper, Bruker Daltonics, Germany). Antimicrobial susceptibility was determined using automatic analyzers Microscan Walk Away 40/96+ (Siemens, Germany) and Vitek 2 (BioMerieux, France). Comparative data of foreign researchers are presented.

Results. 3794 blood cultures were obtained, 600 of which (15.8 %) demonstrated growth. Of 392 strains, only 210 (53.6 %) strains were considered true causative agents of bacteremia. No statistically significant differences in the frequency of isolation of Gram-positive cocci (47.6 %) and Gram-negative rods (39.5 %) were found. Fungi were significantly less common than Gram-positive cocci and Gram-negative rods (9 %; < 0.0001). Other microorganisms constituted 3.8 %.

Conclusion. Therapy and prevention of infectious complications in adult patients with hematological malignancies are accompanied by development of growing antibiotic resistance of pathogens. Changes in taxonomic structure of pathogens of bloodstream infections should be taken into account when prescribing the empirical and etiotropic treatment.


Keywords: infections, cancer, bloodstream infections, bacteriemia, antimicrobial resistance, oncohematological disorders, antimicrobial therapy.

Received: January 12, 2015

Accepted: January 30, 2015

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Influence of chemotherapy on reproductive system: methods of protection and preservation of ovarian function

M.V. Volochayeva1, R.G. Shmakov1, and Ye.A. Demina2

1 V.I. Kulakov Research Center of Obstetrics, Gynecology, and Perinatology, RF Ministry of Health, Moscow, Russian Federation

2 N.N. Blokhin Russian Cancer Research Centre, RAMS, Moscow, Russian Federation


ABSTRACT

The recent studies showed the great importance of discussing the issue of protection and preservation of the ovarian function in cancer patients. Nowadays, when new effective methods of treatment are available, many cancer patients wish to realize their reproductive function. In this review, we discuss the methods of ovarian protection such as pharmacological protection and IVF program including a cryopreservation and transplantation of ovarian tissue or cryopreservation of oocytes and embryos.

Keywords: fertility preservation, cancer, cryopreservation tissue, oocytes, embryos

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Anemias and iron deficiency in cancer patients

V.V. Ptushkin

Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology named after Dmitriy Rogachev, Moscow, Russian Federation


ABSTRACT

Anemia is frequent in cancer patients and its incidence increases with chemotherapy. Anemia negatively impacts survival and accentuates fatigue in cancer patients. Cancer promotes inflammatory cytokine production, which suppresses erythropoiesis and erythropoietin production. Erythropoiesis-stimulating agents improve erythropoiesis and reduce transfusion needs in anemic cancer patients receiving chemotherapy. However, meta-analyses have shown an increased risk of thromboembolic events with еrythropoiesis-stimulating agents use during chemotherapy, but not increased on-study mortality or reduced overall survival. Inflammatory cytokine production in patients with cancer, reduce the availability of iron for effective erythropoiesis. This review summarises clinical consequences of iron deficiency and anaemia in cancer patients, mechanisms how impaired iron homeostasis affects diagnosis and treatment of iron deficiency, and data from clinical trials evaluating i.v. iron with or without concomitant erythropoiesis-stimulating agents.


Keywords: Anemia, cancer, erythropoietin, iron propagates, ferric carboxymaltose, ferritin, transferrin

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