REVIEWS

Basic mechanisms of angiogenesis in hematological malignancies

REVIEWS , , ,

А.А. Vartanyan

N.N. Blokhin Russian Cancer Research Center, RAMS, Moscow, Russian Federation

ABSTRACT

Currently, the concept of VEGF-induced angiogenesis as a growth-limiting factor for solid tumors is generally accepted. Growing evidence indicates that the angiogenic growth factors also play an important role in the development and persistence of hematological malignancies. Neoplastic cells induce angiogenesis within the bone marrow through the secretion of soluble angiogenesis activators. VEGF is thought to be a major angiogenic factor involved in bone marrow vascularization. On the other hand, the increased VEGF secretion leads to the release of several soluble cytokines such as GM-CSF, G-CSF, IL-6, PlGF, HGF, IGF, and angiopoietins by the bone marrow microenvironment cells that promote survival and proliferation of malignant cells. The increased plasma VEGF level in the patients with hematological malignancies is considered the most important prognostic factor indicating an unfavorable outcome.

In this review, we discuss the autocrine and paracrine mechanisms of VEGF accumulation in the bone marrow, as well as the angiogenesis-related and -unrelated effects of VEGF. In conclusion, the potential of VEGF signaling inhibition in various hematological malignancies for therapy and its outcomes is discussed.

Keywords: oncohematology, bone marrow, angiogenesis, antiangiogenic therapy.

Read in  PDF (RUS)pdficon

References

  1. Folkman J. Fundamental concepts of the angiogenic process. Curr. Mol. Med. 2003; 3: 643–51.
  2. Bouck N., Stellmach V., Hsu S.C. How tumors become angiogenic. Adv. Cancer Res. 1996; 69: 135–74.
  3. Eiken H.M., Adams R.M. Dynamics of endothelial cell behaviour in sprouting angiogenesis. Curr. Opin. Cell Biol. 2010; 22(5): 617–25.
  4. Feige J.J. Tumour angiogenesis: recent progress and remaining challenges. Bull. Cancer 2010; 97(11): 1305–10.
  5. Tischer E., Mitchell R., Hartman T. et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 1991; 266(18): 11947–54.
  6. Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J. Biochem. Mol. Biol. 2006; 39: 469–78.
  7. Hauser S., Weich H.A. A heparin-binding form of placenta growth factor (PlGF-2) is expressed in human umbilical vein EC and in placenta. Growth Factors 1993; 9(4): 259–68.
  8. Straume O., Akslen L.A. Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and Ephrin-A1/EphA2 on melanoma progression. Am. J. Pathol. 2002; 160: 1009–19.
  9. Maisonpierre P.C., Suri C., Jones P.F. et al. Angiopoietin-2, a natural antagonist for Tie-2 that disrupts in vivo angiogenesis. Science (London) 1997; 277: 55–60.
  10. Sharma P.S., Sharma R., Tyagi T. VEGF/VEGFR pathway inhibitors as anti-angiogenic agents: Present and Future. Curr. Cancer Drug Targets 2011; 11(5): 624–33.
  11. Fliedner T.M., Feinendegen L.E., Hopewell J.W. et al. Chronic irradiation: tolerance and failure in complex biological system. Br. J. Radiol. 2002; Supp. 126: 21–6.
  12. Podar K., Andersen K. Emerging therapies targeting tumor vasculature in multiple myeloma and other haematological malignancies. Curr. Cancer Drug Targets 2011; 11(9): 1005–24.
  13. Bradford G.B., Williams B., Rossi R. et al. Quiescence, cycling and turnover in the hematopoietic stem cell compartment. Exp. Hematol. 1997; 25(5): 445–53.
  14. Cuiffo B.G., Karnoub A.E. Mesenchimal stem cells in tumor development: emerging roles and concepts. Cell Adh. Migr. 2012; 6(3): 220–30.
  15. Schofield R. The relationship between the spleen colony-forming cell and the hematopoietic stem cell: A hypothesis. Blood Cells 1978; 4(1–2): 7–25.
  16. Vila L., Thomas X., Campos L. et al. Expression of VLA molecules on acute leukemia cells: relationship with disease characteristics. Exp. Hematol. 1995; 23: 514–8.
  17. Gong J.K. Endosteal marrow: a rich source of hematopoietic stem cells. Science 1978; 199: 1443–5.
  18. Taichman R.S., Reil W.J., Emerson S.G. Human osteoblasts support human hematopoietic progenitor stem cell in vitro bone marrow cultures. Blood 1996; 87: 518–24.
  19. Calvi L.M., Adams G.B., Weibrecht K.W. et al. Osteoblast cells regulate the hematopoietic stem cell niche. Nature 2003; 425: 841–6.
  20. Zhang J., Niu C., Ye L. et al. Identification of the hematopoietic stem cell niches and control of the niche size. Nature 2003; 425: 836–41.
  21. Yin T., Li L. The stem cell niches in bone. J. Clin. Invest. 2006; 116(5): 1195–201.
  22. Doan P.L., Chute J.P. The vascular niche: home for normal and malignant hematopoietic stem cells. Leukemia 2012; 26: 54–62.
  23. Raffi S., Shapiro F., Pettengell R. et al. Human bone marrow microvascular endothelial cells support long-term proliferation and differentiation of myeloid and megakaryocytic progenitors. Blood 1995; 86: 3753–63.
  24. Davis T.A., Robinson D.N., Lee K.P. et al. Porcine microvascular endothelial cells support the in vitro expansion of the human primitive hematopoietic bone marrow progenitor cells with a high replanting potential: requirement for cell-to-cell interaction and colony-stimulating factors. Blood 1995; 85: 1751–61.
  25. Chute J.P., Muramoto G.G., Fung J. et al. Soluble factors elaborated by human brain endothelial cells induce the concomitant expansion of purified human BM CD34+CD38-cells and SCID-repopulating cells. Blood 2005; 105: 576–83.
  26. Kaplan R.N., Psaila B., Lyden C. Niche-to-niche migration of bone marrow-derived cells. Trends Mol. Med. 2007; 13(2): 72–81.
  27. Gerber H.P., Ferrara N. The role of VEGF in normal and neoplastic hematopoiesis. J. Mol. Med. (Berlin) 2003; 81: 20–31.
  28. Grandage V.L., Gale R.E., Linch D.C. et al. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, MAPK and p53 pathways. Leukemia 2005; 19: 586–94.
  29. Lewis T.S., Shapiro P.S., Ahn N.G. Signal transduction through MAP kinase cascades. Adv. Cancer Res. 1998; 74: 49–139.
  30. Weber-Nordt R.M., Mertelsmann R., Finke J. The JAK-STAT pathway: signal transduction involved in proliferation, differentiation and transformation. Leuk. Lymphoma 1998; 28: 459–67.
  31. Dias S., Hattori K., Zhu Z. et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J. Clin. Invest. 2000; 106: 511–21.
  32. Glenjen N.I., Hatfield K., Bruserud O. et al. Coculture of native human acute myelogenous leukemia blasts with fibroblasts and osteoblasts results in an increase of vascular endothelial growth factor levels. Eur. J. Haematol. 2005; 74: 24–34.
  33. Podar K., Anderson K.C. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 2005; 105: 1383–95.
  34. Paesler J., Gehrke I., Poll-Wolbeck S.J., Kreuzer K.A. Targeting the vascular endothelial growth factor in hematologic malignancies. Eur. J. Hematol. 2012; 89: 373–84.
  35. Wegiel B., Ekberg J., Talasila K.M. et al. The role of VEGF and a functional link between VEGF and p27Kip1 in acute myeloid leukemia. Leukemia 2009; 23: 251–61.
  36. Ramakrishnan V., Timm M., Haug J.L. et al. Sorafenib, a dual Raf kinase/ vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs. Oncogene 2010; 29: 1190–202.
  37. Podar K., Catley L.P., Tai Y.T. et al. GW654652, the paninhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment. Blood 2004; 103: 3474–9.
  38. Kovacs M.J., Reece D.E., Marcellus D. et al. A phase II study of ZD6474 (Zactima, a selective inhibitor of VEGFR and EGFR tyrosine kinase) in patients with relapsed multiple myeloma–NCIC CTG IND. Invest. New Drugs 2006; 24: 529–35.
  39. Karp J.E., Gojo I., Pili R. et al. Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-darabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin. Cancer Res. 2004; 10: 3577–85.
  40. Barbarroja N., Torres L.A., Luque M.J. et al. Additive effect of PTK787/ ZK 222584, a potent inhibitor of VEGFR phosphorylation, with Idarubicin in the treatment of acute myeloid leukemia. Exp. Hematol. 2009; 37: 679–91.
  41. Smolich B.D., Yuen H.A., West K.A. et al. The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood 2001; 97: 1413–21.
  42. Paesler J., Gehrke I., Gandhirajan R.K. et al. The vascular endothelial growth factor receptor tyrosine kinase inhibitors vatalanib and pazopanib potently induce apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo. Clin. Cancer Res. 2010; 16: 3390–8.
  43. Huber S., Oelsner M., Decker T. et al. Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1. Leukemia 2011; 25: 838–47.
  44. Shanafelt T., Zent C., Byrd J. et al. Phase II trials of single agent anti-VEGF therapy for patients with chronic lymphocytic leukemia. Leuk. Lymphoma 2010; 51: 2222–9.
  45. Lee Y.K., Shanafelt T.D., Bone N.D. et al. VEGF receptors on chronic lymphocytic leukemia (CLL) B cells interact with STAT 1 and 3: implication for apoptosis resistance. Leukemia 2005; 19: 513–23.
  46. Li F.F., Zheng G.H., Xu Y.H. et al. Effect of siRNA targeting VEGF on cell apoptosis and the expression of surviving in K562 cells. Zhonghua Xue Ye Xue Za Zhi. 2009; 30: 825–8.
  47. Reiners K.S., Gossmann A., von Strandmann E.P. et al. Effects of the antiVEGF monoclonal antibody bevacizumab in a preclinical model and in patients with refractory and multiple relapsed Hodgkin lymphoma. J. Immunother. 2009; 32: 508–12.
  48. Moehler T.M., Ho A.D., Goldschmidt H. et al. Angiogenesis in hematologic malignancies. Crit. Rev. Oncol. Hematol. 2003; 45: 227–44.
  49. Aguayo A., Kantarjian H., Manshouri T. et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000; 96: 2240–5.
  50. Flater J.L., Kay M.E., Goolsby C.L. et al. Dysregulated angiogenesis in B-chronic lymphocytic leukemia: morphologic, immunohistochemical and cytometric evidence. Diagn. Pathol. 2008; 3: 1–16.
  51. Lee C.Y., Tien H.F., Hu C.Y. et al. Marrow angiogenesis-associated factors as prognosric biomarkers in patients with acute myelogenous leukemia. Br. J. Cancer 2007; 97(7): 877–82.
  52. Lin N.I., Lin D.T., Chang C.J. et al. Marrow matrix metalloptoteinases (MMPs) and tissue inhibitor of MMP in acute leukemia: potential role of MMP-9 as surrogate marker to monitor leukemic status in patients with acute myelogenous leukemia. Br. J. Leuk. 2002; 117: 835–41.
  53. Hattori K., Heissig B., Wu Y. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat. Med. 2002; 8: 841–9.
  54. Fragoso R., Pereira T., Wu Y. et al. VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease. Blood 2006; 107: 1608–16.
  55. Van de Veire S., Stalmans I., Heindryckx F. et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 2010; 141: 178–90.
  56. Schmidt T., Kharabi Masouleh B., Loges S. et al. Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1+ leukemia. Cancer Cell 2011; 19(6): 740–53.
  57. Yetgin S., Yenicesu I., Cetin M. et al. Clinical importance of serum vascular endothelial and basic fibroblast growth factors in children with acute lymphoblastic leukemia. Leuk. Lymphoma 2001; 42(1–2): 83–8.
  58. De Raeve H., Van Mark E., Van Camp B. et al. Angiogenesis and the role of bone marrow endothelial cells in hematologic malignancies. Histol. Histopathol. 2004; 19: 935–50.
  59. Arai H., Hirao A., Suda T. Regulation of hematopoietic stem cells by the niche. Trends Cardiovasc. Med. 2005; 15: 75–9.
  60. Rabitsch W., Sperr W.R., Lechner K. et al. Bone marrow microvessel density and its prognostic significance in AML. Leuk. Lymphoma 2004; 45(7): 1369–73.
  61. Pule M.A., Gulmann C., Derris D. et al. Increased angiogenesis in bone marrow of children with acute lymphoblastic leukemia has no prognostic significance. Br. J. Haematol. 2002; 118(4): 991–8.
  62. Kasparova P., Smolei L. Angiogenesis in the bone marrow of patients with chronic lymphocytic leukemia. Cesk. Patol. 2007; 43(2): 50–8.
  63. Zhelvazkova A.G., Tochev A.B., Kolova P. et al. Prognostic significance of hepatocyte growth factor and microvessel bone marrow density in patients with chronic myeloid leukemia. Scand. J. Clin. Lab. Invest. 2008; 68(6): 492–500.
  64. Zhao S., Zhang Q.Y., Ma W.J. et al. Analysis of 31 cases of primary breast lymphoma: the effect of nodal involvement and microvascular density. Clin. Lymphoma Myeloma Leuk. 2011; 11(1): 33–7.
  65. De Raeve H., Van Marck E., Van Camp B. et al. Angiogenesis and the role of bone marrow endothelial cells in haematological malignancies. Histol. Histopathol. 2004; 19(3): 935–50.
  66. Kvasnicka H.M., Thiele J. Bone marrow angiogenesis: methods of quantification and changes evolving in chronic myeloproliferative disorders. Histol. Histopathol. 2004; 19(4): 1245–60.
  67. Shih T.T., Hou H.A., Liu C.Y. et al. Bone marrow angiogenesis magnetic resonance imaging in patients with acute myeloid leukemia: peak enhancement ratio is an independent predictor for overall survival. Blood 2009; 113(14): 3161–7.
  68. Chen B.-B., Hsu C.-Y., Yu C.-W. et al. Dynamic contrast-enhanced MR imaging measurement of vertebral bone marrow perfusion may be indicator of outcome of acute leukemia patients in remission. Radiology 2011; 258(3): 821–31.
  69. Singhal S., Mehta J., Desikan R. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 1999; 341(21): 1565–71.
  70. Rehman W., Arfons L.M., Lazarus H.M. The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development. Ther. Adv. Hematol. 2011; 2(5): 291–308.
  71. Maiolino A., Hungria V.T., Garnica M. et al. Multiple Myeloma Study Group (BMMSG/GEMOH). Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progressionfree survival in multiple myeloma. Am. J. Hematol. 2012; 87(10): 948–52.
  72. Sher T., Ailawadhi S., Miller K.C. et al. A steroid-independent regimen of bortezomib, liposomal doxorubicin and thalidomide demonstrate high response rates in newly diagnosed multiple myeloma patients. Br. J. Haematol. 2011; 154(1): 104–10.
  73. Fayers P.M., Palumbo A., Hulin C. et al. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patients from 6 randomized clinical trials. Blood 2011; 118: 1239–47.
  74. Kotla V., Goel S., Nischal S. et al. Mechanism of action of thalidomide in hematological malignancies. J. Hematol. Oncol. 2009; 2: 36–46.
  75. Li S., Gill N., Lentzsch S. Recent advances of IMiDs in cancer therapy. Curr. Opin. Oncol. 2010; 22(6): 579–85.
  76. Shortt J., Hsu A.K., Johnstone R.W. Thalidomide-analogue biology: immunological, molecular and epigenetic targets in cancer therapy. Oncogene 2013; 32(1): 1–18.
  77. Wang M., Dimopoulos M.A., Chen C. et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 2008; 112(12): 4445–51.
  78. Dimopoulos M.A., Kastritis E., Christoulas D. et al. Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenic abnormalities and of previous therapies. Leukemia 2010; 24 (10): 1769–78.
  79. Williams S., Pettaway C., Song R. et al. Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts. Mol. Cancer Ther. 2003; 2(9): 835–43.
  80. Chen Y., Borthakur G. Lenalidomide as a novel treatment of acute myeloid leukemia. Exp. Opin. Invest. Drugs 2013; 22(3): 389–97.
  81. Wiernik P.H. Lenalidomide in lymphomas and chronic lymphocytic leukemia. Exp. Opin. Pharmacother. 2013; 14(4): 475–88.
  82. Blum W., Klisovic R.B., Becker H. et al. Dose escalation of lenalidomide in relapsed or refractory acute leukemias. J. Clin. Oncol. 2010; 28: 4919–25.
  83. Tageja N. Lenalidomide — current understanding of mechanistic properties. Anticancer Agents Med. Chem. 2011; 11(3): 315–26.
  84. Davies F., Baz R. Lenalidomide mode of action: linking bench and clinical findings. Blood Rev. 2010; Suppl. 1: S13–9.
  85. San-Miguel J.F. Long-term disease control in multiple myeloma: the impact of the dual mechanism of action of lenalidomide. Introduction and overview. Blood Rev. 2010; Suppl. 1: S1–3.
  86. Li Z.W., Chen H., Campbell R.A. et al. NF-kappaB in the pathogenesis and treatment of multiple myeloma. Curr. Opin. Hematol. 2008; 15(4): 391–9.
  87. Bartlett J.B., Tozer A., Stirling D. et al. Recent clinical studies of the immunomodulatory drug (IMiD) lenalidomide. Br. J. Cancer 2005; 93(6): 613–9.
  88. Ribatti D., Mangialaedi G., Vacca A. Antiangiogenic therapeutic approaches in multiple myeloma. Curr. Cancer Drug Targets 2012; 12: 768–75.
  89. Lin B., Podar K., Gupta D. et al. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 2002; 62(17): 5019–26.
  90. Zangari M., Anaissie E., Stopeck A. et al. Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma. Clin. Cancer Res. 2004; 10(1 Pt. 1): 88–9.
  91. Podar K., Catley L.P., Tai Y.T. et al. GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment. Blood 2004; 103 (9): 3474–9.
  92. Ramakrishnan V., Timm M., Haug J.L. et al. Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant antimyeloma activity and synergizes with common anti-myeloma drugs. Oncogene 2010; 29(8): 1190–202.
  93. Breccia M., Salaroli A., Molica M. et al. Systematic review of dasatinib in chronic myeloid leukemia. Oncol. Targets Ther. 2013; 6: 257–65.
  94. Wiernik P.H. FLT3 inhibitors for the treatment of acute myeloid leukemia. Clin. Adv. Hematol. Oncol. 2010; 8(6): 429–36.
  95. Roboz G.J., Giles F.J., List A.F. et al. Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. Leukemia 2006; 20(6): 952–7.
  96. Macdonald D.A., Assouline S.E., Brandwein J. et al. A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. Leuk. Lymphoma 2013; 54(4): 760–6.
  97. Nishioka C., Ikezoe T., Yang J. et al. Sunitinib, an orally available receptor tyrosine kinase inhibitor, induces monocytic differentiation of acute myelogenous leukemia cells that is enhanced by 1,25-dihydroxyvitamin D(3). Leukemia 2009; 23(11): 2171–3.
  98. Stopeck A., Sheldon M., Vanedian M. et al. Results of a Phase I Dose-escalating Study of the Antiangiogenic Agent, SU5416, in Patients with Advanced Malignancies. Clin. Cancer Res. 2002; 8: 2798–3011.
  99. Fiedler W., Mesters R., Heuser M. et al. An open-label, Phase I study of cediranib (RECENTIN) in patients with acute myeloid leukemia. Leuk. Res. 2010; 34(2): 196–202.
  100. Thomas X. Acute lymphoblastic leukemia with Philadelphia chromosome: treatment with kinase inhibitors. Bull. Cancer 2007; 94(10): 871–80.
  101. Mirshahi P., Raffi A., Vincent I. et al. Vasculogenic mimicry of acute leukemic bone marrow stromal cells. Leukemia 2009; 23: 1039–48.
  102. Scavelli C., Nico B., Cirulli T. et al. Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene 2008; 27(5): 663–74.
  103. Nico B., Margieri D., Crivellato E. et al. Mast cells contribute to vasculogenic mimicry in multiple myeloma. Stem Cell Dev. 2008; 17(1): 19–22.

 

Hodgkin’s lymphoma and male fertility disorders

REVIEWS , , ,

A.А. Vinokurov

Federal Clinical-and-Research Center of Pediatric Hematology, Oncology, and Immunology n.a. Dmitriy Rogachev, Moscow, Russian Federation

ABSTRACT

This literature review is focused on the mechanisms of the impact that cytotoxic drugs cause in male reproductive cells and the rate of infertility induced by the various regimens of combined chemotherapy for Hodgkin’s lymphoma. The specific endocrine abnormalities associated with antitumor treatment are described in detail and, also, routine and experimental methods for fertility preservation in cancer patients are presented.

Keywords: Hodgkin’s lymphoma, male infertility, sperm cryopreservation, male fertility preservation.

Read in PDF (RUS)pdficon

REFERNCES

  1. Steliarova-Foucher E., Stiller C., Kaatsch P. et al. Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCIS project): an epidemiological study. Lancet 2004; 364(9451): 2097–105.
  2. Ferlay J., Shin H.R., Bray F. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 2010; 127(12): 2893–917.
  3. Parkin D.M., Bray F., Ferlay J., Pisani P. Global cancer statistics, 2002. CA Cancer J. Clin. 2005; 55(2): 74–108.
  4. Давыдов М.И., Аксель Е.М. Заболеваемость злокачественными ново- образованиями населения России странах СНГ в 2004 г. Вестн. РОНЦ им. Н.Н. Блохина РАМН 2006; 17(3, прил. 1): 45–77. [Davydov M.I., Aksel Ye.M. Zabolevayemost zlokachestvennymi novoobrazovaniyami naseleniya Rossii stranakh SNG v 2004 g (Cancer incidence in population of Russia and CIS in 2004. In: Bullet. of N.N.Blokhin RCC, RAMS). Vestn. RONTS im. N.N. Blokhina RAMN 2006; 17(3, pril. 1): 45–77.]
  5. Чиссов В.И., Старинский В.В., Петрова Г.В. Злокачественные ново- образования в России в 2010 г. (Заболеваемость и смертность). М.: ФГБУ «МНИОИ им. П.А. Герцена» МЗ РФ, 2012. [Chissov V.I., Starinskiy V.V., Petrova G.V. Zlokachestvennye novoobrazovaniya v Rossii v 2010 g. (Zabolevayemost i smertnost) (Cancer in Russia in 2010. (Incidence and mortality)). M.: FGBU «MNIOI im. P.A. Gertsena» MZ RF, 2012.]
  6. Evens A.M., Antillon M., Aschebrook-Kilfoy B., Chiu B.C. Racial disparities in Hodgkin’s lymphoma: a comprehensive population-based analysis. Ann. Oncol. 2012; 23(8): 2128–37.
  7. Miller B.A., Chu K.C., Hankey B.F., Ries L.A. Cancer incidence and mortality patterns among specific Asian and Pacific Islander populations in the U.S. Cancer Causes Control 2008; 19(3): 227–56.
  8. Волкова М.А. Клиническая онкогематология: Руководство для врачей, 2-е изд. М.: Медицина, 2007: 679–80. [Volkova M.A. Klinicheskaya onkogematologiya: Rukovodstvo dlya vrachey, 2-e izd (Clinical oncohematology: manual for medical practitioners. 2nd ed.). M.: Meditsina, 2007: 679–80.]
  9. Bleyer A., Viny A., Barr R. Cancer in 15- to 29-year-olds by primary site. Oncologist 2006; 11(6): 590–601.
  10. Armitage J.O. Early-stage Hodgkin’s lymphoma. N. Engl. J. Med. 2010; 363(7): 653–62.
  11. Hewitt M.W. Childhood Cancer survivorship: improving care and quality of life. Washington DC: The National Academy Press, 2003.
  12. Пивник А.В., Растригин Н.А., Моисеева Т.Н. и др. Результаты лечения лимфогранулематоза по протоколу МОРР-АВVD в сочетании с лучевой терапией (десятилетнее наблюдение). Тер. арх. 2006; 8: 57–62. [Pivnik A.V., Rastrigin N.A., Moiseyeva T.N. i dr. Rezultaty lecheniya limfogranulematoza po protokolu MORR-AVVD v sochetanii s luchevoy terapiyey (desyatiletneye nablyudeniye) (Outcomes of Hodgkin’s disease treated according to МОРР-АВVD protocol in combination with radiotherapy (10-year observations)). Ter. arkh. 2006; 8: 57–62.]
  13. Donaldson S.S., Link M.P. Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin’s disease. J. Clin. Oncol. 1987; 5(5): 742–9.
  14. Куприна И.В. Состояние щитовидной железы и особенности липид- ного обмена у больных лимфогранулематозом молодого и среднего возраста после комбинированной химиолучевой терапии: Автореф. дис. … канд. мед. наук. М., 2008.
  15. Kuprina I.V. Sostoyaniye shchitovidnoy zhelezy i osobennosti lipidnogo obmena u bolnykh limfogranulematozom molodogo i srednego vozrasta posle kombinirovannoy khimioluchevoy terapii: Avtoref. dis. … kand. med. nauk (State¼: of thyroid gland and lipid metabolism in young and middle-aged patients with Hodgkin’s disease after combination chemoradiotherapy. Author’s summary of dissertation for the degree of PHD). M., 2008.
  16. Насибов О.М. Фиброз легких, кардиопатии и вторичные опухоли у канд.¼лиц в длительной ремиссии лимфогранулематоза: Автореф. дис. мед. наук. М., 2000. [Nasibov O.M. Fibroz legkikh, kardiopatii i vtorichnye opukholi u lits v dlitelnoy remissii limfogranulematoza: Avtoref. dis. … kand. med. nauk (Pulmonary fibrosis, cardiopathies and secondary tumors during Hodgkin’s disease in long remission. Author’s summary of dissertation for the degree of PHD). M., 2000.]
  17. Шилин Д.Е., Пивник А.В., Расстригин Н.А., Игнашина Е.В., Марголин О.В. Профилактика репродуктивных нарушений, возникающих в процессе химиотерапии у женщин детородного возраста, страдающих болезнью Ходжкина. Тер. арх. 1998; 7: 49–53. [Shilin D.Ye., Pivnik A.V., Rasstrigin N.A., Ignashina Ye.V., Margolin O.V. Profilaktika reproduktivnykh narusheniy, voznikayushchikh v protsesse khimioterapii u zhenshchin detorodnogo vozrasta, stradayushchikh boleznyu Khodzhkina (Prevention of chemotherapy-related reproductive disorders in women of reproductive age with Hodgkin’s disease). Ter. arkh. 1998; 7: 49–53.]
  18. Schrader M., Muller M., Straub B., Miller K. The impact of chemotherapy on male fertility: a survey of the biologic basis and clinical aspects. Reprod. Toxicol. 2001; 15(6): 611–7.
  19. Myrehaug S., Pintilie M., Yun L. et al. A population-based study of cardiac morbidity among Hodgkin lymphoma patients with preexisting heart disease. Blood 2010; 116(13): 2237–40.
  20. Meistrich M.L., Vassilopoulou-Sellin R., Lipshultz L.I. Adverse effects of treatment: gonadal dysfunction, 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2005.
  21. Tilmann C., Capel B. Cellular and molecular pathways regulating mammalian sex determination. Rec. Prog. Horm. Res. 2002; 57: 1–18.
  22. Bendel-Stenzel M., Anderson R., Heasman J., Wylie C. The origin and migration of primordial germ cells in the mouse. Semin. Cell Dev. Biol. 1998; 9(4): 393–400.
  23. Meachem S., von Schonfeldt V., Schlatt S. Spermatogonia: stem cells with a great perspective. Reproduction 2001; 121(6): 825–34.
  24. Nieschlag E., Behre H. Andrology. Male Reproductive Health and Dysfunction, 3d ed. Berlin Heidelberg: Springer-Verlag, 2010: 35–6.
  25. Chuma S., Kanatsu-Shinohara M., Inoue K. et al. Spermatogenesis from epiblast and primordial germ cells following transplantation into postnatal mouse testis. Development 2005; 132(1): 117–22.
  26. Nayernia K., Drabent B., Meinhardt A. et al. Triple knockouts reveal gene interactions affecting fertility of male mice. Mol. Reprod. Dev. 2005; 70(4): 406–16.
  27. Creemers L.B., den Ouden K., van Pelt A.M., de Rooij D.G. Maintenance of adult mouse type A spermatogonia in vitro: influence of serum and growth factors and comparison with prepubertal spermatogonial cell culture. Reproduction 2002; 124(6): 791–9.
  28. Feng L., Chen Y., Dettin L. et al. Generation and in vitro differentiation of a spermatogonial cell line. Science 2002; 297(5580): 392–5.
  29. Geijsen N., Horoschak M., Kim K. et al. Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature 2004; 427(6970): 148–54.
  30. Nagano M., Shinohara T., Avarbock M., Brinster R. Retrovirus-mediated gene delivery into male germ line stem cells. FEBS Lett. 2000; 475(1): 7–10.
  31. van Pelt A.M., Roepers-Gajadien H.L., Gademan I.S., Creemers L.B., de Rooij D.G. Establishment of cell lines with rat spermatogonial stem cell characteristics. Endocrinology 2002; 143(5): 1845–50.
  32. Clermont Y., Antar M. Duration of the cycle of the seminiferous epithelium and the spermatogonial renewal in the monkey Macaca arctoides. Am. J. Anat. 1973; 136(2): 153–65.
  33. Fouquet J.P., Dadoune J.P. Renewal of spermatogonia in the monkey (Macaca fascicularis). Biol. Reprod. 1986; 35(1): 199–207.
  34. Hermann B., Sukhwani M., Simorangkir D., Chu T., Orwig K. Molecular dissection of the male germ cell lineage identifies putative spermatogonial stem cells in rhesus macaques. Hum. Reprod. 2009; 24(7): 1704–16.
  35. Kluin P.M., Kramer M.F., de Rooij D.G. Testicular development in Macaca virus after birth. Int. J. Androl. 1983; 6(1): 25–43.
  36. Zhengwei Y., McLachlan R., Bremner W., Wreford N. Quantitative (stereological) study of the normal spermatogenesis in the adult monkey (Macaca fascicularis). J. Androl. 1997; 18(6): 681–7.
  37. de Rooij D.G. The spermatogonial stem cell niche. Microsc. Res. Tech. 2009; 72(8): 580–5.
  38. Dettin L., Ravindranath N., Hofmann M., Dym M. Morphological characterization of the spermatogonial subtypes in the neonatal mouse testis. Biol. Reprod. 2003; 69(5): 1565–71.
  39. Jahnukainen K., Ehmcke J., Soder O., Schlatt S. Clinical potential and putative risks of fertility preservation in children utilizing gonadal tissue or germline stem cells. Pediatr. Res. 2006; 59(4 Pt. 2): 40R–7R.
  40. Nieschlag E., Behre H. Andrology. Male Reproductive Health and Dysfunction, 3d ed. Berlin Heidelberg: Springer-Verlag, 2010: 16–7.
  41. Allenby G., Foster P.M., Sharpe R.M. Evidence that secretion of immunoactive inhibin by seminiferous tubules from the adult rat testis is regulated by specific germ cell types: correlation between in vivo and in vitro studies. Endocrinology 1991; 128(1): 467–76.
  42. Pineau C., Sharpe R.M., Saunders P.T., Gerard N., Jegou B. Regulation of Sertoli cell inhibin production and of inhibin alpha-subunit mRNA levels by specific germ cell types. Mol. Cell Endocrinol. 1990; 72(1): 13–22.
  43. Нишлаг Э., Бере Г. Андрология. Мужское здоровье и дисфункция репродуктивной системы, 2-е изд. М.: МИА, 2005: 40–1. [Nishlag E., Bere G. Andrologiya. Muzhskoye zdorovye i disfunktsiya reproduktivnoy sistemy, 2-e izd (Andrology. Men’s health and reproductive system dysfunctions. 2nd ed.). M.: MIA, 2005: 40–1.]
  44. Chung K., Irani J., Knee G. et al. Sperm cryopreservation for male patients with cancer: an epidemiological analysis at the University of Pennsylvania. Eur. J. Obstet. Gynecol. Reprod. Biol. 2004; 113(Suppl. 1): S7–11.
  45. Williams D., Karpman E., Sander J., Spiess P., Pisters L. Pretreatment semen parameters in men with cancer. J. Urol. 2009; 181(2): 736–40.
  46. Bahadur G., Ozturk O., Muneer A. et al. Semen quality before and after gonadotoxic treatment. Hum. Reprod. 2005; 20(3): 774–81.
  47. Gandini L., Lombardo F., Salacone P. et al. Testicular cancer and Hodgkin’s disease: evaluation of semen quality. Hum. Reprod. 2003; 18(4): 796–801.
  48. Rofeim O., Gilbert B. Normal semen parameters in cancer patients presenting for cryopreservation before gonadotoxic therapy. Fertil. Steril. 2004; 82(2): 505–6.
  49. Rueffer U., Breuer K., Josting A. et al. Male gonadal dysfunction in patients with Hodgkin’s disease prior to treatment. Ann. Oncol. 2001; 12(9): 1307–11.
  50. van der Kaaij M., Heutte N., van Echten-Arends J. et al. Sperm quality before treatment in patients with early stage Hodgkin’s lymphoma enrolled in EORTC-GELA Lymphoma Group trials. Haematologica 2009; 94(12): 1691–7.
  51. Marmor D., Elefant E., Dauchez C., Roux C. Semen analysis in Hodgkin’s disease before the onset of treatment. Cancer 1986; 57(10): 1986–7.
  52. Padron O.F., Sharma R.K., Thomas A.J. Jr., Agarwal A. Effects of cancer on spermatozoa quality after cryopreservation: a 12-year experience. Fertil. Steril. 1997; 67(2): 326–31.
  53. Viviani S., Ragni G., Santoro A. et al. Testicular dysfunction in Hodgkin’s disease before and after treatment. Eur. J. Cancer 1991; 27(11): 1389–92.
  54. Barr R.D., Clark D.A., Booth J.D. Dyspermia in men with localized Hodgkin’s disease. A potentially reversible, immune-mediated disorder. Med. Hypotheses 1993; 40(3): 165–8.
  55. Buch J.P., Kolon T.F., Maulik N., Kreutzer D.L., Das D.K. Cytokines stimulate lipid membrane peroxidation of human sperm. Fertil. Steril. 1994; 62(1): 186–8.
  56. Dousset B., Hussenet F., Daudin M., Bujan L., Foliguet B. Seminal cytokine concentrations (IL-1beta, IL-2, IL-6, sR IL-2, sR IL-6), semen parameters and blood hormonal status in male infertility. Hum. Reprod. 1997; 12(7): 1476–9.
  57. Fedder J., Ellerman-Eriksen S. Effect of cytokines on sperm motility and ionophore-stimulated acrosome reaction. Arch. Androl. 1995; 35(3): 173–85.
  58. Gruschwitz M.S., Brezinschek R., Brezinschek H.P. Cytokine levels in the seminal plasma of infertile males. J. Androl. 1996; 17(2): 158–63.
  59. Huleihel M., Lunenfeld E., Levy A., Potashnik G., Glezerman M. Distinct expression levels of cytokines and soluble cytokine receptors in seminal plasma of fertile and infertile men. Fertil. Steril. 1996; 66(1): 135–9.
  60. Schulte H.M., Bamberger C.M., Elsen H., Herrmann G., Bamberger A.M. Systemic interleukin-1 alpha and interleukin-2 secretion in response to acute stress and to corticotropin-releasing hormone in humans. Eur. J. Clin. Invest. 1994; 24(11): 773–7.
  61. Shimonovitz S., Barak V., Zacut D., Ever-Hadani P., Ben C.A. High concentration of soluble interleukin-2 receptors in ejaculate with low sperm motility. Hum. Reprod. 1994; 9(4): 653–5.
  62. Agarwal A., Allamaneni S.S. Disruption of spermatogenesis by the cancer disease process. J. Natl. Cancer Inst. Monogr. 2005; 34: 9–12.
  63. Ho G.T., Gardner H., De Wolf W.C, Loughlin K.R., Morgentaler A. Influence of testicular carcinoma on ipsilateral spermatogenesis. J. Urol. 1992; 148(3): 821–5.
  64. Skakkebaek N.E., Jorgensen N., Main K.M. et al. Is human fecundity declining? Int. J. Androl. 2006; 29(1): 2–11.
  65. Spitz S. The histological effects of nitrogen mustards on human tumors and tissues. Cancer 1948; 1(3): 383–98.
  66. Magelssen H., Brydoy M., Fossa S.D. The effects of cancer and cancer treatments on male reproductive function. Nat. Clin. Pract. Urol. 2006; 3(6): 312–22.
  67. Trottmann M., Becker A.J., Stadler T. et al. Semen quality in men with malignant diseases before and after therapy and the role of cryopreservation. Eur. Urol. 2007; 52(2): 355–67.
  68. Meistrich M.L., Finch M., da Cunha M.F., Hacker U., Au W.W. Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells. Cancer Res. 1982; 42(1): 122–31.
  69. Dejaco C., Mittermaier C., Reinisch W. et al. Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterology 2001; 121(5): 1048–53.
  70. Abu-Baker S.O. Gemcitabine impacts histological structure of mice testis and embryonic organs. Pak. J. Biol. Sci. 2009; 12(8): 607–15.
  71. Savkovic N., Green S., Pecevski J., Maric N. The effect of mitomycin on the fertility and the induction of meiotic chromosome rearrangements in mice and their first generation progeny. Can. J. Genet. Cytol. 1977; 19(3): 387–93.
  72. Colpi G.M., Contalbi G.F., Nerva F., Sagone P., Piediferro G. Testicular function following chemo-radiotherapy. Eur. J. Obstet. Gynecol. Reprod. Biol. 2004; 113(Suppl. 1): S2–6.
  73. Kirchhoff C. CD52 is the ‘major maturation-associated’ sperm membrane antigen. Mol. Hum. Reprod. 1996; 2(1): 9–17.
  74. Vogel E.W., Nivard M.J. International Commission for Protection Against Environmental Mutagens and Carcinogens. The subtlety of alkylating agents in reactions with biological macromolecules. Mutat. Res. 1994; 305(1): 13–32.
  75. Vogel E.W., Barbin A., Nivard M.J., Bartsch H. Nucleophilic selectivity of alkylating agents and their hypermutability in Drosophila as predictors of carcinogenic potency in rodents. Carcinogenesis 1990; 11(12): 2211–7.
  76. Angerer J., Ewers U., Wilhelm M. Human biomonitoring: state of the art. Int. J. Hyg. Environ. Health 2007; 210(3–4): 201–28.
  77. Ehrenberg L. Covalent binding of genotoxic agents to proteins and nucleic acids. IARC Sci. Publ. 1984; 59: 107–14.
  78. Волкова М.А. Клиническая онкогематология: Руководство для врачей, 2-е изд. М.: Медицина, 2007: 699–700.  [Volkova M.A. Klinicheskaya onkogematologiya: Rukovodstvo dlya vrachey, 2-e izd. (Clinical oncohematology: manual for medical practitioners. 2nd ed.). M.: Meditsina, 2007: 699–700.]
  79. Sanders J.E., Hawley J., Levy W. et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996; 87(7): 3045–52.
  80. Marina S., Barcelo P. Permanent sterility after immunosuppressive therapy. Intern. J. Androl. 1979; 2: 6–13.
  81. Buchanan J.D., Fairley K.F., Barrie J.U. Return of spermatogenesis after stopping cyclophosphamide therapy. Lancet 1975; 2(7926): 156–7.
  82. da Cunha M.F., Meistrich M.L., Fuller L.M. et al. Recovery of spermatogenesis after treatment for Hodgkin’s disease: limiting dose of MOPP chemotherapy. J. Clin. Oncol. 1984; 2(6): 571–7.
  83. Jacob A., Barker H., Goodman A., Holmes J. Recovery of spermatogenesis following bone marrow transplantation. Bone Marrow Transplant. 1998; 22(3): 277–9.
  84. Hansen P.V., Trykker H., Helkjoer P.E., Andersen J. Testicular function in patients with testicular cancer treated with orchiectomy alone or orchiectomy plus cisplatin-based chemotherapy. J. Natl. Cancer Inst. 1989; 81(16): 1246–50.
  85. Ahmed S.R., Shalet S.M., Campbell R.H., Deakin D.P. Primary gonadal damage following treatment of brain tumors in childhood. J. Pediatr. 1983; 103(4): 562–5.
  86. Kulkarni S.S., Sastry P.S., Saikia T.K., Parikh P.M., Gopal R. Gonadal function following ABVD therapy for Hodgkin’s disease. Am. J. Clin. Oncol. 1997; 20(4): 354–7.
  87. Radford J.A., Clark S., Crowther D., Shalet S.M. Male fertility after VAPECB chemotherapy for Hodgkin’s disease and non-Hodgkin’s lymphoma. Br. J. Cancer 1994; 69: 379–81.
  88. Sieniawski M., Reineke T., Josting A. et al. Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann. Oncol. 2008; 19(10): 1795–801.
  89. Hobbie W.L., Ginsberg J.P., Ogle S.K., Carlson C.A., Meadows A.T. Fertility in males treated for Hodgkins disease with COPP/ABV hybrid. Pediatr. Blood Cancer 2005; 44(2): 193–6.
  90. Marmor D., Duyck F. Male reproductive potential after MOPP therapy for Hodgkin’s disease: a long-term survey. Andrologia 1995; 27(2): 99–106.
  91. Whitehead E., Shalet S.M., Blackledge G., Todd I., Crowther D. The effects of Hodgkin’s disease and combination chemotherapy on gonadal function in the adult male. Cancer 1982; 49(3): 418–22.
  92. Viviani S., Santoro A., Ragni G., Bonfante V., Bonadonna G. Gonadal toxicity after combination chemotherapy for Hodgkin’s disease. Comparative results of MOPP vs ABVD. Eur. J. Cancer Clin. Oncol. 1985; 21(5): 601–5.
  93. Anselmo A.P., Cartoni C., Bellantuono P., Maurizi-Enrici R., Aboulkair N. Risk of infertility in patients with Hodgkin’s disease treated with ABVD vs MOPP vs ABVD/MOPP. Haematologica 1990; 75(2): 155–8.
  94. Shafford E.A., Kingston J.E., Malpas J.S. et al. Testicular function following the treatment of Hodgkin’s disease in childhood. Br. J. Cancer 1993; 68(6): 1199–204.
  95. Charak B.S., Gupta R., Mandrekar P. et al. Testicular dysfunction after cyclophosphamide-vincristine-procarbazine-prednisolone chemotherapy for advanced Hodgkin’s disease. A long-term follow-up study. Cancer 1990; 65(9): 1903–6.
  96. Puscheck E., Philip P.A., Jeyendran R.S. Male fertility preservation and cancer treatment. Cancer Treat. Rev. 2004; 30(2): 173–80.
  97. Chapman R.M., Sutcliffe S.B., Rees L.H., Edwards C.R., Malpas J.S. Cyclical combination chemotherapy and gonadal function. Retrospective study in males. Lancet 1979; 1(8111): 285–9.
  98. Brougham M.F., Kelnar C.J., Sharpe R.M., Wallace W.H. Male fertility following childhood cancer: current concepts and future therapies. Asian J. Androl. 2003; 5(4): 325–37.
  99. Thomson A.B., Critchley H.O., Kelnar C.J., Wallace W.H. Late reproductive sequelae following treatment of childhood cancer and options for fertility preservation. Best Pract. Res. Clin. Endocrinol. Metab. 2002; 16(2): 311–34.
  100. Viviani S., Bonfante V., Santoro A. et al. Long-term results of an intensive regimen: VEBEP plus involved-field radiotherapy in advanced Hodgkin’s disease. Cancer J. Sci. Am. 1999; 5(5): 275–82.
  101. Sieniawski M., Reineke T., Nogova L. et al. Fertility in male patients with advanced Hodgkin lymphoma treated with BEACOPP: a report of the German Hodgkin Study Group (GHSG). Blood 2008; 111(1): 71–6.
  102. Ferme C., Bastion Y., Lepage E. et al. The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin’s disease. Ann. Oncol. 1995; 6(6): 543–9.
  103. Bartlett N.L., Niedzwiecki D., Johnson J.L. et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804. Ann. Oncol. 2007; 18(6): 1071–9.
  104. Hansen P.V., Trykker H., Svennekjaer I.L., Hvolby J. Long-term recovery of spermatogenesis after radiotherapy in patients with testicular cancer. Radiother. Oncol. 1990; 18(2): 117–25.
  105. Meistrich M.L. Quantitative Correlation Between Testicular Stem Cell Survival, Sperm Production, and Fertility in the Mouse After Treatment With Different Cytotoxic Agents. J. Androl. 1982; 3(1): 58–68.
  106. van Alphen M.M., van de Kant H.J., de Rooij D.G. Repopulation of the seminiferous epithelium of the rhesus monkey after Х irradiation. Radiat. Res. 1988; 113(3): 487–500.
  107. Zhang Z., Shao S., Meistrich M.L. The radiation-induced block in spermatogonial differentiation is due to damage to the somatic environment, not the germ cells. J. Cell Physiol. 2007; 211(1): 149–58.
  108. Anserini P., Chiodi S., Spinelli S. et al. Semen analysis following allogeneic bone marrow transplantation. Additional data for evidence-based counselling. Bone Marrow Transplant. 2002; 30(7): 447–51.
  109. Hahn E.W., Feingold S.M., Simpson L., Batata M. Recovery from aspermia induced by low-dose radiation in seminoma patients. Cancer 1982; 50(2): 337–40.
  110. Bonadonna G., Santoro A., Viviani S., Lombardi C., Ragni G. Gonadal damage in Hodgkin’s disease from cancer chemotherapeutic regimens. Arch. Toxicol. Suppl. 1984; 7: 140–5.
  111. Muller H.L., Klinkhammer-Schalke M., Seelbach-Gobel B., Hartmann A.A., Kuhl J. Gonadal function of young adults after therapy of malignancies during childhood or adolescence. Eur. J. Pediatr. 1996; 155(9): 763–9.
  112. Tal R., Botchan A., Hauser R., Yogev L., Paz G. Follow-up of sperm concentration and motility in patients with lymphoma. Hum. Reprod. 2000; 15(9): 1985–8.
  113. van Dorp W., van Beek R.D., Laven J.S., Pieters R., de Muinck KeizerSchrama S.M. Long-term endocrine side effects of childhood Hodgkin’s lymphoma treatment: a review. Hum. Reprod. Update 2012; 18(1): 12–28.
  114. Heikens J., Behrendt H., Adriaanse R., Berghout A. Irreversible gonadal damage in male survivors of pediatric Hodgkin’s disease. Cancer 1996; 78(9): 2020–4.
  115. Aubier F., Flamant F., Brauner R., Caillaud J.M., Chaussain J.M. Male gonadal function after chemotherapy for solid tumors in childhood. J. Clin. Oncol. 1989; 7(3): 304–9.
  116. Ben Arush M.W., Solt I., Lightman A., Linn S., Kuten A. Male gonadal function in survivors of childhood Hodgkin and non-Hodgkin lymphoma. Pediatr. Hematol. Oncol. 2000; 17(3): 239–45.
  117. Dhabhar B.N., Malhotra H., Joseph R. et al. Gonadal function in prepubertal boys following treatment for Hodgkin’s disease. Am. J. Pediatr. Hematol. Oncol. 1993; 15(3): 306–10.
  118. Sherins R.J., Olweny C.L., Ziegler J.L. Gynecomastia and gonadal dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin’s disease. N. Engl. J. Med. 1978; 299(1): 12–6.
  119. Green D.M., Brecher M.L., Lindsay A.N. et al. Gonadal function in pediatric patients following treatment for Hodgkin disease. Med. Pediatr. Oncol. 1981; 9(3): 235–44.
  120. Ash P. The influence of radiation on fertility in man. Br. J. Radiol. 1980; 53(628): 271–8.
  121. Lee S.J., Schover L.R., Partridge A.H. et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J. Clin. Oncol. 2006; 24(18): 2917–31.
  122. Kinsella T.J., Trivette G., Rowland J. et al. Long-term follow-up of testicular function following radiation therapy for early-stage Hodgkin’s disease. J. Clin. Oncol. 1989; 7(6): 718–24.
  123. Rowley M.J., Leach D.R., Warner G.A., Heller C.G. Effect of graded doses of ionizing radiation on the human testis. Radiat. Res. 1974; 59(3): 665–78.
  124. Howell S.J., Shalet S.M. Spermatogenesis after cancer treatment: damage and recovery. J. Natl. Cancer Inst. Monogr. 2005; 34: 12–7.
  125. Giwercman A., von der Maase H., Berthelsen J.G., Rorth M., Skakkebaek N.E. Localized irradiation of testes with carcinoma in situ: effects on Leydig cell function and eradication of malignant germ cells in 20 patients. J. Clin. Endocrinol. Metab. 1991; 73(3): 596–603.
  126. Hahn E.W., Feingold S.M., Nisce L. Aspermia and recovery of spermatogenesis in cancer patients following incidental gonadal irradiation during treatment: a progress report. Radiology 1976; 119(1): 223–5.
  127. Socie G., Salooja N., Cohen A. et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 2003; 101(9): 3373–85.
  128. Howell S.J., Radford J.A., Ryder W.D., Shalet S.M. Testicular function after cytotoxic chemotherapy: evidence of Leydig cell insufficiency. J. Clin. Oncol. 1999; 17(5): 1493–8.
  129. Petersen P.M., Andersson A.M., Rorth M., Daugaard G., Skakkebaek N.E. Undetectable inhibin B serum levels in men after testicular irradiation. J. Clin. Endocrinol. Metab. 1999; 84(1): 213–5.
  130. Нишлаг Э., Бере Г.М. Андрология. Мужское здоровье и дисфункция репродуктивной системы, 2-е изд. М.: МИА, 2005: 32–4.
  131. [Nishlag E., Bere G.M. Andrologiya. Muzhskoye zdorovye i disfunktsiya reproduktivnoy sistemy, 2-e izd. (Andrology. Men’s health and reproductive system dysfunctions. 2nd ed.). M.: MIA, 2005: 32–4.]
  132. Bohring C., Krause W. Serum levels of inhibin B in men with different causes of spermatogenic failure. Andrologia 1999; 31(3): 137–41.
  133. van Beek R.D., Smit M., van den Heuvel-Eibrink M.M. et al. Inhibin B is superior to FSH as a serum marker for spermatogenesis in men treated for Hodgkin’s lymphoma with chemotherapy during childhood. Hum. Reprod. 2007; 22(12): 3215–22.
  134. Halder A., Fauzdar A., Kumar A. Serum inhibin B and follicle-stimulating hormone levels as markers in the evaluation of azoospermic men: a comparison. Andrologia 2005; 37(5): 173–9.
  135. Carreau S. Paracrine control of human Leydig cell and Sertoli cell functions. Folia Histochem. Cytobiol. 1996; 34(3–4): 111–9.
  136. Huhtaniemi I., Toppari J. Endocrine, paracrine and autocrine regulation of testicular steroidogenesis. Adv. Exp. Med. Biol. 1995; 377: 33–54.
  137. Castillo L.A., Craft A.W., Kernahan J., Evans R.G., Aynsley-Green A. Gonadal function after 12-Gy testicular irradiation in childhood acute lymphoblastic leukaemia. Med. Pediatr. Oncol. 1990; 18(3): 185–9.
  138. Hobbie W.L., Schwartz C.L. Endocrine late effects among survivors of cancer. Semin. Oncol. Nurs. 1989; 5(1): 14–21.
  139. Shalet S.M., Horner A., Ahmed S.R., Morris-Jones P.H. Leydig cell damage after testicular irradiation for lymphoblastic leukaemia. Med. Pediatr. Oncol. 1985; 13(2): 65–8.
  140. Orwig K.E., Schlatt S. Cryopreservation and transplantation of spermatogonia and testicular tissue for preservation of male fertility. J. Natl. Cancer Inst. Monogr. 2005; 34: 51–6.
  141. Res U., Res P., Kastelic D., Stanovnik M., Kmetec A. Birth after treatment of a male with seminoma and azoospermia with cryopreserved-thawed testicular tissue. Hum. Reprod. 2000; 15(4): 861–4.
  142. Dohle G.R., Colpi G.M., Hargreave T.B., Papp G.K., Jungwirth A. EAU guidelines on male infertility. Eur. Urol. 2005; 48(5): 703–11.
  143. Hirsch M., Lunenfeld B., Modan M., Ovadia J., Shemesh J. Spermarche the age of onset of sperm emission. J. Adolesc. Health Care 1985; 6(1): 35–9.
  144. Nielsen C.T., Skakkebaek N.E., Richardson D.W. et al. Onset of the release of spermatozoa (spermarche) in boys in relation to age, testicular growth, pubic hair, and height. J. Clin. Endocrinol. Metab. 1986; 62(3): 532–5.
  145. Kamischke A., Jurgens H., Hertle L., Berdel W.E., Nieschlag E. Cryopreservation of sperm from adolescents and adults with malignancies. J. Androl. 2004; 25(4): 586–92.
  146. Hagenas I., Jorgensen N., Rechnitzer C. et al. Clinical and biochemical correlates of successful semen collection for cryopreservation from 12–18-yearold patients: a single-center study of 86 adolescents. Hum. Reprod. 2010; 25(8): 2031–8.
  147. Bahadur G., Ling K.L., Hart R. et al. Semen quality and cryopreservation in adolescent cancer patients. Hum. Reprod. 2002; 17(12): 3157–61.
  148. Naysmith T.E., Blake D.A., Harvey V.J., Johnson N.P. Do men undergoing sterilizing cancer treatments have a fertile future? Hum. Reprod. 1998; 13(11): 3250–5.
  149. Park Y.S., Lee S.H., Song S.J., Jun J.H., Koong M.K. Influence of motility on the outcome of in vitro fertilization/intracytoplasmic sperm injection with fresh vs. frozen testicular sperm from men with obstructive azoospermia. Fertil. Steril. 2003; 80(3): 526–30.
  150. Cryopreservation of spermatozoa. Laboratory manual for the examination and processing of human semen, 5th ed. Geneva: World Health Organization press, 2010: 169–71.
  151. Perloff W.H., Steinberger E., Sherman J.K. Conception with human spermatozoa frosen by nirogen vapor technic. Fertil. Steril. 1964; 15: 501–4.
  152. David G., Czyglik F., Mayaux M.J., Schwartz D. The success of A.I.D. and semen characteristics: study on 1489 cycles and 192 ejaculates. Int. J. Androl. 1980; 3(6): 613–9.
  153. Clarke G.N., Bourne H., Hill P. et al. Artificial insemination and in-vitro fertilization using donor spermatozoa: a report on 15 years of experience. Hum. Reprod. 1997; 12(4): 722–6.
  154. Leibo S.P., Picton H.M., Gosden R.G. Cryopreservation of human spermatozoa. In: Current Practices and Controversies in Assisted Reproduction. Ed. by E. Vayena, P.J. Rowe et al. Geneva: World Health Organization, 2002: 152–65.
  155. Keel B.A., Webster B.W. Semen analysis data from fresh and cryopreserved donor ejaculates: comparison of cryoprotectants and pregnancy rates. Fertil. Steril. 1989; 52(1): 100–5.
  156. Watson P.F. Recent developments and concepts in the cryopreservation of spermatozoa and the assessment of their post-thawing function. Reprod. Fertil. Dev. 1995; 7(4): 871–91.
  157. Bagchi A., Woods E.J., Critser J.K. Cryopreservation and vitrification: recent advances in fertility preservation technologies. Expert. Rev. Med. Devices 2008; 5(3): 359–70.
  158. Sherman G.K. Cryopreservation of human semen. In: Handbook of Laboratory Diagnosis and Treatment of Infertility, 1st ed. Ed. by D.F. Keel, B.W. Webster. CRC-Press, 1990: 229–59.
  159. Vutyavanich T., Piromlertamorn W., Nunta S. Rapid freezing versus slow programmable freezing of human spermatozoa. Fertil. Steril. 2010; 93(6): 1921–8.
  160. Zribi N., Feki C.N., El E.H., Gargouri J., Bahloul A. Effects of cryopreservation on human sperm deoxyribonucleic acid integrity. Fertil. Steril. 2010; 93(1): 159–66.
  161. O’Flaherty C., Hales B.F., Chan P., Robaire B. Impact of chemotherapeutics and advanced testicular cancer or Hodgkin lymphoma on sperm deoxyribonucleic acid integrity. Fertil. Steril. 2010; 94(4): 1374–9.
  162. Woods E.J., Benson J.D., Agca Y., Critser J.K. Fundamental cryobiology of reproductive cells and tissues. Cryobiology 2004; 48(2): 146–56.
  163. Shin D., Lo K.C., Lipshultz L.I. Treatment options for the infertile male with cancer. J. Natl. Cancer Inst. Monogr. 2005; 34: 48–50.
  164. Meistrich M.L. Male gonadal toxicity. Pediatr. Blood Cancer 2009; 53(2): 261–6. 163. Feldschuh J., Brassel J., Durso N., Levine A. Successful sperm storage for 28 years. Fertil. Steril. 2005; 84(4): 1017.
  165. Horne G., Atkinson A.D., Pease E.H., Logue J.P., Brison D.R. Live birth with sperm cryopreserved for 21 years prior to cancer treatment: case report. Hum. Reprod. 2004; 19(6): 1448–9.
  166. Clarke G.N., Liu D.Y., Baker H.W. Recovery of human sperm motility and ability to interact with the human zona pellucida after more than 28 years of storage in liquid nitrogen. Fertil. Steril. 2006; 86(3): 721–2.
  167. Agarwal A., Ranganathan P., Kattal N. et al. Fertility after cancer: a prospective review of assisted reproductive outcome with banked semen specimens. Fertil. Steril. 2004; 81(2): 342–8.
  168. Saito K., Suzuki K., Iwasaki A., Yumura Y., Kubota Y. Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer 2005; 104(3): 521–4.
  169. Schover L.R., Brey K., Lichtin A., Lipshultz L.I., Jeha S. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J. Clin. Oncol. 2002; 20(7): 1880–9.
  170. Janssens P.M., Beerendonk C.C., Blokzijl E., Braat D.D., Westphal J.R. Cryopreservation of semen of adolescents and young adult men with cancer. Ned. Tijdschr. Geneeskd. 2004; 148(40): 1981–4.
  171. Brinster R.L., Nagano M. Spermatogonial stem cell transplantation, cryopreservation and culture. Semin. Cell Dev. Biol. 1998; 9(4): 401–9.
  172. Nagano M., Patrizio P., Brinster R.L. Long-term survival of human spermatogonial stem cells in mouse testes. Fertil. Steril. 2002; 78(6): 1225–33.
  173. Avarbock M.R., Brinster C.J., Brinster R.L. Reconstitution of spermatogenesis from frozen spermatogonial stem cells. Nat. Med. 1996; 2(6): 693–6.
  174. Brook P.F., Radford J.A., Shalet S.M., Joyce A.D., Gosden R.G. Isolation of germ cells from human testicular tissue for low temperature storage and autotransplantation. Fertil. Steril. 2001; 75(2): 269–74.
  175. Keros V., Rosenlund B., Hultenby K., Aghajanova L., Levkov L. Optimizing cryopreservation of human testicular tissue: comparison of protocols with glycerol, propanediol and dimethylsulphoxide as cryoprotectants. Hum. Reprod. 2005; 20(6): 1676–87.
  176. Kvist K., Thorup J., Byskov A.G., Hoyer P.E., Mollgard K. Cryopreservation of intact testicular tissue from boys with cryptorchidism. Hum. Reprod. 2006; 21(2): 484–91.
  177. Radford J., Shalet S., Lieberman B. Fertility after treatment for cancer. Questions remain over ways of preserving ovarian and testicular tissue. BMJ 1999; 319(7215): 935–6.
  178. Radford J. Restoration of fertility after treatment for cancer. Horm. Res. 2003; 59(Suppl. 1): 21–3.
  179. Schlatt S., Rosiepen G., Weinbauer G.F., Rolf C., Nieschlag E. Germ cell transfer into rat, bovine, monkey and human testes. Hum. Reprod. 1999; 14(1): 144–50.
  180. Toyooka Y., Tsunekawa N., Akasu R., Noce T. Embryonic stem cells can form germ cells in vitro. Proc. Natl. Acad. Sci. USA 2003; 100(20): 11457–62.
  181. Yang S., Bo J., Hu H. et al. Derivation of male germ cells from induced pluripotent stem cells in vitro and in reconstituted seminiferous tubules. Cell Prolif. 2012; 45(2): 91–100.
  182. Honaramooz A., Snedaker A., Boiani M., Dobrinski I., Schlatt S. Sperm from neonatal mammalian testes grafted in mice. Nature 2002; 418(6899): 778–81.
  183. Honaramooz A., Li M.W., Penedo M.C., Meyers S., Dobrinski I. Accelerated maturation of primate testis by xenografting into mice. Biol. Reprod. 2004; 70(5): 1500–3.
  184. Ma P., Ge Y., Wang S., Ma J., Xue S. Spermatogenesis following syngeneic testicular transplantation in Balb/c mice. Reproduction 2004; 128(2): 163–70.
  185. Oatley J.M., de Avila D.M., Reeves J.J., McLean D.J. Spermatogenesis and germ cell transgene expression in xenografted bovine testicular tissue. Biol. Reprod. 2004; 71(2): 494–501.
  186. Schlatt S., Kim S.S., Gosden R. Spermatogenesis and steroidogenesis in mouse, hamster and monkey testicular tissue after cryopreservation and heterotopic grafting to castrated hosts. Reproduction 2002; 124(3): 339–46.
  187. Schlatt S., Honaramooz A., Boiani M., Scholer H.R., Dobrinski I. Progeny from sperm obtained after ectopic grafting of neonatal mouse testes. Biol. Reprod. 2003; 68(6): 2331–5.
  188. Shinohara T., Inoue K., Ogonuki N. et al. Birth of offspring following transplantation of cryopreserved immature testicular pieces and in-vitro microinsemination. Hum. Reprod. 2002; 17(12): 3039–45.
  189. Shinohara T., Orwig K.E., Avarbock M.R., Brinster R.L. Remodeling of the postnatal mouse testis is accompanied by dramatic changes in stem cell number and niche accessibility. Proc. Natl. Acad. Sci. USA 2001; 98(11): 6186–91.
  190. Ryu B.Y., Orwig K.E., Avarbock M.R., Brinster R.L. Stem cell and niche development in the postnatal rat testis. Dev. Biol. 2003; 263(2): 253–63.
  191. Jahnukainen K., Hou M., Petersen C., Setchell B., Soder O. Intratesticular transplantation of testicular cells from leukemic rats causes transmission of leukemia. Cancer Res. 2001; 61(2): 706–10.
  192. Gui Y.L., He C.H., Amory J.K. et al. Male hormonal contraception: suppression of spermatogenesis by injectable testosterone undecanoate alone or with levonorgestrel implants in Chinese men. J. Androl. 2004; 25(5): 720–7.
  193. Nieschlag E., Vorona E., Wenk M., Hemker A.K., Kamischke A. Hormonal male contraception in men with normal and subnormal semen parameters. Int. J. Androl. 2011; 34(6 Pt. 1): 556–67.
  194. Meistrich M.L., Zhang Z., Porter K.L. Prevention of adverse effects of cancer treatment on the germline. In: Male-mediated developmental toxicity. Ed. by D. Anderson, M.H. Brinkworth. Royal Society of Chemistry, 2007: 114–23.
  195. Dobrinski I., Ogawa T., Avarbock M.R., Brinster R.L. Effect of the GnRHagonist leuprolide on colonization of recipient testes by donor spermatogonial stem cells after transplantation in mice. Tissue Cell 2001; 33(2): 200–7.
  196. Meistrich M.L., Shetty G. Inhibition of spermatogonial differentiation by testosterone. J. Androl. 2003; 24(2): 135–48.
  197. Meistrich M.L., Shetty G. Hormonal suppression for fertility preservation in males and females. Reproduction 2008; 136(6): 691–701.
  198. Shetty G., Meistrich M.L. Hormonal approaches to preservation and restoration of male fertility after cancer treatment. J. Natl. Cancer Inst. Monogr. 2005; 34: 36–9.
  199. Howell S.J., Shalet S.M. Fertility preservation and management of gonadal failure associated with lymphoma therapy. Curr. Oncol. Rep. 2002; 4(5): 443–52.
  200. Meseguer M., Garrido N., Remohi J. et al. Testicular sperm extraction (TESE) and ICSI in patients with permanent azoospermia after chemotherapy. Hum. Reprod. 2003; 18(6): 1281–5.
  201. Binsaleh S., Sircar K., Chan P.T. Feasibility of simultaneous testicular microdissection for sperm retrieval and ipsilateral testicular tumor resection in azoospermic men. J. Androl. 2004; 25(6): 867–71.
  202. Baniel J., Sella A. Sperm extraction at orchiectomy for testis cancer. Fertil. Steril. 2001; 75(2): 260–2.
  203. Schrader M., Muller M., Sofikitis N. et al. “Onco-tese”: testicular sperm extraction in azoospermic cancer patients before chemotherapy-new guidelines? Urology 2003; 61(2): 421–5.
  204. Chan P.T., Palermo G.D., Veeck L.L., Rosenwaks Z., Schlegel P.N. Testicular sperm extraction combined with intracytoplasmic sperm injection in the treatment of men with persistent azoospermia postchemotherapy. Cancer 2001; 92(6): 1632–7.
  205. Damani M.N., Master V., Meng M.V. et al. Postchemotherapy ejaculatory azoospermia: fatherhood with sperm from testis tissue with intracytoplasmic sperm injection. J. Clin. Oncol. 2002; 20(4): 930–6.
  206. Zorn B., Virant-Klun I., Stanovnik M., Drobnic S., Meden-Vrtovec H. Intracytoplasmic sperm injection by testicular sperm in patients with aspermia or azoospermia after cancer treatment. Int. J. Androl. 2006; 29(5): 521–7.
  207. de Rooij D.G., van de Kant H.J., Dol R. et al. Long-term effects of irradiation before adulthood on reproductive function in the male rhesus monkey. Biol. Reprod. 2002; 66(2): 486–94.
  208. Hibi H., Ohori T., Yamada Y., Honda N., Hashiba Y. Testicular sperm extraction and ICSI in patients with post-chemotherapy non-obstructive azoospermia. Arch. Androl. 2007; 53(2): 63–5.
  209. Wyrobek A.J., Gordon L.A., Burkhart J.G. et al. An evaluation of human sperm as indicators of chemically induced alterations of spermatogenic function. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat. Res. 1983; 115(1): 73–148.
  210. Robbins W.A., Meistrich M.L., Moore D. et al. Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm. Nat. Genet. 1997; 16: 74–8.
  211. Frias S., Van H.P., Meistrich M.L. et al. NOVP chemotherapy for Hodgkin’s disease transiently induces sperm aneuploidies associated with the major clinical aneuploidy syndromes involving chromosomes X, Y, 18, and 21. Cancer Res. 2003; 63(1): 44–51.
  212. Meistrich M.L. Effects of chemotherapy and radiotherapy on spermatogenesis. Eur. Urol. 1993; 23(1): 136–41.
  213. Wyrobek A.J., Schmid T.E., Marchetti F. Relative susceptibilities of male germ cells to genetic defects induced by cancer chemotherapies. J. Natl. Cancer Inst. Monogr. 2005; 34: 31–5.
  214. Chatterjee R., Haines G.A., Perera D.M., Goldstone A., Morris I.D. Testicular and sperm DNA damage after treatment with fludarabine for chronic lymphocytic leukaemia. Hum. Reprod. 2000; 15(4): 762–6.
  215. Meistrich M.L. Potential genetic risks of using semen collected during chemotherapy. Hum. Reprod. 1993; 8(1): 8–10. 215. Stahl O., Eberhard J., Jepson K. et al. Sperm DNA integrity in testicular cancer patients. Hum. Reprod. 2006; 21(12): 3199–205.
  216. Spermon J.R., Ramos L., Wetzels A.M. et al. Sperm integrity pre- and post-chemotherapy in men with testicular germ cell cancer. Hum. Reprod. 2006; 21(7): 1781–6.
  217. Dubrova Y.E., Grant G., Chumak A.A., Stezhka V.A., Karakasian A.N. Elevated minisatellite mutation rate in the post-Chernobyl families from Ukraine. Am. J. Hum. Genet. 2002; 71(4): 801–9.
  218. Brandriff B.F., Meistrich M.L., Gordon L.A., Carrano A.V., Liang J.C. Chromosomal damage in sperm of patients surviving Hodgkin’s disease following MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) therapy with and without radiotherapy. Hum. Genet. 1994; 93(3): 295–9.
  219. Tempest H.G., Ko E., Chan P., Robaire B., Rademaker A. Sperm aneuploidy frequencies analysed before and after chemotherapy in testicular cancer and Hodgkin’s lymphoma patients. Hum. Reprod. 2008; 23(2): 251–8.
  220. De M.P., Daudin M., Vincent M.C. et al. Increased aneuploidy in spermatozoa from testicular tumour patients after chemotherapy with cisplatin, etoposide and bleomycin. Hum. Reprod. 2001; 16(6): 1204–8.
  221. Winther J.F., Boice J.D. Jr., Mulvihill J.J. et al. Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: a populationbased study. Am. J. Hum. Genet. 2004; 74(6): 1282–5.
  222. Blatt J. Pregnancy outcome in long-term survivors of childhood cancer. Med. Pediatr. Oncol. 1999; 33(1): 29–33.
  223. Byrne J., Rasmussen S.A., Steinhorn S.C. et al. Genetic disease in offspring of long-term survivors of childhood and adolescent cancer. Am. J. Hum. Genet. 1998; 62(1): 45–52.
  224. Dodds L., Marrett L.D., Tomkins D.J., Green B., Sherman G. Casecontrol study of congenital anomalies in children of cancer patients. BMJ 1993; 307(6897): 164–8.
  225. Green D.M., Whitton J.A., Stovall M. et al. Pregnancy outcome of partners of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 2003; 21(4): 716–21.
  226. Kenney L.B., Nicholson H.S., Brasseux C. et al. Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia. A Childrens Cancer Group/National Institutes of Health Report. Cancer 1996; 78(1): 169–76.
  227. Meistrich M.L., Byrne J. Genetic disease in offspring of long-term survivors of childhood and adolescent cancer treated with potentially mutagenic therapies. Am. J. Hum. Genet. 2002; 70(4): 1069–71.
  228. Senturia Y.D., Peckham C.S. Children fathered by men treated with chemotherapy for testicular cancer. Eur. J. Cancer 1990; 26(4): 429–32.
  229. Signorello L.B., Mulvihill J.J., Green D.M. et al. Congenital anomalies in the children of cancer survivors: a report from the childhood cancer survivor study. J. Clin. Oncol. 2012; 30(3): 239–45.
  230. Tiemann-Boege I., Navidi W., Grewal R. et al. The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect. Proc. Natl. Acad. Sci. USA 2002; 99(23): 14952–7.
  231. Glaser R.L., Broman K.W., Schulman R.L. et al. The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am. J. Hum. Genet. 2003; 73(4): 939–47.
  232. Giwercman A. Gonadotoxic cancer treatment in males—a reason for andrological counselling? Radiother. Oncol. 2003; 68(3): 213–5.
  233. Pierik F.H., Dohle G.R., van Muiswinkel J.M., Vreeburg J.T., Weber R.F. Is routine scrotal ultrasound advantageous in infertile men? J. Urol. 1999; 162(5): 1618–20.
  234. Pierik F.H., Van Ginneken A.M., Dohle G.R., Vreeburg J.T., Weber R.F. The advantages of standardized evaluation of male infertility. Int. J. Androl. 2000; 23(6): 340–6.
  235. Wang J., Galil K.A., Setchell B.P. Changes in testicular blood flow and testosterone production during aspermatogenesis after irradiation. J. Endocrinol. 1983; 98(1): 35–46.
  236. Setchell B.P., Galil K.A. Limitations imposed by testicular blood flow on the function of Leydig cells in rats in vivo. Aust. J. Biol. Sci. 1983; 36(3): 285–93.

Multiple myeloma (pathogenesis, clinical features, diagnosis, differential diagnosis). Part I

REVIEWS , , ,

S.S. Bessmeltsev

Russian Research Institute of Hematology and Transfusiology, Saint Petersburg, Russian Federation

ABSTRACT

Multiple myeloma (MM) is a malignancy characterized by bone marrow infiltration with plasma cell and extensive skeletal bone destruction resulting in bone pain and fractures. This review presents typical laboratory findings and clinical presentation of multiple myeloma. Multiple myeloma is definite when the following hallmarks are present: ³ 10% of clonal plasma cells in the bone marrow, M protein in serum or urine (except nonsecretory myeloma), hypercalcemia, renal insufficiency, anemia, or osteolytic lesions in skeletal bones. Monoclonal (M) proteins are detected using serum protein electrophoresis and immunofixation. In addition, urine protein electrophoresis and immunofixation or a serum free light-chain assay are essential. The International Staging System classifies MM patients into three groups of risk — standard, intermediate, or high — depending on the b2-microglobulin and albumin serum levels. The presence of any one of the following indicates high-risk myeloma: a 13q deletion or hypodiploidy on metaphase cytogenetic studies, a 17p deletion, immunoglobulin heavy-chain translocations t(4;14) or t(14;16), or a plasma cell labeling index ³ 3%.

This review presents laboratory findings and clinical manifestations of monoclonal gammopathy of undetermined significance, asymptomatic myeloma (‘smouldering myeloma’), nonsecretory myeloma, solitary bone plasmacytoma, extramedullary plasmacytoma, plasma cell leukemia, Waldenstrom’s macroglobulinemia, amyloidosis, and other diseases.

Keywords: multiple myeloma, monoclonal gammopathy of undetermined significance, asymptomatic myeloma, M protein, clonal plasma cells.

Read in PDF (RUS)pdficon

REFERENCES

  1. Harousseau J.-L., Dreyling M., on behalf of the ESMO Guidelines Working Group. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Oncology 2010; 21(Suppl. 5): v155–7.
  2. Бессмельцев С.С., Абдукадыров К.М. Множественная миелома. Современный взгляд на проблему. Алматы, 2007. [Bessmeltsev S.S., Abdukadyrov K.M. Mnozhestvennaya miyeloma. Sovremennyy vzglyad na problemu (Multiple myeloma. Current view of the problem). Almaty, 2007.]
  3. Kyle R.A., Rajkumar S.V. Multiple myeloma. Engl. J. Med. 2004; 351(18): 1860–73.
  4. Fonseca R., Bergsagel P.L., Drach J. et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009; 23(12): 2210–21.
  5. Anderson K.C. Targeted therapy for multiple myeloma. Hematol. 2001; 38: 286–94.
  6. Barker H.F., Ball J., Drew M. et al. The role of adhesion molecules in multiple myeloma. Lymphoma 1992; 8: 189–96.
  7. Харченко М.Ф., Бессмельцев С.С. Значение протеогликанов в патоге- незе множественной миеломы. Биомед. журн. Medline.ru. 2010; 11: 404–23. [Kharchenko M.F., Bessmeltsev S.S. Znacheniye proteoglikanov v patogeneze mnozhestvennoy miyelomy (Significance of proteoglycans in pathogenesis of multiple myeloma. In: Biomed. journ.). Biomed. zhurn. Medline.ru. 2010; 11: 404–23.]
  8. Stringer S.E. The role of heparan sulfate proteoglycans in angiogenesis. Soc. Trans. 2006; 34: 451–3.
  9. Andersen N., Standal T., Nielsen J. et al. Syndecan-1 and angiogenic cytokines in multiple myeloma: correlation with bone marrow angiogenesis and survival. J. Haemat. 2004; 128: 210–7.
  10. Klein B., Tarte K., Jourdan M. et al. Survival and proliferation factors of normal and malignant plasma cells. J. Hematol. 2003; 78: 106–13.
  11. Mahtouk K., Cremer F., Reme T. et al. Heparan sulfate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma. Oncogene 2006; 25: 7180–91.
  12. Purushothaman A., Uyama T., Kobayashi F. Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis. Blood 2010; 115: 2449–57.
  13. Damiano J.S., Gress A.E., Hazlehurst L.A. et al. Cell adhesion mediated drug resistance: Role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999; 93: 1658–67.
  14. Damiano J.S., Dalton W.S. Integrin-mediated drug resistance in multiple myeloma. Lymphoma 2000; 38: 71–81.
  15. Shain K., Landowski T., Dalton W.S. Cellular adhesion via Beta 1 integrins increases c-FLIPL levels and inhibits CD95/Fas-mediated apoptosis in hematologic malignancies: A mechanism of immune evasion. 2001.
  16. Davies F.E., Anderson K.C. Novel therapeutic targets in multiple myeloma. J. Hematol. 2000; 64: 359–67.
  17. Anderson K.C. Targeted therapy for multiple myeloma. Hematol. 2001; 38: 286–94.
  18. Klein B., Zhang X., Lu Z. Interleukin-6 in multiple myeloma. Blood 1995; 85: 863–7.
  19. Karin M., Cao Y., Greten F.R., Li Z.W. NF-kappaB in cancer: from innocent bystander to major culprit. Rev. Cancer 2002; 2: 301–10.
  20. Barlogie B., Epstein J., Selvanayagam P., Alexanian R. Plasma cell myeloma — new biological insights and advances in therapy. Blood 1998; 73: 865–70.
  21. Fonseca R., Oken M.H., Harrington D. et al. deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia 2001; 15: 981–6.
  22. Fonseca R., Debes-Marun C.S., Picken E.B. et al. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood 2003; 102(7): 2562–7.
  23. Mohamed A.N., Bentley G., Bonnett M.L. et al. Chromosome aberrations in a series of 120 multiple myeloma cases with abnormal karyotypes. J. Hematol. 2007; 82: 1080–7.
  24. Chesi M., Nardini E., Lim R.C. et al. The t(4;14) translocation in multiple myeloma disregulates both FGFR 3 and novel gene, MMSET, resulting in IgH/ MMSET hybrid transcripts. Blood 1998; 92: 3025–34.
  25. Avet-Loiseau H., Attal M., Campion L. et al. Long-term analysis of the IFM 99 trials for myeloma: Cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. Clin. Oncol. 2012; 30: 1949–52.
  26. Avet-Loiseau H., Minvielle S., Mellerin M.P. et al. 14q32 chromosomal translocations: A hallmark of plasma cell dyscrasias? J. 2000; 1: 292–4.
  27. Fonseca R., Debes-Marun C.S., Picken E.B. et al. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood 2003; 102(7): 2562–7.
  28. Avet-Loiseau H., Facon T., Daviet A. et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. Cancer Res. 1999; 59: 4546–50.
  29. Shaughnessy J.Jr., Cabren A.Q. Cyclin D3 at 6h21 is deregulated by recurrent chromosome translocation to immunoglobulin loci in multiple myeloma. Blood 2001; 98: 217–23.
  30. Santra M., Zhan F., Tian E. et al. A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 2003; 101: 2374–6.
  31. Broyl A., Hose D., Lokhorst H. et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood 2010; 116: 2543–6.
  32. Sawyer J.R., Lukacs J.L., Thomas E.L. et al. Multicolour spectral karyotyping identifies new translocation and a recurring pathway for chromosome loss in multiple myeloma. J. Haematol. 2000; 112: 1–9.
  33. Bednarek A.K., Keck-Waggoner C.L., Daniel R.L. et al. WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res. 2001; 61: 8068–73.
  34. Shou Y., Martelli M.L., Gabrea A. et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Natl. Acad. Sci. USA 2000; 97: 228–33.
  35. Shaughnessy J.Jr., Tian E., Sawyer J. et al. High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH. Blood 2000; 96: 1505–11.
  36. Fonseca R., Oken M.H., Harrington D. et al. deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia 2001; 15: 981–6.
  37. Boersma-Vreugdenhill G.R., Kuipers J., Bast B.J. Breakpoint analysis of a novel recurrent chromosomal translocation t(14;20)(q32;q12) in a human multiple myeloma cell line. VIIIth International Myeloma Workshop. Banff, Alberta, Canada, 2001: 124.
  38. Fonseca R., Bergsagel P.L., Drach J. et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009; 23: 2210–21.
  39. Walker B.A., Leone P.E., Chiecchio L. et al. A compendium of myelomaassociated chromosomal copy number abnormalities and their prognostic value. Blood 2010; 116: e56–65.
  40. Hanamura I., Stewart J.P., Huang Y. et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 2006; 108: 1724–32.
  41. Liu P.C., Leong T., Quam L. et al. Activating mutations of N- and K-ras in multiple myeloma show different clinical associations — analysis of the Eastern Cooperative Oncology Group phase III trial. Blood 1996; 88: 2699–706.
  42. Urashima M., Teoh G., Ogata A. et al. Characterization of p16(INK4A) expression in multiple myeloma and plasma cell leukemia. Cancer Res. 1997; 3: 2173–9.
  43. Dimopoulos M., Kyle R., Fermand J.-P. et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus. Panel 3. Blood 2011; 117(18): 4701–5.
  44. Baur-Melnyk A., Buhmann S., Durr H.R., Reiser M. Role of MRI for the diagnosis and prognosis of multiple myeloma. J. Radiol. 2005; 55(1): 56–63.
  45. Moulopoulos L.A., Gika D., Anagnostopoulos A. et al. Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma. Oncol. 2005; 16(11): 1824–8.
  46. Walker R., Barlogie B., Haessler J. et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. Clin. Oncol. 2007; 25(9): 1121–8.
  47. Durie B.G., Waxman A.D., D’Angolo A., Williams C.M. Whole-body FDG PET identifies high-risk myeloma. Nucl. Med. 2002; 43(11): 1457–63.
  48. Sezer O. Myeloma bone disease. Hematology 2005; 10(Suppl. 1): 19–24.
  49. Piarse R.N., Sordillo E.M., Yaccoby S. et al. Multiple myeloma disrupts the TRANCE/osteoprotegerin cytocine axons to trigger bone destruction and promote tumor progression. Natl. Acad. Sci. USA 2001; 98: 11581–6.
  50. Heider U., Langelotz C., Jakob C. et al. Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Cancer Res. 2003; 9: 1436–40.
  51. Seidel C., Hirtner O., Abildgaard N. et al. Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease. Blood 2001; 98: 2269–71.
  52. Abe M., Hiura K., Wilde J. et al. Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma. Blood 2002; 100: 2195–202.
  53. Zannettino A.C., Farrugia A.N., Kortesidis A. et al. Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Res. 2005; 65: 1700–9.
  54. Tian E., Zhan F., Walker R. et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. Engl. J. Med. 2003; 349: 2483–6.
  55. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Частота, характеристика и методы лечения периферической нейропатии у больных множественной миеломой, получающих бортезомиб (велкейд). Онкогема- тология 2008; 3: 52–62. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V. i dr. Chastota, kharakteristika i metody lecheniya perifericheskoy neyropatii u bolnykh mnozhestvennoy miyelomoy, poluchayushchikh bortezomib (velkeyd) (Incidence, characteristics, and methods of therapy for peripheral neuropathy in patients with multiple myeloma treated with bortezomib (Velcade). In: Oncohematology). Onkogematologiya 2008; 3: 52–62.]
  56. Rajkumar S.V., Fonseca R., Dispenzieri A. et al. Methods for estimation of bone marrow plasma cell involvement in myeloma: predictive value for response and survival in patients undergoing autologous stem cell transplantation. J. Hematol. 2001; 68(4): 269–75.
  57. Ругаль В.И., Бессмельцев С.С. Оценка опухолевой инфильтрации костного мозга при множественной миеломе по результатам исследования трепанобиоптатов. Вестн. гематол. 2009; 5(1): 49–50. [Rugal V.I., Bessmeltsev S.S. Otsenka opukholevoy infiltratsii kostnogo mozga pri mnozhestvennoy miyelome po rezultatam issledovaniya trepanobioptatov (Assessment of bone marrow tumor infiltration based on trephine biopsy findings. In: Hematol. bullet.). Vestn. gematol. 2009; 5(1): 49–50.]
  58. Людвиг Х., Остерборг А. Анемия и терапия эритропоэтином при множе- ственной миеломе. Анемия у онкологических больных. 2002; 1(Вып. 1): 3–10. [Lyudvig Kh., Osterborg A. Anemiya i terapiya eritropoetinom pri mnozhestvennoy miyelome (Anemia and erythropoietin therapy in multiple myeloma. In: Anemia in cancer patients). Anemiya u onkologicheskikh bolnykh. 2002; 1(Vyp. 1): 3–10.]
  59. Бессмельцев С.С., Гусева С.А. Современные принципы лечения анемии у пациентов с онкогематологическими заболеваниями. Украiн. журн. гематол. та трансфузiол. 2009; 1: 5–17. [Bessmeltsev S.S., Guseva S.A. Sovremennye printsipy lecheniya anemii u patsientov s onkogematologicheskimi zabolevaniyami (Current principles of therapy for anemia in patients with hematological malignancies. In: Ukraine journal of hematol. & transfusiol.). Ukrain. zhurn. gematol. ta transfuziol. 2009; 1: 5–17.]
  60. Abdulkadyrov K.M., Bessmeltsev S.S. Renal insufficiency in multiple myeloma: Basic mechanisms in its development and methods for treatment. Renal Fail. 1996; 18(1): 139–46.
  61. Faiman B.M., Spong J., Tariman J.D. Renal Complications in Multiple Myeloma and Related Disorders: Survivorship Care Plan of the International Myeloma Foundation Nurse Leadership Board. J. Oncol. Nurs. 2011; 15(4): 66–76.
  62. Бессмельцев С.С. Бисфосфонаты и их роль в лечении множественной миеломы. Украiн. журн. гематол. та трансфузiол. 2011; 1: 5–18. [Bessmeltsev S.S. Bisfosfonaty i ikh rol v lechenii mnozhestvennoy miyelomy (Bisphosphonates and their role in therapy for multiple myeloma. In: Ukraine journ. of hematol. & transfusiol.). Ukrain. zhurn. gematol. ta transfuziol. 2011; 1: 5–18.]
  63. Чубукина Ж.В., Бубнова Л.Н., Бессмельцев С.С. и др. Неспецифические факторы защиты и гуморальный иммунитет у больных множественной миеломой. Мед. экстрем. ситуаций 2012; 2: 93–8. [Chubukina Zh.V., Bubnova L.N., Bessmeltsev S.S. i dr. Nespetsificheskiye faktory zashchity i gumoralnyy immunitet u bolnykh mnozhestvennoy miyelomoy (Non-specific protective factors and humoral immunity in patients with multiple myeloma. In: Med. of extr. situations). Med. ekstrem. situatsiy 2012; 2: 93–8.]
  64. Бессмельцев С.С., Стельмашено Л.В., Степанова Н.В. и др. Бортезомиб (велкейд) и мелфалан с преднизолоном в лечении множественной миеломы у пожилых больных. Онкогематология 2010; 2: 40–5. [Bessmeltsev S.S., Stelmasheno L.V., Stepanova N.V. i dr. Bortezomib (velkeyd) i melfalan s prednizolonom v lechenii mnozhestvennoy miyelomy u pozhilykh bolnykh (Bortezomib (Velcade) and melphalan combined with prednisolone in therapy for multiple myeloma in older patients. In: Oncohematology). Onkogematologiya 2010; 2: 40–5.]
  65. Noel C., Ales D.O., Jasmine T. et al. Multiple Myeloma-Associated Amyloidosis Manifesting as Fulminant Hepatic Failure. South Med. J. 2001; 94(10) http://www.medscape.com/viewarticle/415092_5
  66. Dispenzieri A., Kyle R., Merlini G. et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 2009; 23(2): 215–24.
  67. Blade J., Lust J.A., Kyle R.A. Immunoglobulin D multiple myeloma: presenting features, response to therapy, and survival in a series of 53 cases. Clin. Oncol. 1994; 12: 2398–404.
  68. Reece D.E., Vesole D.H. Outcome of Patients With IgD and IgM Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Retrospective CIBMTR Study Clinical Lymphoma. Leuk. 2010; 10(6): 458–63.
  69. Avet-Loiseau H., Garand R., Lode L. et al. Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and nonsecretory multiple myeloma variants. Blood 2003; 101: 1570–1.
  70. Durie B.G.M., Salmon S.E. A clinical staging system for multiple myeloma: Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975; 36: 842–54.
  71. Greipp P.R., San Miguel J., Durie B.G.M. et al. International Staging System for Multiple Myeloma. Clin. Oncol. 2005; 23: 3412–20.
  72. Tuchman S.A., Sagar Lonial. High-Risk Multiple Myeloma: Does it Still Exist? Lymph. Myel. Leuk. 2011; 11(1): S70–6.
  73. Kyle R.A., Rajkumar S.V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23: 3–9.
  74. Hari P.N., Zhang M.J., Roy V. et al. Is the international staging system superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant. Leukemia 2009; 23: 1528–34.
  75. Avet-Loiseau H., Attal M., Moreau P. et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 2007; 109: 3489–95.
  76. Dimopoulos M.A., Kastritis E., Christoulas D. et al. Treatment of patients with relapsed/refractory multiple myeloma (MM) with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities. Blood (ASH Annual Meeting Abstracts) 2009; 114: Abstract 958.
  77. Sawyer J., Shaughnessy J.D., Haussler J. et al. Gene expression profiling (GEP) in multiple myeloma (MM): Distinguishing relapses with high-risk transformation from those with sustained low risk. Clin. Oncol. 2010; 28: 15s (suppl; abstr. 8122).
  78. Kumar S.K., Mikhael J.R. Management of Newly Diagnosed Symptomatic Multiple Myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines. Mayo Clin. Proc. 2009; 84(12): 1095–110.
  79. Fonseca R., Blood E., Rue M. et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003; 101(11): 4569–75.
  80. Gertz M.A., Lacy M.Q., Dispenzieri A. et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 2005; 106(8): 2837–40.
  81. Dispenzieri A., Rajkumar S.V., Gertz M.A. et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-Adapted therapy (mSMART). Mayo Clin. Proc. 2007; 82: 323–41.
  82. Бессмельцев С.С. Диагностика и дифференциальная диагностика множественной миеломы. Вопр. онкол. 2004; 4: 406–16. [Bessmeltsev S.S. Diagnostika i differentsialnaya diagnostika mnozhestvennoy miyelomy (Detection and differential diagnosis of multiple myeloma. In: Issues of oncol.). Vopr. onkol. 2004; 4: 406–16.]
  83. Kyle R.A. Sequence of testing for monoclonal gammopathies: serum and urine assays. Pathol. Lab. Med. 1999; 123(2): 114–8.
  84. Drayson M., Tang L.X., Drew R. et al. Serum free light chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood 2001; 97(9): 2900–2.
  85. Dingli D., Kyle R.A., Rajkumar S.V. et al. Immunoglobulin free light chains and solitary plasmacytoma of bone. Blood 2006; 108(6): 1979–83.
  86. Dispenzieri A., Kyle R.A., Katzmann J.A. et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 2008; 111(2): 785–9.
  87. Katzmann J.A., Clark R.J., Abrahman R.S. et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Chem. 2002; 48: 1437–44.
  88. Smith A., Wisloff F., Samson D. Guidelines on the diagnosis and management of multiple myeloma 2005. J. Haematol. 2006; 132(4): 410–51.
  89. Kyle R.A., Rajkumar S.V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23(1): 3–9.
  90. Rajkumar S.V., Dispenzieri A., Kyle R. Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clin. Proc. 2006; 81: 693–703.
  91. Drayson M., Tang L.X., Drew R. et al. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood 2001; 97: 2900–2.
  92. Rajkumar S.V., Kyle R.A., Therneau T.M. et al. Serum free light ration is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005; 106(3): 812–7.
  93. Kyle R.A. Monoclonal gammopathy of undetermined significance and solitary plasmacytoma: implications for progression to overt multiple myeloma. Oncol. Clin. N. Am. 1997; 11: 71–87.
  94. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. J. Haematol. 2003; 121(5): 749–57.
  95. Kyle R.A., Greipp P.R. ‘Idiopathic’ Bence Jones proteinuria: long-term follow-up in seven patients. Engl. J. Med. 1982; 306: 564–7.
  96. Diop P.A., Haudrechy D., Sylla-Niang M. et al. Laboratory diagnosis of monoclonal gammopathies. Prospective study of 14 cases in Dakar, Senegal. Bull. Soc. Pathol. 1998; 91: 242–6.
  97. Sezer O., Heider U., Zavrski I., Possinger K. Differentiation of monoclonal gammopathy of undetermined significance and multiple myeloma using flow cytometric characteristics of plasma cells. Haematologica 2001; 86: 837–43.
  98. Gandara D.R., Mackenzie M.R. Differential diagnosis of monoclonal gammopathy. Clin. N. Am. 1988; 72(5): 1155–68.
  99. Weber D., Wang L.M., Delasalle K. et al. Risk factors for early progression of asymptomatic multiple myeloma. Hematology J. 2003; 4(Suppl. 1): S31.
  100. Cesana C., Klersy C., Barbarano L. et al. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J. Clin. Oncol. 2002; 20: 1625–34.
  101. Vachon C.M., Kyle R.A., Therneau N.M. et al. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood 2009; 114: 785–7.
  102. Rajkumar S.V., Kyle R.A., Buadj F.K. Advances in the diagnosis, classification, risk stratification, and management of monoclonal gammopathy of undetermined significance: implications for recategorizing disease entities in the presence of evolving scientific evidence. Mayo Clin. Proc. 2010; 85(10): 945–8.
  103. Kyle R.A., Therneau T.M., Rajkumar S.V. et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 2002; 346: 564–9.
  104. Landgren O., Kyle R.A., Pfeiffer R.M. et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009; 113(22): 5412–5.
  105. Weiss B.M., Abadie J., Verma P. et al. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009; 113(22): 5418–21.
  106. Kyle R.A., Remstein E., Therneau T.M. et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N. Engl. J. Med. 2007; 356: 2582–90.
  107. Moulopoulos L.A., Dimopoulos M.A., Weber D. et al. Magnetic resonance imaging in the staging of solitary plasmacytoma of bone. J. Clin. Oncol. 1993; 11: 1311–5.
  108. Tsang R.W., Gospodarowicz M.K., Pintilie M. et al. Solitary plasmacytoma treated with radiotherapy: Impact of tumor size on outcome. Intern. J. Rad. Oncol. Biol. Phys. 2011; 50: 113–20.
  109. Knowling M.A., Harwood A.R., Bergsagel D.E. Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone. J. Clin. Oncol. 1983; 1: 255–62.
  110. Alexiou C., Kau R.J., Dietzfelbinger H. et al. Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 1999; 85: 2305–14.
  111. McKenna R.W., Kyle R.A., Kuehl W.M. et al. Plasma cell neoplasms. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Ed. by S.H. Swerdlow, E. Campo, N.L. Harris et al., 4th ed. Lyon: IARC Press, 2008: 200–13.
  112. Costello R., Sainty D., Bouabdallah R. et al. Primary plasma cell leuukemia: a report of 18 cases. Leuk. Res. 2001; 25: 103–7.
  113. Vela-Ojeda J., Garcia-Ruiz Esparza M.A., Rosas-Cabral A. et al. Intermediate doses of melphalan and dexamethasone are better than vincristine, adriamycin, and dexamethasone (VAD) and polychemotherapy for the treatment of primary plasma cell leukemia. Ann. Hematol. 2002; 81: 362–7.
  114. Lebovic D., Zhang L., Alsina M. et al. Clinical Outcomes of Patients With Plasma Cell Leukemia in the Era of Novel Therapies and Hematopoietic Stem Cell Transplantation Strategies: A Single-Institution Experience. Clin. Lymph. Myel. Leuk. 2012; 11(6): 507–11.
  115. Gutierez N.C., Hernandez J.M., Garcia J.L. et al. Differences in genetic changes between multiple myeloma and plasma cell leukemia demonstrated by comparative genomic hybridization. Leukemia 2001; 5: 840–5.
  116. Tiedemann R.E., Gonzalez-Paz N., Kyle R.A. et al. Genetic aberrations and survival in plasma cell leukemia. Leukemia 2008; 22: 1044–52.
  117. Chang H., Qi X., Yeung J. et al. Genetic aberrations including chromosome 1 abnormalities and clinical features of plasma cell leukemia. Leuk. Res. 2009; 33: 259–62.
  118. Dierlamm T., Laack E., Dierlamm J. IgM myeloma: a report of four cases. Ann. Hematol. 2002; 81: 136–9.
  119. Owen R.G., Treon S.P., Al-Katib A. et al. Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin. Oncol. 2003; 30(2): 110–5.
  120. Gertz M.A. Waldenstrom macroglobulinemia: 2011 update on diagnosis, risk stratification, and management. J. Hematol. 2011; 86(5): 411–6.
  121. Криволапов Ю.А., Леенман Е.Е. Морфологическая диагностика лимфом. СПб.: Издательско-полиграфическая компания «Коста», 2006.
  122. Krivolapov Yu.A., Leyenman Ye.Ye. Morfologicheskaya diagnostika limfom (Morphologic diagnosis of lymphomas). Spb.: Izdatelskopoligraficheskaya kompaniya «Kosta», 2006.
  123. Kyle R.A., Treon S.P., Alexanian R. et al. Prognostic markers and criteria to initiate therapy in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia [review]. Oncol. 2003; 30(2): 116–20.
  124. Михайлов А.М., Бессмельцев С.С., Пожарисский К.М. и др. Болезнь Кастлемана и POEMS-синдром, их проявления и взаимосвязь. В кн.: Редкие гематологические болезни и синдромы. Под ред. М.А. Волковой. М.: Практическая медицина, 2011: 360–83. [Mikhaylov A.M., Bessmeltsev S.S., Pozharisskiy K.M. i dr. Bolezn Kastlemana i POEMS-sindrom, ikh proyavleniya i vzaimosvyaz. V kn.: Redkiye gematologicheskiye bolezni i sindromy. Pod red. M.A. Volkovoy (Castleman’s disease and POEMS syndrome, their presentation and interrelations. In: Rare hematological disorders and syndromes. Ed. by M.A. Volkova). : Prakticheskaya meditsina, 2011: 360–83.]
  125. Алексеев В.В. Диагностика и лечение болей в пояснице, вызванных компрессионной радикулопатией. Справ. поликлин. врача 2002; 4: 28–32. Alekseyev V.V. Diagnostika i lecheniye boley v poyasnitse, vyzvannykh kompressionnoy radikulopatiyey [Diagnosis and treatment of lower back pain caused by compression radiculopathy. In: Desk book of polycl. doctor]. Sprav. poliklin. vracha 2002; 4: 28–32.
  126. Балаболкин М.И. Эндокринология. М.: Универсум паблишинг, 1998. [Balabolkin M.I. Endokrinologiya (Endocrinology). : Universum pablishing, 1998.]
  127. Колондаев А.Ф., Балберкин А.Ф. Болезнь Педжета (деформиру- ющий остит). Врач 2003; 4: 13–6. [Kolondayev A.F., Balberkin A.F. Bolezn Pedzheta (deformiruyushchiy ostit) (Paget’s disease (osteitis deformans). In: Medical practitioner). Vrach 2003; 4: 13–6.]
  128. Васильев Ю.В. Боль за грудиной: дифференциальная диагностика и лечение. Consilium medicum (Приложение). 2002; 3: 3–5. [Vasilyev Yu.V. Bol za grudinoy: differentsialnaya diagnostika i lecheniye (Retrosternal pain, differential diagnosis and treatment. In: Consilium medicum (Addendum)). Consilium medicum (Prilozheniye). 2002; 3: 3–5.]
  129. Бессмельцев С.С. Клиническая трактовка увеличенной скорости оседания эритроцитов практикующим врачом (Часть 1). Вестн. гематол. 2005; 2: 54–62. [Bessmeltsev S.S. Klinicheskaya traktovka uvelichennoy skorosti osedaniya eritrotsitov praktikuyushchim vrachom (Chast 1) (Clinical interpretation of elevated erythrocyte sedimentation rate by medical practitioner (Part I). In: Hematol. bullet.). Vestn. gematol. 2005; 2: 54–62.]
  130. Coleman R.E. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat. Rev. 2001; 27: 165–76. 131. Mundy G.R. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2002; 2: 584–93. 132. Fukutomi M. Increased incidence of bone metastases in hepatocellular carcinoma. J. Gastroenterol. Hepatol. 2001; 13: 1083–8.